CN110799218A - Antibody conjugates comprising STING agonists - Google Patents

Antibody conjugates comprising STING agonists Download PDF

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CN110799218A
CN110799218A CN201880043438.4A CN201880043438A CN110799218A CN 110799218 A CN110799218 A CN 110799218A CN 201880043438 A CN201880043438 A CN 201880043438A CN 110799218 A CN110799218 A CN 110799218A
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alkyl
alkynyl
alkenyl
radical
independently selected
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T·W·小杜本斯基
J·R·布鲁姆
S·坎汉
C·Y·周
K·高蒂尔
L·H·格利克曼
郝学士
D·凯恩
S·卡斯布哈特拉
G·E·卡蒂巴
T·N·L·勒
J·莱昂
J·麦肯纳
S·麦克沃特
C·O·恩杜巴库
W·欧
L·宋
G·S·特里亚
宇野哲郎
T·Y-H·吴
万咏勤
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Novartis AG
Chinook Therapeutics Inc
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Novartis AG
Aduro Biotech Inc
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Abstract

Provided herein are immunoconjugates comprising STING agonists. Also disclosed are methods of making the immunoconjugates and methods of using the immunoconjugates for treating cancer.

Description

Antibody conjugates comprising STING agonists
Technical Field
The present invention provides antibody conjugates (also referred to as immunoconjugates) comprising agonists of STING (stimulator of interferon genes) receptors, and the use of such conjugates for the treatment of cancer.
Background
Innate immunity is a rapid, non-specific immune response that is resistant to environmental insults, including but not limited to pathogens (e.g., bacteria or viruses). Adaptive immunity is a slower but more specific immune response that confers long-term or protective immunity to the host and involves initial T lymphocyte differentiation and activation into CD4+ T helper cells and/or CD8+ cytotoxic T cells, thereby promoting cellular and humoral immunity. Antigen-presenting cells of the innate immune system (e.g., dendritic cells or macrophages) serve as a key link between the innate and adaptive immune systems by phagocytosing and processing foreign antigens and presenting them on the cell surface to T cells thereby activating T cell responses.
STING (interferon gene stimulating factor) is an endoplasmic reticulum adaptor that promotes innate immune signaling (Ishikawa and Barber, Nature [ Nature ]2008,455(7213):674-678) STING is reported to contain four putative transmembrane domains (Ouyang et al, Immunity [ 2012 ] 36,1073), located primarily in the endoplasmic reticulum, and capable of activating NF-kB, STAT6, and IRF3 transcriptional pathways to induce expression of type I interferons (e.g., IFN- α and IFN- β) and to exert an effective antiviral state upon expression (Ishikawa and Barber, Nature [ Nature ]2008, 7213 ]: 674-678; Chen et al, Cell [ Cell ] (2011)147,436-446) as opposed to the absence of STING rendering the mouse embryonic fibroblast Cell very susceptible to negative strand viruses (including vesicular stomatitis virus) (ishika) 455, natura [ Nature ] 7213 ], (674: (nath) (austikawa, kohlrabas) and nath 7213).
There remains a need for new immunotherapies for the treatment of diseases, particularly cancer.
Disclosure of Invention
The present invention provides immunoconjugates comprising an antibody conjugated to a STING agonist, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof, which are useful for treating diseases, particularly cancer. The invention further provides methods of treating, preventing or ameliorating cancer, the methods comprising administering to a subject in need thereof an effective amount of an immunoconjugate of the invention. The terms "immunoconjugate" and "antibody conjugate" are used interchangeably herein. The present invention also provides compounds comprising a STING agonist and a linker, which compounds are useful for conjugation to an antibody, thereby making an immunostimulatory conjugate (or immunostimulatory factor antibody conjugate (ISAC)) of the invention. Various embodiments of the invention are described herein.
In one embodiment, the present application discloses immunoconjugates comprising an antibody (Ab) or a functional fragment thereof coupled via a linker (L) to an agonist of the stimulator of interferon genes (STING) receptor (D), wherein the linker optionally comprises one or more cleavage elements.
In one embodiment, the immunoconjugate comprises formula (I):
Ab-(L-(D)m)n(formula (I))
Wherein:
ab is an antibody or functional fragment thereof;
l is a linker comprising one or more cutting elements;
d is a drug moiety having agonist activity against STING receptors;
m is an integer from 1 to 8; and is
n is an integer from 1 to 20.
In another embodiment, the immunoconjugate comprises formula (I):
Ab-(L-(D)m)n(formula (I))
Wherein:
ab is an antibody or functional fragment thereof;
l is a linker;
d is a drug moiety that binds to STING receptors;
m is an integer from 1 to 8; and is
n is an integer from 1 to 20;
wherein D or a cleavage product thereof released from the immunoconjugate has STING agonist activity.
In another embodiment, the immunoconjugate comprises formula (I):
Ab-(L-(D)m)n(formula (I))
Wherein:
ab is an antibody or functional fragment thereof;
l is a linker;
d is a drug moiety that binds to STING receptors;
m is an integer from 1 to 8; and is
n is an integer from 1 to 20;
wherein the immunoconjugate delivers D or a cleavage product thereof to a cell targeted by the Ab, and wherein D or a cleavage product thereof has STING agonist activity.
In another embodiment, the immunoconjugate comprises formula (I):
Ab-(L-(D)m)n(formula (I))
Wherein:
ab is an antibody or functional fragment thereof;
l is a linker comprising one or more cutting elements;
d is a drug moiety that binds to STING receptors;
m is an integer from 1 to 8; and is
n is an integer from 1 to 20;
wherein the immunoconjugate releases D or a cleavage product thereof in the Ab-targeted cells, and wherein D or a cleavage product thereof has STING agonist activity.
In another embodiment, the immunoconjugate comprises formula (I):
Ab-(L-(D)m)n(formula (I))
Wherein:
ab is an antibody or functional fragment thereof;
l is a linker comprising one or more cutting elements;
d is a drug moiety having agonist activity against STING receptors;
m is an integer from 1 to 8; and is
n is an integer from 1 to 20;
wherein the immunoconjugate releases D or a cleavage product thereof in a cell targeted by the Ab, and wherein D or a cleavage product thereof has STING agonist activity in the cell.
In another embodiment, the application discloses an immunoconjugate for delivering a STING receptor agonist to a cell, the immunoconjugate comprising formula (I):
Ab-(L-(D)m)n(formula (I))
Wherein:
ab is an antibody or functional fragment thereof;
l is a linker comprising one or more cutting elements;
d is a drug moiety that binds to STING receptors;
m is an integer from 1 to 8; and is
n is an integer from 1 to 20;
wherein the immunoconjugate specifically binds to an antigen expressed on the cell surface and is internalized into the cell, and wherein D or a cleavage product thereof cleaves from L and has STING agonist activity as determined by one or more STING agonist assays selected from: an interferon stimulation assay, a hSTING wt assay, a THP 1-double assay, a TANK binding kinase 1(TBK1) assay, or an interferon- γ -inducible protein 10(IP-10) secretion assay.
In some embodiments, if D or its cleavage product binds to STING and is capable of stimulating at least 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold or more of one or more STING-dependent cytokines in a cell expressing STING and is capable of stimulating at least 1.1-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold or more of a luciferase or luciferase in a cell expressing STING-dependent luciferase, as measured by the stimulating factor, 1-fold, 10-fold, or more of a luciferase or luciferase expression in a cell expressing a luciferase, 2-fold, 10-fold, 2-fold, 10-fold higher expression of a luciferase, 10-fold, 2-fold, or more of a luciferase, 2-dependent cytokine, 2-fold, or more of a luciferase, or a luciferase, as measured by a wild-10-fold, 10-fold higher binding to a luciferase, 10-fold, 2-fold, or more of a luciferase, 2-fold of a luciferase, or 2-dependent cytokine, or a luciferase, 2-fold higher binding to a luciferase, or a luciferase, and is expressed in another example, 2-fold of a luciferase, 2-dependent cytokine, 2-fold, 2-expressing a luciferase, 2-fold, 2-expressing a luciferase, or a luciferase, 2-fold, or a luciferase, 2-expressing a luciferase, 2-fold in a luciferase, 2, or a luciferase, 2-expressing a cell expressing a luciferase, or a polypeptide, or a luciferase, or a protein, or a luciferase, or a protein, or a luciferase, or.
In some embodiments disclosed herein, the immunoconjugate is administered parenterally.
In other embodiments, the immunoconjugate comprises an Ab that specifically binds to a target antigen. In some embodiments, the target antigen is a tumor antigen. In some embodiments, the Ab is human or humanized. In other embodiments, the Ab is a monoclonal antibody.
In some embodiments of the immunoconjugates disclosed herein, the Ab comprises a modified Fc region. In one embodiment, the Ab comprises cysteine at one or more of the following positions, numbered according to EU numbering:
(a) positions 152, 360 and 375 of the antibody heavy chain; and
(b) positions 107, 159 and 165 of the antibody light chain.
In some embodiments, L is attached to the Ab via conjugation to one or more modified cysteine residues in the Ab. In one embodiment, L is conjugated to the Ab via modified cysteine residues at positions 152 and 375 of the Ab heavy chain, wherein the positions are determined according to EU numbering. In some embodiments, L is conjugated to the cysteine via a maleimide bond.
In one embodiment of the immunoconjugate disclosed herein, D is a dinucleotide. In some cases, D is a Cyclic Dinucleotide (CDN). In other embodiments, D is a compound selected from any one of the compounds of table 1, table 2, table 3, or table 4.
In some embodiments disclosed herein, D is a compound selected from the group consisting of:
Figure BDA0002340450700000061
Figure BDA0002340450700000071
in some embodiments disclosed herein, D is a compound selected from the group consisting of:
in some embodiments disclosed herein, D is a compound selected from the group consisting of:
Figure BDA0002340450700000073
Figure BDA0002340450700000081
in one embodiment, the application discloses immunoconjugates wherein L is a cleavable linker comprising one or more cleavage elements. In some embodiments, L comprises two or more cutting elements, and each cutting element is independently selected from a self-immolative spacer (self-immolative spacer) and a group susceptible to cleavage. In some embodiments, the cleavage is selected from acid-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, glycosidase-induced cleavage, phosphodiesterase-induced cleavage, phosphatase-induced cleavage, protease-induced cleavage, lipase-induced cleavage, or disulfide bond cleavage.
In one embodiment of the immunoconjugates disclosed herein, L has a structure selected from the group consisting of:
Figure BDA0002340450700000082
wherein:
lc is a linker component, and each Lc is independently selected from a linker component as disclosed herein;
x is an integer selected from 1,2,3, 4,5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19 and 20;
y is an integer selected from 1,2,3, 4,5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19 and 20;
p is an integer selected from 1,2,3, 4,5, 6,7, 8, 9 and 10;
d is a compound selected from any one of examples 55 to 69;
and each cutting element (C)E) Independently selected from the group consisting of a suicide spacer and a group susceptible to cleavage selected from the group consisting of acid-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, glycosidase-induced cleavage, phosphodiesterase-induced cleavage, phosphatase-induced cleavage, protease-induced cleavage, lipase-induced cleavage, and disulfide bond cleavage.
In some embodiments, L has a structure selected from the group consisting of:
Figure BDA0002340450700000092
Figure BDA0002340450700000101
in some embodiments disclosed herein, the immunoconjugate is selected from the following:
Figure BDA0002340450700000121
Figure BDA0002340450700000131
Figure BDA0002340450700000141
Figure BDA0002340450700000161
Figure BDA0002340450700000181
Figure BDA0002340450700000191
wherein:
each G1Is independently selected from
Figure BDA0002340450700000192
Wherein indicates and-CR8R9-an attachment point of;
XAis C (═ O) -, -C (═ S) -, or-C (═ NR) -11) -, and each Z1Is NR12；
XBIs C, and each Z2Is N;
G2is that
Figure BDA0002340450700000193
Wherein indicates and-CR8aR9a-an attachment point of;
XCis C (═ O) -, -C (═ S) -, or-C (═ NR) -11) -, and each Z3Is NR12；
XDIs C, and each Z4Is N;
Y1is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
Y2is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
Y3Is OH, O-、OR10、N(R10)2、SR10、SeH、Se-、BH3SH or S-；
Y4Is OH, O-、OR10、N(R10)2、SR10、SeH、Se-、BH3SH or S-；
Y5is-CH2-, -NH-, -O-or-S;
Y6is-CH2-, -NH-, -O-or-S;
Y7is O or S;
Y8is O or S;
Y9is-CH2-, -NH-, -O-or-S;
Y10is-CH2-, -NH-, -O-or-S;
Y11is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
q is 1,2 or 3;
R1is a partially saturated or aromatic monocyclic heterocyclic group or a partially saturated or aromatic fused bicyclic heterocyclic group comprising from 5 to 10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatom is independently selected from O, N or S, or a tautomer thereof, wherein R is1Is substituted with 0,1, 2,3 or 4 substituents independently selected from-NHL1R115、F、Cl、Br、OH、SH、NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl), and-N (C)3-C8Cycloalkyl radicals2；
R1aIs a partially saturated or aromatic monocyclic heterocyclic group or a partially saturated or aromatic fused bicyclic heterocyclic group comprising from 5 to 10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatom is independently selected from O, N or S, or a tautomer thereof, wherein R is1aIs substituted with 0,1, 2,3 or 4 substituents independently selected from-NHL1R115、F、Cl、Br、OH、SH、NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl), and-N (C)3-C8Cycloalkyl radicals2；
R1bIs a partially saturated or aromatic monocyclic heterocyclic group or a partially saturated or aromatic fused bicyclic heterocyclic group comprising from 5 to 10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatom is independently selected from O, N or S, or a tautomer thereof, wherein R is1bIs substituted with 0,1, 2,3 or 4 substituents independently selected from-NHL1R115、F、Cl、Br、OH、SH、NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O)) (phenyl group), and-N (C)3-C8Cycloalkyl radicals2；
Each R2Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and OC (O) C2-C6Alkynyl, wherein R2of-OC (O) O phenyl and R2C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R3Independently selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3of-OC (O) O phenyl and R3C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R4Independently selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R4of-OC (O) O phenyl and R4C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN or N3；
Each R5Independently selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (O)H)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5of-OC (O) O phenyl and R5C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN or N3；
Each R6Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R6of-OC (O) O phenyl and R6C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R7Independently selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R7Of (a) to (b) OC(O) O phenyl and R7C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN or N3；
Each R8Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R8of-OC (O) O phenyl and R8C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R9Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R9of-OC (O) O phenyl and R9C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl radical、-OC(O)OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R2aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R2aof-OC (O) O phenyl and R2aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3
R3aSelected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3aof-OC (O) O phenyl and R3aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R4aSelected from the group consisting ofGroup (2): -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R4aof-OC (O) O phenyl and R4aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R5aSelected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl radical、C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5aof-OC (O) O phenyl and R5aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R6aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl radical)、-OP(＝O)(OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R6aof-OC (O) O phenyl and R6aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R7aSelected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R7aof-OC (O) O phenyl and R7aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R8aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R8ais-OC (O) O phenylAnd R8C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R9aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R9aof-OC (O) O phenyl and R9aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Halogenated alkynesRadical, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R10Independently selected from the group consisting of: H. c1-C12Alkyl radical, C1-C6Heteroalkyl, - (CH)2CH2O)nCH2CH2C(＝O)OC1-C6Alkyl radicals and
Figure BDA0002340450700000281
wherein R is10C of (A)1-C12Alkyl and C1-C6The heteroalkyl is substituted with 0,1, 2, or 3 substituents independently selected from-OH, C1-C12Alkoxy, -S-C (═ O) C1-C6Alkyl, halo, -CN, C1-C12Alkyl, -O-aryl, -O-heteroaryl, -O-cycloalkyl, oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl, -OC (O) OC1-C6Alkyl and C (O) OC1-C6Alkyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is substituted with 0,1, 2 or 3 substituents independently selected from C1-C12Alkyl, O-C1-C12Alkyl radical, C1-C12Heteroalkyl, halo, CN, OH, oxo, aryl, heteroaryl, O-aryl, O-heteroaryl, -C (═ O) C1-C12Alkyl, -OC (═ O) C1-C12Alkyl, -C (═ O) OC1-C12Alkyl, -OC (═ O) OC1-C12Alkyl, -C (═ O) N (R)11)-C1-C12Alkyl, -N (R)11)C(＝O)-C1-C12An alkyl group; -OC (═ O) N (R)11)-C1-C12Alkyl, -C (═ O) -aryl, -C (═ O) -heteroaryl, -OC (═ O) -aryl, -C (═ O) O-aryl, -OC (═ O) -heteroaryl, -C (═ O) O-aryl, -C (═ O) O-heteroaryl, -C (═ O) N (R) (═ O) O-heteroaryl11) -aryl, -C (═ O) N (R)11) -heteroaryl, -N (R)11) C (O) -aryl, -N (R)11)2C (O) -aryl, -N (R)11) C (O) -heteroaryl and S (O)2N(R11) -an aryl group;
each R11Independently selected from H and C1-C6An alkyl group;
each R12Independently selected from H and C1-C6An alkyl group;
optionally, R3And R6Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R3And R6When taken together, O is at R3Bonding at the position;
optionally, R3aAnd R6aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R3aAnd R6aWhen taken together, O is at R3aBonding at the position;
optionally, R2And R3Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R2And R3When taken together, O is at R3Bonding at the position;
optionally, R2aAnd R3aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R2aAnd R3aWhen taken together, O is at R3aBonding at the position;
optionally, R4And R3Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R4And R3When taken together, O is at R3Bonding at the position;
optionally, R4aAnd R3aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R4aAnd R3aWhen taken together, O is at R3aBonding at the position;
optionally, R5And R6Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5And R6When taken together, O is at R5Bonding at the position;
optionally, R5aAnd R6aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5aAnd R6aWhen taken together, O is at R5aBonding at the position;
optionally, R5And R7Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5And R7When taken together, O is at R5Bonding at the position;
optionally, R5aAnd R7aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5aAnd R7aWhen taken together, O is at R5aBonding at the position;
optionally, R8And R9Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6An alkynylene group; and is
Optionally, R8aAnd R9aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6An alkynylene group which is a substituent of a heterocyclic ring,
L1is a joint;
R115is that
Figure BDA0002340450700000301
Figure BDA0002340450700000302
-C(＝O)-、-ON＝***、-S-、-NHC(＝O)CH2-***、-S(＝O)2CH2CH2-***、-(CH2)2S(＝O)2CH2CH2-***、-NHS(＝O)2CH2CH2-***,、-NHC(＝O)CH2CH2-***、-CH2NHCH2CH2-***、-NHCH2CH2-***、
Figure BDA0002340450700000303
Figure BDA0002340450700000311
Figure BDA0002340450700000312
Wherein indicates the point of attachment to Ab;
R13is H or methyl;
R14is H, -CH3Or phenyl;
each R110Independently selected from H, C1-C6Alkyl, F, Cl, and-OH;
each R111Independently selected from H, C1-C6Alkyl radical F, Cl, -NH2、-OCH3、-OCH2CH3、-N(CH3)2、-CN、-NO2and-OH;
each R112Independently selected from H, C1-6Alkyl, fluoro, benzyloxy substituted by-C (═ O) OH, benzyl substituted by-C (═ O) OH, C substituted by-C (═ O) OH1-4Alkoxy and C substituted by-C (═ O) OH1-4An alkyl group;
ab is an antibody or functional fragment thereof; and is
y is 1,2,3, 4,5, 6,7, 8, 9 or 10.
In some embodiments disclosed herein, the immunoconjugate comprises a structure selected from the group consisting of:
Figure BDA0002340450700000313
Figure BDA0002340450700000321
Figure BDA0002340450700000331
Figure BDA0002340450700000341
Figure BDA0002340450700000351
Figure BDA0002340450700000361
Figure BDA0002340450700000381
Figure BDA0002340450700000391
Figure BDA0002340450700000401
in other embodiments disclosed herein, the immunoconjugate comprises a structure selected from the group consisting of:
Figure BDA0002340450700000402
Figure BDA0002340450700000411
Figure BDA0002340450700000441
Figure BDA0002340450700000451
Figure BDA0002340450700000461
Figure BDA0002340450700000471
Figure BDA0002340450700000481
Figure BDA0002340450700000491
Figure BDA0002340450700000511
Figure BDA0002340450700000521
Figure BDA0002340450700000541
and
Figure BDA0002340450700000542
in some embodiments, the immunoconjugate has anti-tumor activity in vivo.
Also disclosed herein are pharmaceutical compositions comprising an immunoconjugate as disclosed herein, and a pharmaceutically acceptable excipient.
The present application also discloses immunoconjugates as disclosed herein for use in combination with one or more additional therapeutic agents. In one embodiment, the additional therapeutic agent is selected from the group consisting of: an inhibitor of a co-inhibitory molecule, an activator of a co-stimulatory molecule, a cytokine, an agent that reduces Cytokine Release Syndrome (CRS), chemotherapy, targeted anti-cancer therapy, an oncolytic drug, a cytotoxic agent, an immune-based therapy, a vaccine, or a cell therapy. In another embodiment, the additional therapeutic agent is an inhibitor of a co-inhibitory molecule, an activator of a co-stimulatory molecule, or a cytokine, wherein:
(i) the co-inhibitory molecule is selected from programmed death-1 (PD-1), programmed death-ligand 1(PD-L1), lymphocyte activation gene-3 (LAG-3), or T cell immunoglobulin domain and mucin domain 3 (TIM-3);
(ii) the co-stimulatory molecule is glucocorticoid-induced TNFR-related protein (GITR), and
(iii) the cytokine is IL-15 complexed with a soluble form of IL-15 receptor α (IL-15 Ra).
Also disclosed herein are methods of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of an immunoconjugate as disclosed herein, a pharmaceutical composition thereof, or a composition comprising the immunoconjugate in combination with one or more additional therapeutic agents.
Also disclosed is the use of an immunoconjugate as disclosed herein, a pharmaceutical composition thereof, or a composition comprising the immunoconjugate in combination with one or more additional therapeutic agents, for treating cancer in a subject in need thereof.
In another embodiment, the application discloses an immunoconjugate as disclosed herein, a pharmaceutical composition thereof, or a composition comprising the immunoconjugate in combination with one or more additional therapeutic agents, for use in the treatment of cancer.
In yet another embodiment, disclosed herein is the use of an immunoconjugate as disclosed herein, a pharmaceutical composition thereof, or a composition comprising the immunoconjugate in combination with one or more additional therapeutic agents, in the manufacture of a medicament for the treatment of cancer.
In some embodiments, the cancer is selected from sarcoma, adenocarcinoma, blastoma, carcinoma, liver cancer, lung cancer, non-small cell lung cancer, breast cancer, lymphatic cancer, colon cancer, kidney cancer, urothelial cancer, prostate cancer, pharynx cancer, rectum cancer, renal cell cancer, small intestine cancer, esophageal cancer, melanoma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, colorectal cancer, cancer of the anal region, peritoneal cancer, stomach cancer (stomachic cancer), esophageal cancer, salivary gland cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulval cancer, penile cancer, glioblastoma, neuroblastoma, cervical cancer, hodgkin's lymphoma, non-hodgkin's lymphoma, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, thyroid cancer, prostate cancer, bladder cancer, cervical cancer, bladder, Adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia (including acute myelogenous leukemia), chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, carcinoma of the renal pelvis, tumors of the Central Nervous System (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, neuroendocrine tumors (including carcinoid tumors, gastrinomas, and islet cell carcinoma), mesothelioma, schwannoma (including acoustic neuroma), meningioma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancer (including asbestos-induced cancer), leukemia, lymphoma, Acute Myelogenous Leukemia (AML), Acute Lymphocytic Leukemia (ALL), Chronic Myelogenous Leukemia (CML), Chronic Lymphocytic Leukemia (CLL), myelodysplastic syndrome, B-cell acute lymphocytic leukemia ("BALL"), T-cell acute lymphocytic leukemia ("TALL"), B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell tumor, burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small-or large-cell follicular lymphoma, malignant lymphoproliferative disorder, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia, myelodysplastic syndrome, plasmacytic lymphoma, plasmacytoid dendritic cell tumor, and fahrenheit macroglobulinemia.
In some embodiments, the immunoconjugate is administered to the subject intravenously, intratumorally, or subcutaneously.
The present application also discloses immunoconjugates as disclosed herein, pharmaceutical compositions thereof, or compositions comprising the immunoconjugates in combination with one or more additional therapeutic agents for use as a medicament.
The present application also discloses a method of making any one of the immunoconjugates as disclosed herein, comprising the steps of:
a) reacting D and L to form (L- (D)m(ii) a And is
b) Make (L- (D)mAnd Ab to form an immunoconjugate Ab- (L- (D)m)n(formula (I)).
In another embodiment, the present application discloses compounds having a structure selected from the group consisting of: formula (A), formula (B), formula (C), formula (D), formula (E), or formula (F), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
Figure BDA0002340450700000561
Figure BDA0002340450700000571
wherein:
each G1Is independently selected from
Figure BDA0002340450700000572
Wherein indicates and-CR8R9-an attachment point of;
XAis C (═ O) -, -C (═ S) -, or-C (═ NR) -11) -, and each Z1Is NR12；
XBIs C, and each Z2Is N;
G2is that
Figure BDA0002340450700000573
Wherein indicates and-CR8aR9a-an attachment point of;
XCis C (═ O) -, -C (═ S) -, or-C (═ NR) -11) -, and each Z3Is NR12；
XDIs C, and each Z4Is N;
Y1is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
Y2is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
Y3Is OH, O-、OR10、N(R10)2、SR10、SeH、Se-、BH3SH or S-；
Y4Is OH, O-、OR10、N(R10)2、SR10、SeH、Se-、BH3SH or S-；
Y5is-CH2-, -NH-, -O-or-S;
Y6is-CH2-, -NH-, -O-or-S;
Y7is O or S;
Y8is O or S;
Y9is-CH2-, -NH-, -O-or-S;
Y10is-CH2-, -NH-, -O-or-S;
Y11is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
q is 1,2 or 3;
R1is a partially saturated or aromatic monocyclic heterocyclic group or a partially saturated or aromatic fused bicyclic heterocyclic group comprising from 5 to 10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatom is independently selected from O, N or S, or a tautomer thereof, wherein R is1Is substituted with 0,1, 2,3 or 4 substituents independently selected from-NHL1R15、F、Cl、Br、OH、SH、NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl), and-N (C)3-C8Cycloalkyl radicals2；
R1aIs a partially saturated or aromatic monocyclic heterocyclic group or a partially saturated or aromatic fused bicyclic heterocyclic group containing 1 to 1 carbon atomFrom 5 to 10 ring members of 5 heteroatoms, and each heteroatom is independently selected from O, N or S, or a tautomer thereof, wherein R is1aIs substituted with 0,1, 2,3 or 4 substituents independently selected from-NHL1R15、F、Cl、Br、OH、SH、NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl), and-N (C)3-C8Cycloalkyl radicals2；
R1bIs a partially saturated or aromatic monocyclic heterocyclic group or a partially saturated or aromatic fused bicyclic heterocyclic group comprising from 5 to 10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatom is independently selected from O, N or S, or a tautomer thereof, wherein R is1bIs substituted with 0,1, 2,3 or 4 substituents independently selected from-NHL1R15、F、Cl、Br、OH、SH、NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered with 1 to 2 heteroatoms independently selected from O, N and SHeterocyclyl, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH,-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl) and-N (C)3-C8Cycloalkyl radicals2；
Each R2Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and OC (O) C2-C6Alkynyl, wherein R2of-OC (O) O phenyl and R2C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R3Independently selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3of-OC (O) O phenyl and R3C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6An alkenyl group,-OC(O)OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R4Independently selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R4of-OC (O) O phenyl and R4C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical、C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN or N3；
Each R5Independently selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5of-OC (O) O phenyl and R5C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN or N3；
Each R6Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R6of-OC (O) O phenyl and R6C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R7Independently selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R7of-OC (O) O phenyl and R7C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN or N3；
Each R8Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R8of-OC (O) O phenyl and R8C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R9Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R9of-OC (O) O phenyl and R9C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R2aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R2aof-OC (O) O phenyl and R2aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3
R3aSelected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3aof-OC (O) O phenyl and R3aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R4aSelected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R4aof-OC (O) O phenyl and R4aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R5aSelected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5aof-OC (O) O phenyl and R5aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R6aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R6aof-OC (O) O phenyl and R6aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R7aSelected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R7aof-OC (O) O phenyl and R7aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R8aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R8aof-OC (O) O phenyl and R8C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R9aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R9aof-OC (O) O phenyl and R9aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R10Independently selected from the group consisting of: H. c1-C12Alkyl radical, C1-C6Heteroalkyl, - (CH)2CH2O)nCH2CH2C(＝O)OC1-C6Alkyl radicals and
Figure BDA0002340450700000661
wherein R is10C of (A)1-C12Alkyl and C1-C6The heteroalkyl is substituted with 0,1, 2, or 3 substituents independently selected from-OH, C1-C12Alkoxy, -S-C (═ O) C1-C6Alkyl, halo, -CN, C1-C12Alkyl, -O-aryl, -O-heteroaryl, -O-cycloalkyl, oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl, -OC (O) OC1-C6Alkyl and C (O) OC1-C6Alkyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is substituted with 0,1, 2 or 3 substituents independently selected from C1-C12Alkyl, O-C1-C12Alkyl radical, C1-C12Heteroalkyl, halo, CN, OH, oxo, aryl, heteroaryl, O-aryl, O-heteroaryl, -C (═ O) C1-C12Alkyl, -OC (═ O) C1-C12Alkyl, -C (═ O) OC1-C12Alkyl, -OC (═ O) OC1-C12Alkyl, -C (═ O) N (R)11)-C1-C12Alkyl, -N (R)11)C(＝O)-C1-C12An alkyl group; -OC (═ O) N (R)11)-C1-C12Alkyl, -C (═ O) -aryl, -C (═ O) -heteroaryl, -OC (═ O) -aryl, -C (═ O) O-aryl, -OC (═ O) -heteroaryl, -C (═ O) O-aryl, -C (═ O) O-heteroaryl, -C (═ O) N (R) (═ O) O-heteroaryl11) -aryl, -C (═ O) N (R)11) -heteroaryl, -N (R)11) C (O) -aryl, -N (R)11)2C (O) -aryl, -N (R)11) C (O) -heteroaryl and S (O)2N(R11) -an aryl group;
each R11Independently selected from H and C1-C6An alkyl group;
each R12Independently selected from H and C1-C6An alkyl group;
optionally, R3And R6Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R3And R6When taken together, O is at R3Bonding at the position;
optionally, R3aAnd R6aAre connected together to formC1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R3aAnd R6aWhen taken together, O is at R3aBonding at the position;
optionally, R2And R3Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R2And R3When taken together, O is at R3Bonding at the position;
optionally, R2aAnd R3aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R2aAnd R3aWhen taken together, O is at R3aBonding at the position;
optionally, R4And R3Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R4And R3When taken together, O is at R3Bonding at the position;
optionally, R4aAnd R3aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R4aAnd R3aAre connected togetherWhen O is in R3aBonding at the position;
optionally, R5And R6Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5And R6When taken together, O is at R5Bonding at the position;
optionally, R5aAnd R6aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5aAnd R6aWhen taken together, O is at R5aBonding at the position;
optionally, R5And R7Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5And R7When taken together, O is at R5Bonding at the position;
optionally, R5aAnd R7aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5aAnd R7aWhen taken together, O is at R5aBonding at the position;
optionally, R8And R9Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6An alkynylene group; and is
Optionally, R8aAnd R9aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6An alkynylene group which is a substituent of a heterocyclic ring,
L1is-C (═ O) O (CH)2)mNR11C(＝O)(CH2)m-**；
-C(＝O)O(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；
-C(＝O)OC(R12)2(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；
-C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)mC(＝O)-**；
-C(＝O)O(CH2)mNR11C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)O(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)(CH2)mNR11X2C(＝O)(CH2)m-**；
-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)(CH2)m-**，
-C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-**，
-C(＝O)O(CH2)mX6C(＝O)(CH2)m-**，
-C(＝O)O(CH2)mX6C(＝O)(CH2)mO(CH2)m-**，
-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)(CH2)m-**，
-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)(CH2)mO(CH2)m-**，
-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)(CH2)mO(CH2)mC(＝O)-**，
-C(＝O)O(CH2)mX6C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**，
-C(＝O)X4C(＝O)X6(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**，
-C(＝O)(CH2)mX6C(＝O)X1X2C(＝O)(CH2)m-**，
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O))X5C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mX3(CH2)m-**；-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mNR11((CH2)mO)n(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-**；-C(＝O)O(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)m-**；-C(＝O)O(CH2)mNR11(CH2)m-**；
-C(＝O)O(CH2)mNR11(CH2)mC(＝O)X2X1C(＝O)-**；
-C(＝O)O(CH2)mX3(CH2)m-**；-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)m-**；-C(＝O)O((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)O(CH2)mNR11C(＝O(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)nX3(CH2)m-**；-C(＝O)O((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mC(＝O)NR11(CH2)m-**；-C(＝O)O(CH2)mC(R12)2-**；
-C(＝O)OCH2)mC(R12)2SS(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)O(CH2)mC(＝O)NR11(CH2)m-**；-C(＝O)(CH2)m-**；-C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)(CH2)mNR11(CH2)m-**；-C(＝O)(CH2)mNR11(CH2)mC(＝O)X2X1C(＝O)-**；
-C(＝O)(CH2)mX3(CH2)m-**；-C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；-C(＝O)(CH2)mNR11C(＝O(CH2)mX3(CH2)m-**；-(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-(CH2)m(CHOH)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；-C(＝O)((CH2)mO)nX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；-C(＝O)((CH2)mO)n(CH2)mC(＝O)NR11(CH2)m-**；-C(＝O)(CH2)mC(R12)2-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O))X5C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mNR11((CH2)mO)n(CH2)m-**；-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)m-**；-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-**；-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-**；-C(＝O)(CH2)mC(R12)2SS(CH2)mNR11C(＝O)(CH2)m-**；-C(＝O)(CH2)mC(＝O)NR11(CH2)m-**；
-C(＝O)X1X2C(＝O)(CH2)m-**；-
C(＝O)X1X2C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)X1X2C(＝O)(CH2)mX3(CH2)m-**；-C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)X1X2C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)X1X2C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)X1X2(CH2)mX3(CH2)m-**；-C(＝O)X1X2((CH2)mO)n(CH2)m-**；
-C(＝O)X1X2((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)X1X2((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)X1X2((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)X1X2(CH2)mNR11((CH2)mO)n(CH2)m-**；-C(＝O)X1X2C(＝O)(CH2)mNR11((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)m-**；-C(＝O)NR11(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)O(CH2)m-**；-C(＝O)NR11(CH2)mNR11C(＝O)X1X2-**；-C(＝O)NR11(CH2)mNR11C(＝O)X5-；-C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mX5(CH2)m-**；-C(＝O)X1C(＝O)NR11(CH2)mX5(CH2)m-**；-C(＝O)X6C(＝O)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)NR11(CH2)mNR11C(＝O)(CH2)m-**；-C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)mC(＝O)-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5(CH2)mNR11((CH2)mO)n(CH2)m-**；-
C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5(CH2)m-**；-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-**；-C(＝O)X1C(＝O)NR11(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)X1C(＝O)NR11(CH2)mX3(CH2)m-**；-C(＝O)NR11(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；-C(＝O)NR11(CH2)mNR11C(＝O)-**；
-C(＝O)X1X2(CH2)m-**；-C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)X1X2(CH2)mX3(CH2)m-**；-C(＝O)NR11(CH2)mX3(CH2)m-**；-C(＝O)NR11((CH2)mO)n(CH2)mX3(CH2)m-**；-C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)X1C(＝O)(CH2)mNR11C(＝O)(CH2)m-; and
-C(＝O)X1C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-**；
wherein indicates with R15The attachment point of (a);
R15is that
Figure BDA0002340450700000751
-ONH2、-NH2、
Figure BDA0002340450700000752
Figure BDA0002340450700000753
-N3、
Figure BDA0002340450700000754
-SH、-SR12、-SSR17、-S(＝O)2(CH＝CH2)、-(CH2)2S(＝O)2(CH＝CH2)、-NHS(＝O)2(CH＝CH2)、-NHC(＝O)CH2Br、-NHC(＝O)CH2I、
Figure BDA0002340450700000761
-C(O)NHNH2、
Figure BDA0002340450700000762
Figure BDA0002340450700000763
X1Is that
Figure BDA0002340450700000764
Wherein indicates with X2The attachment point of (a);
X2is selected from
Figure BDA0002340450700000772
Figure BDA0002340450700000773
Wherein indicates with X1Or with NR11The attachment point of (a);
X3is that
X4is-O (CH)2)nSSC(R12)2(CH2)n-or- (CH)2)nC(R12)2SS(CH2)nO-；
X5Is that
Figure BDA0002340450700000775
Wherein indicates the direction towards the drug moiety;
X6is that
Figure BDA0002340450700000776
Wherein indicates the direction towards the drug moiety;
R17is 2-pyridyl or 4-pyridyl;
each R11Independently selected from H and C1-C6An alkyl group;
each R12Independently selected from H and C1-C6An alkyl group;
each m is independently selected from 1,2,3, 4,5, 6,7, 8, 9, and 10; and is
Each n is independently selected from 1,2,3, 4,5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18.
Each R110Independently selected from H, C1-C6Alkyl, F, Cl, and-OH;
each R111Independently selected from H, C1-C6Alkyl radical F, Cl, -NH2、-OCH3、-OCH2CH3、-N(CH3)2、-CN、-NO2and-OH;
each R112Independently selected from H, C1-6Alkyl, fluoro, benzyloxy substituted by-C (═ O) OH, benzyl substituted by-C (═ O) OH, C substituted by-C (═ O) OH1-4Alkoxy and C substituted by-C (═ O) OH1-4An alkyl group;
and with the proviso that R1、R1aOr R1bIs at least one-NHL1R15Substituted, or R3、R4、R5、R7、R3a、R4a、R5aOr R7ais-OL1R15。
In some embodiments, L1is-C (═ O) O (CH)2)mNR11C(＝O)(CH2)m-**；-C(＝O)O(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；-C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)OC(R12)2(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)O(CH2)mNR8C(＝O)X1X2C(＝O)(CH2)mO(CH2)m-**；-C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)mC(＝O)-**；-C(＝O)O(CH2)mNR11C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)O(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)m-**；-(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-(CH2)m(CHOH)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m**；-C(＝O)X6C(＝O)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；-C(＝O)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)(CH2)m-, or-C (═ O) (CH)2)mNR11C(＝O)((CH2)mO)n(CH2)m-**，
Wherein indicates with R15The attachment point of (a).
In some embodiments, the compound is selected from:
Figure BDA0002340450700000801
Figure BDA0002340450700000811
Figure BDA0002340450700000831
Figure BDA0002340450700000841
in some embodiments, the compound is selected from:
Figure BDA0002340450700000842
Figure BDA0002340450700000851
Figure BDA0002340450700000861
in some embodiments, the compound is selected from:
Figure BDA0002340450700000862
in some embodiments, the compound is:
Figure BDA0002340450700000863
drawings
FIGS. 1A-1O are a series of tables listing various transcripts in HCC1954 cells whose expression was increased at least 5-fold after exposure to cGAMP or compound T1-1.
FIGS. 2A-2L are a series of tables listing various transcripts in THP1 dual cells whose expression was increased at least 5-fold upon exposure to compound T1-2.
Figure 3 is a line graph showing STING agonist payload retention as determined by IPMS (intact protein mass spectrometry).
Figure 4 is a line graph showing that the anti-HER 2-STING agonist conjugate induces IP-10 secretion from HER2+ HCC1954 breast cancer cells.
Figure 5 is a line graph showing that anti-HER 2 mAb1-C1 conjugate inhibits growth of N87 gastric tumor in mice.
Figure 6 is a line graph showing that anti-HER 2 mAb1-C1 conjugate is well tolerated in N87 gastric tumor xenograft mice.
Figure 7 is a line graph showing that anti-HER 2 mAb1-C1 conjugate inhibits growth of HCC1954 breast tumor in mice.
Figure 8 is a line graph showing that anti-HER 2 mAb1-C1 conjugate is well tolerated in HCC1954 breast tumor xenograft mice.
Figure 9A is a line graph showing that anti-HER 2 mAb1-C1 conjugate inhibits SKOV3 ovarian cancer growth in mice.
Figure 9B is a line graph showing that anti-HER 2 mAb1-C1 conjugate was well tolerated in SKOV3 ovarian cancer xenograft mice.
Figure 10 illustrates certain compounds that can be used as drug moieties.
Figure 11 illustrates certain compounds that can be used as drug moieties.
Figure 12 illustrates certain compounds that can be used as drug moieties.
Fig. 13A is a graph depicting the efficacy of P-Cad mAb1-C1 conjugate in a MC38 murine colon adenocarcinoma model in mice.
Fig. 13B is a graph showing that the P-Cad mAb1-C1 conjugate was well tolerated in the MC38 murine colon adenocarcinoma model in mice.
Fig. 14 is a graph depicting the efficacy of target B mAb1-C1 in a breast cancer xenograft model in mice.
Fig. 15 is a graph depicting the efficacy of the target C mAb1-C1 conjugate in a lung cancer xenograft model in mice.
Detailed Description
Various illustrative embodiments of the invention are described herein. It is to be appreciated that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the invention.
Throughout this application, the specification text controls if there is a difference between the specification text (e.g., table 8) and the sequence listing.
Definition of
As used herein, the term "C1-C6Alkyl "refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, which group is free of unsaturation, has from one to six carbon atoms, and is attached to the rest of the molecule by a single bond. "C1-C6Non-limiting examples of alkyl "groups include methyl, ethyl, 1-methylethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, and hexyl.
As used herein, the term "C2-C6Alkenyl "refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, said group comprising at least one double bond, having from two to six carbon atoms, attached to the rest of the molecule by a single bond. "C2-C6Non-limiting examples of alkenyl "groups include vinyl, prop-1-enyl, but-1-enyl, pent-4-enyl, and pent-1, 4-dienyl.
As used herein, the term "C2-C6Alkynyl "refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, said group containing at least one triple bond, having from two to six carbon atoms, and being attached to the rest of the molecule by a single bond. "C2-C6Non-limiting examples of alkynyl "groups include ethynyl, prop-1-ynyl, but-1-ynyl, pent-4-ynyl and pent-1, 4-diynyl.
As used herein, the term "C1-C6Alkylene "refers to a divalent straight or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, with no unsaturation present in the radical, having from one to six carbon atoms.
As used herein, the term "C2-C6Alkenyl "means a divalent straight or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, said radical comprising at leastA double bond having from two to six carbon atoms.
As used herein, the term "C2-C6Alkynyl "refers to a divalent straight or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, said radical containing at least one triple bond, having from two to six carbon atoms.
As used herein, the term "C1-6Alkoxyalkyl "refers to a group of the formula-Ra-O-Ra, wherein each Ra is independently C as defined above1-6An alkyl group. The oxygen atom may be bonded to any carbon atom in any alkyl group. C1-6Examples of alkoxy groups include, but are not limited to, methoxy-methyl, methoxy-ethyl, ethoxy-ethyl, 1-ethoxy-propyl, and 2-methoxy-butyl.
As used herein, the term "C1-C6Hydroxyalkyl "means C as defined above1-6Alkyl radical, wherein C1-6One of the hydrogen atoms of the alkyl group is replaced by OH. Hydroxy radical C1-6Examples of alkyl groups include, but are not limited to, hydroxy-methyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, 3-hydroxy-propyl, and 5-hydroxy-pentyl.
As used herein, the term "C3-C8Cycloalkyl "refers to a saturated, monocyclic, fused bicyclic, fused tricyclic, or bridged polycyclic ring system. Non-limiting examples of fused bicyclic or bridged polycyclic ring systems include bicyclo [1.1.1]Pentane, bicyclo [2.1.1]Hexane, bicyclo [2.2.1 ]]Heptane, bicyclo [3.1.1]Heptane, bicyclo [3.2.1]Octane, bicyclo [2.2.2]Octane and adamantyl. Monocyclic ring C3-C8Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.
As used herein, the term "C1-C6Haloalkyl "means" C "as defined individually herein1-C6Alkyl radical "wherein said" C1-C6At least one of the hydrogen atoms of the alkyl group "is replaced with a halogen atom. Said C is1-C6The haloalkyl group may be mono C1-C6Haloalkyl, wherein such C1-C6Haloalkyl groups have one iodo, one bromo, one chloro or one fluoro. In addition, the C1-C6The haloalkyl group may be di-C1-C6Haloalkyl, wherein such C1-C6The haloalkyl group can have two halogen atoms independently selected from iodine, bromine, chlorine, or fluorine. Further, the C1-C6The haloalkyl group may be a poly C1-C6Haloalkyl, wherein such C1-C6Haloalkyl groups can have two or more of the same halogen atoms or a combination of two or more different halogen atoms. Such a polymer C1-C6The haloalkyl group may be perhalo C1-C6Haloalkyl, wherein each C1-C6All hydrogen atoms of the alkyl group have been replaced by halogen atoms and these halogen atoms may be the same or a combination of different halogen atoms. C1-C6Non-limiting examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, trifluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl.
As used herein, the term "C2-C6Haloalkenyl "refers to" C "individually as defined herein1-C6Alkenyl group "wherein said" C1-C6At least one of the hydrogen atoms of the alkenyl group "is replaced with a halogen atom. Said C is2-C6The haloalkenyl group may be mono C1-C6Haloalkenyl, wherein C is1-C6Haloalkenyl groups have one iodo, one bromo, one chloro or one fluoro. In addition, the C2-C6The haloalkenyl group may be di-C2-C6Haloalkenyl, wherein C is2-C6The haloalkenyl group can have two halogen atoms independently selected from iodine, bromine, chlorine, or fluorine. Further, the C2-C6The haloalkenyl group may be poly C2-C6Haloalkenyl, wherein C is2-C6HalogenatedAn alkenyl group can have two or more of the same halogen atoms or a combination of two or more different halogen atoms.
As used herein, the term "C2-C6Haloalkynyl "refers to" C "as defined individually herein1-C6Alkynyl group "wherein said" C "is1-C6At least one of the hydrogen atoms of the alkynyl group "is replaced with a halogen atom. Said C is2-C6The haloalkynyl group can be mono C1-C6Haloalkynyl, wherein C is1-C6Haloalkynyl has one iodo, one bromo, one chloro or one fluoro. In addition, the C2-C6The haloalkynyl group can be di C2-C6Haloalkynyl, wherein C is2-C6Haloalkynyl groups can have two halogen atoms independently selected from iodine, bromine, chlorine or fluorine. Further, the C2-C6The haloalkynyl group can be poly C2-C6Haloalkynyl, wherein C is2-C6Haloalkenyl groups can have two or more of the same halogen atoms or a combination of two or more different halogen atoms.
As used herein, the term "heteroalkyl" refers to an "alkyl" moiety in which at least one of the carbon atoms has been replaced with a heteroatom (e.g., O, S or N).
As used herein, the term "3-to 6-membered heterocycloalkyl" refers to a monocyclic ring structure having 3 to 6 ring members, wherein one to two of the ring members are independently selected from N, NH, NR16O or-S-, wherein R16Is C1-C6An alkyl group. As used herein, non-limiting examples of 3-to 6-membered heterocycloalkyl groups include aziridin-1-yl, aziridin-2-yl, aziridin-3-yl, azetidinyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, oxetanyl, oxetan-2-yl, oxetan-3-yl, oxetan-4-yl, thietanyl, thietane-2-yl, thietane-3-yl, thietane-4-yl, pyrrolidinyl, pyrrolidinonyl-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolidin-4-yl, pyrrolidin-5-yl, tetrahydrofuryl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrofuran-4-yl, tetrahydrofuran-5-yl, tetrahydrothiophenyl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, tetrahydrothiophen-4-yl, tetrahydrothiophen-5-yl, piperidinyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperidin-5-yl, piperidin-6-yl, tetrahydropyranyl, tetrahydropyran-2-yl, pyrrolidin-5-yl, and the like, Tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydropyran-5-yl, tetrahydropyran-6-yl, tetrahydrothiopyranyl, tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl, tetrahydrothiopyran-4-yl, tetrahydrothiopyran-5-yl, tetrahydrothiopyran-6-yl, piperazinyl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, piperazin-4-yl, piperazin-5-yl, piperazin-6-yl, morpholinyl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, morpholin-5-yl, morpholin-6-yl, tetrahydropyran-5-yl, tetrahydrothiopyranyl, tetrahydrothiopyran-2-yl, piperazin-5-yl, piperazin-6-yl, morpholin, Thiomorpholin, thiomorpholin-2-yl, thiomorpholin-3-yl, thiomorpholin-4-yl, thiomorpholin-5-yl, thiomorpholin-6-yl, oxathiolan-2-yl, oxathiolan-3-yl, oxathiolan-5-yl, oxathiolan-6-yl, dithianyl-2-yl, dithianyl-3-yl, dithianyl-5-yl, dithianyl-6-yl, dioxolanyl, dioxolan-2-yl, dioxolan-4-yl, dioxolan-5-yl, oxathiolan-2-yl, oxathiolan-3-yl, Oxathian-4-yl, oxathian-5-yl, dithiolane-2-yl, dithiolane-4-yl, dithiolane-5-yl, pyrazolidinyl, pyrazolidin-1-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, pyrazolidin-4-yl and pyrazolidin-5-yl.
As used herein, the term "heterocyclyl" includes partially saturated or aromatic monocyclic or fused bicyclic heterocyclic groups containing 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatom is independently selected from O, N or S. In a preferred embodiment, the heteroatom is nitrogen. Non-limiting examples of substituents include oxo, halo, C1-6Alkyl radical, C1-6Alkoxy, amino, C1-6Alkylamino radical, di-C1-6An alkylamino group. The heterocyclic group may be attached at a heteroatom or carbon atom.
For fused bicyclic heterocyclyl systems, the system may be fully aromatic (i.e., both rings are aromatic). When fully aromatic, the heterocyclyl may be referred to as heteroaryl. Examples of the aromatic bicyclic heteroaryl group include a 9-to 10-membered fused bicyclic heteroaryl group having 2 to 5 hetero atoms (preferably nitrogen atoms). Non-limiting examples are: pyrrolo [2,3-b]Pyridyl, pyrrolo [3,2-c]Pyridyl, pyrrolo [3,2-c]Pyridyl, pyrrolo [3,2-b]Pyridyl, imidazo [4,5-b ]]Pyridyl, imidazo [4, 5-c)]Pyridyl, pyrazolo [4,3-d]Pyridyl, pyrazolo [4, 3-c)]Pyridyl, pyrazolo [3,4-c]Pyridyl, pyrazolo [3,4-d]Pyridyl, pyrazolo [3,4-b]Pyridyl, imidazo [1,2-a ]]Pyridyl, pyrazolo [1,5-a]Pyridyl, pyrrolo [1,2-b]Pyridazinyl, imidazo [1,2-c ]]Pyrimidinyl, pyrido [3,2-d ]]Pyrimidinyl, pyrido [4,3-d ]]Pyrimidinyl, pyrido [3,4-d ]]Pyrimidinyl, pyrido [2,3-d ]]Pyrimidinyl, pyrido [2,3-b ]]Pyrazinyl, pyrido [3,4-b ]]Pyrazinyl, pyrimido [5,4-d ]]Pyrimidinyl, pyrazino [2,3-b ]]Pyrazinyl, or pyrimido [4,5-d ]]A pyrimidinyl group. Other non-limiting examples of fused bicyclic heterocyclic groups include
Figure BDA0002340450700000922
In addition, bicyclic heterocyclyl ring systems include heterocyclyl ring systems in which one of the fused rings is aromatic and the other is non-aromatic. For such systems, the heterocyclic group is considered to be partially saturated. Examples of partially saturated bicyclic systems are, for example, dihydropurines, such as 2-amino-1, 9-dihydro-6H-purin-9-yl-6-one and 1, 9-dihydro-6H-purin-9-yl-6-one. Other examples of partially saturated bicyclic systems are
Figure BDA0002340450700000923
Figure BDA0002340450700000924
Heterocyclyl also includes 5-or 6-membered cyclic aromatic heterocyclyl groups (also referred to as 5-to 6-membered heteroaryl groups) having 2 to 3 heteroatoms (preferably nitrogen). Examples of monocyclic heteroaryls are: imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazolyl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1,2, 4-triazol-3-yl, 1,2, 4-triazol-5-yl, 1,2, 3-triazol-4-yl, 1,2, 3-triazol-5-yl, tetrazolyl, pyridin-2-yl, pyridin-3-yl, or pyridyl-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-3-yl, 2-pyrazin-2-yl, pyrazin-4-yl, pyrazin-5-yl, 2-, 4-, or 5-pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl.
Heterocyclyl also includes 6-membered monocyclic partially saturated rings having 1-3 heteroatoms, preferably nitrogen. Examples of partially saturated monocyclic heterocyclyl radicals are pyrimidin-ones and pyrimidin-diones, in particular pyrimidin-2 (1H) -one and pyrimidin-1-yl-2, 4(1H,3H) -dione.
Heterocyclic groups can exist in a variety of tautomeric forms. For example, when the heterocyclyl moiety is substituted with an oxo group next to the nitrogen atom, the invention also relates to the hydroxy tautomeric forms thereof. For example, 2-amino-1, 9-dihydro-6H-purin-6-one can tautomerize to 2-amino-9H-purin-6-ol. The tautomerization is shown below:
Figure BDA0002340450700000931
as used herein, the term tautomer is used to denote 2 molecules having the same molecular formula but different connectivity, which are capable of interconverting in a rapid equilibrium state. Other examples of tautomers are phosphorothioates which can exist in equilibrium, as shown below.
Figure BDA0002340450700000932
Similarly, phosphoric acid exists in 2 tautomeric forms, which are interconverted in equilibrium.
Other examples of tautomers are phosphorothioates which can exist in equilibrium, as shown below.
Similarly, phosphoric acid exists in 2 tautomeric forms, which are interconverted in equilibrium.
In addition, as shown below, the phosphorothioate and phosphate moieties can exist in their respective equilibrium states.
Figure BDA0002340450700000941
As used herein, the term "drug moiety" refers to a compound that binds to an interferon gene stimulating factor (STING) receptor and comprises one or more functional groups, each functional group capable of forming a covalent bond with a linker. Examples of such functional groups include, but are not limited to, primary amines, secondary amines, hydroxyl groups, thiols, alkenes, alkynes, and nitrides. In certain embodiments, such functional groups include the reactive groups of table 5 provided herein.
As used herein, the term "sugar moiety" refers to the following ring structure of the compounds of the present invention:wherein Y is1、Y2And Y3Each independently selected from-O-, -S (═ O) -, -SO2-、-CH2-, or-CF2-。
As used herein, a wavy line when displaying a partial structure of a compound
Figure BDA0002340450700000943
Indicating the partial structure andattachment points for the rest of the molecule.
As used herein, "HER 2" (also known as ERBB 2; NEU; NGL; TKR 1; CD 340; p 185; MLN 19; HER-2/NEU) refers to transmembrane tyrosine kinase receptors of the Epidermal Growth Factor (EGF) receptor family. HER2 comprises an extracellular binding domain, a transmembrane domain and an intracellular tyrosine kinase domain. HER2 does not have its own ligand binding domain and therefore is unable to bind growth factors, however, HER2 binds tightly to other ligand-binding EGF receptor family members (e.g. HER1 or HER3) to form heterodimers, stabilize ligand binding and enhance kinase-mediated activation of downstream signaling pathways. The human HER2/NEU gene maps to chromosomal position 17q12, and the genomic sequence of the HER2/NEU gene is found at NG _007503.1 in GenBank. In humans, there are five isoforms of HER 2: A. b, C, D and E; the term "HER 2" as used herein refers collectively to all HER2 isoforms. As used herein, a human HER2 protein also encompasses proteins having at least about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the HER2 isoform (A, B, C, D and E) over their entire length, wherein such proteins still have at least one function of HER 2. The mRNA and protein sequences of human HER2 isoform a (the longest isoform) are:
homo sapiens erb-b2 receptor tyrosine kinase 2(ERBB2), transcript variant 1, mRNA [ NM-004448.3 ]
Figure BDA0002340450700000951
Figure BDA0002340450700000961
Figure BDA0002340450700000971
Receptor tyrosine-protein kinase erbB-2 isoform precursor [ homo sapiens ] [ NP-004439.2 ]
The mRNA and protein sequences of the other human HER2 isoforms can be found in GeneBank with the following accession numbers:
HER2 isoform B: NM _001005862.2(mRNA) → NP _001005862.1 (protein);
HER2 isoform C: NM _001289936.1(mRNA) → NP _001276865.1 (protein);
HER2 isoform D: NM _001289937.1(mRNA) → NP _001276866.1 (protein);
HER2 isoform E: NM _001289938.1(mRNA) → NP _001276867.1 (protein).
As used herein, the term "antibody" refers to a protein, or polypeptide sequence derived from an immunoglobulin molecule that specifically binds an antigen. Antibodies may be polyclonal or monoclonal, multi-or single-chain, or intact immunoglobulins and may be derived from natural sources or from recombinant sources. A naturally occurring "antibody" is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain consists of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region consists of three domains (CH1, CH2, and CH 3). Each light chain consists of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region comprises one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed Complementarity Determining Regions (CDRs), between which more conserved regions, termed Framework Regions (FRs), are interspersed. Each VH and VL is composed of three CDRs and four FRs arranged in the following order from amino-terminus to carboxy-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR 4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant region of the antibody may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component of the classical complement system (C1 q). The antibody may be a monoclonal antibody, a human antibody, a humanized antibody, a camelized (camelized) antibody, or a chimeric antibody. These antibodies may be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass.
The term "antibody fragment" or "antigen-binding fragment" or "functional fragment" refers to at least a portion of an antibody that retains the ability to specifically interact with an antigenic epitope (e.g., by binding, steric hindrance, stabilization/destabilization, spatial distribution). Examples of antibody fragments include, but are not limited to, Fab ', F (ab')2, Fv fragments, scFv antibody fragments, disulfide linked Fv (sdfv), Fd fragments consisting of VH and CH1 domains, linear antibodies, single domain antibodies such as sdAb (VL or VH), camelid VHH domains, multispecific antibodies formed from antibody fragments (e.g., a bivalent fragment comprising two Fab fragments linked by a disulfide bond at the hinge region), and isolated CDRs, or other epitope-binding fragments of an antibody. Antigen-binding fragments may also be incorporated into single domain antibodies, macroantibodies (maxibodes), minibodies (minibodies), nanobodies, intrabodies, diabodies, triabodies, tetrabodies, v-NARs, and bis-scFvs (see, e.g., Hollinger and Hudson, Nature Biotechnology [ Nature Biotechnology ]23: 1126-. Antigen-binding fragments may also be grafted into scaffolds based on polypeptides such as fibronectin type III (Fn3) (see us patent No. 6,703,199, which describes fibronectin polypeptide miniantibodies). The term "scFv" refers to a fusion protein comprising at least one antibody fragment comprising a light chain variable region and at least one antibody fragment comprising a heavy chain variable region, wherein the light chain variable region and the heavy chain variable region are contiguously linked, e.g., by a synthetic linker (e.g., a short flexible polypeptide linker), and are capable of being expressed as a single chain polypeptide, and wherein the scFv retains the specificity of the intact antibody from which it is derived. Unless otherwise specified, as used herein, a scFv can have VL and VH variable regions, e.g., in any order relative to the N-terminus and C-terminus of a polypeptide, can comprise a VL-linker-VH or can comprise a VH-linker-VL.
As used herein, the term "complementarity determining region" or "CDR" refers to the sequence of amino acids within an antibody variable region that confers antigen specificity and binding affinity. For example, in general, there are three CDRs (e.g., HCDR1, HCDR2, and HCDR3) per heavy chain variable region and three CDRs (LCDR1, LCDR2, and LCDR3) per light chain variable region. The precise amino acid sequence boundaries of a given CDR can be determined using any of a number of well-known protocols, including those described by: kabat et al (1991), "Sequences of Proteins of immunological Interest" [ protein Sequences of immunological importance ], 5 th edition, national institutes of health, department of public health, Besserda, Maryland ("Kabat" numbering scheme); Al-Lazikani et Al, (1997) JMB273,927-948 ("Georgia" numbering scheme), or combinations thereof, and ImmunoGenTics (IMGT) numbering (Lefranc, M. -P., The Immunoglogist [ immunomer ],7,132-136 (1999); Lefranc, M. -P. et Al, Dev. Comp. Immunol. [ developmental immunology and comparative immunology ],27,55-77(2003) ("IMGT" numbering scheme), in a combined Carbart and Georgia numbering scheme for a given CDR region (e.g., HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, or LC CDR3), in some embodiments, these CDRs correspond to amino acid residues defined as part of The Carbart CDRs, and amino acid residues defined as part of Georgia, such as The Georgia's high variation loop numbering scheme, also sometimes referred to herein.
For example, according to kabat, CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35(HCDR1) (e.g., one or more insertions after position 35), 50-65(HCDR2), and 95-102(HCDR 3); and CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34(LCDR1) (e.g., one or more insertions following position 27), 50-56(LCDR2), and 89-97(LCDR 3). As another example, according to GeoSiya, the CDR amino acid numbers in the VH are 26-32(HCDR1) (e.g., one or more insertions after position 31), 52-56(HCDR2), and 95-102(HCDR 3); and amino acid residues in the VL are numbered 26-32(LCDR1) (e.g., one or more insertions after position 30), 50-52(LCDR2), and 91-96(LCDR 3). By combining the CDR definitions of kabat and GeoXia, the CDRs comprise or consist of, for example, amino acid residues 26-35(HCDR1), 50-65(HCDR2) and 95-102(HCDR3) in the human VH and amino acid residues 24-34(LCDR1), 50-56(LCDR2) and 89-97(LCDR3) in the human VL. According to IMGT, the CDR amino acid residues in the VH are numbered approximately 26-35(CDR1), 51-57(CDR2) and 93-102(CDR3), and the CDR amino acid residues in the VL are numbered approximately 27-32(CDR1), 50-52(CDR2) and 89-97(CDR3) (numbered according to "kabat"). Under IMGT, the program IMGT/DomainGap Align can be used to determine the CDR regions of antibodies.
The term "epitope" includes any protein determinant capable of specifically binding to an immunoglobulin or otherwise interacting with a molecule. Epitopic determinants are typically composed of chemically active surface groups of molecules, such as amino acids or carbohydrates or sugar side chains, and may have specific three-dimensional structural characteristics as well as specific charge characteristics. Epitopes can be "linear" or "conformational". Conformational and linear epitopes differ by: in the presence of denaturing solvents, binding to conformational epitopes (but not to non-conformational epitopes) is lost.
The phrase "monoclonal antibody" or "monoclonal antibody composition" as used herein refers to polypeptides (including antibodies, bispecific antibodies, etc.) having substantially the same amino acid sequence or derived from the same genetic source. The term also includes preparations of antibody molecules having a single molecular composition. Monoclonal antibody compositions exhibit a single binding specificity and affinity for a particular epitope.
As used herein, the phrase "human antibody" includes antibodies having variable regions in which both the framework and CDR regions are derived from human-derived sequences. Furthermore, if the antibody contains a constant region, the constant region is also derived from such human sequences, e.g., human germline sequences or mutated forms of human germline sequences, or antibodies containing consensus framework sequences derived from analysis of human framework sequences, e.g., as described in Knappik et al (2000.J Mol Biol [ journal of molecular biology ]296, 57-86). The structure and location of immunoglobulin variable domains (e.g., CDRs) may be defined using well known numbering schemes, e.g., the Carbart numbering scheme, the Western numbering scheme, or a combination of Carbart and Western, and ImmunoGenTiCs (IMGT) numbering (see, e.g., Sequences of Proteins of Immunological Interest [ immunologically relevant protein Sequences ], U.S. department of Health and public Services (U.S. department of Health and Human Services) (1991), editors of Kabat et Al, Al Lazikani et Al, (1997) J.mol.Bio. [ molecular biology ]273: 927948; Kabat et Al, (1991) Sequences of Proteins of Immunological Interest [ immunologically relevant protein Sequences ], 5 th edition, NIH publication No. 91-3242, U.S. department of Health and Services (1987) journal of molecular biology 917J. [ 901.51. 51. Bioservices, (1989) nature [ Nature ]342: 877-883; Al-Lazikani et Al, (1997) J.Mal.biol. [ J.M.biol. ]273: 927-948; and Lefranc, M. -P., The Immunologist [ Immunologist ],7,132-136 (1999); lefranc, m. -p. et al, dev.comp.immunol. [ developmental and comparative immunology ],27,55-77 (2003)).
The human antibodies of the invention may include amino acid residues that are not encoded by human sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro, or by somatic mutation in vivo, or conservative substitutions to promote stability or production). However, the term "human antibody" as used herein is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species (e.g., a mouse) have been grafted into human framework sequences.
The phrase "recombinant human antibody" as used herein includes all human antibodies prepared, expressed, produced, or isolated by recombinant means, such as antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or hybridomas prepared therefrom; antibodies isolated from host cells transformed to express human antibodies (e.g., from transfectomas); antibodies isolated from a library of recombinantly combinatorial human antibodies; and antibodies prepared, expressed, produced or isolated by any other means involving splicing of all or part of a human immunoglobulin gene, sequence, to other DNA sequences. Such recombinant human antibodies have variable regions in which the framework and CDR regions are derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when animals with transgenic human Ig sequences are used, in vivo somatic mutagenesis) and, thus, the amino acid sequences of the VH and VL regions of the recombinant antibodies are those derived from and related to human germline VH and VL sequences that may not naturally exist in the human antibody germline repertoire in vivo.
The term "Fc region" as used herein refers to a polypeptide comprising at least a portion of the CH3, CH2, and hinge regions of the constant domains of an antibody. Optionally, the Fc region may comprise the CH4 domain present in some antibody classes. The Fc region may comprise the entire hinge region of the antibody constant region. In one embodiment, the invention includes the Fc region and the CH1 region of an antibody. In one embodiment, the invention includes the Fc region and the CH3 region of an antibody. In another embodiment, the invention includes an Fc region, a CH1 region, and a ck/λ region from an antibody constant domain. In one embodiment, the binding molecules of the invention comprise a constant region, e.g., a heavy chain constant region. In one embodiment, such constant regions are modified as compared to the wild-type constant region. That is, the polypeptides of the invention disclosed herein may comprise alterations or modifications to one or more of the three heavy chain constant domains (CH1, CH2, or CH3) and/or to the light chain constant region domain (CL). Example modifications include the addition, deletion, or substitution of one or more amino acids in one or more domains. Such changes may be included to optimize effector function, half-life, and the like.
As used herein, the term "binding specificity" refers to the ability of a single antibody binding site to react with one antigenic determinant, but not with a different antigenic determinant. The binding site of an antibody is located in the Fab portion of the molecule and is constructed from hypervariable regions of the heavy and light chains. The binding affinity of an antibody is the strength of the reaction between a single antigenic determinant and a single binding site on the antibody. It is the sum of the attractive and repulsive forces that operate between the antigenic determinant and the binding site of the antibody.
As used herein, the term "affinity" refers to the strength of the interaction between an antibody and an antigen at a single point of antigen localization. Within each antigenic site, the variable region of the antibody "arm" interacts with the antigen at many sites through weak non-covalent forces; the more interactions, the stronger the affinity.
The term "conservative sequence modification" refers to amino acid modifications that do not significantly affect or alter the binding characteristics of an antibody or antibody fragment containing the amino acid sequence.
The term "homologous" or "identity" refers to subunit sequence identity between two polymeric molecules (e.g., between two nucleic acid molecules (e.g., two DNA molecules or two RNA molecules), or between two polypeptide molecules). When a subunit position in both molecules is occupied by the same monomeric subunit; for example, if a position in each of two DNA molecules is occupied by adenine, they are homologous or identical at that position. Homology between two sequences is a direct function of the number of matching positions or homologous positions; for example, two sequences are 50% homologous if half of the positions in the sequences (e.g., five positions in a polymer ten subunits in length) are homologous; if 90% of the positions (e.g., 9 out of 10) are matched or homologous, then the two sequences are 90% homologous. The percentage of "sequence identity" can be determined by comparing two optimally aligned sequences over a comparison window, where a fragment of the amino acid sequence in the comparison window can comprise additions or deletions (e.g., vacancies or overhangs) as compared to the reference sequence (which does not comprise additions or deletions) to optimally align the two sequences. The percentage may be calculated by: determining the number of positions at which the identical amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison, and multiplying the result by 100 to yield the percentage of sequence identity. The output is the percent identity of the subject sequence with respect to the query sequence. Taking into account the number of gaps, and the length of each gap, the percent identity between two sequences is a function of the number of identical positions shared by the sequences, and the gaps need to be introduced in order to perform an optimal alignment of the two sequences.
Sequence comparison and percent identity determination between two sequences can be accomplished using a mathematical algorithm. In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J.mol.biol. [ J.M. J.48: 444-. In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available from www.gcg.com), using the nwsgapdna. cmp matrix and GAP weights of 40, 50, 60, 70, or 80 and length weights of 1,2,3, 4,5, or 6. A particularly preferred set of parameters (and parameters that should be used as stated unless otherwise specified) is the Blossum 62 scoring matrix, with a gap penalty of 12, a gap extension penalty of 4, and a frameshift gap penalty of 5.
The percentage identity between two amino acid or nucleotide sequences can be determined using the PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4 using the algorithm of e.meyers and w.miller ((1989) CABIOS [ computer application in bioscience ]4:11-17), which has been incorporated into the ALIGN program (version 2.0).
The nucleic acid sequences and protein sequences described herein can be used as "query sequences" to search public databases, for example, to identify other family members or related sequences. These searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul et al (1990) J.mol.biol. [ J. Mol ]215: 403-10. A BLAST nucleotide search can be performed using NBLAST program (score 100, word length 12) to obtain nucleotide sequences homologous to the nucleic acid molecules of the present invention. BLAST protein searches can be performed using the XBLAST program (score 50, word length 3) to obtain amino acid sequences homologous to the protein molecules of the invention. To obtain gap alignments for comparison purposes, gap BLAST (gapped BLAST) can be used as described in Altschul et al, (1997) Nucleic Acids Res. [ Nucleic Acids research ]25: 3389-3402. When BLAST and gapped BLAST programs are used, the default parameters of the corresponding programs (e.g., XBLAST and NBLAST) can be used. See www.ncbi.nlm.nih.gov.
The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancers include, but are not limited to, solid tumors and hematological cancers, including carcinomas, lymphomas, blastomas (including medulloblastoma and retinoblastoma), sarcomas (including liposarcoma and synovial cell sarcoma), neuroendocrine tumors (including carcinoid tumors, gastrinomas, and islet cell carcinoma), mesothelioma, schwannomas (including acoustic neuroma), meningiomas, adenocarcinomas, melanomas, and leukemias or lymphoid malignancies. More specific examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer (including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung), cancer of the peritoneum, hepatocellular cancer, gastric cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, neuroblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, urethral cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal canal cancer, penile carcinoma, testicular cancer, esophageal cancer, biliary tract tumor, and head and neck cancer. Other cancer indications are disclosed herein.
The term "tumor antigen" or "cancer-associated antigen" refers interchangeably to a molecule (typically a protein, carbohydrate, or lipid) that is expressed, either completely or as a fragment (e.g., MHC/peptide), on the surface of a cancer cell, and which can be used to preferentially target a pharmacological agent to the cancer cell. In some embodiments, the tumor antigen is a marker expressed by both normal and cancer cells, e.g., a lineage marker, such as CD19 on B cells. In some embodiments, the tumor antigen is a cell surface molecule that is overexpressed in cancer cells compared to normal cells, e.g., 1-fold overexpressed, 2-fold overexpressed, 3-fold overexpressed, or more compared to normal cells. In some embodiments, the tumor antigen is a cell surface molecule that is improperly synthesized in cancer cells, e.g., a molecule that contains deletions, additions, or mutations compared to molecules expressed on normal cells. In some embodiments, the tumor antigen will be expressed exclusively on the cell surface of cancer cells, either completely or as a fragment (e.g., MHC/peptide), and not synthesized or expressed on the surface of normal cells. Typically, peptides derived from endogenous proteins fill the pocket of Major Histocompatibility Complex (MHC) class I molecules and are recognized by T Cell Receptors (TCRs) on CD8+ T lymphocytes. MHC class I complexes are constitutively expressed by all nucleated cells. In cancer, virus-specific and/or tumor-specific peptide/MHC complexes represent a unique class of cell surface targets for immunotherapy.
The term "tumor-supporting antigen" or "cancer-supporting antigen" refers interchangeably to a molecule (typically a protein, carbohydrate or lipid) expressed on the surface of a cell that is not cancerous itself but supports a cancer cell, for example by promoting its growth or survival, for example resistance to immune cells. The tumor-supporting antigen itself need not be functional in supporting tumor cells, so long as the antigen is present on the cells that support the cancer cells.
A "HER 2 positive cancer" or "HER 2 expressing cancer" is a cancer comprising a cell having a HER2 protein present on its cell surface. Many methods are known in the art for detecting or determining the presence of HER2 on cancer cells. For example, in some embodiments, the presence of HER2 on the cell surface can be determined by Immunohistochemistry (IHC), flow cytometry, western blotting, immunofluorescence assays, Radioimmunoassays (RIA), enzyme-linked immunosorbent assays (ELISA), homogeneous time-resolved fluorescence (HTRF), or Positron Emission Tomography (PET).
The term "combination" or "pharmaceutical combination" as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients (e.g., a compound of the invention and one or more additional therapeutic agents) are administered to a subject simultaneously in the form of a single entity or dose. The term "non-fixed combination" means that the active ingredients (e.g., a compound of the invention and one or more additional therapeutic agents) are administered to a subject as separate entities simultaneously, concurrently or sequentially without specific time constraints, wherein such administration provides therapeutically effective levels of these active ingredients in the body of the subject. The latter also applies to mixture therapy, for example, the administration of 3 or more active ingredients.
The term "composition" or "pharmaceutical composition" as used herein refers to a mixture of a compound of the invention with at least one and optionally more than one other pharmaceutically acceptable chemical component, such as a carrier, stabilizer, diluent, dispersant, suspending agent, thickening agent and/or excipient.
The term "optical isomer" or "stereoisomer" as used herein refers to any of a variety of stereoisomeric configurations that may exist for a given compound of the invention and includes geometric isomers. It is understood that the substituent may be attached at a chiral center at a carbon atom. The term "chiral" refers to a molecule having non-overlapping properties on its mirror image partners, while the term "achiral" refers to a molecule that is superimposable on its mirror image partners. Thus, the present invention includes enantiomers, diastereomers or racemates of said compounds. "enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. The 1:1 mixture of enantiomeric pairs is a "racemic" mixture. The term is used to denote, where appropriate, a racemic mixture. "diastereoisomers" are stereoisomers having at least two asymmetric atoms, but which are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-lngold-Prelog R-S system. When the compounds are pure enantiomers, the stereochemistry at each chiral carbon may be represented by R or S. A resolved compound of unknown absolute configuration can be designated (+) or (-) depending on the direction (dextro-or laevorotary) it rotates plane-polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers or axes and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms, which can be defined in terms of absolute stereochemistry as (R) -or (S) -.
The term "P-cadherin" (also known as P-cadherin, P-Cad, Pcad, cadherin 3, cadherin-3, Cad3, Cad-3, Cad3, Cad-3, CDH3 or CDH-3) refers to the nucleic and amino acid sequences of P-cadherin which have been disclosed in GenBank accession nos. NP _001784, NP _001784.2 (amino acid sequence) and NM _001793.4, GenBank accession nos. AA14462, NG _009096 and NG _009096.1 (nucleotide sequence). Sequence information for human P-cadherin domains 1-5 is extracellular and disclosed in GenBank accession nos. NM _001793.4 and NP _001784.
"P-cadherin" also refers to proteins and amino acid sequences having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity over their entire length to the amino acid sequence of GenBank accession No. NP _001784, NP _001784.2 above.
Structurally, the P-cadherin nucleic acid sequence has at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity in its extracellular domain to the nucleic acid sequence of GenBank accession No. NM _001793.4, GenBank accession No. AA14462, NG _009096 and NG _ 009096.1.
As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, pharmaceutical stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof, as known to those of ordinary skill in the art (see, e.g., Remington's pharmaceutical sciences, 18 th edition, Mack publishing Company (Mack Printing Company, 1990, pages 1289 to 1329). Unless any conventional carrier is incompatible with the active ingredient, it is contemplated that it may be used in therapeutic or pharmaceutical compositions.
The term "pharmaceutically acceptable salt" as used herein refers to a salt that does not abrogate the biological activity and properties of the compounds of the present invention, and does not cause significant irritation to the subject to which it is administered.
The term "subject" as used herein includes mammals as well as non-mammals. Examples of mammals include, but are not limited to, humans, chimpanzees, apes, monkeys, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, mice, guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like. Typically the subject is a human.
The term "subject in need of such treatment" refers to a subject who would benefit biologically, pharmaceutically, or qualitatively from such treatment.
The term "STING" refers to an interferon gene stimulating factor receptor, also known as TMEM173, ERIS, MITA, MPYS, SAVI or NET 23. As used herein, the terms "STING" and "STING receptor" are used interchangeably and include different isoforms and variants of STING. The mRNA and protein sequences of human STING isoform 1 (the longest isoform) are:
homo sapiens transmembrane protein 173(TMEM173), transcript variant 1, mRNA [ NM-198282.3 ]
Figure BDA0002340450700001091
Figure BDA0002340450700001111
Intelligent human interferon gene stimulating factor protein isoform 1[ NP-938023.1 ]
MPHSSLHPSIPCPRGHGAQKAALVLLSACLVTLWGLGEPPEHTLRYLVLHLASLQLGLLLNGVCSLAEELRHIHSRYRGSYWRTVRACLGCPLRRGALLLLSIYFYYSLPNAVGPPFTWMLALLGLSQALNILLGLKGLAPAEISAVCEKGNFNVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTGDHAGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFCRTLEDILADAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEVTVGSLKTSAVPSTSTMSQEPELLISGMEKPLPLRTDFS[SEQ ID NO:181]
The mRNA and protein sequences of human STING isoform 2 (shorter isoform) are:
homo sapiens transmembrane protein 173(TMEM173), transcript variant 2, mRNA [ NM-001301738.1 ]
Figure BDA0002340450700001112
Figure BDA0002340450700001121
Intelligent human interferon gene stimulating factor protein isoform 2[ NP-001288667.1 ]
MPHSSLHPSIPCPRGHGAQKAALVLLSACLVTLWGLGEPPEHTLRYLVLHLASLQLGLLLNGVCSLAEELRHIHSRYRGSYWRTVRACLGCPLRRGALLLLSIYFYYSLPNAVGPPFTWMLALLGLSQALNILLGLKGLAPAEISAVCEKGNFNVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTGDHAGIKDRVYSNSIYELLENGQRNLQMTAASRCPRRFSGTCGRRKRKRLLWAA[SEQ ID NO:183]
Other sequences of human STING isoforms/SNPs (single nucleotide polymorphisms) include the following and those described in: yi, PLoS One. [ public science library ]2013, 10 months, 21 days; e77846 (8) (10).
hSTING wt (wild type): reference snp (refsnp) cluster report: rs1131769
atgccccactccagcctgcatccatccatcccgtgtcccaggggtcacggggcccagaaggcagccttggttctgctgagtgcctgcctggtgaccctttgggggctaggagagccaccagagcacactctccggtacctggtgctccacctagcctccctgcagctgggactgctgttaaacggggtctgcagcctggctgaggagctgcgccacatccactccaggtaccggggcagctactggaggactgtgcgggcctgcctgggctgccccctccgccgtggggccctgttgctgctgtccatctatttctactactccctcccaaatgcggtcggcccgcccttcacttggatgcttgccctcctgggcctctcgcaggcactgaacatcctcctgggcctcaagggcctggccccagctgagatctctgcagtgtgtgaaaaagggaatttcaacgtggcccatgggctggcatggtcatattacatcggatatctgcggctgatcctgccagagctccaggcccggattcgaacttacaatcagcattacaacaacctgctacggggtgcagtgagccagcggctgtatattctcctcccattggactgtggggtgcctgataacctgagtatggctgaccccaacattcgcttcctggataaactgccccagcagaccggtgaccgtgctggcatcaaggatcgggtttacagcaacagcatctatgagcttctggagaacgggcagcgggcgggcacctgtgtcctggagtacgccacccccttgcagactttgtttgccatgtcacaatacagtcaagctggctttagccgggaggataggcttgagcaggccaaactcttctgccggacacttgaggacatcctggcagatgcccctgagtctcagaacaactgccgcctcattgcctaccaggaacctgcagatgacagcagcttctcgctgtcccaggaggttctccggcacctgcggcaggaggaaaaggaagaggttactgtgggcagcttgaagacctcagcggtgcccagtacctccacgatgtcccaagagcctgagctcctcatcagtggaatggaaaagcccctccctctccgcacggatttctcttga[SEQ ID NO:184]
hSTING R293Q: reference snp (refsnp) cluster report: rs1131769rs7380824
atgccccactccagcctgcatccatccatcccgtgtcccaggggtcacggggcccagaaggcagccttggttctgctgagtgcctgcctggtgaccctttgggggctaggagagccaccagagcacactctccggtacctggtgctccacctagcctccctgcagctgggactgctgttaaacggggtctgcagcctggctgaggagctgcgccacatccactccaggtaccggggcagctactggaggactgtgcgggcctgcctgggctgccccctccgccgtggggccctgttgctgctgtccatctatttctactactccctcccaaatgcggtcggcccgcccttcacttggatgcttgccctcctgggcctctcgcaggcactgaacatcctcctgggcctcaagggcctggccccagctgagatctctgcagtgtgtgaaaaagggaatttcaacgtggcccatgggctggcatggtcatattacatcggatatctgcggctgatcctgccagagctccaggcccggattcgaacttacaatcagcattacaacaacctgctacggggtgcagtgagccagcggctgtatattctcctcccattggactgtggggtgcctgataacctgagtatggctgaccccaacattcgcttcctggataaactgccccagcagaccggtgaccgtgctggcatcaaggatcgggtttacagcaacagcatctatgagcttctggagaacgggcagcgggcgggcacctgtgtcctggagtacgccacccccttgcagactttgtttgccatgtcacaatacagtcaagctggctttagccgggaggataggcttgagcaggccaaactcttctgccagacacttgaggacatcctggcagatgcccctgagtctcagaacaactgccgcctcattgcctaccaggaacctgcagatgacagcagcttctcgctgtcccaggaggttctccggcacctgcggcaggaggaaaaggaagaggttactgtgggcagcttgaagacctcagcggtgcccagtacctccacgatgtcccaagagcctgagctcctcatcagtggaatggaaaagcccctccctctccgcacggatttctcttga[SEQ ID NO:185]
hSTING 230A/R293Q reference SNP (refSNP) cluster report: rs1131769rs7380824rs78233829
atgccccactccagcctgcatccatccatcccgtgtcccaggggtcacggggcccagaaggcagccttggttctgctgagtgcctgcctggtgaccctttgggggctaggagagccaccagagcacactctccggtacctggtgctccacctagcctccctgcagctgggactgctgttaaacggggtctgcagcctggctgaggagctgcgccacatccactccaggtaccggggcagctactggaggactgtgcgggcctgcctgggctgccccctccgccgtggggccctgttgctgctgtccatctatttctactactccctcccaaatgcggtcggcccgcccttcacttggatgcttgccctcctgggcctctcgcaggcactgaacatcctcctgggcctcaagggcctggccccagctgagatctctgcagtgtgtgaaaaagggaatttcaacgtggcccatgggctggcatggtcatattacatcggatatctgcggctgatcctgccagagctccaggcccggattcgaacttacaatcagcattacaacaacctgctacggggtgcagtgagccagcggctgtatattctcctcccattggactgtggggtgcctgataacctgagtatggctgaccccaacattcgcttcctggataaactgccccagcagaccgctgaccgtgctggcatcaaggatcgggtttacagcaacagcatctatgagcttctggagaacgggcagcgggcgggcacctgtgtcctggagtacgccacccccttgcagactttgtttgccatgtcacaatacagtcaagctggctttagccgggaggataggcttgagcaggccaaactcttctgccagacacttgaggacatcctggcagatgcccctgagtctcagaacaactgccgcctcattgcctaccaggaacctgcagatgacagcagcttctcgctgtcccaggaggttctccggcacctgcggcaggaggaaaaggaagaggttactgtgggcagcttgaagacctcagcggtgcccagtacctccacgatgtcccaagagcctgagctcctcatcagtggaatggaaaagcccctccctctccgcacggatttctcttga[SEQ ID NO:186]
hSTING R71H/G230A/R293Q reference SNP (refSNP) cluster report: rs1131769rs7380824rs78233829rs11554776
atgccccactccagcctgcatccatccatcccgtgtcccaggggtcacggggcccagaaggcagccttggttctgctgagtgcctgcctggtgaccctttgggggctaggagagccaccagagcacactctccggtacctggtgctccacctagcctccctgcagctgggactgctgttaaacggggtctgcagcctggctgaggagctgcaccacatccactccaggtaccggggcagctactggaggactgtgcgggcctgcctgggctgccccctccgccgtggggccctgttgctgctgtccatctatttctactactccctcccaaatgcggtcggcccgcccttcacttggatgcttgccctcctgggcctctcgcaggcactgaacatcctcctgggcctcaagggcctggccccagctgagatctctgcagtgtgtgaaaaagggaatttcaacgtggcccatgggctggcatggtcatattacatcggatatctgcggctgatcctgccagagctccaggcccggattcgaacttacaatcagcattacaacaacctgctacggggtgcagtgagccagcggctgtatattctcctcccattggactgtggggtgcctgataacctgagtatggctgaccccaacattcgcttcctggataaactgccccagcagaccgctgaccgtgctggcatcaaggatcgggtttacagcaacagcatctatgagcttctggagaacgggcagcgggcgggcacctgtgtcctggagtacgccacccccttgcagactttgtttgccatgtcacaatacagtcaagctggctttagccgggaggataggcttgagcaggccaaactcttctgccagacacttgaggacatcctggcagatgcccctgagtctcagaacaactgccgcctcattgcctaccaggaacctgcagatgacagcagcttctcgctgtcccaggaggttctccggcacctgcggcaggaggaaaaggaagaggttactgtgggcagcttgaagacctcagcggtgcccagtacctccacgatgtcccaagagcctgagctcctcatcagtggaatggaaaagcccctccctctccgcacggatttctcttga[SEQ ID NO:187]
As used herein, the term "STING agonist" refers to a compound or antibody conjugate that is capable of binding to STING and activating STING, activation of STING activity can include, for example, stimulation of inflammatory cytokines including interferons, such as type 1 interferons (including IFN- α, IFN- β), type 3 interferons (e.g., IFN λ, IP10, TNF, IL-6, CXCL9, CCL4, CXCL11, CCL5, CCL3, or CCL8), STING agonist activity can also include stimulation of TANK Binding Kinase (TBK)1 phosphorylation, Interferon Regulatory Factor (IRF) activation (e.g., IRF3 activation), interferon- γ -inducible protein (IP-10), or secretion of other inflammatory proteins and cytokines, STING agonist activity can be determined, for example, by the ability of the compound to stimulate activation of STING pathway, as determined by the ability of the compound to stimulate STING pathway activation, such as by a dual agonist assay using interferon stimulating, reporter gene (e.g. hfing) or agonist activity, whether the compound or antibody conjugate has been detected in a biochemical assay for which a transcriptional activity of STING pathway-specific agonist activity is determined by a person in the field test assay.
As used herein, the term "treating" or "treatment" of any disease or disorder refers, in one embodiment, to alleviating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In another embodiment, "treating" or "treatment" refers to alleviating or reducing at least one physical parameter, including those that are not discernible by the patient. In yet another embodiment, "treating" or "treatment" refers to modulating a disease or disorder, either physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both.
As used herein, the term "prevention" of any disease or disorder refers to prophylactic treatment of the disease or disorder; or delay the onset or progression of the disease or disorder.
The terms "therapeutically effective amount" or "therapeutically effective dose" interchangeably refer to an amount sufficient to achieve a desired result (i.e., reduce or inhibit enzyme or protein activity, ameliorate symptoms, alleviate symptoms or conditions, delay disease progression, reduce tumor size, inhibit tumor growth, prevent metastasis, inhibit or prevent viral, bacterial, fungal, or parasitic infection). In some embodiments, the therapeutically effective amount does not induce or cause undesirable side effects. In some embodiments, the therapeutically effective amount induces or causesSide effects, but only those that are acceptable by the healthcare provider in terms of the patient's condition. A therapeutically effective amount may be determined by first administering a low dose and then incrementally increasing the dose until the desired effect is achieved. A "prophylactically effective dose" or "prophylactically effective amount" of a molecule of the invention can prevent the onset of disease symptoms, including symptoms associated with cancer. A "therapeutically effective dose" or "therapeutically effective amount" of a molecule of the invention may result in a reduction in the severity of disease symptoms, including those associated with cancer. The compound name provided herein uses ChemDraw Ultra (version 14.0)
Figure BDA0002340450700001161
And (4) obtaining.
As used herein, the terms "a", "an", "the" and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
Immunostimulatory compounds of the invention
Drug moiety (D)
The drug moiety (D) of the immunoconjugate of the invention is a compound that binds to an interferon gene stimulating factor (STING) receptor and comprises one or more reactive moieties, each reactive moiety capable of forming a covalent bond with the linker (L). In one aspect, the drug moiety (D) of the immunoconjugate of the invention is a dinucleotide that binds to an interferon gene stimulating factor (STING) receptor and comprises one or more reactive moieties capable of forming a covalent bond with the linker (L).
In one aspect, the drug moiety (D) of the immunoconjugate of the invention is a cyclic dinucleotide that binds to an interferon gene stimulating factor (STING) receptor and comprises one or more reactive moieties capable of forming a covalent bond with the linker (L).
In one aspect, the drug moiety (D) of the immunoconjugate of the invention is a compound having the structure of formula (A), formula (B), formula (C), formula (D), formula (E), or formula (F), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
Figure BDA0002340450700001171
Figure BDA0002340450700001181
wherein:
each G1Is independently selected fromWherein is represented by the formula and-CR8R9-an attachment point of;
XAis C (═ O) -, -C (═ S) -, or-C (═ NR) -11) -, and each Z1Is NR12；
XBIs C, and each Z2Is N;
G2is thatWherein indicates and-CR8aR9a-an attachment point of;
XCis C (═ O) -, -C (═ S) -, or-C (═ NR) -11) -, and each Z3Is NR12；
XDIs C, and each Z4Is N;
Y1is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
Y2is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
Y3Is OH, O-、OR10、N(R10)2、SR10、SeH、Se-、BH3SH or S-；
Y4Is OH, O-、OR10、N(R10)2、SR10、SeH、Se-、BH3SH or S-；
Y5is-CH2-, -NH-, -O-or-S;
Y6is-CH2-, -NH-, -O-or-S;
Y7is O or S;
Y8is O or S;
Y9is-CH2-, -NH-, -O-or-S;
Y10is-CH2-, -NH-, -O-or-S;
Y11is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
q is 1,2 or 3;
R1is a partially saturated or aromatic monocyclic heterocyclic group or a partially saturated or aromatic fused bicyclic heterocyclic group comprising from 5 to 10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatom is independently selected from O, N or S, or a tautomer thereof, wherein R is1Is substituted with 0,1, 2,3 or 4 substituents independently selected from F, Cl, Br, OH, SH, NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl) and-N (C)3-C8Cycloalkyl radicals2；
R1aIs a partially saturated or aromatic monocyclic heterocyclic group or a partially saturated or aromatic fused bicyclic heterocyclic group containing from 5 to 10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatom is independently selected from O, N or S, or a tautomer thereof, wherein R is1aIs substituted with 0,1, 2,3 or 4 substituents independently selected from F, Cl, Br, OH, SH, NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH,-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl) and-N (C)3-C8Cycloalkyl radicals2；
R1bIs a partially saturated or aromatic monocyclic heterocyclic group or a partially saturated or aromatic fused bicyclic heterocyclic group comprising from 5 to 10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatom is independently selected from O, N or S, or a tautomer thereof, wherein R is1bIs covered by 0,1, 2,3 or 4 substituents independently selected from F, Cl, Br, OH, SH, NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH,-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl) and-N (C)3-C8Cycloalkyl radicals2；
Each R2Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and OC (O) C2-C6Alkynyl, wherein R2of-OC (O) O phenyl and R2C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R3Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3of-OC (O) O phenyl and R3C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R4Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R4of-OC (O) O phenyl and R4C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R5Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5of-OC (O) O phenyl and R5C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R6Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R6of-OC (O) O phenyl and R6C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R7Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R7of-OC (O) O phenyl and R7C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R8Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6An alkenyl group,C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R8of-OC (O) O phenyl and R8C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R9Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R9of-OC (O) O phenyl and R9C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R2aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R2aof-OC (O) O phenyl and R2aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3
R3aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3aOf (a) — OC (O)O phenyl and R3aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R4aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R4aof-OC (O) O phenyl and R4aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R5aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5aof-OC (O) O phenyl and R5aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R6aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R6aof-OC (O) O phenyl and R6aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R7aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R7aof-OC (O) O phenyl and R7aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R8aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R8aof-OC (O) O phenyl and R8C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R9aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6HalogenatedAlkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R9aof-OC (O) O phenyl and R9aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R10Independently selected from the group consisting of: H. c1-C12Alkyl radical, C1-C6Heteroalkyl, - (CH)2CH2O)nCH2CH2C(＝O)OC1-C6Alkyl radicals and
Figure BDA0002340450700001271
wherein R is10C of (A)1-C12Alkyl and C1-C6The heteroalkyl is substituted with 0,1, 2, or 3 substituents independently selected from-OH, C1-C12Alkoxy, -S-C (═ O) C1-C6Alkyl, halo, -CN, C1-C12Alkyl, -O-aryl, -O-heteroaryl, -O-cycloalkyl, oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl, -OC (O) OC1-C6Alkyl and C (O) OC1-C6Alkyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is substituted with 0,1, 2 or 3 substituents independently selected from C1-C12Alkyl, O-C1-C12Alkyl radical, C1-C12Heteroalkyl, halo, CN, OH, oxo, aryl, heteroaryl, O-aryl, O-heteroaryl, -C (═ O) C1-C12Alkyl, -OC (═ O) C1-C12Alkyl, -C (═ O) OC1-C12Alkyl, -OC (═ O) OC1-C12Alkyl, -C (═ O) N (R)11)-C1-C12Alkyl, -N (R)11)C(＝O)-C1-C12An alkyl group; -OC (═ O) N (R)11)-C1-C12Alkyl, -C (═ O) -aryl, -C (═ O) -heteroaryl, -OC (═ O) -aryl, -C (═ O) O-aryl, -OC (═ O) -heteroaryl, -C (═ O) O-aryl, -C (═ O) O-heteroaryl, -C (═ O) N (R) (═ O) O-heteroaryl11) -aryl, -C (═ O) N (R)11) -heteroaryl, -N (R)11) C (O) -aryl, -N (R)11)2C (O) -aryl, -N (R)11) C (O) -heteroaryl and S (O)2N(R11) -an aryl group;
each R11Independently selected from H and C1-C6An alkyl group;
each R12Independently selected from H and C1-C6An alkyl group;
optionally, R3And R6Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R3And R6When taken together, O is at R3Bonding at the position;
optionally, R3aAnd R6aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R3aAnd R6aWhen taken together, O is at R3aBonding at the position;
optionally, R2And R3Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R2And R3When taken together, O is at R3Bonding at the position;
optionally, R2aAnd R3aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R2aAnd R3aWhen taken together, O is at R3aBonding at the position;
optionally, R4And R3Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R4And R3When taken together, O is at R3Bonding at the position;
optionally, R4aAnd R3aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R4aAnd R3aWhen taken together, O is at R3aBonding at the position;
optionally, R5And R6Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5And R6When taken together, O is at R5Bonding at the position;
optionally, R5aAnd R6aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5aAnd R6aWhen taken together, O is at R5aBonding at the position;
optionally, R5And R7Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5And R7When taken together, O is at R5Bonding at the position;
optionally, R5aAnd R7aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5aAnd R7aWhen taken together, O is at R5aBonding at the position;
optionally, R8And R9Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6An alkynylene group; and is
Optionally, R8aAnd R9aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene radical.
Certain aspects and examples of compounds that may be incorporated as drug moiety (D) in the immunoconjugates of the invention are provided in the following list of additional enumerated examples. It is to be appreciated that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the invention.
Example 1A compound having formula (A-1), formula (B-1), formula (C-1), formula (D-1), formula (E-1) or formula (F-1), or a stereoisomer or pharmaceutically acceptable salt thereof,
Figure BDA0002340450700001301
wherein R is1、R1a、R1b、R2、R2a、R3、R3a、R4、R4a、R5、R5a、R6、R6a、R7、R7a、R8、R8a、R9、Y1、Y2、Y3、Y4、Y5、Y6、Y7、Y8、Y9、Y10And Y11Are as defined above for compounds having formula (A), formula (B), formula (C), formula (D), formula (E) and formula (F).
Example 2A compound having formula (A), formula (B), formula (C), formula (D), formula (A-1), formula (B-1), formula (C-1), formula (D-1), formula (E-1), or formula (F-1), wherein R is1Is a pyrimidine or purine nucleobase or an analogue thereof, R1aIs a pyrimidine or purine nucleobase or an analogue thereof, and R1bIs a pyrimidine or purine nucleusAn acid base or the like, each of which is R of the formula (A), the formula (BB), the formula (C), the formula (D), the formula (A-1), the formula (B-1), the formula (C-1), the formula (D-1), the formula (E-1), or the formula (F-1)1、R1aOr R1bSubstituted as described in (1).
Example 3. A compound having formula (A-2), formula (B-2), formula (C-2), formula (D-2), formula (E-2), or formula (F-2):
Figure BDA0002340450700001302
Figure BDA0002340450700001311
wherein R is1、R1a、R1b、R2、R2a、R3、R3a、R4、R4a、R5、R5a、R6、R6a、R7、R7a、R8、R8a、R9、Y1、Y2、Y3、Y4、Y5、Y6、Y7、Y8、Y9、Y10And Y11Are as defined above for compounds having formula (A), formula (B), formula (C), formula (D), formula (E) and formula (F).
Embodiment 4. compounds of formula (a), formula (a-1) or formula (a-2) as described in embodiments 1,2 or 3, wherein:
R2and R2aIs H;
R3and R4One of H and the other is selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3Or R4and-OC (O) O phenyl and R3Or R4C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R7And R7aIs H;
R6and R6aIs H;
R8、R9、R8aand R9aIndependently is H or C1-C6Alkyl radical, and
R3aand R4aOne of H and the other is selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3aAnd R4aand-OC (O) O phenyl and R3aOr R4aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3。
Embodiment 5. compounds of formula (a), formula (a-1) or formula (a-2) as described in embodiments 1,2,3 or 4, wherein:
Y1and Y2Is O, CH2Or S;
Y3is OH, O-、OR10、N(R10)2SH or S-；
Y4Is OH, O-、OR10、N(R10)2SH or S-；
Y5And Y6Is O or S;
Y7and Y8Is O or S;
Y9and Y10Is O or S;
R2、R2a、R6、R6a、R7and R7aIs H;
R3aand R4aOne is H and the other is H, OH or F;
R3and R4One is H and the other is H, OH or F; and is
R8a、R9a、R8And R9Independently selected from H or C1-C6An alkyl group.
Embodiment 6. compounds of formula (B), formula (B-1), or formula (B-2) as described in embodiments 1,2, or 3, wherein:
R2and R2aIs H;
R3aand R4aOne of H and the other is selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3aAnd R4aand-OC (O) O phenyl and R3aOr R4aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R7a andR6ais H;
R6and R4Is H;
R8、R9、R8aand R9aIndependently is H or C1-C6Alkyl radical, and
R5and R7One of H and the other is selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6An alkynyl group,wherein R is5And R7and-OC (O) O phenyl and R5Or R7C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3。
Embodiment 7. compounds of formula (B), formula (B-1), or formula (B-2) as described in embodiments 1,2,3, or 6, wherein:
Y1and Y2Is O, CH2Or S;
Y3is OH, O-、OR10、N(R10)2SH or S-；
Y4Is OH, O-、OR10、N(R10)2SH or S-；
Y5And Y6Is O or S;
Y7and Y8Is O or S;
Y9and Y10Is O or S;
R2、R2a、R7a、R6a、R6and R4Is H;
R3aand R4aOne is H and the other is H, OH or F;
R5and R7One of is H and the other is H, OH or F, and
R8a、R9a、R8and R9Independently selected from H or C1-C6An alkyl group.
Embodiment 8. a compound of formula (C), formula (C-1), or formula (C-2) as described in embodiments 1,2, or 3, wherein:
R2and R2aIs H;
R3and R4One of H and the other is selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3And R4and-OC (O) O phenyl and R3Or R4C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R4aAnd R6aIs H;
R6and R7Is H;
R8、R9、R8aand R9aIndependently is H or C1-C6An alkyl group;
R5aand R7aOne is H, and the other is selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5aAnd R7aand-OC (O) O phenyl and R5aOr R7aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3。
Embodiment 9. the compound of formula (C), formula (C-1), or formula (C-2) as described in embodiments 1,2,3, or 8, wherein:
Y1and Y2Is O, CH2Or S;
Y3is OH, O-、OR10、N(R10)2SH or S-；
Y4Is OH, O-、OR10、N(R10)2SH or S-；
Y5And Y6Is O or S;
Y7and Y8Is O or S;
Y9and Y10Is O or S;
R2、R2a、R4a、R6a、R6and R7Is H;
R3and R4One is H and the other is H, OH or F;
R5aand R7aOne of is H and the other is H, OH or F, and
R8a、R9a、R8and R9Independently selected from H or C1-C6An alkyl group.
Embodiment 10. a compound of formula (D), formula (D-1), or formula (D-2) as described in embodiments 1,2, or 3, wherein:
R2and R2aIs H;
R5aand R7aOne of H and the other is selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical、C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5aAnd R7aand-OC (O) O phenyl and R5aOr R7aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R4a andR6ais H;
R6and R4Is H;
R8、R9、R8aand R9aIndependently is H or C1-C6Alkyl radical, and
R5and R7Is H, andanother is selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5And R7and-OC (O) O phenyl and R5Or R7C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3。
Embodiment 11. compounds of formula (D), formula (D-1), or formula (D-2) as described in embodiments 1,2,3, or 10, wherein:
Y1and Y2Is O, CH2Or S;
Y3is OH, O-、OR10、N(R10)2SH or S-；
Y4Is OH, O-、OR10、N(R10)2SH or S-；
Y5And Y6Is O or S;
Y7and Y8Is O or S;
Y9and Y10Is O or S;
R2、R2a、R4a、R6a、R6and R4Is H;
R5a、R7aone is H and the other is H, OH or F;
R5and R7One of is H and the other is H, OH or F, and
R8、R9、R8aand R9aIndependently is H or C1-C6An alkyl group.
Embodiment 12. compounds of formula (E), formula (E-1), or formula (E-2) as described in embodiments 1,2, or 3, wherein:
R2and R2aIs H;
R6 andR6ais H;
R7ais H;
R8、R9、R8aand R9aIndependently is H or C1-C6Alkyl radical, and
R3aand R4aOne of H and the other is selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3aAnd R4aand-OC (O) O phenyl and R3aOr R4aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R3And R4One of H and the other is selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2、-OC(O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3And R4and-OC (O) O phenyl and R3Or R4C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3And is and
R5and R7One of H and the other is selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl,-OC(O)C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5And R7and-OC (O) O phenyl and R5Or R7C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3。
An embodiment 13. a compound of formula (E), formula (E-1), or formula (E-2) as described in embodiments 1,2,3, or 12, wherein:
Y1and Y2Is O, CH2Or S;
Y3is OH, O-、OR10、N(R10)2SH or S-；
Y5Is O or S;
Y7is O or S;
Y9is O or S;
R2、R2a、R5a、R6a、R6and R7aIs H;
R3a、R4aone of which is H and the other is H, OH, OCH3Or F;
R3、R4one of which is H and the other is H, OH, OCH3Or F;
R5and R7One of which is H and the other is H, OH, OCH3Or F, and
R8、R9、R8aand R9aIndependently is H or C1-C6An alkyl group.
Embodiment 14. compounds of formula (F), formula (F-1), or formula (F-2) as described in embodiments 1,2, or 3, wherein:
R2and R2aIs H;
each R6 andR6ais H;
each R7aAnd R7Is H;
R8、R9、R8aand R9aIndependently is H or C1-C6Alkyl radical, and
R3aand R4aOne of H and the other is selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3aAnd R4aand-OC (O) O phenyl and R3aOr R4aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R3And R4One of H and the other is selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3And R4and-OC (O) O phenyl and R3Or R4C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3And is and
R5selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5of-OC (O) O phenyl and R5C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3。
Embodiment 15. compounds of formula (F), formula (F-1), or formula (F-2) as described in embodiments 1,2,3, or 12, wherein:
Y1and Y2Is O, CH2Or S;
each Y3Is OH, O-、OR10、N(R10)2SH or S-；
Each Y5Is O or S;
each Y7Independently is O or S;
each Y9Independently is O or S;
Y11is O, CH2Or S;
R2、R2a、R6、R6a、R6、R7and R7aIs H;
R3a、R4aone of which is H and the other is H, OH, OCH3Or F;
R3、R4one of which is H and the other is H, OH, OCH3Or F;
R5is H, OH, OCH3Or F, and
R8、R9、R8aand R9aIndependently is H or C1-C6An alkyl group.
The compound of any one of embodiments 1 to 15, wherein: r1Is that
Figure BDA0002340450700001421
Figure BDA0002340450700001422
Wherein R is1Is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl) and-N (C)3-C8Cycloalkyl radicals2；
R1aIs that
Figure BDA0002340450700001432
Figure BDA0002340450700001433
Figure BDA0002340450700001441
Figure BDA0002340450700001442
Wherein: r1aIs substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl) and-N (C)3-C8Cycloalkyl radicals2；
And is
R1bIs that
Figure BDA0002340450700001443
Figure BDA0002340450700001444
Figure BDA0002340450700001451
Wherein R is1bIs substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl) and-N (C)3-C8Cycloalkyl radicals2。
Example 17A compound having formula (A-3), formula (B-3), formula (C-3), formula (D-3), formula (E-3), or formula (F-3):
Figure BDA0002340450700001453
wherein:
Y1is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
Y2is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
Y11is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
Y3Is OH, O-、OR10、N(R10)2SH or S-；
Y4Is OH, O-、OR10、N(R10)2SH or S-；
Y7Is O or S;
Y8is O or S;
R1is that
Figure BDA0002340450700001462
Figure BDA0002340450700001471
Wherein R is1Is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl) and-N (C)3-C8Cycloalkyl radicals2；
R1aIs that
Figure BDA0002340450700001473
Wherein: r1aIs substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl) and-N (C)3-C8Cycloalkyl radicals2；
And is
R1bIs that
Figure BDA0002340450700001483
Figure BDA0002340450700001491
Figure BDA0002340450700001492
Wherein R is1bIs substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl radicals having3-to 6-membered heterocyclyl of 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl) and-N (C)3-C8Cycloalkyl radicals2；
Each R2Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and OC (O) C2-C6Alkynyl, wherein R2of-OC (O) O phenyl and R2C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R3Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3of-OC (O) O phenyl and R3C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R4Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R4of-OC (O) O phenyl and R4C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl, aryl, heteroaryl, and heteroaryl,C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R5Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5of-OC (O) O phenyl and R5C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R6Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R6of-OC (O) O phenyl and R6C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R7Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R7of-OC (O) O phenyl and R7C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R2aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R2aof-OC (O) O phenyl and R2aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3
R3aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3aof-OC (O) O phenyl and R3aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R4aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R4aof-OC (O) O phenyl and R4aC of (A)1-C6Alkyl radical、C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R5aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5aof-OC (O) O phenyl and R5aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R6aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R6aof-OC (O) O phenyl and R6aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, aryl, heteroaryl, and heteroaryl,-OC(O)C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R7aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R7aof-OC (O) O phenyl and R7aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independentlyIs selected from F, Cl, Br, I, OH, CN and N3；
Each R10Independently selected from the group consisting of: H. c1-C12Alkyl, - (CH)2CH2O)nCH2CH2C(＝O)OC1-C6Alkyl radicals and
Figure BDA0002340450700001551
wherein R is10C of (A)1-C12Alkyl is substituted with 0,1, 2 or 3 substituents independently selected from-OH, C1-C12Alkoxy, -S-C (═ O) C1-C6Alkyl and C (O) OC1-C6An alkyl group;
optionally, R3And R6Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R3And R6When taken together, O is at R3Bonding at the position;
optionally, R3aAnd R6aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R3aAnd R6aWhen taken together, O is at R3aBonding at the position;
optionally, R2And R3Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R2And R3When taken together, O is at R3Bonding at the position;
optionally, optionally，R2aAnd R3aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R2aAnd R3aWhen taken together, O is at R3aBonding at the position;
optionally, R4And R3Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R4And R3When taken together, O is at R3Bonding at the position;
optionally, R4aAnd R3aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R4aAnd R3aWhen taken together, O is at R3aBonding at the position;
optionally, R5And R6Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5And R6When taken together, O is at R5Bonding at the position;
optionally, R5aAnd R6aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6An alkynylene group which is a substituent of a heterocyclic ring,such that R is5aAnd R6aWhen taken together, O is at R5aBonding at the position;
optionally, R5And R7Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5And R7When taken together, O is at R5Bonding at the position; and is
Optionally, R5aAnd R7aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5aAnd R7aWhen taken together, O is at R5aAnd bonding at the position.
Example 18. a compound having formula (a-3), or a pharmaceutically acceptable salt thereof, having the structure of formula (a-4), or a pharmaceutically acceptable salt thereof:
Figure BDA0002340450700001561
wherein: r1、R1a、R3、R3a、R6、R6a、Y3And Y4As defined in example 17.
Example 19. a compound having formula (a-4), or a pharmaceutically acceptable salt thereof, having the structure of formula (a-4a), formula a-4b), formula a-4c), or formula a-4d), or a pharmaceutically acceptable salt thereof:
Figure BDA0002340450700001562
Figure BDA0002340450700001571
wherein: r1、R1a、R3、R3a、R6And R6aAs defined in example 17;
Y3is OR10、N(R10)2SH or S-And is and
Y4is OR10、N(R10)2SH or S-。
Example 20 a compound having formula (a-4), or a pharmaceutically acceptable salt thereof, having a structure of formula (a-4e), formula (a-4f), formula (a-4g), formula (a-4h), formula (a-4i), formula (a-4j), formula (a-4k), formula (a-4l), formula (a-4m), formula (a-4n), formula (a-4o), or formula (a-4p), or a pharmaceutically acceptable salt thereof:
Figure BDA0002340450700001572
wherein: r1、R1a、R3、R3a、R6And R6aAs defined in example 17;
Y3is OR10、N(R10)2SH or S-And is and
Y4is OR10、N(R10)2SH or S-。
Example 21. a compound having formula (B-3), having the structure of formula (B-4), or a pharmaceutically acceptable salt thereof:
wherein: r1、R1a、R3、R3a、R5、R6a、Y3And Y4As defined in example 17.
Example 22. a compound having formula (B-4), or a pharmaceutically acceptable salt thereof, having the structure of formula (B-4a), formula (B-4B), formula (B-4c), or formula (B-4d), or a pharmaceutically acceptable salt thereof:
Figure BDA0002340450700001591
wherein: r1、R1a、R3a、R5And R6aAs defined in example 13;
Y3is OR10、N(R10)2SH or S-And is and
Y4is OR10、N(R10)2SH or S-。
Example 23 a compound having formula (B-4), or a pharmaceutically acceptable salt thereof, having the structure of formula (B-4e), formula (B-4f), formula (B-4g), or formula (B-4h), or a pharmaceutically acceptable salt thereof:
wherein: r1、R1aAnd R5As defined in example 17;
Y3is OR10、N(R10)2SH or S-And is and
Y4is OR10、N(R10)2SH or S-。
Example 24. a compound having formula (C-3), having the structure of formula (C-4), or a pharmaceutically acceptable salt thereof:
Figure BDA0002340450700001601
wherein: r1、R1a、R3、R5a、R6、R6a、Y3And Y4As defined in example 17.
Example 25. a compound having formula (C-4), or a pharmaceutically acceptable salt thereof, having the structure of formula (C-4a), formula (C-4b), formula (C-4C), or formula (C-4d), or a pharmaceutically acceptable salt thereof:
Figure BDA0002340450700001602
wherein: r1、R1a、R3、R5aAnd R6As defined in example 17;
Y3is OR10、N(R10)2SH or S-And is and
Y4is OR10、N(R10)2SH or S-。
Example 26. a compound having formula (C-4), or a pharmaceutically acceptable salt thereof, having the structure of formula (C-4e), formula (C-4f), formula (C-4g), or formula (C-4h), or a pharmaceutically acceptable salt thereof:
Figure BDA0002340450700001611
wherein: r1、R1aAnd R5aAs defined in example 17;
Y3is OR10、N(R10)2SH or S-And is and
Y4is OR10、N(R10)2SH or S-。
Example 27 a compound having formula (D-3), or a pharmaceutically acceptable salt thereof, having the structure of formula (D-4), or a pharmaceutically acceptable salt thereof:
Figure BDA0002340450700001612
wherein: r1、R1a、R5、R5a、Y3And Y4As defined in example 17.
Example 28 a compound having formula (D-4), or a pharmaceutically acceptable salt thereof, having the structure of formula (D-4a), formula (D-4b), formula (D-4c), or formula (D-4D), or a pharmaceutically acceptable salt thereof:
Figure BDA0002340450700001621
wherein: r1、R1a、R5And R5aAs defined in example 17;
Y3is OR10、N(R10)2SH or S-And is and
Y4is OR10、N(R10)2SH or S-。
Example 29. a compound having formula (E-3), or a pharmaceutically acceptable salt thereof, having the structure of formula (E-4), or a pharmaceutically acceptable salt thereof:
Figure BDA0002340450700001622
wherein: r1、R1a、R3、R3a、R4、R4a、R5And R7As defined in example 17.
Example 30a compound having formula (E-4), or a pharmaceutically acceptable salt thereof, having the structure of formula (E-4a) or formula (E-4b), or a pharmaceutically acceptable salt thereof:
Figure BDA0002340450700001631
wherein: r1、R1a、R3、R3a、R4、R4a、R5And R7As defined in example 17;
and is
Y3Is OR10、N(R10)2SH or S-。
Example 31. a compound having formula (F-3), or a pharmaceutically acceptable salt thereof, having the structure of formula (F-4), or a pharmaceutically acceptable salt thereof:
wherein: r1、R1a、R1b、R3、R3a、R4、R4a、R5And R7As defined in example 17.
Example 32. a compound having formula (F-4), or a pharmaceutically acceptable salt thereof, having the structure of formula (F-4a), formula (F-4b), formula (F-4c), or formula (F-4d), or a pharmaceutically acceptable salt thereof:
Figure BDA0002340450700001641
wherein: r1、R1a、R1b、R3、R3a、R4、R4a、R5And R7As defined in example 17;
and is
Each Y3Independently selected from OR10、N(R10)2SH and S-。
Embodiment 33. the compound of any of embodiments 1 to 32, wherein R1Is that
Figure BDA0002340450700001642
Embodiment 34. the compound of any one of embodiments 1 to 32, wherein R1aIs that
Figure BDA0002340450700001651
Embodiment 35. the compound of any one of embodiments 1 to 32, wherein R1bIs that
Figure BDA0002340450700001652
Embodiment 36. the compound of any one of embodiments 1 to 32, wherein R1Is that
Figure BDA0002340450700001653
Embodiment 37. the compound of any one of embodiments 1 to 32, wherein R1aIs that
Figure BDA0002340450700001654
Embodiment 38. the compound of any one of embodiments 1 to 32, wherein R1bIs that
Figure BDA0002340450700001655
Embodiment 39. the compound of any one of embodiments 1 to 32, wherein R1Is that
Figure BDA0002340450700001656
And R is1aIs that
Figure BDA0002340450700001657
Embodiment 40. the compound of any one of embodiments 1 to 32, wherein R1Is that
Figure BDA0002340450700001658
And R1aIs that
Embodiment 41. the compound of any one of embodiments 1 to 32, wherein R1Is that
Figure BDA0002340450700001661
And R is1aIs that
Figure BDA0002340450700001662
Embodiment 42. the compound of any one of embodiments 1 to 32, wherein R1Is that
Figure BDA0002340450700001663
And R is1aIs that
Embodiment 43. the compound of any one of embodiments 1 to 32, wherein R1Is that
Figure BDA0002340450700001665
And R is1aIs that
Figure BDA0002340450700001666
Embodiment 44. the compound of any one of embodiments 1 to 32, wherein R1Is that
Figure BDA0002340450700001667
R1bIs that
Figure BDA0002340450700001668
And R1aIs that
Figure BDA0002340450700001669
The compound of any one of embodiments 1-44, wherein:
Y3is OH, O-SH or S-And is and
Y4is OH, O-SH or S-。
The compound of any one of embodiments 1 to 44, wherein:
Y3is OH or O-And is and
Y4is OH or O-。
The compound of any one of embodiments 1 to 44, wherein:
Y3is SH or S-And is and
Y4is OH or O-。
The compound of any one of embodiments 1 to 44, wherein:
Y3is OH or O-And is and
Y4is SH or S-。
The compound of any one of embodiments 1 to 44, wherein:
Y3is SH or S-.And is and
Y4is SH or S-。
The compound of any one of embodiments 1 to 49, wherein:
R3is-OH or F;
R3ais-OH or F;
R5is-OH or F;
R5ais-OH or F;
R6is H, and
R6ais H.
The compound of any one of embodiments 1 to 49, wherein:
R3is H, -OH or F;
R3ais H, -OCH3-OH or F;
R5is-OH or F;
R4、R4a、R6、R6a、R7、R7ais H, and
R6ais H.
Example 52. drug moiety (D) is a compound of table 1:
TABLE 1
Figure BDA0002340450700001671
Figure BDA0002340450700001681
Figure BDA0002340450700001701
Figure BDA0002340450700001711
Figure BDA0002340450700001721
Example 53 drug moiety (D) is a compound of table 2:
TABLE 2
Figure BDA0002340450700001722
Figure BDA0002340450700001731
Figure BDA0002340450700001741
Example 54 drug moiety (D) is a compound of table 3:
TABLE 3
Figure BDA0002340450700001761
Figure BDA0002340450700001771
Example 55 drug moiety (D) is
Figure BDA0002340450700001772
EXAMPLE 56 drug moiety (D) is
Figure BDA0002340450700001773
Example 57 pharmaceutical moiety (D) is
Figure BDA0002340450700001774
EXAMPLE 58 drug moiety (D) is
Figure BDA0002340450700001775
Example 59 drug moiety (D) is
EXAMPLE 60 drug moiety (D) is
Figure BDA0002340450700001777
Example 61 drug moiety (D) is
Figure BDA0002340450700001781
Figure BDA0002340450700001782
EXAMPLE 62 drug moiety (D) is
Figure BDA0002340450700001783
Example 63 drug moiety (D) is
Figure BDA0002340450700001784
EXAMPLE 64 drug moiety (D) is
Figure BDA0002340450700001785
Example 65 drug moiety (D) is
Figure BDA0002340450700001786
EXAMPLE 66 drug moiety (D) is
Figure BDA0002340450700001787
Example 67 drug moiety (D) is
Figure BDA0002340450700001788
EXAMPLE 68 drug moiety (D) is
Figure BDA0002340450700001789
EXAMPLE 69 drug moiety (D) is
In another aspect, the drug moiety (D) of the immunoconjugate of the invention is a compound disclosed in adoro (WO 2016/145102).
In another aspect, the drug moiety (D) of the immunoconjugate of the invention is a compound disclosed in adoro biotech (WO 2014/093936).
In another aspect, the drug moiety (D) of the immunoconjugates of the invention are compounds disclosed in the unpublished U.S. provisional application USSN:62/362907 filed 2016, 7, 15.d.by Aduro and Novartis.
In another aspect, the drug moiety (D) of the immunoconjugate of the invention is a compound disclosed in the unpublished PCT application PCT/US2016/059506 filed 2016, 10, 28, by Adirole and Norwalk, Inc.
In another aspect, the drug moiety (D) of the immunoconjugate of the invention is a compound disclosed in Memorial Sloan kertering et al (WO 2014/179335). Such compounds are listed in table 4.
In another aspect, the drug moiety (D) of the immunoconjugate of the invention is a compound disclosed in Merck & Co (WO 2017/027646). Such compounds are listed in table 4.
In another aspect, the drug moiety (D) of the immunoconjugate of the invention is a compound disclosed in Merck & Co (WO 2017/027645). Such compounds are listed in table 4.
In another aspect, the drug moiety (D) of the immunoconjugate of the invention is a compound disclosed in the gillanin smith corporation (WO 2015/185565). Such compounds are listed in table 4.
In another aspect, the drug moiety (D) of the immunoconjugate of the invention is a compound disclosed in university of brueck (brock university) (WO 2015/074145). Such compounds are listed in table 4.
In another aspect, the pharmaceutical moiety (D) of the immunoconjugate of the invention is a compound disclosed in the rogers company (Rutgers) (US 9315523). Such compounds are listed in table 4.
In another aspect, the drug moiety (D) of the immunoconjugate of the invention is a compound disclosed in sibpringbank (SpringBank) (WO 2007070598, WO 2017004499, and WO 2017011622). Such compounds are listed in table 4.
In another aspect, the drug moiety (D) of the immunoconjugate of the invention is a compound disclosed in invitrogen (WO 2016/096174). Such compounds are listed in table 4.
In another aspect, the drug moiety (D) of the immunoconjugate of the invention is a compound disclosed in the board of california university (Regents of univ. california) and the adoro biotechnology company (WO 2014/189805). Such compounds are disclosed in fig. 10, 11, and 12 herein.
In another aspect, the drug moiety (D) of the immunoconjugate of the invention is a compound disclosed in sobeyro corporation (Sperovie) (WO 2018009648).
In another aspect, the drug moiety (D) of the immunoconjugate of the invention is a compound disclosed in sobetiova (Sperovie) (WO 2018009652).
In another aspect, the drug moiety (D) of the immunoconjugate of the invention is a compound disclosed in sbeirovie corporation (Sperovie) (WO 2018013887).
In another aspect, the drug moiety (D) of the immunoconjugate of the invention is a compound disclosed in sbeirov corporation (WO 2018013908). Each of the foregoing applications is incorporated herein by reference in its entirety.
TABLE 4
Figure BDA0002340450700001801
Figure BDA0002340450700001811
Figure BDA0002340450700001821
Figure BDA0002340450700001831
Figure BDA0002340450700001841
Figure BDA0002340450700001851
Figure BDA0002340450700001861
Figure BDA0002340450700001871
Figure BDA0002340450700001891
Figure BDA0002340450700001901
Figure BDA0002340450700001911
Figure BDA0002340450700001921
Figure BDA0002340450700001931
Figure BDA0002340450700001941
Figure BDA0002340450700001951
Figure BDA0002340450700001961
Figure BDA0002340450700001971
Figure BDA0002340450700001981
Figure BDA0002340450700001991
Figure BDA0002340450700002001
Figure BDA0002340450700002011
Figure BDA0002340450700002021
Figure BDA0002340450700002031
Figure BDA0002340450700002041
Figure BDA0002340450700002051
Figure BDA0002340450700002061
Figure BDA0002340450700002071
Figure BDA0002340450700002081
Figure BDA0002340450700002091
Figure BDA0002340450700002111
Figure BDA0002340450700002121
Figure BDA0002340450700002131
Examples of synthesis of compounds having formula (A)
The compound having formula (a) was prepared according to the synthetic description in WO 2016145102.
Specifically, (2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR) -2, 9-bis (6-amino-9H-purin-9-yl) -3, 10-difluorooctahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphospholadodecane-5, 12-bis (thiolate) 5, 12-dioxide (T1-1) and (2R,3R,3aR,5R,7aR,9R,10R,10aR,12S,14aR) -2, 9-bis (6-amino-9H-purin-9-yl) -3, 10-difluorooctahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphospholane-5, 12-bis (thiolate) 5, 12-dioxide (T1-6) was synthesized according to the following scheme:
Figure BDA0002340450700002151
step 1: preparation of (2R,3R,4R,5R) -5- (6-benzamido-9H-purin-9-yl) -4-fluoro-2- (hydroxymethyl) tetrahydrofuran-3-ylhydrogenphosphonate (2): to a solution of N- (9- ((2R,3R,4R,5R) -5- ((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -3-fluoro-4-hydroxytetrahydrofuran-2-yl) -9-H-purin-6-yl) benzamide (1, 2.0g, 3.0mmol, chemie genes (chemwes)) in 1, 4-dioxane (25mL) and pyridine (8mL) was added a solution of 2-chloro-1, 3, 2-benzodioxan-4-one (SalPCl) (0.84g, 4.1mmol) in 1, 4-dioxane (12 mL). After 30 minutes, water (4mL) was introduced into the stirred reaction mixture at room temperature and the resulting mixture was poured into 1N NaHCO3Aqueous solution (100 mL). The aqueous mixture was extracted with EtOAc (3 × 100mL) and the layers were partitioned. The EtOAc extracts were combined and concentrated to dryness in vacuo to give a colorless foam. Dissolving the colorless foam in CH2Cl2(30mL) in a solvent, in order toA colorless solution is given. To this solution was added water (0.5mL) and dichloroacetic acid (DCA) in CH2Cl2(30mL) in 6% (v/v). After stirring at room temperature for ten minutes, the red solution was filled with pyridine (3.5 mL). The resulting white mixture was concentrated under vacuum and water was removed as an azeotrope after concentration with MeCN (30 mL). This azeotropic procedure was repeated two more times with MeCN (30 mL). In the last evaporation, a white slurry of the resulting compound 2 was left in MeCN (15 mL).
Step 2: preparation of (2R,3R,4R,5R) -5- (6-benzamido-9H-purin-9-yl) -2- (((((((((2R, 3R,4R,5R) -5- (6-benzamido-9H-purin-9-yl) -2- ((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -4-fluorotetrahydrofuran-3-yl) oxy) (2-cyanoethoxy) phosphorylthio) oxy) methyl) -4-fluorotetrahydrofuran-3-ylhydrogenphosphonate (4): a solution of (2R,3R,4R,5R) -5- (6-benzamido-9H-purin-9-yl) -2- ((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -4-fluorotetrahydrofuran-3-yl (2-cyanoethyl) diisopropylphosphoramidite (3, 2.5g, 2.9mmol, ChemGen. company (ChemGenes)) in MeCN (20mL) was dried by concentration under vacuum. This process was repeated two more times to remove water as an azeotrope. In the last azeotrope, ten were introduced into a solution of compound 3 in MeCN (7mL)
Figure BDA0002340450700002161
Molecular sieves, and storing the solution under a nitrogen atmosphere. To a stirred mixture of compound 2 and residual pyridin-1-ium dichloroacetate in MeCN (15mL) was added a solution of compound 3 in MeCN (7 mL). After five minutes, 3- ((dimethylamino-methylene) amino) -3H-1,2, 4-dithiazole-3-thione (DDTT) (650mg, 3.2mmol) was added to the stirred mixture. After 30 minutes, the yellow mixture was concentrated in vacuo to give compound 4 as a yellow oil.
And step 3: n, N ' - (((2R,3R,3aR,7aR,9R,10R,10aR,12R,14aR) -5- (2-cyanoethoxy) -3, 10-difluoro-12-mercapto-12-oxo-5-thioxooctahydro-2H, 7H-difluoro [3,2-d:3',2' -j)][1,3,7,9]Tetraoxa [2,8]]Preparation of diphosphacyclododecane-2, 9-diyl) bis (9H-purine-9, 6-diyl)) benzamide (5): oriented foodCompound 4 in CH2Cl2(60mL) to the solution were added water (0.35mL) and dichloroacetic acid (DCA) in CH2Cl2(60mL) in 6% (v/v). After ten minutes at room temperature, pyridine (20mL) was introduced into the red solution. The resulting yellow mixture was concentrated in vacuo until about 20mL of yellow mixture remained. Pyridine (20mL) was introduced to the yellow mixture and the mixture was concentrated in vacuo until about 20mL of yellow mixture remained. Pyridine (30mL) was added to the yellow mixture, and the mixture was concentrated in vacuo until about 30mL of yellow mixture remained. To a stirred yellow mixture in pyridine (30mL) was added 2-chloro-5, 5-dimethyl-1, 3, 2-dioxaphosphorinane-2-oxide (DMOCP) (1.6g, 8.4 mmol). Seven minutes later, water (1.4mL) was added to the dark orange solution followed immediately by the introduction of 3H-1, 2-benzodithiol-3-one (0.71mg, 4.2 mmol). After five minutes, the dark orange solution was poured into 1N NaHCO3Aqueous solution (400 mL). After ten minutes, the biphasic mixture was extracted with EtOAc (200mL) and diethyl ether (200 mL). After separation, the aqueous layer was back-extracted with EtOAc (200mL) and diethyl ether (200 mL). The organic extracts were combined and concentrated in vacuo. Toluene (75mL) was added to the concentrated yellow oil and the mixture was evaporated under vacuum to remove residual pyridine. This process was repeated twice with toluene (75 mL). The oil was chromatographed on silica gel (on CH)2 Cl 20% to 10% MeOH) to provide compound 5 as an orange oil (67mg, 2.5% yield).
And 4, step 4: preparation of Compound (T1-1): to a stirred solution of compound 5(65mg, 0.07mmol) in MeOH (0.9mL) was added aqueous ammonium hydroxide (0.9mL) and the orange slurry was heated at 50 ℃. After two hours, the orange solution was allowed to cool and concentrated under vacuum. The orange residue was purified by reverse phase silica gel chromatography (0% to 30% MeCN in 10mM aqueous triethylammonium acetate (TEAA)) to give compound (T1-1) as a white mono-triethylammonium salt after lyophilization (18mg, 38% yield). LCMS-ESI: 693.25[ M-H]- (for C)20H22F2N10O8P2S2Calculated value 694.305); rt 16.698' min, according toHPLC conditions (10mM TEAA, 2% to 20%); rt 20.026'. min, according to LCMS conditions (20mM NH)4OAc, 2% to 20%).1H NMR(400MHz,45℃,D2O)δ8.44(s,2H),8.24(s,2H),6.52(d,J＝16.4Hz,2H),5.80(d,J＝3.6Hz,1H),5.67(d,J＝4.0Hz,1H),5.37-5.26(m,2H),4.77-4.65(m,4H),4.22(dd,J＝11.4Hz,6.0Hz,2H),3.34(q,J＝7.0Hz,6H),1.43(t,J＝7.0Hz,9H)。19FNMR(400MHz,45℃,D2O) delta-200.74 to-200.98 (m).31P NMR(45℃,D2O)δ54.46。
As shown, the stereochemistry of this compound was confirmed by the co-crystal structure binding to the wild-type STING protein.
After purification in the reverse phase chromatography step, the Rp, Sp isomers were also isolated to provide the compound as the ditriethylammonium salt after lyophilization (T1-6). LCMS-ESI: 693.30[ M-H]- (for C)20H22F2N10O8P2S2694.05); rt13.830min, according to HPLC conditions (10mM TEAA, 2% to 20%). Rt 15.032min, according to LCMS conditions (20mM NH)4OAc, 2% to 20%).1H NMR.(400MHz,45℃,D2O)δ8.65(s,1H),8.50(s,1H),8.34(s,1H),8.26(s,1H),6.58(dd,J＝16.4,2.8Hz,2H),6.00(dd,J＝51.2,3.6Hz,1H),5.69(dd,J＝51.2,3.8Hz,1H),5.32-5.15(m,2H),4.77-4.67(m,3H),4.61(d,J＝12.4Hz,1H),4.25(dd,J＝11.8,4.2Hz,2H),3.33(q,J＝7.2Hz,12H),1.43(t,J＝7.2Hz,18H)。19F NMR(400MHz,45℃,D2O)δ-200.75to-201.31(m)。31P NMR(45℃,D2O)δ54.69,54.64。
Examples of the synthesis of compounds having the formula (B)
The compound having formula (B) was prepared according to the synthetic description in WO 2014189805.
Specifically, compound (T1-2) was synthesized according to the following scheme
Figure BDA0002340450700002191
To a solution of 5g (5.15mmol) of N-benzoyl-5 '-O- (4,4' -dimethoxytrityl) -2 '-O-tert-butyldimethylsilyl-3' -O- [ (2-cyanoethyl) -N, N-diisopropylaminophenyl ] adenosine (1) in 25ml of acetonitrile was added 0.18ml (10 mmol) of water and 1.20g (6.2 mmol) of pyridinium trifluoroacetate. After stirring at room temperature for 5 minutes, 25ml of tert-butylamine were added and the reaction was stirred at room temperature for 15 minutes. The solvent was removed under reduced pressure to give (2R,3R,4R,5R) -5- (6-benzamido-9H-purin-9-yl) -2- ((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -4- ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-3-ylhydrogenphosphonate as a foam, which was then co-evaporated with acetonitrile (2x 50mL) and then dissolved in 60mL dichloromethane. To this solution were added water (0.9ml, 50mmol) and 60ml of 6% (v/v) dichloroacetic acid (44mmol) in dichloromethane. After 10min at room temperature, the reaction was quenched by addition of pyridine (7.0ml, 87mmol) and concentrated to an oil which was dried by co-evaporation three times with 40ml of anhydrous acetonitrile to give (2) in a volume of 12 ml.
Reacting N-benzoyl-5 '-O- (4,4' -dimethoxytrityl) -3 '-O-tert-butyldimethylsilyl-2' -O- [ (2-cyanoethyl) -N, N-diisopropylaminophenyl]Adenosine ((3), 6.4g, 6.6 mmol) was dissolved in 40ml of anhydrous acetonitrile and dried by co-evaporation three times with 40ml of anhydrous acetonitrile, 20ml remaining for the last time. Adding
Figure BDA0002340450700002201
Molecular sieves and the solution was stored under argon until used. Azeotrope dry (3) (6.4g, 6.6 mmol) in 20ml acetonitrile was added via syringe to a solution of (2) (5.15mmol) in 12ml anhydrous acetonitrile. After stirring for 5 minutes at room temperature, 1.14g (5.6mmol) of 3- ((N, N-dimethylaminomethylene) amino) -3H-1,2, 4-dithiazole-5-thione (DDTT) were added and the reaction was stirred for 30 minutes at room temperature. The reaction was concentrated and the residual oil was dissolved in 80ml dichloromethane. Water (0.9ml, 50mmol) and 80ml of 6% (v/v) dichloroacetic acid (58mmol) in dichloromethane were added and the reaction was stirred at room temperature for 10 min. Adding50ml of pyridine were used to quench the dichloroacetic acid. The solvent was removed under reduced pressure to give crude (2R,3R,4R,5R) -5- (6-benzamido-9H-purin-9-yl) -2- (((((((((2R, 3R,4R,5R) -2- (6-benzamido-9H-purin-9-yl) -4- ((tert-butyldimethylsilyl) oxy) -5- (hydroxymethyl) tetrahydrofuran-3-yl) oxy) (2-cyanoethoxy) phosphorylthio) oxy) methyl) -4- ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-3-ylhydrogenphosphonate as a solid, it was then dissolved in 150ml of dry pyridine and concentrated down to a volume of about 100 ml. 2-chloro-5, 5-dimethyl-1, 3, 2-dioxaphosphorinane-2-oxide (DMOCP, 3.44g, 18 mmol) is then added and the reaction is stirred at room temperature for 5 minutes. 3.2ml of water were immediately added followed by 3-H-1, 2-benzodithiol-3-one (1.3g, 7.7 mmol) and the reaction was stirred at room temperature for 5 minutes. The reaction mixture was then poured into a flask containing 20g NaHCO3And stirred at room temperature for 5 minutes, then poured into a separatory funnel and extracted with 800ml of 1:1 ethyl acetate diethyl ether. The aqueous layer was re-extracted with 600ml of 1:1 ethyl acetate diethyl ether. The organic layers were combined and concentrated under reduced pressure to yield about 11g of an oil containing diastereomers (5a) and (5 b). The above crude mixture was dissolved in dichloromethane and applied to a 250g silica gel column. The desired diastereomer was eluted from the column using an ethanol gradient (0-10%) in dichloromethane. Fractions containing the desired diastereomers (5a) and (5b) were combined and concentrated to give 2.26g of 50% (5b) of about 50% (5 a).
2.26g of crude (5a) and (5b) from the silica gel column were transferred into a thick-walled glass pressure tube. 60ml methanol and 60ml concentrated aqueous ammonia were added and the tube was heated while stirring in an oil bath at 50 ℃ for 16 hours. The reaction mixture was cooled to near ambient temperature, bubbled with a stream of nitrogen for 30 minutes, and then transferred to a large round bottom flask. Most of the volatiles were carefully removed under reduced pressure to avoid foaming and bumping. If water is still present, the residue is frozen and lyophilized to dryness. The crude lyophilized mixture was taken up in about 50ml of CH3CN/10mM aqueous triethylammonium acetate (60/40). After 0.45 micron PTFE filtration, 4-5ml sample portions were applied to C-18DynamaxColumn (40X250 mm). With acetonitrile and 10mM aqueous triethylammonium acetate (over 20 minutes, at a flow rate of 50ml/min, 30% to 50% CH)3CN) was eluted. Fractions from preparative HPLC runs containing pure (6) were combined and evaporated to remove CH3CN and lyophilized to give 360mg of pure (6) (RpRp diastereomer) as the bis-triethylammonium salt.
To 270mg (0.24mmol) of (6) was added 5.0ml of pure trimethylamine trihydrofluoride. The mixture was stirred at room temperature for about 40 hours. Completion of the reaction was confirmed by analytical HPLC and the sample was neutralized by dropwise addition to 45ml of cooled, stirred 1M triethylammonium bicarbonate. The neutralized solution was desalted on Waters C-18Sep-Pak and the product was diluted with CH3CN/10mM aqueous triethylammonium acetate (5: 1). Will CH3CN was evaporated under reduced pressure and the remaining aqueous solution was frozen and lyophilized. Multiple rounds of lyophilization from water gave 122mg (57%) of (T1-2) as the bis-triethylammonium salt.1H NMR(500MHz,45℃,(CD3)2SO-15μL D2O)δ8.58(s,1H),8.41(s,1H),8.18(s,1H),8.15(s,1H),6.12(d,J＝8.0,1H),5.92(d,J＝7.0,1H),5.30(td,J＝8.5,4.0,1H),5.24-5.21(m,1H),5.03(dd,J＝7.5,4.5,1H),4.39(d,J＝4,1H),4.23(dd,J＝10.5,4.0,1H),4.18(s,1H),4.14-4.08(m,2H),3.85-3.83(m,1H),3.73(d,J＝12.0,1H),3.06(q,J＝7.5,12H),1.15(t,J＝7.5,1H)；31P NMR(200MHz,45℃,(CD3)ISO-15pL D2O)658.81, 52.54; HRMS (FT-ICR) I/z, calculated 689.0521 for C20H24O10N10P2S2(M-H), found 689.0514.
Examples of synthesis of compounds having formula (A)
(2R,3R,3aS,5R,7aR,9S,10R,10aS,12R,14aR) -2, 9-bis (6-amino-9H-purin-9-yl) -5, 12-dimercaptotetrahydro-2H, 7H,9H,14H-3,14a:10,7 a-bis (epoxymethylene bridge) difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphosphacyclododecane 5, 12-dioxide (T2-45) and (2R,3R,3aS,5R,7aR,9S,10R,10aS,12S,14aR) -2, 9-bis (6-amino-9H-purin-9-yl) -5, 12-dimercaptotetrahydro-2H, synthesis of 7H,9H,14H-3,14a:10,7 a-bis (epoxymethylene bridge) difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphospholane 5, 12-dioxide (T2-44) was prepared according to the following scheme:
Figure BDA0002340450700002221
step 1: (1S,3R,4R,7S) -3- (6-benzamido-9H-purin-9-yl) -1- (hydroxymethyl) -2, 5-dioxabicyclo [2.2.1]Preparation of Heptane-7-yl hydrogen phosphonate (2): to (1R,3R,4R,7S) -3- (6-benzamido-9H-purin-9-yl) -1- ((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -2, 5-dioxabicyclo [2.2.1]Heptane-7-yl (2-cyanoethyl) diisopropylphosphoramidite (1, 1.0g, 1.2mmol, Exiqon, Wobbe, Mass.) in MeCN (10mL) and H2To a solution of O (0.05mL) was added pyridinium trifluoroacetate (270g, 1.5 mmol). After 25 minutes, tert-butylamine (5.0mL) was added to the stirred reaction mixture at room temperature. After 15 min, the reaction solution was concentrated under vacuum and water was removed as an azeotrope after concentration with MeCN (3 × 15mL) to obtain a white foam. To a solution of white foam in 1, 4-dioxane (13mL) was added a solution of SalPCl (226mg, 1.0mmol) in 1, 4-dioxane (5 mL). After 7 minutes, pyridine (3mL) was added to the cloudy white mixture. After 1 hour, water (2mL) was introduced into the turbid reaction mixture. After 5 minutes, the mixture was poured into 1N NaHCO3In solution (100 mL). The solution was extracted with EtOAc (3 × 100mL) and the organic layer was concentrated to dryness in vacuo. Dissolving the residue in CH2Cl2(10mL) to give a white mixture. To this solution was added water (150. mu.L) and DCA in CH2Cl2(10mL) in a 9% (v/v) solution. After stirring at room temperature for 10 minutes, the orange solution was charged with pyridine (1.5 mL). The resulting clear solution was concentrated under vacuum and water was removed as an azeotrope after concentration with MeCN (3 × 20 mL). In the last evaporation, the resulting cloudy slurry of compound 2 was left in MeCN (20 mL).
Step 2: (1R,3R,4R,7S) -3- (6-benzamido-9H-purin-9-yl) -1- (((((((1R, 3R,4R,7S) -3- (6-benzamido-9H-purin-9-yl) -1- ((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -2, 5-dioxabicyclo [ 2.2.1)]Heptane-7-yl) oxy) (2-cyanoethoxy)) Phosphorylthio) oxy) methyl) -2, 5-dioxabicyclo [2.2.1]Preparation of Heptane-7-yl hydrogen phosphonate (3): a solution of Compound 1(1.0g, 1.2mmol, Ekun (Exiqon) in MeCN (10mL) was dried by concentration under vacuum
Figure BDA0002340450700002231
Molecular sieves, and storing the solution under a nitrogen atmosphere. To a stirred mixture of compound 2 and residual pyridinium dichloroacetate in MeCN (20mL) was added a solution of compound 1 in MeCN (10 mL). After 40 min, DDTT (263mg, 1.3mmol) was added to the stirred mixture. After 70 minutes, the yellow solution was concentrated in vacuo to give compound 3as a yellow paste.
And step 3: n, N ' - (((2S,3R,3aS,7aR,9R,10R,10aS,12R,14aR) -5- (2-cyanoethoxy) -12-mercapto-12-oxo-5-thiotetrahydro-2H, 7H,9H,14H-3,14a:10,7 a-bis (epoxymethylene bridge) difluoro [3,2-d:3',2' -j-][1,3,7,9]Tetraoxa [2,8]]Preparation of diphosphacyclododecane-2, 9-diyl) bis (9H-purine-9, 6-diyl)) benzamide (4): to compound 3 in CH2Cl2(30mL) in solution Water (180. mu.L) and DCA in CH2Cl2(20mL) in 8.5% (v/v). After stirring at room temperature for 15 minutes, pyridine (10mL) was introduced into the red-orange solution. The resulting yellow solution was concentrated in vacuo until about 10mL of yellow mixture remained. Pyridine (30mL) was introduced to the yellow mixture and the mixture was concentrated in vacuo until about 10mL of yellow mixture remained. Pyridine (30mL) was added to the yellow mixture, and the mixture was concentrated in vacuo until about 10mL of yellow mixture remained. To a stirred yellow mixture in pyridine (50mL) was added DMOCP (631mg, 3.4 mmol). After 15 min, water (750. mu.L) was added to the brownish yellow solution, followed immediately by the introduction of 3H-1, 2-benzodithiol-3-one (304mg, 1.8 mmol). After 30 minutes, the brownish yellow solution is poured into 1N NaHCO3Aqueous solution (250 mL). After 15 min, the biphasic mixture was extracted with EtOAc (200 mL). Is divided intoAfter separation, the aqueous layer was back-extracted with EtOAc (2 × 150 mL). The organic extracts were combined and concentrated in vacuo. Toluene (20mL) was added to the concentrated yellow oil and the mixture was evaporated under vacuum to remove residual pyridine. The process was repeated again with toluene (30 mL). The resulting oil was chromatographed on silica gel (on CH)2 Cl 20% to 50% MeOH) to provide a mixture of compound 4(604mg, 52% yield) as a beige solid.
And 4, step 4: preparation of (T2-45) and (T2-44): to a stirred solution of compound 4(472mg, 0.5mmol) in EtOH (5.0mL) was added AMA (ammonium hydroxide/40% methylamine solution in water) (6.5mL) and the yellow solution was heated at 50 ℃. After 2 hours, the yellow solution was allowed to cool and concentrated under vacuum. The yellow residue in 10mM TEAA (3mL) was purified by reverse phase silica gel chromatography (0% to 25% MeCN in 10mM aqueous TEAA) to obtain compound (T2-45) as white triethylammonium salt after lyophilization (92mg, 27% yield). LCMS-ESI: 712.95[ M-H]-(for C)22H24N10O10P2S2714.56); rt: 1.06min, according to UPLC (20mM NH)4OAc, 2% to 80% MeCN).1H NMR(400MHz,45℃,D2O)δ8.45(d,J＝4.4Hz,2H),8.30(d,J＝5.6Hz,2H),6.36(d,J＝4.4Hz,2H),5.12(s,4H),4.63(d,J＝12.4Hz,2H),4.34-4.24(m,6H),3.33(q,J＝7.2Hz,12H),2.09(m,1H),1.40(t,J＝5.2Hz,18H)。31P NMR(45℃,D2O)δ54.57。
After purification in the reverse phase chromatography step, the Rp/Sp isomers were also separated to provide compound (T2-44) as the triethylammonium salt after lyophilization (35mg, 10% yield). LCMS-ESI: 712.95[ M-H]-(for C)22H24N10O10P2S2714.56); rt: 1.01min, according to UPLC (20mM NH)4OAc, 2% to 80% MeCN).1H NMR(400MHz,45℃,D2O)δ8.58(s,1H),8.46(s,1H),8.31(s,1H),8.27(s,1H),6.38(s,2H),5.32(s,1H),5.11(s,1H),5.07(d,J＝10.4Hz,2H),4.62(d,J＝11.2Hz,1H),4.53(d,J＝11.2Hz,1H),4.41-4.31(m,4H),4.24(t,J＝16.4Hz,1H),3.33(q,J＝7.2Hz,10H),1.41(t,J＝7.2Hz,15H)。31PNMR(45℃,D2O)δ55.33,54.48。
Examples of the synthesis of compounds having the formula (B)
Certain compounds having formula (B) are prepared enzymatically. Specifically, compound T1-25 was prepared enzymatically according to the following synthetic scheme:
Figure BDA0002340450700002251
the reactions were performed in parallel in duplicate: to 100mM aqueous (((2S,3R,4R,5R) -5- (6-amino-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methyl) phosphonic acid diphosphate anhydride (a) (250. mu.L, 0.025 mmol; N-1007, Reinforcement Biotechnology, TriLink Biotechnologies, san Diego, Calif., USA), 100mM aqueous (((2S,3S,4R,5R) -5- (2-amino-6-oxo-1, 6-dihydro-9H-purin-9-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methyl) phosphonic acid diphosphate anhydride (b) (250. mu.L, 0.025mmol, Sigma Cat. No. (Sigma) catalog No. 51120), Herring sperm DNA solution (250. mu.L, 10mg/mL solution; #9605-5-D, Teviki Inc. (Trevigen Inc.), Gathersburg, Md., USA) and human cGAS (1500. mu.L, 2.1mg/mL, prepared as described in the following paragraphs) reaction buffer (50mM TRIS, 2.5mM magnesium acetate, 10mM KCl, pH adjusted to 8.2 with aqueous NaOH 5M; 25mL) was added. The reaction was incubated on an orbital shaker at 37 ℃ and 150rpm for 16 hours. Completion of the reaction was confirmed by analyzing an aliquot (100. mu.L) of the reaction mixture, diluted with acetonitrile (100. mu.L), centrifuged, and the formation of the desired compound was determined by UV analysis. The reaction was mixed with acetonitrile (20mL), incubated on an orbital shaker for 10 minutes at room temperature, and after subsequent centrifugation (7000g, for 5 minutes), the supernatant was filtered through a paper filter. The filtrate was mixed with acetic acid (100. mu.L) and loaded directly onto a 20X 250mM Inertsil Amide 5 μm column (flow rate 30 mL/min; solvent A: aqueous 10mM ammonium acetate, 2mM acetic acid, solvent B: acetonitrile; using isocratic elution, using 26% phase A/74% phase B, fraction size 50 mL). Will contain the desiredFractions of compound (T1-25) were combined and the solvent was evaporated under vacuum to a final volume of about 10 mL. The concentrated compound (T1-25) solution from the first chromatography was repurified by direct injection onto a 1X 50cm Sephadex G10 HPLC column (flow rate 1.0 mL/min; mobile phase containing 0.25mM ammonium hydroxide and 25% acetonitrile) with UV detection at 250 nm. All fractions containing the desired compound (T1-25) were combined and dried by lyophilization to give 4.5mg of the compound (T1-25) as the bis-ammonium salt;1H NMR(600.1MHz,D2O)δ8.35(br s,1H),8.06(br s,1H),7.77(s,1H),6.31(d,J＝12.8Hz,1H),5.86(s,1H),5.62(s,1H),5.35(d,J＝50.8Hz,1H),4.97(d,J＝19.0Hz,1H),4.46(s,1H),4.42(s,1H),4.33(s,1H),4.24(s,1H),4.21(s,2H),3.97(s,1H)；MS m/z 677.2[M+H]+。
the cGAS used in this and the following examples was prepared by cloning and expression of human and mouse cGAS. The coding region for human or mouse cGAS comprising amino acids 155-522 (human) and 147-507 (mouse) was cloned into a pET-based expression vector. The resulting expression construct contained an N-terminal 6x-His tag (SEQ ID NO:930) followed by a ZZ tag and an engineered protease cleavage side of HRV3C that allowed the generation of N-terminally extended human cGAS 155-. Both plasmids were transformed into E.coli strain BL21(DE3) phage-resistant cells (C2527H, New England BioLabs, Ipposite, Mass.) for bacterial expression. Phage-resistant E.coli cells BL21(DE3) harboring the cGAs expression plasmid were expressed in the Infors bioreactor at a scale of 1.5L. The preculture was grown in LB medium. Will contain kanamycin1.5L of AutoInduction Medium (student, Protein Expr purify) [ Protein expression and purification ]]5 months in 2005; 41(1) 207-34) were incubated with 100mL of preculture under the following conditions and cultured to an OD of about 10: the temperature is 37 ℃; stirrer (cascade regulation via pO 2) 500; pH 7.0; pO2 (cascade regulation on) 5%; the flow rate is 2.5L/min; and gas mix (cascade regulation via pO 2) 0. Then theThe temperature was lowered to 18 ℃ and overnight expression was performed. Cells were harvested by centrifugation and lysed using an Avestin EmulsiFlex French press. Purification was according to Kato et al (PLoS One [ public science library integration)]2013,8(10) e76983), using Ni-affinity chromatography, a heparin purification step to remove DNA and finally size exclusion chromatography. cGAS eluted as a homogeneous fraction and was concentrated to at least 5 mg/mL.
Human cGAS:
Figure BDA0002340450700002271
Figure BDA0002340450700002272
examples of the synthesis of compounds having the formula (B)
Certain compounds having formula (B) are prepared enzymatically. Specifically, compound T1-28 was prepared enzymatically according to the following synthetic scheme:
Figure BDA0002340450700002281
the reaction was run in parallel four times, each on a 26mL scale: to a 100mM aqueous (((2S,3R,4R,5R) -5- (6-amino-9H-purin-9-yl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) methyl) phosphonic acid diphosphate anhydride (a) (250. mu.L, 0.025mmol), 100mM aqueous (((2S,3S,4S,5R) -5- (2-amino-6-oxo-1, 6-dihydro-9H-purin-9-yl) -3-fluoro-4-hydroxytetrahydrofuran-2-yl) methyl) phosphonic acid diphosphate anhydride (c) (250. mu.L, 0.025 mmol; N-3002, Reilin Biotechnologies), herring sperm DNA solution (800. mu.L, 10mg/mL solution; #9605-5-D, Tevigator Inc. (Trevigen Inc.)) and mouse cGAS formulation (250 μ L, 6.5mg/mL, prepared as described for human cGAS above) reaction buffer (50mM TRIS, 2.5mM magnesium acetate, pH adjusted to 8.2 with aqueous NaOH 5M; 25 mL). The reaction was incubated on an orbital shaker at 37 ℃ and 150rpm for 16 hours. The reaction was mixed with acetonitrile (20mL) and incubated on an orbital shaker at room temperature for 10 minutes. At the followingAfter centrifugation (7000g for 5 min), the supernatants of all four reactions were combined and filtered through a paper filter. The filtrate was evaporated in vacuo to a residual volume of about 20mL and combined with 0.5mL of acetic acid (0.5mL) and 1.0M aqueous triethylammonium acetate (5 mL). The crude material was injected directly onto a column of Chromolith RP18e2.1x 10 cm. Chromatography (flow rate 80 mL/min; isocratic flow 10mM triethylammonium acetate and 1 vol% acetonitrile) yielded fractions of the desired compound (T1-28), which were combined, mixed with 25% aqueous ammonia solution (20. mu.L), and dried by lyophilization. Obtaining a compound (T1-28) as a bis-triethylammonium salt; 39.8 mg;1H NMR(600.1MHz,D2O)δ8.16(s,1H),8.13(s,1H),7.73(s,1H),6.33(d,J＝13.9Hz,1H),5.91(d,J＝8.6Hz,1H),5.61(m,1H),5.40(dd,J＝51.5,2.6Hz,1H),5.30(dd,J＝53.3,3.2Hz,1H),4.98(m,1H),4.56(d,J＝25.8Hz,1H),4.44(d,J＝9.0Hz,1H),4.39(d,J＝11.8Hz,1H),4.20(m,1H),4.08(d,J＝12.4Hz,1H),4.04(d,J＝11.8Hz,1H),3.06(q,J＝7.3Hz,12H),1.13(t,J＝7.3Hz,18H)；31P NMR(376.4MHz,D2O)δ-1.68,-2.77；19F NMR(376.4MHz,D2O)δ-199.72,-203.23；MS 677.2[M-1]-。
mouse cGAS:
Figure BDA0002340450700002291
examples of synthesis of compounds having formula (D)
Specifically, (1S,3R,6R,8R,9S,11R,14R,16R,17R,18R) -8, 16-bis (6-amino-9H-purin-9-yl) -17, 18-difluoro-2, 4,7,10,12, 15-hexaoxa-3, 11-diphosphotricyclo [12.2.1.16,9] octadecane-3, 11-bis (thiolate) 3, 11-dioxide (8) (corresponding to compound (T2-46)) was synthesized according to the following scheme:
Figure BDA0002340450700002293
step 1: preparation of (2R,3S,4R,5R) -2- (6-benzoylamino-9H-purin-9-yl) -5- ((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -4-fluorotetrahydrofuran-3-yl (2-cyanoethyl) diisopropylphosphoramidite (2): to a solution of compound i6(1, 1g, 1.5mmol, 1 equiv) (dried by co-evaporation in vacuo with anhydrous MeCN (3 × 3 mL)) in anhydrous THF (6mL) was added DMAP (18mg, 0.15mmol, 0.1 equiv) and DIPEA (0.98mL, 5.9mmol, 4 equiv). 2-cyanoethyl N, N-diisopropyl chlorophosphamide (360. mu.L, 1.6mmol, 1.1 eq., GenBank) was added and the reaction stirred overnight. The mixture was diluted with 100mL EtOAc (with 5% NaHCO)3Pre-wash) and washed with brine (5x50 mL). The EtOAc layer was washed with Na2SO4Dried, filtered and concentrated in vacuo. Flash chromatography (40g silica gel, isocratic gradient-50: 44:4DCM: hexanes: TEA) afforded 1.08g of Compound 2.
Step 2: preparation of (2R,3S,4R,5R) -2- (6-benzoylamino-9H-purin-9-yl) -5- ((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -4-fluorotetrahydrofuran-3-ylhydrogenphosphonate (4): to a solution of compound i6(1.5g, 2.7mmol, 1 eq) in anhydrous dioxane (17mL) was added anhydrous pyridine (4.7mL, 69mmol, 26 eq) followed by a solution of 2-chloro-1, 3, 2-benzodioxan-4-one (3, 540mg, 3.2mmol, 1.2 eq, Sigma Aldrich) in 1, 4-dioxane (8.3 mL). The reaction mixture was stirred for 1h, then 10mL of water and NaHCO3(3.72 g in 100mL water). The suspension was extracted with EtOAc (3X 100mL), and the organic layers were combined and Na2SO4Dried, filtered and concentrated. Chromatography (80g of SiO20-50% MeOH (containing 0.5% pyridine) and DCM) gave compound 4.
And step 3: preparation of (2R,3S,4R,5R) -2- (6-benzoylamino-9H-purin-9-yl) -4-fluoro-5- (hydroxymethyl) tetrahydrofuran-3-ylhydrogenphosphonate (5): to a solution of compound 4(0.78g, 1.1mmol, 1 equiv) in DCM (13mL) was added a solution of water (190. mu.L, 11mmol, 10 equiv.) and DCA (760. mu.L, 9.2mmol, 8.7 equiv.) in DCM (13 mL). The mixture was stirred for 10min and quenched with pyridine (1.5mL, 18mmol, 17 equiv.). The mixture was concentrated in vacuo and co-evaporated with anhydrous MeCN (3 × 10mL) to provide compound 5 in 4mL of MeCN.
And 4, step 4: preparation of (2R,3S,4R,5R) -2- (6-benzoylamino-9H-purin-9-yl) -5- (((((((((2R, 3S,4R,5R) -2- (6-benzoylamino-9H-purin-9-yl) -5- ((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -4-fluorotetrahydrofuran-3-yl) oxy) (2-cyanoethoxy) phosphorylthio) oxy) methyl) -4-fluorotetrahydrofuran-3-ylhydrogenphosphonate (6): compound 2(1.1g, 1.2mmol, 1.1 equiv.) was dried by co-evaporation in vacuo with anhydrous MeCN (3 × 10mL, remaining 8 mL). This solution was added to the solution of compound 5 of step 3 and stirred for 5 min. DDTT (240mg, 1.2mmol, 1.1 equiv) was added and the mixture was stirred for 30min, then concentrated in vacuo to afford compound 6.
And 5: n, N' - (((1S,3R,6R,8R,9S,11R,14R,16R,17R,18R) -3- (2-cyanoethoxy) -17, 18-difluoro-11-mercapto-11-oxo-3-thioxo-2, 4,7,10,12, 15-hexaoxa-3, 11-diphosphotricyclo [12.2.1.1 ]6,9]Preparation of octadecane-8, 16-diyl) bis (9H-purine-9, 6-diyl)) benzamide (7A): to a solution of compound 6 in DCM (25mL) was added a solution of water (190 μ L, 11mmol, 10 equivalents) and DCA (1.5mL, 18mmol, 17 equivalents) in DCM (25 mL). The mixture was stirred for 10min, then quenched with pyridine (11mL, 130mmol, 120 equivalents), then concentrated in vacuo to about 13 mL. An additional 30mL of anhydrous pyridine was added. The solution was treated with DMOCP (580mg, 3.2mmol, 3 equiv.) and stirred for 3min, then water (570. mu.L, 32mmol, 30 equiv.) was added, followed immediately by 3H-1, 2-benzodithiol-3-one (260mg, 1.6mmol, 1.5 equiv.). After 5min, the solution was poured into saturated NaHCO3(100mL) and extracted with EtOAc (2X 100 mL). The organic layers were combined and concentrated to give about 2.5g of a crude mixture of isomer 7A/B. Chromatography (80 gSiO)2MeOH-DCM 0-15% over 54min) gave 128mg of Compound 7A.
Step 6: (1S,3R,6R,8R,9S,11R,14R,16R,17R,18R) -8, 16-bis (6-amino-9H-purin-9-yl) -17, 18-difluoro-3, 11-dimercapto-2, 4,7,10,12, 15-hexaoxa-3, 11-diphosphotricyclo [12.2.1.1 [ ] -8, 6R,8R,9S,11R,14R,16R,17R,18R ] -bis6,9]Preparation of octadecane 3, 11-dioxide (8) (corresponding to compound (T2-46)): to 7A (70mg) in MeONH was added to a solution in H (1.5mL)4OH (1.5 mL). The reaction mixture was heated to 50 ℃ for 2.5h, then cooled, with N2Bubbling was performed and concentrated in vacuo. Purify (RP MPLC-5.5g C18-0-20% MeCN/TEAA (10mM) over 90 column volumes to give 10mg of Compound 8 after lyophilization. LCMS-ESI: 693.70[ M-H]-(for C)20H22F2N10O8P2S2694.05); rt: 8.174min, according to LCMS conditions (20mM NH)4OAc, 2% to 50%).1H NMR.(400MHz,45℃,D2O)δ8.08(s,1H),7.99(s,1H),6.17(d,J＝8.4,1H),5.84(dd,J＝52.4,3.61H),5.19-5.11(m,1H),4.77(m,1H),4.46-4.2(m,1H),4.10-4.09(m,1H),3.09(q,J＝7.2,6H),1.17(t,J＝7.6Hz,9H)。
Intermediate i6 (used above) was prepared according to the following scheme
Figure BDA0002340450700002331
Step 1: preparation of (2R,3R,4R,5R) -5- (6-benzamido-9H-purin-9-yl) -2- ((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -4- ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-3-yl trifluoromethane-sulfonate (i 2): a mixture of N- (9- ((2R,3R,4R,5R) -5- ((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -3- ((tert-butyldimethylsilyl) oxy) -4-hydroxytetrahydrofuran-2-yl) -9H-purin-6-yl) benzamide (i1, 5.6g, 7.11mmol, ChemGen (ChemGenes)) and DMAP (0.174g, 1.42mmol) was suspended in anhydrous THF (35mL), DIPEA (6.21mL, 35.5mmol) was added to produce a solution to which N-phenyltrifluormethanesulfonamide (5.08g, 14.21mmol) was added. The mixture was stirred at rt for 3.5h, then poured into 5% brine (100mL) and extracted with EtOAc (2 × 100 mL). The combined organic phases were dried (Na)2SO4) The drying agent was filtered off and concentrated in vacuo on silica gel (10 g). The crude material was purified by silica gel chromatography (gradient elution 25% to 100% EtOAc/heptane) to give the desired compound i2 as a tan solid; 5.53 g;1H NMR(400MHz,CDCl3) δ 9.05(s,1H),8.68(s,1H),8.18(s,1H),8.06(d, J ═ 7.5Hz,2H),7.66(t, J ═ 7.4Hz,1H),7.61-7.48(m,4H),7.48-7.25(m,7H),6.88(d, J ═ 8.8Hz,4H),6.04(d, J ═ 7.6Hz,1H),5.50(dd, J ═ 7.5,4.7Hz,1H),5.32(d, J ═ 4.5Hz,1H),4.50(t, J ═ 4.1Hz,1H),3.82(s,6H),3.77(dt, J ═ 10.8,5.2, 1H),3.41 (t, J ═ 4.1Hz,1H), 3.77 (dd, 3.8H), 3.8 (3.8, 7H), 3.8 (H), 3.8 (dd, 0, 0.7H), 3.46H); LCMS (method A) Rt＝1.65min；m/z 920.5[M+H]+。
Step 2: preparation of (2R,3S,4R,5R) -5- (6-benzamido-9H-purin-9-yl) -2- ((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -4- ((tert-butyldimethylsilyl) oxy) tetrahydrofuran-3-ylacetate (i 3): a mixture of compound i2(5.5g, 5.98mmol), KOAc (2.93g, 29.9mmol) and 18-crown-6 (1,4,7,10,13, 16-hexaoxacyclooctadecane, 0.79g, 2.99mmol) in toluene (40mL) was heated at 110 ℃ for 4 h. The reaction mixture was then cooled to room temperature and silica gel (10g) was added and the solvent was removed in vacuo. The crude material was purified by silica gel chromatography (gradient elution 25% to 100% EtOAc/heptane) to give the desired compound i3 as a tan solid: 3.3 g;1H NMR(400MHz,CDCl3) δ 8.70(s,1H),8.58(s,1H),7.93(s,1H),7.84(d, J ═ 7.5Hz,2H),7.44(t, J ═ 7.4Hz,1H),7.35(t, J ═ 7.6Hz,2H),7.28(d, J ═ 7.2Hz,2H),7.21-7.02(m,7H),6.67(dd, J ═ 8.9,2.1Hz,4H),5.98(s,1H),4.97(dd, J ═ 3.6,1.4Hz,1H),4.61-4.52(m,1H),4.35(s,1H),3.62(s,6H),3.41(dd, J ═ 9.8,6.2, 1H), 3.53 (dd, 3.7H), 3.7.7 (m,3H), 3.3.3.6H), 3.53 (dd, 3.7H). LCMS (method A) Rt1.68min；m/z 830.2[M+H]+。
And step 3: preparation of N- (9- ((2R,3R,4S,5R) -5- ((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -3- ((tert-butyldimethylsilyl) oxy) -4-hydroxytetrahydrofuran-2-yl) -9H-purin-6-yl) benzamide (i 4):
compound i3(6.78g, 8.17mmol) was dissolved in MeOH (120mL) and a 2.0M solution of dimethylamine in MeOH (20.4mL, 40.8mmol) was added. The reaction mixture was stirred at rt for 17 h. Silica gel (12g) was added and the solvent was removed in vacuo. The crude material was purified by silica gel chromatography (gradient elution 25% -75% EtOAc/heptane) to give a tan solidDesired compound i 4: 3.9 g;1H NMR(400MHz,CDCl3) δ 8.94(s,1H),8.65(s,1H),8.16(s,1H),7.97-7.90(m,2H),7.58-7.38(m,3H),7.38-7.32(m,2H),7.32-7.00(m,7H),6.80-6.65(m,4H),5.83(d, J ═ 1.2Hz,1H),5.38(d, J ═ 8.0Hz,1H),4.42(s,1H),4.29(t, J ═ 4.6Hz,1H),4.02-3.95(m,1H),3.75-3.61(m,6H),3.53(d, J ═ 5.0Hz,2H),0.81(s,9H),0.0(s, 6H). LCMS (method A) Rt1.57min；m/z 788.2[M+H]+。
And 4, step 4: preparation of N- (9- ((2R,3S,4S,5R) -5- ((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -3- ((tert-butyldimethylsilyl) oxy) -4-fluorotetrahydrofuran-2-yl) -9H-purin-6-yl) benzamide (i5a) and N- (9- ((2R,3S,4R,5R) -5- ((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -3- ((tert-butyldimethylsilyl) oxy) -4-fluorotetrahydrofuran-2-yl) -9H-purin-6-yl) benzamide (i5 b): under an inert nitrogen atmosphere, compound i4(750mg, 0.952mmol) was dissolved in anhydrous DCM (7mL) and the solution was cooled to 0 ℃. A1.0M DAST solution (1.90mL, 1.90mmol) was added, followed by stirring the reaction at 5 ℃ for-17 h using a cryocooler to control the reaction temperature. The vessel was warmed to 0 ℃ and saturated NaHCO was added3(2 mL). After stirring for 30min, the mixture was diluted with 5% brine (20mL) and extracted with EtOAc (2X 20 mL). The combined organics were dried (Na)2SO4) The drying agent was filtered off, silica gel (2g) was added to the filtrate, and the solvent was removed in vacuo. The crude material was purified by silica gel chromatography (gradient elution 10% -75% EtOAc/heptane) to give 193mg of a mixture of diastereomers i5a and i5b as tan solids; major (2R,3S,4S,5R) diastereomer LCMS (method A) Rt1.53min；m/z 790.4(M+H)+(ii) a Minor (2R,3S,4R,5R) diastereomer Rt1.58min；m/z 790.4[M+H]+。
And 5: preparation of N- (9- ((2R,3S,4S,5R) -5- ((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) -9H-purin-6-yl) benzamide (i 6): the diastereomeric mixture of i5a and i5b (2.0g, 2.53mmol) was dissolved in anhydrous THF (100mL) and cooled to-42 ℃ under an inert nitrogen atmosphere, then 1.0M TBAF (3.80mL, 3.80M) was addedmol). The reaction was stirred for 2.5h, then saturated NaHCO3Quench (20 mL). The cold bath was removed and the slurry was stirred for 10min, then the mixture was diluted with 5% brine (150mL) and extracted with DCM (2X 100 mL). The combined organic phases were dried (Na)2SO4) The drying agent was filtered off, silica gel (4g) was added to the filtrate, and the solvent was removed in vacuo. The crude material was purified by silica gel chromatography (gradient elution 25% to 100% EtOAc/heptane) to give the desired compound i6 as a white solid: 355 mg;1H NMR(400MHz,CDCl3)δ9.16(s,1H),8.64(s,1H),8.23(s,1H),7.99(d,J＝7.5Hz,2H),7.59(t,J＝7.4Hz,1H),7.48(t,J＝7.6Hz,2H),7.41-7.31(m,3H),7.31-7.11(m,7H),6.79(d,J＝8.9Hz,4H),6.16(d,J＝7.3Hz,1H),5.77(br s,1H),5.27-5.10(m,2H),4.53(dt,J＝28.0Hz,3.4Hz,1H),3.77(s,6H),3.51(dd,J＝10.7,3.7Hz,1H),3.34(dd,J＝10.7,3.3Hz,1H)；19F NMR(376.4MHz,CDCl3)δ-197.5；13C NMR(101MHz,CDCl3) δ 164.66,158.64,158.62,152.60,151.43,149.34,144.22,141.66,135.29,135.13,133.40,132.93,129.96,128.87,127.99,127.93,127.86,127.07,122.65,113.26,93.85,92.02,87.56(d, J ═ 144Hz),83.56(d, J ═ 23Hz),77.30,74.63(d, J ═ 16Hz),62.82(d, J ═ 11Hz), 55.26; LCMS (method A) Rt0.89min；m/z 676.3[M+H]+。
Alternatively, intermediate i6 was also prepared according to scheme 1A' below:
Figure BDA0002340450700002371
step 1: preparation of (2R,3R,4R,5R) -5- (6-amino-9H-purin-9-yl) -2- (hydroxymethyl) -4- ((4-methoxybenzyl) oxy) tetrahydrofuran-3-ol (i 8): to a suspension of adenosine (i7, 100g, 374mmol) in DMF (2.64L) under nitrogen at 4 ℃ was added 60% sodium hydride (19.46g, 486mmol) in one portion and the reaction mixture was stirred under nitrogen for 60 min. 4-methoxybenzyl chloride (60.9ml, 449mmol) was added dropwise over a period of 10 minutes and the suspension was stirred and warmed to room temperature for 16 hours. The reaction was quenched with water (50mL), then a short-path condenser was installed, and the light yellow mixture was heated in vacuo (115 deg.C)To remove DMF (60 ℃ -90 ℃). The reaction volume was reduced to about 300mL and then partitioned between water (2.5L) and EtOAc (2X 500mL) with an aqueous phase pH of about 8. The aqueous phase was separated and then extracted with 4:1DCM-IPA (8X 500 mL). The combined DCM-IPA phases were dried (Na)2SO4) The drying agent was filtered off and the filtrate was concentrated in vacuo to give a semi-solid residue. The crude residue was stirred in EtOH (130mL) at 55 ℃ for 1h, filtered off, the solid washed with EtOH and dried in vacuo to afford a white solid (55.7g, 38%, positional isomer ratio 86: 14). This material was replaced in hot EtOH slurry (100mL at 55 ℃), hot filtered and the solid washed with cold EtOH to give the desired compound i8 as a white crystalline solid (47.22 g):1H NMR(400MHz,DMSO-d6) δ 8.30(s,1H),8.08(s,1H),7.33(brs,2H),7.06(d, J ═ 8.6Hz,2H),6.73(d, J ═ 8.6Hz,2H),6.03(d, J ═ 6.3Hz,1H),5.46(dd, J ═ 7.3,4.4Hz,1H),5.28(d, J ═ 5.1Hz,1H),4.57(d, J ═ 11.6Hz,1H),4.53(dd, J ═ 6.4,5.0Hz,1H),4.37(d, J ═ 11.6Hz,1H),4.33(dd, J ═ 5.0,2.9Hz,1H),4.02(q, J ═ 3.3, 3H), 69(s,3H),3.67 (H), 3.3H), 3.67(m, 3H), 3.3.3H, 3(m ═ 6Hz, 1H); LCMS (method B) Rt 1.86 mins; m/z 388.0(M + H)+)。
Step 2: preparation of (2R,3R,4R,5R) -4- ((4-methoxybenzyl) oxy) -5- (6- (tritylamino) -9H-purin-9-yl) -2- ((trityloxy) methyl) tetrahydrofuran-3-ol (i 9): to compound i8(45.5g, 117mmol) in DMF (310mL) was added 2, 6-lutidine (68.4mL, 587mmol), DMAP (3.59g, 29.4mmol) and trityl chloride (82g, 294 mmol). The reaction mixture was slowly heated to 80 ℃. The reaction mixture was stirred at 80 ℃ for 15h and then cooled to room temperature. The reaction was poured into aqueous saturated NH4Cl (1500mL) and extracted with EtOAc (3 × 1L). The combined organic phases were dried (Na)2SO4) The drying agent was filtered off and the filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography (gradient elution EtOAc-heptane 0-100%) to give the desired compound i9(85.79g) as an off-white solid:1H NMR(400MHz,CDCl3)δ8.01(s,1H),7.87(s,1H),7.41(m,12H),7.28(m,18H),7.18(d,J＝8.6Hz,2H),6.95(s,1H),6.80(d,J＝8.6Hz,2H),6.11(d,J＝4.4Hz,1H),4.77-4.67(m,2H),4.62(d,J＝11.6Hz,1H),4.32(q, J ═ 5.3Hz,1H),4.21(m,1H),3.79(s,3H),3.49(dd, J ═ 10.5,3.3Hz,1H),3.36(dd, J ═ 10.5,4.5Hz,1H),2.66(d, J ═ 5.7Hz, 1H); LCMS (method G) Rt1.53mins; m/z 872.0(M + H)+)。
And step 3: preparation of (2R,4S,5R) -4- ((4-methoxybenzyl) oxy) -5- (6- (tritylamino) -9H-purin-9-yl) -2- ((trityloxy) methyl) dihydrofuran-3 (2H) -one (i 10): to a solution of dess-martin periodinane (DMP, 3.04g, 7.17mmol) in DCM (72mL) was added tert-butanol (0.713mL, 7.45mmol) and sodium carbonate (0.134g, 1.261mmol) at room temperature, then a solution of compound i9(5.00g, 5.73mmol) in DCM (72mL) was added dropwise over 1 hour. The resulting reaction mixture was stirred at room temperature for 4h, then additional DCM (110mL) was added. After an additional 3 hours, additional DMP (0.63g) and DCM (50mL) were added. The reaction was stirred for 13h, then saturated Na was added2S2O5(40mL), saturated NaHCO3(150mL) and brine (50 mL). The organic phase was separated and the aqueous phase was re-extracted with DCM (2 × 150 mL). The combined DCM was dried (Na)2SO4) The drying agent was filtered off and the filtrate was concentrated in vacuo. The crude material was purified by silica gel chromatography (gradient elution EtOAc/heptane 0-80%) to provide compound i10(4.36g) as a white foam:1H NMR(400MHz,CDCl3) δ 7.95(s,1H),7.78(s,1H),7.46-7.15(m,30H),7.05(d, J ═ 8.6Hz,2H),6.98(s,1H),6.73(d, J ═ 8.6Hz,2H),6.13(d, J ═ 7.8Hz,1H),5.23(dd, J ═ 7.9,0.8Hz,1H),4.80(d, J ═ 11.8Hz,1H),4.72(d, J ═ 11.8Hz,1H),4.35(ddd, J ═ 4.0,2.4,0.8Hz,1H),3.76(s,3H),3.52(dd, J ═ 10.5,4.0, 1H),3.43 (ddd, 10.5, 1H); LCMS (method C) Rt1.53mins; m/z 870.0(M + H)+)。
And 4, step 4: preparation of (2R,3S,4R,5R) -4- ((4-methoxybenzyl) oxy) -5- (6- (tritylamino) -9H-purin-9-yl) -2- ((trityloxy) methyl) tetrahydrofuran-3-ol (i 11): to a solution of compound i10(98mg, 0.113mmol) in DCM (3mL) at-20 deg.C was added glacial AcOH (0.15mL), followed by NaBH4(13mg, 0.34 mmol). After 1h, the reaction mixture was quenched with 5% brine (20mL) and extracted with EtOAc (25 mL). The organic phase was separated and dried (Na)2SO4) The drying agent was filtered off and the filtrate was concentrated in vacuo to a white solid. The crude solid (3S:3R ratio 7:1) was slurried in hot MeOH (3mL, warmed to 50 deg.C) and DCM (ca. 0.5mL) was added dropwise and the suspension was cooled. The mother liquor was decanted and the solid was dried in vacuo (63mg, 3S:3R ratio 13: 1). Recrystallization from MeOH: DCM (4mL, v/v 5:1) gave compound i11 as a single diastereoisomer (ratio 50: 1):1H NMR(400MHz,CDCl3) δ 7.90(s,1H),7.74(s,1H),7.48-7.13(m,32H),6.95-6.84(m,2H),5.80(s,1H),4.68(d, J11.3 Hz,1H),4.49(d, J11.3 Hz,1H),4.36(s,1H),4.33-4.27(m,1H),4.23(d, J3 Hz,1H),3.83(s,3H),3.59-3.52(m, 2H); LCMS (method H) Rt 1.76 mins; m/z 872.2(M + H)+。
And 5: preparation of 9- ((2R,3S,4R,5R) -4-fluoro-3- ((4-methoxybenzyl) oxy) -5- ((trityloxy) methyl) tetrahydro-furan-2-yl) -N-trityl-9H-purin-6-amine (i 12): to a solution of compound i11(240mg, 0.275mmol) in anhydrous DCM (15mL) at 0 deg.C was added anhydrous pyridine (0.223mL, 2.75 mmol). After 5min, diethylaminosulfur trifluoride (DAST, 0.182mL, 1.38mmol) was added dropwise. After 5 minutes, the cooling bath was removed and the reaction was stirred for 4.5 h. The reaction mixture was diluted with chloroform (20mL), dried silica gel was added, and the mixture was concentrated in vacuo, then toluene (20mL) was added, and concentrated to dryness in vacuo. The crude material was purified by silica gel chromatography (gradient elution 10% -50% EtOAc/heptane) to give the desired compound i12(121mg) as a white solid:1H NMR(400MHz,CDCl3)δ7.93(s,1H),7.82(s,1H),7.42-7.20(m,30H),7.13-7.05(m,3H),6.74(d,J 8.3Hz,2H),6.09-6.05(m,1H),5.15-5.06(m,1H),5.00(dd,J 54.4,and 4.4Hz,1H),4.60-4.50(m,2H),4.49-4.39(m,1H),3.77(s,3H),3.51-3.38(m,1H),3.32(dd,J＝10.6,4.0Hz,1H)；19FNMR(376.4MHz,CDCl3) Delta-198.09; LCMS (method I) Rt 1.27 mins; m/z 874.5(M + H)+。
Step 6: preparation of (2R,3S,4S,5R) -2- (6-amino-9H-purin-9-yl) -4-fluoro-5- (hydroxymethyl) tetrahydrofuran-3-ol (i 13): to a solution of compound i12(70mg, 0.080mmol) in DCM (1mL) was added TFA (0.5mL, 6.49 mmol). After 45min, the reaction mixture was washed with MeOH (10)mL) and concentrated in vacuo. The crude material was dissolved in MeOH (10mL) and TEA (0.1mL) was added before the addition of silica gel and the suspension was concentrated in vacuo. The crude material was purified by silica gel chromatography (gradient elution 0-10% MeOH/DCM) to give the desired compound i13(21mg) as a white solid containing a tea.tfa salt and used as received:1h NMR (400MHz, methanol-d)4)δ8.33(s,1H),8.21(s,1H),6.02(d,J7.9Hz,1H),5.12(dd,J 54.5,4.3Hz,1H),4.96(ddd,J 25.1,8.0,4.3Hz,1H),4.44(dt,J27.6,2.5Hz,1H),3.94-3.69(m,2H)；19F NMR (376.4MHz, methanol-d)4) Delta-200.02; LCMS (method G) Rt0.51mins; m/z 270.1(M + H)+。
And 7: preparation of N- (9- ((2R,3S,4S,5R) -4-fluoro-3-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) -9H-purin-6-yl) benzamide (i 14): to compound i13(3.88g, 14.41mmol) in pyridine (65mL) was added benzoyl chloride (8.36mL, 72.1mmol) slowly followed by TMSCl (9.21mL, 72.1mmol) at 0 ℃. The reaction mixture was stirred while warming to rt for 4 h. After a further 1h, the solution is quenched with water (35mL), after 5min with concentrated NH4OH (17mL) quenched to give a pale tan solid. The mixture was diluted with water (100mL) and extracted with MeTHF (3 × 75 mL). The combined organic phases were dried (Na)2SO4) The drying agent was filtered off and the filtrate was concentrated in vacuo to a tan semi-solid crude material which was purified by silica gel chromatography (gradient elution 0-20% MeOH/DCM) to give the desired compound i14(2.75 g):1H NMR(400MHz,CDCl3)δ8.78(s,1H),8.09(s,1H),8.08-8.01(m,2H),7.66(t,J＝7.4Hz,1H),7.57(t,J＝7.5Hz,2H),6.13(br s,1H),5.92(d,J＝7.9Hz,1H),5.41-5.11(m,2H),4.60(d,J＝28.4Hz,1H),4.13-3.98(m,2H),3.86(d,J＝13.0Hz,1H).19F NMR(376.4MHz,CDCl3) Delta-199.36; LCMS (method G) Rt 0.72 mins; m/z 374.2(M + H)+。
And 8: preparation of N- (9- ((2R,3S,4S,5R) -5- ((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) -4-fluoro-3-hydroxytetrahydrofuran-2-yl) -9H-purin-6-yl) benzamide (i 6): to compound i14(2.73g, 10.14mmol) in pyridine (55mL) was added DMTCl (4.12g, 12.17mmol) in one portion. The reaction was stirred at room temperatureStir 72h, then quench the light yellow solution by addition of MeOH (20mL), then concentrate to a semi-solid in vacuo after addition of toluene (2 × 50mL) to the azeotropic residual pyridine. The resulting material was dissolved in DCM (100mL) and saturated NaHCO was used3(100mL), washed with brine and then dried (Na)2SO4). The drying agent was filtered off and the filtrate was evaporated in vacuo. The crude material was purified by silica gel chromatography (gradient elution 0-10% MeOH in DCM containing 0.04% TEA) to give compound i6 as a white solid (3.70 g):1HNMR(400MHz,CDCl3)δ9.16(s,1H),8.64(s,1H),8.23(s,1H),7.99(d,J 7.5Hz,2H),7.59(t,J 7.4Hz,1H),7.48(t,J 7.6Hz,2H),7.41-7.31(m,3H),7.31-7.11(m,7H),6.79(d,J8.9Hz,4H),6.16(d,J 7.3Hz,1H),5.77(br s,1H),5.27-5.10(m,2H),4.53(dt,J 28.0Hz,3.4Hz,1H),3.77(s,6H),3.51(dd,J 10.7,3.7Hz,1H),3.34(dd,J 10.7,3.3Hz,1H)；19F NMR(376.4MHz,CDCl3)δ-197.5；13C NMR(101MHz,CDCl3) δ 164.66,158.64,158.62,152.60,151.43,149.34,144.22,141.66,135.29,135.13,133.40,132.93,129.96,128.87,127.99,127.93,127.86,127.07,122.65,113.26,93.85,92.02,87.56(d, J144 Hz),83.56(d, J23Hz),77.30,74.63(d, J16 Hz),62.82(d, J11 Hz), 55.26; LCMS (method C) Rt 2.72 mins; m/z676.3(M + H)+。
Note that: the LCMS or HRMS data indicated in this example and in the following examples were recorded using the methods indicated below. In all cases, the reported masses are the masses of the protonated parent ion, unless otherwise indicated.
The method A comprises the following steps: LCMS data were recorded using the waters system: a micro-mass ZQ mass spectrometer; column: sunfire C183.5 microns, 3.0x 30 mm; gradient: 40% -98% MeCN in water with 0.05% TFA over a 2.0min period; the flow rate is 2 mL/min; the column temperature was 40 ℃.
The method B comprises the following steps: LCMS was recorded using waters system: a Micromass SQ mass spectrometer; column: acquity UPLCBEH C181.7 microns, 2.1x 30 mm; gradient 1% to 30% MeCN to 3.20min, then gradient: in the presence of 5mM NH during the 1.55min period 430% -98% MeCN in OH water, then return 1% MeCN at 5.19 min-total run time 5.2 min; flow rate 1mL/min; the column temperature was 50 ℃.
The method C comprises the following steps: LCMS was recorded using waters system: a Micromass SQ mass spectrometer; column: acquity UPLCBEH C181.7 microns, 2.1x 50 mm; gradient: in the presence of 5mM NH during a period of 4.40min (isocratic 0.65min)42% -98% MeCN in OH water, then return 2% MeCN at 5.19 min-total run time 5.2 min; the flow rate is 1 mL/min; the column temperature was 50 ℃.
The method E comprises the following steps: HRMS data was recorded using the waters system: acquity G2 Xevo QTof mass spectrometer; column: acquity BEH 1.7 microns, 2.1x 50 mm; gradient: 40% -98% MeCN in water with 0.1% formic acid over a period of 3.4min, 98% MeCN isocratically over 1.75min, 40% return at 5.2 min; the flow rate is 1 mL/min; the column temperature was 50 ℃.
Method G: LCMS data were recorded using the waters system: a Micromass SQ mass spectrometer; column: AcquisytUPLC BEH C181.7 micron, 2.1 × 30 mm; gradient 1% to 30% MeCN to 1.20min, then gradient: in the presence of 5mM NH during a period of 0.55min 430% -98% MeCN in OAc water, then return 1% MeCN at 2.19 min-total run time 2.2 min; the flow rate is 1 mL/min; the column temperature was 50 ℃.
Method H: LCMS data were recorded using the waters system: a Micromass SQ mass spectrometer; column: AcquisytUPLC BEH C181.7 micron, 2.1 × 30 mm; gradient from 2% to 98% MeCN to 1.76min, then isocratic to 2.00min, then return 2% MeCN to 2.20min using a gradient in water containing 0.1% formic acid; the flow rate is 1 mL/min; the column temperature was 50 ℃.
The method comprises the following steps: LCMS data were recorded using the waters system: a Micromass SQ mass spectrometer; column: AcquisytUPLC BEH C181.7 micron, 2.1 × 30 mm; gradient 40% to 98% MeCN to 1.40min, then isocratic to 2.05min, then return 40% MeCN to 2.20min using a gradient in water containing 0.1% formic acid; the flow rate is 1 mL/min; the column temperature was 50 ℃.
The compounds listed in tables 1-4 can be easily prepared in consideration of the synthetic methods described above, and the synthetic methods described in WO 2016/145102, WO2014/093936, WO 2017/027646, WO 2017/027645, WO 2015/185565, WO 2016/096174, WO 2014/189805, US2015158886, WO 2017011622, WO 2017004499 and WO 2007070598.
nLinker-drug moiety (L- (D))
Joint
As used herein, a "linker" is any chemical moiety capable of linking an antibody, antibody fragment (e.g., antigen-binding fragment), or functional equivalent to another moiety, such as a drug moiety (e.g., a cyclic dinucleotide or a cyclic dinucleotide), that binds to an interferon gene stimulating factor (STING) receptor.
The linker of the immunoconjugates of the invention can comprise one or more cleavage elements and in certain embodiments, the linker of the immunoconjugates of the invention comprises two or more cleavage elements, wherein each cleavage element is independently selected from a suicide spacer and a group susceptible to cleavage (such as a group susceptible to acid-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, glycosidase-induced cleavage, phosphodiesterase-induced cleavage, phosphatase-induced cleavage, protease-induced cleavage, lipase-induced cleavage, or disulfide bond cleavage).
In some aspects, the linker is a pre-charged linker, a hydrophilic linker, or a dicarboxylic acid-based linker.
An acid labile linker is a linker that is cleavable at acidic pH. For example, certain intracellular compartments such as endosomes and lysosomes have an acidic pH (pH 4-5) and provide conditions suitable for cleavage of acid labile linkers.
Some linkers can be cleaved by peptidases, i.e., peptidases can cleave linkers only certain peptides are readily cleaved either inside or outside the cell, see, e.g., Trout et al, 79Proc. Natl.Acad.Sci.USA [ Proc. Natl.Acad.Sci.USA ],626-629(1982) and Umemoto et al, 43int.J.cancer [ J.International journal of cancer ],677-684 (1989). furthermore, peptides are composed of α -amino acids and peptide bonds which are chemically amide bonds between the carboxylate of one amino acid and the amino group of a second amino acid.
Some linkers may be cleaved by an esterase, i.e., an esterase may cleave the linker. Likewise, only certain esters may be cleaved by esterases present inside or outside the cell. Esters are formed by the condensation of carboxylic acids and alcohols. Simple esters are esters produced with simple alcohols such as aliphatic and small cyclic and aromatic alcohols.
Cleavable linkers, such as those containing hydrazones, disulfide bonds, and dipeptides (e.g., Val-Cit), are well known in the art and may be used. See, e.g., Ducry, et al,bioconjugate Chem. [ organism Conjugate chemistry], Vol 21, 5-13 (2010).
In addition, cleavable linkers containing glucuronidase cleavable moieties are well known in the art and can be used. See, e.g., Ducry, et al,bioconjugate Chem. [ Bioconjugate chemistry], Vol 21, 5-13 (2010).
For immunoconjugates of the invention comprising a cleavable linker, the linker is substantially stable in vivo until the immunoconjugate binds or enters a cell, at which time intracellular enzymes or intracellular chemical conditions (pH, reducing power) cleave the linker to release the drug moiety.
The pre-charged linker is derived from charged cross-linking reagents that retain their charge after incorporation into the antibody drug conjugate. An example of a pre-charged linker can be found in US 2009/0274713.
The linker (L) may be attached to the antibody, antigen-binding fragment or functional equivalent thereof at any suitable available position on the antibody, antigen-binding fragment or functional equivalent thereof: typically, the linker (L) is attached to an available amino nitrogen atom (i.e., a primary or secondary amine rather than an amide) or hydroxyl oxygen atom, or to an available sulfhydryl group, for example on cysteine.
The linker (L) of the immunoconjugate of the invention may be bivalent, wherein the linker serves to link only one drug moiety/linker to the antibody, antigen binding moiety or functional equivalent, or the linker (L) of the immunoconjugate of the invention may be trivalent and capable of linking two drug moieties/linkers to the antibody, antigen binding moiety or functional equivalent. In addition, the linker (L) in the immunoconjugates of the invention may also be multivalent and capable of linking multiple drug moieties/linkers to an antibody, antigen binding moiety or functional equivalent.
The linker (L) of the immunoconjugates of the invention is a linking moiety comprising one or more linker components. Some preferred linkers and linker components are described herein.
The linker component of the linker (L) of the immunoconjugates of the invention may be, for example,
a) alkylene group: - (CH)2)n- (in this case n is 1-18);
b) an alkenyl group;
c) an alkynyl group;
d) ethylene glycol unit: -CH2CH2O-；
e) Polyethylene glycol unit: (-CH)2CH2O-)x(in this case x is 2-20);
f)-O-；
g)-S-；
h) carbonyl: -C (═ O) -;
i) ester: -C (═ O) -O-or-O-C (═ O) -;
j) carbonate ester: -OC (═ O) O-;
k) amine: -NH-;
l) an amide: -C (═ O) -NH-, -NH-C (═ O) -or-C (═ O) N (C)1-6Alkyl) -;
m) carbamates: -OC (═ O) NH — or-NHC (═ O) O —;
n) urea: -NHC (═ O) NH-;
o) alkylene substituted with one or more groups independently selected from carboxy, sulfonate, hydroxy, amine, amino acid, sugar, phosphate, and phosphonate;
p)C1-C10alkylene wherein one or more methylene groups are replaced by one or more-S-, -NH-or-O-moieties;
q) a ring system with two available attachment points, for example a bivalent ring selected from: phenyl (including 1,2-, 1,3-, and 1, 4-disubstituted phenyl)、C5-C6Heteroaryl group, C3-C8Cycloalkyl (including 1, 1-disubstituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and 1, 4-disubstituted cyclohexyl), and C4-C8A heterocycloalkyl group;
r) residues selected from the following amino acids: alanine (Ala), cysteine (Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (gin), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), citrulline (Cit), glutamic acid (Nva), norleucine (Nle), selenocysteine (Sec), pyrrolysine (Pyl), homoserine, homocysteine, and desmethyl-pyrrolysine;
a combination of 2 or more amino acid residues, wherein each residue is independently selected from the group consisting of: alanine (Ala), cysteine (Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (gin), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), citrulline (Cit), glutamic acid (Nva), norleucine (Nle), selenocysteine (Sec), pyrrolysine (Pyl), homoserine, homocysteine, and desmethylpyrrolysine, e for example Val-Cit; Cit-ValAla-Ala, Ala-Cit, Cit-Ala, Asn-Cit, Cit-Asn, Cit-Cit, Val-Glu, Glu-Val, Ser-Cit, Cit-Ser, Lys-Cit, Cit-Lys, Asp-Cit, Cit-Asp, Ala-Val, Val-Ala, Phe-Lys, Lys-Phe, Val-Lys, Lys-Val, Ala-Lys, Lys-Ala, Phe-Cit, Cit-Phe, Leu-Cit, Cit-Leu, Ile-Cit, Cit-Ile, Phe-Arg, Arg-Phe, Cit-Trp, and Trp-Cit;
and is
s) a suicide spacer, wherein said suicide spacer comprises
i. One or more protecting (triggering) groups susceptible to acid-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, glycosidase-induced cleavage, phosphodiesterase-induced cleavage, phosphatase-induced cleavage, protease-induced cleavage, lipase-induced cleavage, or disulfide bond cleavage
And is
One or more groups which can undergo 1, 4-elimination, 1, 6-elimination, 1, 8-elimination, 1, 6-cyclization elimination, 1, 5-cyclization elimination, 1, 3-cyclization elimination, intramolecular 5-exo-trig or 6-exo-trig cyclization,
non-limiting examples of such suicide spacers include:
Figure BDA0002340450700002472
wherein:
PG is a protecting (trigger) group;
Xais O, NH or S;
Xbis O, NH, NCH3Or S;
Xcis O or NH;
Yais CH2O or NH;
Ybis a bond, CH2O or NH, and LG is a leaving group, e.g., drug moiety (D) of an immunoconjugate of the invention.
Additional non-limiting examples of such suicide spacers are described in Angew. chem. int. Ed. [ applied chemistry-International edition ]2015,54, 7492-.
By way of example only, certain suicide spacers useful in the immunoconjugates of the invention are
Figure BDA0002340450700002481
In addition, the linker component may be a chemical moiety that is readily formed by a reaction between two reactive groups. Non-limiting examples of such chemical moieties are given in table 5.
TABLE 5
Figure BDA0002340450700002482
Figure BDA0002340450700002491
Figure BDA0002340450700002501
Figure BDA0002340450700002511
Figure BDA0002340450700002521
Figure BDA0002340450700002531
Wherein: r in Table 532Is H, C1-4Alkyl, phenyl, pyrimidine or pyridine; r in Table 535Is H, C1-6Alkyl, phenyl or C substituted by 1 to 3-OH groups1-4An alkyl group; each R in Table 536Independently selected from H, C1-6Alkyl, fluoro, benzyloxy substituted by-C (═ O) OH, benzyl substituted by-C (═ O) OH, C substituted by-C (═ O) OH1-4Alkoxy and C substituted by-C (═ O) OH1-4An alkyl group; r in Table 537Independently selected from H, phenyl and pyridine; n in table 5 is 0,1, 2 or 3; r in Table 513Is H or methyl; r in Table 550Is H or nitro; and R in Table 514Is H, -CH3Or a phenyl group.
In some embodiments, the linker component of linker L of the immunoconjugates of the invention is the side chain of the reactive functional group with the amino acid residue typically used for conjugation (e.g., thiol for cysteine residues, or free-NH for lysine residues)2) Reaction timeThe resulting radical. In other embodiments, the linker component of the linker L of the immunoconjugates of the invention is a group formed when a reactive functional group reacts with the side chain of an amino acid residue of a non-naturally occurring amino acid (e.g., para-acetyl Phe or para-azidophe). In other embodiments, the linker component of linker L of the immunoconjugates of the invention is a group formed when a reactive functional group reacts with a side chain of an amino acid residue that has been engineered into an antibody, antigen-binding fragment, or functional equivalent thereof (e.g., a thiol of a cysteine residue, a hydroxyl of a serine residue, a pyrroline of a pyrrolysine residue, or a pyrroline of a demethylpyrrolysine residue that has been engineered into an antibody). See, for example, Ou et al,PNAS[ Proc. of the national academy of sciences of the United states of America]108(26),10437-42(2011)。
Linker components formed by thiol reaction with cysteine residues of antibodies, antigen binding fragments, or functional equivalents thereof include, but are not limited to
Figure BDA0002340450700002541
Figure BDA0002340450700002542
Linker components formed by reaction with amines of lysine residues of antibodies, antigen binding fragments, or functional equivalents thereof include, but are not limited to,
Figure BDA0002340450700002543
Figure BDA0002340450700002544
wherein each p is 1-10 and each R is independently H or C1-4Alkyl (preferably methyl).
Linker components formed by reaction with pyrrolysine residues or demethylpyrrolysine residues include, but are not limited to
Figure BDA0002340450700002545
Wherein R is13Is H or methyl, and R14Is H, methyl or phenyl.
In some embodiments, the linker component of linker L of the immunoconjugates of the invention is between hydroxylamine andformed during partial reaction
Figure BDA0002340450700002547
Wherein said
Figure BDA0002340450700002548
In part, by reducing the interchain disulfide bridges of the antibody and re-bridging using 1, 3-dihaloacetone (e.g., 1, 3-dichloroacetone, 1, 3-dibromoacetone, 1, 3-diiodoacetone) and the disulfonate of 1, 3-dihydroxyacetone. In some embodiments, the linker component of linker L of the immunoconjugates of the invention is between hydrazine andformed during partial reaction
Figure BDA0002340450700002552
Wherein said
Figure BDA0002340450700002553
In part, by reducing the interchain disulfide bridges of the antibody and re-bridging using 1, 3-dihaloacetone (e.g., 1, 3-dichloroacetone, 1, 3-dibromoacetone, 1, 3-diiodoacetone) and the disulfonate of 1, 3-dihydroxyacetone.
In some embodiments, the linker component of linker L of the immunoconjugates of the invention is selected from the group shown in table 6 below:
TABLE 6
Figure BDA0002340450700002554
Figure BDA0002340450700002561
Figure BDA0002340450700002571
The linker L in the immunoconjugates of the invention typically comprises two or more linker components that can be selected to facilitate assembly of the conjugate, or they can be selected to affect the properties of the conjugate.
The linker of the immunoconjugates of the invention comprise one or more cleavage elements, and in certain embodiments, the linker of the immunoconjugates of the invention comprises two or more cleavage elements. In certain embodiments, one of the cutting elements is directly attached to a drug portion that allows for release of the drug portion without the cleaved linker fragment after the cleavage process. For example, the linker of the immunoconjugates of the invention is designed to have one of the following structures:
Figure BDA0002340450700002581
Figure BDA0002340450700002582
wherein:
lc is a linker component, and each Lc is independently selected from the linker components described herein;
x is an integer selected from 1,2, 3,4, 5,6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19 and 20;
y is an integer selected from 1,2, 3,4, 5,6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19 and 20;
p is an integer selected from 1,2, 3,4, 5,6, 7,8, 9 and 10;
d is a drug moiety as described herein;
and each cutting element (C)E) Independently selected from the group consisting of a suicide spacer and a group susceptible to cleavage (e.g., susceptible to acid-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, glycosidase-induced cleavage, phosphodiesterase-induced cleavage, phosphatase-induced cleavage, protease-induced cleavage, lipase-induced cleavage, or disulfide bond cleavage)The group of (1).
As tested in the hSTING wt assay and the THP 1-dual assay, it was observed that the presence of a non-cleavable linker fragment attached directly to the drug moiety described herein reduced the activity of the drug moiety (see below for description of the assay, and results see table 7), thus such linker design allows for the release of the active drug moiety.
hSTING wt assay:
HEK-293T cells were counter-transfected with a mixture of human STING (accession No. BC047779, introducing an Arg mutation at position 232, making the clone a human STING wild-type) and 5 xsser-mfnb-GL 4 plasmid (five interferon-stimulated response elements driving firefly luciferase GL4 and the minimal mouse interferon β promoter). cells were transfected with a FuGENE: DNA mixture by adding the FuGENE: DNA mixture to HEK-293T cells in suspension and plating into 384 well plates using the FuGENE transfection reagent (3:1FuGENE: DNA ratio): incubating the cells overnight and treating with the compound for 9-14 hours, then reading the plates by adding the BrightGlo reagent (Promega) and reading on an Envision plate reader.the fold change against background was calculated and normalized to the 50uM 2 '3' -amp-induced fold change each plate was run in triplicate.the cgec value was calculated as described for IP-10.
THP 1-dual assay:
THP 1-double cells were purchased from Invivogen. The THP 1-duplex cells were seeded in 384-well plates in 20uL tissue culture medium and incubated overnight. The next day compounds were added and incubated for 16-24 hours. The Lucia reporter signal was read by adding Quantiluc reagent (Invivogen) and then read on an Envision plate reader. Fold-change against background was calculated and normalized to 50uM of 2 '3' -cGAMP-induced fold-change. Each plate was run in triplicate. EC50 values were calculated as described in the IP-10 secretion assay.
THP 1-Dual/STING-KO assay
A human STING guide RNA (gRNA) oligonucleotide (TCCATCCATCCCGTGTCCCA (SEQ ID NO:931)) was cloned into the lentiviral vector pNGx _ LV _ g003 and transduced into THP 1-Dual _ Cas9 cells. FACS sorted single clones were then cultured in 96-well cell culture plates. Each individual well also contained 500 THP 1-dual parent cells as supporting cells. After 30 days, 1ug/ml puromycin was added to each well to eliminate the supporting cells. Each individual THP 1-duplex/STING-KO clone was tested using western blotting and NGS to confirm deletion of STING expression and insertion/deletion of nonsense nucleotides in both alleles. Six confirmed clones were then pooled and tested with cGAMP, T1-1, T1-2 using the method described in the THP 1-dual assay above.
TABLE 7
Figure BDA0002340450700002601
Certain aspects and examples of linkers and linker components of the immunoconjugates of the invention are provided in the following list of enumerated embodiments. It is to be appreciated that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the invention.
Example 70 linker component of linker L of the immunoconjugates of the invention or a combination thereof is selected from
Figure BDA0002340450700002602
Figure BDA0002340450700002611
Example 71. a linker L selected from:
-**C(＝O)O(CH2)mNR11C(＝O)(CH2)m-；-**C(＝O)O(CH2)mNR11C(＝O)(CH2)mO(CH2)m-；
-**C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-；
-**C(＝O)OC(R12)2(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-；
-**C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)m-；
-**C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)mC(＝O)-；
-**C(＝O)O(CH2)mNR11C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-；
-**C(＝O)O(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)(CH2)m-；
-**C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-；
-**C(＝O)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-；
-**C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)(CH2)m-；
-**C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-
-**C(＝O)O(CH2)mX6C(＝O)(CH2)m-；-**C(＝O)O(CH2)mX6C(＝O)(CH2)mO(CH2)m-；
-**C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)(CH2)m-；
-**C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)(CH2)mO(CH2)m-；
-**C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)(CH2)mO(CH2)mC(＝O)-；
-**C(＝O)O(CH2)mX6C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-；
-**C(＝O)X4C(＝O)X6(CH2)mNR11C(＝O)(CH2)mO(CH2)m-；
-**C(＝O)(CH2)mX6C(＝O)X1X2C(＝O)(CH2)m-；-**C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)m-；
-**C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)(CH2)m-；
-**C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mX3(CH2)m-；
-**C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-；
-**C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-；
-**C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-；
-**C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O))X5C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-；
-**C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-；
-**C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-；
-**C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-；
-**C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)m-；
-**C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-；
-**C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-；
-**C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mX3(CH2)m-；
-**C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mNR11((CH2)mO)n(CH2)m-；-**C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11((CH2)mO)n(CH2)mX3(CH2)m-；
-**C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)m-；-**C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-；
-**C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-；-**C(＝O)O(CH2)m-；
-**C(＝O)O((CH2)mO)n(CH2)m-；-**C(＝O)O(CH2)mNR11(CH2)m-；
-**C(＝O)O(CH2)mNR11(CH2)mC(＝O)X2X1C(＝O)-；
-**C(＝O)O(CH2)mX3(CH2)m-；-**C(＝O)O((CH2)mO)n(CH2)mX3(CH2)m-；
-**C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-；-**C(＝O)O(CH2)mNR11C(＝O(CH2)mX3(CH2)m-；
-**C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-；
-**C(＝O)O((CH2)mO)nX3(CH2)m-；-**C(＝O)O((CH2)mO)n(CH2)mX3(CH2)m-；
-**C(＝O)O((CH2)mO)n(CH2)mC(＝O)NR11(CH2)m-；-**C(＝O)O(CH2)mC(R12)2-；
-**C(＝O)OCH2)mC(R12)2SS(CH2)mNR11C(＝O)(CH2)m-and
-**C(＝O)O(CH2)mC(＝O)NR11(CH2)m-, wherein: indicates the attachment point to the drug moiety (D);
wherein:
X1is that
Figure BDA0002340450700002641
Wherein indicates with X2The attachment point of (a);
X2is selected from
Figure BDA0002340450700002642
Figure BDA0002340450700002643
Figure BDA0002340450700002644
Wherein indicates with X1The attachment point of (a);
X3is that
Figure BDA0002340450700002645
X4is-O (CH)2)nSSC(R12)2(CH2)n-or- (CH)2)nC(R12)2SS(CH2)nO-；
X5Is that
Figure BDA0002340450700002651
Wherein indicates the direction towards the drug moiety;
X6is that
Figure BDA0002340450700002652
Or, wherein indicates a direction towards the drug moiety;
each R11Independently selected from H and C1-C6An alkyl group;
each R12Independently selected from H and C1-C6An alkyl group;
each m is independently selected from 1,2, 3,4, 5,6, 7,8, 9, and 10, and
each n is independently selected from 1,2, 3,4, 5,6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18.
Example 72. a linker L selected from:
-**C(＝O)(CH2)m-；-**C(＝O)((CH2)mO)n(CH2)m-；-**C(＝O)(CH2)mNR11(CH2)m-；
-**C(＝O)(CH2)mNR11(CH2)mC(＝O)X2X1C(＝O)-；-**C(＝O)(CH2)mX3(CH2)m-；-**C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-；-**C(＝O)(CH2)mNR11C(＝O)(CH2)m-；
-**C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-；-**C(＝O)(CH2)mNR11C(＝O(CH2)mX3(CH2)m-；
-**C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-；-**C(＝O)((CH2)mO)nX3(CH2)m-；
-**C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-；-**C(＝O)((CH2)mO)n(CH2)mC(＝O)NR11(CH2)m-；-**C(＝O)(CH2)mC(R12)2-；-**C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)m-；
-**C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)(CH2)m-；
-**C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mX3(CH2)m-；
-**C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-；
-**C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-；
-**C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-；
-**C(＝O)((CH2)mO)n(CH2)mNR11C(＝O))X5C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-；
-**C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-；
-**C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-；
-**C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-；
-**C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)m-；
-**C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-；
-**C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-；
-**C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mX3(CH2)m-；
-**C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mNR11((CH2)mO)n(CH2)m-；-**C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11((CH2)mO)n(CH2)mX3(CH2)m-；
-**C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)m-；-**C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-；
-**C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-；-**C(＝O)(CH2)mC(R12)2SS(CH2)mNR11C(＝O)(CH2)m-and
-**C(＝O)(CH2)mC(＝O)NR11(CH2)m-，
wherein: indicates the attachment point to the drug moiety (D), and
X1、X2、X3、X4、X5、R11、R12n and m are as defined in example 63.
Example 73. a linker L selected from:
-**C(＝O)X1X2C(＝O)(CH2)m-；-**C(＝O)X1X2C(＝O)(CH2)mNR11C(＝O)(CH2)m-；
-**C(＝O)X1X2C(＝O)(CH2)mX3(CH2)m-；-**C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)m-；
-**C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-；-**C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-；-**C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-；-**C(＝O)X1X2C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-；-**C(＝O)X1X2C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-；-**C(＝O)X1X2(CH2)mX3(CH2)m-；-**C(＝O)X1X2((CH2)mO)n(CH2)m-；
-**C(＝O)X1X2((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-；
-**C(＝O)X1X2((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-；
-**C(＝O)X1X2((CH2)mO)n(CH2)mX3(CH2)m-；-**C(＝O)X1X2(CH2)mNR11((CH2)mO)n(CH2)m-；-**C(＝O)X1X2C(＝O)(CH2)mNR11((CH2)mO)n(CH2)mX3(CH2)m-；-**C(＝O)NR11(CH2)m-；
-**C(＝O)NR11(CH2)mX3(CH2)m-；-**C(＝O)NR11(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-；
-**C(＝O)NR11(CH2)mNR11C(＝O)O(CH2)m-；-**C(＝O)NR11(CH2)mNR11C(＝O)X1X2-；-**C(＝O)NR11(CH2)mNR11C(＝O)X5-；-**C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mX5(CH2)m-；-**C(＝O)X1C(＝O)NR11(CH2)mX5(CH2)m-；-**C(＝O)NR11(CH2)mNR11C(＝O)(CH2)m-；-**C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-；-**C(＝O)NR11(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)m-；
-**C(＝O)NR11(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)mC(＝O)-；
-**C(＝O)NR11(CH2)mNR11C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-；
-**C(＝O)NR11(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-；-**C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)m-；
-**C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)(CH2)m-；
-**C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)mX3(CH2)m-；
-**C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-；
-**C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-；
-**C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-；
-**C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-；
-**C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-；
-**C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-；
-**C(＝O)NR11(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-；
-**C(＝O)NR11(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)m-；
-**C(＝O)NR11(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-；
-**C(＝O)NR11(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-；
-**C(＝O)NR11(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mX3(CH2)m-；
-**C(＝O)NR11(CH2)mNR11C(＝O)X5(CH2)mNR11((CH2)mO)n(CH2)m-；-**C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11((CH2)mO)n(CH2)mX3(CH2)m-；
-**C(＝O)NR11(CH2)mNR11C(＝O)X5(CH2)m-；-**C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-；
-**C(＝O)NR11(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-；-**C(＝O)X1C(＝O)NR11(CH2)mNR11C(＝O)(CH2)m-；
-**C(＝O)X1C(＝O)NR11(CH2)mX3(CH2)m-；
-**C(＝O)NR11(CH2)mNR11C(＝O)(CH2)m-；
-**C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-；-**C(＝O)NR11(CH2)mNR11C(＝O)-；
-**C(＝O)X1X2(CH2)m-；-**C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)m-；
-**C(＝O)X1X2(CH2)mX3(CH2)m-；-**C(＝O)NR11(CH2)mX3(CH2)m-；-**C(＝O)NR11((CH2)mO)n(CH2)mX3(CH2)m-；
-**C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)m-；-**C(＝O)X1X2C(＝O)(CH2)m-；
-**C(＝O)X1C(＝O)(CH2)mNR11C(＝O)(CH2)m-and
-**C(＝O)X1C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-，
wherein: indicates the attachment point to the drug moiety (D), and X1、X2、X3、X4、X5、R11、R12N and m are as defined in example 63.
Example 74. a linker L selected from:
-**C(＝O)O(CH2)mNR11C(＝O)(CH2)m-；-**C(＝O)O(CH2)mNR11C(＝O)(CH2)mO(CH2)m-,
-**C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-；-**C(＝O)OC(R12)2(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-；-**C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)m-；-**C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)mC(＝O)-；-**C(＝O)O(CH2)mNR11C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-；-**C(＝O)O(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)(CH2)m-；-**C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)mC(＝O)-；**-(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-，-**(CH2)m(CHOH)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m；-**C(＝O)X6C(＝O)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-；-**C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-；-**C(＝O)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-；-**(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-；-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)(CH2)m- (O) (CH)2)mNR11C(＝O)((CH2)mO)n(CH2)m-**；
Wherein: indicates the attachment point to the drug moiety (D), and X1、X2、X4、R11、R12N and m are as defined in example 63.
Example 75. a linker L selected from:
Figure BDA0002340450700002701
Figure BDA0002340450700002712
wherein indicates the attachment point to the drug moiety (D).
In one aspect, the linker-drug moiety of the immunoconjugate of the invention comprises one or more drug moieties (D) as described herein.
In one aspect, the linker-drug moiety of the immunoconjugate of the invention comprises one or more drug moieties (D), wherein said drug moieties (D) are compounds that bind to an interferon gene stimulating factor (STING) receptor and comprise one or more reactive moieties capable of forming a covalent bond with the linker (L).
In one aspect, the linker-drug moiety of the immunoconjugates of the invention comprises one or more drug moieties (D), wherein the drug moieties (D) are compounds that bind to an interferon gene stimulating factor (STING) receptor and comprise one or more reactive moieties capable of forming a covalent bond with a linker (L), wherein the linker (L) is a cleavable linker.
In one aspect, the linker-drug moiety of the immunoconjugates of the invention comprises one or more drug moieties (D), wherein the drug moiety (D) is a dinucleotide that binds to an interferon gene stimulating factor (STING) receptor and comprises one or more reactive moieties capable of forming a covalent bond with the one or more linkers (L).
In one aspect, the linker-drug moiety of the immunoconjugates of the invention comprises one or more drug moieties (D), wherein the drug moieties (D) are dinucleotides that bind to an interferon gene stimulating factor (STING) receptor and comprise one or more reactive moieties capable of forming a covalent bond with one or more linkers (L), wherein the linkers (L) are cleavable linkers.
In one aspect, the linker-drug moiety of the immunoconjugates of the invention comprises one or more drug moieties (D), wherein the drug moiety (D) is a cyclic dinucleotide that binds to an interferon gene stimulating factor (STING) receptor and comprises one or more reactive moieties capable of forming a covalent bond with the one or more linkers (L).
In one aspect, the linker-drug moiety of the immunoconjugates of the invention comprises one or more drug moieties (D), wherein the drug moieties (D) are cyclic dinucleotides that bind to an interferon gene stimulating factor (STING) receptor and comprise one or more reactive moieties capable of forming a covalent bond with one or more linkers (L), wherein the linkers (L) are cleavable linkers.
In one aspect, the linker-drug moiety of the invention is a compound having the structure of formula (a), formula (B), formula (C), formula (D), formula (E), or formula (F), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
a) one or more linkers are attached to one or more sugar moieties of formula (A), formula (B), formula (C), formula (D), formula (E) or formula (F), or
b) One or more linkers are attached to one or more R of formula (A), formula (B), formula (C), formula (D), formula (E) or formula (F)1、R1aAnd R1bA group, or
c) One or more linkers are attached to one or more sugar moieties of formula (A), formula (B), formula (C), formula (D), formula (E) or formula (F), and one or more linkers are attached to one or more R of formula (A), formula (B), formula (C), formula (D), formula (E) or formula (F)1、R1aAnd R1bA group.
Certain aspects and examples of linker-drug moieties of the invention are provided in the following list of additional enumerated embodiments. It is to be appreciated that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the invention.
Example 76A compound having the structure of formula (A), formula (B), formula (C), formula (D), formula (E), or formula (F), or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
each G1Is independently selected from
Figure BDA0002340450700002731
Wherein indicates and-CR8R9-an attachment point of;
XAis C (═ O) -, -C (═ S) -, or-C (═ NR) -11) -, and each Z1Is NR12；
XBIs C, and each Z2Is N;
G2is that
Figure BDA0002340450700002732
Wherein indicates and-CR8aR9a-an attachment point of;
XCis C (═ O) -, -C (═ S) -, or-C (═ NR) -11) -, and each Z3Is NR12；
XDIs C, and each Z4Is N;
Y1is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
Y2is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
Y3Is OH, O-、OR10、N(R10)2、SeH、Se-、BH3SH or S-；
Y4Is OH, O-、OR10、N(R10)2、SeH、Se-、BH3SH or S-；
Y5is-CH2-, -NH-, -O-or-S;
Y6is-CH2-, -NH-, -O-or-S;
Y7is O or S;
Y8is O or S;
Y9is-CH2-, -NH-, -O-or-S;
Y10is-CH2-, -NH-, -O-or-S;
Y11is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
q is 1,2 or 3;
R1is a partially saturated or aromatic monocyclic heterocyclic group or a partially saturated or aromatic fused bicyclic heterocyclic group comprising from 5 to 10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatom is independently selected from O, N or S, or a tautomer thereof, wherein R is1Is substituted with 0,1, 2,3 or 4 substituents independently selected from-NHL1R15、F、Cl、Br、OH、SH、NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl), and-N (C)3-C8Cycloalkyl radicals2；
R1aIs a partially saturated or aromatic monocyclic heterocyclic group or a partially saturated or aromatic fused bicyclic heterocyclic group comprising from 5 to 10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatom is independently selected from O, N or S, or a tautomer thereof, wherein R is1aIs substituted with 0,1, 2,3 or 4 substituents independently selected from-NHL1R15、F、Cl、Br、OH、SH、NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl), and-N (C)3-C8Cycloalkyl radicals2；
R1bIs a partially saturated or aromatic monocyclic heterocyclic group or a partially saturated or aromatic fused bicyclic heterocyclic group comprising from 5 to 10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatom is independently selected from O, N or S, or a tautomer thereof, wherein R is1bIs substituted with 0,1, 2,3 or 4 substituents independently selected from-NHL1R15、F、Cl、Br、OH、SH、NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH,-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl) and-N (C)3-C8Cycloalkyl radicals2；
Each R2Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and OC (O) C2-C6Alkynyl, wherein R2of-OC (O) O phenyl and R2C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R3Independently selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3of-OC (O) O phenyl and R3C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R4Independently selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R4of-OC (O) O phenyl and R4C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN or N3；
Each R5Independently selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5of-OC (O) O phenyl and R5C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN or N3；
Each R6Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R6of-OC (O) O phenyl and R6C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R7Independently selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R7of-OC (O) O phenyl and R7C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN or N3；
Each R8Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R8of-OC (O) O phenyl and R8C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R9Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R9of-OC (O) O phenyl and R9C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R2aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, aryl, heteroaryl, and heteroaryl,-OC(O)OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R2aof-OC (O) O phenyl and R2aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3
R3aSelected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3aof-OC (O) O phenyl and R3aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R4aSelected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R4aof-OC (O) O phenyl and R4aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkyl halidesBase, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R5aSelected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5aof-OC (O) O phenyl and R5aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC(O)OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R6aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R6aof-OC (O) O phenyl and R6aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R7aSelected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R7aof-OC (O) O phenyl and R7aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R8aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R8aof-OC (O) O phenyl and R8C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R9aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R9aof-OC (O) O phenyl and R9aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R10Independently selected from the group consisting of: H. c1-C12Alkyl, - (CH)2CH2O)nCH2CH2C(＝O)OC1-C6Alkyl radicals and
Figure BDA0002340450700002821
wherein R is10C of (A)1-C12Alkyl is substituted by 0,1, 2 or 3 substituents, orThe substituents are independently selected from-OH and C1-C12Alkoxy, -S-C (═ O) C1-C6Alkyl and C (O) OC1-C6An alkyl group;
each R11Independently selected from H and C1-C6An alkyl group;
each R12Independently selected from H and C1-C6An alkyl group;
optionally, R3And R6Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R3And R6When taken together, O is at R3Bonding at the position;
optionally, R3aAnd R6aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R3aAnd R6aWhen taken together, O is at R3aBonding at the position;
optionally, R2And R3Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R2And R3When taken together, O is at R3Bonding at the position;
optionally, R2aAnd R3aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R2aAnd R3aWhen taken together, O is at R3aBonding at the position;
optionally, R4And R3Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R4And R3When taken together, O is at R3Bonding at the position;
optionally, R4aAnd R3aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R4aAnd R3aWhen taken together, O is at R3aBonding at the position;
optionally, R5And R6Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5And R6When taken together, O is at R5Bonding at the position;
optionally, R5aAnd R6aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5aAnd R6aWhen taken together, O is at R5aBonding at the position;
optionally, R5And R7Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene radical、-O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5And R7When taken together, O is at R5Bonding at the position;
optionally, R5aAnd R7aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5aAnd R7aWhen taken together, O is at R5aBonding at the position;
optionally, R8And R9Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6An alkynylene group; and is
Optionally, R8aAnd R9aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6An alkynylene group which is a substituent of a heterocyclic ring,
L1is a joint;
R15is a reactive group selected from any one of the groups RG1 in table 5;
and with the proviso that R1、R1aOr R1bIs at least one-NHL1R15Substituted, or R3、R4、R5、R7、R3a、R4a、R5aOr R7ais-OL1R15。
Embodiment 77 the compound of embodiment 76, wherein L1Is a joint that contains one or more cutting elements.
Embodiment 78, Compounds having formula (A-1), formula (B-1), formula (C-1), formula (D-1), formula (E-1), or formula (F-1), or stereoisomers or pharmaceutically acceptable salts thereof, wherein R1、R1a、R1b、R2、R2a、R3、R3a、R4、R4a、R5、R5a、R6、R6a、R7、R7a、R8、R8a、R9、Y1、Y2、Y3、Y4、Y5、Y6、Y7、Y8、Y9、Y10And Y11Is as in example 76, and provided that R1、R1aOr R1bIs at least one-NHL1R15Substituted, or R3、R4、R5、R7、R3a、R4a、R5aOr R7ais-OL1R15。
Example 79 Compounds having formula (A), formula (B), formula (C), formula (D), formula (E), formula (F), formula (A-1), formula (B-1), formula (C-1), formula (D-1), formula (E-1) or formula (F-1), wherein R1Is a pyrimidine or purine nucleobase or analog thereof; r1aIs a pyrimidine or purine nucleobase or analog thereof; and R is1bIs a pyrimidine or purine nucleobase or an analogue thereof, each as R in example 761、R1aAnd R1bIs substituted as described in (1).
Example 80 Compounds having formula (A-2), formula (B-2), formula (C-2), formula (D-2), formula (E-2), or formula (F-2), wherein R1、R1a、R1b、R2、R2a、R3、R3a、R4、R4a、R5、R5a、R6、R6a、R7、R7a、R8、R8a、R9、R9a、Y1、Y2、Y3、Y4、Y5、Y6、Y7、Y8、Y9、Y10And Y11As defined in example 76, and with the proviso that R1、R1aOr R1bIs at least one-NHL1R15Substituted, or R3、R4、R5、R7、R3a、R4a、R5aOr R7ais-OL1R15。
Embodiment 81. a compound of formula (a), formula (a-1), or formula (a-2) as described in any one of embodiments 76 to 80, wherein:
R2and R2aIs H;
R3and R4One of H and the other is selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3Or R4and-OC (O) O phenyl and R3Or R4C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R7And R7aIs H;
R6and R6aIs H;
R8、R9、R8aand R9aIndependently is H or C1-C6Alkyl radical, and
R3aand R4aOne of H and the other is selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3aAnd R4aand-OC (O) O phenyl and R3aOr R4aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC(O)OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3，
And with the proviso that R1Or R1aAt least one quilt-NHL1R15Substituted, or R3、R4、R3aOr R4ais-OL1R15。
Embodiment 82. the compound of formula (a), formula (a-1), or formula (a-2) as described in any one of embodiments 76 to 81, wherein:
Y1and Y2Is O, CH2Or S;
Y5and Y6Is O or S;
Y7and Y8Is O or S;
Y9and Y10Is O or S;
R2、R2a、R6、R6a、R7and R7aIs H
R3aAnd R4aOne of which is H and the other is-OL1R15H, OH or F;
R3and R4One of which is H and the other is-OL1R15H, OH or F; and is
R8a、R9a、R8And R9Independently selected from H or C1-C6An alkyl group, a carboxyl group,
and with the proviso that R1Or R1aAt least one quilt-NHL1R15Substituted, or R3、R4、R3aOr R4ais-OL1R15。
Embodiment 83. a compound of formula (B), formula (B-1), or formula (B-2) as described in any one of embodiments 76 to 80, wherein:
R2and R2aIs H;
R3aand R4aOne of H and the other is selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3aAnd R4a-OC (O) O phenyl and R3aOr R4aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R7a andR6ais H;
R6and R4Is H;
R8、R9、R8aand R9aIndependently is H or C1-C6Alkyl radical, and
R5and R7One of H and the other is selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5And R7and-OC (O) O phenyl and R5Or R7C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3，
And with the proviso that R1Or R1aAt least one quilt-NHL1R15Substituted, or R5、R7、R3aOr R4ais-OL1R15。
Embodiment 84. a compound of formula (B), formula (B-1), or formula (B-2) as described in any one of embodiments 76 to 80 or 83, wherein:
Y1and Y2Is O, CH2Or S;
Y3is OH, O-、OR10、N(R10)2SH or S-；
Y4Is OH, O-、OR10、N(R10)2SH or S-；
Y5And Y6Is O or S;
Y7and Y8Is O or S;
Y9and Y10Is O or S;
R2、R2a、R7a、R6a、R6and R4Is H;
R3aand R4aOne of which is H and the other is-OL1R15H, OH or F;
R5and R7One of which is H and the other is-OL1R15H, OH or F, and
R8a、R9a、R8and R9Independently selected from H or C1-C6An alkyl group, a carboxyl group,
and with the proviso that R1Or R1aAt least one quilt-NHL1R15Substituted, or R5、R7、R3aOr R4ais-OL1R15。
Embodiment 85. the compound of formula (C), formula (C-1), or formula (C-2) as described in any one of embodiments 76 to 80, wherein:
R2and R2aIs H;
R3and R4One of H and the other is selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3And R4and-OC (O) O phenyl and R3Or R4C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl radicals being substituted by 0,1, 2 or 3 substituentsAnd the substituents are independently selected from F, Cl, Br, I, OH, CN and N3；
R4aAnd R6aIs H;
R6and R7Is H;
R8、R9、R8aand R9aIndependently is H or C1-C6An alkyl group;
R5aand R7aOne of H and the other is selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5aAnd R7aand-OC (O) O phenyl and R5aOr R7aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O)C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3，
And with the proviso that R1Or R1aIs at least one-NHL1R15Substituted, or R5a、R7a、R3Or R4is-OL1R15。
Embodiment 86. compounds of formula (C), formula (C-1), or formula (C-2) as described in any one of embodiments 76 to 80 or 85, wherein:
Y1and Y2Is O, CH2Or S;
Y3is OH, O-、OR10、N(R10)2SH or S-；
Y4Is OH, O-、OR10、N(R10)2SH or S-；
Y5And Y6Is O or S;
Y7and Y8Is O or S;
Y9and Y10Is O or S;
R2、R2a、R4a、R6a、R6and R7Is H;
R3and R4One of which is H and the other is-OL1R15H, OH or F;
R5aand R7aOne of which is H and the other is-OL1R15H, OH or F, and
R8a、R9a、R8and R9Independently selected from H or C1-C6An alkyl group, a carboxyl group,
and with the proviso that R1Or R1aIs at least one-NHL1R15Substituted, or R5a、R7a、R3Or R4is-OL1R15。
Embodiment 87. the compound of formula (D), formula (D-1), or formula (D-2) as described in any one of embodiments 76 to 80, wherein:
R2and R2aIs H;
R5aand R7aOne of H and the other is selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5aAnd R7aand-OC (O) O phenyl and R5aOr R7aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R4a andR6ais H;
R6and R4Is H;
R8、R9、R8aand R9aIndependently is H or C1-C6Alkyl radical, and
R5and R7One of H and the other is selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5And R7and-OC (O) O phenyl and R5Or R7C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl radical、-OC(O)C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3，
And with the proviso that R1Or R1aIs at least one-NHL1R15Substituted, or R5a、R7a、R5Or R7is-OL1R15。
Embodiment 88. a compound of formula (D), formula (D-1), or formula (D-2) as described in any one of embodiments 76 to 80 or 87, wherein:
Y1and Y2Is O, CH2Or S;
Y3is OH, O-、OR10、N(R10)2SH or S-；
Y4Is OH, O-、OR10、N(R10)2SH or S-；
Y5And Y6Is O or S;
Y7and Y8Is O or S;
Y9and Y10Is O or S;
R2、R2a、R4a、R6a、R6and R4Is H;
R5a、R7aone of which is H and the other is-OL1R15OH or F;
R5and R7One of which is H and the other is-OL1R15H, OH or F, and
R8、R9、R8aand R9aIndependently is H or C1-C6An alkyl group, a carboxyl group,
and with the proviso that R1Or R1aAt least one ofquilt-NHL1R15Substituted, or R5a、R7a、R5Or R7is-OL1R15。
Embodiment 89 the compound of any one of embodiments 76 to 80 having formula (E), formula (E-1), or formula (E-2), wherein:
R2and R2aIs H;
R6and R6aIs H;
R7ais H;
R8、R9、R8aand R9aIndependently is H or C1-C6Alkyl radical, and
R3aand R4aOne of H and the other is selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3aAnd R4a-OC (O) O phenyl and R3aOr R4aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R3And R4One of H and the other is selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3And R4and-OC (O) O phenyl and R3Or R4C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3And is and
R5and R7One of H and the other is selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5And R7and-OC (O) O phenyl and R5Or R7C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3，
And with the proviso that R1Or R1aIs at least one-NHL1R15Substituted, or R3a、R4a、R3、R4、R5Or R7is-OL1R15。
Embodiment 90. a compound of formula (E), formula (E-1), or formula (E-2) as described in any one of embodiments 76 to 80 or 89, wherein:
Y1and Y2Is O, CH2Or S;
Y3is OH, O-、OR10、N(R10)2SH or S-；
Y5Is O or S;
Y7and Y8Is O or S;
Y9and Y10Is O or S;
R2、R2a、R5a、R6a、R6and R7aIs H;
R3a、R4aone of which is H and the other is-OL1R15、H、OH、OCH3Or F;
R3、R4one of which is H and the other is-OL1R15、H、OH、OCH3Or F;
R5and R7One of which is H and the other is-OL1R15、-OL1R15、H、OH、OCH3Or F, and
R8、R9、R8aand R9aIndependently is H or C1-C6An alkyl group, a carboxyl group,
and stripThe member is R1Or R1aIs at least one-NHL1R15Substituted, or R3a、R4a、R3、R4、R5Or R7is-OL1R15。
Embodiment 91. the compound of formula (F), formula (F-1), or formula (F-2) as described in any one of embodiments 76 to 80, wherein:
R2and R2aIs H;
each R6 andR6ais H;
each R7aAnd R7Is H;
R8、R9、R8aand R9aIndependently is H or C1-C6Alkyl radical, and
R3aand R4aOne of H and the other is selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3aAnd R4a-OC (O) O phenyl and R3aOr R4aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R3And R4One of H and the other is selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3And R4and-OC (O) O phenyl and R3Or R4C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3And is and
R5selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5of-OC (O) O phenyl and R5C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3，
And with the proviso that R1、R1aOr R1bIs at least one-NHL1R15Substituted, or R3a、R4a、R3、R4、R5Or R7is-OL1R15。
Embodiment 92. a compound of formula (F), formula (F-1), or formula (F-2) as described in any one of embodiments 76 to 80 or 91, wherein:
Y1and Y2Is O, CH2Or S;
each Y3Is OH, O-、OR10、N(R10)2SH or S-；
Each Y5Is O or S;
each Y7Independently is O or S;
each Y9Independently is O or S;
Y11is O, CH2Or S;
R2、R2a、R6、R6a、R6、R7and R7aIs H;
R3a、R4aone of which is H and the other is-OL1R15、H、OH、OCH3Or F;
R3、R4one of which is H and the other is-OL1R15、H、OH、OCH3Or F;
R5is-OL1R15、H、OH、OCH3Or F, and
R8、R9、R8aand R9aIndependently is H or C1-C6An alkyl group, a carboxyl group,
and with the proviso that R1、R1aOr R1bIs at least one-NHL1R15Substituted, or R3a、R4a、R3、R4、R5Or R7is-OL1R15。
The compound of any one of embodiments 76 to 92, wherein:
Figure BDA0002340450700002961
Figure BDA0002340450700002962
wherein: r1Is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl) and-N (C)3-C8Cycloalkyl radicals2And is and
each R20Independently selected from H and L1R15；
R1aIs that
Figure BDA0002340450700002972
Figure BDA0002340450700002982
Wherein: r1aIs substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl) and-N (C)3-C8Cycloalkyl radicals2，
And is
Each R21Independently selected from H and L1R15；
And is
R1bIs that
Figure BDA0002340450700002983
Figure BDA0002340450700002984
Figure BDA0002340450700002991
Figure BDA0002340450700002992
Wherein: r1bIs substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl) and-N (C)3-C8Cycloalkyl radicals2，
And is
Each R21Independently selected from H and L1R15。
Embodiment 94. compounds having formula (A-3), formula (B-3), formula (C-3), formula (D-3), formula (E-3), or formula (F-3), wherein:
Y1is-O-),-S-、-S(＝O)-、-SO2-、-CH2-or-CF2-；
Y2is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
Y11is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
Y3Is OH, O-、OR10、N(R10)2SH or S-；
Y4Is OH, O-、OR10、N(R10)2SH or S-；
Y7Is O or S;
Y8is O or S;
R1is that
Figure BDA0002340450700003001
Figure BDA0002340450700003002
Figure BDA0002340450700003011
Figure BDA0002340450700003012
Wherein: r1Is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl) and-N (C)3-C8Cycloalkyl radicals2，
And is
Each R20Independently selected from H and L1R15；
R1aIs that
Figure BDA0002340450700003013
Figure BDA0002340450700003014
Figure BDA0002340450700003021
Figure BDA0002340450700003022
Wherein: r1aIs substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl) and-N (C)3-C8Cycloalkyl radicals2，
And is
Each R21Independently selected from H and L1R15；
And is
R1bIs that
Figure BDA0002340450700003031
Figure BDA0002340450700003032
Figure BDA0002340450700003033
Wherein: r1bIs substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl) and-N (C)3-C8Cycloalkyl radicals2，
And is
Each R21Independently selected from H and L1R15；
Each R2Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and OC (O) C2-C6Alkynyl, wherein R2of-OC (O) O phenyl and R2C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituentsThe radicals are independently selected from F, Cl, Br, I, OH, CN and N3；
Each R3Independently selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3of-OC (O) O phenyl and R3C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R4Independently selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R4of-OC (O) O phenyl and R4C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN or N3；
Each R5Independently selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl group、C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5of-OC (O) O phenyl and R5C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN or N3；
Each R6Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R6of-OC (O) O phenyl and R6C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R7Independently selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R7of-OC (O) O phenyl and R7C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN or N3；
R2aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R2aof-OC (O) O phenyl and R2aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3
R3aSelected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3aof-OC (O) O phenyl and R3aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R4aSelected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R4aof-OC (O) O phenyl and R4aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R5aSelected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5aof-OC (O) O phenyl and R5aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical、C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R6aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R6aof-OC (O) O phenyl and R6aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R7aIs selected from the group consisting ofThe group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R7aof-OC (O) O phenyl and R7aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R10Independently selected from the group consisting of: H. c1-C12Alkyl, - (CH)2CH2O)nCH2CH2C(＝O)OC1-C6Alkyl radicals and
Figure BDA0002340450700003091
wherein R is10C of (A)1-C12Alkyl is substituted with 0,1, 2 or 3 substituents independently selected from-OH, C1-C12Alkoxy, -S-C (═ O) C1-C6Alkyl and C (O) OC1-C6An alkyl group;
optionally, R3And R6Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R3And R6When taken together, O is at R3Bonding at the position;
optionally, R3aAnd R6aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R3aAnd R6aWhen taken together, O is at R3aBonding at the position;
optionally, R2And R3Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R2And R3When taken together, O is at R3Bonding at the position;
optionally, R2aAnd R3aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R2aAnd R3aWhen taken together, O is at R3aBonding at the position;
optionally, R4And R3Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R4And R3When taken together, O is at R3Bonding at the position;
optionally, R4aAnd R3aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R4aAnd R3aWhen taken together, O is at R3aBonding at the position;
optionally, R5And R6Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5And R6When taken together, O is at R5Bonding at the position;
optionally, R5aAnd R6aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5aAnd R6aWhen taken together, O is at R5aBonding at the position;
optionally, R5And R7Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5And R7When taken together, O is at R5Bonding at the position; and is
Optionally, R5aAnd R7aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5aAnd R7aWhen taken together, O is at R5aBonding at the position;
L1is-C (═ O) O (CH)2)mNR11C(＝O)(CH2)m-**；-C(＝O)O(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；
-C(＝O)OC(R12)2(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；
-C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)mC(＝O)-**；
-C(＝O)O(CH2)mNR11C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)O(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)(CH2)mNR11C(＝O)X2C(＝O)(CH2)m-**；
-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)(CH2)m-**；
-C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)O(CH2)mX6C(＝O)(CH2)m-**；
-C(＝O)O(CH2)mX6C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)(CH2)m-**；
-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)(CH2)mO(CH2)mC(＝O)-**；
-C(＝O)O(CH2)mX6C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)X4C(＝O)X6(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)(CH2)mX6C(＝O)X1X2C(＝O)(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O))X5C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mNR11((CH2)mO)n(CH2)m-**；-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-**；-C(＝O)O(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)m-**；-C(＝O)O(CH2)mNR11(CH2)m-**；
-C(＝O)O(CH2)mNR11(CH2)mC(＝O)X2X1C(＝O)-**；
-C(＝O)O(CH2)mX3(CH2)m-**；-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)m-**；-C(＝O)O((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)O(CH2)mNR11C(＝O(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)nX3(CH2)m-**；-C(＝O)O((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mC(＝O)NR11(CH2)m-**；-C(＝O)O(CH2)mC(R12)2-**；
-C(＝O)OCH2)mC(R12)2SS(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)O(CH2)mC(＝O)NR11(CH2)m-**；-C(＝O)(CH2)m-**；-C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)(CH2)mNR11(CH2)m-**；-C(＝O)(CH2)mNR11(CH2)mC(＝O)X2X1C(＝O)-**；
-C(＝O)(CH2)mX3(CH2)m-**；-C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；-C(＝O)(CH2)mNR11C(＝O(CH2)mX3(CH2)m-**；-(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-(CH2)m(CHOH)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；-C(＝O)((CH2)mO)nX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；-C(＝O)((CH2)mO)n(CH2)mC(＝O)NR11(CH2)m-**；-C(＝O)(CH2)mC(R12)2-**；-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O))X5C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mNR11((CH2)mO)n(CH2)m-**；-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)m-**；-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-**；-C(＝O)(CH2)mC(R12)2SS(CH2)mNR11C(＝O)(CH2)m-**；-C(＝O)(CH2)mC(＝O)NR11(CH2)m-**；
-C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)X1X2C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)X1X2C(＝O)(CH2)mX3(CH2)m-**；-C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)X1X2C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)X1X2C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)X1X2(CH2)mX3(CH2)m-**；-C(＝O)X1X2((CH2)mO)n(CH2)m-**；
-C(＝O)X1X2((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)X1X2((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)X1X2((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)X1X2(CH2)mNR11((CH2)mO)n(CH2)m-**；-C(＝O)X1X2C(＝O)(CH2)mNR11((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)m-**；-C(＝O)NR11(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)O(CH2)m-**；-C(＝O)NR11(CH2)mNR11C(＝O)X1X2-**；-C(＝O)NR11(CH2)mNR11C(＝O)X5-；-C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mX5(CH2)m-**；-C(＝O)X1C(＝O)NR11(CH2)mX5(CH2)m-**；-C(＝O)X6C(＝O)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)NR11(CH2)mNR11C(＝O)(CH2)m-**；-C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)mC(＝O)-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5(CH2)mNR11((CH2)mO)n(CH2)m-**；-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5(CH2)m-**；-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-**；-C(＝O)X1C(＝O)NR11(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)X1C(＝O)NR11(CH2)mX3(CH2)m-**；-C(＝O)NR11(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；-C(＝O)NR11(CH2)mNR11C(＝O)-**；
-C(＝O)X1X2(CH2)m-**；-C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)X1X2(CH2)mX3(CH2)m-**；-C(＝O)NR11(CH2)mX3(CH2)m-**；-C(＝O)NR11((CH2)mO)n(CH2)mX3(CH2)m-**；-C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)X1C(＝O)(CH2)mNR11C(＝O)(CH2)m-; and is
-C(＝O)X1C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-**；
Wherein indicates with R15The attachment point of (a);
R15is that
Figure BDA0002340450700003181
-ONH2、-NH2、
Figure BDA0002340450700003182
Figure BDA0002340450700003183
-N3、-SH、-SR12、-SSR17、-S(＝O)2(CH＝CH2)、-(CH2)2S(＝O)2(CH＝CH2)、-NHS(＝O)2(CH＝CH2)、-NHC(＝O)CH2Br、-NHC(＝O)CH2I、
Figure BDA0002340450700003185
-C(O)NHNH2、
Figure BDA0002340450700003191
X1Is that
Figure BDA0002340450700003192
Wherein indicates with X2The attachment point of (a);
X2is selected from
Figure BDA0002340450700003193
Figure BDA0002340450700003194
Figure BDA0002340450700003201
Wherein indicates with X1The attachment point of (a);
X3is that
Figure BDA0002340450700003202
X4is-O (CH)2)nSSC(R12)2(CH2)n-or- (CH)2)nC(R12)2SS(CH2)nO-；
X5Is that
Figure BDA0002340450700003203
Wherein indicates the direction towards the drug moiety;
X6is that
Figure BDA0002340450700003204
Or, wherein indicates a direction towards the drug moiety;
R17is 2-pyridyl or 4-pyridyl;
each R11Independently selected from H andC1-C6an alkyl group;
each R12Independently selected from H and C1-C6An alkyl group;
each m is independently selected from 1,2, 3,4, 5,6, 7,8, 9, and 10; and is
Each n is independently selected from 1,2, 3,4, 5,6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18.
Each R110Independently selected from H, C1-C6Alkyl, F, Cl, and-OH;
each R111Independently selected from H, C1-C6Alkyl radical F, Cl, -NH2、-OCH3、-OCH2CH3、-N(CH3)2、-CN、-NO2and-OH;
each R112Independently selected from H, C1-6Alkyl, fluoro, benzyloxy substituted by-C (═ O) OH, benzyl substituted by-C (═ O) OH, C substituted by-C (═ O) OH1-4Alkoxy and C substituted by-C (═ O) OH1-4An alkyl group;
and with the proviso that R20Or R21is-NHL1R15Or by-NHL1R15Substituted, or R3、R4、R5、R7、R3a、R4a、R5aOr R7ais-OL1R15。
Embodiment 95. a compound having the formula (a-4), or a pharmaceutically acceptable salt thereof, wherein: r1、R1a、R3、R3a、R6、R6a、Y3And Y4As defined in example 94.
The compound of embodiment 96 having formula (a-4a), formula a-4b), formula a-4c), or formula a-4d), or a pharmaceutically acceptable salt thereof, wherein:
R1、R1a、R3、R3a、R6and R6aAs defined in example 94;
Y3is OR9、N(R10)2SH or S-And is and
Y4is OR9、N(R10)2SH or S-。
Embodiment 97. compounds of formula (A-4e), formula (A-4f), formula (A-4g), formula (A-4h), formula (A-4i), formula (A-4j), formula (A-4k), formula (A-4l), formula (A-4m), formula (A-4n), formula (A-4o), or formula (A-4p), or a pharmaceutically acceptable salt thereof, wherein:
R1、R1a、R3、R3a、R6and R6aAs defined in example 94;
Y3is OR9、N(R10)2SH or S-And is and
Y4is OR9、N(R10)2SH or S-。
Embodiment 98. a compound having the formula (B-4), or a pharmaceutically acceptable salt thereof, wherein: r1、R1a、R3a、R5、R6a、Y3And Y4As defined in example 94.
Embodiment 99. compounds having formula (B-4a), formula (B-4B), formula (B-4c), or formula (B-4d), or pharmaceutically acceptable salts thereof, wherein:
R1、R1a、R3a、R5and R6aAs defined in example 94;
Y3is OR9、N(R10)2SH or S-And is and
Y4is OR9、N(R10)2SH or S-。
Embodiment 100. a compound having formula (B-4e), formula (B-4f), formula (B-4g), or formula (B-4h), or a pharmaceutically acceptable salt thereof, wherein:
R1、R1aand R5As defined in example 94;
Y3is OR10、N(R10)2SH or S-And is and
Y4is OR10、N(R10)2SH or S-。
Embodiment 101. a compound having the formula (C-4), or a pharmaceutically acceptable salt thereof, wherein: r1、R1a、R3、R5a、R6、Y3And Y4As defined in example 94.
Embodiment 102. a compound having formula (C-4a), formula (C-4b), formula (C-4C), or formula (C-4d), or a pharmaceutically acceptable salt thereof, wherein:
R1、R1a、R3、R5aand R6As defined in example 94;
Y3is OR10、N(R10)2SH or S-And is and
Y4is OR10、N(R10)2SH or S-。
Embodiment 103. a compound having formula (C-4e), formula (C-4f), formula (C-4g), or formula (C-4h), or a pharmaceutically acceptable salt thereof, wherein:
R1、R1aand R5aAs defined in example 94;
Y3is OR10、N(R10)2SH or S-And is and
Y4is OR10、N(R10)2SH or S-。
Embodiment 104. a compound having the formula (D-4), or a pharmaceutically acceptable salt thereof, wherein: r1、R1a、R5、R5a、Y3And Y4As defined in example 94.
Embodiment 105. a compound having formula (D-4a), formula (D-4b), formula (D-4c), or formula (D-4D), or a pharmaceutically acceptable salt thereof, wherein:
R1、R1a、R5and R5aAs defined in example 94;
Y3is OR10、N(R10)2SH or S-And is and
Y4is OR10、N(R10)2SH or S-。
Embodiment 106. a compound having the formula (E-4), or a pharmaceutically acceptable salt thereof, wherein: r1、R1a、R3、R3a、R4、R4a、R5And R7As defined in example 94.
Embodiment 107. a compound having the formula (E-4a) or formula (E-4b), or a pharmaceutically acceptable salt thereof, wherein:
R1、R1a、R3、R3a、R4、R4a、R5and R7As defined in example 94;
and is
Y3Is OR10、N(R10)2SH or S-。
Embodiment 108. a compound having the formula (F-4), or a pharmaceutically acceptable salt thereof, wherein: r1、R1a、R1b、R3、R3a、R4、R4a、R5And R7As defined in example 94.
Embodiment 109. a compound having formula (F-4a), formula (F-4b), formula (F-4c), or formula (F-4d), or a pharmaceutically acceptable salt thereof, wherein:
R1、R1a、R1b、R3、R3a、R4、R4a、R5and R7As defined in example 94;
and is
Each Y3Independently selected from OR10、N(R10)2SH and S-。
Embodiment 110. the compound of any of embodiments 76 to 109, wherein R1Is that
Figure BDA0002340450700003231
Embodiment 111 the compound of any one of embodiments 76 to 109, wherein R1aIs that
Embodiment 112 the compound of any one of embodiments 76 to 109, wherein R1bIs that
Embodiment 113 the compound of any one of embodiments 76 to 109, wherein R1Is that
Figure BDA0002340450700003234
Embodiment 114. the compound of any one of embodiments 76 to 109, wherein R1aIs that
Figure BDA0002340450700003235
Embodiment 115 the compound of any one of embodiments 76 to 109, wherein R1bIs that
Figure BDA0002340450700003236
The compound of any one of embodiments 76 to 109, wherein R1Is that
Figure BDA0002340450700003241
Wherein R is20is-L1R15。
Embodiment 117. the compound of any one of embodiments 76 to 109, wherein R1aIs that
Figure BDA0002340450700003242
Wherein R is21is-L1R15。
The compound of any one of embodiments 76 to 109, wherein R1bIs that
Figure BDA0002340450700003243
Wherein R is21is-L1R15。
The compound of any one of embodiments 76 to 109, wherein R1Is that
Figure BDA0002340450700003244
Wherein R is20is-L1R15。
Embodiment 120 the compound of any one of embodiments 76 to 109, wherein R1aIs that
Figure BDA0002340450700003245
Wherein R is21is-L1R15。
The compound of embodiment 121. the compound of any one of embodiments 76 to 109, wherein R1bIs that
Figure BDA0002340450700003246
Wherein R is21is-L1R15。
The compound of embodiment 122. the compound of any one of embodiments 76 to 109, wherein R1Is that
Figure BDA0002340450700003247
And R is1aIs thatWherein R is20Is L1R15And R is21Is H.
Embodiment 123. the compound of any one of embodiments 76 to 109, wherein R1Is that
Figure BDA0002340450700003251
And R is1aIs that
Figure BDA0002340450700003252
Wherein R is20Is H and R21Is L1R15。
The compound of any one of embodiments 76 to 109, wherein R1Is that
Figure BDA0002340450700003253
And R is1aIs that
Figure BDA0002340450700003254
Wherein R is20Is L1R15And R is21Is L1R15。
The compound of any one of embodiments 76 to 109, wherein R1Is that
Figure BDA0002340450700003255
And R is1aIs that
Figure BDA0002340450700003256
Wherein R is20Is L1R15And R is21Is H.
Embodiment 126. the compound of any one of embodiments 76 to 109, wherein R1Is that
Figure BDA0002340450700003257
And R is1aIs that
Figure BDA0002340450700003258
Wherein R is20Is H and R21Is L1R15。
The compound of any one of embodiments 76 to 109, wherein R1Is that
Figure BDA0002340450700003259
And R is1aIs that
Figure BDA00023404507000032510
Wherein R is20Is L1R15And R is21Is L1R15。
Embodiment 128. the compound of any one of embodiments 76 to 109, wherein R1Is that
Figure BDA00023404507000032511
And R is1aIs that
Figure BDA00023404507000032512
Wherein R is20Is H and R21Is L1R15。
Embodiment 129 the compound of any one of embodiments 76 to 109, wherein R1Is that
Figure BDA00023404507000032513
And R is1aIs thatWherein R is20Is L1R15And R is21Is H.
Embodiment 130 the compound of any one of embodiments 76 to 109, wherein R1Is that
Figure BDA0002340450700003261
And R is1aIs that
Figure BDA0002340450700003262
Wherein R is20Is L1R15And R is21Is L1R15。
Embodiment 131. the compound of any one of embodiments 76 to 109, wherein R1Is that
Figure BDA0002340450700003263
And R is1aIs that
Figure BDA0002340450700003264
Wherein R is20Is H and R21Is L1R15。
Embodiment 132. the compound of any of embodiments 76 to 109Wherein R is1Is that
Figure BDA0002340450700003265
And R is1aIs thatWherein R is20Is L1R15And R is21Is H.
Embodiment 133 the compound of any one of embodiments 76 to 109, wherein R1Is that
Figure BDA0002340450700003267
And R is1aIs thatWherein R is20Is L1R15And R is21Is L1R15。
The compound of any one of embodiments 76 to 109, wherein R1Is thatAnd R is1aIs thatWherein R is20Is L1R15And R is21Is H.
The compound of any one of embodiments 76 to 109, wherein R1Is that
Figure BDA00023404507000032611
And R is1aIs that
Figure BDA00023404507000032612
Wherein R is20Is H and R21Is L1R15。
Embodiment 136 the compound of any one of embodiments 76 to 109, wherein R1Is that
Figure BDA00023404507000032613
And R1a is
Figure BDA00023404507000032615
Wherein R is20Is L1R15And R is21Is L1R15。
Embodiment 137 the compound of any of embodiments 76 to 109, wherein R1Is thatR1bIs thatAnd R is1aIs that
Figure BDA0002340450700003273
Wherein R is20Is L1R15And each R21Is H.
Embodiment 138. the compound of any one of embodiments 76 to 109, wherein R1Is that
Figure BDA0002340450700003274
R1bIs that
Figure BDA0002340450700003275
And R is1aIs that
Figure BDA0002340450700003276
Wherein R is20Is H, R1bR of (A) to (B)21Is L1R15And R is1aR of (A) to (B)21Is H.
Embodiment 139. the compound of any of embodiments 76 to 109, wherein R1Is that
Figure BDA0002340450700003277
R1bIs that
Figure BDA0002340450700003278
And R is1aIs that
Figure BDA0002340450700003279
Wherein R is20Is H, R1bR of (A) to (B)21Is H, and R1aR of (A) to (B)21Is L1R15。
Embodiment 140. the compound of any one of embodiments 76 to 109, wherein R1aIs that
Figure BDA00023404507000032710
Wherein R is21Is H, and R3、R3a、R5Or R5ais-OL1R15。
Embodiment 141. the compound of any one of embodiments 76 to 109, wherein R1bIs that
Figure BDA00023404507000032711
Wherein R is21Is H, and R3、R3a、R5Or R5ais-OL1R15。
Embodiment 142 the compound of any one of embodiments 76 to 109, wherein R1Is that
Figure BDA00023404507000032712
Wherein R is20Is H, and R3、R3a、R5Or R5ais-OL1R15。
Embodiment 143. the compound of any one of embodiments 76 to 109, wherein R1aIs that
Figure BDA0002340450700003281
Wherein R is21Is H, and R3、R3a、R5Or R5ais-OL1R15。
Embodiment 144 the compound of any one of embodiments 76 to 109, wherein R1bIs that
Figure BDA0002340450700003282
Wherein R is21Is H, and R3、R3a、R5Or R5ais-OL1R15。
Embodiment 145 the compound of any one of embodiments 76 to 109, wherein R1Is that
Figure BDA0002340450700003283
And R is1aIs thatWherein R is20Is H, R21Is H, and R3、R3a、R5Or R5ais-OL1R15。
Embodiment 146 the compound of any one of embodiments 76 to 109, wherein R1Is that
Figure BDA0002340450700003285
And R is1aIs that
Figure BDA0002340450700003286
Wherein R is20Is H, R21Is H, and R3、R3a、R5Or R5ais-OL1R15。
Embodiment 147. the compound of any of embodiments 76 to 109, wherein R1Is that
Figure BDA0002340450700003287
And R is1aIs that
Figure BDA0002340450700003288
Wherein R is20Is H, R21Is H, and R3、R3a、R5Or R5ais-OL1R15。
The compound of any one of embodiments 76 to 109, wherein R1Is that
Figure BDA0002340450700003291
And R is1aIs that
Figure BDA0002340450700003292
Wherein R is20Is H, R21Is H, and R3、R3a、R5Or R5ais-OL1R15。
Embodiment 149. the compound of any one of embodiments 76 to 109, wherein R1Is that
Figure BDA0002340450700003293
And R is1aIs that
Figure BDA0002340450700003294
Wherein R is20Is H, R21Is H, and R3、R3a、R5Or R5ais-OL1R15。
Embodiment 150 the compound of any one of embodiments 76 to 109, wherein R1Is that
Figure BDA0002340450700003295
R1bIs that
Figure BDA0002340450700003296
And R is1aIs that
Figure BDA0002340450700003297
Wherein R is20Is H, each R21Is H and R3、R3a、R5Or R5ais-OL1R15。
The compound of embodiment 151. the compound of any one of embodiments 76 to 150, wherein:
Y3is OH, O-SH or S-And is and
Y4is OH, O-SH or S-。
The compound of any one of embodiments 76 to 150, wherein:
Y3is OH or O-And is and
Y4is OH or O-。
The compound of any one of embodiments 76 to 150, wherein:
Y3is SH or S-And is and
Y4is OH or O-。
The compound of embodiment 154. the compound of any one of embodiments 76 to 150, wherein:
Y3is OH or O-And is and
Y4is SH or S-。
The compound of any one of embodiments 76 to 150, wherein:
Y3is SH or S-.And is and
Y4is SH or S-。
The compound of embodiment 156 of any one of embodiments 76 to 139 or embodiments 151 to 155, wherein: r2、R2a、R4、R4a、R6、R6a、R7And R7aEach is H.
The compound of embodiment 157 or any one of embodiments 76 to 139 or embodiments 151 to 155, wherein: r3is-OH, F or-NH2。
The compound of embodiment 158 any one of embodiments 76 to 139 or embodiments 151 to 155, wherein: r3is-OH or F.
The compound of embodiment 159. the compound of any one of embodiments 76 to 139 or embodiments 151 to 155, wherein: r3ais-OH, F or-NH2。
The compound of any one of embodiments 76 to 139 or embodiments 151 to 155, wherein: r3ais-OH or F.
The compound of embodiment 161. the compound of any one of embodiments 76 to 139 or embodiments 151 to 155, wherein: r5is-OH, F or-NH2。
The compound of embodiment 162 any one of embodiments 76 to 139 or embodiments 151 to 155, wherein: r5is-OH or F.
The compound of any one of embodiments 76 to 139 or embodiments 151 to 155, wherein: r5ais-OH, F or-NH2。
The compound of any one of embodiments 76 to 139 or embodiments 151 to 155, wherein: r5ais-OH or F.
The compound of any one of embodiments 76 to 139 or embodiments 151 to 155, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R3is-OH, and
R3ais F.
The compound of any one of embodiments 76 to 139 or embodiments 151 to 155, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R3is F, and
R3ais-OH.
The compound of any one of embodiments 76 to 139 or embodiments 151 to 155, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R3is F, and
R3ais F.
Embodiment 168. the compound of any one of embodiments 76 to 139 or embodiments 151 to 155, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R3is-OH, and
R3ais-OH.
An embodiment 169 the compound of any one of embodiments 76 to 139 or embodiments 151 to 155, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R3ais-OH, and
R5is F.
The compound of any one of embodiments 76 to 139 or embodiments 151 to 155, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R3ais F, and
R5is-OH.
The compound of embodiment 171, or any one of embodiments 76 to 139 or embodiments 151 to 155, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R3ais F, and
R5is F.
The compound of any one of embodiments 76 to 139 or embodiments 151 to 155, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R3ais-OH, and
R5is-OH.
Embodiment 173 the compound of any one of embodiments 76 to 139 or embodiments 151 to 155, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R3is-OH, and
R5ais F.
The compound of any one of embodiments 76 to 139 or embodiments 151 to 155, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R3is F, and
R5ais-OH.
The compound of any one of embodiments 76 to 139 or embodiments 151 to 155, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R3is F, and
R5ais F.
Embodiment 176 the compound of any one of embodiments 76 to 139 or embodiments 151 to 155, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R3is-OH, and
R5ais-OH.
The compound of embodiment 177 any one of embodiments 76 to 139 or embodiments 151 to 155, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R5is-OH, and
R5ais F.
The compound of any one of embodiments 76 to 139 or embodiments 151 to 155, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R5is F, and
R5ais-OH.
Embodiment 179. the compound of any one of embodiments 76 to 139 or embodiments 151 to 155, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R5is F, and
R5ais F.
The compound of any one of embodiments 76 to 139 or embodiments 151 to 155, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R5is-OH, and
R5ais-OH.
The compound of embodiment 181 any one of embodiments 76 to 139 or embodiments 151 to 155, wherein:
R3is-OH or F;
R3ais-OH or F;
R5is-OH or F;
R5ais-OH or F;
R6is H, and
R6ais H.
The compound of embodiment 182. the compound of any one of embodiments 76 to 139 or embodiments 151 to 155, wherein:
R3is H, -OH or F;
R3ais H, -OCH3-OH or F;
R5is-OH or F;
R4、R4a、R6、R6a、R7、R7ais H, and
R6ais H.
The compound of any one of embodiments 76 to 182, wherein:
L1is-C (═ O) O (CH)2)mNR11C(＝O)(CH2)m-**；-C(＝O)O(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；-C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)OC(R12)2(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)O(CH2)mNR8C(＝O)X1X2C(＝O)(CH2)mO(CH2)m-**；-C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)mC(＝O)-**；-C(＝O)O(CH2)mNR11C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；-C(＝O)O(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)m-**；-(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-(CH2)m(CHOH)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m**；-C(＝O)X6C(＝O)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；-C(＝O)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)(CH2)m-, or-C (═ O) (CH)2)mNR11C(＝O)((CH2)mO)n(CH2)m-**，
Wherein indicates with R15An attachment point of, and
wherein R is11、R12、X1、X2M and n are as defined in example 94.
The compound of embodiment 184, wherein:
L1is that
Figure BDA0002340450700003341
Figure BDA0002340450700003342
Embodiment 185. a compound of formula (a) selected from:
Figure BDA0002340450700003362
Figure BDA0002340450700003381
embodiment 186 a compound having formula (a) selected from:
Figure BDA0002340450700003382
Figure BDA0002340450700003391
Figure BDA0002340450700003401
Figure BDA0002340450700003411
Figure BDA0002340450700003421
embodiment 187. a compound having formula (B) selected from:
Figure BDA0002340450700003422
Figure BDA0002340450700003431
method of conjugation
The present invention provides various methods of conjugating linker-drug moieties to antibodies or antibody fragments to produce antibody drug conjugates (also referred to as immunoconjugates).
A general reaction scheme for forming an immunostimulatory antibody conjugate having formula (I) is shown in scheme 1 below:
scheme 1
Figure BDA0002340450700003441
Wherein: RG (route group)2Is a reactive group which is compatible with R15The radicals reacting to form the corresponding R115Groups (these groups are shown in table 5). D. R15L, Ab, y, m, n and R115Is as defined herein.
This general approach is further illustrated in scheme 2, wherein the antibody comprises a heavy chain variable domain with R15Reactive Groups (RG) reactive with groups (as defined herein)2) To pass through R115A group (as defined herein) covalently attaches a linker-drug moiety to the antibody. For illustrative purposes only, scheme 2 shows four RGs2Antibodies to the group.
Scheme 2
Figure BDA0002340450700003442
In one aspect, the linker-drug moiety is conjugated to the antibody via a modified cysteine residue in the antibody (see, e.g., WO 2014/124316). This approach is illustrated in scheme 3, where the free thiol group and R are generated from engineered cysteine residues in the antibody15Group (wherein R15Is maleimide) to react via R115Group (wherein R115Is a succinimide ring) to covalently attach a linker-drug moiety to the antibody. For illustration purposes only, scheme 3 shows an antibody with four free thiol groups.
Scheme 3
Figure BDA0002340450700003451
In another aspect, the linker-drug moiety is conjugated to the antibody via a lysine residue in the antibody. This approach is illustrated in scheme 4, where the free amine group and R from lysine residues in the antibody15Group (wherein R15NHS ester, pentafluorophenyl or tetrafluorophenyl) to via R115Group (wherein R115Is an amide) to covalently attach a linker-drug moiety to the antibody. For illustration purposes only, scheme 4 shows an antibody with four amine groups.
Scheme 4
Figure BDA0002340450700003452
In another aspect, the linker-drug moiety is conjugated to the antibody via the formation of an oxime bridge at a naturally occurring disulfide bond of the antibody. Oxime bridges are formed by first forming ketone bridges by reducing the interchain disulfide bonds of the antibody and by re-bridging using 1, 3-dihaloacetone (e.g., 1, 3-dichloroacetone). Followed by reaction with a linker-drug moiety comprising hydroxylamine, thereby forming an oxime bond (oxime bridge) that attaches the linker-drug moiety to the antibody (see, e.g., WO 2014/083505). This approach is illustrated in scheme 5.
Scheme 5
Figure BDA0002340450700003461
In yet another aspect, the linker-drug moiety is conjugated to the antibody by inserting a peptide tag containing a serine residue (e.g., the S6, ybbR, or A1 tag) into the antibody sequence, as described in Bioconjugate Chemistry 2015,26, 2554-2562. These tags can serve as substrates for 4' -phosphopan-peptide methyltransferases (pptases) that post-translationally modify serine residues to covalently attach linkers derived from coenzyme a (CoA) or CoA analogs. The linker comprises a side chain ketone that is subsequently reacted with a linker-drug moiety comprising hydroxylamine, thereby forming an oxime bond that attaches the linker-drug moiety to the antibody. This approach is illustrated in scheme 6.
Scheme 6
Figure BDA0002340450700003471
Immunoconjugates of the invention
The present invention provides immunoconjugates, also known as antibody drug conjugates, wherein an antibody or a functional fragment thereof is coupled to an agonist of STING via a linker.
In one aspect, the antibodies, antigen binding fragments, or functional equivalents thereof of the invention are linked via covalent attachment through a linker to one or more compounds that are agonists of the interferon gene stimulating factor (STING) receptor.
In one aspect, the antibodies, antigen binding fragments, or functional equivalents thereof of the invention are linked via a linker via covalent attachment to one or more compounds that are cyclic dinucleotides that bind to interferon gene stimulating factor (STING) receptors.
In one aspect, the antibodies, antigen binding fragments, or functional equivalents thereof of the invention are linked via a linker via covalent attachment to one or more compounds that are cyclic dinucleotides that are agonists of the interferon gene stimulating factor (STING) receptor.
In one aspect, the immunoconjugate of the invention comprises one or more drug moieties (D) as described herein.
In one aspect, the immunoconjugates of the invention comprise one or more drug moieties (D), wherein the drug moiety (D) is a compound that binds to an interferon gene stimulating factor (STING) receptor and comprises one or more reactive moieties capable of forming a covalent bond with one or more linkers (L).
In one aspect, the immunoconjugates of the invention comprise one or more drug moieties (D), wherein the drug moiety (D) is a compound that binds to an interferon gene stimulating factor (STING) receptor and comprises one or more reactive moieties capable of forming a covalent bond with one or more linkers (L), wherein the linker (L) is a cleavable linker.
In one aspect, the immunoconjugates of the invention comprise one or more drug moieties (D), wherein the drug moiety (D) is a dinucleotide that binds to an interferon gene stimulating factor (STING) receptor and comprises one or more reactive moieties capable of forming a covalent bond with one or more linkers (L).
In one aspect, the immunoconjugates of the invention comprise one or more drug moieties (D), wherein the drug moiety (D) is a dinucleotide that binds to an interferon gene stimulating factor (STING) receptor and comprises one or more reactive moieties capable of forming a covalent bond with one or more linkers (L), wherein the linker (L) is a cleavable linker.
In one aspect, the immunoconjugates of the invention comprise one or more drug moieties (D), wherein the drug moiety (D) is a cyclic dinucleotide that binds to an interferon gene stimulating factor (STING) receptor and comprises one or more reactive moieties capable of forming a covalent bond with one or more linkers (L).
In one aspect, the immunoconjugates of the invention comprise one or more drug moieties (D), wherein the drug moiety (D) is a cyclic dinucleotide that binds to an interferon gene stimulating factor (STING) receptor and comprises one or more reactive moieties capable of forming a covalent bond with one or more linkers (L), wherein the linker (L) is a cleavable linker.
In one aspect, the invention provides an immunoconjugate having formula (I):
Ab-(L-(D)m)n(formula (I))
Wherein:
ab is an antibody or fragment thereof;
l is a linker comprising one or more cutting elements;
d is a compound that binds to an interferon gene stimulating factor (STING) receptor;
m is an integer from 1 to 8; and is
n is an integer from 1 to 20.
In another aspect, the invention provides an immunoconjugate having formula (II):
Ab-(L-D)n(formula (II))
Wherein:
ab is an antibody or fragment thereof;
l is a linker comprising one or more cutting elements;
d is a compound that binds to an interferon gene stimulating factor (STING) receptor;
and is
n is an integer from 1 to 20.
In another aspect, the invention provides an immunoconjugate having formula (I):
Ab-(L-(D)m)n(formula (I)
Wherein:
ab is an antibody or fragment thereof;
l is a linker comprising two or more cutting elements;
d is a compound that binds to an interferon gene stimulating factor (STING) receptor;
m is an integer from 1 to 8; and is
n is an integer from 1 to 20.
In the embodiments of formula (I) or formula (II), D is an agonist of an interferon gene stimulating factor (STING) receptor.
In the embodiments of formula (I) or formula (II), D is a cyclic dinucleotide that binds to an interferon gene stimulating factor (STING) receptor.
In the embodiments of formula (I) or formula (II), D is a cyclic dinucleotide that is an agonist of the interferon gene stimulating factor (STING) receptor.
In one aspect, the immunoconjugate of the invention comprises one or more drug moieties (D) as described herein.
In one aspect, the immunoconjugates of the invention comprise one or more drug moieties (D), wherein the drug moiety (D) is a compound that binds to an interferon gene stimulating factor (STING) receptor and comprises one or more reactive moieties capable of forming a covalent bond with a linker.
In one aspect, the immunoconjugates of the invention comprise one or more drug moieties (D), wherein the drug moiety (D) is a compound that binds to an interferon gene stimulating factor (STING) receptor and comprises one or more reactive moieties capable of forming a covalent bond with a linker, wherein linker (L) is a cleavable linker.
In one aspect, the immunoconjugates of the invention comprise one or more drug moieties (D), wherein the drug moiety (D) is a dinucleotide that binds to an interferon gene stimulating factor (STING) receptor and comprises one or more reactive moieties capable of forming a covalent bond with a linker.
In one aspect, the immunoconjugates of the invention comprise one or more drug moieties (D), wherein the drug moiety (D) is a dinucleotide that binds to an interferon gene stimulating factor (STING) receptor and comprises one or more reactive moieties capable of forming a covalent bond with a linker, wherein linker (L) is a cleavable linker.
In one aspect, the immunoconjugates of the invention comprise one or more drug moieties (D), wherein the drug moiety (D) is a cyclic dinucleotide that binds to an interferon gene stimulating factor (STING) receptor and comprises one or more reactive moieties capable of forming a covalent bond with a linker.
In one aspect, the immunoconjugates of the invention comprise one or more drug moieties (D), wherein the drug moiety (D) is a cyclic dinucleotide that binds to an interferon gene stimulating factor (STING) receptor and comprises one or more reactive moieties capable of forming a covalent bond with a linker, wherein linker (L) is a cleavable linker.
As used herein, the term "cleavage product" refers to a drug moiety (D) linked to a fragment of a linker, wherein said fragment comprises one or more linker components (Lc). The cleavage product isFrom Ab- (L- (D) m) nFormed upon cleavage of linker (L), wherein fragments of linker (L)Remains attached to the drug portion (D)。
In one embodiment, the immunoconjugate of the invention comprises formula (I):
Ab-(L-(D)m)n(formula (I))
Wherein:
ab is an antibody or functional fragment thereof;
l is a linker comprising one or more cutting elements;
d is a drug moiety having agonist activity against STING receptors;
m is an integer from 1 to 8; and is
n is an integer from 1 to 20.
In one embodiment, the immunoconjugate of the invention comprises formula (I):
Ab-(L-(D)m)n(formula (I))
Wherein:
ab is an antibody or functional fragment thereof;
l is a linker;
d is a drug moiety that binds to STING receptors;
m is an integer from 1 to 8; and is
n is an integer from 1 to 20;
and wherein the D released from the immunoconjugate or cleavage product thereof has STING agonist activity.
In one embodiment, the immunoconjugate of the invention comprises formula (I):
Ab-(L-(D)m)n(formula (I))
Wherein:
ab is an antibody or functional fragment thereof;
l is a linker;
d is a drug moiety that binds to STING receptors;
m is an integer from 1 to 8; and is
n is an integer from 1 to 20;
wherein the immunoconjugate delivers D or a cleavage product thereof to a cell targeted by the Ab, and wherein D or a cleavage product thereof has STING agonist activity.
In one embodiment, the immunoconjugate of the invention comprises formula (I):
Ab-(L-(D)m)n(formula (I))
Wherein:
ab is an antibody or functional fragment thereof;
l is a linker comprising one or more cutting elements;
d is a drug moiety that binds to STING receptors;
m is an integer from 1 to 8; and is
n is an integer from 1 to 20;
and wherein the immunoconjugate releases D or a cleavage product thereof in the Ab-targeted cells, and wherein D or a cleavage product thereof has STING agonist activity.
In one embodiment, the immunoconjugate of the invention comprises formula (I):
Ab-(L-(D)m)n(formula (I))
Wherein:
ab is an antibody or functional fragment thereof;
l is a linker comprising one or more cutting elements;
d is a drug moiety having agonist activity against STING receptors;
m is an integer from 1 to 8; and is
n is an integer from 1 to 20;
wherein the immunoconjugate releases D or a cleavage product thereof in a cell targeted by the Ab, and wherein D or a cleavage product thereof has STING agonist activity in the cell.
In one embodiment, the immunoconjugate of the invention comprises formula (I):
Ab-(L-(D)m)n(formula (I))
Wherein:
ab is an antibody or functional fragment thereof;
l is a linker comprising one or more cutting elements;
d is a drug moiety that binds to STING receptors;
m is an integer from 1 to 8; and is
n is an integer from 1 to 20;
wherein the immunoconjugate specifically binds to an antigen expressed on the cell surface and is internalized into the cell, and wherein D or a cleavage product thereof cleaves from L and has STING agonist activity as determined by one or more STING agonist assays selected from: an interferon stimulation assay, a hSTING wt assay, a THP 1-double assay, a TANK binding kinase 1(TBK1) assay, or an interferon- γ -inducible protein (IP-10) secretion assay.
In one aspect of the immunoconjugate of the invention, the immunoconjugate is selected from the following:
Figure BDA0002340450700003531
Figure BDA0002340450700003541
Figure BDA0002340450700003561
Figure BDA0002340450700003571
Figure BDA0002340450700003581
Figure BDA0002340450700003591
Figure BDA0002340450700003601
wherein:
each G1Is independently selected from
Figure BDA0002340450700003602
Wherein indicates and-CR8R9-an attachment point of;
XAis C (═ O) -, -C (═ S) -, or-C (═ NR) -11) -, and each Z1Is NR12；
XBIs C, and each Z2Is N;
G2is that
Figure BDA0002340450700003603
Wherein indicates and-CR8aR9a-an attachment point of;
XCis C (═ O) -, -C (═ S) -, or-C (═ NR) -11) -, and each Z3Is NR12；
XDIs C, and each Z4Is N;
Y1is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
Y2is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
Y3Is OH, O-、OR10、N(R10)2、SR10、SeH、Se-、BH3SH or S-；
Y4Is OH, O-、OR10、N(R10)2、SR10、SeH、Se-、BH3SH or S-；
Y5is-CH2-, -NH-, -O-or-S;
Y6is-CH2-, -NH-, -O-or-S;
Y7is O or S;
Y8is O or S;
Y9is-CH2-, -NH-, -O-or-S;
Y10is-CH2-, -NH-, -O-or-S;
Y11is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
q is 1,2 or 3;
R1is a partially saturated or aromatic monocyclic heterocyclic group or a partially saturated or aromatic fused bicyclic heterocyclic group comprising from 5 to 10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatom is independently selected from O, N or S, or a tautomer thereof, wherein R is1Is substituted with 0,1, 2,3 or 4 substituents independently selected from-NHL1R115、F、Cl、Br、OH、SH、NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl), and-N (C)3-C8Cycloalkyl radicals2；
R1aIs a partially saturated or aromatic monocyclic heterocyclic group or a partially saturated or aromatic fused bicyclic heterocyclic group comprising from 5 to 10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatom is independently selected from O, N or S, or a tautomer thereof, wherein R is1aSubstituted by 0,1, 2,3 or 4 substituentsThe substituents are independently selected from-NHL1R115、F、Cl、Br、OH、SH、NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl), and-N (C)3-C8Cycloalkyl radicals2；
R1bIs a partially saturated or aromatic monocyclic heterocyclic group or a partially saturated or aromatic fused bicyclic heterocyclic group comprising from 5 to 10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatom is independently selected from O, N or S, or a tautomer thereof, wherein R is1bIs substituted with 0,1, 2,3 or 4 substituents independently selected from-NHL1R115、F、Cl、Br、OH、SH、NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl radicals),-S(C1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl), and-N (C)3-C8Cycloalkyl radicals2；
Each R2Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and OC (O) C2-C6Alkynyl, wherein R2of-OC (O) O phenyl and R2C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R3Independently selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3of-OC (O) O phenyl and R3C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R4Independently selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R4of-OC (O) O phenyl and R4C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN or N3；
Each R5Independently selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5of-OC (O) O phenyl and R5C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN or N3；
Each R6Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R6of-OC (O) O phenyl and R6C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R7Independently selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R7of-OC (O) O phenyl and R7C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN or N3；
Each R8Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R8of-OC (O) O phenyl and R8C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R9Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, aryl, heteroaryl, and heteroaryl,-OC(O)C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R9of-OC (O) O phenyl and R9C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R2aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R2aof-OC (O) O phenyl and R2aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, alkynyl,C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3
R3aSelected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3aof-OC (O) O phenyl and R3aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R4aSelected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R4aof-OC (O) O phenyl and R4aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R5aSelected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5aof-OC (O) O phenyl and R5aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl radicals being substituted by 0,1, 2 or 3 substituentsAnd the substituents are independently selected from F, Cl, Br, I, OH, CN and N3；
R6aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R6aof-OC (O) O phenyl and R6aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R7aSelected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R7aof-OC (O) O phenyl and R7aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R8aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Halogenated alkynyl、-O(C1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R8aof-OC (O) O phenyl and R8C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R9aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R9aof-OC (O) O phenyl and R9aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R10Independently selected from the group consisting of: H. c1-C12Alkyl radical, C1-C6Heteroalkyl, - (CH)2CH2O)nCH2CH2C(＝O)OC1-C6Alkyl radicals and
Figure BDA0002340450700003691
wherein R is10C of (A)1-C12Alkyl and C1-C6The heteroalkyl is substituted with 0,1, 2, or 3 substituents independently selected from-OH, C1-C12Alkoxy, -S-C (═ O) C1-C6Alkyl, halo, -CN, C1-C12Alkyl, -O-aryl, -O-heteroaryl, -O-cycloalkyl, oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl, -OC (O) OC1-C6Alkyl radicals andC(O)OC1-C6alkyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is substituted with 0,1, 2 or 3 substituents independently selected from C1-C12Alkyl, O-C1-C12Alkyl radical, C1-C12Heteroalkyl, halo, CN, OH, oxo, aryl, heteroaryl, O-aryl, O-heteroaryl, -C (═ O) C1-C12Alkyl, -OC (═ O) C1-C12Alkyl, -C (═ O) OC1-C12Alkyl, -OC (═ O) OC1-C12Alkyl, -C (═ O) N (R)11)-C1-C12Alkyl, -N (R)11)C(＝O)-C1-C12An alkyl group; -OC (═ O) N (R)11)-C1-C12Alkyl, -C (═ O) -aryl, -C (═ O) -heteroaryl, -OC (═ O) -aryl, -C (═ O) O-aryl, -OC (═ O) -heteroaryl, -C (═ O) O-aryl, -C (═ O) O-heteroaryl, -C (═ O) N (R) (═ O) O-heteroaryl11) -aryl, -C (═ O) N (R)11) -heteroaryl, -N (R)11) C (O) -aryl, -N (R)11)2C (O) -aryl, -N (R)11) C (O) -heteroaryl and S (O)2N(R11) -an aryl group;
each R11Independently selected from H and C1-C6An alkyl group;
each R12Independently selected from H and C1-C6An alkyl group;
optionally, R3And R6Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R3And R6When taken together, O is at R3Bonding at the position;
optionally, R3aAnd R6aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R3aAnd R6aWhen taken together, O is at R3aBonding at the position;
optionally, R2And R3Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R2And R3When taken together, O is at R3Bonding at the position;
optionally, R2aAnd R3aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R2aAnd R3aWhen taken together, O is at R3aBonding at the position;
optionally, R4And R3Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R4And R3When taken together, O is at R3Bonding at the position;
optionally, R4aAnd R3aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R4aAnd R3aWhen taken together, O is at R3aBonding at the position;
optionally, R5And R6Are joined together to form C1-C6Alkylene, or a mixture thereof,C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5And R6When taken together, O is at R5Bonding at the position;
optionally, R5aAnd R6aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5aAnd R6aWhen taken together, O is at R5aBonding at the position;
optionally, R5And R7Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5And R7When taken together, O is at R5Bonding at the position;
optionally, R5aAnd R7aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5aAnd R7aWhen taken together, O is at R5aBonding at the position;
optionally, R8And R9Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6An alkynylene group; and is
Optionally, R8aAnd R9aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene radical，
L1Is a joint;
R115is that
Figure BDA0002340450700003711
-C(＝O)-、-ON＝***、-S-、-NHC(＝O)CH2-***、-S(＝O)2CH2CH2-***、-(CH2)2S(＝O)2CH2CH2-***、-NHS(＝O)2CH2CH2-**、-NHC(＝O)CH2CH2-***、-CH2NHCH2CH2-***、-NHCH2CH2-***、
Figure BDA0002340450700003713
Figure BDA0002340450700003714
Figure BDA0002340450700003721
Wherein indicates the point of attachment to Ab;
R13is H or methyl;
R14is H, -CH3Or phenyl;
each R110Independently selected from H, C1-C6Alkyl, F, Cl, and-OH;
each R111Independently selected from H, C1-C6Alkyl radical F, Cl, -NH2、-OCH3、-OCH2CH3、-N(CH3)2、-CN、-NO2and-OH;
each R112Independently selected from H, C1-6Alkyl, fluoro, benzyloxy substituted by-C (═ O) OH, benzyl substituted by-C (═ O) OH substituted C1-4Alkoxy and C substituted by-C (═ O) OH1-4An alkyl group;
ab is an antibody or fragment thereof; and is
y is 1,2, 3,4, 5,6, 7,8, 9 or 10,
and with the proviso that R1、R1aOr R1bIs at least one-NHL1R115Substituted, or R3、R4、R5、R7、R3a、R4a、R5aOr R7ais-OL1R115。
Certain aspects and examples of the immunoconjugates of the invention are provided in the following list of additional enumerated embodiments. It is to be appreciated that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the invention.
Embodiment 188 an immunoconjugate having formula (AA-a to AA-f), formula (BB-a to BB-f), formula (CC-a to CC-f), formula (DD-a to DD-f), formula (EE-a to EE-h), or formula (FF-a to FF-k), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein L1Is a joint comprising one or more cutting elements;
embodiment 189 an immunoconjugate having formula (AA-a to AA-f), formula (BB-a to BB-f), formula (CC-a to CC-f), formula (DD-a to DD-f), formula (EE-a to EE-h), or formula (FF-a to FF-k), or a stereoisomer or pharmaceutically acceptable salt thereof, selected from:
Figure BDA0002340450700003731
Figure BDA0002340450700003741
Figure BDA0002340450700003751
Figure BDA0002340450700003761
Figure BDA0002340450700003781
Figure BDA0002340450700003791
Figure BDA0002340450700003801
wherein y, Ab and R1、R1a、R1b、R2、R2a、R3、R3a、R4、R4a、R5、R5a、R6、R6a、R7、R7a、R8、R8a、R9、R9a、Y1、Y2、Y3、Y4、Y5、Y6、Y7、Y8、Y9、Y10And Y11Is as defined above for an immunoconjugate having formula (AA-a to AA-f), formula (BB-a to BB-f), formula (CC-a to CC-f), formula (DD-a to DD-f), formula (EE-a to EE-h), and formula (FF-a to FF-k), and with the proviso that R is1、R1aOr R1bIs at least one-NHL1R115Substituted, or R3、R4、R5、R7、R3a、R4a、R5aOr R7ais-OL1R115。
Embodiment 190 the immunoconjugate of embodiment 146, wherein R1Is a pyrimidine or purine nucleobase or an analogue thereof, R1aIs a pyrimidine or purine nucleobase or an analogue thereof, and R1bIs a pyrimidine or purine nucleobase or an analogue thereof, each of which has the formula (AA-a to AA-f), formula (BB-a to BB-f)R of immunoconjugates of formulae (CC-a to CC-f), formulae (DD-a to DD-f), formulae (EE-a to EE-h) and formulae (FF-a to FF-k)1、R1aOr R1bSubstituted as described in (1).
Example 191 the immunoconjugate of example 148, selected from:
Figure BDA0002340450700003811
Figure BDA0002340450700003821
Figure BDA0002340450700003831
Figure BDA0002340450700003841
Figure BDA0002340450700003851
Figure BDA0002340450700003871
Figure BDA0002340450700003881
wherein y, Ab and R1、R1a、R1b、R2、R2a、R3、R3a、R4、R4a、R5、R5a、R6、R6a、R7、R7a、R8、R8a、R9、R9a、Y1、Y2、Y3、Y4、Y5、Y6、Y7、Y8、Y9、Y10And Y11Is as defined above for an immunoconjugate having formula (AA-a to AA-f), formula (BB-a to BB-f), formula (CC-a to CC-f), formula (DD-a to DD-f), formula (EE-a to EE-h), and formula (FF-a to FF-k), and with the proviso that R is1、R1aOr R1bIs at least one-NHL1R115Substituted, or R3、R4、R5、R7、R3a、R4a、R5aOr R7ais-OL1R115。
Example 192-an immunoconjugate having formula (AA-a to AA-f), formula (AA-1a to AA-1f), or formula (AA-2a to AA-2f), wherein
R2And R2aIs H;
R3and R4One of H and the other is selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3Or R4and-OC (O) O phenyl and R3Or R4C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R5And R5aIs H;
R6and R6aIs H;
R8、R9、R8aand R9aIndependently is H or C1-C6Alkyl radical, and
R3aand R4aOne of H and the other is selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3aAnd R4aand-OC (O) O phenyl and R3aOr R4aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3，
And with the proviso that R1Or R1aIs at least one-NHL1R115Substituted, or R3、R4、R3aOr R4ais-OL1R115。
Embodiment 193 immunoconjugates having the formula (AA-a to AA-f), formula (AA-1a to AA-1f) or formula (AA-2a to AA-2f), wherein:
Y1and Y2Is O, CH2Or S;
Y3is OH, O-、OR10、N(R10)2SH or S-；
Y4Is OH, O-、OR10、N(R10)2SH or S-；
Y5And Y6Is O or S;
Y7and Y8Is O or S;
Y9and Y10Is O or S;
R2、R2a、R6、R6a、R5and R5aIs H
R3aAnd R4aOne of which is H and the other is-OL1R115H, OH or F;
R3and R4One of which is H and the other is-OL1R115H, OH or F; and is
R8a、R9a、R8And R9Independently selected from H or C1-C6An alkyl group, a carboxyl group,
and with the proviso that R1Or R1aIs at least one-NHL1R115Substituted, or R3、R4、R3aOr R4ais-OL1R115。
The embodiment 194 an immunoconjugate having formula (BB-a to BB-f), formula (BB-1a to BB-1f), or formula (BB-2a to BB-2f), wherein:
R2and R2aIs H;
R3aand R4aOne of H and the other is selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3aAnd R4a-OC (O) O phenyl and R3aOr R4aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical、C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R5a andR6ais H;
R6and R4Is H;
R8、R9、R8aand R9aIndependently is H or C1-C6Alkyl radical, and
R5and R7One of H and the other is selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5And R7and-OC (O) O phenyl and R5Or R7C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3，
And with the proviso that R1Or R1aIs at least one-NHL1R115Substituted, or R5、R7、R3aOr R4ais-OL1R115。
Embodiment 195 the immunoconjugate of formula (BB-a to BB-f), formula (BB-1a to BB-1f), or formula (BB-2a to BB-2f), wherein:
Y1and Y2Is O, CH2Or S;
Y3is OH, O-、OR10、N(R10)2SH or S-；
Y4Is OH, O-、OR10、N(R10)2SH or S-；
Y5And Y6Is O or S;
Y7and Y8Is O or S;
Y9and Y10Is O or S;
R2、R2a、R5a、R6a、R6and R4Is H;
R3aand R4aOne of which is H and the other is-OL1R115H, OH or F;
R5and R7One of which is H and the other is-OL1R115H, OH or F, and
R8a、R9a、R8and R9Independently selected from H or C1-C6An alkyl group, a carboxyl group,
and with the proviso that R1Or R1aIs at least one-NHL1R115Substituted, or R5、R7、R3aOr R4ais-OL1R115。
Embodiment 196 immunoconjugates having the formula (CC-a to CC-f), formula (CC-1a to CC-1f) or formula (CC-2a to CC-2f), wherein:
R2and R2aIs H;
R3and R4One of H and the other is selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3And R4and-OC (O) O phenyl and R3Or R4C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R4aAnd R6aIs H;
R6and R5Is H;
R8、R9、R8aand R9aIndependently is H or C1-C6An alkyl group;
R5aand R7aOne of H and the other is selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5aAnd R7aand-OC (O) O phenyl and R5aOr R7aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3，
And with the proviso that R1Or R1aIs at least one-NHL1R115Substituted, or R5a、R7a、R3aOr R4ais-OL1R115。
Embodiment 197. immunoconjugates having the formula (CC-a to CC-f), formula (CC-1a to CC-1f), or formula (CC-2a to CC-2f), wherein:
Y1and Y2Is O, CH2Or S;
Y3is OH, O-、OR10、N(R10)2SH or S-；
Y4Is OH, O-、OR10、N(R10)2SH or S-；
Y5And Y6Is O or S;
Y7and Y8Is O or S;
Y9and Y10Is O or S;
R2、R2a、R4a、R6a、R6and R5Is H;
R3and R4One of which is H and the other is-OL1R115H, OH or F;
R5aand R7aOne of which is H and the other is-OL1R115H, OH or F, and
R8a、R9a、R8and R9Independently selected from H or C1-C6An alkyl group, a carboxyl group,
and with the proviso that R1Or R1aIs at least one-NHL1R115Substituted, or R5a、R7a、R3aOr R4ais-OL1R115。
Embodiment 198. immunoconjugates having the formula (DD-a to DD-f), the formula (DD-1a to DD-1f), or the formula (DD-2a to DD-2f), wherein:
R2and R2aIs H;
R5aand R7aOne of H and the other is selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5aAnd R7aand-OC (O) O phenyl and R5aOr R7aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R4a andR6ais H;
R6and R4Is H;
R8、R9、R8aand R9aIndependently is H or C1-C6Alkyl radical, and
R5and R7One of H and the other is selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5And R7and-OC (O) O phenyl and R5Or R7C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3，
And with the proviso that R1Or R1aIs at least one-NHL1R115Substituted, or R5a、R7a、R5Or R7is-OL1R115。
Embodiment 199. an immunoconjugate having formula (DD-a to DD-f), formula (DD-1a to DD-1f), or formula (DD-2a to DD-2f), wherein:
Y1and Y2Is O, CH2Or S;
Y3is OH, O-、OR10、N(R10)2SH or S-；
Y4Is OH, O-、OR10、N(R10)2SH or S-；
Y5And Y6Is O or S;
Y7and Y8Is O or S;
Y9and Y10Is O or S;
R2、R2a、R4a、R6a、R6and R4Is H;
R5aand R7aOne of which is H and the other is-OL1R115OH or F;
R5and R7One of which is H and the other is-OL1R115H, OH or F, and
R8、R9、R8aand R9aIndependently is H or C1-C6Alkyl, aryl, heteroaryl, and heteroaryl,
And with the proviso that R1Or R1aIs at least one-NHL1R115Substituted, or R5a、R7a、R5Or R7is-OL1R115。
Example 200 an immunoconjugate having formula (EE-a to EE-h), formula (EE-1a to EE-1h), or formula (EE-2a to EE-2h), wherein:
R2and R2aIs H;
R6and R6aIs H;
R7is H;
R8、R9、R8aand R9aIndependently is H or C1-C6Alkyl radical, and
R3aand R4aOne of H and the other is selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3aAnd R4a-OC (O) O phenyl and R3aOr R4aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R3And R4One of H and the other is selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3And R4and-OC (O) O phenyl and R3Or R4C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3And is and
R5and R7One of H and the other is selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5And R7and-OC (O) O phenyl and R5Or R7C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3，
And with the proviso that R1Or R1aIs at least one-NHL1R115Substituted, or R3a、R4a、R3、R4、R5Or R7is-OL1R115。
Example 201 an immunoconjugate having formula (EE-a to EE-h), formula (EE-1a to EE-1h), or formula (EE-2a to EE-2h), wherein:
Y1and Y2Is O, CH2Or S;
Y3is OH, O-、OR10、N(R10)2SH or S-；
Y5Is O or S;
Y7is O or S;
Y9is O or S;
R2、R2a、R5、R6a、R6and R7Is H;
R3a、R4aone of which is H and the other is-OL1R115、H、OH、OCH3Or F;
R3、R4one of which is H and the other is-OL1R115、H、OH、OCH3Or F;
R5and R7One of which is H and the other is-OL1R115、H、OH、OCH3Or F, and
R8、R9、R8aand R9aIndependently is H or C1-C6Alkyl, aryl, heteroaryl, and heteroaryl,
And with the proviso that R1Or R1aIs at least one-NHL1R115Substituted, or R3a、R4a、R3、R4、R5Or R7is-OL1R115。
Embodiment 202 an immunoconjugate having formula (FF-a through FF-k), formula (FF-1a through FF-1k), or formula (FF-2a through FF-2k), wherein:
R2and R2aIs H;
each R6 andR6ais H;
R5aand R7Is H;
R8、R9、R8aand R9aIndependently is H or C1-C6Alkyl radical, and
R3aand R4aOne of H and the other is selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3aAnd R4a-OC (O) O phenyl and R3aOr R4aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R3And R4One of H and the other is selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3And R4and-OC (O) O phenyl and R3Or R4C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3And is and
R5selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl、-OC(O)C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5of-OC (O) O phenyl and R5C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3，
And with the proviso that R1、R1aOr R1bIs at least one-NHL1R115Substituted, or R3a、R4a、R3、R4、R5Or R7is-OL1R115。
Embodiment 203. an immunoconjugate having formula (FF-a through FF-k), formula (FF-1a through FF-1k), or formula (FF-2a through FF-2k), wherein:
Y1and Y2Is O, CH2Or S;
each Y3Independently is OH, O-、OR10、N(R10)2SH or S-；
Each Y5Independently is O or S;
each Y7Independently is O or S;
each Y9Independently is O or S;
Y11is O, CH2Or S;
R2、R2a、R6、R6a、R5aand R7aIs H;
R3aand R4aOne of which is H and the other is-OL1R115、H、OH、OCH3Or F;
R3and R4One of which is H and the other is-OL1R115、H、OH、OCH3Or F;
R5and R7One of which is H and the other is-OL1R115、H、OH、OCH3Or F, and
R8、R9、R8aand R9aIndependently is H or C1-C6Alkyl, aryl, heteroaryl, and heteroaryl,
And with the proviso that R1、R1aOr R1bIs at least one-NHL1R115Substituted, or R3a、R4a、R3、R4、R5Or R7is-OL1R115。
Embodiment 204 an immunoconjugate having formula (AA-a to AA-f), formula (BB-a to BB-f), formula (CC-a to CC-f), formula (DD-a to DD-f), formula (EE-a to EE-h), formula (FF-a to FF-k), or the immunoconjugate of any one of embodiments 146 to 161, wherein:
R1is that
Figure BDA0002340450700004001
Figure BDA0002340450700004011
Wherein: r1Is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH2、D、CD3、C1-C6Alkyl radical, C1-C6An alkoxyalkyl group,C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1- 10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl) and-N (C)3-C8Cycloalkyl radicals2，
And is
Each R200Independently selected from H and L1R115；
R1aIs that
Figure BDA0002340450700004012
Wherein: r1aIs substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl) and-N (C)3-C8Cycloalkyl radicals2，
And is
Each R210Independently selected from H and L1R115，
And is
R1bIs that
Figure BDA0002340450700004031
Figure BDA0002340450700004041
Wherein: r1bIs substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl) and-N (C)3-C8Cycloalkyl radicals2，
And is
Each R210Independently selected from H and L1R115。
Example 205 an immunoconjugate selected from:
Figure BDA0002340450700004051
Figure BDA0002340450700004061
Figure BDA0002340450700004071
Figure BDA0002340450700004081
Figure BDA0002340450700004091
Figure BDA0002340450700004101
Figure BDA0002340450700004111
wherein:
Y1is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
Y2is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
Y3Is OH, O-、OR10、N(R10)2SH or S-；
Y4Is OH, O-、OR10、N(R10)2SH or S-；
Y7Is O or S;
Y8is O or S;
Y11is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
R1Is that
Figure BDA0002340450700004121
Figure BDA0002340450700004122
Wherein: r1Is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1- 10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl) and-N (C)3-C8Cycloalkyl radicals2，
And is
Each R200Independently selected from H and L1R115
R1aIs that
Figure BDA0002340450700004131
Figure BDA0002340450700004132
Figure BDA0002340450700004141
Wherein: r1aIs substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl) and-N (C)3-C8Cycloalkyl radicals2，
And is
Each R210Independently selected from H and L1R115，
R1bIs that
Figure BDA0002340450700004151
Wherein: r1bIs substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, OH, SH, NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl) and-N (C)3-C8Cycloalkyl radicals2，
And is
Each R210Independently of each otherSelected from H and L1R115；
Each R2Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and OC (O) C2-C6Alkynyl, wherein R2of-OC (O) O phenyl and R2C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R3Independently selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3of-OC (O) O phenyl and R3C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R4Independently selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R4of-OC (O) O phenyl and R4C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN or N3；
Each R5Independently selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5of-OC (O) O phenyl and R5C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN or N3；
Each R6Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl radical-OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R6of-OC (O) O phenyl and R6C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R7Independently selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R7of-OC (O) O phenyl and R7C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN or N3；
R2aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R2aof-OC (O) O phenyl and R2aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3
R3aSelected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3aof-OC (O) O phenyl and R3aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R4aSelected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R4aof-OC (O) O phenyl and R4aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R5aSelected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5aof-OC (O) O phenyl and R5aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R6aIs selected from the group consisting ofThe group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R6aof-OC (O) O phenyl and R6aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R7aSelected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R7aof-OC (O) O phenyl and R7aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R10Independently selected from the group consisting of: H. c1-C12Alkyl, - (CH)2CH2O)nCH2CH2C(＝O)OC1-C6Alkyl radicals andwherein R is10C of (A)1-C12Alkyl is substituted with 0,1, 2 or 3 substituents independently selected from-OH, C1-C12Alkoxy, -S-C (═ O) C1-C6Alkyl and C (O) OC1-C6An alkyl group;
optionally, R3And R6Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R3And R6When taken together, O is at R3Bonding at the position;
optionally, R3aAnd R6aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R3aAnd R6aWhen taken together, O is at R3aBonding at the position;
optionally, R2And R3Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R2And R3When taken together, O is at R3Bonding at the position;
optionally, R2aAnd R3aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R2aAnd R3aWhen taken together, O is at R3aBonding at the position;
optionally, R4And R3Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical、C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R4And R3When taken together, O is at R3Bonding at the position;
optionally, R4aAnd R3aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R4aAnd R3aWhen taken together, O is at R3aBonding at the position;
optionally, R5And R6Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5And R6When taken together, O is at R5Bonding at the position;
optionally, R5aAnd R6aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5aAnd R6aWhen taken together, O is at R5aBonding at the position;
optionally, R5And R7Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5And R7When taken together, O is at R5Bonding at the position; and is
Optionally, R5aAnd R7aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5aAnd R7aWhen taken together, O is at R5aBonding at the position;
L1is-C (═ O) O (CH)2)mNR11C(＝O)(CH2)m-**；-C(＝O)O(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；
-C(＝O)OC(R12)2(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；
-C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)mC(＝O)-**；
-C(＝O)O(CH2)mNR11C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；-C(＝O)O(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)(CH2)mNR11C(＝O)X2C(＝O)(CH2)m-**；
-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)(CH2)m-**、
-C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-**，-C(＝O)O(CH2)mX6C(＝O)(CH2)m-**，
-C(＝O)O(CH2)mX6C(＝O)(CH2)mO(CH2)m-**，-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)(CH2)m-**，
-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)(CH2)mO(CH2)m-**，
-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)(CH2)mO(CH2)mC(＝O)-**，
-C(＝O)O(CH2)mX6C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**，
-C(＝O)X4C(＝O)X6(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**，
-C(＝O)(CH2)mX6C(＝O)X1X2C(＝O)(CH2)m-**，-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O))X5C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mNR11((CH2)mO)n(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-**；
-C(＝O)O(CH2)m-**；-C(＝O)O((CH2)mO)n(CH2)m-**；-C(＝O)O(CH2)mNR11(CH2)m-**；
-C(＝O)O(CH2)mNR11(CH2)mC(＝O)X2X1C(＝O)-**；-C(＝O)O(CH2)mX3(CH2)m-**；-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mX3(CH2)m-**；-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)O(CH2)mNR11C(＝O(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)nX3(CH2)m-**；-C(＝O)O((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mC(＝O)NR11(CH2)m-**；-C(＝O)O(CH2)mC(R12)2-**；
-C(＝O)OCH2)mC(R12)2SS(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)O(CH2)mC(＝O)NR11(CH2)m-**；
-C(＝O)(CH2)m-**；-C(＝O)((CH2)mO)n(CH2)m-**；-C(＝O)(CH2)mNR11(CH2)m-**；
-C(＝O)(CH2)mNR11(CH2)mC(＝O)X2X1C(＝O)-**；-C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；-C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；-C(＝O)(CH2)mNR11C(＝O(CH2)mX3(CH2)m-**；-(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-(CH2)m(CHOH)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)nX3(CH2)m-**；-C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mC(＝O)NR11(CH2)m-**；-C(＝O)(CH2)mC(R12)2-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O))X5C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mNR11((CH2)mO)n(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-**；
-C(＝O)(CH2)mC(R12)2SS(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)(CH2)mC(＝O)NR11(CH2)m-**；-C(＝O)X1X2C(＝O)(CH2)m-**；
-C(＝O)X1X2C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；-C(＝O)X1X2C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)X1X2C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)X1X2C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)X1X2(CH2)mX3(CH2)m-**；-C(＝O)X1X2((CH2)mO)n(CH2)m-**；
-C(＝O)X1X2((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)X1X2((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)X1X2((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)X1X2(CH2)mNR11((CH2)mO)n(CH2)m-**；
-C(＝O)X1X2C(＝O)(CH2)mNR11((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)m-**；-C(＝O)NR11(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)O(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X1X2-**；-C(＝O)NR11(CH2)mNR11C(＝O)X5-；
-C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mX5(CH2)m-**；
-C(＝O)X1C(＝O)NR11(CH2)mX5(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)mC(＝O)-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5(CH2)mNR11((CH2)mO)n(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-**；
-C(＝O)X1C(＝O)NR11(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)X1C(＝O)NR11(CH2)mX3(CH2)m-**；-C(＝O)NR11(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；-C(＝O)NR11(CH2)mNR11C(＝O)-**；
-C(＝O)X1X2(CH2)m-**；-C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)X1X2(CH2)mX3(CH2)m-**；-C(＝O)NR11(CH2)mX3(CH2)m-**；
-C(＝O)NR11((CH2)mO)n(CH2)mX3(CH2)m-**；-C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)X1C(＝O)(CH2)mNR11C(＝O)(CH2)m-; and is
-C(＝O)X1C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-**；
Wherein indicates with R115The attachment point of (a);
R115is that
Figure BDA0002340450700004301
Figure BDA0002340450700004302
-C(＝O)-、-ON＝***、-S-、-NHC(＝O)CH2-、-S(＝O)2CH2CH2-、-(CH2)2S(＝O)2CH2CH2-、-NHS(＝O)2CH2CH2、-NHC(＝O)CH2CH2-、-CH2NHCH2CH2-、-NHCH2CH2-、
Figure BDA0002340450700004304
Figure BDA0002340450700004311
Wherein indicates the point of attachment to Ab;
X1is that
Figure BDA0002340450700004312
Wherein indicates with X2The attachment point of (a);
X2is selected from
Figure BDA0002340450700004313
Figure BDA0002340450700004315
Wherein indicates with X1The attachment point of (a);
X3is that
Figure BDA0002340450700004321
X4is-O (CH)2)nSSC(R12)2(CH2)n-or- (CH)2)nC(R12)2SS(CH2)nO-；
X5Is that
Figure BDA0002340450700004322
Wherein indicates the direction towards the drug moiety;
X6is that
Figure BDA0002340450700004323
Or, wherein indicates a direction towards the drug moiety;
each R11Is independently selected fromH and C1-C6An alkyl group;
each R12Independently selected from H and C1-C6An alkyl group;
R13is H or methyl;
R14is H, -CH3Or phenyl;
each R110Independently selected from H, C1-C6Alkyl, F, Cl, and-OH;
each R111Independently selected from H, C1-C6Alkyl radical F, Cl, -NH2、-OCH3、-OCH2CH3、-N(CH3)2、-CN、-NO2and-OH;
each R112Independently selected from H, C1-6Alkyl, fluoro, benzyloxy substituted by-C (═ O) OH, benzyl substituted by-C (═ O) OH, C substituted by-C (═ O) OH1-4Alkoxy and C substituted by-C (═ O) OH1-4An alkyl group;
each m is independently selected from 1,2, 3,4, 5,6, 7,8, 9, and 10; each n is independently selected from 1,2, 3,4, 5,6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18.
Ab is an antibody or fragment thereof, and
each y is independently selected from 1,2, 3,4, 5,6, 7,8, 9 or 10,
and with the proviso that R200Or R210Is at least one of-L1R115Or by-NHL1R115Substituted, or R3、R4、R5、R7、R3a、R4a、R5aOr R7ais-OL1R115。
Example 206. an immunoconjugate selected from:
Figure BDA0002340450700004331
wherein: ab. y, R1、R1a、R3、R3a、R6、R6a、Y3And Y4As defined in example 205.
Embodiment 207. an immunoconjugate selected from:
Figure BDA0002340450700004332
Figure BDA0002340450700004341
Figure BDA0002340450700004351
wherein: ab. y, R1、R1a、R3、R3a、R6And R6aAs defined in example 205;
Y3is OR9、N(R10)2SH or S-And is and
Y4is OR9、N(R10)2SH or S-。
Example 208. an immunoconjugate selected from:
Figure BDA0002340450700004352
Figure BDA0002340450700004361
Figure BDA0002340450700004371
Figure BDA0002340450700004381
Figure BDA0002340450700004391
wherein: ab. y, R1、R1a、R3、R3a、R6And R6aAs defined in example 205;
Y3is OR9、N(R10)2SH or S-And is and
Y4is OR9、N(R10)2SH or S-。
Embodiment 209 an immunoconjugate selected from:
Figure BDA0002340450700004392
wherein: ab. y, R1、R1a、R3、R3a、R5、R6a、Y3And Y4As defined in example 205.
Example 210. an immunoconjugate selected from:
Figure BDA0002340450700004411
wherein: ab. y, R1、R1a、R3a、R5And R6aAs defined in example 205;
Y3is OR9、N(R10)2SH or S-And is and
Y4is OR9、N(R10)2SH or S-。
Example 211. an immunoconjugate selected from:
Figure BDA0002340450700004421
Figure BDA0002340450700004431
wherein: ab. y, R1、R1aAnd R5As defined in example 205;
Y3is OR9、N(R10)2SH or S-And is and
Y4is OR9、N(R10)2SH or S-。
Embodiment 212. an immunoconjugate selected from:
Figure BDA0002340450700004432
wherein: ab. y, R1、R1a、R3、R5a、R6、R6a、Y3And Y4As defined in example 205.
Example 213. an immunoconjugate selected from:
Figure BDA0002340450700004441
Figure BDA0002340450700004451
wherein: ab. y, R1、R1a、R3、R5a、R6And R6aAs defined in example 205;
Y3is OR9、N(R10)2SH or S-And is and
Y4is OR9、N(R10)2SH or S-。
Example 214. an immunoconjugate selected from:
Figure BDA0002340450700004461
wherein: ab. y, R1、R1a、R5aAnd R6aAs defined in example 205;
Y3is OR9、N(R10)2SH or S-And is and
Y4is OR9、N(R10)2SH or S-。
Example 215. an immunoconjugate selected from:
Figure BDA0002340450700004472
wherein: ab. y, R1、R1a、R5、R5a、Y3And Y4As defined in example 205.
Example 216. an immunoconjugate selected from:
Figure BDA0002340450700004473
Figure BDA0002340450700004481
Figure BDA0002340450700004491
wherein: ab. y, R1、R1a、R5And R5aAs defined in example 205;
Y3is OR9、N(R10)2SH or S-And is and
Y4is OR9、N(R10)2SH or S-。
Example 217 an immunoconjugate selected from:
Figure BDA0002340450700004492
wherein: ab. y, R1、R1a、R3、R3a、R4、R4a、R5、R7And Y3As defined in example 205.
Example 218. an immunoconjugate selected from:
Figure BDA0002340450700004511
Figure BDA0002340450700004521
Figure BDA0002340450700004531
wherein: ab. y, R1、R1a、R3、R3a、R4、R4a、R5、R7And Y3As defined in example 205;
and Y is3Is OR9、N(R10)2SH or S-。
Example 219. an immunoconjugate selected from:
Figure BDA0002340450700004532
Figure BDA0002340450700004551
wherein: ab. y, R1、R1a、R1b、R3、R3a、R4、R4a、R5、R7And Y3As defined in the example 205, it is,
example 220. an immunoconjugate selected from:
Figure BDA0002340450700004561
Figure BDA0002340450700004571
Figure BDA0002340450700004581
wherein: ab. y, R1、R1a、R1b、R3、R3a、R4、R4a、R5And R7As defined in example 205, and each Y3Independently selected from OR10、N(R10)2SH and S-。
Embodiment 221. an immunoconjugate selected from:
Figure BDA0002340450700004582
Figure BDA0002340450700004591
Figure BDA0002340450700004601
wherein: ab. y, R1、R1a、R1b、R3、R3a、R4、R4a、R5And R7As defined in example 205, and each Y3Independently selected from OR10、N(R10)2SH and S-。
Embodiment 222. an immunoconjugate selected from:
Figure BDA0002340450700004611
Figure BDA0002340450700004631
wherein: ab. y, R1、R1a、R1b、R3、R3a、R4、R4a、R5And R7As defined in example 205, and each Y3Independently selected from OR10、N(R10)2SH and S-。
Example 223. an immunoconjugate selected from:
Figure BDA0002340450700004632
Figure BDA0002340450700004641
Figure BDA0002340450700004651
wherein: ab. y, R1、R1a、R1b、R3、R3a、R4、R4a、R5And R7As defined in example 205, and each Y3Independently selected from OR10、N(R10)2SH and S-。
Examples224. The immunoconjugate of any one of embodiments 188 to 223, wherein R1Is that
Figure BDA0002340450700004652
The immunoconjugate of any one of embodiments 188 to 223, wherein R1aIs that
The immunoconjugate of any one of embodiments 188 to 223, wherein R1bIs that
Figure BDA0002340450700004662
The immunoconjugate of any one of embodiments 188 to 223, wherein R1Is that
Figure BDA0002340450700004663
The immunoconjugate of any one of embodiments 188 to 223, wherein R1aIs that
Figure BDA0002340450700004664
The immunoconjugate of any one of embodiments 188 to 223, wherein R1bIs that
Figure BDA0002340450700004665
The compound of any one of embodiments 188 to 223, wherein R1Is that
Figure BDA0002340450700004666
Wherein R is200is-L1R115。
The compound of any one of embodiments 188 to 223, wherein R1aIs thatWherein R is210is-L1R115。
The compound of any one of embodiments 188 to 223, wherein R1bIs that
Figure BDA0002340450700004672
Wherein R is210is-L1R115。
Embodiment 233. the compound of any one of embodiments 188 to 223, wherein R1Is that
Figure BDA0002340450700004673
Wherein R is200is-L1R115。
The compound of embodiment 234. the compound of any one of embodiments 188 to 223, wherein R1aIs that
Figure BDA0002340450700004674
Wherein R is210is-L1R115。
The compound of any one of embodiments 235 to 223, wherein R1bIs that
Figure BDA0002340450700004675
Wherein R is210is-L1R115。
The immunoconjugate of any one of embodiments 188 to 223, wherein R1Is that
Figure BDA0002340450700004676
And R is1aIs that
Figure BDA0002340450700004677
Wherein R is200Is L1R115And R is210Is H.
The immunoconjugate of any one of embodiments 188 to 223, wherein R1Is that
Figure BDA0002340450700004681
And R is1aIs that
Figure BDA0002340450700004682
Wherein R is200Is H, and R210Is L1R115。
The immunoconjugate of any one of embodiments 188 to 223, wherein R1Is that
Figure BDA0002340450700004683
And R is1aIs that
Figure BDA0002340450700004684
Wherein R is200Is L1R115And R is210Is L1R115。
The immunoconjugate of any one of embodiments 188 to 223, wherein R1Is that
Figure BDA0002340450700004685
And R is1aIs thatWherein R is200Is L1R115And R is210Is H.
The immunoconjugate of any one of embodiments 188 to 223, wherein R1Is thatAnd R is1aIs that
Figure BDA0002340450700004688
Wherein R is200Is H, and R210Is L1R115。
The immunoconjugate of any one of embodiments 188 to 223, wherein R1Is thatAnd R is1aIs that
Figure BDA00023404507000046810
Wherein R is200Is L1R115And R is210Is L1R115。
The immunoconjugate of any one of embodiments 188 to 223, wherein R1Is that
Figure BDA00023404507000046811
And R is1aIs that
Figure BDA00023404507000046812
Wherein R is200Is H, and R210Is L1R115。
The immunoconjugate of any one of embodiments 188 to 223, wherein R1Is that
Figure BDA0002340450700004691
And R is1aIs thatWherein R is200Is L1R115And R is210Is H.
The immunoconjugate of any one of embodiments 188 to 223, wherein R1Is thatAnd R is1aIs that
Figure BDA0002340450700004694
Wherein R is200Is L1R115And R is210Is L1R115。
The immunoconjugate of any one of embodiments 188 to 223, wherein R1Is that
Figure BDA0002340450700004695
And R is1aIs thatWherein R is200Is H, and R210Is L1R115。
The immunoconjugate of any one of embodiments 188 to 223, wherein R1Is thatAnd R is1aIs that
Figure BDA0002340450700004698
Wherein R is200Is L1R115And R is210Is H.
The immunoconjugate of any one of embodiments 188 to 223, wherein R1Is that
Figure BDA0002340450700004699
And R is1aIs that
Figure BDA00023404507000046910
Wherein R is200Is L1R115And R is210Is L1R115。
The immunoconjugate of any one of embodiments 188 to 223, wherein R1Is that
Figure BDA00023404507000046911
And R is1aIs that
Figure BDA00023404507000046912
Wherein R is200Is L1R115And R is210Is H.
The immunoconjugate of any one of embodiments 188 to 223, wherein R1Is that
Figure BDA0002340450700004701
And R is1aIs that
Figure BDA0002340450700004702
Wherein R is200Is H, and R210Is L1R115。
The immunoconjugate of any one of embodiments 188 to 223, wherein R1Is that
Figure BDA0002340450700004703
And R is1aIs that
Figure BDA0002340450700004704
Wherein R is200Is L1R115And R is210Is L1R115。
The immunoconjugate of any one of embodiments 188 to 223, wherein R1Is that
Figure BDA0002340450700004705
R1bIs that
Figure BDA0002340450700004706
And R is1aIs that
Figure BDA0002340450700004707
Wherein R is200Is L1R115And each R is210Is H.
The immunoconjugate of any one of embodiments 188 to 223, wherein R1Is that
Figure BDA0002340450700004708
R1bIs thatAnd R is1aIs that
Figure BDA00023404507000047010
Wherein R is200Is H, R1bR of (A) to (B)210Is L1R115And R is1aR of (A) to (B)21Is H.
The immunoconjugate of any one of embodiments 188 to 223, wherein R1Is that
Figure BDA00023404507000047011
R1bIs thatAnd R is1aIs that
Figure BDA00023404507000047013
Wherein R is200Is H, R1bR of (A) to (B)210Is H, and R1aR of (A) to (B)210Is L1R115。
The compound of any one of embodiments 254 to 223, wherein R1Is thatWherein R is200Is H, and R3、R3a、R5Or R5ais-OL1R115。
Embodiment 255 the compound of any of embodiments 188 to 223, wherein R1aIs that
Figure BDA0002340450700004711
Wherein R is210Is H, and R3、R3a、R5Or R5ais-OL1R115。
Embodiment 256. the compound of any of embodiments 188 to 223, wherein R1bIs that
Figure BDA0002340450700004712
Wherein R is210Is H, and R3、R3a、R5Or R5ais-OL1R115。
Embodiment 257. the compound of any one of embodiments 188 to 223, wherein R1Is that
Figure BDA0002340450700004713
Wherein R is200Is H, and R3、R3a、R5Or R5ais-OL1R115。
Embodiment 258. the compound of any of embodiments 188 to 223, wherein R1aIs that
Figure BDA0002340450700004714
Wherein R is210Is H, and R3、R3a、R5Or R5ais-OL1R115。
The compound of any one of embodiments 259-223, wherein R1bIs that
Figure BDA0002340450700004715
Wherein R is210Is H, and R3、R3a、R5Or R5ais-OL1R115。
The immunoconjugate of any one of embodiments 188 to 223, wherein
R1Is thatAnd R is1aIs that
Figure BDA0002340450700004722
Wherein R is200Is H, R210Is H, and R3、R3a、R5Or R5ais-OL1R115。
Embodiment 261 the immunoconjugate of any one of embodiments 188 to 223, wherein R1Is that
Figure BDA0002340450700004723
And R is1aIs that
Figure BDA0002340450700004724
Wherein R is200Is H, R210Is H, and R3、R3a、R5Or R5ais-OL1R115。
The immunoconjugate of any one of embodiments 188 to 223, wherein R1Is thatAnd R is1aIs that
Figure BDA0002340450700004726
Wherein R is200Is H, R210Is H, and R3、R3a、R5Or R5ais-OL1R115。
The immunoconjugate of any one of embodiments 188 to 223, wherein R1Is that
Figure BDA0002340450700004727
And R is1aIs that
Figure BDA0002340450700004728
Wherein R is200Is H, R210Is H, and R3、R3a、R5Or R5ais-OL1R115。
The immunoconjugate of any one of embodiments 188 to 223, wherein R1Is that
Figure BDA0002340450700004729
And R is1aIs that
Figure BDA00023404507000047210
Wherein R is200Is H, R210Is H, and R3、R3a、R5Or R5ais-OL1R115。
The immunoconjugate of any one of embodiments 188 to 223, wherein
Example 266.R1Is that
Figure BDA0002340450700004731
R1bIs thatAnd R is1aIs that
Figure BDA0002340450700004733
Wherein R is200Is H, R210Is H, and R3、R3a、R5Or R5ais-OL1R115。
The immunoconjugate of any one of embodiments 188 to 266, wherein:
Y3is OH, O-SH or S-And is and
Y4is OH, O-SH or S-。
The immunoconjugate of any one of embodiments 188 to 266, wherein:
Y3is OH or O-And is and
Y4is OH or O-。
The immunoconjugate of any one of embodiments 188 to 266, wherein:
Y3is SH or S-And is and
Y4is OH or O-。
The immunoconjugate of any one of embodiments 188 to 266, wherein:
Y3is OH or O-And is and
Y4is SH or S-。
The immunoconjugate of any one of embodiments 188 to 266, wherein:
Y3is SH or S-.And is and
Y4is SH or S-。
The compound of embodiment 272 as described in any one of embodiments 188 to 253 or embodiments 267 to 271, wherein: r2、R2a、R4、R4a、R6、R6a、R7And R7aEach is H.
The compound of any one of embodiments 188 to 253 or embodiments 267 to 271, wherein: r3is-OH, F or-NH2。
Embodiment 274 the compound of any one of embodiments 188 to 253 or embodiments 267 to 271, wherein: r3is-OH or F.
The compound of any one of embodiments 188-253 or embodiments 267-271, wherein: r3ais-OH, F or-NH2。
The compound of embodiment 276, as described in any one of embodiments 188-253 or embodiments 267-271, wherein: r3ais-OH or F.
The compound of any one of embodiments 188 to 253 or embodiments 267 to 271, wherein: r5is-OH, F or-NH2。
Embodiment 278. the compound of any one of embodiments 188 to 253 or embodiments 267 to 271, wherein: r5is-OH or F.
The compound of any one of embodiments 188-253 or embodiments 267-271, wherein: r5ais-OH, F or-NH2。
The compound of embodiment 280, as described in any one of embodiments 188-253 or embodiments 267-271, wherein: r5ais-OH or F.
Embodiment 281 the compound of any one of embodiments 188 to 253 or embodiments 267 to 271, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R3is-OH, and
R3ais F.
Embodiment 282 the compound of any one of embodiments 188 to 253 or embodiments 267 to 271, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R3is F, and
R3ais-OH.
The compound of any one of embodiments 188-253 or embodiments 267-271, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R3is F, and
R3ais F.
Embodiment 284 the compound of any one of embodiments 188 to 253 or embodiments 267 to 271, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R3is-OH, and
R3ais-OH.
The compound of any one of embodiments 188 to 253 or embodiments 267 to 271, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R3ais-OH, and
R5is F.
The compound of embodiment 286 any one of embodiments 188-253 or embodiments 267-271, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R3ais F, and
R5is-OH.
The compound of any one of embodiments 188 to 253 or embodiments 267 to 271, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R3ais F, and
R5is F.
Embodiment 288 the compound of any one of embodiments 188 to 253 or embodiments 267 to 271, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R3ais-OH, and
R5is-OH.
The compound of any one of embodiments 188 to 253 or embodiments 267 to 271, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R3is-OH, and
R5ais F.
Embodiment 290. the compound of any one of embodiments 188 to 253 or embodiments 267 to 271, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R3is F, and
R5ais-OH.
Embodiment 291. the compound of any one of embodiments 188 to 253 or embodiments 267 to 271, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R3is F, and
R5ais F.
Embodiment 292 the compound of any one of embodiments 188 to 253 or embodiments 267 to 271, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R3is-OH, and
R5ais-OH.
Embodiment 293. the compound of any one of embodiments 188 to 253 or embodiments 267 to 271, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R5is-OH, and
R5ais F.
The compound of embodiment 294, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R5is F, and
R5ais-OH.
Embodiment 295. the compound of any one of embodiments 188 to 253 or embodiments 267 to 271, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R5is F, and
R5ais F.
Embodiment 296. the compound of any one of embodiments 188 to 253 or embodiments 267 to 271, wherein when present:
R2、R2a、R4、R4a、R6、R6a、R7and R7aEach is H;
R5is-OH, and
R5ais-OH.
The immunoconjugate of any one of embodiments 188 to 253 or embodiments 267 to 271, wherein:
R3is-OH or F;
R3ais-OH or F;
R5is-OH or F;
R5ais-OH or F;
R6is H, and
R6ais H.
The immunoconjugate of any one of embodiments 188 to 253 or embodiments 267 to 271, wherein:
R3is H, -OH or F;
R3ais H, -OCH3-OH or F;
R5is-OH or F;
R4、R4a、R6、R6a、R7、R7ais H, and
R6ais H.
The immunoconjugate of any one of embodiments 188 to 298, wherein:
L1is-C (═ O) O (CH)2)mNR11C(＝O)(CH2)m-**；-C(＝O)O(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；-C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)OC(R12)2(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)O(CH2)mNR8C(＝O)X1X2C(＝O)(CH2)mO(CH2)m-**；-C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)mC(＝O)-**；-C(＝O)O(CH2)mNR11C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；-C(＝O)O(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)m-**；-(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-(CH2)m(CHOH)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m**；-C(＝O)X6C(＝O)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；-C(＝O)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)(CH2)m- (O) (CH)2)mNR11C(＝O)((CH2)mO)n(CH2)m-**；
Wherein indicates with R115An attachment point of, and
wherein R is11、R12、X1、X2M and n are as defined in example 205.
Example 300 an immunoconjugate selected from:
Figure BDA0002340450700004781
Figure BDA0002340450700004791
Figure BDA0002340450700004801
Figure BDA0002340450700004811
Figure BDA0002340450700004821
Figure BDA0002340450700004831
Figure BDA0002340450700004841
Figure BDA0002340450700004861
Figure BDA0002340450700004881
Figure BDA0002340450700004901
Figure BDA0002340450700004911
Figure BDA0002340450700004921
Figure BDA0002340450700004931
Figure BDA0002340450700004941
example 301. an immunoconjugate selected from:
Figure BDA0002340450700004952
Figure BDA0002340450700004961
Figure BDA0002340450700004971
Figure BDA0002340450700004981
Figure BDA0002340450700005001
Figure BDA0002340450700005011
Figure BDA0002340450700005021
also provided are protocols for assessing certain aspects of the analytical methodology of the antibody conjugates of the invention. Such analytical methods and results may demonstrate that the conjugates have advantageous properties, such as properties that make them easier to manufacture, easier to administer to a patient, more effective for a patient, and/or potentially safer. One example is the determination of molecular size by Size Exclusion Chromatography (SEC), where the amount of the desired antibody species in the sample is determined relative to the amount of high molecular weight contaminants (e.g., dimers, multimers, or aggregated antibodies) or low molecular weight contaminants (e.g., antibody fragments, degradation products, or individual antibody chains) present in the sample. Generally, it is desirable to have higher amounts of monomers and lower amounts of, for example, aggregated antibodies due to, for example, the effect of the aggregates on other properties of the antibody sample, such as, but not limited to, clearance, immunogenicity, and toxicity. Another example is the determination of hydrophobicity by Hydrophobic Interaction Chromatography (HIC), where the hydrophobicity of a sample is evaluated against a set of standard antibodies of known properties. Generally, low hydrophobicity is desirable due to the effect of hydrophobicity on other properties of the antibody sample, such as, but not limited to, aggregation over time, adhesion to surfaces, hepatotoxicity, clearance, and pharmacokinetic exposure. See Damle, n.k., Nat Biotechnol [ natural biotechnology ] 2008; 26(8) 884-885; singh, s.k., Pharm Res. [ pharmaceutical research ] 2015; 32(11) 3541-71 higher hydrophobicity index scores (i.e., faster elution from HIC column) reflect lower hydrophobicity of the conjugate when measured by hydrophobic interaction chromatography. As shown in the examples below, most of the tested antibody conjugates showed a hydrophobicity index of greater than 0.8. In some embodiments, antibody conjugates are provided having a hydrophobicity index of 0.8 or greater as measured by hydrophobic interaction chromatography.
anti-HER 2 antibody
In some embodiments, the antibody conjugates provided herein include an antibody or antibody fragment thereof (e.g., an antigen-binding fragment) that specifically binds human HER2 (an anti-HER 2 antibody). HER2 overexpression is observed in many cancer types, such as gastric, esophageal, colon, rectal, breast, ovarian, cervical, uterine, endometrial, bladder, pancreatic, lung, prostate, osteosarcoma, neuroblastoma, or head and neck cancer. Antibody conjugates comprising an anti-HER 2 antibody can specifically target HER2 positive cancers or tumors.
In some embodiments, the antibody conjugates provided herein include a monoclonal antibody or antibody fragment thereof that specifically binds human HER2 (e.g., a human or humanized anti-HER 2 monoclonal antibody). In some embodiments, the antibody or antibody fragment thereof that specifically binds to human HER2 may be selected from trastuzumab, pertuzumab, margeritumab, or HT-19, or an antibody fragment thereof or a site-specific cysteine mutant thereof.
Trastuzumab (trade name Herceptin (Herceptin) or heclon) is a humanized monoclonal antibody that binds to the membrane-proximal portion of the extracellular domain of the HER2 receptor (Hudis CA, N Engl J Med. [ new england journal of medicine ] 2007; 357(1): 39-51). The amino acid sequences of the trastuzumab heavy and light chain variable regions are described in U.S. Pat. No. 5,821,337. Trastuzumab interacts with three loop regions formed by residues 557-561, 570-573 and 593-603 of human HER2 (Cho et al, Nature [ Nature ]421:756-760, 2003). Trastuzumab interferes with HER2 signaling by preventing HER2 receptor dimerization, promoting endocytic destruction of the HER2 receptor, inhibiting extracellular domain shedding (Hudis CA, N Engl J Med. [ new england journal of medicine ] 2007; 357(1): 39-51). Another important mechanism of action of the anti-HER 2 antibody is the mediation of Antibody Dependent Cellular Cytotoxicity (ADCC). In ADCC, an anti-HER 2 antibody binds to tumor cells and then recruits immune cells (e.g. macrophages) through Fc γ receptor (Fc γ R) interactions. Trastuzumab has a conserved human IgG Fc region and is able to recruit immune effector cells responsible for antibody-dependent cellular cytotoxicity (Hudis CA, NEngl J Med [ new england journal of medicine ] 2007; 357(1): 39-51). Trastuzumab received U.S. FDA approval at 9 months 1998 for the treatment of metastatic breast cancer in patients whose tumors overexpress HER2 and receive one or more chemotherapeutic regimens for its metastatic disease.
Pertuzumab (also known as 2C4, Omnitarg (Omnitarg), pargeta) is a humanized monoclonal antibody that binds to the extracellular domain of the HER2 receptor and inhibits dimerization of HER2 with other HER receptors. The amino acid sequences of the pertuzumab heavy and light chains are described in U.S. patent No. 7,560,111. Pertuzumab interacts primarily with residues in region 245-333 of human HER2, in particular residues His 245, Val 286, Ser 288, Leu295, His 296 or Lys 311(Franklin et al, Cancer Cell [ Cancer Cell ]5:317-328, 2004). Pertuzumab appears to be more effective than trastuzumab in disrupting the formation of HER1-HER2 and HER3-HER2 complexes in breast and prostate cancer cell lines (Agus et al, J Clin Oncol [ journal of clinical oncology ] 2005; 23(11):2534-43.Epub 2005, 2 months and 7 days). For efficacy, pertuzumab does not require antibody-dependent cytotoxicity because the intact Fc region is not required for its activity (Agus et al, J Clin Oncol. [ J. Clin Oncol ] 2005; 23(11):2534-43. Epub.2005, 2/7). Pertuzumab obtained us FDA approval at 6 months 2012 for use in combination with trastuzumab and docetaxel for treating patients with HER2 positive metastatic breast cancer who did not receive anti-HER 2 therapy or chemotherapy for metastatic disease.
Margaruximab (also known as MGAH22) is another anti-HER 2 monoclonal antibody (see http:// www.macrogenics.com/products-margetuximab. html). The Fc region of margeritumab was optimized such that the region had increased binding to activating Fc γ R but decreased binding to inhibitory Fc γ R on immune effector cells. Maciteximab is currently in clinical trials for the treatment of patients with recurrent or refractory advanced breast cancer whose tumors express HER2 at the 2+ level by immunohistochemistry and lack evidence of amplification by the FISH HER2 gene.
HT-19 is another anti-HER 2 monoclonal antibody that binds to an epitope in human HER2 that is different from the epitope of trastuzumab or pertuzumab, and has been shown to inhibit HER2 signaling comparable to trastuzumab, and in combination with trastuzumab and pertuzumab enhances the degradation of HER2 (Bergstrom d.a. et al, Cancer Res. [ Cancer research ] 2015; 75: LB-231).
Other suitable anti-HER 2 monoclonal antibodies include, but are not limited to, the anti-HER 2 antibody described in U.S. patent nos.: 9,096,877, respectively; 9,017,671, respectively; 8,975,382, respectively; 8,974,785, respectively; 8,968,730, respectively; 8,937,159, respectively; 8,840,896, respectively; 8,802,093, respectively; 8,753,829, respectively; 8,741,586, respectively; 8,722,362, respectively; 8,697,071, respectively; 8,652,474, respectively; 8,652,466, respectively; 8,609,095, respectively; 8,512,967, respectively; 8,349,585, respectively; 8,241,630, respectively; 8,217,147, respectively; 8,192,737, respectively; 7,879,325, respectively; 7,850,966, respectively; 7,560,111, respectively; 7,435,797, respectively; 7,306,801, respectively; 6,399,063, respectively; 6,387,371; 6,165,464, respectively; 5,772,997, respectively; 5,770,195, respectively; 5,725,856, respectively; 5,720,954, respectively; 5,677,171.
In some embodiments, the anti-HER 2 antibody or antibody fragment (e.g., antigen-binding fragment) comprises a VH domain having the amino acid sequence of any of the VH domains described in table 8. Other suitable anti-HER 2 antibodies or antibody fragments (e.g., antigen-binding fragments) may include amino acids that have been mutated but are at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical in the VH domain to the VH region depicted in the sequences described in table 8. In certain embodiments, the disclosure also provides antibodies or antibody fragments (e.g., antigen-binding fragments) that specifically bind HER2, wherein the antibodies or antibody fragments (e.g., antigen-binding fragments) comprise a VHCDR having the amino acid sequence of any one of the VH CDRs listed in table 8. In particular embodiments, the invention provides antibodies or antibody fragments (e.g., antigen-binding fragments) that specifically bind HER2, the antibodies or antibody fragments comprising (or, optionally, consisting of) one, two, three, four, five or more VH CDRs having the amino acid sequence of any of the VH CDRs listed in table 8.
In some embodiments, an anti-HER 2 antibody or antibody fragment (e.g., antigen-binding fragment) comprises a VL domain having the amino acid sequence of any of the VL domains described in table 8. Other suitable anti-HER 2 antibodies or antibody fragments (e.g., antigen-binding fragments) can include amino acids that have been mutated but have at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity in the VL domain to the VL region depicted in the sequences described in table 8. The disclosure also provides antibodies or antibody fragments (e.g., antigen-binding fragments) that specifically bind HER2, the antibodies or antibody fragments (e.g., antigen-binding fragments) comprising a VL CDR having the amino acid sequence of any one of the VL CDRs listed in table 8. In particular, the invention provides antibodies or antibody fragments (e.g., antigen-binding fragments) that specifically bind HER2, the antibodies or antibody fragments comprising (or, optionally, consisting of) one, two, three, or more VL CDRs having the amino acid sequence of any of the VL CDRs listed in table 8.
TABLE 8 sequences of exemplary anti-HER 2 monoclonal antibodies
Figure BDA0002340450700005061
Figure BDA0002340450700005071
Figure BDA0002340450700005081
Figure BDA0002340450700005091
Figure BDA0002340450700005121
Figure BDA0002340450700005131
Figure BDA0002340450700005141
Figure BDA0002340450700005151
Other anti-HER 2 antibodies or antibody fragments (e.g., antigen-binding fragments) disclosed herein include amino acids that have been mutated but have at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity in the CDR regions to the CDR regions depicted in the sequences depicted in table 8. In some embodiments, it comprises a mutant amino acid sequence in which no more than 1,2,3, 4, or5 amino acids in the CDR regions have been mutated when compared to the CDR regions depicted in the sequences described in table 8.
Also provided herein are nucleic acid sequences encoding VH, VL, full length heavy chain, and full length light chain of antibodies and antigen-binding fragments thereof that specifically bind to HER2 (e.g., the nucleic acid sequences in table 8). Such nucleic acid sequences may be optimized for expression in mammalian cells.
Other anti-HER 2 antibodies disclosed herein include those antibodies in which the amino acids or nucleic acids encoding the amino acids have been mutated but are at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to the sequences described in table 8. In some embodiments, the antibody or antigen-binding fragment thereof comprises a mutated amino acid sequence in which no more than 8,2, 3,4, or5 amino acids have been mutated in the variable region when compared to the variable region depicted in the sequences described in table 1, but while maintaining substantially the same therapeutic activity.
As each provided antibody binds to HER2, VH, VL, full-length light chain and full-length heavy chain sequences (amino acid sequences and nucleotide sequences encoding the amino acid sequences) may be "mixed and matched" to produce other HER2 binding antibodies disclosed herein. Such "mixed and matched" HER2 binding antibodies can be tested using binding assays known in the art (e.g., ELISA, assays described in the examples). When the chains are mixed and matched, the VH sequences from a particular VH/VL pairing should be replaced with structurally similar VH sequences. The full-length heavy chain sequence from a particular full-length heavy chain/full-length light chain pairing should be replaced with a structurally similar full-length heavy chain sequence. VL sequences from a particular VH/VL pairing should be replaced with structurally similar VL sequences. The full-length light chain sequence from a particular full-length heavy chain/full-length light chain pairing should be replaced with a structurally similar full-length light chain sequence.
Accordingly, in one embodiment, the present invention provides an isolated monoclonal antibody, or antigen binding region thereof, having: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO 7; and a light chain variable region comprising the amino acid sequence of SEQ ID NO 17; wherein the antibody specifically binds HER 2. In another embodiment, the invention provides (i) an isolated monoclonal antibody having: a full-length heavy chain comprising the amino acid sequence of any one of SEQ id nos 9, 21,23, 30, or 32; and a full length light chain comprising the amino acid sequence of any one of SEQ ID NOs 19 or 34; or (ii) a functional protein comprising an antigen-binding portion thereof.
In another embodiment, the disclosure provides HER2 binding antibodies comprising heavy chain CDR1, CDR2 and CDR3 and light chain CDR1, CDR2 and CDR3 as described in table 8, or a combination thereof. The amino acid sequence of the VH CDR1 of the antibody is shown in SEQ ID NOs 1,4 and 6. The amino acid sequence of VH CDR2 of the antibody is shown in SEQ ID NO 2 and 5. The amino acid sequence of VHCDR3 of the antibody is shown in SEQ ID NO. 3. The amino acid sequence of the VL CDR1 of the antibody is shown in SEQ ID NO 11 and 14. The amino acid sequence of the VL CDR2 of the antibody is shown in SEQ ID NO 12 and 15. The amino acid sequence of the VL CDR3 of the antibody is shown in SEQ ID NO 13 and 16.
Whereas each of these antibodies can bind to HER2 and antigen binding specificity is provided primarily by the CDR1, CDR2, and CDR3 regions, the VH CDR1, CDR2, and CDR3 sequences and the VL CDR1, CDR2, and CDR3 sequences can be "mixed and matched" (i.e., the CDRs from different antibodies can be mixed and matched), but each antibody must contain VH CDR1, CDR2, and CDR3 and VL CDR1, CDR2, and CDR3 to produce the other HER2 binding molecules disclosed herein. Such "mixed and matched" HER2 binding antibodies can be tested using binding assays known in the art and those described in the examples (e.g., ELISA). When VH CDR sequences are mixed and matched, the CDR1, CDR2, and/or CDR3 sequences from a particular VH sequence should be replaced with one or more structurally similar CDR sequences. Likewise, when mixing and matching VL CDR sequences, the CDR1, CDR2, and/or CDR3 sequences from a particular VL sequence should be replaced with one or more structurally similar CDR sequences. It will be readily apparent to one of ordinary skill that novel VH and VL sequences can be generated by substituting one or more VH and/or VL CDR region sequences having structurally similar sequences from the CDR sequences shown herein for the monoclonal antibodies of the disclosure.
Accordingly, the present disclosure provides an isolated monoclonal antibody, or antigen binding region thereof, comprising: a heavy chain CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs 1,4, and 6; a heavy chain CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs 2 and 5; a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO. 3; a light chain CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs 11 and 14; a light chain CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs 12 and 15; and a light chain CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs 13 and 16; wherein the antibody specifically binds HER 2.
In certain embodiments, the antibody that specifically binds HER2 is an antibody or antibody fragment (e.g., an antigen-binding fragment) described in table 8.
In some embodiments, an antibody that specifically binds human HER2 comprises: heavy chain complementarity determining region 1(HCDR1) comprising the amino acid sequence of SEQ ID NO: 1; heavy chain complementarity determining region 2(HCDR2) comprising the amino acid sequence of SEQ ID NO: 2; heavy chain complementarity determining region 3(HCDR3) comprising the amino acid sequence of SEQ ID NO: 3; light chain complementarity determining region 1(LCDR1) comprising the amino acid sequence of SEQ ID NO: 11; light chain complementarity determining region 2(LCDR2) comprising the amino acid sequence of SEQ ID NO. 12; and light chain complementarity determining region 3(LCDR3) comprising the amino acid sequence of SEQ ID NO: 13.
In some embodiments, an antibody that specifically binds human HER2 comprises: HCDR1 comprising the amino acid sequence of SEQ ID NO 4; HCDR2 comprising the amino acid sequence of SEQ ID NO 5; HCDR3 comprising the amino acid sequence of SEQ ID NO. 3; LCDR1 comprising the amino acid sequence of SEQ ID NO. 14; LCDR2 comprising the amino acid sequence of SEQ ID NO. 15; and LCDR3 comprising the amino acid sequence of SEQ ID NO: 16.
In some embodiments, an antibody that specifically binds human HER2 comprises: the heavy chain variable region comprising the amino acid sequence of SEQ ID NO. 7 and the light chain variable region comprising the amino acid sequence of SEQ ID NO. 17.
In some embodiments, an antibody that specifically binds human HER2 comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO 9, and a light chain comprising the amino acid sequence of SEQ ID NO 19.
In some embodiments, an antibody that specifically binds human HER2 comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO 21 and a light chain comprising the amino acid sequence of SEQ ID NO 19.
In some embodiments, an antibody that specifically binds human HER2 comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO. 23, and a light chain comprising the amino acid sequence of SEQ ID NO. 19.
In some embodiments, an antibody that specifically binds human HER2 comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO. 30, and a light chain comprising the amino acid sequence of SEQ ID NO. 19.
In some embodiments, an antibody that specifically binds human HER2 comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO. 32, and a light chain comprising the amino acid sequence of SEQ ID NO. 19.
In some embodiments, an antibody that specifically binds human HER2 comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO. 35, and a light chain comprising the amino acid sequence of SEQ ID NO. 19.
In some embodiments, an antibody that specifically binds human HER2 comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO. 23, and a light chain comprising the amino acid sequence of SEQ ID NO. 34.
In some embodiments, the disclosure provides an antibody or antibody fragment (e.g., an antigen-binding fragment) that specifically binds to an epitope in human HER 2. In some embodiments, the disclosure provides an antibody or antibody fragment (e.g., an antigen-binding fragment) that specifically binds to an epitope in human HER2, wherein the epitope comprises one or more of residues 557-. In some embodiments, the disclosure provides an antibody or antibody fragment (e.g., antigen-binding fragment) that specifically binds to an epitope in human HER2, wherein the epitope comprises one or more of residues 245-333 of SEQ ID NO: 26. In some embodiments, the disclosure provides an antibody or antibody fragment (e.g., antigen binding fragment) that specifically binds to an epitope in human HER2, wherein the epitope comprises one or more of the following residues of SEQ ID NO: 26: his245, Val 286, Ser 288, Leu 295, His 296 or Lys 311.
Once the desired epitope on the antigen has been determined, it is possible to generate antibodies against the epitope, for example using the techniques described in the present invention. Alternatively, in the discovery process, the production and characterization of antibodies can elucidate information about the desired epitope. Based on this information, antibodies can then be competitively screened to bind to the same epitope. The approach to achieve this is to conduct cross-competition studies to find antibodies that compete for binding to each other, e.g., antibodies compete for binding to antigen. High throughput methods for "binning" these antibodies based on cross-competition of the antibodies are described in international patent application No. WO 2003/48731. As understood by those skilled in the art, virtually anything that an antibody can specifically bind can be an epitope. An epitope may comprise those residues to which an antibody binds.
Antibodies to P-cadherin
In some embodiments disclosed herein, an antibody conjugate comprises an antibody or fragment thereof (e.g., an antigen-binding fragment thereof) that specifically binds human P-cadherin (an anti-Pcad antibody). Antibodies or antibody fragments (e.g., antigen-binding fragments) of the invention include, but are not limited to, human monoclonal antibodies or fragments thereof isolated as described in the examples.
The invention also provides anti-P-cadherin antibodies or antigen-binding fragments comprising modifications in the constant region of the heavy chain, the light chain, or both the heavy and light chains, wherein particular amino acid residues have been mutated to cysteine, also referred to herein as "cysmabs" or "Cys" antibodies. As discussed herein, a drug moiety can be conjugated to a cysteine residue on an antibody in a site-specific manner and to control the number of drug moieties ("DAR-controlled"). Cysteine modifications of antibodies for the purpose of site-specific controlled immunoconjugates are disclosed, for example, in WO2014/124316, which is incorporated herein by reference in its entirety.
In some embodiments, the anti-P-cadherin antibody has been modified at positions 152 and 375 of the heavy chain, wherein positions are defined according to the EU numbering system. That is, the modifications are E152C and S375C. In other embodiments, the anti-P-cadherin antibody has been modified at position 360 of the heavy chain and position 107 of the kappa light chain, wherein the positions are defined according to the EU numbering system. Namely, the modifications are K360C and K107C. For example, the positions of these mutations are illustrated in the context of the human IgG1 heavy chain and kappa light chain constant regions in table 8A. Cysteine modifications from the wild-type sequence are underlined throughout table 8A.
The invention also provides nucleic acid sequences encoding the VH, VL, full length heavy chain and full length light chain of an antibody that specifically binds to P-cadherin. Such nucleic acid sequences may be optimized for expression in mammalian cells.
TABLE 8A. examples of anti-P-cadherin antibodies
Figure BDA0002340450700005201
Figure BDA0002340450700005211
Figure BDA0002340450700005221
Figure BDA0002340450700005231
Figure BDA0002340450700005241
Figure BDA0002340450700005261
Figure BDA0002340450700005281
Figure BDA0002340450700005282
Figure BDA0002340450700005301
Figure BDA0002340450700005311
Figure BDA0002340450700005312
Figure BDA0002340450700005331
Figure BDA0002340450700005341
Figure BDA0002340450700005342
Figure BDA0002340450700005351
Figure BDA0002340450700005361
Figure BDA0002340450700005381
Figure BDA0002340450700005391
Figure BDA0002340450700005401
Modification of framework or Fc regions
The antibodies and antibody conjugates disclosed herein may comprise modified antibodies or antigen-binding fragments thereof comprising modifications to framework residues within the VH and/or VL, for example to improve the properties of the antibody/antibody conjugate.
In some embodiments, such framework modifications are made to reduce the immunogenicity of the antibody. For example, one approach is to "back mutate" one or more framework residues into the corresponding germline sequence. Such residues can be identified by comparing the antibody framework sequences to the germline sequences from which the antibody was derived. In order to "match" the framework region sequences to the desired germline configuration, residues can be "back mutated" to the corresponding germline sequence by, for example, site-directed mutagenesis. Such "back-mutated" antibodies are also intended to be encompassed by the present invention.
Another type of framework modification includes mutating one or more residues within the framework regions or even within one or more CDR regions to remove T cell epitopes, thereby reducing the potential immunogenicity of the antibody. This method is also referred to as "deimmunization" and is described in further detail in U.S. patent publication No. 20030153043 to Carr et al.
In addition to or as an alternative to modifications made within the framework or CDR regions, the antibodies disclosed herein can be engineered to include modifications within the Fc region, typically in order to alter one or more functional properties of the antibody, such as serum half-life, complement binding, Fc receptor binding and/or antigen-dependent cellular cytotoxicity.
Furthermore, the antibodies disclosed herein can be chemically modified (e.g., one or more chemical moieties can be attached to the antibody) or modified to alter the glycosylation thereof, thereby again altering one or more functional properties of the antibody. Each of these embodiments is described in more detail below.
In one embodiment, the hinge region of CH1 is modified such that the number of cysteine residues in the hinge region is altered, e.g., increased or decreased. The process is further described in U.S. Pat. No. 5,677,425 to Bodmer et al. The number of cysteine residues in the CH1 hinge region is altered, for example, to facilitate assembly of the light and heavy chains or to increase or decrease the stability of the antibody.
In some embodiments, antibodies or antibody fragments (e.g., antigen-binding fragments) useful in the antibody conjugates disclosed herein include modified or engineered antibodies, e.g., antibodies modified to introduce one or more cysteine residues as a site of conjugation to a drug moiety (Junutula JR, et al: Nat Biotechnol [ Nature Biotechnology ]2008,26: 925-932). In one embodiment, the invention provides a modified antibody or antibody fragment thereof comprising a substitution of one or more amino acids with cysteine at a position described herein. The sites for cysteine substitution are in the constant region of the antibody and are therefore applicable to a variety of antibodies, and are selected to provide stable and homogeneous conjugates. The modified antibody or fragment may have two or more cysteine substitutions, and these substitutions may be used in combination with other antibody modification and conjugation methods as described herein. Methods for inserting cysteines at specific positions of antibodies are known in the art, see, e.g., Lyons et al, (1990) Protein Eng. [ Protein engineering ],3:703-708, WO 2011/005481, WO2014/124316, WO 2015/138615. In certain embodiments, the modified antibody or antibody fragment comprises a substitution of one or more amino acids with cysteine at a position on its constant region selected from the group consisting of: positions 117, 119, 121, 124, 139, 152, 153, 155, 157, 164, 169, 171, 174, 189, 205, 207, 246, 258, 269, 274, 286, 288, 290, 292, 293, 320, 322, 326, 333, 334, 335, 337, 344, 355, 360, 375, 382, 390, 392, 398, 400 and 422 of the heavy chain of the antibody or antibody fragment, and wherein these positions are numbered according to the EU system. In some embodiments, the modified antibody or antibody fragment comprises a substitution of one or more amino acids with cysteine on its constant region at a position selected from the group consisting of: positions 107, 108, 109, 114, 129, 142, 143, 145, 152, 154, 156, 159, 161, 165, 168, 169, 170, 182, 183, 197, 199, and 203 of a light chain of the antibody or antibody fragment, wherein positions are numbered according to the EU system, and wherein the light chain is a human kappa light chain. In certain embodiments, the modified antibody or antibody fragment thereof comprises a combination of substitutions of two or more amino acids with cysteine on its constant region, wherein the combination comprises a substitution at position 375 of the antibody heavy chain, position 152 of the antibody heavy chain, position 360 of the antibody heavy chain, or position 107 of the antibody light chain, and wherein positions are numbered according to the EU system. In certain embodiments, the modified antibody or antibody fragment thereof comprises a substitution of one amino acid with cysteine on its constant region, wherein the substitution is position 375 of the antibody heavy chain, position 152 of the antibody heavy chain, position 360 of the antibody heavy chain, position 107 of the antibody light chain, position 165 of the antibody light chain, or position 159 of the antibody light chain and wherein positions are numbered according to the EU system, and wherein the light chain is a kappa chain.
In particular embodiments, the modified antibody or antibody fragment thereof comprises a combination of substitution of two amino acids with cysteine on its constant region, wherein the modified antibody or antibody fragment thereof comprises cysteines at positions 152 and 375 of the antibody heavy chain, wherein these positions are numbered according to the EU system.
In other specific embodiments, the modified antibody or antibody fragment thereof comprises a substitution of one amino acid with cysteine at position 360 of the heavy chain of the antibody, and wherein position is numbered according to the EU system.
In other specific embodiments, the modified antibody or antibody fragment thereof comprises a substitution of one amino acid with cysteine at position 107 of the antibody light chain and wherein position is numbered according to the EU system, and wherein the light chain is a kappa chain.
In further examples, antibodies or antibody fragments (e.g., antigen-binding fragments) useful in the antibody conjugates disclosed herein include modified or engineered antibodies, such as antibodies modified to introduce one or more other reactive amino acids (other than cysteine) including Pcl (pyrroline-carboxy-lysine), pyrrolysine, peptide tags (such as S6, A1, and ybbR tags) and non-natural amino acids, in place of at least one amino acid of the native sequence, providing a reaction site on the antibody or antigen-binding fragment for conjugation with a drug moiety of formula (I) or its subformula (for example, the antibody or antibody fragment may be modified to incorporate Pcl or pyrrolysine (W.Ou et al, (W.Ou) PNAS [ ProAS [ Proc. Acad. Sci ]108(26), 10437-10442; WO 2014124258) or non-natural amino acids (J.Y.upu et al, Proc Natl Acadsi S A [ AcadSci ] A [ USA ] 120, 20137, 20142, WO 2014124258) or the non-natural amino acids (J.Y.201u., WO 120, 11, 35, for the methods for conjugation with a Biokura, 7, 12,7, 12, for the methods for the use of the conjugation of the methods for the conjugation of natural enzymes for the conjugation of the biological conjugates of the methods for the conjugation of the biological chemistry of the methods of the peptide for the methods of the conjugation of the biological chemistry of the methods of the peptide for the methods of conjugation of the methods of.
In another embodiment, the Fc hinge region of the antibody is mutated to reduce the biological half-life of the antibody. More specifically, one or more amino acid mutations are introduced into the CH2-CH3 domain interface region of the Fc hinge fragment such that the antibody has impaired staphylococcal protein a (SpA) binding relative to native Fc hinge domain SpA binding. The method is described in further detail in U.S. Pat. No. 6,165,745 to Ward et al.
In yet other embodiments, the Fc region is altered by substituting at least one amino acid residue with a different amino acid residue to alter the effector function of the antibody. For example, one or more amino acids may be substituted with different amino acid residues such that the antibody has an altered affinity for the effector ligand, but retains the antigen binding ability of the parent antibody. The affinity-altering effector ligand may be, for example, an Fc receptor or the C1 component of complement. Such methods are described, for example, in U.S. Pat. Nos. 5,624,821 and 5,648,260 to Winter et al.
In another example, one or more amino acids selected from the group consisting of amino acid residues may be substituted with a different amino acid residue such that the antibody has altered C1q binding and/or reduced or eliminated Complement Dependent Cytotoxicity (CDC). Such methods are described, for example, in U.S. Pat. No. 6,194,551 to Idusogene et al.
In another embodiment, one or more amino acid residues are altered, thereby altering the ability of the antibody to fix complement. This method is described, for example, in PCT publication WO 94/29351 to Bodmer et al. Allotypic amino acid residues include, but are not limited to: the constant regions of the heavy chains of the IgG1, IgG2, and IgG3 subclasses, and the constant region of the light chain of the kappa isotype, as described in Jefferis et al, MAbs.1:332-338 (2009).
In additional embodiments, the Fc region is modified to "silence" the effector function of the antibody, e.g., reduce or eliminate the ability of the antibody to mediate antibody-dependent cellular cytotoxicity (ADCC) and/or antibody-dependent cellular phagocytosis (ADCP). This can be achieved, for example, by introducing mutations in the Fc region of the antibody. Such mutations have been described in the art: LALA and N297A (Strohl, W.,2009, Curr, Opin, Biotechnol. [ Current Biotechnology View ] vol.20(6): 685-; and D265A (Baudino et al, 2008, j. immunol. [ journal of immunology ]181: 6664-69; Strohl, w., supra). Examples of silent Fc IgG1 antibodies include so-called LALA mutants comprising L234A and L235A mutations in the IgG1 Fc amino acid sequence. Another example of a silent IgG1 antibody comprises a D265A mutation. Another silent IgG1 antibody comprises an N297A mutation that results in an aglycosylated/aglycosylated antibody.
In yet another embodiment, the Fc region is modified to increase the ability of the antibody to mediate antibody-dependent cellular cytotoxicity (ADCC) and/or antibody-dependent cellular phagocytosis (ADCP), for example, by modifying one or more amino acid residues to increase the affinity of the antibody for an activating fey receptor, or to decrease the affinity of the antibody for an inhibiting fey receptor. Human activating Fc γ receptors include Fc γ RIa, Fc γ RIIa, Fc γ RIIIa and Fc γ RIIIb, and human inhibiting Fc γ receptor includes Fc γ RIIb. Such a process is described, for example, by Presta in PCT publication WO 00/42072. Furthermore, binding sites for Fc γ Rl, Fc γ RII, Fc γ RIII and FcRn have been mapped on human IgG1 and variants with improved binding have been described (see Shield et al, J.biol.chem. [ J.Biol.J. [ J.Biol ]276:6591-6604, 2001). Optimization of Fc-mediated effector functions, such as enhanced ADCC/ADCP function, has been described for monoclonal antibodies (see Strohl, w.r., Current Opinion in Biotechnology [ Current Biotechnology view ] 2009; 20: 685-. In some embodiments, the antibody conjugate comprises an immunoglobulin heavy chain comprising a mutation or combination of mutations that confer enhanced ADCC/ADCP function, e.g., one or more mutations selected from G236A, S239D, F243L, P247I, D280H, K290S, R292P, S298A, S298D, S298V, Y300L, V305I, a330L, I332E, E333A, K334A, a339D, a339Q, a339T, P396L (all positions by EU numbering).
In another embodiment, the Fc region is modified to increase the ability of the antibody to mediate ADCC and/or ADCP, for example, by modifying one or more amino acids to increase the affinity of the antibody for an activating receptor that typically does not recognize the parent antibody (e.g., Fc α RI.) the methods are described, for example, in Borhook et al, mAbs.7(4): 743-.
In yet another embodiment, glycosylation of the antibody is modified. For example, antibodies can be made that are aglycosylated (i.e., the antibodies lack glycosylation). Glycosylation can be altered, for example, to increase the affinity of an antibody for an "antigen". Such carbohydrate modifications can be achieved, for example, by altering one or more glycosylation sites within the antibody sequence. For example, one or more amino acid substitutions may be made which result in the elimination of one or more variable region framework glycosylation sites, thereby eliminating glycosylation at such sites. This aglycosylation may increase the affinity of the antibody for the antigen. Such methods are described, for example, in U.S. Pat. Nos. 5,714,350 and 6,350,861 to Co et al.
Additionally or alternatively, antibodies with altered glycosylation patterns, such as low fucosylated antibodies with reduced amounts of fucosyl residues or antibodies with increased bisecting GlcNac structures, have been demonstrated that such altered glycosylation patterns increase the ADCC capacity of antibodies such carbohydrate modification can be achieved by expressing the antibodies, for example, in host cells with altered glycosylation mechanisms, cells with altered glycosylation mechanisms have been described in the art and can be used as host cells in which recombinant antibodies of the invention are expressed, thereby producing antibodies with altered glycosylation, for example, EP1,176,195 to Hang et al describes cell lines with a functionally disrupted FUT8 gene encoding fucosyltransferase such that antibodies expressed in such cell lines exhibit low glycosylation.Presta in PCT publication WO 03/035835 describes CHO cell line Lecl3 cells which have a reduced capacity for attaching fucose-linked carbohydrates Asn (297) and also results in the engineered fucose structures of antibodies expressed in host cells such that antibodies expressed in PCT publication WO 277, et al, (see also for the Biotech. modified antibodies) 27, which are expressed in Biotech. Na + -27 et al, (see also for the naturally engineered fucosylation protein engineering lines 36733, see PCT publication WO 26: Biotech. β, et al, (see also for the publication No. (see Biotech. 3627) for the modified antibodies, Biotech. β, see Biotech. β, et al, (see Biotech. β for the publication No.: see the publication No.: β et al, [ see Biotech. β for the publication No.: see Nattokyo-27 et al,: why the publication No.: see Nattokyo-27 for the biological engineering of the publication No.: see Nattokyo-7 et al.
In another embodiment, the antibody is modified to increase its biological half-life. Various methods may be employed. For example, one or more of the following mutations may be introduced: such as T252L, T254S, T256F described by Ward in U.S. patent No. 6,277,375. Alternatively, to increase biological half-life, antibodies may be altered within the CH1 or CL regions to contain salvage receptor binding epitopes taken from the two loops of the CH2 domain of the Fc region of IgG, as described in U.S. patent nos. 5,869,046 and 6,121,022 to Presta et al.
Production of antibodies
Antibodies and antibody fragments (e.g., antigen-binding fragments) thereof can be produced by any means known in the art, including but not limited to recombinant expression, chemical synthesis, and enzymatic digestion of antibody tetramers, while full-length monoclonal antibodies can be obtained, for example, by hybridoma or recombinant production. Recombinant expression may be from any suitable host cell known in the art, such as mammalian host cells, bacterial host cells, yeast host cells, insect host cells, and the like.
Also provided herein are polynucleotides encoding the antibodies described herein, e.g., polynucleotides encoding the heavy or light chain variable regions or segments comprising complementarity determining regions as described herein. In some embodiments, the polynucleotide encoding the heavy chain variable region has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% nucleic acid sequence identity to the polynucleotide of SEQ ID No. 8. In some embodiments, the polynucleotide encoding the light chain variable region has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% nucleic acid sequence identity to the polynucleotide encoding the antibody.
In some embodiments, the polynucleotide encoding the heavy chain has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% nucleic acid sequence identity to a polynucleotide as disclosed herein. In some embodiments, the polynucleotide encoding the light chain has at least 85%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% nucleic acid sequence identity to a polynucleotide as disclosed herein.
Some polynucleotides disclosed herein encode the variable regions of an anti-HER 2 antibody. Some of the polynucleotides disclosed herein encode the variable and constant regions of an anti-HER 2 antibody. Some polynucleotide sequences encode polypeptides comprising the variable regions of the heavy and light chains of an anti-HER 2 antibody. Some polynucleotides encode two polypeptide segments that are substantially identical to the variable regions of the heavy and light chains, respectively, of any of the anti-HER 2 antibodies disclosed herein.
Some polynucleotides disclosed herein encode the variable regions of anti-P-Cad antibodies. Some of the polynucleotides disclosed herein encode the variable and constant regions of an anti-P-Cad antibody. Some polynucleotide sequences encode polypeptides comprising the variable regions of the heavy and light chains of an anti-P-Cad antibody. Some polynucleotides encode two polypeptide segments that are substantially identical to the variable regions of the heavy and light chains, respectively, of any of the anti-P-cad antibodies disclosed herein.
The polynucleotide sequence may be generated by de novo solid phase DNA synthesis or by PCR mutagenesis of an existing sequence encoding the antibody or binding fragment thereof. Direct chemical synthesis of nucleic acids can be accomplished by methods known in the art, such as the phosphodiester method of Narang et al, meth.enzymol. [ methods of enzymology ]68:90,1979; the phosphodiester method of Brown et al, meth.enzymol. [ methods of enzymology ]68:109,1979; the diethylphosphoramidite method of Beaucage et al, tetra.Lett. [ tetrahedron letters ],22:1859,1981; and U.S. Pat. No. 4,458,066. The introduction of mutations into polynucleotide sequences by PCR can be carried out as described in, for example, PCR Technology: Principles and applications for DNA Amplification [ PCR Technology: principle and application of DNA amplification ], h.a. erlich (editors), Freeman Press [ frieman Press ], new york city, new york state, 1992; PCR Protocols A Guide methods and Applications [ PCR protocol: methods and application guidelines ], Innis et al, (eds.), academic Press, San Diego, Calif., 1990; mattila et al, nucleic acids Res. [ nucleic acids research ]19:967,1991; and Eckert et al, PCR Methods and Applications [ PCR Methods and Applications ]1:17, 1991.
Expression vectors and host cells for producing the antibodies described herein are also provided. A variety of expression vectors can be used to express polynucleotides encoding antibody chains or binding fragments. Both viral-based vectors and non-viral expression vectors can be used to produce antibodies in mammalian host cells.
Non-viral vectors and systems include plasmids, episomal vectors (typically with expression cassettes for expression of proteins or RNA), and human artificial chromosomes (see, e.g., Harrington et al, Nat Genet. [ Nature genetics ]15:345,1997). For example, non-viral vectors that may be used to express polynucleotides and polypeptides in mammalian (e.g., human) cells include pThioHis A, B and C, pCDNADM 3.1/His, pEBVHis A, B and C (Invitrogen, san Diego, Calif.), MPSV vectors and many other vectors known in the art for the expression of other proteins. Useful viral vectors include retroviral, adenoviral, adeno-associated viral, herpes virus based vectors, SV40, papilloma virus, HBPEB virus, vaccinia virus vectors, and Semliki Forest Virus (SFV) based vectors. See, Brent et al, supra; smith, annu.rev.microbiol. [ microbiological annual review ]49:807,1995; and Rosenfeld et al, Cell [ Cell ]68:143,1992.
The choice of expression vector will depend on the intended host cell in which the vector is to be expressed. Typically, expression vectors contain a promoter and other regulatory sequences (e.g., enhancers) operably linked to a polynucleotide encoding an antibody chain or fragment. In some embodiments, an inducible promoter is employed to prevent expression of the inserted sequence under conditions other than inducing conditions. Inducible promoters include, for example, arabinose, lacZ, metallothionein promoters, or heat shock promoters. The culture of the transformed organism can be expanded under non-inducing conditions without biasing the population of host cells to better tolerate the coding sequences of their expression products. In addition to the promoter, other regulatory elements may be required or desired for efficient expression of the antibody chain or fragment. The elements typically include an ATG initiation codon and an adjacent ribosome binding site or other sequence. Furthermore, expression efficiency can be increased by including enhancers suitable for the cell system in use (see, e.g., Scharf et al, ResultsProbl. cell Differ. [ results and problems in cell differentiation ]20:125,1994; and Bittner et al, meth. enzymol. [ methods of enzymology ],153:516, 1987). For example, the SV40 enhancer or the CMV enhancer may be used to increase expression in a mammalian host cell.
The expression vector may also provide a secretion signal sequence position to form a fusion protein with the polypeptide encoded by the inserted antibody sequence. More typically, the inserted antibody sequence is linked to a signal sequence prior to inclusion in the vector. Vectors used to receive sequences encoding antibody light and heavy chain variable domains sometimes also encode constant regions or portions thereof. Such vectors allow the expression of variable regions as fusion proteins with constant regions, resulting in the production of whole antibodies or fragments thereof. Typically, such constant regions are human.
In these prokaryotic hosts, expression vectors can also be prepared, which generally contain expression control sequences (e.g., origins of replication) compatible with the host cell.
In some specific embodiments, mammalian host cells are used to express and produce the polypeptides of the present disclosure. For example, they may be hybridoma cell lines expressing endogenous immunoglobulin genes (e.g., myeloma hybridoma clones) or mammalian cell lines containing exogenous expression vectors (e.g., SP2/0 myeloma cells). These include any normal dying or normal or abnormal immortalized animal or human cell. For example, a number of suitable host cell lines capable of secreting intact immunoglobulins have been developed, including various CHO cell lines, Cos cell lines, HeLa cells, myeloma cell lines, transformed B cells, and hybridomas. Expression of polypeptides using mammalian tissue cell cultures is generally discussed, for example, in Winnacker, From Genes to Clones, VCH Publishers, New York City, New York State, 1987. Expression vectors for use in mammalian host cells may comprise expression control sequences such as origins of replication, promoters and enhancers (see, e.g., Queen et al, immunol. rev. [ immunological reviews ]89:49-68,1986), and necessary processing information sites such as ribosome binding sites, RNA splice sites, polyadenylation sites and transcription terminator sequences. Expression vectors typically contain promoters derived from mammalian genes or from mammalian viruses. Suitable promoters may be constitutive, cell type specific, stage specific and/or regulatable. Useful promoters include, but are not limited to, the metallothionein promoter, the constitutive adenovirus major late promoter, the dexamethasone-inducible MMTV promoter, the SV40 promoter, the MRP polIII promoter, the constitutive MPSV promoter, the tetracycline-inducible CMV promoter (e.g., the human CMV immediate early promoter), the constitutive CMV promoter, and promoter-enhancer combinations known in the art.
The method used to introduce the expression vector containing the polynucleotide sequence of interest varies depending on the type of cellular host. For example, calcium chloride transfection is commonly used for prokaryotic cells, while calcium phosphate treatment or electroporation may be used for other cellular hosts (see, generally, Sambrook et al, supra). Other methods include, for example, electroporation, calcium phosphate treatment, liposome-mediated transformation, injection and microinjection, ballistic methods, virosomes, immunoliposomes, polycations nucleic acid conjugates, naked DNA, artificial virions, fusions with the herpes virus structural protein VP22 (Elliot and O' Hare, Cell [ Cell ]88:223,1997), agent-enhanced DNA uptake, and ex vivo transduction. For long-term high-yield production of recombinant proteins, stable expression is often desired. For example, cell lines stably expressing antibody chains or binding fragments can be prepared using expression vectors disclosed herein that contain viral origins of replication or endogenous expression elements and selectable marker genes. After introducing the vector, the cells can be grown in enriched medium for 1-2 days before they are switched to selective medium. The purpose of the selectable marker is to confer resistance to selection and its presence allows the growth of cells that successfully express the introduced sequence in a selective medium. Resistant, stably transfected cells can be propagated using tissue culture techniques appropriate to the cell type.
Therapeutic uses and methods of treatment
The antibody conjugates provided are useful in a variety of applications, including but not limited to the treatment of cancer. In certain embodiments, the antibody conjugates provided herein are useful for inhibiting tumor growth, reducing tumor volume, inducing differentiation, and/or reducing the tumorigenicity of a tumor. The method of use may be in vitro, ex vivo or in vivo.
In some embodiments, provided herein are methods of treating, preventing, or ameliorating a disease, e.g., cancer, in a subject, e.g., a human patient, in need thereof by administering to the subject any of the antibody conjugates described herein. Also provided is the use of an antibody conjugate of the invention for treating or preventing a disease in a subject (e.g., a human patient). Further provided is the use of the antibody conjugates in the treatment or prevention of a disease in a subject. In some embodiments, there is provided an antibody conjugate for use in the manufacture of a medicament for treating or preventing a disease in a subject. In certain embodiments, the disease treated with the antibody conjugate is cancer.
In one aspect, the immunoconjugates described herein are useful for treating solid tumors. Examples of solid tumors include malignancies of various organ systems, such as sarcomas, adenocarcinomas, blast cell carcinomas, and carcinomas, such as those affecting the liver, lungs, breast, lymph, the biliary tract (e.g., colon), urogenital tract (e.g., kidney, urothelial cells), prostate, and pharynx. Adenocarcinoma includes malignant tumors (e.g., most colon, rectal, renal cell, liver, small cell lung, non-small cell lung, small bowel, and esophageal cancers). In one embodiment, the cancer is melanoma, e.g., advanced melanoma. Examples of other cancers that may be treated include bone, pancreatic, skin, head or neck, cutaneous or intraocular malignant melanoma, uterine, ovarian, rectal, colorectal, anal, peritoneal, gastric (stomatic or gastric cancer), esophageal, salivary gland, testicular, uterine, fallopian tube, endometrial, cervical, vaginal, vulval, penile, glioblastoma, neuroblastoma, cervical, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal, small intestine, endocrine, thyroid, parathyroid, adrenal, soft tissue sarcoma, urinary tract, penile, chronic or acute leukemia (including acute myeloid, chronic myeloid, acute lymphoblastic, chronic lymphoblastic, solid tumors in children), cervical cancer, cervical, Lymphocytic lymphomas, bladder cancer, kidney or ureter cancer, renal pelvis cancer, central nervous system tumors (CNS), primary CNS lymphomas, tumor angiogenesis, spinal axis tumors, brain stem glioma, pituitary adenoma, kaposi's sarcoma, neuroendocrine tumors (including carcinoid tumors, gastrinomas, and islet cell cancers), mesothelioma, schwannoma (including acoustic neuroma), meningioma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers (including asbestos-induced cancers), and combinations thereof.
In another aspect, the immunoconjugates described herein can be used to treat a hematologic cancer. Hematologic cancers include leukemias, lymphomas, and malignant lymphoproliferative diseases that affect the blood, bone marrow, and lymphatic system.
Leukemias can be classified as acute leukemias and chronic leukemias. Acute leukemias can be further classified as Acute Myelogenous Leukemia (AML) and Acute Lymphocytic Leukemia (ALL). Chronic leukemias include Chronic Myelogenous Leukemia (CML) and Chronic Lymphocytic Leukemia (CLL). Other related conditions include myelodysplastic syndrome (MDS, formerly known as "preleukemia"), which is a diverse collection of hematological conditions that are combined by inefficient production (or dysplasia) of myeloid blood cells and risk of transformation to AML.
Lymphomas are a group of blood cell tumors that develop from lymphocytes. Exemplary lymphomas include non-hodgkin lymphoma and hodgkin lymphoma.
In some embodiments, the cancer is a hematologic cancer, including, but not limited to, for example, acute leukemias, including, but not limited to, B-cell acute lymphoblastic leukemia ("BALL"), T-cell acute lymphoblastic leukemia ("TALL"), Acute Lymphoblastic Leukemia (ALL); one or more chronic leukemias, including but not limited to, for example, Chronic Myelogenous Leukemia (CML), Chronic Lymphocytic Leukemia (CLL); additional hematologic cancers or hematologic conditions include, but are not limited to, e.g., B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell tumors, burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small or large cell follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplastic and myelodysplastic syndromes, non-hodgkin lymphoma, plasmablatic lymphoma, plasmacytoid dendritic cell tumors, fahrenheit (Waldenstrom) macroglobulinemia, and "preleukemia" which is a collection of multiple hematologic conditions linked together by inefficient production (or dysplasia) of myeloid blood cells, and the like. Other diseases associated with tumor antigen expression include, but are not limited to, for example, atypical and/or non-classical cancers, malignancies, pre-cancerous conditions, or proliferative diseases expressing a tumor antigen as described herein. The methods and compositions of the present invention may also be used to treat or prevent metastatic disease of the above-mentioned cancers.
In certain embodiments, the cancer is characterized by cells that express a target tumor antigen to which an antibody or antibody fragment (e.g., antigen-binding fragment) of the antibody conjugate binds. In some embodiments, an immunoconjugate as described herein can comprise an antigen binding domain (e.g., an antibody or antibody fragment) that binds a tumor antigen (e.g., a tumor antigen as described herein). Methods of detecting the presence or overexpression of such tumor antigens are known to those of skill in the art and include, for example, Immunohistocompatibility (IHC) assays using antibodies that specifically bind to tumor antigens, methods of detecting RNA expression levels of tumor antigens, and the like.
The tumor antigen is selected from one OR more of the following targets, receptor tyrosine-protein kinase ERBB (Her/neu), receptor tyrosine-protein kinase ERBB (Her), Epidermal Growth Factor Receptor (EGFR), E-cadherin, P-cadherin, cadherin 6, cathepsin D, estrogen receptor, progesterone receptor, CA125, CA-3, CA-9, P-glycoprotein (CD243), CD179, CD123, CD137, EMR 19A, protein-1 (CLL-1 OR CLL), receptor motif of human tumor epithelial-receptor protein receptor, VEGF-receptor, VEGF-2 receptor, endothelial receptor, VEGF-2 receptor, VEGF-2 receptor, protein receptor motif of human tumor cell line, endothelial receptor protein receptor, VEGF-2 receptor related to epithelial cell line, endothelial cell line, receptor protein receptor, endothelial cell line, VEGF-receptor protein receptor, endothelial receptor, VEGF-receptor protein receptor, VEGF-7, endothelial cell line, receptor, VEGF-7, VEGF-2 receptor, VEGF-receptor, endothelial cell line, VEGF-receptor, VEGF-2 receptor, VEGF-receptor protein receptor, VEGF-2 receptor, VEGF-7, VEGF-receptor protein receptor, VEGF-7, VEGF-receptor, VEGF-7, VEGF-receptor, VEGF-2 receptor, VEGF-protein receptor, VEGF-2 receptor, VEGF-7, VEGF-human granulocyte receptor, VEGF-2 receptor, VEGF-protein receptor, VEGF-protein receptor, VEGF-2 receptor, VEGF-related protein receptor, VEGF-receptor, protein receptor, VEGF-protein receptor, VEGF-related protein receptor, VEGF-protein receptor, VEGF-7, VEGF-2 receptor, VEGF-7, VEGF-receptor, VEGF-2 receptor, VEGF-7, VEGF-related protein receptor, VEGF-2 receptor, VEGF-protein receptor, VEGF-related protein receptor, VEGF-7, protein receptor, VEGF-related protein receptor, VEGF-related protein receptor, VEGF-related protein receptor, VEGF-7, VEGF-receptor, VEGF-2 receptor, VEGF-1 protein receptor, VEGF-2 receptor, VEGF-related protein receptor, VEGF-1 protein receptor, VEGF-2, VEGF-receptor, VEGF-7, VEGF-related protein receptor, VEGF-2, VEGF-related protein receptor, VEGF-motif, VEGF-protein receptor, VEGF-related protein receptor, VEGF-motif, VEGF-related protein receptor, VEGF-1 protein receptor, VEGF-glycoprotein, VEGF-related protein receptor, VEGF-related protein receptor, VEGF-glycoprotein, VEGF-receptor, VEGF-1 protein receptor, VEGF-7, protein receptor, VEGF-related protein receptor, VEGF-2, VEGF-related protein receptor, VEGF-7, VEGF-motif, VEGF-1 protein receptor, VEGF-1, VEGF-motif, VEGF-7, VEGF-related protein receptor, VEGF-7, VEGF-protein receptor, VEGF-motif, VEGF-glycoprotein-motif, VEGF-related protein receptor, VEGF-motif, VEGF-protein receptor, VEGF-motif, VEGF-protein receptor, VEGF-related protein receptor, VEGF-motif, VEGF-protein receptor, VEGF-glycoprotein-protein receptor, VEGF-related protein receptor, VEGF-motif, VEGF-related protein receptor, VEGF-motif, VEGF-related protein receptor, VEGF-motif, VEGF-related protein receptor, VEGF-motif, protein receptor, human-motif, protein receptor, VEGF-motif, human-glycoprotein, human-motif, protein receptor, human-motif, VEGF-motif, protein receptor, human-motif, protein receptor, VEGF-motif, human-motif, VEGF-related protein receptor, human-motif, protein receptor, human-7, VEGF-motif, protein receptor, VEGF-motif, protein receptor, human-motif, protein receptor, VEGF-related protein receptor, VEGF-motif, protein receptor, human-motif, protein receptor, human-motif, protein receptor, VEGF (VEGF-motif, VEGF (VEGF-protein receptor, protein.
Tumor supporting antigens
In some embodiments, an immunoconjugate antigen as described herein comprises an antigen binding domain (e.g., an antibody or antibody fragment) that binds to a tumor-supporting antigen (e.g., a tumor-supporting antigen as described herein).
In some embodiments, the tumor-supporting antigen is an antigen present on stromal cells, antigen presenting cells, or Myeloid Derived Suppressor Cells (MDSCs). Stromal cells may secrete growth factors to promote cell division in the microenvironment. MDSC cells can inhibit T cell proliferation and activation. In some embodiments, the stromal cell antigen is selected from one or more of: bone marrow stromal cell antigen 2(BST2), Fibroblast Activation Protein (FAP), and tenascin. In embodiments, the MDSC antigen is selected from one or more of the following: CD33, CD11b, C14, CD15, and CD66 b. Thus, in some embodiments, the tumor-supporting antigen is selected from one or more of the following: bone marrow stromal cell antigen 2(BST2), Fibroblast Activation Protein (FAP) or tenascin, CD33, CD11b, C14, CD15, and CD66 b.
It is also contemplated that the antibody conjugates described herein may be used to treat a variety of non-malignant diseases or disorders, such as Inflammatory Bowel Disease (IBD), gastrointestinal ulcers, menetier's disease, hepatitis b, hepatitis c, secretory adenoma or protein loss syndrome, renal disease, angiogenic disorders, ocular diseases (e.g., age-related macular degeneration, presumed ocular histoplasmosis syndrome, or age-related macular degeneration), bone-related pathologies (e.g., osteoarthritis, rickets, and osteoporosis), systemic hyperviscosity syndrome, Osler-Weber-lambert disease (osweber-rendisease), chronic obstructive pulmonary disease (chronogenic pulmonary disease), or edema (burns, trauma, radiation, stroke, hypoxia or ischemia), diabetic nephropathy, Paget's disease, photoaging (e.g., caused by ultraviolet radiation of the human skin), benign prostatic hypertrophy, certain microbial infections including microbial pathogens selected from adenovirus, hantavirus, Borrelia burgdorferi (Borrelia burgdorferi), Yersinia spp (Yersinia spp.), and Bordetella pertussis (Bordetella pertussis), thrombi caused by platelet aggregation, reproductive disorders (e.g. endometriosis, ovarian hyperstimulation syndrome, preeclampsia, dysfunctional uterine bleeding or menorrhagia), acute and chronic kidney diseases (including proliferative glomerulonephritis), hypertrophic scarring, endotoxic shock and fungal infections, familial adenomatous polyposis, myelodysplastic syndrome, aplastic anemia, ischemic injury, fibrosis of the lung, kidney or liver, infantile hypertrophic pyloric stenosis, uroocclusive syndrome, psoriatic arthritis.
Methods of administration of such antibody conjugates include, but are not limited to, parenteral (e.g., intravenous) administration, such as injection in a bolus injection or continuous infusion over a period of time, oral administration, intramuscular administration, intratumoral administration, intramuscular administration, intraperitoneal administration, intracerobrospinal administration, subcutaneous administration, intraarticular administration, intrasynovial administration, lymph node injection, or intrathecal administration.
For the treatment of diseases, the appropriate dosage of the antibody conjugates of the invention depends on a variety of factors, such as the type of disease to be treated, the severity and course of the disease, the responsiveness of the disease, previous therapy, patient clinical history, and the like. The antibody conjugate can be administered at once or over a series of treatments for several days to several months or until a cure is achieved or a reduction in the disease state (e.g., a reduction in tumor size) is achieved. Optimal dosing regimens can be calculated from measuring the cumulative amount of drug in the patient and will vary according to the relative potency of the particular antibody conjugate. In some embodiments, the dose is from 0.01mg to 20mg (e.g., 0.01mg, 0.02mg, 0.03mg, 0.04mg, 0.05mg, 0.06mg, 0.07mg, 0.08mg, 0.09mg, 0.1mg, 0.2mg, 0.3mg, 0.4mg, 0.5mg, 0.6mg, 0.7mg, 0.8mg, 0.9mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, or 20mg) per kg body weight, and may be administered once or more a day, week, month, or year. In certain embodiments, the antibody conjugates of the invention are administered once every two weeks or once every three weeks. In certain embodiments, the antibody conjugates of the invention are administered only once. The treating physician can estimate the repeat dosing rate based on the measured residence time and concentration of the drug in the body fluid or tissue.
Combination therapy
In certain instances, the antibody conjugates of the invention can be combined with other therapeutic agents, such as other anti-cancer agents, anti-allergic agents, anti-nausea agents (or antiemetics), analgesic agents, cytoprotective agents, and combinations thereof.
Typical chemotherapeutic agents contemplated for combination therapy include anastrozoleBicalutamideBleomycin sulfate
Figure BDA0002340450700005573
Busulfan medicine
Figure BDA0002340450700005574
Busulfan injection
Figure BDA0002340450700005575
Capecitabine
Figure BDA0002340450700005576
N4-Pentyloxycarbonyl-5-deoxy-5-fluorocytidine, Carboplatin
Figure BDA0002340450700005577
CarmustineChlorambucilCis-platinumCladribine
Figure BDA00023404507000055711
Cyclophosphamide (b)
Figure BDA00023404507000055712
Or
Figure BDA00023404507000055713
) Cytarabine and cytosine arabinoside
Figure BDA00023404507000055714
Cytarabine liposome injection
Figure BDA00023404507000055715
Dacarbazine
Figure BDA00023404507000055716
Dactinomycin (actinomycin D, Cosmegan) and daunorubicin hydrochloride
Figure BDA00023404507000055717
Citric acid daunorubicin liposome injection
Figure BDA00023404507000055718
Dexamethasone and docetaxel
Figure BDA00023404507000055719
Doxorubicin hydrochloride
Figure BDA00023404507000055720
Etoposide
Figure BDA00023404507000055721
Fludarabine phosphate
Figure BDA00023404507000055722
5-Fluorouracil
Figure BDA00023404507000055723
Figure BDA00023404507000055724
Flutamide
Figure BDA00023404507000055725
tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea
Figure BDA00023404507000055726
Idarubicin (Idarubicin)
Figure BDA00023404507000055727
Isocyclophosphamide (ACS)
Figure BDA00023404507000055728
Irinotecan
Figure BDA00023404507000055729
L-asparaginase
Figure BDA00023404507000055730
Formyl tetrahydrofolic acid calcium, melphalan
Figure BDA00023404507000055731
6-mercaptopurine
Figure BDA00023404507000055732
Methotrexate (MTX)
Figure BDA00023404507000055733
Mitoxantrone (mitoxantrone)
Figure BDA00023404507000055734
Gemtuzumab ozogarg, taxol
Figure BDA00023404507000055735
Phoenix (Yttrium90/MX-DTPA), pentostatin, polifeprosan 20 cocardistin implants
Figure BDA00023404507000055736
Tamoxifen citrate
Figure BDA00023404507000055737
Teniposide
Figure BDA00023404507000055738
6-thioguanine, thiotepa (thiotepa), tirapazamine (tirapazamine)
Figure BDA0002340450700005581
Topotecan hydrochloride for injection
Figure BDA0002340450700005582
Catharanthine
Figure BDA0002340450700005583
Vincristine
Figure BDA0002340450700005584
Vinorelbine
Figure BDA0002340450700005585
Epirubicin
Figure BDA0002340450700005586
Oxaliplatin
Figure BDA0002340450700005587
Exemestane
Figure BDA0002340450700005588
Letrozole
Figure BDA0002340450700005589
And fulvestrant
Figure BDA00023404507000055810
The term "pharmaceutical combination" as used herein refers to a fixed combination in one dosage unit form, or a non-fixed combination or kit of parts for combined administration, wherein two or more therapeutic agents may be administered independently at the same time or separately within time intervals, in particular wherein these time intervals allow the combination partners to show a cooperative, e.g. synergistic effect.
The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule with a fixed ratio of active ingredients. Alternatively, such administration encompasses co-administration in multiple containers or in separate containers (e.g., capsules, powders, and liquids) for each active ingredient. The powder and/or liquid may be reconstituted or diluted to a desired dosage prior to administration. Further, such administration also encompasses the use of each type of therapeutic agent in a sequential manner at approximately the same time or at different times. In either case, the treatment regimen will provide the beneficial effects of the drug combination in treating the conditions or disorders described herein.
Combination therapy may provide "synergy" and prove "synergistic," i.e., the effect achieved when the active ingredients are used together is greater than the sum of the effects produced by the separate use of these compounds. A synergistic effect can be obtained when the active ingredients are in the following cases: (1) co-formulated and simultaneously applied or delivered in the form of a combined unit dose formulation; (2) delivered alternately or in parallel as separate formulations; or (3) by some other protocol. When delivered in alternating therapy, a synergistic effect may be obtained when the compounds are administered or delivered sequentially (e.g., by different injections in separate syringes). Typically, during alternation therapy, an effective dose of each active ingredient is administered sequentially, i.e., sequentially, whereas in combination therapy, an effective dose of two or more active ingredients are administered together.
In one embodiment, the invention provides methods of treating cancer by administering to a subject in need thereof a therapeutic agent with one or more other anti-HER 2 antibodies (e.g., trastuzumab, pertuzumab, marmotuximab, or HT-19 described above) or with other anti-HER 2 conjugates (e.g., ado-trastuzumab emtansinoid (also known as ado-trastuzumab emtansinoid)
Figure BDA0002340450700005591
Or T-DM1) in combination.
In one embodiment, the invention provides a method of treating cancer by administering to a subject in need thereof an antibody conjugate of the invention in combination with one or more tyrosine kinase inhibitors (including but not limited to EGFR inhibitors, Her3 inhibitors, IGFR inhibitors, and Met inhibitors).
For example, tyrosine kinase inhibitors include, but are not limited to, erlotinib hydrochloride (erlotinib)
Figure BDA0002340450700005592
Linifanib (N- [4- (3-amino-1H-indazol-4-yl) phenyl)]-N' - (2-fluoro-5-methylphenyl) urea, also known as ABT869, available from Genentech); sunitinib malate
Figure BDA0002340450700005593
Bosutinib (4- [ (2, 4-dichloro-5-methoxyphenyl) amino)]-6-methoxy-7- [3- (4-methylpiperazin-1-yl) propoxy]Quinoline-3-carbonitrile, also known as SKI-606 and described in U.S. Pat. No. 6,780,996); dasatinib
Figure BDA0002340450700005594
PazopanibSorafenib
Figure BDA0002340450700005596
Vandetanib (ZD 6474); and imatinib or imatinib mesylate (
Figure BDA0002340450700005597
And
Figure BDA0002340450700005598
)。
epidermal Growth Factor Receptor (EGFR) inhibitors include, but are not limited to, erlotinib hydrochloride (erlotinib)
Figure BDA0002340450700005599
Gefitinib
Figure BDA00023404507000055910
N- [4- [ (3-chloro-4-fluorophenyl) amino group]-7- [ [ (3 "S") -tetrahydro-3-furanyl]Oxy radical]-6-quinazolinyl]-4 (dimethylamino) -2-butenamide,
Figure BDA00023404507000055911
) (ii) a Vandetanib (Vandetanib)
Figure BDA00023404507000055912
Lapatinib
Figure BDA00023404507000055913
(3R,4R) -4-amino-1- ((4- ((3-methoxyphenyl) amino) pyrrolo [2, 1-f)][1,2,4]Triazin-5-yl) methyl) piperidin-3-ol (BMS 690514); canertinib dihydrochloride (CI-1033); 6- [4- [ (4-ethyl-1-piperazinyl) methyl group]Phenyl radical]-N- [ (1R) -1-phenylethyl]-7H-pyrrolo [2,3-d]Pyrimidin-4-amine (AEE788, CAS 497839-62-0); lignitinib (Mubritinib) (TAK 165); pelitinib (EKB 569); afatinib (Afatinib)
Figure BDA00023404507000055914
Neratinib (Neratinib) (HKI-272); n- [4- [ [1- [ (3-fluorophenyl) methyl group]-1H-indazol-5-yl]Amino group]-5-methylpyrrolo [2,1-f][1,2,4]Triazin-6-yl]Carbamic acid, (3S) -3-morpholinylmethyl ester (BMS599626), N- (3, 4-dichloro-2-fluorophenyl) -6-methoxy-7- [ [ (3a α,5 β,6a α) -octahydro-2-methylcyclopenta [ c ] methyl ester]Pyrrol-5-yl]Methoxy radical]-4-quinazolinamine (XL647, CAS 781613-23-8); and 4- [4- [ [ (1R) -1-phenylethyl group]Amino group]-7H-pyrrolo [2,3-d]Pyrimidin-6-yl]Phenol (PKI166, CAS 187724-61-4).
EGFR antibodies include, but are not limited to, cetuximab
Figure BDA0002340450700005601
Panitumumab
Figure BDA0002340450700005602
Matuzumab (EMD-72000); nimotuzumab: (A), (B), (C)Nimotuzumab) (hR 3); zatuzumab (Zalutumumab); TheraCIM h-R3; MDX0447(CAS 339151-96-1); and ch806(mAb-806, CAS 946414-09-1).
Other HER2 inhibitors include, but are not limited to, Neratinib (HKI-272, (2E) -N- [4- [ [ 3-chloro-4- [ (pyridin-2-yl) methoxy)]Phenyl radical]Amino group]-3-cyano-7-ethoxyquinolin-6-yl]-4- (dimethylamino) but-2-enamide and is described in PCT publication No. WO 05/028443); lapatinib or lapatinib ditosylate
Figure BDA0002340450700005603
(3R,4R) -4-amino-1- ((4- ((3-methoxyphenyl) amino) pyrrolo [2, 1-f)][1,2,4]Triazin-5-yl) methyl) piperidin-3-ol (BMS 690514); (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino group]-7- [ [ (3S) -tetrahydro-3-furanyl]Oxy radical]-6-quinazolinyl]-4- (dimethylamino) -2-butenamide (BIBW-2992, CAS 850140-72-6); n- [4- [ [1- [ (3-fluorophenyl) methyl group]-1H-indazol-5-yl]Amino group]-5-methylpyrrolo [2,1-f][1,2,4]Triazin-6-yl]Carbamic acid, (3S) -3-morpholinylmethyl ester (BMS599626, CAS 714971-09-2), canertinib dihydrochloride (PD183805 or CI-1033), and N- (3, 4-dichloro-2-fluorophenyl) -6-methoxy-7- [ [ (3a α,5 β,6a α) -octahydro-2-methylcyclopenta [ c ] ester]Pyrrol-5-yl]Methoxy radical]-4-quinazolinamine (XL647, CAS 781613-23-8).
HER3 inhibitors include, but are not limited to, LJM716, MM-121, AMG-888, RG7116, REGN-1400, AV-203, MP-RM-1, MM-111, and MEHD-7945A.
MET inhibitors include, but are not limited to, Cabozantinib (XL184, CAS 849217-68-1); fluoritebride (Foretinib) (GSK1363089, formerly XL880, CAS 849217-64-7); tenavancib (Tivantiniib) (ARQ197, CAS 1000873-98-2); 1- (2-hydroxy-2-methylpropyl) -N- (5- (7-methoxyquinolin-4-yloxy) pyridin-2-yl) -5-methyl-3-oxo-2-phenyl-2, 3-dihydro-1H-pyrazole-4-carboxamide (AMG 458); crizotinib (
Figure BDA0002340450700005604
PF-02341066); (3Z) -5- (2, 3-dihydro-1H-indol-1-ylsulfonyl) -3- ({3, 5-dimethyl-4- [ (4-methylpiperazin-1-yl) carbonyl]-1H-pyrrole-2-yl } methylene) -1, 3-dihydro-2H-indol-2-one (SU 11271); (3Z) -N- (3-chlorophenyl) -3- ({3, 5-dimethyl-4- [ (4-methylpiperazin-1-yl) carbonyl)]-1H-pyrrol-2-yl } methylene) -N-methyl-2-oxoindoline-5-sulfonamide (SU 11274); (3Z) -N- (3-chlorophenyl) -3- { [3, 5-dimethyl-4- (3-morpholin-4-ylpropyl) -1H-pyrrol-2-yl]Methylene } -N-methyl-2-oxoindoline-5-sulfonamide (SU 11606); 6- [ difluoro [6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ]]Pyridazin-3-yl radicals]Methyl radical]-quinoline (JNJ38877605, CAS 943540-75-8); 2- [4- [1- (quinolin-6-ylmethyl) -1H- [1,2,3]Triazolo [4,5-b]Pyrazin-6-yl]-1H-pyrazol-1-yl]Ethanol (PF04217903, CAS 956905-27-4); n- ((2R) -1, 4-dioxan-2-ylmethyl) -N-methyl-N' - [3- (1-methyl-1H-pyrazol-4-yl) -5-oxo-5H-benzo [4,5 ]]Cyclohepta [1,2-b ]]Pyridin-7-yl]Sulfonamides (MK2461, CAS 917879-39-1); 6- [ [6- (1-methyl-1H-pyrazol-4-yl) -1,2, 4-triazolo [4,3-b ]]Pyridazin-3-yl radicals]Thio group]-quinoline (SGX523, CAS 1022150-57-7); and (3Z) -5- [ [ (2, 6-dichlorophenyl) methyl]Sulfonyl radical]-3- [ [3, 5-dimethyl-4- [ [ (2R) -2- (1-pyrrolidinylmethyl) -1-pyrrolidinyl]Carbonyl radical]-1H-pyrrol-2-yl]Methylene group]1, 3-dihydro-2H-indol-2-one (PHA665752, CAS 477575-56-7).
IGFR inhibitors include, but are not limited to BMS-754807, XL-228, OSI-906, GSK0904529A, A-928605, AXL1717, KW-2450, MK0646, AMG479, IMCA12, MEDI-573, and BI 836845. See, e.g., Yee, JNCI [ journal of national cancer institute ], 104; 975 (2012).
In another embodiment, the invention provides a method of treating cancer by administering to a subject in need thereof an antibody conjugate of the invention in combination with one or more proliferation signaling pathway inhibitors (including but not limited to MEK inhibitors, BRAF inhibitors, PI3K/Akt inhibitors, SHP2 inhibitors, and mTOR inhibitors and CDK inhibitors).
For example, mitogen-activated protein kinase (MEK) inhibitors include, but are not limited to, XL-518 (also known as GDC-0973, Cas number 1029872-29-4, available from the ACC group (ACC Corp.)); 2- [ (2-chloro-4-iodophenyl) amino ] -N- (cyclopropylmethoxy) -3, 4-difluoro-benzamide (also known as CI-1040 or PD184352 and described in PCT publication No. WO 2000035436); n- [ (2R) -2, 3-dihydroxypropoxy ] -3, 4-difluoro-2- [ (2-fluoro-4-iodophenyl) amino ] -benzamide (also known as PD0325901 and described in PCT publication No. WO 2002006213); 2, 3-bis [ amino [ (2-aminophenyl) thio ] methylene ] -succinonitrile (also known as U0126 and described in U.S. patent No. 2,779,780); n- [3, 4-difluoro-2- [ (2-fluoro-4-iodophenyl) amino ] -6-methoxyphenyl ] -1- [ (2R) -2, 3-dihydroxypropyl ] -cyclopropanesulfonamide (also known as RDEA119 or BAY869766, and described in PCT publication No. WO 2007014011); (3S,4R,5Z,8S,9S,11E) -14- (ethylamino) -8,9, 16-trihydroxy-3, 4-dimethyl-3, 4,9, 19-tetrahydro-1H-2-benzoxacyclotetradecyne-1, 7(8H) -dione ] (also known as E6201 and described in PCT publication No. WO 2003076424); 2 '-amino-3' -methoxyflavone (also known as PD98059, available from Biaffin GmbH & co, KG, germany); vemurafenib (PLX-4032, CAS 918504-65-1); (R) -3- (2, 3-dihydroxypropyl) -6-fluoro-5- (2-fluoro-4-iodophenylamino) -8-methylpyrido [2,3-d ] pyrimidine-4, 7(3H,8H) -dione (TAK-733, CAS 1035555-63-5); pimaritis (Pimasertib) (AS-703026, CAS 1204531-26-9); and trametinib dimethyl sulfoxide (GSK-1120212, CAS 1204531-25-80).
BRAF inhibitors include, but are not limited to, Vemurafenib (or
Figure BDA0002340450700005621
) GDC-0879, PLX-4720 (available from Symansis), dabrafenib (or GSK2118436), LGX 818, CEP-32496, UI-152, RAF265, Regorafenib (BAY 73-4506), CCT239065, or sorafenib tosylate
Figure BDA0002340450700005622
) Or ipilimumab (or MDX-010, MDX-101, or Yervoy).
Phosphoinositide 3-kinase (PI3K) inhibitors include, but are not limited to, 4- [2- (1H-indazol-4-yl) -6- [ [4- (methylsulfonyl) piperazin-1-yl ] methyl ] thieno [3,2-d ] pyrimidin-4-yl ] morpholine (also known as GDC0941, RG7321, GNE0941, pityrinib (Pictrelisib), or Pictilisin (Piciliib); and described in PCT publication Nos. WO09/036082 and WO 09/055730); 2-methyl-2- [4- [ 3-methyl-2-oxo-8- (quinolin-3-yl) -2, 3-dihydroimidazo [4,5-c ] quinolin-1-yl ] phenyl ] propionitrile (also known as BEZ 235 or NVP-BEZ 235 and described in PCT publication No. WO 06/122806); 4- (trifluoromethyl) -5- (2, 6-dimorpholinopyrimidin-4-yl) pyridin-2-amine (also known as BKM120 or NVP-BKM120 and described in PCT publication No. WO 2007/084786); tozasertib (Tozasertib) (VX680 or MK-0457, CAS 639089-54-6); (5Z) -5- [ [4- (4-pyridinyl) -6-quinolinyl ] methylene ] -2, 4-thiazolidinedione (GSK1059615, CAS 958852-01-2); (1E,4S,4aR,5R,6aS,9aR) -5- (acetyloxy) -1- [ (di-2-propenylamino) methylene ] -4,4a,5,6,6a,8,9,9 a-octahydro-11-hydroxy-4- (methoxymethyl) -4a,6 a-dimethylcyclopenta [5,6] naphtho [1,2-c ] pyran-2, 7,10(1H) -trione (PX866, CAS 502632-66-8); 8-phenyl-2- (morpholin-4-yl) -chromen-4-one (LY294002, CAS 154447-36-6); (S) -N1- (4-methyl-5- (2- (1,1, 1-trifluoro-2-methylpropan-2-yl) pyridin-4-yl) thiazol-2-yl) pyrrolidin-1, 2-dicarboxamide (also known as BYL719 or abactericin); 2- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f ] imidazo [1,2-d ] [1,4] oxazepin-9-yl) -1H-pyrazol-1-yl) -2-methylpropanamide (also known as GDC0032, RG7604, or Taselisib).
mTOR inhibitors include, but are not limited to, temsirolimusRidaforolimus (formally known as deferolimus), (1R,2R,4S) -4- [ (2R) -2[ (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R) -1, 18-dihydroxy-19, 30-dimethoxy-15, 17,21,23,29, 35-hexamethyl-2, 3,10,14, 20-pentaoxo-11, 36-dioxa-4-azatricyclo [30.3.1.04,9]Trihexa-16, 24,26, 28-tetraen-12-yl]Propyl radical]2-methoxycyclohexyl dimethyl phosphinate, also known as AP23573 and MK8669 and described in PCT publication No. WO 03/064383); everolimus (A)
Figure BDA0002340450700005632
Or RAD 001); rapamycin (AY22989,
Figure BDA0002340450700005633
) (ii) a Sammimod (simapimod) (CAS 164301-51-3); (5- {2, 4-bis [ (3S) -3-methylmorpholin-4-yl)]Pyrido [2,3-d]Pyrimidin-7-yl } -2-methoxyphenyl) methanol (AZD 8055); 2-amino-8- [ trans-4- (2-hydroxyethoxy) cyclohexyl]-6- (6-methoxy-3-pyridyl) -4-methyl-pyrido [2,3-d]Pyrimidin-7 (8H) -one (PF04691502, CAS 1013101-36-4); and N2- [1, 4-dioxo-4- [ [4- (4-oxo-8-phenyl-4H-1-benzopyran-2-yl) morpholinium-4-yl]Methoxy radical]Butyl radical]-L-arginylglycyl-L- α -aspartylL-serine- (SEQ ID NO:932), inner salts (SF1126, CAS 936487-67-1).
CDK inhibitors include but are not limited to palebricide (also known as PD-0332991,
Figure BDA0002340450700005634
6-acetyl-8-cyclopentyl-5-methyl-2- { [5- (1-piperazinyl) -2-pyridinyl]Amino } pyrido [2,3-d]Pyrimidin-7 (8H) -one).
In yet another embodiment, the invention provides a method of treating cancer by administering to a subject in need thereof an antibody conjugate of the invention in combination with one or more pro-apoptotic agents including, but not limited to, IAP inhibitors, BCL2 inhibitors, MCL1 inhibitors, TRAIL agents, CHK inhibitors.
For example, IAP inhibitors include, but are not limited to, LCL161, GDC-0917, AEG-35156, AT406, and TL 32711. Other examples of IAP inhibitors include, but are not limited to, those disclosed in WO 04/005284, WO 04/007529, WO 05/097791, WO 05/069894, WO 05/069888, WO 05/094818, US 2006/0014700, US 2006/0025347, WO 06/069063, WO 06/010118, WO 06/017295, and WO 08/134679 (all of which are incorporated herein by reference).
BCL-2 inhibitors include, but are not limited to, 4- [4- [ [2- (4-chlorophenyl) -5, 5-dimethyl-1-cyclohexen-1-yl]Methyl radical]-1-piperazinyl]-N- [ [4- [ [ (1R) -3- (4-morpholinyl) -1- [ (phenylthio) methyl ] methyl]Propyl radical]Amino group]-3- [ (trifluoromethyl) sulfonyl group]Phenyl radical]Sulfonyl radical]Benzamide (also known as ABT-263 and described in PCT publication No. WO 09/155386); preparing carcinostatic A; anti-mycin; gossypol ((-) BL-193); olbarola(Obatoclax); ethyl-2-amino-6-cyclopentyl-4- (1-cyano-2-ethoxy-2-oxoethyl) -4H chromone-3-carboxylate (HA 14-1); olymersen (obimersen) (G3139,
Figure BDA0002340450700005641
) (ii) a Bak BH3 peptide; (-) -gossypol acetic acid (AT-101); 4- [4- [ (4 '-chloro [1,1' -biphenyl ] yl)]-2-yl) methyl]-1-piperazinyl]-N- [ [4- [ [ (1R) -3- (dimethylamino) -1- [ (phenylthio) methyl ] phenyl]Propyl radical]Amino group]-3-nitrophenyl]Sulfonyl radical]-benzamide (ABT-737, CAS 852808-04-9); and Navitoxrex (Navitoclax) (ABT-263, CAS 923564-51-6).
Pro-apoptotic receptor agonists (PARA) include DR4(TRAILR1) and DR5(TRAILR2), including but not limited to Duralamine (Dulanermin) (AMG-951, Rhapo 2L/TRAIL); mapatumumab (Mapatumumab) (HRS-ETR1, CAS 658052-09-6); lyitumumab (Lexatumumab) (HGS-ETR2, CAS 845816-02-6); apomab (Apomab)Sitaglipta beads (Conatumumab) (AMG655, CAS 896731-82-1); and tegafuzumab (Tigatuzumab) (CS1008, CAS 946415-34-5, available from the first three co-company, Daiichi Sankyo).
Checkpoint kinase (CHK) inhibitors include, but are not limited to, 7-hydroxystearic acid (UCN-01); 6-bromo-3- (1-methyl-1H-pyrazol-4-yl) -5- (3R) -3-piperidinylpyrazolo [1,5-a ] pyrimidin-7-amine (SCH900776, CAS 891494-63-6); 5- (3-fluorophenyl) -3-ureidothiophene-2-carboxylic acid N- [ (S) -piperidin-3-yl ] amide (AZD7762, CAS 860352-01-8); 4- [ ((3S) -1-azabicyclo [2.2.2] oct-3-yl) amino ] -3- (1H-benzoimidazol-2-yl) -6-chloroquinolin-2 (1H) -one (CHIR 124, CAS 405168-58-3); 7-aminodactinomycin (7-AAD), Isogranulatide, debromohymenialdisine; n- [ 5-bromo-4-methyl-2- [ (2S) -2-morpholinylmethoxy ] -phenyl ] -N' - (5-methyl-2-pyrazinyl) urea (LY2603618, CAS 911222-45-2); sulforaphane (CAS4478-93-7, 4-methylsulfinylbutylisothiocyanate); 9,10,11, 12-tetrahydro-9, 12-epoxy-1H-diindole [1,2,3-fg:3',2',1' -kl ] pyrrolo [3,4-i ] [1,6] benzodiazocine-1, 3(2H) -dione (SB-218078, CAS 135897-06-2); and TAT-S216A (YGRKKRRQRRRLYRSPAMPENL (SEQ ID NO:929)), and CBP501((d-Bpa) sws (d-Phe-F5) (d-Cha) rrrqrr).
In additional embodiments, the invention provides a method of treating or preventing cancer by administering to a subject in need thereof an antibody conjugate of the invention in combination with one or more immune modulators (e.g., one or more of an activator of a co-stimulatory molecule or an inhibitor of an immune checkpoint molecule).
In certain embodiments, the immunomodulator is an activator of a costimulatory molecule. In one embodiment, the agonist of the co-stimulatory molecule is selected from the group consisting of an agonist (e.g., an agonistic antibody or antigen-binding fragment thereof, or a soluble fusion) of OX40, CD2, CD27, CDS, ICAM-1, LFA-1(CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or CD83 ligand.
GITR agonists
In certain embodiments, the agonist of the costimulatory molecule is a GITR agonist. In some embodiments, the GITR agonist is GWN323 (noval (NVS)), BMS-986156, MK-4166, or MK-1248 (Merck), TRX518 (Leap Therapeutics), incagnn 1876 (lnyte)/aginss (Agenus)), AMG 228 (Amgen), or INBRX-110 (inshibrx).
Exemplary GITR agonists
In one embodiment, the GITR agonist is an anti-GITR antibody molecule. In one embodiment, the GITR agonist is an anti-GITR antibody molecule as described in WO 2016/057846 (incorporated by reference in its entirety) published on day 14/4 of 2016 entitled Compositions and Methods for enhanced immune Response and Cancer Therapy.
In one embodiment, the anti-GITR antibody molecule comprises at least one, two, three, four, five, or six Complementarity Determining Regions (CDRs) (or all CDRs in total) from a heavy chain and light chain variable region comprising an amino acid sequence set forth in table 14 (e.g., a heavy chain and light chain variable region sequence from MAB7 disclosed in table 14), or an amino acid sequence encoded by a nucleotide sequence set forth in table 14. In some embodiments, the CDRs are defined according to Kabat (e.g., as listed in table 14). In some embodiments, the CDRs are defined according to georgia (Chothia) (e.g., as listed in table 14). In one embodiment, one or more of the CDRs (or the overall all CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to the amino acid sequences set forth in table 14, or the amino acid sequences encoded by the nucleotide sequences set forth in table 14.
In one embodiment, the anti-GITR antibody molecule comprises: a heavy chain variable region (VH) comprising the amino acid sequence VHCDR1 of SEQ ID NO:909, the amino acid sequence VHCDR2 of SEQ ID NO:911, and the amino acid sequence VHCDR3 of SEQ ID NO: 913; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO 914, the VLCDR2 amino acid sequence of SEQ ID NO 916, and the VLCDR3 amino acid sequence of SEQ ID NO 918, each as disclosed in Table 14.
In one embodiment, the anti-GITR antibody molecule comprises: a VH comprising the amino acid sequence of SEQ ID NO:901, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 901. In one embodiment, the anti-GITR antibody molecule comprises: VL comprising the amino acid sequence of SEQ ID NO. 902, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO. 902. In one embodiment, the anti-GITR antibody molecule comprises: a VH comprising the amino acid sequence of SEQ ID NO:901 and a VL comprising the amino acid sequence of SEQ ID NO: 902.
In one embodiment, the antibody molecule comprises: a VH encoded by the nucleotide sequence of SEQ ID NO:905, or a nucleotide sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 905. In one embodiment, the antibody molecule comprises: a VL encoded by the nucleotide sequence of SEQ ID NO:906, or a nucleotide sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 906. In one embodiment, the antibody molecule comprises the VH encoded by the nucleotide sequence of SEQ ID NO:905 and the VL encoded by the nucleotide sequence of SEQ ID NO: 906.
In one embodiment, the anti-GITR antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO 903, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO 903. In one embodiment, the anti-GITR antibody molecule comprises: a light chain comprising the amino acid sequence of SEQ ID NO:904, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more identity to SEQ ID NO: 904. In one embodiment, the anti-GITR antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO 903 and a light chain comprising the amino acid sequence of SEQ ID NO 904.
In one embodiment, the antibody molecule comprises: a heavy chain encoded by the nucleotide sequence of SEQ ID NO. 907, or a nucleotide sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO. 907. In one embodiment, the antibody molecule comprises: a light chain encoded by the nucleotide sequence of SEQ ID NO:908, or a nucleotide sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 908. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO 907 and a light chain encoded by the nucleotide sequence of SEQ ID NO 908.
The antibody molecules described herein can be made by vectors, host cells, and methods described in WO 2016/057846 (which is incorporated by reference in its entirety).
Table 14: amino acid and nucleotide sequences of exemplary anti-GITR antibody molecules
Figure BDA0002340450700005671
Figure BDA0002340450700005681
Figure BDA0002340450700005691
Figure BDA0002340450700005701
Other exemplary GITR agonists
In one embodiment, the anti-GITR antibody molecule is BMS-986156 (Bristol-Myers Squibb), also known as BMS986156 or BMS 986156. BMS-986156 and other anti-GITR antibodies are disclosed, for example, in US9,228,016 and WO 2016/196792, which are incorporated by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more of: the CDR sequences (or overall all CDR sequences), the heavy or light chain variable region sequences, or the heavy or light chain sequences of BMS-986156, e.g., as disclosed in table 15.
In one embodiment, the anti-GITR antibody molecule is MK-4166 or MK-1248 (Merck). MK-4166, MK-1248, and other anti-GITR antibodies are disclosed in, for example, US 8,709,424, WO 2011/028683, WO 2015/026684, and Mahne et al, Cancer Res [ Cancer research ] 2017; 77(5) 1108-. In one embodiment, the anti-GITR antibody molecule comprises one or more of: the CDR sequences (or overall all CDR sequences) of MK-4166 or MK-1248, the heavy or light chain variable region sequences, or the heavy or light chain sequences.
In one embodiment, the anti-GITR antibody molecule is TRX518 (lepp therapeutics). TRX518 and other anti-GITR antibodies are disclosed, for example, in US 7,812,135, US 8,388,967, US9,028,823, WO 2006/105021, and Ponte J et al, (2010) Clinical Immunology; 135: S96, which are incorporated by reference in their entirety. In one embodiment, the anti-GITR antibody molecule comprises one or more of: the CDR sequence (or all CDR sequences in general), the heavy or light chain variable region sequence, or the heavy or light chain sequence of TRX 518.
In one embodiment, the anti-GITR antibody molecule is incag 1876 (genepott/agilaws). INCAGN1876 and other anti-GITR antibodies are disclosed, for example, in US 2015/0368349 and WO 2015/184099 (which are incorporated by reference in their entirety). In one embodiment, the anti-GITR antibody molecule comprises one or more of: a CDR sequence (or overall all CDR sequences) of INCAGN1876, a heavy or light chain variable region sequence, or a heavy or light chain sequence.
In one embodiment, the anti-GITR antibody molecule is AMG 228 (america ann company). AMG 228 and other anti-GITR antibodies are disclosed, for example, in US9,464,139 and WO 2015/031667 (which are incorporated by reference in their entirety). In one embodiment, the anti-GITR antibody molecule comprises one or more of: the CDR sequences (or overall all CDR sequences) of AMG 228, the heavy or light chain variable region sequences, or the heavy or light chain sequences.
In one embodiment, the anti-GITR antibody molecule is INBRX-110 (print sier). INBRX-110 and other anti-GITR antibodies are disclosed, for example, in US 2017/0022284 and WO 2017/015623, which are incorporated by reference in their entirety. In one embodiment, the GITR agonist comprises one or more of: the CDR sequences (or all CDR sequences in general), the heavy or light chain variable region sequences, or the heavy or light chain sequences of INBRX-110.
In one embodiment, the GITR agonist (e.g., fusion protein) is MEDI1873 (mediimmune, inc., midi, also known as MEDI 1873). MEDI1873 and other GITR agonists are disclosed in, for example, US 2017/0073386, WO 2017/025610, and Ross et al, Cancer Res [ Cancer research ] 2016; 76(14 suppl) abstract nr 561 (which is incorporated by reference in its entirety). In one embodiment, the GITR agonist comprises one or more of an IgG Fc domain of MEDI1873, a functional multimerization domain, and a receptor binding domain of a glucocorticoid-induced TNF receptor ligand (GITRL).
Additional known GITR agonists (e.g., anti-GITR antibodies) include, for example, those described in WO 2016/054638 (which is incorporated by reference in its entirety).
In one embodiment, the anti-GITR antibody is an antibody that competes with one of the anti-GITR antibodies described herein for binding to and/or binding to the same epitope on GITR.
In one embodiment, the GITR agonist is a peptide that activates the GITR signaling pathway. In one embodiment, the GITR agonist is an immunoadhesin-binding fragment (e.g., an immunoadhesin-binding fragment comprising an extracellular or GITR-binding portion of GITRL) fused to a constant region (e.g., an Fc region of an immunoglobulin sequence).
Table 15: amino acid sequences of other exemplary anti-GITR antibody molecules
Figure BDA0002340450700005731
In certain embodiments, the immunomodulator is an inhibitor of an immune checkpoint molecule, in one embodiment, the immunomodulator is an inhibitor of PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, and/or TGFR β in one embodiment, an inhibitor of an immune checkpoint molecule inhibits PD-1, PD-L1, LAG-3, TIM-3, or CTLA4, or any combination thereof.
In other embodiments, the inhibitor of the inhibitory signal is a polypeptide, e.g., a soluble ligand (e.g., PD-1-Ig or CTLA-4Ig) or an antibody or antigen-binding fragment thereof that binds to the inhibitory molecule, e.g., an antibody or fragment thereof (also referred to herein as an "antibody molecule") that binds to PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, and/or TGFR β, or a combination thereof.
In one embodiment, the antibody molecule is a complete antibody or a fragment thereof (e.g., Fab, F (ab')2, Fv, or single chain Fv fragment (scFv)). In yet other embodiments, the antibody molecule has a heavy chain constant region (Fc) selected from heavy chain constant regions of, for example, IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE; in particular, a heavy chain constant region selected from, for example, IgG1, IgG2, IgG3, and IgG4, more particularly, IgG1 or IgG4 (e.g., human IgG1 or IgG 4). In one embodiment, the heavy chain constant region is human IgG1 or human IgG 4. In one embodiment, the constant region is altered (e.g., mutated) to modify a property of the antibody molecule (e.g., to increase or decrease one or more of Fc receptor binding, antibody glycosylation, number of cysteine residues, effector cell function, or complement function).
In certain embodiments, the antibody molecule is in the form of a bispecific or multispecific antibody molecule. In one embodiment, the bispecific antibody molecule has a first binding specificity for PD-1 or PD-L1, and a second binding specificity, e.g., a second binding specificity for TIM-3, LAG-3, or PD-L2. In one embodiment, the bispecific antibody molecule binds to PD-1 or PD-L1 and TIM-3. In another embodiment, the bispecific antibody molecule binds to PD-1 or PD-L1 and LAG-3. In another embodiment, the bispecific antibody molecule binds to PD-1 and PD-L1. In yet another embodiment, the bispecific antibody molecule binds to PD-1 and PD-L2. In another embodiment, the bispecific antibody molecule binds to TIM-3 and LAG-3. Any combination of the above molecules can be made in a multispecific antibody molecule (e.g., a trispecific antibody comprising a first binding specificity for PD-1 or PD-1, and second and third binding specificities for two or more of TIM-3, LAG-3, or PD-L2).
In certain embodiments, the immunomodulator is an inhibitor of PD-1 (e.g., human PD-1). In another embodiment, the immunomodulatory agent is an inhibitor of PD-L1 (e.g., human PD-L1). In one embodiment, the inhibitor of PD-1 or PD-L1 is an antibody molecule to PD-1 or PD-L1. The PD-1 or PD-L1 inhibitor may be administered alone, or in combination with other immunomodulators, for example, in combination with an inhibitor of LAG-3, TIM-3 or CTLA 4. In exemplary embodiments, an inhibitor of PD-1 or PD-L1 (e.g., an anti-PD-1 or PD-L1 antibody molecule) is administered in combination with a LAG-3 inhibitor (e.g., an anti-LAG-3 antibody molecule). In another embodiment, an inhibitor of PD-1 or PD-L1 (e.g., an anti-PD-1 or PD-L1 antibody molecule) is administered in combination with a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody molecule). In yet other embodiments, an inhibitor of PD-1 or PD-L1 (e.g., an anti-PD-1 antibody molecule) is administered in combination with a LAG-3 inhibitor (e.g., an anti-LAG-3 antibody molecule) and a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody molecule).
Other combinations of immunomodulatory agents with PD-1 inhibitors (e.g., one or more of PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, and/or TGFR) are also within the scope of the invention. Any antibody molecule known in the art or disclosed herein can be used in combination with the checkpoint molecule inhibitors described above.
PD-1 inhibitors
In some embodiments, the antibody conjugates of the invention are administered in combination with a PD-1 inhibitor. In some embodiments, the PD-1 inhibitor is selected from PDR001 (Nowawa), nivolumab (Beshizubao Corp.), pembrolizumab (Merck & Co)), pidilizumab (CureTech), MEDI0680 (Mercedmuir Co., Ltd., England), REGN2810 (Regeneron), TSR-042 (Tesaroro), PF-06801591 (Feitegan (Pfizer)), BGB-A317 (Beigene), BGB-108 (State of Paris), INCHR 1210 (Netscher Saite), or AMP-224 (Amplimun).
Exemplary PD-1 inhibitionAgent for treating cancer
In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule. In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule, as described in US2015/0210769 (which is incorporated by reference in its entirety) published on 30/7/2015 entitled "antibody molecule of PD-1 and uses thereof".
In one embodiment, the anti-PD-1 antibody molecule comprises at least one, two, three, four, five, or six Complementarity Determining Regions (CDRs) (or all CDRs in total) from heavy and light chain variable regions comprising, or encoded by, the amino acid sequences set forth in table 16 (e.g., from the heavy and light chain variable region sequences of BAP 049-clone-E or BAP 049-clone-B disclosed in table 16). In some embodiments, the CDRs are defined according to kabat (e.g., as listed in table 16). In some embodiments, the CDRs are according to the georgia definition (e.g., as listed in table 16). In some embodiments, these CDRs are defined according to a combined CDR of both kabat and georgia (e.g., as listed in table 16). In one embodiment, the combination of the kabat and the georgia CDRs of VH CDR1 comprises the amino acid sequence GYTFTTYWMH (SEQ ID NO: 541). In one embodiment, one or more of the CDRs (or the overall all of the CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to the amino acid sequences set forth in table 16, or the amino acid sequences encoded by the nucleotide sequences set forth in table 16.
In one embodiment, the anti-PD-1 antibody molecule comprises: a heavy chain variable region (VH) comprising the amino acid sequence VHCDR1 of SEQ ID NO 501, the amino acid sequence VHCDR2 of SEQ ID NO 502, and the amino acid sequence VHCDR3 of SEQ ID NO 503; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:510, the VLCDR2 amino acid sequence of SEQ ID NO:511, and the VLCDR3 amino acid sequence of SEQ ID NO:512, each as disclosed in Table 16.
In one embodiment, the antibody molecule comprises: a VH comprising VHCDR1 encoded by the nucleotide sequence of SEQ ID NO. 524, VHCDR2 encoded by the nucleotide sequence of SEQ ID NO. 525, and VHCDR3 encoded by the nucleotide sequence of SEQ ID NO. 526; and a VL comprising the VLCDR1 encoded by the nucleotide sequence of SEQ ID NO:529, the VLCDR2 encoded by the nucleotide sequence of SEQ ID NO:530, and the VLCDR3 encoded by the nucleotide sequence of SEQ ID NO:531, each as disclosed in Table 16.
In one embodiment, the anti-PD-1 antibody molecule comprises: a VH comprising the amino acid sequence of SEQ ID NO:506, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 506. In one embodiment, the anti-PD-1 antibody molecule comprises: VL comprising the amino acid sequence of SEQ ID NO. 520, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO. 520. In one embodiment, the anti-PD-1 antibody molecule comprises: VL comprising the amino acid sequence of SEQ ID NO. 516, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO. 516. In one embodiment, the anti-PD-1 antibody molecule comprises: VH comprising the amino acid sequence of SEQ ID NO 506 and VL comprising the amino acid sequence of SEQ ID NO 520. In one embodiment, the anti-PD-1 antibody molecule comprises: VH comprising the amino acid sequence of SEQ ID NO 506 and VL comprising the amino acid sequence of SEQ ID NO 516.
In one embodiment, the antibody molecule comprises: VH encoded by the nucleotide sequence of SEQ ID NO:507, or a nucleotide sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 507. In one embodiment, the antibody molecule comprises: a VL encoded by the nucleotide sequence of SEQ ID NO. 521 or 517, or a nucleotide sequence having at least 85%, 90%, 95%, or 99% or more identity to SEQ ID NO. 521 or 517. In one embodiment, the antibody molecule comprises the VH encoded by the nucleotide sequence of SEQ ID NO. 507 and the VL encoded by the nucleotide sequence of SEQ ID NO. 521 or 517.
In one embodiment, the anti-PD-1 antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO 508, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO 508. In one embodiment, the anti-PD-1 antibody molecule comprises: a light chain comprising the amino acid sequence of SEQ ID NO:522, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more identity to SEQ ID NO: 522. In one embodiment, the anti-PD-1 antibody molecule comprises: a light chain comprising the amino acid sequence of SEQ ID NO. 518, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO. 518. In one embodiment, the anti-PD-1 antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO 508 and a light chain comprising the amino acid sequence of SEQ ID NO 522. In one embodiment, the anti-PD-1 antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO 508 and a light chain comprising the amino acid sequence of SEQ ID NO 518.
In one embodiment, the antibody molecule comprises: a heavy chain encoded by the nucleotide sequence of SEQ ID NO. 509, or a nucleotide sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO. 509. In one embodiment, the antibody molecule comprises: a light chain encoded by the nucleotide sequence of SEQ ID NO 523 or 519, or a nucleotide sequence having at least 85%, 90%, 95%, or 99% or more identity to SEQ ID NO 523 or 519. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO 509 and a light chain encoded by the nucleotide sequence of SEQ ID NO 523 or 519.
The antibody molecules described herein can be made by vectors, host cells, and methods described in US2015/0210769 (which is incorporated by reference in its entirety).
TABLE 16 amino acid and nucleotide sequences of exemplary anti-PD-1 antibody molecules
Figure BDA0002340450700005771
Figure BDA0002340450700005781
Figure BDA0002340450700005791
Figure BDA0002340450700005801
Figure BDA0002340450700005811
Figure BDA0002340450700005821
Figure BDA0002340450700005831
Other exemplary PD-1 inhibitors
In some embodiments, the anti-PD-1 antibody is nivolumab (CAS registry number 946414-94-4). Alternative names for nivolumab include MDX-1106, MDX-1106-04, ONO-4538, BMS-936558 or
Figure BDA0002340450700005832
Nivolumab is a fully human IgG4 monoclonal antibody that specifically blocks PD 1. Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind to PD1 are disclosed in U.S. patent No. 8,008,449 and PCT publication No. WO2006/121168, which are incorporated by reference in their entirety. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of: the CDR sequences (or overall all CDR sequences), heavy or light chain variable region sequences, or heavy or light chain sequences of nivolumab, for example, as disclosed in table 17.
In other embodiments, the anti-PD-1 antibody is pembrolizumab. Pambrolizumab (trade name KEYTRUDA, formerly Lambrolizumab, also known as Merck 3745, MK-3475 or SCH-900475) is a humanized IgG4 monoclonal antibody that binds to PD 1. Pamumab is disclosed, for example, in Hamid, o. et al (2013) New england journal of Medicine 369(2):134-44, PCT publication No. WO 2009/114335, and U.S. patent No. 8,354,509, which is incorporated by reference in its entirety. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of: the CDR sequences (or overall all CDR sequences), the heavy or light chain variable region sequences, or the heavy or light chain sequences of pamumab, for example, as disclosed in table 17.
In some embodiments, the anti-PD-1 antibody is pidilizumab. Pidilizumab (CT-011; Cure Tech) is a humanized IgG1k monoclonal antibody that binds to PD 1. Pidilizumab and other humanized anti-PD-1 monoclonal antibodies are disclosed in PCT publication No. WO 2009/101611 (which is incorporated by reference in its entirety). In one embodiment, the anti-PD-1 antibody molecule comprises one or more of: the CDR sequences (or overall all CDR sequences), heavy chain or light chain variable region sequences, or heavy chain or light chain sequences of pidilizumab, for example, as disclosed in table 17.
Other anti-PD 1 antibodies are disclosed in U.S. patent No. 8,609,089, U.S. publication No. 2010028330, and/or U.S. publication No. 20120114649 (which is incorporated by reference in its entirety). Other anti-PD 1 antibodies include AMP 514 (Anpril).
In one embodiment, the anti-PD-1 antibody molecule is MEDI0680 (meidimuir ltd, english), also known as AMP-514. MEDI0680 and other anti-PD-1 antibodies are disclosed in US9,205,148 and WO 2012/145493 (which are incorporated by reference in their entirety). In one embodiment, the anti-PD-1 antibody molecule comprises one or more of: a CDR sequence (or overall all CDR sequences), a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence of MEDI 0680.
In one embodiment, the anti-PD-1 antibody molecule is REGN2810 (revascularization). In one embodiment, the anti-PD-1 antibody molecule comprises one or more of: the CDR sequence (or overall CDR sequence), the heavy or light chain variable region sequence, or the heavy or light chain sequence of REGN 2810.
In one embodiment, the anti-PD-1 antibody molecule is PF-06801591 (feverfew). In one embodiment, the anti-PD-1 antibody molecule comprises one or more of: the CDR sequences (or overall all CDR sequences) of PF-06801591, the heavy or light chain variable region sequences, or the heavy or light chain sequences.
In one embodiment, the anti-PD-1 antibody molecule is BGB-A317 or BGB-108 (Baiji Shenzhou Co.). In one embodiment, the anti-PD-1 antibody molecule comprises one or more of: BGB-A317, or a CDR sequence (or all CDR sequences in general) of BGB-108, a heavy or light chain variable region sequence, or a heavy or light chain sequence.
In one embodiment, the anti-PD-1 antibody molecule is INCSAR 1210 (Nersett Corp.), also known as INCSAR 01210 or SHR-1210. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of: the CDR sequences (or overall all CDR sequences) of the incsrr 1210, the heavy or light chain variable region sequences, or the heavy or light chain sequences.
In one embodiment, the anti-PD-1 antibody molecule is TSR-042 (Tasalo corporation), also known as ANB 011. In one embodiment, the anti-PD-1 antibody molecule comprises one or more of: a CDR sequence (or overall all CDR sequences), a heavy or light chain variable region sequence, or a heavy or light chain sequence of TSR-042.
Other known anti-PD-1 antibodies include those described, for example, in: WO 2015/112800, WO2016/092419, WO 2015/085847, WO 2014/179664, WO 2014/194302, WO 2014/209804, WO2015/200119, US 8,735,553, US 7,488,802, US 8,927,697, US 8,993,731, and US9,102,727 (which are incorporated by reference in their entirety).
In one embodiment, the anti-PD-1 antibody is an antibody that competes for binding to and/or binds to the same epitope on PD-1 as one of the anti-PD-1 antibodies described herein.
In one embodiment, the PD-1 inhibitor is a peptide that inhibits the PD-1 signaling pathway, for example as described in US 8,907,053 (which is incorporated by reference in its entirety). In some embodiments, the PD-1 inhibitor is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., the Fc region of an immunoglobulin sequence). In some embodiments, the PD-1 inhibitor is AMP-224(B7-DCIg (Anpril corporation), for example, as disclosed in WO2010/027827 and WO 2011/066342 (incorporated by reference in their entirety).
TABLE 17 amino acid sequences of other exemplary anti-PD-1 antibody molecules
Figure BDA0002340450700005851
Figure BDA0002340450700005861
PD-L1 inhibitors
In certain embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1. In some embodiments, the antibody conjugates of the invention are administered in combination with a PD-L1 inhibitor. In some embodiments, the PD-L1 inhibitor is selected from FAZ053 (novain), alezumab (atezolizumab) (genetag/Roche), avizumab (Merck Serono and feverie), doxoruzumab (english medic meimuir ltd/AstraZeneca) or BMS-936559 (behme schrobo).
Exemplary PD-L1 inhibitors
In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule. In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule, as disclosed in US2016/0108123 (which is incorporated by reference in its entirety) published on 21/4/2016, entitled "antibody molecule of PD-L1 and uses thereof".
In one embodiment, the anti-PD-L1 antibody molecule comprises at least one, two, three, four, five, or six Complementarity Determining Regions (CDRs) (or all CDRs in total) from heavy and light chain variable regions comprising, or encoded by, the amino acid sequences set forth in table 18 (e.g., the heavy and light chain variable region sequences from BAP 058-clone O, or BAP 058-clone N disclosed in table 18). In some embodiments, the CDRs are defined according to kabat (e.g., as listed in table 18). In some embodiments, the CDRs are according to the georgia definition (e.g., as listed in table 18). In some embodiments, these CDRs are defined from a combined CDR of both kabat and georgia (e.g., as listed in table 18). In one embodiment, the combination of the kabat and the joxiya CDRs of VH CDR1 comprises amino acid sequence GYTFTSYWMY (SEQ ID NO: 647). In one embodiment, one or more of the CDRs (or the overall all of the CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to the amino acid sequences set forth in table 18, or the amino acid sequences encoded by the nucleotide sequences set forth in table 18.
In one embodiment, the anti-PD-L1 antibody molecule comprises: a heavy chain variable region (VH) comprising the amino acid sequence VHCDR1 of SEQ ID NO 601, the amino acid sequence VHCDR2 of SEQ ID NO 602, and the amino acid sequence VHCDR3 of SEQ ID NO 603; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO 609, the VLCDR2 amino acid sequence of SEQ ID NO 610, and the VLCDR3 amino acid sequence of SEQ ID NO 611, each as set forth in Table 18.
In one embodiment, the anti-PD-L1 antibody molecule comprises: a VH comprising the VHCDR1 encoded by the nucleotide sequence of SEQ ID NO:628, the VHCDR2 encoded by the nucleotide sequence of SEQ ID NO:629, and the VHCDR3 encoded by the nucleotide sequence of SEQ ID NO: 630; and a VL comprising VLCDR1 encoded by the nucleotide sequence of SEQ ID No. 633, VLCDR2 encoded by the nucleotide sequence of SEQ ID No. 634, and VLCDR3 encoded by the nucleotide sequence of SEQ ID No. 635, each as disclosed in table 18.
In one embodiment, the anti-PD-1 antibody molecule comprises: a VH comprising the amino acid sequence of SEQ ID NO:606, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 606. In one embodiment, the anti-PD-L1 antibody molecule comprises: VL comprising the amino acid sequence of SEQ ID NO. 616, or an amino acid sequence having at least 616%, 90%, 95%, or 99%, or more, identity to SEQ ID NO. 85. In one embodiment, the anti-PD-1 antibody molecule comprises: a VH comprising the amino acid sequence of SEQ ID NO:620, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 620. In one embodiment, the anti-PD-L1 antibody molecule comprises: VL comprising the amino acid sequence of SEQ ID NO. 624, or an amino acid sequence having at least 624%, 90%, 95%, or 99%, or more, identity to SEQ ID NO. 85. In one embodiment, the anti-PD-L1 antibody molecule comprises: VH comprising the amino acid sequence of SEQ ID NO:606 and VL comprising the amino acid sequence of SEQ ID NO: 616. In one embodiment, the anti-PD-L1 antibody molecule comprises: VH comprising the amino acid sequence of SEQ ID NO:620 and VL comprising the amino acid sequence of SEQ ID NO: 624.
In one embodiment, the antibody molecule comprises: a VH encoded by the nucleotide sequence of SEQ ID NO. 607, or a nucleotide sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO. 607. In one embodiment, the antibody molecule comprises: a VL encoded by the nucleotide sequence of SEQ ID NO:617, or a nucleotide sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 617. In one embodiment, the antibody molecule comprises: VH encoded by the nucleotide sequence of SEQ ID NO 621, or a nucleotide sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO 621. In one embodiment, the antibody molecule comprises: VL encoded by the nucleotide sequence of SEQ ID NO. 625, or a nucleotide sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO. 625. In one embodiment, the antibody molecule comprises the VH encoded by the nucleotide sequence of SEQ ID NO. 607 and the VL encoded by the nucleotide sequence of SEQ ID NO. 617. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO 621 and a VL encoded by the nucleotide sequence of SEQ ID NO 625.
In one embodiment, the anti-PD-L1 antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO 608, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more identity to SEQ ID NO 608. In one embodiment, the anti-PD-L1 antibody molecule comprises: a light chain comprising the amino acid sequence of SEQ ID NO:618, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 618. In one embodiment, the anti-PD-L1 antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO 622, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO 622. In one embodiment, the anti-PD-L1 antibody molecule comprises: a light chain comprising the amino acid sequence of SEQ ID NO:626, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 626. In one embodiment, the anti-PD-L1 antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO 608 and a light chain comprising the amino acid sequence of SEQ ID NO 618. In one embodiment, the anti-PD-L1 antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO 622 and a light chain comprising the amino acid sequence of SEQ ID NO 626.
In one embodiment, the antibody molecule comprises: a heavy chain encoded by the nucleotide sequence of SEQ ID NO. 615, or a nucleotide sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO. 615. In one embodiment, the antibody molecule comprises: a light chain encoded by the nucleotide sequence of SEQ ID NO 619, or a nucleotide sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO 619. In one embodiment, the antibody molecule comprises: a heavy chain encoded by the nucleotide sequence of SEQ ID NO:623, or a nucleotide sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 623. In one embodiment, the antibody molecule comprises: a light chain encoded by the nucleotide sequence of SEQ ID NO:627, or a nucleotide sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 627. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO. 615 and a light chain encoded by the nucleotide sequence of SEQ ID NO. 619. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO 623 and a light chain encoded by the nucleotide sequence of SEQ ID NO 627.
The antibody molecules described herein can be made by vectors, host cells, and the methods described in US2016/0108123 (which is incorporated by reference in its entirety).
TABLE 18 amino acid and nucleotide sequences of exemplary anti-PD-L1 antibody molecules
Figure BDA0002340450700005901
Figure BDA0002340450700005941
Figure BDA0002340450700005951
Figure BDA0002340450700005961
Other exemplary PD-L1 inhibitors
In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 inhibitor is selected from yw243.55.s70, MPDL3280A, MEDI-4736, or MDX-1105MSB-0010718C (also referred to as a09-246-2), disclosed in, e.g., WO 2013/0179174, and having a sequence disclosed herein (or a sequence substantially identical or similar thereto, e.g., a sequence having at least 85%, 90%, 95%, or higher identity to a specified sequence).
In one embodiment, the PD-L1 inhibitor is MDX-1105. MDX-1105 (also known as BMS-936559) is an anti-PD-L1 antibody, described in PCT publication No. WO 2007/005874.
In one embodiment, the PD-L1 inhibitor is yw243.55. s70. The yw243.55.s70 antibody is anti-PD-L1, described in PCT publication No. WO 2010/077634.
In one embodiment, the PD-L1 inhibitor is MDPL3280A (geneva/roche), also known as atelizumab, RG7446, RO5541267, yw243.55.s70, or TECENTRIQTM. MDPL3280A is a human Fc optimized IgG1 monoclonal antibody that binds to PD-L1. MDPL3280A and other human monoclonal antibodies to PD-L1 are disclosed in U.S. Pat. Nos.: 7,943,743 and U.S. publication nos.: 20120039906 (which is incorporated by reference in its entirety). In one embodiment, the anti-PD-L1 antibody molecule comprises one or more of: the CDR sequences (or overall all CDR sequences), the heavy or light chain variable region sequences, or the heavy or light chain sequences of atezumab, e.g., as disclosed in table 19.
In other embodiments, the PD-L2 inhibitor is AMP-224. AMP-224 is a PD-L2 Fc fusion soluble receptor that blocks the interaction between PD1 and B7-H1 (B7-DCIg; Anpril corporation; e.g., as disclosed in PCT publication Nos. WO2010/027827 and WO 2011/066342).
In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule. In one embodiment, the anti-PD-L1 antibody molecule is avizumab (merck snow lnco and feverfew), also known as MSB 0010718C. Abelmumab and other anti-PD-L1 antibodies are disclosed in WO2013/079174 (which is incorporated by reference in its entirety). In one embodiment, the anti-PD-L1 antibody molecule comprises one or more of: the CDR sequences (or overall all CDR sequences), the heavy or light chain variable region sequences, or the heavy or light chain sequences of avilumab, for example, as disclosed in table 19.
In one embodiment, the anti-PD-L1 antibody molecule is dutvacizumab (engleri meduius ltd/astrikon), also known as MEDI 4736. Duvaluzumab and other anti-PD-L1 antibodies are disclosed in US 8,779,108 (which is incorporated by reference in its entirety). In one embodiment, the anti-PD-L1 antibody molecule comprises one or more of: the CDR sequences (or overall all CDR sequences), heavy or light chain variable region sequences, or heavy or light chain sequences of dolvacizumab, for example, as disclosed in table 19.
In one embodiment, the anti-PD-L1 antibody molecule is BMS-936559 (jacobian), also known as MDX-1105 or 12a 4. BMS-936559 and other anti-PD-L1 antibodies are disclosed in US 7,943,743 and WO 2015/081158 (which are incorporated by reference in their entirety). In one embodiment, the anti-PD-L1 antibody molecule comprises one or more of: the CDR sequences (or overall all CDR sequences), the heavy or light chain variable region sequences, or the heavy or light chain sequences of BMS-936559, e.g., as disclosed in table 19.
Other known anti-PD-L1 antibodies include those described, for example, in: WO 2015/181342, WO2014/100079, WO 2016/000619, WO 2014/022758, WO 2014/055897, WO 2015/061668, WO2013/079174, WO 2012/145493, WO 2015/112805, WO 2015/109124, WO 2015/195163, US 8,168,179, US 8,552,154, US 8,460,927, and US9,175,082 (which are incorporated by reference in their entirety).
In one embodiment, the anti-PD-L1 antibody is an antibody that competes with one of the anti-PD-L1 antibodies described herein for binding to the same epitope on PD-L1 and/or binding to the same epitope on PD-L1.
TABLE 19 amino acid sequences of other exemplary anti-PD-L1 antibody molecules
Figure BDA0002340450700005981
Figure BDA0002340450700005991
LAG-3 inhibitors
In certain embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG-3. In some embodiments, the antibody conjugates of the invention are administered in combination with a LAG-3 inhibitor. In some embodiments, the LAG-3 inhibitor is selected from LAG525 (nova corporation), BMS-986016 (behmean nobel corporation), or TSR-033 (tasarol corporation).
Exemplary LAG-3 inhibitors
In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule. In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule, as disclosed in US2015/0259420 (incorporated by reference in its entirety) published on day 17/9 of 2015 entitled "antibody molecule of LAG-3 and uses thereof".
In one embodiment, the anti-LAG-3 antibody molecule comprises at least one, two, three, four, five, or six Complementarity Determining Regions (CDRs) (or all CDRs in total) from heavy and light chain variable regions comprising, or encoded by, the amino acid sequences set forth in table 20 (e.g., heavy and light chain variable region sequences from BAP 050-clone I, or BAP 050-clone J disclosed in table 20). In some embodiments, the CDRs are defined according to kabat (e.g., as listed in table 20). In some embodiments, the CDRs are defined according to georgia (e.g., as listed in table 20). In some embodiments, these CDRs are defined from a combined CDR of both kabat and georgia (e.g., as listed in table 20). In one embodiment, the combination of the kabat and the geodesia CDRs of VH CDR1 comprises amino acid sequence GFTLTNYGMN (SEQ ID NO: 766). In one embodiment, one or more of the CDRs (or the overall all of the CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to the amino acid sequences set forth in table 20, or the amino acid sequences encoded by the nucleotide sequences set forth in table 20.
In one embodiment, the anti-LAG-3 antibody molecule comprises: a heavy chain variable region (VH) comprising the amino acid sequence VHCDR1 of SEQ ID NO:701, the amino acid sequence VHCDR2 of SEQ ID NO:702, and the amino acid sequence VHCDR3 of SEQ ID NO: 703; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:710, the VLCDR2 amino acid sequence of SEQ ID NO:711, and the VLCDR3 amino acid sequence of SEQ ID NO:712, each as disclosed in Table 20.
In one embodiment, the anti-LAG-3 antibody molecule comprises: a VH comprising a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO:736 or 737, a VHCDR2 encoded by the nucleotide sequence of SEQ ID NO:738 or 739, and a VHCDR3 encoded by the nucleotide sequence of SEQ ID NO:740 or 741; and a VL comprising VLCDR1 encoded by the nucleotide sequence of SEQ ID No. 746 or 747, VLCDR2 encoded by the nucleotide sequence of SEQ ID No. 748 or 749, and VLCDR3 encoded by the nucleotide sequence of SEQ ID No. 750 or 751, each of which is disclosed in table 20. In one embodiment, the anti-LAG-3 antibody molecule comprises: a VH comprising a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO:758 or 737, a VHCDR2 encoded by the nucleotide sequence of SEQ ID NO:759 or 739, and a VHCDR3 encoded by the nucleotide sequence of SEQ ID NO:760 or 741; and a VL comprising VLCDR1 encoded by the nucleotide sequence of SEQ ID No. 746 or 747, VLCDR2 encoded by the nucleotide sequence of SEQ ID No. 748 or 749, and VLCDR3 encoded by the nucleotide sequence of SEQ ID No. 750 or 751, each of which is disclosed in table 20.
In one embodiment, the anti-LAG-3 antibody molecule comprises: a VH comprising the amino acid sequence of SEQ ID NO. 706, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO. 706. In one embodiment, the anti-LAG-3 antibody molecule comprises: VL comprising the amino acid sequence of SEQ ID NO. 718, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO. 718. In one embodiment, the anti-LAG-3 antibody molecule comprises: a VH comprising the amino acid sequence of SEQ ID NO:724, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 724. In one embodiment, the anti-LAG-3 antibody molecule comprises: a VL comprising the amino acid sequence of SEQ ID NO:730, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 730. In one embodiment, the anti-LAG-3 antibody molecule comprises: VH comprising the amino acid sequence of SEQ ID NO. 706 and VL comprising the amino acid sequence of SEQ ID NO. 718. In one embodiment, the anti-LAG-3 antibody molecule comprises: VH comprising the amino acid sequence of SEQ ID NO:724 and VL comprising the amino acid sequence of SEQ ID NO: 730.
In one embodiment, the antibody molecule comprises: a VH encoded by the nucleotide sequence of SEQ ID NO:707 or 708, or a nucleotide sequence having at least 85%, 90%, 95%, or 99% or more identity to SEQ ID NO:707 or 708. In one embodiment, the antibody molecule comprises: VL encoded by a nucleotide sequence of SEQ ID NO. 719 or 720, or a nucleotide sequence having at least 85%, 90%, 95%, or 99% or more identity to SEQ ID NO. 719 or 720. In one embodiment, the antibody molecule comprises: a VH encoded by the nucleotide sequence of SEQ ID NO:725 or 726, or a nucleotide sequence having at least 85%, 90%, 95%, or 99% or more identity to SEQ ID NO:725 or 726. In one embodiment, the antibody molecule comprises: a VL encoded by the nucleotide sequence of SEQ ID NO:731 or 732, or a nucleotide sequence having at least 85%, 90%, 95%, or 99% or more identity to SEQ ID NO:731 or 732. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO:707 or 708 and a VL encoded by the nucleotide sequence of SEQ ID NO:719 or 720. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO:725 or 726 and a VL encoded by the nucleotide sequence of SEQ ID NO:731 or 732.
In one embodiment, the anti-LAG-3 antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO 709, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO 709. In one embodiment, the anti-LAG-3 antibody molecule comprises: a light chain comprising the amino acid sequence of SEQ ID NO. 721, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO. 721. In one embodiment, the anti-LAG-3 antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO:727, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 727. In one embodiment, the anti-LAG-3 antibody molecule comprises: a light chain comprising the amino acid sequence of SEQ ID NO:733, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 733. In one embodiment, the anti-LAG-3 antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO 709 and a light chain comprising the amino acid sequence of SEQ ID NO 721. In one embodiment, the anti-LAG-3 antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO 727 and a light chain comprising the amino acid sequence of SEQ ID NO 733.
In one embodiment, the antibody molecule comprises: a heavy chain encoded by the nucleotide sequence of SEQ ID NO. 716 or 717, or a nucleotide sequence having at least 85%, 90%, 95%, or 99% or more identity to SEQ ID NO. 716 or 717. In one embodiment, the antibody molecule comprises: a light chain encoded by the nucleotide sequence of SEQ ID NO. 722 or 723, or a nucleotide sequence having at least 85%, 90%, 95%, or 99% or more identity to SEQ ID NO. 722 or 723. In one embodiment, the antibody molecule comprises: heavy chain encoded by the nucleotide sequence of SEQ ID No. 728 or 729, or a nucleotide sequence having at least 85%, 90%, 95%, or 99% or more identity to SEQ ID No. 728 or 729. In one embodiment, the antibody molecule comprises: a light chain encoded by the nucleotide sequence of SEQ ID NO. 734 or 735, or a nucleotide sequence having at least 85%, 90%, 95%, or 99% or more identity to SEQ ID NO. 734 or 735. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO. 716 or 717 and a light chain encoded by the nucleotide sequence of SEQ ID NO. 722 or 723. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO:728 or 729 and a light chain encoded by the nucleotide sequence of SEQ ID NO:734 or 735.
The antibody molecules described herein can be made by vectors, host cells, and methods described in US2015/0259420 (which is incorporated by reference in its entirety).
TABLE 20 amino acid and nucleotide sequences of exemplary anti-LAG-3 antibody molecules
Figure BDA0002340450700006021
Figure BDA0002340450700006041
Figure BDA0002340450700006051
Figure BDA0002340450700006071
Figure BDA0002340450700006081
Figure BDA0002340450700006091
Figure BDA0002340450700006101
Figure BDA0002340450700006121
Other exemplary LAG-3 inhibitors
In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule. In one embodiment, the LAG-3 inhibitor is BMS-986016 (behcet masuibao corporation), also known as BMS 986016. BMS-986016 and other anti-LAG-3 antibodies are disclosed in WO 2015/116539 and US9,505,839 (which are incorporated by reference in their entirety). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more of: the CDR sequences (or overall all CDR sequences), the heavy or light chain variable region sequences, or the heavy or light chain sequences of BMS-986016, e.g., as disclosed in table 11.
In one embodiment, the anti-LAG-3 antibody molecule is TSR-033 (tasaro). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more of: the CDR sequences (or overall all CDR sequences) of TSR-033, the heavy or light chain variable region sequences, or the heavy or light chain sequences.
In one embodiment, the anti-LAG-3 antibody molecule is IMP731 or GSK2831781(GSK corporation and Prima BioMed). IMP731 and other anti-LAG-3 antibodies are disclosed in WO 2008/132601 and US9,244,059 (which are incorporated by reference in their entirety). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more of: the CDR sequences (or overall CDR sequences) of IMP731, the heavy or light chain variable region sequences, or the heavy or light chain sequences, e.g., as disclosed in table 11. In one embodiment, the anti-LAG-3 antibody molecule comprises one or more of: the CDR sequences (or overall all CDR sequences) of GSK2831781, the heavy or light chain variable region sequences, or the heavy or light chain sequences.
In one embodiment, the anti-LAG-3 antibody molecule is IMP761 (prrema biomedical corporation). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more of: the CDR sequences (or overall CDR sequences) of IMP761, the heavy or light chain variable region sequences, or the heavy or light chain sequences.
Other known anti-LAG-3 antibodies include those described in, for example, WO 2008/132601, WO 2010/019570, WO 2014/140180, WO 2015/116539, WO2015/200119, WO 2016/028672, US9,244,059, US9,505,839 (which are incorporated by reference in their entirety).
In one embodiment, the anti-LAG-3 antibody is an antibody that competes with one of the anti-LAG-3 antibodies described herein for binding to the same epitope on LAG-3 and/or binding to the same epitope on LAG-3.
In one embodiment, the anti-LAG-3 inhibitor is a soluble LAG-3 protein, e.g., IMP321 (procima biomedical corporation), e.g., as disclosed in WO 2009/044273 (which is incorporated by reference in its entirety).
TABLE 11 amino acid sequences of other exemplary anti-LAG-3 antibody molecules
Figure BDA0002340450700006131
Figure BDA0002340450700006141
TIM-3 inhibitors
In certain embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TIM-3. In some embodiments, the antibody conjugates of the present invention are administered in combination with a TIM-3 inhibitor. In some embodiments, the TIM-3 inhibitor is MGB453 (Nowa) or TSR-022 (Tasaxole).
Exemplary TIM-3 inhibitors
In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule. In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule, as disclosed in US 2015/0218274 published 2015 8/6 (which is incorporated by reference in its entirety) entitled "antibody molecule of TIM-3 and uses thereof".
In one embodiment, the anti-TIM-3 antibody molecule comprises at least one, two, three, four, five, or six Complementarity Determining Regions (CDRs) (or all CDRs in total) from a heavy and light chain variable region comprising an amino acid sequence shown in table 12 (e.g., a heavy and light chain variable region sequence from ABTIM3-hum11, or ABTIM3-hum03 disclosed in table 12), or an amino acid sequence encoded by a nucleotide sequence shown in table 12. In some embodiments, the CDRs are defined according to kabat (e.g., as listed in table 12). In some embodiments, the CDRs are according to the georgia definition (e.g., as listed in table 12). In one embodiment, one or more of the CDRs (or the overall all of the CDRs) have one, two, three, four, five, six or more changes, such as amino acid substitutions (e.g., conservative amino acid substitutions) or deletions, relative to the amino acid sequences set forth in table 12, or the amino acid sequences encoded by the nucleotide sequences set forth in table 12.
In one embodiment, the anti-TIM-3 antibody molecule comprises: a heavy chain variable region (VH) comprising the amino acid sequence VHCDR1 of SEQ ID NO:801, the amino acid sequence VHCDR2 of SEQ ID NO:802, and the amino acid sequence VHCDR3 of SEQ ID NO: 803; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:810, the VLCDR2 amino acid sequence of SEQ ID NO:811, and the VLCDR3 amino acid sequence of SEQ ID NO:812, each as disclosed in Table 12. In one embodiment, the anti-TIM-3 antibody molecule comprises: a heavy chain variable region (VH) comprising the amino acid sequence VHCDR1 of SEQ ID NO:801, the amino acid sequence VHCDR2 of SEQ ID NO:820, and the amino acid sequence VHCDR3 of SEQ ID NO: 803; and a light chain variable region (VL) comprising the VLCDR1 amino acid sequence of SEQ ID NO:810, the VLCDR2 amino acid sequence of SEQ ID NO:811, and the VLCDR3 amino acid sequence of SEQ ID NO:812, each as disclosed in Table 12.
In one embodiment, the anti-TIM-3 antibody molecule comprises: a VH comprising the amino acid sequence of SEQ ID NO:806, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 806. In one embodiment, the anti-TIM-3 antibody molecule comprises: VL comprising the amino acid sequence of SEQ ID NO 816 or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO 816. In one embodiment, the anti-TIM-3 antibody molecule comprises: a VH comprising the amino acid sequence of SEQ ID NO 822, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO 822. In one embodiment, the anti-TIM-3 antibody molecule comprises: VL comprising the amino acid sequence of SEQ ID NO:826, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 826. In one embodiment, the anti-TIM-3 antibody molecule comprises: a VH comprising the amino acid sequence of SEQ ID NO. 806 and a VL comprising the amino acid sequence of SEQ ID NO. 816. In one embodiment, the anti-TIM-3 antibody molecule comprises: a VH comprising the amino acid sequence of SEQ ID NO 822 and a VL comprising the amino acid sequence of SEQ ID NO 826.
In one embodiment, the antibody molecule comprises: a VH encoded by the nucleotide sequence of SEQ ID NO:807, or a nucleotide sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 807. In one embodiment, the antibody molecule comprises: a VL encoded by the nucleotide sequence of SEQ ID NO:817, or a nucleotide sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 817. In one embodiment, the antibody molecule comprises: a VH encoded by the nucleotide sequence of SEQ ID NO:823, or a nucleotide sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 823. In one embodiment, the antibody molecule comprises: VL encoded by the nucleotide sequence of SEQ ID NO:827, or a nucleotide sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 827. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO:807 and a VL encoded by the nucleotide sequence of SEQ ID NO: 817. In one embodiment, the antibody molecule comprises the VH encoded by the nucleotide sequence of SEQ ID NO 823 and the VL encoded by the nucleotide sequence of SEQ ID NO 827.
In one embodiment, the anti-TIM-3 antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO:808, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 808. In one embodiment, the anti-TIM-3 antibody molecule comprises: a light chain comprising the amino acid sequence of SEQ ID NO. 818, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO. 818. In one embodiment, the anti-TIM-3 antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO. 824, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO. 824. In one embodiment, the anti-TIM-3 antibody molecule comprises: a light chain comprising the amino acid sequence of SEQ ID NO. 828, or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO. 828. In one embodiment, an anti-TIM-3 antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO:808 and a light chain comprising the amino acid sequence of SEQ ID NO: 818. In one embodiment, an anti-TIM-3 antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO 824 and a light chain comprising the amino acid sequence of SEQ ID NO 828.
In one embodiment, the antibody molecule comprises: a heavy chain encoded by the nucleotide sequence of SEQ ID NO:809, or a nucleotide sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 809. In one embodiment, the antibody molecule comprises: a light chain encoded by the nucleotide sequence of SEQ ID NO 819 or a nucleotide sequence that has at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO 819. In one embodiment, the antibody molecule comprises: a heavy chain encoded by the nucleotide sequence of SEQ ID NO. 825, or a nucleotide sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO. 825. In one embodiment, the antibody molecule comprises: a light chain encoded by the nucleotide sequence of SEQ ID NO:829 or a nucleotide sequence having at least 85%, 90%, 95%, or 99%, or more, identity to SEQ ID NO: 829. In one embodiment, the antibody molecule comprises: a heavy chain encoded by the nucleotide sequence of SEQ ID NO. 809 and a light chain encoded by the nucleotide sequence of SEQ ID NO. 819. In one embodiment, the antibody molecule comprises: a heavy chain encoded by the nucleotide sequence of SEQ ID NO. 825 and a light chain encoded by the nucleotide sequence of SEQ ID NO. 829.
The antibody molecules described herein may be made by vectors, host cells, and methods described in US 2015/0218274 (which is incorporated by reference in its entirety).
TABLE 12 amino acid and nucleotide sequences of exemplary anti-TIM-3 antibody molecules
Figure BDA0002340450700006181
Figure BDA0002340450700006191
Figure BDA0002340450700006201
Figure BDA0002340450700006211
Other exemplary TIM-3 inhibitors
In one embodiment, the anti-TIM-3 antibody molecule is TSR-022 (aneptatys bio/thazaro). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of: the CDR sequences (or overall all CDR sequences) of TSR-022, the heavy or light chain variable region sequences, or the heavy or light chain sequences. In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of: APE5137, or a CDR sequence (or overall all CDR sequences) of APE5121, a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence, e.g., as disclosed in table 13. APE5137, APE5121 and other anti-TIM-3 antibodies are disclosed in WO 2016/161270 (which is incorporated by reference in its entirety).
In one embodiment, the anti-TIM-3 antibody molecule is antibody clone F38-2E 2. In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of: a CDR sequence (or overall all CDR sequences), a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence of F38-2E 2.
Other known anti-TIM-3 antibodies include, for example, those described in WO 2016/111947, WO 2016/071448, WO 2016/144803, US 8,552,156, US 8,841,418, and US9,163,087 (which are incorporated by reference in their entirety).
In one embodiment, the anti-TIM-3 antibody is an antibody that competes with one of the anti-TIM-3 antibodies described herein for binding to the same epitope on TIM-3 and/or binding to the same epitope on TIM-3.
TABLE 13 amino acid sequences of other exemplary anti-TIM-3 antibody molecules
Figure BDA0002340450700006222
Figure BDA0002340450700006231
Cytokine
In yet another embodiment, the invention provides a method of treating cancer by administering to a subject in need thereof an antibody conjugate of the invention in combination with one or more cytokines including, but not limited to, interferon, IL-2, IL-15, IL-7, or IL 21. In certain embodiments, the antibody conjugate is administered in combination with an IL-15/IL-15Ra complex. In some embodiments, the IL-15/IL-15Ra complex is selected from NIZ985 (nova), ATL-803 (Altor), or CYP0150 (Cytune).
Exemplary IL-15/IL-15Ra complexes
In one embodiment, the cytokine is IL-15 complexed with a soluble form of IL-15 receptor α (IL-15Ra) the IL-15/IL-15Ra complex can comprise a soluble form of IL-15 covalently or non-covalently bound to IL-15Ra in a particular embodiment, human IL-15 non-covalently binds to a soluble form of IL-15Ra in a particular embodiment, the human IL-15 of the composition comprises the amino acid sequence of SEQ ID NO:922 in Table 21 or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more identity to SEQ ID NO:922, and the soluble form of human IL-15Ra comprises the amino acid sequence of SEQ ID NO:923 in Table 21 or an amino acid sequence having at least 85%, 90%, 95%, or 99%, or more identity to SEQ ID NO:923, as described in WO 2014/066527 (which is incorporated by reference in its entirety).
TABLE 21 amino acid and nucleotide sequences of exemplary IL-15/IL-15Ra complexes
Figure BDA0002340450700006232
Other exemplary IL-15/IL-15Ra complexes
In one embodiment, the IL-15/IL-15Ra complex is ALT-803(IL-15/IL-15Ra Fc fusion protein (IL-15N72D: IL-15RaSu/Fc soluble complex)). ALT-803 is described in WO 2008/143794 (which is incorporated by reference in its entirety). In one embodiment, the IL-15/IL-15Ra Fc fusion protein comprises a sequence as disclosed in table 22.
In one embodiment, the IL-15/IL-15Ra complex comprises IL-15 fused to the sushi domain of IL-15Ra (CYP0150, Saiteng pharmaceutical). The sushi domain of IL-15Ra refers to a domain that begins at the first cysteine residue after the signal peptide of IL-15Ra and ends at the fourth cysteine residue after the signal peptide. Complexes of IL-15 fused to the sushi domain of IL-15Ra are described in WO 2007/04606 and WO 2012/175222 (which are incorporated by reference in their entirety). In one embodiment, the IL-15/IL-15Ra sushi domain fusion comprises a sequence as disclosed in Table 22.
TABLE 22 amino acid sequences of other exemplary IL-15/IL-15Ra complexes
Figure BDA0002340450700006241
In yet another embodiment, the invention provides a method of treating cancer by administering to a subject in need thereof an antibody conjugate of the invention in combination with one or more Toll-like receptor agonists (TLRs, e.g., TLR7, TLR8, TLR 9). In some embodiments, the antibody conjugates of the invention may be used in combination with a TLR7 agonist or a TLR7 agonist conjugate.
In another embodiment, the invention provides a method of treating cancer by administering to a subject in need thereof an antibody conjugate of the invention in combination with one or more of the following angiogenesis inhibitors: such as bevacizumab
Figure BDA0002340450700006251
Asitinib
Figure BDA0002340450700006252
Alanine brimonib (Brivanib alaninate) (BMS-582664, (S) - ((R) -1- (4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -5-methylpyrrolo [2, 1-f)][1,2,4]Triazin-6-yloxy) propan-2-yl) 2-aminopropionic acid); sorafenib
Figure BDA0002340450700006253
Pazopanib
Figure BDA0002340450700006254
Sunitinib malate
Figure BDA0002340450700006255
Cediranib (AZD2171, CA)S288383-20-1); vigatde (Vargatef) (BIBF1120, CAS 928326-83-4); fluoroeritib (Foretinib) (GSK 1363089); tilapinib (Telatinib) (BAY57-9352, CAS 332012-40-5); apatinib (Apatinib) (YN968D1, CAS 811803-05-1); imatinib (Imatinib)
Figure BDA0002340450700006256
Ponatinib (Ponatinib) (AP 245734, CAS 943319-70-8); tivozanib (Tivozanib) (AV951, CAS 475108-18-0); regorafenib (BAY73-4506, CAS 755037-03-7); vartanib dihydrochloride (Vatalanib dihydrochloride) (PTK787, CAS 212141-51-0); brivanil (Brivanib) (BMS-540215, CAS 649735-46-6); vandetanib (b)
Figure BDA0002340450700006257
Or AZD 6474); motesanib diphosphate (AMG706, CAS 857876-30-3, N- (2, 3-dihydro-3, 3-dimethyl-1H-indol-6-yl) -2- [ (4-pyridylmethyl) amino group]-3-pyridinecarboxamide, described in PCT publication No. WO 02/066470); dolitinib dilactatic acid (TKI258, CAS 852433-84-2); linfanib (Linfanib) (ABT869, CAS 796967-16-3); cabozantinib (XL184, CAS 849217-68-1); lestaurtinib (Lestaurtinib) (CAS 111358-88-4); n- [5- [ [ [5- (1, 1-dimethylethyl) -2-oxazolyl ] radical]Methyl radical]Thio group]-2-thiazolyl]-4-piperidinecarboxamide (BMS38703, CAS 345627-80-7); (3R,4R) -4-amino-1- ((4- ((3-methoxyphenyl) amino) pyrrolo [2, 1-f)][1,2,4]Triazin-5-yl) methyl) piperidin-3-ol (BMS690514), N- (3, 4-dichloro-2-fluorophenyl) -6-methoxy-7- [ [ (3a α,5 β,6a α) -octahydro-2-methylcyclopenta [ c]Pyrrol-5-yl]Methoxy radical]-4-quinazolinamine (XL647, CAS 781613-23-8); 4-methyl-3- [ [ 1-methyl-6- (3-pyridinyl) -1H-pyrazolo [3,4-d]Pyrimidin-4-yl]Amino group]-N- [3- (trifluoromethyl) phenyl]-benzamide (BHG712, CAS 940310-85-0); or Abelia arborvitae
In another embodiment, the present invention provides a method of treating cancer by administering to a subject in need thereof an antibody conjugate of the present invention in combination with one or more of the following heat shock protein inhibitors: such as tanespimycins (17-allylamino-17-demethoxygeldanamycin, also known as KOS-953 and 17-AAG, available from Sigma, Sigma and described in U.S. Pat. No. 4,261,989); retaxomycin (Retaspmycin) (IPI504), Ganetespib (STA-9090); [ 6-chloro-9- (4-methoxy-3, 5-dimethylpyridin-2-ylmethyl) -9H-purin-2-yl ] amine (BIIB021 or CNF2024, CAS 848695-25-0); trans-4- [ [2- (aminocarbonyl) -5- [4,5,6, 7-tetrahydro-6, 6-dimethyl-4-oxo-3- (trifluoromethyl) -1H-indazol-1-yl ] phenyl ] amino ] cyclohexyl glycinate (SNX5422 or PF04929113, CAS 908115-27-5); 5- [2, 4-dihydroxy-5- (1-methylethyl) phenyl ] -N-ethyl-4- [4- (4-morpholinomethyl) phenyl ] -3-isoxazolecarboxamide (AUY922, CAS 747412-49-3); or 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG).
In another embodiment, the invention provides a method of treating cancer by administering to a subject in need thereof an antibody conjugate of the invention in combination with one or more HDAC inhibitors or other epigenetic modifiers. Exemplary HDAC inhibitors include, but are not limited to, Voninostat
Figure BDA0002340450700006261
Romidepsin (Romidepsin)
Figure BDA0002340450700006262
Trichostatin a (treichostatin a) (tsa); oxamflatin; vorinostat (Vorinostat) (ii)
Figure BDA0002340450700006263
Suberoylanilide hydroxamic acid), Pyroxamide (symboloyl-3-aminopyridine amide hydroxamic acid), Trapoxin A (RF-1023A), Trapoxin B (RF-10238), cyclo [ (α S,2S) - α -amino- η -oxo-2-oxiranoyl-O-methyl-D-tyrosyl-L-isoleucyl-L-prolyl](Cyl-1); ring [ (α S,2S) - α -amino- η -oxo-2-oxiraneoctanoyl-O-methyl-D-tyrosyl-L-isoleucyl- (2S)) -2-piperidinecarbonyl group](Cyl-2); cyclo [ L-alanyl-D-alanyl- (2S) - η -oxo-L- α -aminooxirane octanoyl-D-prolyl](HC-toxin); cyclo [ (α S,2S) - α -amino- η -oxo-2-oxiranoyl-D-phenylalanyl-L-leucyl- (2S) -2-piperidinecarbonyl group](WF-3161) ((S) -Ring (2-Methylalaninyl-L-phenylalanyl-D-prolyl- η -oxo-L- α -aminooxirane octanoyl) ((Chlamydocin); Histone deacetylase inhibitor (Apicidin) (Ring (8-oxo-L-2-aminodecanoyl-1-methoxy-L-tryptophanyl-L-isoleucyl-D-2-piperidinecarbonyl); romidepsin: (TM) ((S))
Figure BDA0002340450700006264
FR-901228); 4-phenylbutyrate; spiruchostatin a; mylprotin (valproic acid); ennostat (MS-275, N- (2-aminophenyl) -4- [ N- (pyridin-3-yl-methoxycarbonyl) -amino-methyl]-benzamide); depudecin (4,5:8, 9-dianhydro-1, 2,6,7, 11-pentadeoxy-D-threo-D-ido-undec-1, 6-dienol); 4- (acetylamino) -N- (2-aminophenyl) -benzamide (also known as CI-994); n1- (2-aminophenyl) -N8-phenyl-octanediamide (also known as BML-210); 4- (dimethylamino) -N- (7- (hydroxyamino) -7-oxoheptyl) benzamide (also known as M344); (E) -3- (4- (((2- (1H-indol-3-yl) ethyl) (2-hydroxyethyl) amino) -methyl) phenyl) -N-hydroxyacrylamide; panobinostat
Figure BDA0002340450700006271
Mornostat (Mocetinostat) and belinostat (also known as PXD101, b,Or (2E) -N-hydroxy-3- [3- (phenylsulfamoyl) phenyl]Prop-2-enamide) or chidamide (also known as CS055 or HBI-8000, (E) -N- (2-amino-5-fluorophenyl) -4- ((3- (pyridin-3-yl) acrylamido) methyl) benzamide). Other appearance modifying agents include, but are not limited to, inhibitors of EZH2 (enhancer of zeste homolog 2), EED (embryonic ectodermal development) or LSD1 (lysine-specific histone demethylase 1A or KDM 1A).
In yet another embodiment, the present invention provides a method of treating cancer by administering to a subject in need thereof an antibody conjugate of the present invention in combination with one or more indoleamine-pyrrole 2, 3-dioxygenase (IDO) inhibitors (e.g., insipidotimod (also known as NLG-8189), α -cyclohexyl-5H-imidazo [5,1-a ] isoindol-5-ethanol (also known as NLG919) or (4E) -4- [ (3-chloro-4-fluoroanilino) -nitrosomethylene ] -1,2, 5-oxadiazol-3-amine (also known as INCB 024360).
In yet another embodiment, the invention provides a method of treating cancer by administering to a subject in need thereof an antibody conjugate of the invention in combination with one or more agents that control or treat Cytokine Release Syndrome (CRS). Therapies directed against CRS include, but are not limited to, IL-6 inhibitors or IL-6 receptor (IL-6R) inhibitors (e.g., tollizumab or cetuximab), bazedoxifene, sgp130 blockers, vasoactive drugs, corticosteroids, immunosuppressants, histamine H2Receptor antagonists, antipyretics, analgesics (e.g., acetaminophen), and mechanical ventilation. Exemplary therapies for CRS are described in international application WO 2014011984, which is hereby incorporated by reference.
Tulizumab is a humanized immunoglobulin G1 kappa anti-human IL-6R monoclonal antibody. Tulizumab blocks the binding of IL-6 to soluble and membrane-bound IL-6 receptor (IL-6R) and thereby inhibits classical and trans-IL-6 signaling. In embodiments, the tositumumab is administered at a dose of about 4-12mg/kg (e.g., about 4-8mg/kg) for an adult and about 8-12mg/kg for a pediatric subject, e.g., within 1 hour.
In some embodiments, the CRS therapeutic is an inhibitor of IL-6 signaling, e.g., an inhibitor of IL-6 or an IL-6 receptor. In one embodiment, the inhibitor is an anti-IL-6 antibody, e.g., an anti-IL-6 chimeric monoclonal antibody (e.g., siltuximab). In other embodiments, the inhibitor comprises soluble gp130(sgp130) or a fragment thereof capable of blocking IL-6 signaling. In some embodiments, sgp130 or a fragment thereof is fused to a heterologous domain, e.g., an Fc domain, e.g., is a gp130-Fc fusion protein (e.g., FE 301). In embodiments, the inhibitor of IL-6 signaling comprises an antibody, e.g., an antibody directed against an IL-6 receptor, such as sarilumab, olokizumab (CDP6038), elsilimomab, sirukumab (CNTO136), ALD518/BMS-945429, ARGX-109, or FM 101. In some embodiments, the inhibitor of IL-6 signaling comprises a small molecule (e.g., CPSI-2364).
Exemplary vasoactive drugs include, but are not limited to, angiotensin-11, endothelin-1, α adrenergic agonists, rostannoid, phosphodiesterase inhibitors, endothelin antagonists, inotropes (e.g., epinephrine, dobutamine, isoproterenol, ephedrine), vasopressors (e.g., norepinephrine, vasopressin, metahydroxylamine, vasopressin, methylene blue), vasodilators (e.g., milrinone, levosimendan), and dopamine.
Exemplary vasopressors include, but are not limited to, norepinephrine, dopamine, phenylephrine, epinephrine, and vasopressin. In some embodiments, the high dose vasopressors include one or more of: norepinephrine monotherapy no less than 20ug/min, dopamine monotherapy no less than 10ug/kg/min, phenylephrine monotherapy no less than 200ug/min, and/or epinephrine monotherapy no less than 10 ug/min. In some embodiments, if the subject is on vasopressin, the high dose vasopressor comprises vasopressin + norepinephrine at an equivalent of ≧ 10ug/min, where norepinephrine equivalent dose ═ norepinephrine (ug/min) ] + [ dopamine (ug/kg/min)/2] + [ epinephrine (ug/min) ] + [ phenylephrine (ug/min)/10 ]. In some embodiments, if the subject is on a combination vasopressor (non-vasopressin), the high dose vasopressor comprises norepinephrine at an equivalent weight of ≧ 20ug/min, where norepinephrine equivalent dose ═ norepinephrine (ug/min) ] + [ dopamine (ug/kg/min)/2] + [ epinephrine (ug/min) ] + [ phenylephrine (ug/min)/10. See, e.g., above.
In some embodiments, the low dose vasopressor is a vasopressor administered at a dose less than one or more of the doses listed above for the high dose vasopressor.
Exemplary corticosteroids include, but are not limited to, dexamethasone, hydrocortisone, and methylprednisolone. In the examples, a dose of 0.5mg/kg dexamethasone was used. In the examples, a maximum dose of 10 mg/dose of dexamethasone was used. In the examples, a2 mg/kg/day dose of methylprednisolone was used.
In embodiments, the inhibitor of TNF α comprises a soluble TNF α receptor (e.g., etanercept).
Exemplary Histamine H2Receptor antagonists include, but are not limited to cimetidine
Figure BDA0002340450700006291
RanitidineFamotidine
Figure BDA0002340450700006293
And nizatidine
Figure BDA0002340450700006294
Exemplary antipyretics and analgesics include, but are not limited to, acetaminophen
Figure BDA0002340450700006295
Ibuprofen and aspirin.
In some embodiments, the invention provides methods of treating cancer by administering to a subject in need thereof an antibody conjugate of the invention in combination with two or more of any of the inhibitors, activators, immunomodulators, agonists or modifying agents described above. For example, the antibody conjugates of the invention may be used in combination with one or more checkpoint inhibitors and/or one or more sets of immune activators.
In addition to the above treatment regimens, the patient may be subjected to surgical removal of cancer cells and/or radiation therapy.
Pharmaceutical composition
To prepare a pharmaceutical or sterile composition comprising one or more of the antibody conjugates described herein, the antibody conjugates provided can be admixed with a pharmaceutically acceptable carrier or excipient.
Formulations of therapeutic and diagnostic agents may be prepared, for example, by mixing with a physiologically acceptable carrier, excipient, or stabilizer in The form of a lyophilized powder, slurry, aqueous solution, lotion, or suspension (see, e.g., Hardman et al, Goodman and Gilman's The Pharmacological Basis of Therapeutics [ Goodman and Gilman's Pharmacological Basis ], McGraw-Hill [ Maillard-Hill group ], New York City, New York State, 2001; Gennaro, Remington: The Science and Practice of medicine [ Remington: Pharmaceutical Science and Practice ], Lepidote-Weiss and Wilkins publishing Co., Lippincom, Williams, and Wilkins, New York medicine, New York state, 2000; Avis et al (eds.), Pharmaceutical dosaging: pharmaceuticals [ drugs: parenteral Tablets ], Mardie Pharmaceutical compositions [ drugs: Pharmaceutical compositions [ drug: cells ], New York cells [ 1993; Tanker edition: Pharmaceutical compositions [ drug: Pharmaceutical Tablets ], Pharmaceutical compositions [ drug: Lepids, Inc.: 1993 ], (Pharmaceutical compositions: Pharmaceutical compositions [ drug: Western research, Inc.: New York, Pharmaceutical Dosage Forms; Lipman, Inc.: 1993; Pharmaceutical composition, Pharmaceutical Dosage Forms, Inc.: see, Pharmaceutical Dosage Forms, Inc.: New York, Inc.: see, Pharmaceutical Dosage Forms, Inc.: see, Inc., marcel dekke [ massel dekker ], new york, 1990; lieberman et al (eds.) Pharmaceutical dosage forms: Dispersion Systems [ Pharmaceutical dosage forms: dispersion system ], massel Dekker (Marcel Dekker), new york, 1990; weiner and Kotkoskie, Excipient Toxicity and Safety, Marcel Dekker, Inc. [ massel Dekker ], new york city, new york state, 2000).
In some embodiments, the pharmaceutical composition comprising the antibody conjugate of the invention is a lyophile formulation. In certain embodiments, the pharmaceutical composition comprising the antibody conjugate is a lyophilizate comprising the antibody conjugate, histidine, sucrose and polysorbate 20 in a vial. In certain embodiments, the pharmaceutical composition comprising the antibody conjugate is a lyophilizate comprising the antibody conjugate, sodium succinate, and polysorbate 20 in a vial. In certain embodiments, the pharmaceutical composition comprising the antibody conjugate is a lyophilizate comprising the antibody conjugate, trehalose, citrate, and polysorbate 8 in a vial. The lyophilizate can be reconstituted, for example, with water, saline for injection. In a particular embodiment, the solution comprises an antibody conjugate having a pH of about 5.0, histidine, sucrose and polysorbate 20. In another specific embodiment, the solution comprises an antibody conjugate, sodium succinate, and polysorbate 20. In another specific embodiment, the solution comprises an antibody conjugate having a pH of about 6.6, anhydrotrehalose, citrate dehydrate, citric acid and polysorbate 8. For intravenous administration, the obtained solution is usually further diluted in a carrier solution.
The choice of administration regimen for a therapeutic agent depends on several factors, including the serum or tissue turnover rate of the entity, the level of symptoms, the immunogenicity of the entity, and the accessibility of target cells in the biological matrix. In certain embodiments, the administration regimen maximizes the amount of therapeutic agent delivered to the patient, consistent with acceptable levels of side effects. Thus, the amount of biological product delivered depends in part on the particular entity and the severity of the condition being treated. A guide to select appropriate doses of Antibodies, Cytokines and small molecules is available (see, e.g., Wawrynczak, Antibody Therapy [ Antibody Therapy ], BiosScientific Pub.Ltd. [ Bios science publishers, Ltd. ], Oxfordshire [ Oxfordshire county ], UK, 1996; Kresina (eds.), Monoclonal Antibodies, Cytokines and Arthritis [ Monoclonal Antibodies, Cytokines and Arthritis ], Marcel Dekker [ Masseidel, N.Y., N.J., 1991; Bach (eds.), Monoclonal Antibodies and Peptide Therapy in Autoimmune Diseases [ Med Antibodies and Peptide Therapy in Autoimmune Diseases ], Marcel Dekker [ Mark Dekker, N.Y., 1991; Bach (eds.), Monoclonal Antibodies and Peptide Therapy [ Mitsugam. Mitsum. J.2001 ] New Engli. J.2003, J.1983, New Engli. J.201, J.2003, EP.2003: J.EP. 2003: EP. 344,201,201,201,201,201,201, med [ New Engl. J. Med. [ New England journal of medicine ]342: 613-; ghosh et al, New Engl.J.Med. [ New England journal of medicine ]348:24-32,2003; lipsky et al, New Engl. J. Med. [ New England journal of medicine ]343: 1594-.
The appropriate dosage is determined by the clinician, for example, using parameters or factors known or suspected to affect the treatment or expected to affect the treatment. Generally, the dose is started with an amount more or less than the optimal dose and thereafter it is increased in small increments until the desired or optimal effect is achieved with respect to any adverse side effects. Important diagnostic measures include those of symptoms (e.g., inflammation) or levels of inflammatory cytokines produced.
The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without toxicity to the patient. The selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular composition of the invention or ester, salt or amide thereof employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular composition employed, the age, sex, body weight, condition, general health and past medical history of the patient being treated, and like factors known in the medical arts.
Compositions comprising the antibody conjugates of the invention can be provided by continuous infusion, or by intermittent dosing, for example, 1-7 times per day, week, or week, once per three weeks, once per four weeks, once per five weeks, once per six weeks, once per seven weeks, or once per eight weeks. The dosage may be provided intravenously, subcutaneously, topically, orally, nasally, rectally, intramuscularly, intracerebrally or by inhalation. A particular dosage regimen is one that involves a maximum dose or frequency of administration that avoids significant undesirable side effects.
For the antibody conjugates of the invention, the dose administered to the patient may be from 0.0001mg/kg to 100mg/kg of patient body weight. The dose may be between 0.001mg/kg and 50mg/kg patient weight, between 0.005mg/kg and 20mg/kg patient weight, between 0.01mg/kg and 20mg/kg patient weight, between 0.02mg/kg and 10mg/kg patient weight, between 0.05mg/kg and 5mg/kg patient weight, between 0.1mg/kg and 10mg/kg patient weight, between 0.1mg/kg and 8mg/kg patient weight, between 0.1mg/kg and 5mg/kg patient weight, between 0.1mg/kg and 2mg/kg patient weight, between 0.1mg/kg and 1mg/kg patient weight. The dosage of the antibody conjugate can be calculated using the patient's body weight in kilograms (kg) multiplied by the dose to be administered in mg/kg.
The dosage of the antibody conjugates of the invention can be repeated and the administrations can be separated by less than 1 day, at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, 4 months, 5 months, or at least 6 months. In some embodiments, an antibody conjugate of the invention is administered twice weekly, once every two weeks, once every three weeks, once every four weeks, or less frequently. In a specific embodiment, the dosage of the antibody conjugate of the invention is repeated every 2 weeks.
The effective amount for a particular patient may vary depending on factors such as: the condition being treated, the general health of the patient, the method, route and dosage of administration, and the severity of side effects (see, e.g., Maynard et al, AHandboot of SOPs for Good Clinical Practice SOP guidelines for Good Clinical Practice, International pharmaceutical Press (Interpharm Press), Pokaton, Florida (Boca Raton, Fla.), 1996; Dent, Good laboratory and Good Clinical Practice, Urch publication [ Erqi Press ], London, UK, 2001).
Routes of administration may be injection or infusion, for example, by topical or dermal application, by subcutaneous, intravenous, intraperitoneal, intracerebral, intramuscular, intraocular, intraarterial, intracerebroventricular, intralesional administration, or by sustained release systems or implants (see, e.g., Sidman et al, Biopolymers [ Biopolymers ]22:547-556, 1983; Langer et al, J.biomed.Mater.Res. [ J.Biomedical materials research ]15:167-277, 1981; Langer, chem.Tech. [ chemical technology ]12:98-105,1982; Epstein et al, Proc.Natl.Acad.Sci.USA [ Proc.Acad.Sci ]82:3688-3692, 1985; Hwang et al, Proc.Natl.Acad.Sci.USA [ national academy of sciences ] 40377: 4030; 6,350,466; 024 6,024 316). If desired, the composition may also contain a solubilizing agent or a local anesthetic such as lidocaine for reducing pain at the injection site, or both. Furthermore, pulmonary administration may also be employed, for example by using an inhaler or nebulizer and formulation with an aerosolizing agent. See, e.g., U.S. patent nos. 6,019,968, 5,985,320, 5,985,309, 5,934,272, 5,874,064, 5,855,913, 5,290,540, and 4,880,078; and PCT publication nos. WO 92/19244, WO 97/32572, WO 97/44013, WO 98/31346, and WO 99/66903, each of which is incorporated by reference herein in its entirety.
Examples of such additional ingredients are well known in the art.
Methods of co-administration or treatment with a second therapeutic agent (e.g., a cytokine, steroid, chemotherapeutic agent, antibiotic or radiation) are known in The art (see, e.g., Hardman et al, (ed.) (2001) Goodman and Gilman's The Pharmacological Basis of therapy by Goodman and Gilman ],10 th edition, McGraw-Hill, New York, N.Y., Poole and Peterson (ed.) (2001) Pharmacological assays for Advanced practicalities: A Practical Approach [ Advanced practices of pharmacotherapy ], Utility, Risperidol and Wilkinson publishing Co., Williams & Willis, Philadelphia, Chaxinia, Chabtlekura and Lobst corporation [ Lab.) (Wilkinson & Wilkins, Inc.; Chabton and Lobst edition [ Biologicals ] and Wilkins & Wilkins [ and Wilkinson & Chemicals [ laws ] (Wilkinson & Chemicals ], Wilkinson & Wilkins [ and Biologics ], and Wilkins [ Pharmans ] publications [ methods of cancer (Wilkinson & Chemicals ], philadelphia, Pa.). An effective amount of a therapeutic agent can reduce symptoms by at least 10%; at least 20%; at least about 30%; at least 40%, or at least 50%.
Additional therapies (e.g., prophylactic or therapeutic agents) that can be administered in combination with an antibody conjugate of the invention can be less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, about 1 hour to about 2 hours apart, about 2 hours to about 3 hours apart, about 3 hours to about 4 hours apart, about 4 hours to about 5 hours apart, about 5 hours to about 6 hours apart, about 6 hours to about 7 hours apart, about 7 hours to about 8 hours apart, about 8 hours to about 9 hours apart, about 9 hours to about 10 hours apart, about 10 hours to about 11 hours apart, about 11 hours to about 12 hours apart, about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, a therapeutic agent, Administration is performed 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours apart. Two or more therapies may be administered in the same patient visit.
In certain embodiments, the antibody conjugates of the invention can be formulated to ensure proper in vivo distribution. Exemplary targeting moieties include folate or biotin (see, e.g., U.S. Pat. No. 5,416,016 to Low et al); mannoside (Umezawa et al, 1988, biochem. biophysis. Res. Commun. [ biochemical and biophysical research communication ]153: 1038); antibodies (Blueman et al, 1995, FEBS Lett. [ Prov. Federation of European Biochemical Association ]357: 140; Owais et al (1995) antimicrob. Agents Chemother. [ antimicrobial chemotherapy ]39: 180); the surfactant protein a receptor (Briscoe et al, 1995, am.j. physiol. [ journal of U.S. physiology ]1233: 134); p 120(Schreier et al, 1994, J.biol.chem. [ J.Biol ]269: 9090); see also k.keinanen; l.laukkkanen (1994) FEBS Lett [ fast press of european association of biochemistry ]346: 123; j.j.killion; fidler (1994) Immunomethods [ Immunity methods ]4: 273.
The invention provides regimens for administering to a subject in need thereof a pharmaceutical composition comprising an antibody conjugate of the invention, alone or in combination with other therapies. The therapies (e.g., prophylactic or therapeutic agents) of the combination therapies of the invention can be administered to a subject simultaneously or sequentially. The therapies (e.g., prophylactic or therapeutic agents) of the combination therapies of the invention can also be administered cyclically. Cycling therapy involves administering a first therapy (e.g., a first prophylactic or therapeutic agent) for a period of time, followed by administering a second therapy (e.g., a second prophylactic or therapeutic agent) for a period of time and repeating such sequential administration, i.e., the cycling, to reduce the formation of resistance to one therapy (e.g., agent), to avoid or reduce side effects of one therapy (e.g., agent) and/or to improve the efficacy of the therapy.
The therapies (e.g., prophylactic or therapeutic agents) of the combination therapies of the invention can be administered concurrently to the subject.
The term "concurrently" is not limited to administration of therapies (e.g., prophylactic or therapeutic agents) at exactly the same time, but means that a pharmaceutical composition comprising an antibody or fragment thereof is administered to a subject in an order and within a time interval such that the antibody or antibody conjugate of the invention can act with one or more other therapies to provide an increased benefit as compared to if they were otherwise administered. For example, each therapy may be administered to a subject at the same time or sequentially at different time points in any order; however, if not administered at the same time, they should be administered sufficiently close in time to provide the desired therapeutic or prophylactic effect. Each therapy may be administered separately to the subject in any suitable form and by any suitable route. In various embodiments, therapies (e.g., prophylactic or therapeutic agents) are administered to a subject less than 5 minutes apart, less than 15 minutes apart, less than 30 minutes apart, less than 1 hour apart, about 1 hour to about 2 hours apart, about 2 hours to about 3 hours apart, about 3 hours to about 4 hours apart, about 4 hours to about 5 hours apart, about 5 hours to about 6 hours apart, about 6 hours to about 7 hours apart, about 7 hours to about 8 hours apart, about 8 hours to about 9 hours apart, about 9 hours to about 10 hours apart, about 10 hours to about 11 hours apart, about 11 hours to about 12 hours apart, 24 hours apart, 48 hours apart, 72 hours apart, or1 week apart. In other embodiments, two or more therapies (e.g., prophylactic or therapeutic agents) are administered in the same patient visit.
The prophylactic or therapeutic agents of the combination therapy can be administered to the subject in the same pharmaceutical composition. Alternatively, the prophylactic or therapeutic agents of the combination therapy may be administered concurrently to the subject in separate pharmaceutical compositions. The prophylactic or therapeutic agents can be administered to the subject by the same or different routes of administration.
It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims.
Examples of the invention
The invention is further described in the following examples, which are not intended to limit the scope of the invention described in the claims.
Example 1: synthesis of linker intermediates
Examples 1-1: synthesis of 5,5,9,12,15, 15-hexamethyl-8, 13-dioxo-14-oxa-3, 4-dithia-9, 12-diazacyclo-chloroformate (LI-1)
Figure BDA0002340450700006361
Step 1: acetic acid (0.025mL, 1.3mmol) was added to a solution of 4-mercapto-4-methylpentanoic acid (250mg, 1.69mmol) and 2- (pyridin-2-yldisulfonyl) ethanol (380mg, 2.02mmol) in MeOH (15mL) and the mixture was heated at 45 ℃ for 5 days and then concentrated and purified by ISCO using a15 g C18 column eluting with 5% -40% Acetonitrile (ACN) in water containing 0.05% TFA. The fractions containing the desired product were concentrated to give 4- ((2-hydroxyethyl) disulfonyl) -4-methylpentanoic acid (220mg, 58.1% yield). LCMS M +23 247.1, tr 0.768 min. 1H NMR (500MHz, chloroform-d) δ 3.86(t, J ═ 5.8Hz,1H),2.84(t, J ═ 5.8Hz,2H),2.49-2.37(m,2H),2.00-1.86(m,2H),1.29(s, 6H).
Step 2: DIEA (0.082mL, 0.47mmol) and tert-butylmethyl (2- (methylamino) ethyl) carbamate (44mg, 0.23mmol) were added to a solution of 4- ((2-hydroxyethyl) disulfonyl) -4-methylpentanoic acid (35mg, 0.16mmol) in Dichloromethane (DCM) (5mL), followed by N1- ((ethyliminoimino) was added) Methylene) -N3, N3-dimethylpropane-1, 3-diamine hydrochloride (EDCI) (45mg, 0.23 mmol). The mixture was stirred at rt for 16 h, then quenched with water, extracted with DCM, dried, concentrated and purified by ISCO using 15g C18 column, eluting with ACN-water containing 0.05% TFA to give tert-butyl (2- (4- ((2-hydroxyethyl) disulfonyl) -N, 4-dimethylpentanamido) ethyl) (methyl) carbamate (34mg, 50% yield). LCMS M +1 ═ 395.2, tr ═ 1.044 min.1H NMR (500MHz, chloroform-d) δ 3.84(t, J ═ 6.0Hz,2H),3.49(s,2H),3.35(t, J ═ 6.1Hz,2H),3.03(s,2H),2.94(s,1H),2.89-2.78(m,5H),2.38(d, J ═ 7.3Hz,2H),2.01-1.90(m,2H),1.83(s,3H),1.44(s,9H),1.30(s, 6H).
And step 3: pyridine (0.010ml, 0.12mmol) was added to a solution of tert-butyl (2- (4- ((2-hydroxyethyl) disulfonyl) -N, 4-dimethylpentanamido) ethyl) (methyl) carbamate (27mg, 0.068mmol) in DCM (4ml) at 0 ℃ followed by a 20% phosgene solution in toluene (0.3 ml). The reaction was stirred for 15 minutes and then concentrated to give 5,5,9,12,15, 15-hexamethyl-8, 13-dioxo-14-oxa-3, 4-dithia-9, 12-diazacyclo chloroformate (LI-1), which was used immediately without purification.
Examples 1 to 2: synthesis of 18- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) -5,5,9, 12-tetramethyl-8, 13-dioxo-16-oxa-3, 4-dithia-9, 12-dioxaoctadecanyl (4-nitrophenyl) carbonate (LI-2)
Figure BDA0002340450700006371
Step 1: trifluoroacetic acid (TFA) (1mL) was added to a flask containing tert-butyl (2- (4- ((2-hydroxyethyl) disulfonyl) -N, 4-dimethylpentanamido) ethyl) (methyl) carbamate (34mg, 0.086mmol) and the mixture was immediately concentrated to give 4- ((2-hydroxyethyl) disulfonyl) -N, 4-dimethyl-N- (2- (methylamino) ethyl) pentanamide as the TFA salt. LCMS M +1 ═ 295.3, tr ═ 0.619 min.
Step 2: n, N-Diisopropylethylamine (DIEA) (0.075ml, 0.431mmol) was added to 3- (2- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) ethoxy) propionic acid (Mal)-PEG 1-acid) (18.4mg, 0.086mmol) in DMF (2mL) followed by the addition of 3- [ bis (dimethylamino) methylonium group]-3H-benzotriazole-1-oxide Hexafluorophosphate (HBTU) (33mg, 0.086 mmol). The mixture was stirred at room temperature for 5 minutes, then added dropwise to a solution of 4- ((2-hydroxyethyl) disulfonyl) -N, 4-dimethyl-N- (2- (methylamino) ethyl) pentanamide TFA salt (35mg, 0.086mmol) in N, N-Dimethylformamide (DMF) (1 ml). The mixture was then stirred at room temperature for 2 hours and purified by mass triggered reverse phase HPLC using a C18 column with 10% -40% acetonitrile-H containing 0.05% TFA2And (4) eluting with O. The fractions containing the desired product were concentrated to obtain N- (2- (3- (2- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) ethoxy) -N-methylpropanamido) ethyl) -4- ((2-hydroxyethyl) disulfonyl) -N, 4-dimethylpentanamide (40.1mg, 90% yield). LCMS M +1 ═ 490.3tr ═ 0.841 min.
And step 3: to a solution of N- (2- (3- (2- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) ethoxy) -N-methylpropanamido) ethyl) -4- ((2-hydroxyethyl) disulfonyl) -N, 4-dimethylpentanamide (40.1mg, 0.082mmol) obtained in step 2 in DCM (3mL) was added bis (4-nitrophenyl) carbonate (125mg, 0.409mmol) followed by DIEA (0.043mL, 0.246 mmol). It was stirred at room temperature for 4 days and the reaction was completed to form the desired product. It was concentrated and the residue was dissolved in ACN and purified by ISCO using 50g C18 column eluting with 25% -75% aqueous ACN containing 0.035% TFA. The fractions containing the desired product were combined and lyophilized to give 18- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) -5,5,9, 12-tetramethyl-8, 13-dioxo-16-oxa-3, 4-dithio-9, 12-dioxaoctadecyl (4-nitrophenyl) carbonate (LI-2) (44mg, 73% yield). LCMS M +1 ═ 655.2, tr ═ 1.177 min. It was contaminated with small amounts of bis (4-nitrophenyl) carbonate and hydrolyzed alcohol by-product.
Examples 1 to 3: synthesis of 4- ((S) -2- ((S) -2- (3- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) propanamido) -3-methylbutanamido) -5-ureidopentanamido) benzyl (4-nitrophenyl) carbonate (LI-3)
Figure BDA0002340450700006391
Step 1: (S) -2- ((S) -2-amino-3-methylbutanamide) -N- (4- (hydroxymethyl) phenyl) -5-ureido-pentanamide (valcit-pab-OH) (100mg, 0.264mmol) (purchased from Union biopharmaceutical, Levena Biopharma, san Diego) was added to 2, 5-dioxopyrrolidin-1-yl 3- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) propionate (77mg, 0.29mmol) in DMF (5ml) at room temperature followed by DIEA (70mg, 0.54 mmol). The mixture was stirred at room temperature for 2 hours, concentrated, and then purified by ISCO using 50g C18 aqueous column, eluting with 10% -25% ACN-water containing 0.05% TFA. The fractions containing (S) -2- ((S) -2- (3- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) propanamido) -3-methylbutanamido) -N- (4- (hydroxymethyl) phenyl) -5-ureidopentanamide (MP-valcit-pab-OH) were combined and concentrated (79.8mg, 0.150mmol, 57.1% yield). LCMS M +1 ═ 531.3, tr ═ 0.687 min.
Step 2: a solution of MP-valcit-pab-OH (33mg, 0.062mmol), bis (4-nitrophenyl) carbonate (189mg, 0.622mmol), and DIEA (0.033mL, 0.19mmol) in DMF-DCM (1:4, 5mL) was stirred at room temperature for 1 week, then concentrated and purified by silica gel column eluting with MeOH: DCM (2% to 10%). The fractions containing the desired compound were combined and concentrated to give 4- ((S) -2- (3- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) propanamido) -3-methylbutanamido) -5-ureidopentanamido) benzyl (4-nitrophenyl) carbonate (LI-3) (20mg, 0.029mmol, 46% yield). LCMS M +1 ═ 696.3, tr ═ 1.039 min.
Examples 1 to 4: synthesis of (S) -4- (2- (3- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) propanamido) -3-phenylpropionamido) benzyl (4-nitrophenyl) carbonate (LI-4)
Figure BDA0002340450700006401
Step 1: N-Hydroxybenzotriazole (HOBT) (509mg, 3.77mmol) and DMF (6ml) were added to a solution of BocPhe-OH (500mg, 1.89mmol) and (4-aminophenyl) methanol (464mg, 3.77mmol) in DCM (30ml), followed by diisopropylcarbodiimide (476mg, 3.77 mmol). The mixture was stirred at room temperature for 16 hours, concentrated to remove DCM, and then purified by silica gel column eluting with 10% MeOH in DCM to give tert-butyl (S) - (1- ((4- (hydroxymethyl) phenyl) amino) -1-oxo-3-phenylpropan-2-yl) carbamate (1.12g, 97% yield). LCMS M +1 ═ 275.2.tr ═ 0.561 min. 1H NMR (500MHz, chloroform-d) δ 7.99(s,1H),7.88(d, J ═ 7.1Hz,1H),7.39-7.18(m,9H),5.17(s,1H),4.60(s,2H),4.46(s,1H),3.12(d, J ═ 6.9Hz,2H),1.40(s, 9H).
Step 2: TFA (5mL) and DCM (1mL) were added to tert-butyl (S) - (1- ((4- (hydroxymethyl) phenyl) amino) -1-oxo-3-phenylpropan-2-yl) carbamate (1.12g, 1.82mmol) and the mixture was immediately concentrated. The solid was then dissolved in MeOH-DCM (5%) and extracted from 2M Na2CO3The aqueous solution was extracted, dried and concentrated to obtain (S) -2-amino-N- (4- (hydroxymethyl) phenyl) -3-phenylpropanamide (Phe-pab-OH), which was used in the next step without further purification. LCMS M + 1-271.3 tr-0.618 min.
And step 3: HOBT (200mg, 1.48mmol) was added to a solution of Phe-pab-OH (400mg, 1.48mmol) and 3- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) propionic acid (250mg, 1.480mmol) in DCM-DMF (5:1, 24ml), followed by diisopropylcarbodiimide (187mg, 1.48 mmol). The mixture was stirred at room temperature for 16 h, concentrated and purified by silica gel column eluting with 5% MeOH in DCM. Fractions containing the desired product were combined and concentrated. The mixture was further purified by reverse phase ISCO using 50g C18 aqueous column eluting with 10% -50% acetonitrile-H2O containing 0.05% TFA. The fractions containing the desired product were concentrated to obtain (S) -2- (3- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) propanamido) -N- (4- (hydroxymethyl) phenyl) -3-phenylpropanamide (MP-Phe-pab-OH) as the free base (0.214g, 32.6% yield). LCMS M +1 ═ 422.2, tr ═ 0.851 min. 1H NMR (500MHz, acetonitrile-d 3) δ 8.40(s,1H),7.45(d, J ═ 8.5Hz,2H),7.25(ddd, J ═ 20.2,7.7,3.3Hz,7H),6.80(d, J ═ 7.8Hz,1H),6.70(s,2H),4.62(td, J ═ 8.0,6.2Hz,1H),4.51(s,2H),3.64(t, J ═ 7.0Hz,2H),3.13(dd, J ═ 13.9,6.2Hz,1 ddh), 2.93(dd, J ═ 13.9,8.1Hz,1H),2.54-2.31(m, 2H).
And 4, step 4: a solution of (S) -2- (3- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) propionamido) -N- (4- (hydroxymethyl) phenyl) -3-phenylpropionamide (MP-Phe-pab-OH) (89.3mg, 0.212mmol), bis (4-nitrophenyl) carbonate (645mg, 2.119mmol), and DIEA (0.111mL, 0.636mmol) was stirred at room temperature for 2 days, then concentrated and purified by a silica gel column eluting with 2% -6% MeOH: DCM. The fractions containing the desired product were collected and concentrated to give (S) -4- (2- (3- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) propanamido) -3-phenylpropionamido) benzyl (4-nitrophenyl) carbonate (LI-4) (116mg, 89% yield). LCMS M +1 ═ 587.2, tr ═ 1.268 min. 1H NMR (500MHz, DMSO-d6) δ 10.21(s,1H),8.46(d, J ═ 8.1Hz,1H),8.40-8.23(m,2H),7.68-7.56(m,4H),7.45(d, J ═ 8.6Hz,2H),7.30(d, J ═ 4.4Hz,4H),7.01(s,2H),5.28(s,2H),4.68(dt, J ═ 8.7,4.4Hz,1H),3.63-3.48(m,2H),3.36(s,4H),3.05(dd, J ═ 13.7,5.5Hz,1H),2.92-2.83(m,2H),2.44-2.34(m, 2H).
Examples 1 to 5: synthesis of 4- ((S) -2- ((S) -2- (3- (2- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) ethoxy) propanamido) -3-methylbutanamido) -5-ureidopentanamido) benzyl (4-nitrophenyl) carbonate (LI-5)
Figure BDA0002340450700006421
Step 1: DIEA (204mg, 1.6mmol) was added to a solution of Mal-PEG 1-acid (112mg, 0.53mmol) in DMF (10ml) followed by 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium 3-oxide Hexafluorophosphate (HATU) (200mg, 0.53 mmol). The mixture was stirred at room temperature for 5 minutes and then added to a solution of (S) -2- ((S) -2-amino-3-methylbutanamido) -N- (4- (hydroxymethyl) phenyl) -5-ureido-pentanamide (valcit-pab-OH) (purchased from the company alline biopharmaceutical (Levena Biopharma), san diego) (200mg, 0.527mmol) in DMF (5 ml). The mixture was stirred at room temperature for 1 hour, then concentrated and purified by reverse phase ISCO using 50g C18 column eluting with 10% -40% acetonitrile-H2O containing 0.05% TFA. The fractions containing the desired product were concentrated to obtain (S) -2- ((S) -2- (3- (2- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) ethoxy) propionamido) -3-methylbutanamido) -N- (4- (hydroxymethyl) phenyl) -5-ureidopentanamide (MPEG1-vc-pab-OH) as the free base (190mg, 57% yield). LCMS M +1 ═ 575.3, tr ═ 0.658 min.
Step 2: a solution of (S) -2- ((S) -2- (3- (2- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) ethoxy) propionamido) -3-methylbutanamido) -N- (4- (hydroxymethyl) phenyl) -5-ureidopentanamide (MPEG1-valcit-pabOH) (57.5mg, 0.100mmol), bis (4-nitrophenyl) carbonate (130mg, 1.0mmol) and DIEA (0.056mL, 0.32mmol) was stirred at room temperature for 2 days. The mixture was then concentrated and purified by silica gel column eluting with 2% -6% MeOH: DCM, and the fractions containing the desired product were collected and concentrated to give 4- ((S) -2- (3- (2- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) ethoxy) propionamido) -3-methylbutanamido) -5-ureidopentanamido) benzyl (4-nitrophenyl) carbonate (LI-5) (59mg, 80% yield). LCMS M +1 ═ 740.2, tr ═ 1.02 min.
Examples 1-6 Synthesis of tert-butyl (2S,4S) -2- (((Chlorocarbonyl) oxy) methyl) -4-fluoropyrrolidine-1-carboxylate (LI-6)
Figure BDA0002340450700006431
To the dried flask was introduced potassium carbonate (257mg, 1.7 equivalents) followed by toluene (5 mL). Phosgene in toluene (2.4mL, 15% in toluene, 3.0 equivalents) was added under nitrogen at-35 ℃. To this vigorously stirred suspension was added dropwise a solution of (2S,4S) -tert-butyl 4-fluoro-2- (hydroxymethyl) pyrrolidine-1-carboxylate (1.093mmol, 1.0 equiv.) in toluene (3.6 ml). After the addition was complete, the mixture was stirred at low temperature (about-35 ℃ to 0 ℃) for 30 minutes. The cooling bath was removed and the mixture was stirred at room temperature for a further 1h and then filtered through a syringe filter with 0.45 micron pores. The volatiles were removed under vacuum using a rotary evaporator and the resulting clear yellow-light oil was used without further purification.
Examples 1 to 7: synthesis of Keto-CoA analog (LI-7)
Figure BDA0002340450700006432
The coenzyme A trilithium salt (259mg, Sigma, Ltd.) was measured>93%) was dissolved in 2.0mL of 100mM phosphate buffer (pH 7.5) containing 5mM EDTA, followed by addition of 3-buten-2-one (29.0. mu.L, Aldrich, 99%). The reaction was carried out at 20 ℃ for 75 minutes. Next, the reaction mixture was loaded onto a reverse phase RediSep RfC18Aq column (Teledyne Isco) on which the product was applied at 100% H2And (4) eluting with O. The product-containing fractions were combined and lyophilized to give the linker intermediate (LI-7) as a crystalline solid. MS (ESI +) M/z838.2(M + 1). H-NMR (400MHz, D)2O) δ 8.525(S,1H),8.235(S,1H),6.140(d,1H, J ═ 7.2Hz),4.746(m,1H),4.546(bs,1H),4.195(bs,1H),3.979(S,1H),3.786(dd,1H, J ═ 4.8,9.6Hz),3.510(dd,1H, J ═ 4.8,9.6Hz),3.429(t,2H, J ═ 6.6Hz),3.294S (t,2H, J ═ 6.6Hz),2.812(t,2H, J ═ 6.8Hz),2.676(t,2H, J ═ 6.8Hz),2.604(t,2H, J ═ 6.8Hz),2.420(t,2H, J ═ 6.6), 2.168(S,3H, 3.711 (H, 3H), 3.711 (S: some not reported with D2O overlapping peaks).
Examples 1 to 8: synthesis of 4- ((tert-butoxycarbonyl) amino) butyric anhydride (LI-8)
Figure BDA0002340450700006441
To a solution of 4- ((tert-butoxycarbonyl) amino) butyric acid (1.0g, 4.9mmol) in anhydrous dichloromethane (30ml) was added a solution of DCC (0.53g, 2.56mmol) in anhydrous dichloromethane (5ml) via syringe. After stirring for 1 hour, the urea precipitate was filtered through a syringe filter and the solvent was removed under vacuum. 4- ((tert-butoxycarbonyl) amino) butyric anhydride (LI-8) (1g, 105% yield) was obtained as a white solid, which was used without further purification.
Examples 1 to 9: synthesis of ((4- ((S) -2- ((S) -2- (3- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) propanamido) -3-methylbutanamido) -5-ureidopentanamido) benzyl) oxy) carbonyl) glycine (LI-9)
Figure BDA0002340450700006442
DIEA (25.8mg, 0.2mmol) was added to glycine (16.7mg, 0.06mmol) dissolved in 1mL DMF and linker intermediate (LI-3) (34.8mg, 0.05mmol) was added followed by HOAT (8.2mg, 0.06 mmol). The mixture was then stirred at room temperature overnight. After completion, DMF was removed under reduced pressure and the crude product was purified by reverse phase ISCO using 5% -50% acetonitrile-H2And (4) eluting with O. Fractions containing the desired product were combined and lyophilized to obtain (((4- ((S) -2- (3- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) propanamido) -3-methylbutanamido) -5-ureidopentamido) benzyl) oxy) carbonyl) glycine (LI-9) (16.4mg, 49% yield). LCMS M +1 ═ 632.3, tr ═ 0.714 min.
Example 2: synthesis of Cyclic Dinucleotide (CDN) intermediates
Example 2-1: synthesis of 2- (methylamino) ethyl (9- ((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR) -9- (6-amino-9H-purin-9-yl) -3, 10-difluoro-5, 12-dimercapto-5, 12-dioxido octahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphosphododecan-2-yl) -9H-purin-6-yl) carbamate (CDNI-1)
Step 1:
Figure BDA0002340450700006451
to a solution of 15% phosgene in toluene (14.4ml, 21.7mmol) in dry DCM (30ml) was added a solution of tert-butyl (2-hydroxyethyl) (methyl) carbamate (1.76g, 10.0mmol) and pyridine (1.85ml, 23.4mmol) in DCM (10ml) at-78 deg.C. The mixture was stirred at-78 ℃ for 10 minutes, warmed to room temperature, stirred for an additional 20 minutes, then concentrated, and the residual solvent was further removed under vacuum. Compound (T1-1) Et3The N salt (300mg, 0.334mmol) was dissolved in pyridine (5ml), which was then added to the residue, and the mixture was stirred at room temperature for 1 hour,about 60% conversion was obtained with about 30% of the binary adduct. Water was added to the mixture, and the mixture was stirred for 10 minutes and then concentrated. The residue was suspended in DMSO and purified by ISCO using a 15.5g C18 aqueous column, using a column containing 10mM HOAc-Et 35% -50% of ACN-water of N, and water-phase elution. Will contain the unaddressed Et3The fractions of N salt were collected and concentrated. (131mg) LCMS M +1 ═ 896.1, tr ═ 0.770 min.1H NMR (500MHz, methanol-d)4)δ8.96(d,J＝6.0Hz,1H),8.64(s,1H),8.57(s,1H),8.42(s,1H),8.18(s,1H),6.44(d,J＝16.8Hz,1H),6.36(d,J＝17.3Hz,1H),5.46(ddd,J＝51.9,15.5,3.8Hz,2H),5.24-4.99(m,2H),4.64-4.50(m,2H),4.47-4.30(m,4H),4.00(dt,J＝10.3,4.8Hz,2H),3.64(t,J＝5.9Hz,2H),3.58(s,2H),3.18(q,J＝7.3Hz,22H),3.01-2.83(m,7H),1.46(s,8H),1.41(d,J＝7.6Hz,10H),1.29(t,J＝7.3Hz,35H)。
Note that: fractions containing the binary adduct were collected and concentrated (218 mg). LCMSM +1 ═ 1097.1, tr ═ 0.958 min). The monoadduct and the starting compound (T1-1) were then obtained by treating the diadduct with NaOH. Specifically, the binary adduct was dissolved in ACN (10ml), then water (20ml) was added followed by 1.2g NaOH. The mixture was stirred at 50 ℃ for 4 hours, neutralized with 10% HCl, and then concentrated. The residue was purified by reverse phase ISCO C18 column with Et 10mM310% -40% acetonitrile-H of N HOAc2O eluted to give the monoadduct (106 mg).
Step 2:
Figure BDA0002340450700006461
to a flask containing 4-methylphenylthiol sodium salt (318mg, 2.16mmol) was added TFA (5ml) and the mixture was stirred until the solid was almost completely dissolved. The mixture was then added to a flask (237mg, 0.216mmol) containing the monoadduct from step 1 and the mixture was stirred for 2 minutes and then concentrated. LCMS showed complete Boc deprotection, but about 1/3 of tert-butylthio adduct remained. The residue was dissolved in DMSO and purified by ISCO using a C18 aqueous column eluting with 5% -30% ACN-water containing 0.05% TFA. Fractions containing the desired product were collected and concentrated to give (CDNI-1) (107mg, 39.2% yield) (LCMS M +1 ═ 796.1, tr ═ 0.555 min). 1H NMR (500MHz, DMSO-d6) δ 10.34(s,1H),8.83(b,7H),8.09(s,1H),6.41(d, J ═ 15.2Hz,1H),6.30(d, J ═ 15.2Hz,1H),5.70-5.51(m,1H),5.44(d, J ═ 51.8Hz,1H),5.03(d, J ═ 25.7Hz,2H),4.49-4.33(m,4H),4.27(s,2H),3.90-3.55(m,2H),3.10(d, J ═ 51.8Hz,1H),2.91-2.57(m,2H)
Note that: the fractions containing the tert-butylthio adduct were collected (LCMS M +1 ═ 852.1, tr ═ 0.792min), and after standing for 3 days, the tert-butylthio adduct was converted to (CDNI-1) (37mg, 0.029mmol, 13% yield).
Example 2-1: synthesis of 4- ((S) -2- ((S) -2-amino-3-methylbutanamido) -5-ureidopentanamido) benzyl (2- (((9- ((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR) -9- (6-amino-9H-purin-9-yl) -3, 10-difluoro-5, 12-dimercapto-5, 12-dioxaoctahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphosphododecan-2-yl) -9H-purin-6-yl) carbamoyl) oxy) ethyl) (methyl) carbamate (CDNI-2).
Step 1: 4- ((S) -2- ((S) -2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -3-methylbutanamido) -5-ureidopentanamido) benzyl 2- (4-nitrophenyl) acetate (Fmoc-Val-Cit-PABC-PNP) (23.18mg, 0.030mmol) (purchased from Binning biopharmaceutical company (Levena Biopharma), san Diego), DIEA (0.024mL, 0.137mmol), and 3-hydroxytriazole [4,5-b ] pyridine (HOAT) (3.74mg, 0.027mmol) were added to a round-bottomed flask containing (NI CDNI-1) (25mg, 0.027mmol) in DMF (2 mL). The reaction was stirred at room temperature for 4 hours, then heated to 45 ℃ and stirred for an additional 1 hour. The mixture was then concentrated and the residue was purified by ISCO using a 15.5g C18 aqueous column eluting with 5% -60% ACN-water containing 0.05% TFA. Fmoc-vc-pabc- (CDNI-2) was obtained (34.4mg, 81% yield). LCMS M/2+ 1-712.3, tr-1.007 min.
Step 2: piperidine (0.200ml) was added to Fmoc-vc-pabc- (CDNI-2) ((R))34.4mg, 0.022mmol) of TFA salt in DMF (5mL) and the mixture was stirred at room temperature for 30 min and then concentrated. The residue was purified by reverse phase ISCO using a C18 aqueous column, with 5% -35% acetonitrile-H containing 0.05% TFA2And (4) eluting with O. The fractions containing the desired product were concentrated to (CDNI-2) (31.1mg, 92% yield) as a TFA salt. LCMS M +1 ═ 1201.2tr ═ 0.671 min.
Examples 2 to 3: (CDNI-3)
Figure BDA0002340450700006481
Synthesis of (2)
Step 1: a) adding Et3N (1ml) was added to an ammonium salt of compound (T1-2) (400mg, 0.552mmol) in pyridine (30ml), and the mixture was concentrated. The procedure was repeated twice to obtain triethylammonium salt of compound (T1-2).
b) A solution of tert-butyl (2-hydroxyethyl) (methyl) carbamate (290mg, 1.66mmol) in DCM (10mL) was added with pyridine (0.313mL, 3.86mmol) to a solution of 15% phosgene toluene (4.4mL) in DCM (20mL) at-78 ℃ and the mixture was stirred for 15 min, then warmed to room temperature and concentrated to give 2- ((tert-butoxycarbonyl) (methyl) amino) ethyl chloroformate.
Step 2: compound (T1-2) Et3The N salt was resuspended in anhydrous pyridine (30ml) and then added to the 2- ((tert-butoxycarbonyl) (methyl) amino) ethyl chloroformate of step 1b), and the mixture was stirred at room temperature for 30 minutes. Water was then added and the mixture was concentrated. The residue was suspended in DMSO-water and then purified by reverse phase ISCO using C18 column, 15.5g aqueous column, with Et containing 10mM32% -40% acetonitrile-H of N HOAc2And (4) eluting with O. The fraction containing the desired Boc-protected monoadduct (387mg, 57.7% yield) was collected and lyophilized. M +1 892.2 tr 0.770 min. 1H NMR (500MHz, methanol-d)4)δ8.83(s,1H),8.34(s,1H),8.24(s,1H),8.18(s,1H),6.33(dd,J＝25.9,6.9Hz,2H),6.10(s,1H),5.51(s,1H),5.33(s,1H),4.68(s,1H),4.51-4.14(m,7H),4.03(d,J＝9.5Hz,1H),3.70-3.56(m,1H),3.45(s,2H),3.17(d,J＝7.3Hz,22H),2.88(s,4H),1.40(s,4H),1.29(t,J＝7.3Hz,33H)。
And step 3: TFA (5mL) was added to a flask containing 4-methylphenylsulfanyl alcohol sodium salt (200mg, 1.36mmol), and the mixture was stirred until complete dissolution. The mixture was then added to another flask (250mg, 0.228mmol) containing the Boc-protected monoadduct from step 2 and TFA was removed after 1min at room temperature. The mixture was then dissolved in DMSO and purified by reverse phase ISCO using a15 g C18 aqueous column with 2% -20% acetonitrile-H containing 0.05% TFA2And (4) eluting with O. The fractions containing the desired product were concentrated to obtain the deprotected monoadduct (CDNI-3) as TFA salt. LCMS M +1 ═ 792.0, tr ═ 0.611 min.1H NMR(500MHz,DMSO-d6)δ9.37(d,J＝41.6Hz,2H),8.89(s,1H),8.70(s,1H),8.43(s,1H),8.30(s,1H),6.33(d,J＝7.8Hz,1H),6.21(d,J＝8.2Hz,1H),5.51-5.24(m,2H),4.72-4.62(m,1H),4.49(s,1H),4.41(s,1H),4.31(s,3H),4.07(s,2H),3.85(s,1H),3.43(s,1H),3.23(s,1H),2.67(s,2H)。
Note that: fractions containing the tert-butylthio adduct were collected and after standing for 3 days the tert-butylthio adduct was converted to (CDNI-3).
Examples 2 to 4: synthesis of (CDNI-4)
Figure BDA0002340450700006491
Figure BDA0002340450700006492
Step 1: di-tert-butyldicarbonate (4.26g, 19.5mmol) was added dropwise over 10 min to 4- (methylamino) butanoic acid hydrochloride (2.0g, 13.0mmol) in MeOH (25mL) and Et3N (7.26mL, 52.1 mmol). The reaction mixture was stirred at room temperature for 22 hours, then concentrated. The residue was dissolved in EtOAc (100mL) and washed with ice-cold 0.1N HCl solution (20.0 mL). The organic layer was then washed with water to neutral pH and then with saturated NaCl. The EtOAc layer was washed with Na2SO4Dried and concentrated to give 4- ((tert-butoxycarbonyl) (methyl) amino) butanoic acid (2.08g, 70%). 1HNMR (500MHz, chloroform-d) δ 3.28(t, J ═ 6.9Hz,2H),2.84(s,3H),2.35(t, J ═ 7.2Hz,2H),1.84(p,J＝7.1Hz,2H),1.45(s,9H)。
Step 2: in N2Next, a solution of dicyclohexylcarbodiimide (704mg, 3.41mmol) in 10ml of anhydrous DCM was added dropwise to a flask containing 4- ((tert-butoxycarbonyl) (methyl) amino) butyric acid (1.43g, 6.56mmol) in anhydrous DCM (20 ml). The mixture was stirred for 2 hours, then concentrated to about 15mL, filtered and the solvent removed under vacuum. The crude product was filtered twice through a 0.45 micron filter to give 4- ((tert-butoxycarbonyl) (methyl) amino) butyric anhydride (1.36g, 99% yield) as a pale yellow oil.1H NMR (500MHz, chloroform-d) δ 3.28(t, J ═ 6.9Hz,2H),2.84(s,3H),2.46(t, J ═ 7.3Hz,2H),1.87(p, J ═ 7.2Hz,2H),1.45(s, 9H).
And step 3: 4- ((tert-Butoxycarbonyl) (methyl) amino) butyric anhydride (152.0mg, 0.366mmol) in DMF (1.6mL) was added to compound (T1-2) (63.1mg, 0.091mmol) in pyridine (0.8 mL). The reaction mixture was stirred at room temperature for 3 days, and then the solvent was removed. The residue was purified by reverse phase ISCO using a C18 column, 50g aqueous column, with 5% -50% MeCN/water (containing 10mM Et3N HOAc) elution. Fractions containing the desired boc-protected monoadduct were collected and lyophilized (45.3mg, 56% yield). LCMS M + 1-890.20, tr-0.787 min.
And 4, step 4: TFA (2mL) was added to the flask containing the sodium salt of 4-methylphenylsulfanyl and the mixture was stirred until complete dissolution and then added to another flask containing the boc protected mono adduct from step 3. TFA was immediately removed and the mixture was dissolved in DMSO and purified by reverse phase ISCO C18 column, 15g C18 aqueous column, using 2% -20% acetonitrile-H containing 0.05% TFA2And (4) eluting with O. The fractions containing the desired product were concentrated to obtain (CDNI-4) as a TFA salt (35.0mg, 89% yield). LCMS M +1 ═ 790.2, tr ═ 0.220 min.
Examples 2-5 Synthesis of (CDNI-5)
Figure BDA0002340450700006512
Step 1: a) ammonium salt of Compound (T1-2) (20mg, 0.028mmol) was dissolved in 5ml of pyridine, and then 0.06ml of Et was added3And N is added. The mixture was concentrated, and the process was repeated twice to obtain compound (T1-2) triethylammonium salt.
b) A solution of tert-butyl (2-hydroxyethyl) (methyl) carbamate (84mg, 0.44mmol) in DCM (3mL) and pyridine (0.072mL, 0.88mmol) were added to a solution of 15% phosgene in toluene (0.88mL) in DCM (10mL) at-78 deg.C. The mixture was stirred for 15 minutes, then warmed to room temperature and concentrated to give 1- ((tert-butoxycarbonyl) (methyl) amino) propan-2-yl chloroformate.
Step 2: compound (T1-2) Et3The N salt was resuspended in anhydrous pyridine (1mL) and then added to 1- ((tert-butoxycarbonyl) (methyl) amino) propan-2-yl chloroformate. The mixture was stirred for 30 minutes, then water was added. The mixture was concentrated, dissolved in DMSO-water and purified by reverse phase ISCO using C18 column, 15.5g aqueous column, with Et 10mM 32% -40% acetonitrile-H of NHOAc2And (4) eluting with O. The fractions containing the desired Boc-protected monoadduct were collected and lyophilized (33mg, 43% yield). M +1 906.1, tr 0.785 min.
And step 3: TFA (2mL) was added to a flask containing the sodium salt of 4-methylphenylsulfanyl and the mixture was stirred until complete dissolution, then added to another flask containing the boc protected mono adduct from step 3 (33mg, 0.030 mmol). TFA was immediately removed and the mixture was then dissolved in DMSO and purified by reverse phase ISCO using a 15.5g C18 aqueous column with 2% -20% acetonitrile-H containing 0.05% TFA2And (4) eluting with O. The fractions containing the desired product were concentrated to obtain (CDNI-5) as a TFA salt (21mg, 55% yield). LCMS M +1 ═ 806.0, tr ═ 0.586 min.
Examples 2 to 6: (CDNI-6)
Figure BDA0002340450700006521
Synthesis of (2)
Intermediate (CDNI-6) was prepared using the procedure described for the synthesis of intermediate (CDNI-3) except that compound (T1-5) was used instead of compound (T1-2).
Intermediate (CDNI-6) as TFA salt (25.6mg, 66.8% yield). LCMS M +1 ═ 794.1, tr ═ 0.518 min.
Examples 2 to 7: synthesis of (CDNI-7)
Figure BDA0002340450700006522
Figure BDA0002340450700006523
Intermediate (CDNI-7) was prepared using the procedure described for the synthesis of intermediate (CDNI-4) except that compound (T1-5) was used instead of compound (T1-2).
Intermediate (CDNI-7) as TFA salt (10.0mg, 8% yield). LCMS M +1 ═ 792.2, tr ═ 0.381 min.
Examples 2 to 8: synthesis of (CDNI-8)
Figure BDA0002340450700006531
Intermediate (CDNI-8) was prepared using the procedure described for the synthesis of intermediate (CDNI-3) except that compound (T1-3) was used instead of compound (T1-2).
Examples 2 to 9: synthesis of (CDNI-9a) and (CDNI-9 b):
a) (CDNI-9a) Synthesis:
intermediate (CDNI-9a) was prepared using the procedure described for the synthesis of intermediate (CDNI-3) except that compound (T1-6) was used instead of compound (T1-2).
Intermediate (CDNI-9a) (32.1mg, 39.0% yield) (LCMS M +1 ═ 796.0, tr ═ 0.406 min).
However, step 1 of the preparation of 2- ((tert-butoxycarbonyl) (methyl) amino) ethyl chloroformate was modified as follows:
in N2Next, tert-butyl (2-hydroxyethyl) (methyl) carbamate (175mg, 0.73)6mmol) and K2CO3(43mg, 0.626mmol) was added to the flask, and then toluene (10mL) was added, and the mixture was cooled to-15 ℃. The mixture was stirred and a solution of phosgene in toluene (1.1mmol, 15% in toluene) was added dropwise. The mixture was stirred at low temperature (-15 ℃ to 0 ℃) for another 30 minutes, warmed to room temperature and stirred for an additional 1 hour. The mixture was filtered through a syringe filter (0.45 micron pores) and the solvent was removed to give 2- ((tert-butoxycarbonyl) (methyl) amino) ethyl chloroformate as a clear pale yellow oil, which was used without further purification.
b) (CDNI-9b) Synthesis:
Figure BDA0002340450700006541
intermediate (CDNI-9b) was also obtained during the synthesis of intermediate (CDNI-9 a). CDN intermediate (CDNI-9a) and CDN intermediate (CDNI-9b) could not be separated. (CDNI-9 a). CDN intermediate (CDNI-9a) and CDN intermediate (CDNI-9b) (32.1mg, 39.0% yield) (LCMS M +1 ═ 796.0, tr ═ 0.406 min).
Examples 2 to 10: synthesis of (2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR) -2- (6-amino-9H-purin-9-yl) -9- (6- ((3-aminopropyl) amino) -9H-purin-9-yl) -3, 10-difluoro-5, 12-dimercaptooctahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphosphacyclododecane 5, 12-dioxide (CDNI-10)
Figure BDA0002340450700006542
Step 1: HOAc (0.020ml) and tert-butyl (3-oxopropyl) carbamate (10mg, 0.058mmol) were added to a suspension of compound (T1-1) (5mg, 0.0056mmol) in MeOH (1ml) and the mixture was heated at 50 ℃ for 16 h (LCMS showed slow imine formation, M + 1850.2 tr ═ 0.680min) and then NaBH was added3CN (0.35mg, 0.0056mmol), and the reaction was stirred at room temperature for 2 hours. LCMS indicated about 25% conversion. M + 1-852.1 tr-0.708 min. An additional 5mg of tert-butyl (3-oxopropyl) carbamate was added and the mixture was heated at 50 ℃ for 2 hours, thenPost addition of 5mg NaBH3And (C) CN. The mixture was stirred for 1 hour and the conversion was monitored by LCMS. Repeat addition of 5mg additional t-butyl (3-oxopropyl) carbamate and 5mg additional NaBH3CN until about 50% conversion is obtained. The mixture was concentrated and the residue was dissolved in 2ml MeOH and purified by mass triggered reverse phase HPLC using C18 column with 13% -29% acetonitrile-H containing 0.05% TFA2And (4) eluting with O. The fractions containing the desired product were concentrated to obtain tert-butyl (3- ((9- ((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR) -9- (6-amino-9H-purin-9-yl) -3, 10-difluoro-5, 12-dimercapto-5, 12-octahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] as TFA salt][1,3,7,9]Tetraoxa [2,8]]Diphosphacyclododec-2-yl) -9H-purin-6-yl) amino) propyl) carbamate. LCMSM +1 ═ 852.1tr ═ 0.695 min.
Step 2: treatment of tert-butyl (3- ((9- ((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR) -9- (6-amino-9H-purin-9-yl) -3, 10-difluoro-5, 12-dimercapto-5, 12-octahydro-2H dioxide, 7H-difluoro [3,2-d:3',2' -j) with TFA (1mL)][1,3,7,9]Tetraoxa [2,8]]Diphosphacyclododec-2-yl) -9H-purin-6-yl) amino) propyl) carbamate (1mg, 0.001mmol), and concentrated immediately. Addition of H2O and ACN (1:1) and the sample was lyophilized to give (2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR) -2- (6-amino-9H-purin-9-yl) -9- (6- ((3-aminopropyl) amino) -9H-purin-9-yl) -3, 10-difluoro-5, 12-dimercaptooctahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] as TFA salt][1,3,7,9]Tetraoxa [2,8]]Diphosphacyclododecane 5, 12-dioxide (0.9mg, 30% yield). LCMS M +1 ═ 748.0, tr ═ 0.227 min.
Examples 2 to 11:
a) synthesis of ((2S,4S) -4-fluoropyrrolidin-2-yl) methyl (9- ((2R,3R,3aR,5R,7aR,9R,10R,10aR,12S,14aR) -9- (6-amino-9H-purin-9-yl) -3, 10-difluoro-5, 12-dimercapto-5, 12-dioxido-octahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphosphododecan-2-yl) -9H-purin-6-yl) carbamate (CDNI-11a)
Step 1: compound (T1-6) Et in NMP (0.5mL) and DCM (1.5mL) over 5min3The N salt (224mg, 0.25mmol) and pyridine (88uL, 7.0 equiv) were added to (2S,4S) -tert-butyl 2- (((chlorocarbonyl) oxy) methyl) -4-fluoropyrrolidine-1-carboxylate (LI-6) in DCM (1.5 mL). The mixture was stirred at room temperature for one hour. Water was added to the reaction and it was stirred for another 10 minutes and then concentrated. The mixture was resuspended in DMSO and purified by ISCO using a 15.5g C18 aqueous column, using a column containing 10mM HOAc-Et3ACN-Water 5% -50% aqueous phase of N eluted to give a binary adduct, di-tert-butyl 5,5' - (((((((((2R, 3R,3aR,5R,7aR,9R,10R,10aR,12S,14aR) -3, 10-difluoro-5, 12-dimercapto-5, 12-octahydro-2H, 7H-difluoro [3,2-d:3',2' -j) octahydro-5, 12-dithio-5, 12-dioxido][1,3,7,9]Tetraoxa [2,8]]Diphosphacyclododecane-2, 9-diyl) bis (9H-purine-9, 6-diyl)) bis (azaalkanediyl)) bis (carbonyl)) bis (oxy)) bis (methylene)) (3S,3'S, 5' S) -bis (3-fluoropyrrolidine-1-carboxylate) (149.5 mg). LCMS M +1 ═ 1185.1, tr ═ 0.944 min.
Step 2: the binary adduct from step 1 (149.5mg) was dissolved in ACN (5ml), then water (10ml) was added followed by 0.6g NaOH. The mixture was stirred at 50 ℃ for 4 hours, then neutralized with 4M HCl, and then concentrated. The residue was purified by reverse phase ISCO, C18 column with Et 10mM310% -50% acetonitrile-H of N HOAc2O to give a protected mono adduct, tert-butyl (2S,4S) -2- ((((9- ((2R,3R,3aR,5R,7aR,9R,10R,10aR,12S,14aR) -9- (6-amino-9H-purin-9-yl) -3, 10-difluoro-5, 12-dimercapto-5, 12-octahydro-2H dioxide, 7H-difluoro [3,2-d:3',2' -j)][1,3,7,9]Tetraoxa [2,8]]Diphosphacyclododec-2-yl) -9H-purin-6-yl) carbamoyl) oxy) methyl) -4-fluoropyrrolidine-1-carboxylate (32.0 mg). LCMS M +1 ═ 940.1, tr ═ 0.750 min.
And step 3: TFA (2.0ml) was added to a flask (32.0mg, 0.028mmol) containing the monoadduct from step 2 and the mixture was stirred for 2min and then concentrated. The residue was dissolved in DMSO and purified by ISCO using a C18 aqueous column, eluting with 5% to 30% ACN-water containing 0.05% TFA to give ((2S,4S) -4-fluoropyrrolidin-2-yl) methyl (9- ((2R, 3aR,5R,7aR,9R,10 aR,12S,14aR) -9- (6-amino-9H-purin-9-yl) -3, 10-difluoro-5, 12-dimercapto-5, 12-dioxyoctahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphospholododec-2-yl) -9H-purin-6-yl) carbamate (CDNI-11a) (13.1mg, 44.0% yield) (LCMS M +1 ═ 840.0, tr ═ 0.407 min).
b) Synthesis of ((2S,4S) -4-fluoropyrrolidin-2-yl) methyl (9- ((2R,3R,3aR,5S,7aR,9R,10R,10aR,12R,14aR) -9- (6-amino-9H-purin-9-yl) -3, 10-difluoro-5, 12-dimercapto-5, 12-dioxido-octahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphosphododecan-2-yl) -9H-purin-6-yl) carbamate (CDNI-11b)
Figure BDA0002340450700006571
Intermediate (CDNI-11b) was also obtained during the synthesis of intermediate (CDNI-1 a). CDN intermediate (CDNI-11a) and CDN intermediate (CDNI-11b) could not be separated. (CDNI-1 a). CDN intermediate (CDNI-11a) and CDN intermediate (CDNI-9b) (13.1mg, 44.0% yield) (LCMS M +1 ═ 840.0, tr ═ 0.407 min).
Examples 2 to 12: synthesis of N- (9- ((2R,3R,5R,7aR,9R,10R,12R,14aR) -9- (6-amino-9H-purin-9-yl) -3, 10-difluoro-5, 12-dimercapto-5, 12-octahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphosphododecan-2-yl) -9H-purin-6-yl) -4- (methylamino) butanamide (CDNI-12)
Figure BDA0002340450700006581
Step 1: 4- ((tert-Butoxycarbonyl) (methyl) amino) butyric anhydride (241mg, 0.580mmol) is added to Compound (T1-1) Et3A solution of the N salt (40mg, 0.045mmol) in pyridine (5mL) and heated to 50 ℃ and stirred for 72 hours. DMAP (10mg) and 50mg more anhydride were added and the reaction was stirred at 50 ℃ for 8 hours, then concentrated and purified using a 15g C18 aqueous column with reverse phase ISCO and 5% -45% acetonitrile-H2O (containing 10mM Et)3Aqueous phase of N HOAc). Will contain the desired productCollected separately and lyophilized to obtain Et as3Boc-protected intermediate CDNI-12 as the N salt (8mg, 16% yield). LCMS M +1 ═ 894.0, tr ═ 0.776 min.
Note that: 4- ((tert-butoxycarbonyl) (methyl) amino) butyric anhydride was synthesized as described in the synthesis of CDNI-4.
Step 2: TFA (1ml) was added to intermediate CDNI-12Et containing boc protection3N salt (8mg, 0.007mmol) in a flask, then concentrated immediately. The residue was purified by reverse phase ISCO using a 15g C18 column, using 5% -45% acetonitrile-H with 0.05% TFA2And (4) eluting with O. The fractions containing the desired product were concentrated to obtain intermediate CDNI-12 as a TFA salt (3.7mg, 49.6% yield). LCMS M +1 ═ 794.0, tr ═ 0.636 min.
Examples 2 to 13: synthesis of 4-amino-N- (9- ((2R,3R,5R,7aR,9R,10R,12R,14aR) -9- (6-amino-9H-purin-9-yl) -3, 10-difluoro-5, 12-dimercapto-5, 12-dioxyoctahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphosphacyclododecane-2-yl) -9H-purin-6-yl) butanamide (CDNI-13)
Figure BDA0002340450700006591
Step 1: 4- ((tert-Butoxycarbonyl) amino) butyric anhydride (LI-8) is added to Compound (T1-1) Et3A solution of the N salt (30mg, 0.033mmol) in pyridine (5mL) (390mg, 1.00mmol) was heated at 50 ℃ for 3 days. The reaction mixture was then concentrated and the crude product was purified by reverse phase ISCO using 15g C18 column with 5% -60% acetonitrile-H2O (containing 10mM Et)3Aqueous phase of N HOAc). The fractions containing the desired product were isolated and concentrated to obtain Et as3Boc-protected intermediate CDNI-13 as the N salt (10mg, 28% yield). LCMS M +1 ═ 880.1, tr ═ 0.731 min.
Step 2: TFA (2mL) was added to intermediate CDNI-12Et containing boc protection3N salt (10mg, 0.009mmol) in a flask and concentrated immediately. The crude product was purified by reverse phase ISCO using a 15g C18 aqueous column, using 5% -60% acetonitrile-H containing 0.05% TFA2And (4) eluting with O. Merge contains the hopeFractions of product (a) were lyophilized to obtain intermediate CDNI-13 as a TFA salt (11.2mg, 96% yield). LCMS M +1-H2O＝762.0,tr＝0.608min。
Examples 2 to 14: synthesis of tert-butyl ((S) -1- ((4- ((9- ((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR) -9- (6-amino-9H-purin-9-yl) -3, 10-difluoro-5, 12-dimercapto-5, 12-dioxyoctahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphosphododecan-2-yl) -9H-purin-6-yl) amino) -4-oxobutyl) amino) -1-oxo-5-allopentan-2-yl) carbamate (CDNI-14).
Figure BDA0002340450700006601
Step 1: to a solution of (S) -2- ((tert-butoxycarbonyl) amino) -5-ureidopentanoic acid (Boc-Cit-OH from Baheng, Bachem) (2.7mg, 0.01mmol) in DMF (1mL) was added DIEA (0.017mL, 0.10mmol) and then HATU (3.8mg, 0.01 mmol). The reaction mixture was stirred at room temperature for 5min, then added to a solution of CDN intermediate (CDNI-13) TFA salt (10mg, 0.01mmol) in DMF and the mixture was stirred at room temperature for 5h, then concentrated. The residue was purified by reverse phase ISCO using a 15g C18 aqueous column with 5% -40% acetonitrile-H2O (containing 10mM Et)3Aqueous phase of N HOAc). The fractions containing the desired product were concentrated to obtain Et as3Boc-protected intermediate CDNI-14 as the N salt (2.9mg, 24% yield). LCMS M +1 ═ 1037.1, tr ═ 0.699 min.
Step 2: TFA (1ml) was added to a flask containing boc-protected intermediate CDNI-14Et3N salt (2.9mg, 0.0028mmol), the solution was stirred for 1min, then concentrated to give CDN intermediate (CDNI-14) as a TFA salt (2.9mg, 100% yield). LCMS M +1 ═ 937.1, tr ═ 0.598 min.
Examples 2 to 15: synthesis of (S) -2- ((S) -2-amino-3-methylbutanamido) -N- (4- ((9- ((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR) -9- (6-amino-9H-purin-9-yl) -3, 10-difluoro-5, 12-dimercapto-5, 12-dioxaoctahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphosphododecan-2-yl) -9H-purin-6-yl) amino) -4-oxobutyl) -5-ureidopentanamide (CDNI-15).
Figure BDA0002340450700006611
Step 1: to a vial containing (tert-butyloxycarbonyl) -L-valine (Boc-Val-OH, purchased from Novabiochem) (1.2mg, 0.0056mmol) was added DMF (1ml) followed by HATU (2.1mg, 0.0056mmol) and DIEA (3.6mg, 0.028 mmol). The mixture was stirred for 2min, then added to a solution containing intermediate CDNI-14TFA salt (2.9mg, 0.0028mmol) in DMF (1 ml). The reaction was stirred at room temperature for 1 day and then concentrated. The residue was purified by reverse phase ISCO using a 15g C18 aqueous column with 5% -40% acetonitrile-H2O (containing 10mM Et)3Aqueous phase of N HOAc). The fractions containing the desired product were concentrated to obtain Et as3Boc-protected intermediate CDNI-15 as N salt (1.8mg, 48% yield). LCMS M +1 ═ 1136.2, tr ═ 0.791 min.
Step 2: TFA (1ml) was added to a flask containing boc-protected intermediate CDNI-15Et3N salt (1.8mg, 0.0013mmol), the solution was stirred for 1min, then concentrated to give intermediate CDNI-15 as a TFA salt (1.7mg, 100%). The compound was used in the next step without further purification. LCMS M +1 ═ 1036.1, tr ═ 0.621 min.
Examples 2 to 16: (2S,3S,4S,5R,6S) -6- (4- ((((2- (((9- ((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR) -9- (6-amino-9H-purin-9-yl) -3, 10-difluoro-5, 12-dimercapto-5, 12-octahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphosphododecan-2-yl) -9H-purin-6-yl) carbamoyl) oxy) ethyl) (methyl) carbamoyl) oxy) methyl) -2- (3-aminopropionamido) phenoxy) -3, synthesis of 4, 5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (CDNI-16)
Figure BDA0002340450700006621
Step 1: to intermediate CDNI-1TFA salt (15mg, 0.015mmol) and (2S,3R,4S,5S,6S) -2- (2- (3- ((((9H-fluoren-9-yl)Methoxy) carbonyl) amino) propionamido) -4- (((((4-nitrophenoxy) carbonyl) oxy) methyl) phenoxy) -6- (methoxycarbonyl) tetrahydro-2H-pyran-3, 4, 5-triyltriacetate (see Bioconjugate Chem. [ Bioconjugate chemistry ]]2006,17,831-840) (16mg, 0.018mmol) in DMF (1mL) was added DIEA (0.026mL, 0.15mmol) and HOAT (2.0mg, 0.015 mmol). The reaction was stirred at room temperature for 16 hours. The solvent is then removed by high vacuum and the crude product is purified by reverse phase ISACO using a 15g C18 column with 5% -60% acetonitrile-H2O (containing 10mM Et)3Aqueous phase of N HOAc). The fractions containing the desired product were concentrated to obtain Et as3Fmoc protected intermediate CDNI-16 as N salt (20.2mg, 78% yield). LCMS M/2+1 785.8, tr 1.094 min.
Step 2: a solution of LiOH (9.3mg, 0.388mmol) in water was added to the Fmoc-protected intermediate CDNI-16(20.2mg, 0.011mmol) Et3N salts and MeOH (4mL) in a vial, and the mixture was stirred at room temperature for 16 hours. It was then neutralized with HOAc and concentrated. The crude product was purified by reverse phase ISCO using a 43g C18 aqueous column using 5% -35% acetonitrile-H2O (containing 10mM Et)3Aqueous phase of N HOAc). The fractions containing the desired product were concentrated to obtain Et as3Intermediate CDNI-16(23.2mg, 135% yield) as the N salt. LCMS M +1 ═ 1207.9, tr ═ 0.811 min.
EXAMPLE 2-17 Synthesis of ((2S,4S) -4-fluoropyrrolidin-2-yl) methyl (9- ((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR) -9- (6-amino-9H-purin-9-yl) -3, 10-difluoro-5, 12-dimercapto-5, 12-dioxido-octahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphosphacyclododecane-2-yl) -9H-purin-6-yl) carbamate (CDNI-17)
Figure BDA0002340450700006631
Intermediate (CDNI-17) was synthesized using the procedure described for CDNI intermediate (CDNI-11), except using compound (T1-1) Et3N salt instead of Compound (T1-6) Et3And (3) N salt.
Example 2-18 Synthesis of 2-azidoethyl (9- ((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR) -9- (6-amino-9H-purin-9-yl) -3, 10-difluoro-5, 12-dimercapto-5, 12-dioxaoctahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphosphododecan-2-yl) -9H-purin-6-yl) carbamate (CDNI-18)
Figure BDA0002340450700006641
Step 1: diphosgene solution (275mg, 1.41mmol) was added to a solution of 2-azidoethanol (87mg, 1.00mmol) in DCM (10mL) at-78 ℃ and the mixture was slowly warmed to room temperature. After 15 minutes, the solution became clear. The reaction was concentrated and the solvent and other volatile reagents were removed under vacuum to give 2-azidoethylchloroformate, which was used in step 2 without further purification.
Step 2: 2-azidoethylchloroformate (149mg, 1.00mmol) in DCM (1ml) was added portionwise over 30min to compound (T1-1) Et dissolved in pyridine (2ml)3N salt (30mg, 0.033 mmol). Et was then added3N (0.03ml), and the mixture was stirred at room temperature for 2 hours. The solution was concentrated, then water and acetonitrile were added. 1N NaOH (5ml) was then added and the reaction stirred at 60 ℃ for 2 hours to form mono-and di-basic adducts. The reaction was neutralized with HOAc, concentrated, then suspended in DMSO and purified by reverse phase ISCO using 43g C18 aqueous column with 5% -35% acetonitrile-water (containing 10mM Et)3Aqueous phase of N HOAc). The fractions containing the monoadduct were collected and concentrated to give Et as3CDNI intermediate of N salt (CDNI-18) (20mg, 45% yield). LCMS M +1 ═ 808.0, tr ═ 0.764 min.
Examples 2 to 19: synthesis of N- (9- ((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR) -9- (6-amino-9H-purin-9-yl) -3, 10-difluoro-5, 12-dimercapto-5, 12-dioxyoctahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphosphododecan-2-yl) -9H-purin-6-yl) -4-azidobutyramide (CDNI-19)
Figure BDA0002340450700006651
Step 1: 4-azidobutyric acid (259mg, 2.01mmol) was dissolved in DCM (5mL) and oxalyl chloride (190mg, 1.5mmol) was added followed by DMF (0.005 mL). The reaction was stirred at room temperature for 1 hour, then concentrated to obtain 4-azidobutyryl chloride, which was used in the next step without further purification.
Step 2: 4-azidobutyryl chloride (94mg, 0.64mmol) was dissolved in DCM (0.32mL) and added to di-2' -F-RR-CDA (R277) Et3A solution of the N salt (30mg, 0.033mmol) in pyridine (3 ml). The reaction was stirred at 70 ℃ for 0.5 h, then quenched with 2 drops of water and concentrated. The crude product was purified by reverse phase ISCO using a 50g C18 aqueous column using 5% -50% acetonitrile-H2O (containing 10mM Et)3Aqueous phase of N HOAc). Fractions containing the desired product were isolated and lyophilized to give Et3CDN intermediate (CDNI-19) as N salt (19.7mg, 58.4% yield). LCMS M +1 ═ 806.0, tr ═ 0.807 min.
Examples 2 to 20: synthesis of 3-azidopropyl (9- ((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR) -9- (6-amino-9H-purin-9-yl) -3, 10-difluoro-5, 12-dimercapto-5, 12-dioxyoctahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphosphacyclododecane-2-yl) -9H-purin-6-yl) carbamate (CDNI-20)
Figure BDA0002340450700006652
CDN intermediate (CDNI-20) was synthesized using the method described for the synthesis of CDN intermediate (CDNI-18), except that 3-azidopropan-1-ol was used instead of 2-azidoethanol. CDN intermediate (CDNI-20) Et3N salt (16.3mg, 47% yield). LCMS M +1 ═ 822.0, tr ═ 0.830 min.
Examples 2 to 21: 4-amino-N- (9- ((2R,3R,5S,7aR,9R,10R,12R,14aR) -9- (6-amino-9H-purin-9-yl) -3, 10-difluoro-5, 12-dimercapto-5, 12-dioxaoctahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphosphododecan-2-yl) -9H-purin-6-yl) butanamide (CDNI-21a) and N- (9- ((2R,3R,5R,7aR,9R,10R,12S,14aR) -9- (6-amino-9H-purin-9-yl) -3, synthesis of a mixture of 10-difluoro-5, 12-dimercapto-5, 12-dioxyoctahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphospholance-2-yl) -9H-purin-6-yl) -4- (methylamino) butanamide (CDNI-21b)
Figure BDA0002340450700006661
Step 1: NaH (60% dispersion in oil, 38.5mg, 0.962mmol) was added to Compound (T1-6) Et3A solution of the N salt (86.3mg, 0.096mmol) in DMF (3ml) was added and the mixture stirred for 1min before addition of 4- ((tert-butoxycarbonyl) amino) butyric anhydride (347mg, 0.894 mmol). The reaction was stirred at room temperature for 1 hour and then quenched with HOAc (0.2 ml). The reaction was concentrated and purified using reverse phase ISCO (15g C18 aqueous column) with 5% -45% acetonitrile-H2O (containing 10mM Et)3Aqueous phase of N HOAc). Fractions containing the desired product were collected and lyophilized to obtain Et as3Boc-protected CDN intermediate for the N salt (CDNI-21a) and boc-protected CDN intermediate (CDNI-21b) (20mg, 19% yield). LCMS M +1 ═ 880.0, tr ═ 0.782 min. The mixture did not separate. Note that: 4- ((tert-butoxycarbonyl) (methyl) amino) butyric anhydride was synthesized as described in the synthesis of CDNI-4.
Step 2: to the mixture containing boc-protected CDN intermediate (CDNI-21a) and boc-protected CDN intermediate (CDNI-21b) Et3Acetonitrile (5ml) and TFA (1ml) were added to a flask of N salt (20mg, 0.018mmol), and the mixture was stirred for 30 minutes and then concentrated. The residue was purified by reverse phase ISCO using a 15g C18 column, using 5% -50% acetonitrile-H containing 0.05% TFA2And (4) eluting with O. The fractions containing the desired product were concentrated to obtain a mixture of CDN intermediate (CDNI-21a) and CDN intermediate (CDNI-21b) as TFA salts (13.4mg, 72% yield). LCMS M +1-H2O＝762,tr＝0.268min。
Examples 2 to 22: 4- ((S) -2- ((S) -2-amino-3-methylbutanamido) -5-ureidopentanamide) benzyl (2S,4S) -2- (((9- ((2R,3R,3aR,5R,7aR,9R,10R,10aR,12S,14aR) -9- (6-amino-9H-purin-9-yl) -3, 10-difluoro-5, 12-dimercapto-5, 12-dioxaoctahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphosphododecan-2-yl) -9H-purin-6-yl) carbamoyl) oxy) methyl) -4-fluoropyrrolidine -1-carboxylate (CDNI-22a) and 4- ((S) -2- ((S) -2-amino-3-methylbutanamido) -5-ureidopentanamido) benzyl (2S,4S) -2- ((((9- ((2R,3R,3aR,5S,7aR,9R,10R,10aR,12R,14aR) -9- (6-amino-9H-purin-9-yl) -3, 10-difluoro-5, 12-dimercapto-5, 12-dioxido-octahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphosphacyclododecane-2-yl) -9H-purin-6-yl) carbamoyl Synthesis of (yl) oxy) methyl) -4-fluoropyrrolidine-1-carboxylic acid ester (CDNI-22b)
Figure BDA0002340450700006681
Step 1: Fmoc-Val-Cit-PABC-PNP (25.2mg, 0.033mmol) was added to a solution of CDN intermediates (CDNI-11a) and (CDNI-11b) (31.1mg, 0.030mmol) in DMF (1mL), followed by DIEA (26.0uL, 19.3mg, 0.149mmol) and HOAT (4.1mg, 0.030 mmol). The reaction was stirred at room temperature overnight, then water (1.0mL) was added and the solution was concentrated. The residue was dissolved in DMSO and purified by ISCO using a 50.0g C18 aqueous column, eluting with 5% -60% ACN in water containing 10mM TEA-HOAc. The fractions containing the desired product were concentrated to obtain the compound Fmoc-protected CDN intermediates (CDNI-22a and CDNI-22b) as TEA salts (42.2mg, 80% yield). LCMS M/2+ 1-734.30, tr-1.002 min.
Step 2: piperidine (180.0uL, 0.19mmol) was added to a solution of Fmoc-protected CDN intermediate (CDNI-22) (32.0mg, 0.019mmol) TEA salt in DMF (volume: 3.0mL) and the mixture was stirred at room temperature for 30min, then concentrated. The residue was purified by reverse phase ISCO 50g C18 aqueous column using 5% -35% acetonitrile-H containing 0.05% TFA2And (4) eluting with O. The fractions containing the desired product were concentrated to obtain CDN intermediates (CDNI-22a and CDN22b) (20.0mg, 67.8%) as TFA salts. LCMS M/2+1 623.3, tr 0.790 min.
Examples 2 to 23: synthesis of 2- (methylamino) ethyl (9- ((1S,3R,6R,8R,9S,11R,14R,16R,17R,18R) -16- (6-amino-9H-purin-9-yl) -17, 18-difluoro-3, 11-dimercapto-3, 11-dioxide-2, 4,7,10,12, 15-hexaoxa-3, 11-diphosphatricyclo [12.2.1.16,9] octadecan-8-yl) -9H-purin-6-yl) carbamate (CDNI-23)
Figure BDA0002340450700006691
CDN intermediate (CDNI-23) was synthesized using the method described for the synthesis of CDN intermediate (CDNI-1), except using compound (T2-46) Et3N salt instead of Compound (T1-1) Et3And (3) N salt.
Boc protected CDN intermediate (CDNI-23): LCMS M +1 ═ 796.0, tr ═ 0.625 min.1H NMR(500MHz,DMSO-d6)δ10.71(s,1H),9.36(d,J＝6.1Hz,2H),8.92(s,1H),8.73(s,2H),8.39(s,1H),6.27(dd,J＝44.7,8.4Hz,2H),5.79-5.33(m,4H),4.75-4.55(m,3H),4.38(s,1H),4.00(dd,J＝12.5,5.4Hz,4H),3.35(dd,J＝10.3,6.4Hz,1H),3.25(s,1H),3.12(tt,J＝7.4,3.7Hz,1H)。
CDN intermediate (CDNI-23) TFA salt (8.2mg, 55.0% yield). LCMS M +1 ═ 796.0, tr ═ 0.625 min.1H NMR(500MHz,DMSO-d6)δ10.71(s,1H),9.36(d,J＝6.1Hz,2H),8.92(s,1H),8.73(s,2H),8.39(s,1H),6.27(dd,J＝44.7,8.4Hz,2H),5.79-5.33(m,4H),4.75-4.55(m,3H),4.38(s,1H),4.00(dd,J＝12.5,5.4Hz,4H),3.35(dd,J＝10.3,6.4Hz,1H),3.25(s,1H),3.12(tt,J＝7.4,3.7Hz,1H)。
Examples 2 to 24: synthesis of (2R,3R,3aR,5R,7aR,9R,10R,10aR,12S,14aR) -2- (2-amino-6-oxo-1, 6-dihydro-9H-purin-9-yl) -9- (6-amino-9H-purin-9-yl) -10-fluoro-5, 12-dimercapto-5, 12-octahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphosphododecan-3-yl (2- (methylamino) ethyl) carbonate (CDNI-24)
Figure BDA0002340450700006701
CDN intermediate (CDNI-24) was synthesized using the method described for the synthesis of CDN intermediate (CDNI-3), except using compound (T1-13) Et3N salt instead of Compound (T1-2) Et3And (3) N salt.
Boc protected CDN intermediate (CDNI-24): LCMS M +1 910.1, tr 0.731 min.1H NMR (500MHz, methanol-d)4)δ8.46(s,1H),8.20(d,J＝7.6Hz,2H),6.36(d,J＝17.1Hz,1H),6.07(d,J＝11.8Hz,1H),5.77-5.56(m,2H),5.34(s,1H),5.24-5.04(m,1H),4.60(dt,J＝12.3,2.7Hz,1H),4.42(d,J＝10.2Hz,3H),4.32(d,J＝8.0Hz,3H),4.08-3.95(m,2H),3.64(t,J＝5.9Hz,5H),3.58(s,2H),3.03(q,J＝7.3Hz,31H),2.96(s,4H),2.92(s,9H),1.22(t,J＝7.3Hz,42H)。
CDN intermediate (CDNI-24) TFA salt (8.1mg, 71.7% yield). LCMS M +1 ═ 810.2, tr ═ 0.346 min.1H NMR(500MHz,DMSO-d6)δ10.80(s,1H),9.36(d,J＝42.0Hz,2H),8.48(d,J＝45.8Hz,2H),8.27(s,1H),6.70(s,2H),6.41(d,J＝16.4Hz,1H),6.06(d,J＝7.3Hz,1H),5.70-5.38(m,2H),5.16(dtd,J＝26.2,9.3,4.6Hz,1H),4.90(ddd,J＝11.5,5.4,2.9Hz,1H),4.59(ddd,J＝12.9,6.7,2.4Hz,1H),4.40(dd,J＝11.4,5.3Hz,2H),4.26(ddd,J＝17.0,8.5,5.9Hz,1H),4.23-4.06(m,1H),3.92-3.71(m,2H),3.43-3.17(m,2H),3.13(td,J＝7.3,4.8Hz,1H),2.67(t,J＝5.2Hz,3H)。
Examples 2 to 25: synthesis of (2R,3R,3aR,5R,7aR,9R,10R,10aS,12R,14aR) -2, 9-bis (2-amino-6-oxo-1, 6-dihydro-9H-purin-9-yl) -10-hydroxy-5, 12-dimercapto-5, 12-octahydro-2H dioxide, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphosphododecan-3-yl (2- (methylamino) ethyl) carbonate (CDNI-25)
Figure BDA0002340450700006711
CDN intermediate (CDNI-24) was synthesized using the method described for the synthesis of CDN intermediate (CDNI-3), except using compound (T1-16) Et3N salt instead of Compound (T1-2) Et3And (3) N salt.
Boc protected CDN intermediate (CDNI-25): LCMS M +1 ═ 924.2.tr ═ 0.813 min.
CDN intermediate (CDNI-25) TFA salt (5.9mg, 46.2% yield). LCMS M + 1-824.0 tr-0.410 min.1H NMR(500MHz,DMSO-d6)δ10.64(d,J＝12.1Hz,1H),9.26(d,J＝105.9Hz,1H),8.04(d,J＝5.7Hz,1H),6.59(s,2H),5.96(d,J＝7.8Hz,1H),5.80-5.61(m,1H),4.81(ddd,J＝72.1,9.8,4.4Hz,1H),4.57-4.43(m,1H),4.29-3.88(m,3H),3.28-2.97(m,1H。
Examples 2 to 26: synthesis of ((2R,3R,3aR,5R,7aR,9R,10R,10aR,12S,14aR) -2, 9-bis (6-amino-9H-purin-9-yl) -10-fluoro-5, 12-dimercapto-5, 12-octahydro-2H, 7H-difluoro [3,2-D:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphosphacyclododecane-3-yl D-proline (CDNI-26)
Figure BDA0002340450700006721
Step 1: a solution of dicyclohexylcarbodiimide (0.51 eq) in 5ml of anhydrous DCM was added dropwise under nitrogen with stirring to a solution of (R) -1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid (from Coronto (Combi-Blocks)) (2.152g, 10mmol) in anhydrous dichloromethane (45 ml). The solution was stirred for 150 minutes and the resulting urea precipitate was removed by filtration and the filtrate was concentrated to about 5ml and then filtered through a syringe filter. The solvent was removed under vacuum to give (R) -1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid anhydride (2.169g, 100% yield) as a viscous oil.
Step 2: (R) -1- (tert-Butoxycarbonyl) pyrrolidine-2-carboxylic acid anhydride (501mg, 1.117mmol) in NMP (3mL) was added to the sodium salt of compound (T1-20) (55mg, 0.074mmol) in pyridine (1.5mL) and the mixture was stirred at room temperature for two days. Then, n-butylamine (0.1mL) in water (1.0mL) was added, and the mixture was stirred at room temperature for 10 minutes. Pyridine and water were then removed under vacuum and NMP was removed by lyophilization. The crude product was purified by reverse phase ISCO using a 50g C18 aqueous column using 5% -55% acetonitrile-H2O (containing 10mM Et)3Aqueous phase of N HOAc) eluted to the boc-protected binary adduct of CDN intermediate (CDNI-26). All binary adducts were collected and dried by lyophilization.
And step 3: the boc-protected binary adduct was dissolved in MeOH (5mL) in a 30mL pressure vessel equipped with a Teflon valve. The vessel was heated in an oil bath at 110 ℃ for 5 hours. The volatiles were evaporated and the residue was purified by reverse phase ISCO using a 50g C18 aqueous column, 5% -55% acetonitrile-H2O (containing 10mM Et)3Aqueous phase of N HOAc). Fractions containing the desired product were combined and lyophilized to obtain Et as3Boc-protected CDN intermediate (CDNI-26) as N salt (18.9 mg). LCMS M +1 ═ 890.0, tr ═ 0.722 min.
And 4, step 4: to the boc-protected CDN intermediate (CDNI-26) Et3To a vial of N salt (30.0mg, 0.034mmol) was added TFA (2 mL). The mixture was immediately concentrated and then concentrated. The crude product was purified by reverse phase ISCO using 50g C18 column with 5% -40% acetonitrile-H2O (containing 10mM Et)3Aqueous phase of N HOAc). The fractions containing the desired product were concentrated to obtain CDN intermediate (CDNI-26) as TEA salt (12.4mg, 37.1% yield). LCMS M +1 ═ 790.1, tr ═ 0.350 min.
Examples 2 to 27: synthesis of a mixture of CDN intermediate (CDNI-27a) and CDN intermediate (CDNI-27b)
Figure BDA0002340450700006731
The mixture of CDN intermediate (CDNI-27a) and CDN intermediate (CDNI-27b) was prepared using the method described for the synthesis of intermediate (CDNI-3) except that compound (T1-56) was used instead of compound (T1-2), the reaction mixture of step was stirred for 2 hours instead of 30 minutes, and in step 1, purification was performed using 5% -50% acetonitrile-H2O (containing 10mM Et)3Aqueous phase of NHOAc).
CDN intermediate (CDNI-27a) and CDN intermediate (CDNI-27b) as TEA salts (3.7mg, 55.9% yield). LCMS M +1 ═ 822.0, tr ═ 0.319 min.
Note that: the mixture was not isolated and 2- ((tert-butoxycarbonyl) (methyl) amino) ethyl chloroformate was synthesized as described in the synthesis of CDNI-9, except that the initial temperature was-30 ℃ instead of-15 ℃.
Examples 2 to 28: synthesis of (2R,3R,3aR,5S,7aR,9R,10R,10aR,12R,14aR) -9- (2-amino-6-oxo-1, 6-dihydro-9H-purin-9-yl) -2- (6-amino-9H-purin-9-yl) -10-fluoro-5, 12-dimercapto-5, 12-octahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphosphododecan-3-yl (2- (methylamino) ethyl) carbonate (CDNI-28)
Figure BDA0002340450700006741
CDN intermediate (CDNI-28) was synthesized using the method described for the synthesis of CDN intermediate (CDNI-3), except that compound (T1-11) Et was used3N salt instead of Compound (T1-2) Et3N salt, reaction time in step 2 was 2 hours instead of 30 minutes, and CDN intermediate (CDNI-28) was purified by reverse phase ISCO using 15g C18 column with 5% -40% acetonitrile-H2O elution (containing 10mM Et3Aqueous phase of N HOAc).
As Et3Boc-protected CDN intermediate (CDNI-28) as N salt (8.9mg, 52.1% yield). LCMS M +1 ═ 910.1.tr ═ 0.731 min.
CDN intermediate (CDNI-28) as TEA salt (6.5mg, 62.4% yield). LCMS M +1 ═ 810.0tr ═ 0.350 min.
Examples 2 to 29: synthesis of (2R,3R,3aR,7aR,9R,10R,10aR,14aR) -2- (6- ((3-amino-2-hydroxypropyl) amino) -9H-purin-9-yl) -9- (6-amino-9H-purin-9-yl) -3, 10-difluoro-5, 12-dihydroxyoctahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphosphacyclododecane 5, 12-dioxide (CDNI-29)
Figure BDA0002340450700006751
Step 1: to compound (T1-1) Et3To a solution of N salt (30mg, 0.033mmol) in DMF (3mL) was added tert-butyl (oxiran-2-ylmethyl) carbamate (57.9mg, 0.334mmol) and DIEA (43.2mg, 0.334 mmol). The mixture was heated to 100 ℃ for 4 hours and the solvent was removed. The crude product was purified by reverse phase ISCO using a 50g C18 aqueous column with 5% to 45% acetonitrile-H2O (containing 10mM Et)3Aqueous phase of N HOAc). The fraction containing the boc-protected CDN intermediate (CDNI-29) was isolated and lyophilized to obtain Et3Boc-protected CDN intermediate (CDNI-29) as N salt (20mg, 58% yield). LCMS M +1 ═ 836.0, tr ═ 0.538 min.
Step 2: to the boc-protected CDN intermediate (CDNI-29) Et3To a 25mL round-bottomed flask containing N salt (20mg, 0.019mmol) was added TFA (1mL, 13 mmol). The mixture was stirred for 1 minute and then concentrated. The residue was purified by reverse phase ISCO using a 50g C18 aqueous column with 5% -35% acetonitrile-H2O (containing 10mM Et)3Aqueous phase of N HOAc). The fractions containing the desired product were concentrated to obtain Et as3CDN intermediate for N salt (CDNI-29) (11.1mg, 62% yield). LCMS M +1 ═ 736.0, tr ═ 0.235 min.
Example 3: synthesis of exemplary linker-drug Compounds
Example 3-1: synthesis of Compound 12(C12)
Figure BDA0002340450700006752
Figure BDA0002340450700006761
Step 1:compound (T1-2) (5mg, 0.007mmol) disodium salt was dissolved in anhydrous pyridine (1mL), followed by addition of Et3N (0.005 mL). The mixture was sonicated and then linker intermediate (LI-1) (30mg, 0.068mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes and monitored by LCMS. The mixture was concentrated and then dissolved in MeOH-water, followed by purification by mass triggered reverse phase HPLC using C18 column, with 5% -55% acetonitrile-H containing 0.05% TFA2And (4) eluting with O. Fractions containing the desired boc-protected carbonate (2mg, 22%) were collected LCMS M +1 ═ 1111.1, tr ═ 0.898 min.
Step 2:TFA (1ml) was added to a vial containing the carbonate from step 1(2 mg, 0.0015mmol) and then immediately concentrated. The residue was then dissolved in MeOH and purified by ISCO using a 1g C18 column, eluting with 5% -50% ACN-water containing 0.05% TFA. Fractions containing the desired product were combined and lyophilized to give the deprotected carbonate as a TFA salt (1.0mg, 11% yield). LCMS M/2+1 506.2, tr 0.669 min.
And step 3:DIEA (15mg, 0.116mmol) was added and then HATU (3.4mg, 0.0089mmol) was added to a solution of 3- (2- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) ethoxy) propionic acid (Mal-PEG 1-acid) (1.9mg, 0.0089mmol) in DMF (1ml) and the reaction mixture was stirred at room temperature for 5 min. 10% of the reaction mixture was then added to a flask containing the deprotected carbonate obtained in step 2 (1.0mg, 0.00089mmol) in 0.5ml DMF. The reaction was stirred at room temperature for 2 hours and purified by mass triggered reverse phase HPLC using a C18 column with 5% -37% acetonitrile-H containing 0.05% TFA2And (4) eluting with O. The fractions containing the desired product were concentrated to obtain compound (C12) (0.7mg, 57% yield) as a TFA salt. LCMS M +1 1206.3, M/2+1 603.7, tr 0.784 min.
Example 3-2: synthesis of Compound 13(C13)
Figure BDA0002340450700006771
18- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) -5,5,9, 12-tetramethyl-8, 13-dioxo-16-oxa-3, 4-dithia-9, 12-dioxaoctadecyl (4-nitrophenyl) carbonate (LI-2) (2.5mg, 0.0039mmol) and DIEA (0.013mL, 0.077mmol) were added to a solution of intermediate (CDNI-3) (3.5mg, 0.0039mmol) in DMF (1mL) and the mixture was stirred at room temperature for 5 hours. The crude product was purified by mass triggered reverse phase HPLC using a C18 column eluting with 20% -33% acetonitrile-H2O containing 0.05% TFA. The fractions containing the desired product were concentrated to compound a2(2.2mg, 38.1% yield) as a TFA salt. LCMS M/2+1 654.2, tr 0.799 min.
Examples 3 to 3: synthesis of Compound 14(C14)
Figure BDA0002340450700006781
Will be provided with
Figure BDA0002340450700006782
CDN intermediate (CDNI-3) ((7.4mg, 0.0073mol) TFA salt was dissolved in anhydrous DMF (2ml) and 4- ((S) -2- (6- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) hexanamido) -3-methylbutanamido) -5-ureidopentanamido) benzyl (4-nitrophenyl) carbonate (MC-vc-pab-PNP from the company dianin biopharmaceutical (Levena Biopharma), san diego) (6.3mg, 0.009mmol) was added followed by DIEA (11mg, 0.084mmol) and HOAT (4mg, 0.029mmol) the mixture was stirred at room temperature for 3 days and monitored by LCMS until the reaction was complete the mixture was then purified by mass triggered reverse phase HPLC using a C18 column, with 5% -35% acetonitrile-H containing 0.05% TFA2And (4) eluting with O. Fractions containing the desired product were combined and concentrated to give compound (C14) (3.6mg, 25.8% yield) as a TFA salt. LCMS M/2+1 695.8, tr 0.783 min.
Examples 3 to 4: synthesis of Compound 15(C15)
Figure BDA0002340450700006783
Figure BDA0002340450700006791
CDN intermediate (CDNI-4) (13.5mg, 0.015mmol) TFA salt in DMF was added to a solution of linker intermediate (LI-3) (10.5mg, 0.015mmol, 1.0 eq), followed by DIEA (7.75mg, 0.060mmol) and HOAT (2.45mg, 0.018 mmol). The mixture was allowed to stand at room temperature for 16 hours and then concentrated. The residue was dissolved in DMSO and purified by ISCO using a 15.5g, C18 aqueous column, eluting with 5% -40% ACN in water containing 10mM TFA-HOAc. The fractions containing the desired product were concentrated to obtain compound (C15) (12.2mg, 50% yield) as a TEA salt. M + 1-1346.20, tr-0.732 min.
Examples 3 to 5: synthesis of Compound 16(C16)
Figure BDA0002340450700006792
Compound (C16) was synthesized using the procedure described for the synthesis of compound (C15), except CDN intermediate (CDNI-5) TFA salt was used instead of CDN intermediate (CDNI-4).
Compound (C16) (7.6mg, 31.3% yield) as a TFA salt. LCMS M/2+1 is 681.8, tr is 1.025 min.
Examples 3 to 6: synthesis of Compound 17(C17)
Figure BDA0002340450700006801
TEA (6.7mg, 0.066mmol) and HATU (5.0mg, 0.013mmol) were added to a solution of 3- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) propionic acid (2.2mg, 0.013mmol)) in DMF (1mL) and the mixture was stirred for 5 min. CDN intermediate (CDNI-3) (15mg, 0.013mmol) in DMF (1mL) was then added, and the mixture was stirred at room temperature for 18 hours, then concentrated. The residue was dissolved in DMSO (2ml) and purified by mass triggered reverse phase HPLC using a C18 column eluting with 5% -25% acetonitrile-H2O containing 0.05% TFA. Fractions containing the desired product were lyophilized to obtain compound (C17) as a TFA salt (14.3mg, 88% yield). LCMS M + 1-943.1 tr-0.561 min.
Examples 3 to 7: synthesis of Compound 18(C18)
Figure BDA0002340450700006802
CDN intermediate (CDNI-3) (20mg, 0.018mmol), DIEA (23mg, 0.18mmol) and HOAT (2.4mg, 0.018mmol) were added to a solution of linker intermediate (LI-3) (13.5mg, 0.019mmol) in DMF (1mL) and the mixture was stirred at room temperature for 18 h and then concentrated. The residue was dissolved in DMSO (2ml) and then pre-purified by ISCO using a 15.5g C18 column, eluting with 5% -35% ACN-water containing 0.05% TFA. Fractions containing the desired product were combined and then purified by mass triggered reverse phase HPLC, C18 column, with 10% -30% acetonitrile-H containing 0.05% TFA2And (4) eluting with O. Fractions containing the desired product were combined and lyophilized to obtain compound (C18) (12.3 mg) as a TFA salt39.8% yield). LCMS M +1 ═ 1348.2, M/2+1 ═ 674.8, tr ═ 0.842 min.
Examples 3 to 8: synthesis of Compound 1(C1)
Linker intermediate (LI-3) (36.7mg, 0.053mmol) was added to a solution of CDN intermediate (CDNI-1) (60mg, 0.053mmol) in DMF (5mL), followed by DIEA (68.2mg, 0.527mmol) and HOAT (7.2mg, 0.053 mmol). The mixture was allowed to stand at room temperature for 16 hours and then concentrated. The residue was dissolved in DMSO and pre-purified by ISCO using 15.5g of c18 aqueous column, eluting with 5% -35% ACN in water containing 0.05% TFA. After purification, fractions were concentrated and then purified by mass triggered reverse phase HPLC, C18 column, eluting with 5% -33% acetonitrile-H2O containing 0.05% TFA. The fractions containing the desired product were concentrated to give compound (C1) (55.4mg, 68.1% yield) as a TFA salt. LCMS M/2+ 1-676.8, M + 1-1352.3, and tr-0.753 min.1H NMR(500MHz,DMSO-d6)δ10.01(s,1H),9.42(b,1H),8.56(d,J＝15.2Hz,1H),8.31(s,1H),8.16(dd,J＝13.1,7.4Hz,1H),8.04(d,J＝8.4Hz,1H),7.62(d,J＝8.1Hz,1H),7.48(d,J＝8.0Hz,1H),7.32(d,J＝8.1Hz,1H),7.18(s,1H),7.02(s,2H),6.43(d,J＝16.6Hz,2H),6.18(s,2H),5.61(s,1H),5.50(s,1H),5.13(m,3H),5.02(s,1H),4.93(s,1H),4.55-4.34(m,6H),4.27(t,J＝5.3Hz,2H),4.19(dd,J＝8.5,6.7Hz,1H),3.87(d,J＝12.1Hz,2H),3.63(q,J＝7.0,6.6Hz,2H),3.54(s,2H),3.19-2.88(m,5H),2.48(q,J＝7.4Hz,1H),2.07-1.94(m,1H),1.75(m,1H),1.65(m,1H),1.46(m,3H),0.87(dd,J＝13.9,6.8Hz,6H)。
Examples 3 to 9: synthesis of Compound 2(C2)
Figure BDA0002340450700006821
TEA (1.3mg, 0.013mmol) and HATU (5mg, 0.013mmol) were added to a solution of 3- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) propionic acid (2.2mg, 0.013mmol) in DMF (1mL) and the mixture was stirred for 5 min. CDN intermediate (CD) was then addedNI-1) TFA salt (15mg, 0.013mmol) in DMF (1mL) and the mixture was stirred at room temperature for 18 h and then concentrated. The residue was dissolved in DMSO (2ml) and purified by mass triggered reverse phase HPLC using a C18 column with 5% -25% acetonitrile-H containing 0.05% TFA2And (4) eluting with O. Fractions containing the desired product were lyophilized to obtain compound (C2) as a TFA salt (8.7mg, 59% yield). LCMS M +1 ═ 947.1, tr ═ 0.646 min.
Examples 3 to 10: synthesis of Compound 3(C3)
Compound (C3) was synthesized using the procedure described for the synthesis of compound (C2), except that linker intermediate (LI-4) was used instead of 3- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) propionic acid.
Compound (C3) (4.5mg, 26% yield) as a TFA salt. LCMS M +1 ═ 1243.3, tr ═ 0.924 min.
Examples 3 to 11: synthesis of Compound 4(C4)
Figure BDA0002340450700006831
Compound (C4) was synthesized using the method described for the synthesis of compound (C2), except that bis (perfluorophenyl) 3,3' -oxydipropanate (available from boder pharmaceutical company (Broadpharm), san diego) was used instead of 3- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) propionic acid.
Compound (C4) (10.5mg, 46.5% yield) as a TFA salt. LCMS M +1 ═ 1106.0, tr ═ 0.930 min.
Examples 3 to 12: synthesis of Compound 5(C5)
Figure BDA0002340450700006832
Step 1: DIEA (0.033mL, 0.186mmol) was added to CDN intermediate (CDNI-2) (26.6mg, 0.019mmol) and 2, 5-dioxopyrrolidin-1-yl 2- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) oxy) ethanamideA solution of the acid ester (15.28mg, 0.037mmol) in DMF (1 ml). The mixture was stirred at room temperature for 1 hour, then concentrated. The residue was purified by passage through a reverse phase ISCO C1850 g column containing 10mM HOAc Et 310% -50% acetonitrile-H of N2And (4) eluting with an aqueous solution of O. The fractions containing the desired product were concentrated to obtain Et as34- ((9S,12S) -1- (9H-fluoren-9-yl) -9-isopropyl-3, 7, 10-trioxo-12- (3-ureidopropyl) -2, 5-dioxa-4, 8, 11-triazatridecane-13-amido) benzyl (2- (((9- ((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR) -9- (6-amino-9H-purin-9-yl) -3, 10-difluoro-5, 12-dimercapto-5, 12-dioxidooctahydro-2H, 7H-difluoro [3,2-d:3',2' -j][1,3,7,9]Tetraoxa [2,8]]Diphosphacyclododec-2-yl) -9H-purin-6-yl) carbamoyl) oxy) ethyl) (methyl) carbamate (6mg, 25% yield). LCMS M/2+ 1-748.8, tr-0.966 min.
Step 2: 4- ((9S,12S) -1- (9H-fluoren-9-yl) -9-isopropyl-3, 7, 10-trioxo-12- (3-ureidopropyl) -2, 5-dioxa-4, 8, 11-triazatridecane-13-amido) benzyl (2- (((9- ((2R,3R,3aR,5R,7aR,9R,10R,10aR,12R,14aR) -9- (6-amino-9H-purin-9-yl) -3, 10-difluoro-5, 12-dimercapto-5, 12-dioxidooctahydro-2H, 7H-difluoro [3,2-d:3',2' -j][1,3,7,9]Tetraoxa [2,8]]Diphosphacyclododec-2-yl) -9H-purin-6-yl) carbamoyl) oxy) ethyl) (methyl) carbamate (6.0mg, 0.0035mmol) triethylammonium salt was dissolved in ACN (2mL) and water (2mL) and LiOH (20mg) were added. The mixture was stirred at room temperature for 4 hours, neutralized with HOAc (0.06ml) and then concentrated. The residue was purified by reverse phase ISCO 15.5g C18 aqueous column using 5% -40% acetonitrile-H containing 0.05% TFA2And (4) eluting with O. The fractions containing the desired product were concentrated to give compound (C5) as a TFA salt (2.8mg, 36.9% yield). LCMS M/2+ 1-637.8 tr-0.676 min.
Examples 3 to 13: synthesis of Compound 6(C6)
Figure BDA0002340450700006841
Compound (C6) was synthesized using the procedure described for the synthesis of compound (C14), except CDN intermediate (CDNI-1) was used instead of CDN intermediate (CDNI-3).
Compound (C6) (1.2mg, 24% yield) as a TFA salt. LCMS M/2+ 1-697.8, M + 1-1394.5, and tr-0.782 min.
Examples 3 to 14: synthesis of Compound 7(C7)
Compound (C7) was synthesized using the procedure described for the synthesis of compound (C4), except CDN intermediate (CDNI-2) was used instead of CDN intermediate (CDNI-1).
Compound (C7) (5.3mg, 55.3% yield) as a TFA salt. LCMS M/2+1 756.3, tr 0.975 min.
Examples 3 to 15: synthesis of Compound 8(C8)
Figure BDA0002340450700006851
DIEA (0.01ml, 0.056mmol) was added to a solution of CDN intermediate (CDNI-2) (8mg, 0.0056mmol) and bis (2, 5-oxopyrrolidin-1-yl) 3,3' -oxydipropionate (5.98mg, 0.017mmol) ((bis-PEG 1-NHS ester available from Border pharmaceuticals (Broadpharmarm), san Diego) in DMF (1 ml.) the mixture was stirred at room temperature for 2 hours and then concentrated2And (4) eluting with O. Fractions containing the desired product were lyophilized to obtain compound (C8) as a TFA salt (5.7mg, 62.2% yield). LCMS M/2+1 is 721.8, tr is 0.755 min.
Examples 3 to 16: synthesis of Compound 9(C9)
Figure BDA0002340450700006852
Compound (C9) was synthesized using the procedure described for the synthesis of compound (C1), except that linker intermediate (LI-5) was used instead of linker intermediate (LI-3).
Compound (C9) as a TFA salt (6.8mg, 52.6% yield). LCMS M/2+1 ═ 698.8, tr ═ 0.758 min.
Examples 3 to 17: synthesis of Compound 10(C10)
Figure BDA0002340450700006861
Compound (C10) was synthesized using the procedure described for the synthesis of compound (C1), except that linker intermediate (LI-2) was used instead of linker intermediate (LI-3).
Compound (C10) (7.3mg, 55.3% yield) as a TFA salt. LCMS M +1 ═ 1311.2, M/2+1 ═ 656.2, tr ═ 0.845 min.
Examples 3 to 18: synthesis of Compound 11(C11)
Figure BDA0002340450700006862
Compound (C11) was synthesized using the method described for the synthesis of compound (C1), except that 1- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) -3,6,9, 12-tetraoxapentadecan-15-oic acid (MPEG 4-acid, available from bodhidpharmaceutical company (Broadpharm), san diego) was used instead of linker intermediate (LI-3).
Compound (C11)10.9mg (37.6% yield) LCMS M +1 ═ 1123.1, tr ═ 0.722 min.
Examples 3 to 19: synthesis of Compound 19(C19)
Figure BDA0002340450700006863
Compound (C19) was synthesized using the method described for the synthesis of compound (C2), except CDN intermediate (CDNI-10) was used instead of CDN intermediate (CDNI-1), and
4- ((S) -2- ((S) -2- (6- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) hexanamido) -3-methylbutanamido) -5-ureidopentanamido) benzyl (4-nitrophenyl) carbonate (MC-vc-pab-PNP, available from the company Biopharmaceuticals of Union (Levena Biopharma), san Diego) was used instead of 3- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) propionic acid.
Compound (C19) (1.1mg, 20% yield) as a TFA salt. LCMS M/2+ 1-675.8 tr-0.776 min.
Examples 3 to 20: synthesis of Compound 20(C20)
Figure BDA0002340450700006871
Compound (C20) was synthesized using the procedure described for the synthesis of compound (C1), except CDN intermediate (CDNI-6) was used instead of CDN intermediate (CDNI-1).
Compound (C20) (4.2mg, 30% yield) as a TFA salt. LCMS M/2+ 1-675.8, M + 1-1350.3, and tr-0.751 min. 1H NMR (500MHz, DMSO-d6) δ 9.99(s,1H),9.28(s,2H),8.98(s,3H),8.14(d, J ═ 7.4Hz,2H),8.04(d, J ═ 8.3Hz,2H),7.99(s,1H),7.64(d, J ═ 8.2Hz,2H),7.36(d, J ═ 8.1Hz,2H),7.03(s,2H),6.49(d, J ═ 46.4Hz,2H),6.03(s,1H),5.70(d, J ═ 49.8Hz,2H),5.21-4.83(m,5H),4.68-4.32(m,9H),4.28-4.13(m,2H),3.13 (J ═ 13.13, 3.13, 2H),5.21-4.83(m,5H),4.68-4.32(m, 11H), 6.6.6.6.6.6H, 11H, 6H, 11H, 6.6.6.6 (d, 1H), 6.6.6.6.4H, 6.6H, 1H), 0.86(dd, J ═ 16.0,6.7Hz, 8H).
Examples 3 to 21: synthesis of Compound 21(C21)
Figure BDA0002340450700006872
Compound (C21) was synthesized using the procedure described for the synthesis of compound (C1), except CDN intermediate (CDNI-7) was used instead of CDN intermediate (CDNI-1).
Compound (C21) (12.2mg, 50% yield) as a TEA salt. M + 1-1348.20, tr-0.721 min.
Examples 3 to 22: synthesis of Compound 22(C22)
Figure BDA0002340450700006881
Compound (C22) was synthesized using the procedure described for the synthesis of compound (C19), except CDN intermediate (CDNI-8) was used instead of CDN intermediate (CDNI-10).
Compound (C22) (0.9mg, 34.1% yield) as a TFA salt. LCMS M/2+1 equals 695.8, M +1 equals 1391, and tr equals 0.695 min.
Examples 3 to 23:
synthesis of Compound 23a (C23a)
Figure BDA0002340450700006882
Compound (C23a) was synthesized using the procedure described for the synthesis of compound (C1), except CDN intermediate (CDNI-9) was used instead of CDN intermediate (CDNI-1).
Compound (C23a) (12.7mg, 51.7% yield) as a TFA salt. LCMS M/2+1 ═ 676.7, tr ═ 0.700 min.
b) Synthesis of Compound 23b (C23b)
Figure BDA0002340450700006891
Compound (23b) is obtained during the synthesis of compound (23 a). Compound (C23a) and compound (23b) were not isolated. As TFA salt (12.7mg, 51.7% yield). LCMS M/2+1 ═ 676.7, tr ═ 0.700 min.
Examples 3 to 24: synthesis of Compound 24(C24)
Figure BDA0002340450700006892
HATU (1.9mg, 0.005mmol) was added to a mixture of (Z) -6- (((1-ethoxyethylene) amino) oxy) hexanoic acid (1.2mg, 0.0056mmol) and DIEA (2.2mg, 0.017mmol) in DMF (1 ml). The mixture was then stirred at room temperature for 5 minutes and then added to a solution of CDN intermediate (CDNI-2) (4mg, 0.0028mmol) in DMF (1 ml). The mixture was then stirred for 5 hours, at room temperature for 16 hours, then concentrated to give the protected derivative ethyl (Z) -N- ((6- (((S) -1- ((4- ((((((2- (((9- ((2R, 3aR,5R,7aR,9R,10 aR,12R,14aR) -9- (6-amino-9H-purin-9-yl) -3, 10-difluoro-5, 12-dimercapto-5, 12-dioxyoctahydro-2H, 7H-difluoro [3,2-d:3',2' -j ] [1,3,7,9] tetraoxa [2,8] diphosphacyclododecane-2-yl) -9H-purin-6-yl) carbamoyl ) Oxy) ethyl) (methyl) carbamoyl) oxy) methyl) phenyl) amino) -1-oxo-5-ureidopentan-2-yl) amino) -3-methyl-1-oxobutan-2-yl) amino) -6-oxohexyl) oxy) imidoacetate. LCMS M/2+1 700.8, tr 0.890 min.
The residue was purified by reverse phase HPLC, ISCO C1850 g column, using 10% -50% acetonitrile-H with 0.05% TFA2O elution results in the loss of the protecting group. The fractions containing the desired product compound (C-24) were concentrated and further purified by reverse phase ISCOC18 column using 5% -40% acetonitrile-H containing 0.05% TFA2O elution to give compound (C-24) as a TFA salt (2.2mg, 47.9% yield). LCMS M/2+ 1-665.8, tr-0.697 min.
Note that: (Z) -6- (((1-ethoxyethylidene) amino) oxy) hexanoic acid was prepared from ethyl N-hydroxyacetimidate and 6-bromohexanoic acid in the presence of LiOH using the method described in Biomacromolecules [ Biomacromolecules ]6(5)2648,2005.
Examples 3 to 25:
a) synthesis of Compound 25a (C25a)
Figure BDA0002340450700006901
Compound (C25a) was synthesized using the procedure described for the synthesis of compound (C1), except CDN intermediate (CDNI-11) was used instead of CDN intermediate (CDNI-1).
Compound (C25a) as a TFA salt (7.5mg, 37.1% yield). LCMS M/2+1 ═ 698.8, tr ═ 0.715 min.
b) Synthesis of Compound 25b (C25b)
Figure BDA0002340450700006902
Compound (25b) is obtained during the synthesis of compound (25 a). Compound (C23a) and compound (25b) were not isolated. As TFA salt (7.5mg, 37.1% yield). LCMS M/2+1 ═ 698.8, tr ═ 0.715min
Examples 3 to 26: synthesis of Compound 26(C26)
Figure BDA0002340450700006911
DIEA (0.019mL, 0.110mmol) and HATU (9.2mg, 0.024mmol) were added to a solution of 1- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) -3,6,9, 12-tetraoxapentadecane-15-oic acid (Mal-PEG 4-acid) (8.4mg, 0.024mmol) in DMF (1mL) and the mixture was stirred for 5min before adding a solution of CDN intermediate (CDNI-7) (25mg, 0.022mmol) in DMF (1 mL). The reaction was then stirred at room temperature for 16 hours and then concentrated. The residue was purified by reverse phase ISCO C18 column using 5% -40% acetonitrile-H2O (containing 10mM Et)3Aqueous phase of N HOAc). The fractions containing the desired product were lyophilized to obtain compound (C-26) as a TEA salt (23.2mg, 76% yield). LCMS M +1 ═ 1121.1tr ═ 0.733 min. 1H NMR (500MHz, DMSO-d)6)δ8.66(d,J＝3.7Hz,2H),7.96-7.75(m,2H),7.06(s,2H),6.32(d,J＝14.0Hz,1H),6.26(d,J＝3.1Hz,1H),5.81(t,J＝5.8Hz,1H),5.63(d,J＝52.4Hz,1H),5.24-5.00(m,2H),4.58-4.26(m,6H),3.89-3.72(m,3H),3.72-3.63(m,2H),3.64-3.54(m,3H),3.54-3.47(m,12H),3.16(s,2H),3.01(q,J＝7.2Hz,15H),2.95(s,1H),2.74-2.61(m,2H),1.94(s,1H),1.13(t,J＝7.2Hz,21H)。
Examples 3 to 27: synthesis of Compound 27(C27)
Figure BDA0002340450700006912
Compound (C27) was synthesized using an analogous method as described for the synthesis of compound (C15), except CDN intermediate (CDNI-12) was used instead of CDN intermediate (CDNI-4) and 5% -50% acetonitrile-H was used2O (containing 10mM Et)3Aqueous phase of N HOAc) eluted C18 column. The fractions containing the desired product were concentrated to obtain Et as3Compound (C27) as N salt (1mg, 11% yield). LCMS M/2+1 675.8, tr 0.758 min.
Examples 3 to 28: synthesis of Compound 28(C28)
Figure BDA0002340450700006921
Compound (C28) was synthesized using a similar procedure as described for the synthesis of compound (C15), except CDN intermediate (CDNI-13) was used instead of CDN intermediate (CDNI-4). Compound (C28) (5.8mg, 30% yield). LCMS M/2+1 668.8, tr 0.724 min.
Examples 3 to 29: synthesis of Compound 29(C29)
Figure BDA0002340450700006922
2, 5-dioxopyrrolidin-1-yl 3- (2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) propionate (from Commet corporation (Combi-Blocks)) (0.5mg, 0.002mmol) and DIEA (1.7mg, 0.013mmol) were added to a solution of intermediate CDNI-15TFA salt (1.7mg, 0.0013mmol) in DMF (1ml) and the reaction was stirred at room temperature for 72H and then concentrated. The crude product was purified by reverse phase ISCO using a 15g C18 aqueous column using 5% -40% acetonitrile-H2O (containing 10mM Et)3Aqueous phase of N HOAc). The fractions containing the desired product were concentrated to obtain Et as3Compound 29(C29) as the N salt (2.3mg, 111% yield). LCMS M +1 ═ 1187.1, tr ═ 0.675 min.
Examples 3 to 30: synthesis of Compound 30(C30)
Figure BDA0002340450700006931
Compound (C30) was synthesized using a similar procedure as described for the synthesis of compound (C29) except CDN intermediate (CDNI-16) was used instead of CDN intermediate (CDNI-15), the reaction mixture was stirred for 16 hours, and the crude product was purified by reverse phase ISCO using a 50g C18 aqueous column and eluted with 5% -35% acetonitrile-water (aqueous phase containing 10mM Et3N HOAc). Fractions containing the desired product were combined and lyophilized to give Et as3Compound 30(C30) as the N salt (3.8mg, 14% yield). LCMS M/2+1 680.2, tr 0.705 min.
Examples 3 to 31: synthesis of Compound 31(C31)
Figure BDA0002340450700006932
Compound (C31) was synthesized using the method described for the synthesis of compound (C1) except CDN intermediate (CDNI-17) TFA salt was used instead of CDN intermediate (CDNI-1), the reaction was stirred at room temperature for 20 hours and purified by ISCO using a 15.5C18 aqueous column, with 5% -40% acetonitrile-H2O (containing 10mM Et)3N-HOAc) was eluted. The fractions containing the desired product were concentrated to obtain compound 31(C31) (4.3mg, 76% yield) as a TEA salt. LCMS M/2+1 ═ 698.8, tr ═ 0.800 min.
Examples 3 to 32: synthesis of Compound 32(C32)
Figure BDA0002340450700006941
The CDN intermediate (CDNI-18) Et3A solution of the N salt (20mg, 0.022mmol) and 1- (prop-2-yn-1-yl) -1H-pyrrole-2, 5-dione (11.7mg, 0.087mmol) in a 1:2 mixture of water-t-BuOH (4.5ml) was diluted with N2Degassed and a degassed solution of sodium L-ascorbate (21.5mg, 0.109mmol) in water was added followed by CuSO4(10.4mg, 0.065mmol) in water. The reaction mixture was stirred at room temperature for 1 hour and then lyophilized. The crude product was purified by reverse phase ISCO using 50g C18 column with 10% -30% acetonitrile-H2O (containing 10mM Et)3Aqueous phase of N HOAc). Fractions containing the desired product were combined and lyophilized and repurified with reverse phase ISCO using 50g C18 column, 10% -30% acetonitrile-H containing 0.05% TFA2And (4) eluting with O. Fractions containing the desired product were lyophilized to obtain compound 32(C32) as a TFA salt (1.9mg, 6% yield). LCMS M +1 ═ 943.0, tr ═ 0.725 min.
Examples 3 to 33: synthesis of Compound 33(C33)
Figure BDA0002340450700006942
Compound (C33) was synthesized using the procedure described for the synthesis of compound (C32), except CDN intermediate (CDNI-19) TFA salt was used instead of CDN intermediate (CDNI-18). Compound (C33) TFA salt (2.7mg, 10% yield). LCMSM +1 ═ 941.0, tr ═ 0.725 min.
Examples 3 to 34: synthesis of Compound 34(C34)
Figure BDA0002340450700006951
Compound (C34) was synthesized using the procedure described for the synthesis of compound (C32), except CDN intermediate (CDNI-20) TFA salt was used instead of CDN intermediate (CDNI-18). LCMS M +1 ═ 957.1, tr ═ 0.693 min.
Examples 3 to 35: synthesis of Compound 35(C35)
Figure BDA0002340450700006952
Compound (C35) was synthesized using the method described for the synthesis of compound (C1), except CDN intermediate (CDNI-10) TFA salt was used instead of CDN intermediate (CDNI-1), the reaction was stirred at room temperature for 1 day and purified by reverse phase ISCO using C18 column, with 5% -35% acetonitrile-H2O (containing 10mM Et)3Aqueous phase of N HOAc). The fractions containing the desired product were concentrated to obtain Et as3Compound 35(C35) as the N salt (4.0mg, 120% yield). LCMS M +1 ═ 1308.1, tr ═ 0.761 min.
Examples 3 to 36: synthesis of mixture of Compound 36a (C36a) and Compound 36b (C36b)
Figure BDA0002340450700006961
A mixture of compound 36a (C36a) and compound 36b (C36b) was obtained using the method described for the synthesis of compound (C1), except that a mixture of CDN intermediates (CDNI-21a) and (CDNI-21b) TFA salts was used instead of CDN intermediate (CDNI-1),and initial purification by reverse phase ISCO using 15g C18 column with 5% -45% acetonitrile-H2O (containing 10mM Et 2)3Aqueous phase of N HOAc). The fractions containing the desired product were concentrated and further purified by reverse phase ISCO using 50g C18 aqueous column eluting with 5% -35% acetonitrile-water containing 0.05% TFA. The fractions containing the desired product were concentrated and lyophilized to obtain a mixture of compound 36a (C36a) and compound 36b (C36b) as TFA salts (8.3mg, 41% yield). LCMS M +1 ═ 1336.1, tr ═ 0.799 min.
Examples 3 to 37: synthesis of mixture of Compound 37a (C37a) and Compound 37b (C367b)
Figure BDA0002340450700006962
DIEA (11.0mg, 0.086mmol) was added to a solution of CDN intermediates (CDNI-22a and CDI-22b) (12.6mg, 0.0086mmol) and bis (perfluorophenyl) 3,3' -oxydipropionate (bis-PEG 1-PFP ester available from bodharmarm (Broadpharm)) (12.7mg, 0.026mmol) in DMF (1 ml). The reaction was stirred at room temperature for 2 hours and then concentrated. The residue was purified by reverse phase ISCO using a 30g C18 aqueous column eluting with 5% -100% acetonitrile-water containing 0.05% TFA. The fractions containing the desired product were concentrated and lyophilized to obtain a mixture of compounds 37a and 37b (C37a and C37b) as TFA salts (6.2mg, 38.6% yield). LCMS M/2+1 778.3, tr 0.974 min.
Examples 3 to 38: synthesis of Compound 38(C38)
Figure BDA0002340450700006971
Compound (C38) was synthesized using an analogous method as described for the synthesis of compound (C15), except CDN intermediate (CDNI-12) was used instead of CDN intermediate (CDNI-23) and 5% -50% acetonitrile-H was used2O (containing 10mM Et)3Aqueous phase of N HOAc) eluted C18 column. The fractions containing the desired product were concentrated to obtain Et as3Et as N salt3Compound (C38) as N salt (11.6mg, 88% yield). LCMS M-2+1＝676.8,tr＝0.742min。1H NMR(500MHz,DMSO-d6)δ10.80(s,1H),9.99(s,1H),9.37(s,1H),8.97(s,1H),8.68(s,1H),8.23(s,1H),8.13(d,J＝7.5Hz,1H),8.04(d,J＝8.4Hz,1H),7.62(t,J＝10.0Hz,2H),7.44(s,2H),7.34(t,J＝9.9Hz,2H),7.03(s,1H),6.27(d,J＝8.8Hz,1H),6.17(d,J＝8.8Hz,1H),6.02(s,1H),5.72-5.55(m,1H),5.55-5.39(m,3H),5.05(s,1H),4.54(ddd,J＝27.3,20.2,2.4Hz,2H),4.41(td,J＝8.1,5.2Hz,1H),4.31(s,2H),4.19(dd,J＝8.5,6.7Hz,1H),4.05-3.91(m,3H),3.72-3.60(m,1H),3.59(d,J＝5.9Hz,2H),3.11-3.02(m,1H),3.00(d,J＝9.6Hz,3H),2.80(qd,J＝13.5,6.4Hz,16H),2.52-2.42(m,1H),1.94(s,3H),1.73(s,1H),1.69-1.57(m,1H),1.52-1.34(m,2H),1.02(t,J＝7.2Hz,20H),0.86(dd,J＝15.8,6.8Hz,5H)。
Examples 3 to 39: synthesis of Compound 39(C39)
Compound (C39) was synthesized using an analogous method as described for the synthesis of compound (C18), except CDN intermediate (CDNI-24) was used instead of CDN intermediate (CDNI-3) and 5% -40% acetonitrile-H was used2O (containing 10mM Et)3Aqueous phase of N HOAc) eluted C18 column. The fractions containing the desired product were concentrated to obtain Et as3Compound of N salt (C39): (4.9mg, 41.6% yield). LCMS M/2+1 is 683.8, tr is 0.709 min.1H NMR(500MHz,DMSO-d6)δ9.99(s,1H),8.35(s,1H),8.21(s,1H),8.17-7.99(m,3H),7.68-7.52(m,2H),7.33(s,5H),7.03(s,2H),6.57(s,2H),6.30(d,J＝16.6Hz,1H),6.02(dd,J＝55.5,30.4Hz,2H),5.60(dd,J＝52.2,3.8Hz,1H),5.42(d,J＝30.9Hz,3H),5.01(d,J＝12.8Hz,2H),4.39(d,J＝12.6Hz,2H),4.30(d,J＝10.7Hz,4H),4.27-4.06(m,4H),3.92-3.74(m,2H),3.69-3.50(m,3H),3.14-2.83(m,5H),2.69(q,J＝7.2Hz,33H),1.86-1.56(m,1H),1.56-1.31(m,2H),1.05(t,J＝7.2Hz,44H),0.86(dd,J＝15.5,6.8Hz,6H)。
Examples 3 to 40: synthesis of Compound 40(C40)
Compound (C40) was synthesized using a similar procedure as described for the synthesis of compound (C18), except CDN intermediate (CDNI-25) was used instead of CDN intermediate (CDNI-3). As Et3Compound of N salt (C40): (8.0mg, 74% yield). LCMS M/2+ 1-690.8, tr-0.771 min.1H NMR(500MHz,DMSO-d6)δ10.02(s,1H),8.14(d,J＝7.5Hz,1H),8.04(t,J＝8.9Hz,3H),7.63(d,J＝8.0Hz,2H),7.33(d,J＝9.4Hz,2H),7.03(s,2H),6.71(d,J＝67.7Hz,5H),6.03(s,2H),5.78(d,J＝7.4Hz,1H),5.59(s,1H),5.45(s,2H),5.15(dt,J＝9.2,4.2Hz,1H),5.06-4.83(m,3H),4.58(t,J＝6.3Hz,1H),4.42(d,J＝6.6Hz,1H),4.33-4.09(m,6H),4.06-3.86(m,2H),3.65(td,J＝8.1,6.7Hz,1H),3.15-2.82(m,4H),2.66(q,J＝7.2Hz,33H),1.80-1.54(m,1H),1.54-1.34(m,2H),1.04(t,J＝7.2Hz,45H),0.86(dd,J＝16.3,6.8Hz,5H)。
Examples 3 to 41: synthesis of Compound 41(C41)
Figure BDA0002340450700006992
Compound (C41) was synthesized using an analogous method to that described for the synthesis of compound (C18), except CDN intermediate (CDNI-26) TEA salt was used instead of CDN intermediate (CDNI-3) and linker intermediate (LI-9) was used instead of linker intermediate (LI-3). Fractions containing the desired product were combined and lyophilized to obtain Et as3Compound (C41) as N salt (2.3mg, 11% yield). LCMS M/2+1 702.3, tr 0.691 min.
Examples 3 to 42: synthesis of mixture of Compound 42a (C42a) and Compound 42b (C42b)
A mixture of compound (C42a) and compound (C42b) was synthesized using an analogous method to that described for the synthesis of compound (C18), except that a mixture of CDN intermediate (CDNI-27a) and CDN intermediate (CDNI-27b) was used in place of CDN intermediate (CDNI-3) and 5% -40% acetonitrile-H was used2O (containing 10mM Et)3Aqueous phase of N HOAc) eluted C18 column. Obtained as Et3A mixture of compound (C42a) and compound (C42b) as N salts (2.0mg, 33% yield). LCMS M/2+ 1-689.8, tr-0.694 min.
Examples 3 to 43: synthesis of Compound 43(C43)
Figure BDA0002340450700007002
Compound (C43) was synthesized using a similar procedure as described for the synthesis of compound (C18), except CDN intermediate (CDNI-28) TEA salt was used instead of CDN intermediate (CDNI-3). Fractions containing the desired product were combined and lyophilized to obtain Et as3Compound (C43) as the N salt (3.3mg, 31.1% yield). LCMS M/2+ 1-683.8, tr-0.813 min.
Examples 3 to 44: synthesis of mixture of Compound 44a (C44a) and Compound 44b (C44b)
Compound (C1) (20mg, 0.013mmol) was dissolved in 3:7MeOH and DMSO (1mL) and kept at room temperature for 1 month. The mixture was purified by reverse phase ISCO using 50g C18 aqueous column, eluting with 5% -40% ACN-water containing 0.05% TFA. The fractions containing compound (C44a) and compound (C44b) were separated and lyophilized to obtain a mixture of compound (C44a) and compound (C44b) as TFA salts (4.5mg, 21% yield). LCMS M/2+ 1-668.8, tr-0.694 min.
Examples 3 to 45: synthesis of Compound 45(C45)
Figure BDA0002340450700007012
Compound (C45) was synthesized using a similar procedure as described for the synthesis of compound (C18), except CDN intermediate (CDNI-29) TEA salt was used instead of CDN intermediate (CDNI-3). Fractions containing the desired product were combined and lyophilized to obtain Et as3Compound (C45) as N salt (7.2mg, 38% yield). LCMS M +1＝1292.1,tr＝0.631min。
Example 4: RNAseq analysis of tumor cells treated with STING agonists
THP1 double cells were obtained from InvivoGen and prepared according to the manufacturer's protocol without PMA-induced differentiation (www.invivogen.com/THP 1-dual). The THP1 duplicate cells were then treated with 20uM T1-2 for 6 hours.
HCC1954 cells were obtained from ATCC (catalog number CRL-2338) and cultured in 10% FBS/90% RPMI. Two million cells were seeded in 6-well plates (2mL culture volume) and allowed to attach overnight. Cells were treated with 2'3' -cGAMP (100uM) or T1-1(5uM) for 6 hours and harvested in buffer RLT (RNeasy Plus Kit, Qiagen).
Total RNA was prepared using Qiagen RNeasy kit. Poly-a mRNA was isolated using poly-T oligonucleotides attached to magnetic beads and then fragmented using divalent cations at high temperature. A cDNA library was prepared using random primers. Sequencing was performed on an Illumina HiSeq 1000 with 2,200 to 7,000 million mapping reads per sample aligned to the human transcriptome file. Results are reported as readings per million. Fold change was calculated by dividing the output of the treated samples by the control samples for each gene.
FIGS. 1A-1O list transcripts in HCC1954 cells and found that expression was increased at least 5-fold 6 hours after treatment with 2'3' -cGAMP or T1-1. FIGS. 2A-2L show transcripts in THP1 double cells, whose expression increased at least 5-fold after 6 hours of treatment with T1-2.
Example 5: preparation of anti-HER 2-STING agonist conjugates
A) Preparation of anti-HER 2 antibody with specific cysteine (Cys) mutation
The preparation of anti-HER 2 antibodies (e.g. trastuzumab) and other antibodies with site-specific cysteine mutations has been previously described in WO 2014/124316 and WO 2015/138615, each of which is incorporated herein by reference. Briefly, DNA encoding the variable regions of the heavy and light chains of an anti-HER 2 antibody (e.g., trastuzumab) was chemically synthesized and cloned into two mammalian expression vectors, which contained the constant regions of the human IgG1 heavy chain and the human kappa light chain. The heavy chain vector encodes the constant region of human IgG1 antibody, including the signal peptide (MPLLLPLLWAGALA) (SEQ ID NO:28), the CMV promoter driving expression of the heavy chain, and appropriate signal and selection sequences for stable transfection into CHO cells. The light chain vector encodes the constant region of a human kappa light chain, including a signal peptide (MSVLTQVLALLLLWLTGTRC) (SEQ ID NO:29), the CMV promoter driving expression of the light chain, and appropriate signal and selection sequences for stable transfection into CHO cells. In some examples, the constant region encoded in the vector has been modified by site-directed mutagenesis to introduce a non-native cysteine at a specific site.
For example, a cysteine was introduced at one or more of the following positions (all positions numbered according to EU) of the anti-HER 2 antibody: (a) position 152, 360 and/or 375 of the antibody heavy chain; and (b) positions 107, 159 and/or 165 of the antibody light chain. For example, introduction of cysteines at positions 152 and 375 of the heavy chain resulted in anti-HER 2mAb1 having the heavy chain sequence of SEQ ID NO. 9 and the light chain sequence of SEQ ID NO. 19. In some embodiments, a cysteine was also introduced at position 152 of the heavy chain, resulting in anti-HER 2mAb 4 having the heavy chain sequence of SEQ ID NO:30 and the light chain sequence of SEQ ID NO: 19. In some embodiments, a cysteine was also introduced at position 159 of the light chain, resulting in anti-HER 2mAb 6 having the heavy chain sequence of SEQ ID No. 23 and the light chain sequence of SEQ ID No. 34.
To produce antibodies, the heavy and light chain vectors were co-transfected into CHO cell lines. Cells are selected and then stably transfected cells are cultured under conditions optimized for antibody production. Antibodies were purified from cell supernatants by standard protein a affinity chromatography.
Alternatively, CHO stable lines may be generated by transfecting cells with a single bicistronic vector. In this case, the heavy and light chains were cloned into the same vector, each downstream of the CMV promoter and the appropriate signal peptide coding sequence. In this case, CHO cells were transfected with a single vector and selected, and then stably transfected cells were cultured under conditions optimized for antibody production. Antibodies were purified from cell supernatants by standard protein a affinity chromatography.
Alternatively, the heavy and light chain plasmids were co-transfected at 293Freestyle by using the transient transfection method as described previouslyTMExpression of antibodies or Cys mutants of antibodies in cells (Meissner, et al, Biotechnol Bioeng [ Biotechnology and bioengineering ]].75:197-203(2001)). The expressed antibody was purified from the cell supernatant by standard protein a affinity chromatography.
In some cases, the antibody may be further purified prior to conjugation. One example is to apply the antibody to a Size Exclusion Chromatography (SEC) column, such as a chromatography column with Superdex-200 resin (GE), and collect the peaks corresponding to antibody monomers.
Cys mutant anti-HER 2 antibody reduction, reoxidation and conjugation to STING agonists
Some of the compounds described herein that include a linker are conjugated to a Cys residue of an antibody engineered to resemble that described in Junutula JR et al, Nature Biotechnology 26:925-932 (2008).
Because engineered Cys residues in antibodies expressed in mammalian cells are modified during biosynthesis by adducts (disulfides) such as Glutathione (GSH) and/or cysteine (Chen et al 2009), the originally expressed modified Cys is unreactive towards thiol-reactive reagents such as maleimido or bromoacetamide or iodoacetamide groups. To conjugate engineered Cys residues, glutathione or cysteine adducts need to be removed by reduction of the disulfide, which typically requires reduction of all disulfides in the expressed antibody. This can be accomplished by first exposing the antibody to a reducing agent, such as Dithiothreitol (DTT), and then reoxidizing all of the native disulfide bonds of the antibody to restore and/or stabilize functional antibody structure. Thus, to reduce the disulfide bond between the native disulfide bond and the cysteine or GSH adduct of one or more engineered Cys residues, freshly prepared DTT was added to the previously purified Cys mutant antibody to a final concentration of 10mM or 20 mM. After incubating the antibody with DTT for 1 hour at 37 ℃, the mixture was dialyzed against PBS for 3 days, with daily buffer exchange to remove DTT. Alternatively, DTT may be removed by a gel filtration step. After removal of DTT, the antibody solution is reoxidized to reform the native disulfide bonds. The reoxidation process was monitored by reverse phase HPLC, which was able to separate the antibody tetramers from the individual heavy and light chain molecules. The reaction was analyzed on a PRLP-S4000A column (50 mm. times.2.1 mm, Agilent) heated to 80 ℃ and the column elution was performed by a linear gradient of 30% -60% acetonitrile in water containing 0.1% TFA at a flow rate of 1.5 ml/min. Elution of protein from the column was monitored at 280 nm. Incubation was continued until re-oxidation was complete. After reoxidation, the maleimide-containing compound is added to the reoxidized antibody in PBS buffer (pH 7.2) at a molar ratio to engineered Cys of typically 1:1, 1.5:1, 2.5:1, or 5:1 and incubated for 5 to 60 minutes or more. Typically, the excess free compound is removed by purification on protein a resin by standard methods, and the buffer is then replaced with PBS.
Alternatively, the Cys mutant antibody is reduced and reoxidized using an on-resin method. Protein a agarose beads (1ml per 10mg antibody) were equilibrated in PBS (without calcium or magnesium salts) and then added to the antibody sample in batch mode. A 0.5M cysteine stock solution was prepared by dissolving 850mg cysteine HCl in 10ml of a solution prepared by adding 3.4g NaOH to 250ml 0.5M sodium phosphate pH 8.0, and then 20mM cysteine was added to the antibody/beads and gently mixed for 30-60 minutes at room temperature. The beads were loaded onto a gravity column and washed with 50 bed volumes of PBS in less than 30 minutes, then the column was covered with a bead cap resuspended in 1 bed volume of PBS. To adjust the reoxidation rate, 50nM to 1. mu.M copper chloride is optionally added. The reoxidation process was monitored by: by removing a small test sample of the resin, eluting in IgG elution buffer (Thermo) and analyzing by RP-HPLC as described above. Once the reoxidation has proceeded to the desired completeness, conjugation can be initiated immediately by adding 1-5 molar equivalents of compound relative to the engineered cysteine, and the mixture allowed to react for 5-10 minutes at room temperature, after which the column is washed with at least 20 column volumes of PBS. The antibody conjugate was eluted with IgG elution buffer and neutralized with 0.1 volume 0.5M sodium phosphate pH 8.0 and the buffer was changed to PBS. Alternatively, rather than eliciting conjugation to the antibody on the resin, the column is washed with at least 20 column volumes of PBS and the antibody is eluted with IgG elution buffer and neutralized with pH 8.0 buffer. The antibody is then used in a conjugation reaction or flash frozen for future use.
Figure BDA0002340450700007061
Properties of anti-HER 2-STING agonist conjugates
The antibody-STING agonist conjugate was analyzed to determine the extent of conjugation. The compound to antibody ratio was extrapolated from LC-MS data for reduced and deglycosylated samples. LC-MS allows quantification of the average number of molecules of linker-payload (compound) attached to the antibody in the conjugate sample. HPLC separates the antibody into light and heavy chains, and separates the Heavy (HC) and Light (LC) chains according to the number of linker-payload groups per chain. Mass spectral data enables identification of component species in a mixture, e.g., LC +1, LC +2, HC +1, HC +2, etc. From the average load on the LC and HC chains, the average compound to antibody ratio of the antibody conjugates can be calculated. The compound-to-antibody ratio for a given conjugate sample represents the average number of compound (linker-payload) molecules attached to a tetrameric antibody containing two light chains and two heavy chains.
The conjugates were subjected to spectroscopic analysis using analytical size exclusion chromatography (AnSEC) on Zenix C-3003 um 7.8x 150mm columns (Secoid Technologies); aggregability was analyzed based on analytical size exclusion chromatography.
The pharmacokinetics of the conjugates were studied after injection of 1 or 4mg/kg of conjugate into CD1 mice. Serum samples were taken at different time points and stored frozen for analysis. The level of human antibodies or antibody conjugates in serum samples was measured by immunoassay on a Gyros instrument. In both cases, capture was performed using anti-human Fc reagents. Detection was performed with anti-hIgG antibody to determine the concentration of the antibody and an assay was performed with payload-specific antibody to determine the level of payload remaining on the conjugate. Payload retention was also investigated by LC-MS. Briefly, samples were mixed 1:1 with PBS pH7.2, 5mM EDTA, clarified by centrifugation, and then loaded onto IgG selective sepharose 6 fast flow resin (GE Healthcare) in 96-well plates. The resin was washed with PBS and transferred to fresh plates to avoid background due to serum proteins binding to the plates. The samples were then treated with PNGaseF for 2 hours at 37 ℃. The sample was washed again with PBS and then eluted with 1% formic acid. The samples were reduced with 133mM TCEP, 0.67M ammonium acetate pH 5.0 for 30 minutes at room temperature. The samples were then measured by LC-MS and analyzed for compound to antibody ratios as described above.
Most conjugates achieve high compound to antibody ratios and are predominantly monomeric. Conjugation by this method resulted in conjugation efficiencies of greater than 90% for most compounds (table 9 below). Most conjugates contained less than 10% dimeric and oligomeric material (table 9). In the mouse PK study, most conjugates also had detectable payload retention at 336 hours post injection (figure 3 and table 9). These results indicate that the conjugates can be prepared efficiently and with advantageous properties.
B) Generation of anti-HER 2-STING agonists by partial reduction of the native disulfide bond of non-engineered anti-HER 2 antibodies Conjugates
Some compounds of the invention may also be conjugated to the native cysteine residue of non-engineered antibodies using procedures involving partial reduction of the antibody (Doronina, S.O. et al, nat. Biotechnol. [ Nature Biotechnology ]21,778-784, 2003).
The inter-and intra-chain disulfide bonds of anti-HER 2mAb 3 (at a concentration of 10mg/ml) were first partially reduced in PBS pH 8.0 containing 2mM EDTA by adding TCEP to a final concentration of 10mM and incubating the mixture for 1 hour at 37 ℃. After desalting and addition of 1% w/v PS-20 detergent, a partially reduced antibody sample (1mg/ml) was reacted with C1 in a 5:1 or 10:1 molar ratio at 4 ℃ overnight. The resulting conjugate was purified by protein a chromatography, via standard methods, and buffer exchanged to PBS and chromatographed by MS and AnSEC as described above. Table 9 summarizes the compound to antibody ratios and aggregation data measured and indicates that the conjugates can be prepared efficiently and with good properties.
C) Generation of native interchain disulfide bond using 1, 3-dichloroprop-2-one religation of non-engineered anti-HER 2 antibodies anti-HER 2-STING agonist conjugates
In an alternative approach (us patent application 20150150998), the interchain disulfide bond of a non-engineered recombinant anti-HER 2 antibody may be modified and conjugated to an agonist compound of the invention using the following two steps.
Scheme 15a
Bridging with 1,3 dichloroprop-2-one followed by addition to the introduced ketone, was used, and two steps conjugated to the native cysteine residue.
Figure BDA0002340450700007081
Step 1: reduction of interchain disulfide bridges and re-bridging with 1, 3-dichloroprop-2-one: 1, 3-Dichloroacetone (DCA) was dissolved in DMSO to a final concentration of 1M. Next, 11.9 μ L of the resulting solution was added to 22.0mL of 27 μ M anti-HER 2 antibody (90mg) in 0.1M HEPES buffer (pH 8.0), corresponding to a 20-fold molar excess of DCA over the antibody. Formation of the ketone bridge was then initiated by replenishing the solution with 36.5. mu.L of 200mM TCEP/HCl in water to a final concentration of 0.33 mM. After gentle shaking of the reaction mixture at 4 ℃ for about 16 hours, the antibody construct was purified using 6mL of precipitated rmp protein a agarose fast flow resin (GE healthcare). Incorporation of the ketone bridge was verified by capillary electrophoresis on a PA 800plus drug analysis System (SCIEX). Under reducing conditions, fully cross-linked antibodies comprising two heavy chains and two light chains are the main species with an abundance of 86% by peak area. The yield of modified anti-HER 2 antibody was quantified by absorbance measurement at 280nm on a NanoDrop 1000 spectrophotometer (Thermo Scientific). After protein a affinity chromatography 77mg (86%) of the modified antibody was obtained.
Step 2: to initiate the second step of the conjugation process, the re-bridged anti-HER 2 antibody (anti-HER 2mAb 3-KB) from step 1 was concentrated using a michael Centrifugal Filter unit (Amicon Ultra Centrifugal Filter Units) (EMD Millipore) with a 50kDa cut-off. Oxime ligation was performed with 5mg of modified antibody (final concentration 180. mu.M) and 15-fold molar excess (2.7mM) of aminooxy-functionalized STING agonist C5 in 0.1M aniline acetate buffer supplemented with 14% (v/v) DMSO (pH 4.4). After the coupling reaction was carried out at 37 ℃ for 14 hours, the resulting conjugate was purified by size exclusion chromatography on a HiLoad26/600Superdex 200pg column (GE healthcare Co.) to remove aggregated material. 1.7mg of anti-HER 2(mAb3) -KB-C5 conjugate were obtained as measured by absorbance at 280nm on a NanoDrop 1000 spectrophotometer. The conjugates were analyzed by mass spectrometry, analytical size exclusion chromatography, and analytical hydrophobic interaction chromatography as summarized in table 9. Exemplary conjugates achieve high compound to antibody ratios and are predominantly monomeric.
D) anti-HER 2-STING agonist conjugates generated by conjugation to native lysine residues of wild-type anti-HER 2 antibody Compound (I)
Native antibodies can be functionalized with certain compounds of the invention by established methods. For example, 2mg/ml of anti-HER 2mAb 3 (having the heavy chain of SEQ ID NO:23 and the light chain of SEQ ID NO: 19) in PBSpH 8.0 was mixed with a 20-fold molar excess of C7. The reaction was incubated overnight at room temperature and then buffer exchanged to PBS ph7.2 by standard methods. The average compound to antibody ratio of the resulting conjugates was determined to be 3.5 (table 9).
E) Using ybbR tagged anti-HER 2 mutant antibodies with agonists containing amino-oxy reactive groups Two-step conjugation of the compounds to generate anti-HER 2-STING agonist conjugates
Post-translational 4' -phosphopantetheination is a general method for site-specific labeling of recombinant proteins with structurally diverse small molecules (Yin J, et al, Proc. Natl.Acad.Sci.U.S.A. [ Proc. Natl.Acad.Sci ]102: 15815. multidot. 15820, 2005; Zhou Z, et al, ACS chem.biol. [ ACS. chem. biol. ]2: 337. multidot. 346, 2007). The enzymatic method is based on the catalytic action of a promiscuous 4' -phosphopantetheinyl transferase (PPTase) and is used to prepare highly homogeneous antibody conjugates (see WO 2013184514; Gruenewald et al, Bioconj Chem [ bioconjugate chemistry ]2015,26: 2554-62). Enzymatic labeling was accomplished by incorporating the 11 or 12-mer S6, ybbR and a1 peptide sequences at different sites in the antibody constant region. For example, the ybbR tag of sequence DSLEFIASKLA (SEQ ID NO:36) can be incorporated after residue E388(EU numbering) to produce anti-HER 2mAb7 having the light chain sequence of SEQ ID NO:19 and the heavy chain sequence of SEQ ID NO: 35.
One strategy is a two-step process for the preparation of site-specific antibody-compound conjugates by post-translational 4' -phosphopantetheination (see WO 2013184514). The first step of the method is based on PPTase catalytic labeling of peptide tagged antibodies with CoA analogs containing bio-orthogonal groups such as azide, alkene, alkyne, ketone or aldehyde moieties. After affinity purification of the bioorthogonally labeled antibody, the second step of the two-step process involves conjugation of a compound comprising a moiety reactive with the bioorthogonal group. As an example, the following section describes a two-step process for an anti-HER 2 mutant antibody containing a ybbR tag insertion at a specific site within the constant region of the heavy chain. In addition, although a two-step approach is exemplified for oxime ligation chemistry, the strategy can be extended to other bio-orthogonal chemistries, such as click chemistry (including copper-free click chemistry, staudinger ligation, isonitrile-based click chemistry, and tetrazine ligation).
Scheme 15b
Figure BDA0002340450700007111
Oxime ligation chemistry has been used by various groups as an effective bioorthogonal method for making site-specific protein conjugates (Axup JY, et al, Proc Natl Acad Sci U S A. [ Proc Natl Acad Sci U.S. [ Proc. Natl. Acad. Sci.C. ] -A]109:16101-16106, 2012; rabuka D, et al, Nat Protoc. [ Nature laboratory Manual]7:1052-1067,2012). To combine post-translational 4' -phosphopantetheination with oxime ligation, a ketone-modified CoA analog, LI-7, was prepared as discussed above. Next, bioorthogonal ketone groups were site-specifically conjugated to the embedded ybbR tag of the anti-HER 2 antibody using PPTase catalysis. Specifically, in the presence of 2. mu.M of Sfp PPTase from Bacillus subtilis, supplemented with 12.5mM MgCl at 23 deg.C2And 20mM NaCl in 75mM Tris-HCl buffer (pH 8.0), 2.5. mu.M anti-HER 2mAb7 was conjugated with 100. mu.M ketone-CoA analog (LI-7) (40 molar equivalents relative to the antibody) for 23 hours. Labeling of the anti-HER 2mAb7 antibody with a ketone-CoA analog (LI-7) was verified by obtaining deconvolution ESI-MS spectra of reduced and deglycosylated samples. The masses observed are consistent with the calculated molecular weights of the corresponding ketone-functionalized heavy chains. After removal of PPTase enzyme and excess ketone-CoA analogs by protein A affinity chromatography (rmp protein A agarose fast flow, GE Healthcare Life sciences), Pierce was usedTMIgG elution buffer (Thermo Fisher Scientific) the ketone-activated antibody anti-HER 2mAb 7- (LI-7) was eluted, followed by immediate neutralization with 1M Tris-HCl buffer (pH 8.0). The neutralized antibody solution was buffer exchanged to PBS and concentrated using a 50K Amicon filter.
As a second step of the two-step process, site-specific attachment of the ketone group enables oxime ligation of a subsequent agonist compound to ketone-activated anti-HER 2mAb 7- (LI-7). Specifically, 25. mu.M of ketone functionalized antibody was reacted with 40-fold molar excess (1mM) of aminooxy-agonist C5 in 100mM aniline acetate buffer (pH 4.5) containing 5% (v/v) DMSO. After incubation at room temperature for about 14 hours, insoluble material was removed by centrifugation. The supernatant was purified on a HiLoad26/600Superdex 200pg column (GE healthcare) pre-equilibrated with PBS. The conjugates were subjected to spectroscopic analysis by MS and AnSEC as described above. The measured compound to antibody ratios and aggregation behavior are summarized in table 9. The exemplary conjugate achieved a compound to antibody ratio of 1.4 and was predominantly monomeric after purification. Conjugation by this method resulted in a conjugation efficiency of about 72%. This indicates that the conjugates can be prepared efficiently and with advantageous characteristics.
TABLE 9 Properties of anti-HER 2-STING agonist conjugates
Figure BDA0002340450700007121
Figure BDA0002340450700007131
Figure BDA0002340450700007141
Example 6: the anti-HER 2-STING agonist conjugate induces IP-10 secretion from HER2+ HCC1954 breast cancer cells in a target-dependent manner.
HCC1954 cells were suspended in 384-well plates and allowed to attach overnight. The next day the cells were treated with anti-HER 2-STING agonist conjugate or unconjugated payload and incubated for about 3 days. Cell culture supernatants were harvested and human IP-10 levels in the media were measured using human IP-10 tissue culture kits from Mesoscale Devices. EC is calculated by performing logistic regression on the measured dose-response curves50Values (in triplicate). Data were curve fitted to obtain EC using the following formula50The value:
Figure BDA0002340450700007142
wherein Y is an observed value; bottom is the lowest observed value; top is the highest observed value; and the Hill coefficient gives the maximum absolute value of the slope of the curve. EC (EC)50The value characterizes the concentration of the compound for 50% activation, i.e. Yx＝EC50(max + min)/2. Curve fitting was performed by using the curve fitting program of Matlab.
The maximal activity was compared to 2', 3' -cGAMP (100 μ M) treated cells to determine% efficacy. The reported values are the average of independent experiments in multiple tests of the conjugate or drug. Representative data are summarized in table 10A and fig. 44.
TABLE 10A IP-10 secretion from HER2+ HCC1954 breast cancer cells
Figure BDA0002340450700007151
In addition, the maximal activity of certain conjugates was compared to cells treated with the conjugate anti-HER 2-mAb1-C1 to determine% efficacy. The reported values are the average of independent experiments in multiple tests of the conjugate or drug. Representative data are summarized in table 10B.
TABLE 10B IP-10 secretion from HER2+ HCC1954 breast cancer cells
Figure BDA0002340450700007152
Figure BDA0002340450700007161
Example 7: in vivo testing for anti-HER 2mAb1-C1 in an N87 gastric tumor xenograft model
Materials and methods
For in vivo testing of anti-HER 2mAb1-C1 conjugate in the N87 gastric cancer xenograft mouse model, 6-8 week old female SCID-beige mice (purchased from Harlan Laboratories) were used for implantation. N87 cells (obtained from ATCC, catalog number CRL-5822, supplier batch number 7686255) were aseptically conditioned with 5% CO2At 37 ℃ for two weeks. Cells were grown in RPMI medium containing 10% fetal bovine serum. Every 3-4 days, cells were passaged with 0.05% trypsin/EDTA. On the day of implantation, N87 cells were lifted (passage 17) and concentrated at 5 × 106The individual cells and 50% matrigel/100. mu.l were resuspended in RPMI1640 serum-free medium. Cells were subjected to the Radil test to ensure that they were free of mycoplasma and murine viruses.
Use 281/2G needle (5x 10)6Individual cells/100 μ l injection volume/mouse), N87 cells were platedThe lower flank is implanted by lower injection. After cell implantation, tumors were measured by calipers and once palpable, mice were weighed three times per week. Tumors were measured in two dimensions. Using (L x W)2) The caliper measurement is calculated/2. Mice were fed on normal diets and housed in SPF animal facilities according to the care and use guidelines for experimental animals and the provisions of the institutional animal care and use committee.
When the xenograft tumor reaches about 190mm3In this case, mice were administered 0.1mg/kg, 0.3mg/kg, 1mg/kg or 3mg/kg of anti-HER 2mAb1-C1 or isotype IgG-C1 by intravenous route. Tumor measurements were continued three times a week. Mean tumor volumes were plotted using Prism5(GraphPad) software. When the tumor size reaches 2000mm3At volume of (a), the end point for efficacy studies was reached. After injection, mice were also closely monitored for signs of clinical deterioration. Mice were euthanized if for any reason they showed any signs of morbidity (including respiratory distress, hunched posture, decreased activity, hind leg paralysis, shortness of breath as a sign of pleural effusion, near 20% or 15% weight loss, and other signs) or if the ability to perform normal activities (feeding, activity) was impaired.
Results
N87 gastric tumor xenograft mice (9 mice/group) were treated intravenously with a single dose of 0.1mg/kg, 0.3mg/kg, 1mg/kg or 3mg/kg anti-HER 2mAb1-C1 or 3mg/kg isotype control IgG-C1. anti-HER 2mAb1-C1 showed dose-dependent efficacy on the N87 model in SCID mice. Inhibition of tumor growth was observed in mice treated with 0.3mg/kg, 1mg/kg or 3mg/kg of anti-HER 2mAb1-C1 compared to untreated mice (FIG. 5). Tumor growth in animals dosed with 0.1mg/kg anti-HER 2mAb1-C1 or 3mg/kg isotype control IgG-C1 did not differ statistically at all from tumor growth in the vehicle control group. All treatments were well tolerated, except that moderate (< -4%) but transient weight loss was observed immediately after mice were dosed with 3mg/kg anti-HER 2mAb1-C1 (fig. 6).
Example 8: in vivo testing for anti-HER 2mAb1-C1 in a HCC1954 breast tumor xenograft model
Materials and methods
For in vivo testing of anti-HER 2mAb1-C1 conjugate in HCC1954 breast cancer xenograft mouse model, 6-8 week old female SCID-beige mice (purchased from Harlan Laboratories) were used for implantation. HCC1954 cells (obtained from ATCC (catalog number CRL-2338; lot number 5107643)) were sterilized under sterile conditions with 5% CO2At 37 ℃ for two weeks. Cells were grown in RPMI medium containing 10% fetal bovine serum. Every 3-4 days, cells were passaged with 0.05% trypsin/EDTA. On the day of implantation, HCC1954 cells (harvested) were lifted (passage 15) and concentrated at 5x106The individual cells and 50% matrigel/100. mu.l were resuspended in RPMI1640 serum-free medium. Cells were subjected to the Radil test to ensure that they were free of mycoplasma and murine viruses.
Use 281/2G needle (5x 10)6Individual cells/100 μ l injection volume/mouse), HCC1954 cells were implanted into the left 4 th mammary fat pad. After implantation, tumors were measured by calipers and once palpable, mice were weighed three times per week. Tumors were measured in two dimensions. Using (L x W)2) The caliper measurement is calculated/2. Mice were fed normal diets and maintained in SPF Animal facilities according to guidelines for Care and Use of Laboratory Animals (guidelines) and the regulations of the Institutional Animal Care and Use Committee.
When the xenograft tumor reaches about 140mm3In this case, mice were administered 0.3mg/kg, 1mg/kg or 3mg/kg of anti-HER 2mAb1-C1 or 3mg/kg of isotype IgG-C1 by intravenous route. Tumor measurements were continued three times a week. Mean tumor volumes were plotted using Prism5(GraphPad) software. When the tumor size reaches 2000mm3At volume of (a), the end point for efficacy studies was reached. After injection, mice were also closely monitored for signs of clinical deterioration. If for any reason, the mice show any signs of morbidity (including respiratory distress, hunched posture, decreased activity, hind leg paralysis, shortness of breath as a sign of pleural effusion, near 20% or 15% weight loss, and other signs) or if advancedMice were euthanized with impaired ability to perform normal activities (feeding, mobilization).
Results
HCC1954 breast tumor xenograft mice (10 mice/group) were treated intravenously with a single dose of 0.3mg/kg, 1mg/kg, or 3mg/kg anti-HER 2mAb1-C1 or 3mg/kg isotype IgG-C1. Treatment with a single dose of 0.3mg/kg, 1mg/kg or 3mg/kg of anti-HER 2mAb1-C1 resulted in complete regression of human HCC1954 xenograft tumors (figure 7). No tumor regression was observed in mice treated with 3mg/kg isotype control IgG-C1 (FIG. 7).
These data indicate that tumor regression can be achieved in HCC1954 breast tumor xenografts that highly express HER2 by single low dose treatment with anti-HER 2mAb 1-C1.
All mice in all dosing groups were well tolerated for treatment except that mild and short-term weight loss was observed after initial dosing in mice treated with 3mg/kg anti-HER 2mAb1-C1 and isotype control IgG-C1 (fig. 8).
Example 9: in vivo testing against HER2mAb1-C1 in a SKOV3 ovarian cancer xenograft model
Materials and methods
For in vivo testing of anti-HER 2mAb1-C1 conjugate in the SKOV3 ovarian cancer xenograft mouse model, 6-8 week old female SCID-beige mice (purchased from Harlan Laboratories) were used for implantation. SKOV3 cells (obtained from ATCC (catalog number HTB-77; batch number 7349765)) were sterilized under sterile conditions with 5% CO2At 37 ℃ for two weeks. Cells were grown in McCoy's 5A medium containing 10% fetal bovine serum. Every 3-4 days, cells were passaged with 0.05% trypsin/EDTA. On the day of implantation, SKOV3 cells (harvested) were lifted (passage 10) and concentrated at 5x106The individual cells and 50% matrigel per 100. mu.l were resuspended in McCoy's 5A serum-free medium. Cells were subjected to the Radil test to ensure that they were free of mycoplasma and murine viruses.
Use 281/2G(5x 106Individual cells/100 μ l injection volume/mouse), SKOV3 cells were implanted into the lower flank with subcutaneous injection. After the implantation, the implant is implanted into the body,tumors were measured by calipers and once palpable, mice were weighed three times per week. Tumors were then measured three times per week in two dimensions. Using (L x W)2) The caliper measurement is calculated/2. Mice were fed normal diets and maintained in SPF Animal facilities according to guidelines for Care and Use of Laboratory Animals (Guide for Care and Use of Laboratory Animals) and the regulations of the Institutional Animal Care and Use Committee.
When the xenograft tumor reaches about 200mm3In this case, mice were administered 0.3mg/kg, 1mg/kg or 3mg/kg of anti-HER 2mAb1-C1 or 3mg/kg of isotype IgG-C1 by intravenous route. Tumor measurements were continued three times a week. Mean tumor volumes were plotted using Prism5(GraphPad) software. When the tumor size reaches 2000mm3At volume of (a), the end point for efficacy studies was reached. After injection, mice were also closely monitored for signs of clinical deterioration. Mice were euthanized if for any reason they showed any signs of morbidity (including respiratory distress, hunched posture, decreased activity, hind leg paralysis, shortness of breath as a sign of pleural effusion, near 20% or 15% weight loss, and other signs) or if the ability to perform normal activities (feeding, activity) was impaired.
Results
SKOV3 ovarian cancer xenograft mice were treated intravenously with single doses of 0.3mg/kg, 1mg/kg, and 3mg/kg of anti-HER 2mAb1-C1 or 3mg/kg of isotype IgG-C1. Although treatment with a single dose of 3mg/kg anti-HER 2mAb1-C1 resulted in tumor regression in the human SKOV3 cancer xenograft model, no tumor regression was observed in mice treated with 3mg/kg isotype control IgG-C1 when compared to untreated animals (fig. 9A). All mice were well tolerated for treatment, except that slight and short-term weight loss was observed after initial dosing in mice dosed with 3mg/kg anti-HER 2mAb1-C1 and isotype IgG-C1 (fig. 9B).
Example 10: preparation of P-Cad mAb1-C1 conjugates
anti-P-Cad antibodies with site-specific cysteine mutations were prepared as described in example 5. Briefly, DNA encoding the heavy and light chain variable regions of anti-P-Cad mAb1 was cloned into a single dicistronic vector comprising the constant regions of human IgG1 heavy chain (with cysteines introduced at positions 152 and 375(EU numbering)) and human kappa light chain. CHO stable lines are generated by transfecting cells, then selecting for, and then culturing the stably transfected cells under conditions optimized for antibody production. Antibodies were purified from cell supernatants by protein A affinity chromatography (ToyoPearl AF-rProtein A-650F resin, Tosoh Bioscience). The antibody was further purified by SEC (Superdex-200, GE group) and the peaks corresponding to antibody monomers were collected for conjugation.
The antibody was reduced and reoxidized by a similar method as described in example 5. The antibody was incubated at 14mg/ml in 50mM sodium phosphate pH 8.0, 1mM EDTA, 5mM DTT for 30 minutes at room temperature. DTT was removed by SEC on 50ml G25 ultra-fine columns pre-equilibrated in PBS pH 8.0. The antibody was adjusted to 5mg/ml and incubated at room temperature for 24 hours. Reoxidation was monitored by RP-HPLC as described above.
After completion of reoxidation, compound C1 containing maleimide was added to the reoxidized antibody in PBS buffer (pH 7.2) at a molar ratio of 8: 1. Incubation was carried out for 30 minutes. Excess free compound was removed by standard methods of purification on protein a resin, followed by buffer exchange into PBS.
The resulting conjugate was analyzed as described above against P-Cad mAb1-C1, and had a compound to antibody ratio of 3.8 and aggregation below the limit of quantitation. This sample was used in the following examples.
Example 11: in vivo efficacy of P-Cad mAB1-C1 conjugate against MC38 murine colon adenocarcinoma model in mice
Female C57BL/6 mice were implanted subcutaneously at 5X10 of over-expressed murine CDH3 in suspension with Dulbecco's (Dulbecco) modified MEM (Life Technologies)5MC38 cells. The total injection volume with cells in suspension was 200. mu.l. At implantation, mice were divided into treatment groups (n-8/group) and dosed with P-Cad mAb1-C1(2.5mg/kg), unconjugated P-Cad mAb1(10mg/kg), or vehicle control (PBS) according to table 10C single intravenous injection.The dose was adjusted for individual mouse body weight. The IV dose volume was 10 ml/kg.
Treatment with 2.5mg/kg P-Cad mAb1-C1 (26% Δ T/Δ C) resulted in significantly higher anti-tumor activity at day 21 compared to vehicle control (PBS) treated groups (one-way ANOVA; Tukey test, P < 0.05). On day 21, treatment with 10mg/kg P-Cad mAb1 (48% Δ T/Δ C) was not significantly different from the PBS treated group (fig. 13A). All treatments were well tolerated and no significant clinical signs of toxicity were observed (fig. 13B).
Table 10℃ in vivo activity of P-Cad mAB1-C1 against MC38 murine colon adenocarcinoma model in mice at day 21. The effect of treatment on tumor volume and body weight are expressed as mean ± SEM. Day 21, P <0.05P-Cad mAB1-C1 control PBS (one-way ANOVA/Tukey test).
Figure BDA0002340450700007211
Example 12: preparation of target B Ab and target B mAb1-C1 conjugates
Target B mAb1 with site-specific cysteine mutations was prepared as described in example 5. Briefly, DNA encoding the variable regions of the heavy and light chains of the target BmAb1 were cloned into two mammalian expression vectors comprising the constant regions of human IgG1 heavy chain (with cysteines introduced at positions 152 and 375(EU numbering)) and human kappa light chain. The vectors were co-transfected into CHO cell lines. Cells are selected and then stably transfected cells are cultured under conditions optimized for antibody production. Antibodies were purified from cell supernatants by standard protein a affinity chromatography (MabSelect SuRe resin, GE healthcare).
Target B mAb1 was reduced, reoxidized and conjugated using the on-resin method as described in example 5. The antibody was loaded onto protein A resin (1ml of resin/10 mg of protein), reduced in the presence of 20mM cysteine for 30 minutes, washed with PBS, and then re-oxidized in the presence of 1. mu.M copper chloride. Once reoxidation proceeded to the desired completeness, conjugation was initiated by adding 2.5 molar equivalents of compound C1 relative to the engineered cysteine, and the mixture was allowed to react at room temperature, then the column was washed with 20 column volumes of PBS. The antibody conjugate was eluted with IgG elution buffer and neutralized with 0.1 volume 0.5M sodium phosphate pH 8.0 and the buffer was exchanged to PBS.
The resulting target B mAb1-C1 conjugate was analyzed as described above and had a compound to antibody ratio of 3.8, and an aggregate content of 1.2%. This sample was used in the following examples.
Example 13: in a xenograft tumor model expressing target B, the target B mAb1-C1 conjugate regressed tumor growth.
Subcutaneous implantation of 5X10 in the hind flank of female SCID/beige mice6A human breast cancer cell. Tumors were measured 3 times a week using digital calipers throughout the study, and using the formula (LxW)2) The tumor volume was calculated 2. When the tumor reaches the average size of 100mm3At this time, mice were randomized and dosed with a single intravenous injection of vehicle control (PBS), 10mg/kg target BmAb1, 10mg/kg target B mAb1-C1 conjugate, or isotype control IgG-C1 conjugate. When the tumors in the control group reached an average size of 1000mm3At that time, the mice were sacrificed. As shown in fig. 14, treatment with 10mg/kg target B mAb1-C1 induced regression of human breast cancer tumors, whereas vehicle control and target B mAb1 had no effect on tumor growth. In contrast, treatment with IgG-C1, isotype antibody control-C1 conjugate slowed the growth kinetics of human breast cancer tumors, however, this delay was not significant compared to vehicle control. (FIG. 14, in unpaired student's t-test, indicates a p-value of<0.0001)。
Example 14: preparation of target C mAb1 and target C mAb1-C1 conjugates
Target C mAb1 with site-specific cysteine mutations was prepared as described in example 5. Briefly, DNA encoding the variable regions of the heavy and light chains of the target CmAb1 were cloned into two mammalian expression vectors comprising the constant regions of human IgG1 heavy chain (with cysteines introduced at positions 152 and 375(EU numbering)) and human kappa light chain. Alternatively, the variable region of the heavy chain of target C mAb1 was cloned into another mammalian expression vector comprising the constant region of human IgG1 heavy chain with cysteines introduced at positions 152 and 375 and mutations D265A and P329A (EU numbering). One heavy chain vector and one light chain vector were co-transfected into CHO cell lines at a time. Cells are selected and then stably transfected cells are cultured under conditions optimized for antibody production. Antibodies were purified from cell supernatants by standard protein a affinity chromatography.
Target C mAb1 and mAb1(DAPA) were reduced, reoxidized and conjugated using the on-resin method as described in example 5. The antibody was loaded onto protein A resin (1ml of resin/10 mg of protein), reduced in the presence of 15mM cysteine for 40 min, washed with PBS, and then re-oxidized in the presence of 1. mu.M copper chloride. Once reoxidation proceeded to the desired completeness, conjugation was initiated by adding 2.5 molar equivalents of compound C1 relative to the engineered cysteine, and the mixture was allowed to react at room temperature, then the column was washed with 20 column volumes of PBS. The antibody conjugate was eluted with IgG elution buffer and neutralized with 0.1 volume 0.5M sodium phosphate pH 8.0 and the buffer was changed to PBS.
The resulting conjugates were analyzed as described above. The resulting conjugate target C mAb1-C1 had a compound to antibody ratio of 3.8 and aggregation was below the limit of quantitation. The resulting conjugate target C mAb1(DAPA) -C1 had a compound to antibody ratio of 3.7 and aggregation was below the limit of quantitation. These samples were used in the following examples.
Example 15 in xenograft tumor models expressing target C, the target C mAb1-C1 conjugate retarded tumor growth.
Subcutaneous implantation of 1X 10 in the hind flank of female SCID beige mice6And (C) lung cancer cells expressing target C. Tumors were measured 3 times a week using digital calipers throughout the study, and using the formula (LxW)2) The tumor volume was calculated 2. When the tumor reached an average size of 115mm3At this time, mice were randomized and dosed with a single intravenous injection of vehicle control (PBS) or 8mg/kg target CmAb1-C1, target C mAb1(DAPA) -C1, or isotype IgG-C1 conjugate. As shown in fig. 15, treatment with 8mg/kg of target C mAb1-C1 and target C mAb1(DAPA) -C1 significantly delayed tumor growth compared to vehicle control. The IgG-C1 conjugate also compared to vehicle controlSignificant antitumor efficacy was shown, although less than that of target C mAb1-C1 and target C mAb1(DAPA) -C1. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims.
Figure IDA0002340450760000021
Figure IDA0002340450760000031
Figure IDA0002340450760000041
Figure IDA0002340450760000061
Figure IDA0002340450760000071
Figure IDA0002340450760000081
Figure IDA0002340450760000091
Figure IDA0002340450760000101
Figure IDA0002340450760000121
Figure IDA0002340450760000131
Figure IDA0002340450760000141
Figure IDA0002340450760000161
Figure IDA0002340450760000181
Figure IDA0002340450760000191
Figure IDA0002340450760000201
Figure IDA0002340450760000221
Figure IDA0002340450760000231
Figure IDA0002340450760000241
Figure IDA0002340450760000251
Figure IDA0002340450760000271
Figure IDA0002340450760000281
Figure IDA0002340450760000311
Figure IDA0002340450760000321
Figure IDA0002340450760000341
Figure IDA0002340450760000351
Figure IDA0002340450760000361
Figure IDA0002340450760000371
Figure IDA0002340450760000381
Figure IDA0002340450760000391
Figure IDA0002340450760000401
Figure IDA0002340450760000411
Figure IDA0002340450760000421
Figure IDA0002340450760000431
Figure IDA0002340450760000451
Figure IDA0002340450760000461
Figure IDA0002340450760000471
Figure IDA0002340450760000481
Figure IDA0002340450760000511
Figure IDA0002340450760000521
Figure IDA0002340450760000541
Figure IDA0002340450760000561
Figure IDA0002340450760000571
Figure IDA0002340450760000581
Figure IDA0002340450760000601
Figure IDA0002340450760000611
Figure IDA0002340450760000621
Figure IDA0002340450760000631
Figure IDA0002340450760000641
Figure IDA0002340450760000671
Figure IDA0002340450760000681
Figure IDA0002340450760000691
Figure IDA0002340450760000701
Figure IDA0002340450760000711
Figure IDA0002340450760000721
Figure IDA0002340450760000731
Figure IDA0002340450760000741
Figure IDA0002340450760000751
Figure IDA0002340450760000761
Figure IDA0002340450760000771
Figure IDA0002340450760000781
Figure IDA0002340450760000791
Figure IDA0002340450760000801
Figure IDA0002340450760000821
Figure IDA0002340450760000831
Figure IDA0002340450760000841
Figure IDA0002340450760000851
Figure IDA0002340450760000861
Figure IDA0002340450760000871
Figure IDA0002340450760000881
Figure IDA0002340450760000891
Figure IDA0002340450760000901
Figure IDA0002340450760000911
Figure IDA0002340450760000921
Figure IDA0002340450760000931
Figure IDA0002340450760000941
Figure IDA0002340450760000951
Figure IDA0002340450760000961
Figure IDA0002340450760000971
Figure IDA0002340450760000991
Figure IDA0002340450760001001
Figure IDA0002340450760001011
Figure IDA0002340450760001031
Figure IDA0002340450760001051
Figure IDA0002340450760001061
Figure IDA0002340450760001071
Figure IDA0002340450760001081
Figure IDA0002340450760001101
Figure IDA0002340450760001111
Figure IDA0002340450760001121
Figure IDA0002340450760001141
Figure IDA0002340450760001151
Figure IDA0002340450760001161
Figure IDA0002340450760001181
Figure IDA0002340450760001191
Figure IDA0002340450760001201
Figure IDA0002340450760001211
Figure IDA0002340450760001221
Figure IDA0002340450760001231
Figure IDA0002340450760001241
Figure IDA0002340450760001251
Figure IDA0002340450760001261
Figure IDA0002340450760001271
Figure IDA0002340450760001281
Figure IDA0002340450760001291
Figure IDA0002340450760001301
Figure IDA0002340450760001311
Figure IDA0002340450760001321
Figure IDA0002340450760001331
Figure IDA0002340450760001341
Figure IDA0002340450760001361
Figure IDA0002340450760001371
Figure IDA0002340450760001381
Figure IDA0002340450760001401
Figure IDA0002340450760001411
Figure IDA0002340450760001421
Figure IDA0002340450760001431
Figure IDA0002340450760001441
Figure IDA0002340450760001451
Figure IDA0002340450760001461
Figure IDA0002340450760001471
Figure IDA0002340450760001481
Figure IDA0002340450760001491
Figure IDA0002340450760001501
Figure IDA0002340450760001511
Figure IDA0002340450760001521
Figure IDA0002340450760001531
Figure IDA0002340450760001541
Figure IDA0002340450760001551
Figure IDA0002340450760001571
Figure IDA0002340450760001581
Figure IDA0002340450760001591
Figure IDA0002340450760001601
Figure IDA0002340450760001611
Figure IDA0002340450760001621
Figure IDA0002340450760001631
Figure IDA0002340450760001641
Figure IDA0002340450760001651
Figure IDA0002340450760001661
Figure IDA0002340450760001671
Figure IDA0002340450760001681
Figure IDA0002340450760001691
Figure IDA0002340450760001701
Figure IDA0002340450760001711
Figure IDA0002340450760001721
Figure IDA0002340450760001731
Figure IDA0002340450760001741
Figure IDA0002340450760001751
Figure IDA0002340450760001771
Figure IDA0002340450760001791
Figure IDA0002340450760001801
Figure IDA0002340450760001811
Figure IDA0002340450760001821
Figure IDA0002340450760001831
Figure IDA0002340450760001841
Figure IDA0002340450760001851
Figure IDA0002340450760001861
Figure IDA0002340450760001881
Figure IDA0002340450760001891
Figure IDA0002340450760001901
Figure IDA0002340450760001921
Figure IDA0002340450760001931
Figure IDA0002340450760001941
Figure IDA0002340450760001951
Figure IDA0002340450760001961
Figure IDA0002340450760001971
Figure IDA0002340450760001981
Figure IDA0002340450760001991
Figure IDA0002340450760002001
Figure IDA0002340450760002021
Figure IDA0002340450760002031
Figure IDA0002340450760002041
Figure IDA0002340450760002051
Figure IDA0002340450760002061
Figure IDA0002340450760002071
Figure IDA0002340450760002081
Figure IDA0002340450760002091
Figure IDA0002340450760002101
Figure IDA0002340450760002111
Figure IDA0002340450760002121
Figure IDA0002340450760002141
Figure IDA0002340450760002181
Figure IDA0002340450760002191
Figure IDA0002340450760002201
Figure IDA0002340450760002211
Figure IDA0002340450760002221
Figure IDA0002340450760002231
Figure IDA0002340450760002241
Figure IDA0002340450760002261
Figure IDA0002340450760002281
Figure IDA0002340450760002291
Figure IDA0002340450760002301
Figure IDA0002340450760002311
Figure IDA0002340450760002321
Figure IDA0002340450760002331
Figure IDA0002340450760002341
Figure IDA0002340450760002351
Figure IDA0002340450760002361

Claims (56)

1. An immunoconjugate comprising an antibody (Ab) or a functional fragment thereof coupled to an agonist of an interferon gene stimulating factor (STING) receptor (D) via a linker (L), wherein the linker optionally comprises one or more cleavage elements.
2. The immunoconjugate according to claim 1, comprising formula (I):
Ab-(L-(D)m)n(formula (I))
Wherein:
ab is an antibody or functional fragment thereof;
l is a linker comprising one or more cutting elements;
d is a drug moiety having agonist activity against STING receptors;
m is an integer from 1 to 8; and is
n is an integer from 1 to 20.
3. The immunoconjugate according to claim 1, comprising formula (I):
Ab-(L-(D)m)n(formula (I))
Wherein:
ab is an antibody or functional fragment thereof;
l is a linker;
d is a drug moiety that binds to STING receptors;
m is an integer from 1 to 8; and is
n is an integer from 1 to 20;
wherein D or a cleavage product thereof released from the immunoconjugate has STING agonist activity.
4. The immunoconjugate according to claim 1, comprising formula (I):
Ab-(L-(D)m)n(formula (I))
Wherein:
ab is an antibody or functional fragment thereof;
l is a linker;
d is a drug moiety that binds to STING receptors;
m is an integer from 1 to 8; and is
n is an integer from 1 to 20;
wherein the immunoconjugate delivers D or a cleavage product thereof to a cell targeted by the Ab, and wherein D or a cleavage product thereof has STING agonist activity.
5. The immunoconjugate according to claim 1, comprising formula (I):
Ab-(L-(D)m)n(formula (I))
Wherein:
ab is an antibody or functional fragment thereof;
l is a linker comprising one or more cutting elements;
d is a drug moiety that binds to STING receptors;
m is an integer from 1 to 8; and is
n is an integer from 1 to 20;
wherein the immunoconjugate releases D or a cleavage product thereof in the Ab-targeted cells, and wherein D or a cleavage product thereof has STING agonist activity.
6. The immunoconjugate according to claim 1, comprising formula (I):
Ab-(L-(D)m)n(formula (I))
Wherein:
ab is an antibody or functional fragment thereof;
l is a linker comprising one or more cutting elements;
d is a drug moiety having agonist activity against STING receptors;
m is an integer from 1 to 8; and is
n is an integer from 1 to 20;
wherein the immunoconjugate releases D or a cleavage product thereof in a cell targeted by the Ab, and wherein D or a cleavage product thereof has STING agonist activity in the cell.
7. The immunoconjugate according to claim 1 for delivering a STING receptor agonist to a cell, the immunoconjugate comprising formula (I):
Ab-(L-(D)m)n(formula (I))
Wherein:
ab is an antibody or functional fragment thereof;
l is a linker comprising one or more cutting elements;
d is a drug moiety that binds to STING receptors;
m is an integer from 1 to 8; and is
n is an integer from 1 to 20;
wherein the immunoconjugate specifically binds to an antigen expressed on the cell surface and is internalized into the cell, and wherein D or a cleavage product thereof cleaves from L and has STING agonist activity as determined by one or more STING agonist assays selected from: an interferon stimulation assay, a hSTING wt assay, a THP 1-double assay, a TANK binding kinase 1(TBK1) assay, or an interferon- γ -inducible protein 10(IP-10) secretion assay.
8. The immunoconjugate of any one of the preceding claims, wherein D or a cleavage product thereof has STING agonist activity if it binds to STING and is capable of stimulating the production of one or more STING-dependent cytokines in STING-expressing cells at least 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold or more fold higher than in untreated STING-expressing cells.
9. The immunoconjugate of claim 8, wherein the STING-dependent cytokine is selected from interferon, type 1 interferon, IFN- α, IFN- β, type 3 interferon, IFN λ, IP10, TNF, IL-6, CXCL9, CCL4, CXCL11, CCL5, CCL3, or CCL 8.
10. The immunoconjugate of any one of claims 1-7, wherein D or a cleavage product thereof has STING agonist activity if D or a cleavage product thereof binds to STING and is capable of stimulating phosphorylation of TBK1 in STING-expressing cells at least 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, or more fold higher than untreated STING-expressing cells.
11. The immunoconjugate of any one of claims 1 to 7, wherein D or a cleavage product thereof has STING agonist activity if it binds to STING and is capable of stimulating expression of a STING-dependent transcript of any one of the transcripts selected from those listed in figures 1A-1O and figures 2A-2L in a cell expressing STING by at least 5-fold or more as compared to an untreated cell expressing STING.
12. The immunoconjugate of claim 11, wherein expression of the STING-dependent transcript is increased 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, 14-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 700-fold or more.
13. The immunoconjugate of any one of claims 1-7, wherein D or a cleavage product thereof has STING agonist activity if it binds to STING and is capable of stimulating expression of a luciferase reporter gene controlled by an Interferon (IFN) -stimulated response element in a cell expressing STING with an EC50 of 20 micromolar (μ M), 15 μ M, 10 μ M,9 μ M, 8 μ M, 7 μ M, 6 μ M,5 μ M,4 μ M, 3 μ M,2 μ M, 1 μ M, or lower.
14. The immunoconjugate of any one of claims 1-7, wherein D or a cleavage product thereof has STING agonist activity if it binds to STING and is capable of stimulating in STING-expressing cells the expression level of a luciferase reporter gene controlled by an Interferon (IFN) -stimulated response element to a stimulation level of 2'3' -cGAMP equal to or greater than 50 μ M.
15. The immunoconjugate of claim 13 or 14, wherein the STING-expressing cell is a THP 1-duplex cell and the luciferase reporter is an IRF-Lucia reporter in a THP 1-duplex cell, and optionally the STING agonist activity is determined by a THP 1-duplex assay as described in table 7.
16. The immunoconjugate of claim 13 or 14, wherein the luciferase reporter gene is a 5 xsser-mfnb-GL 4 reporter gene and the STING-expressing cells are wild-type human STING protein-expressing cells, and optionally, the STING agonist activity is determined by the hssting wt assay described in table 7.
17. The immunoconjugate of any one of claims 1-7, wherein said immunoconjugate stimulates secretion of IP-10 from said Ab-targeted STING-expressing cell with an EC50 of 5 nanomolar (nM) or less in an IP-10 secretion assay.
18. The immunoconjugate according to any one of the preceding claims, wherein the immunoconjugate is administered parenterally.
19. The immunoconjugate of any one of the preceding claims, wherein the Ab specifically binds a target antigen.
20. The immunoconjugate according to claim 19, wherein the target antigen is a tumor antigen.
21. The immunoconjugate of any one of the preceding claims, wherein the Ab is human or humanized.
22. The immunoconjugate of any one of the preceding claims, wherein the Ab is a monoclonal antibody.
23. The immunoconjugate of any one of the preceding claims, wherein the Ab comprises a modified Fc region.
24. The immunoconjugate of claim 23, wherein the Ab comprises a cysteine at one or more of the positions numbered according to EU numbering:
(a) positions 152, 360 and 375 of the antibody heavy chain; and
(b) positions 107, 159 and 165 of the antibody light chain.
25. The immunoconjugate of any one of the preceding claims, wherein L is attached to the Ab via conjugation to one or more modified cysteine residues in the Ab.
26. The immunoconjugate of claim 25, wherein L is conjugated to the Ab via modified cysteine residues at positions 152 and 375 of the heavy chain of the Ab, wherein the positions are determined according to EU numbering.
27. The immunoconjugate according to claims 24 to 26, wherein L is conjugated to the cysteine via a maleimide bond.
28. The immunoconjugate according to any one of the preceding claims, wherein D is a dinucleotide.
29. The immunoconjugate according to any one of the preceding claims, wherein D is a Cyclic Dinucleotide (CDN).
30. The immunoconjugate according to any one of the preceding claims, wherein D is a compound selected from any one of the compounds of table 1, table 2, table 3, or table 4.
31. The immunoconjugate according to any one of the preceding claims, wherein D is a compound selected from:
Figure FDA0002340450690000061
Figure FDA0002340450690000071
32. the immunoconjugate of any one of the preceding claims, wherein L is a cleavable linker comprising one or more cleavage elements.
33. The immunoconjugate of claim 32, wherein L comprises two or more cleavage elements, and each cleavage element is independently selected from a suicide spacer and a cleavable group.
34. The immunoconjugate of claim 33, wherein the cleavage is selected from acid-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, glycosidase-induced cleavage, phosphodiesterase-induced cleavage, phosphatase-induced cleavage, protease-induced cleavage, lipase-induced cleavage, or disulfide bond cleavage.
35. The immunoconjugate according to claim 32, wherein L has a structure selected from:
Figure FDA0002340450690000072
wherein:
lc is a linker component and each Lc is independently selected from the linker components as shown in examples 70 to 75;
x is an integer selected from 1, 2, 3,4,5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19 and 20;
y is an integer selected from 1, 2, 3,4,5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19 and 20;
p is an integer selected from 1, 2, 3,4,5, 6, 7,8, 9 and 10;
d is a compound according to claims 28 to 31;
and each cutting element (C)E) Independently selected from the group consisting of a suicide spacer and a group susceptible to cleavage selected from the group consisting of acid-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, glycosidase-induced cleavage, phosphodiesterase-induced cleavage, phosphatase-induced cleavage, protease-induced cleavage, lipase-induced cleavage, and disulfide bond cleavage.
36. The immunoconjugate according to any one of the preceding claims, wherein L comprises a structure selected from:
Figure FDA0002340450690000081
Figure FDA0002340450690000091
Figure FDA0002340450690000101
37. the immunoconjugate according to any one of the preceding claims, wherein the immunoconjugate is selected from the following:
Figure FDA0002340450690000102
Figure FDA0002340450690000111
Figure FDA0002340450690000121
Figure FDA0002340450690000131
Figure FDA0002340450690000141
Figure FDA0002340450690000151
Figure FDA0002340450690000161
Figure FDA0002340450690000171
wherein:
each G1Is independently selected from
Figure FDA0002340450690000172
Wherein indicates and-CR8R9-an attachment point of;
XAis C (═ O) -, -C (═ S) -, or-C (═ NR) -11) -, and each Z1Is NR12；
XBIs C, and each Z2Is N;
G2is that
Figure FDA0002340450690000181
Wherein indicates and-CR8aR9a-an attachment point of;
XCis C (═ O) -, -C (═ S) -, or-C (═ NR) -11) -, and each Z3Is NR12；
XDIs C, and each Z4Is N;
Y1is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
Y2is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
Y3Is OH, O-、OR10、N(R10)2、SR10、SeH、Se-、BH3SH or S-；
Y4Is OH, O-、OR10、N(R10)2、SR10、SeH、Se-、BH3SH or S-；
Y5is-CH2-, -NH-, -O-or-S;
Y6is-CH2-, -NH-, -O-or-S;
Y7is O or S;
Y8is O or S;
Y9is-CH2-, -NH-, -O-or-S;
Y10is-CH2-, -NH-, -O-or-S;
Y11is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
q is 1, 2 or 3;
R1is a partially saturated or aromatic monocyclic heterocyclic group or a partially saturated or aromatic fused bicyclic heterocyclic group comprising from 5 to 10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatom is independently selected from O, N or S, or a tautomer thereof, wherein R is1Is substituted with 0,1, 2, 3 or 4 substituents independently selected from-NHL1R115、F、Cl、Br、OH、SH、NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl)) and-N (C)3-C8Cycloalkyl radicals2；
R1aIs a partially saturated or aromatic monocyclic heterocyclic group or a partially saturated or aromatic fused bicyclic heterocyclic group comprising from 5 to 10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatom is independently selected from O, N or S, or a tautomer thereof, wherein R is1aIs substituted with 0,1, 2, 3 or 4 substituents independently selected from-NHL1R115、F、Cl、Br、OH、SH、NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl), and-N (C)3-C8Cycloalkyl radicals2；
R1bIs a partially saturated or aromatic monocyclic heterocyclic group or a partially saturated or aromatic fused bicyclic heterocyclic group comprising from 5 to 10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatom is independently selected from O, N or S, or a tautomer thereof, wherein R is1bIs substituted with 0,1, 2, 3 or 4 substituents independently selected from-NHL1R115、F、Cl、Br、OH、SH、NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl), and-N (C)3-C8Cycloalkyl radicals2；
Each R2Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and OC (O) C2-C6Alkynyl, wherein R2of-OC (O) O phenyl and R2C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R3Independently selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3of-OC (O) O phenyl and R3C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R4Independently selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R4of-OC (O) O phenyl and R4C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, aryl, heteroaryl, and heteroaryl,-OC(O)OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN or N3；
Each R5Independently selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5of-OC (O) O phenyl and R5C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN or N3；
Each R6Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R6of-OC (O) O phenyl and R6C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R7Independently selected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R7of-OC (O) O phenyl and R7C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN or N3；
Each R8Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R8of-OC (O) O phenyl and R8C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R9Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C) ((C)C2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R9of-OC (O) O phenyl and R9C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R2aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R2aof-OC (O) O phenyl and R2aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3
R3aSelected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3aof-OC (O) O phenyl and R3aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R4aSelected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R4aof-OC (O) O phenyl and R4aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R5aSelected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5aof-OC (O) O phenyl and R5aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R6aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R6aof-OC (O) O phenyl and R6aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R7aSelected from the group consisting of: -OL1R115、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R7aof-OC (O) O phenyl and R7aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH. CN and N3；
R8aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R8aof-OC (O) O phenyl and R8C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R9aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R9aof-OC (O) O phenyl and R9aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R10Independently selected from the group consisting of: H. c1-C12Alkyl radical, C1-C6Heteroalkyl, - (CH)2CH2O)nCH2CH2C(＝O)OC1-C6Alkyl radicals and
Figure FDA0002340450690000271
wherein R is10C of (A)1-C12Alkyl and C1-C6The heteroalkyl is substituted with 0,1, 2, or 3 substituents independently selected from-OH, C1-C12Alkoxy, -S-C (═ O) C1-C6Alkyl, halo, -CN, C1-C12Alkyl, -O-aryl, -O-heteroaryl, -O-cycloalkyl, oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl, -OC (O) OC1-C6Alkyl and C (O) OC1-C6Alkyl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is substituted with 0,1, 2 or 3 substituents independently selected from C1-C12Alkyl, O-C1-C12Alkyl radical, C1-C12Heteroalkyl, halo, CN, OH, oxo, aryl, heteroaryl, O-aryl, O-heteroaryl, -C (═ O) C1-C12Alkyl, -OC (═ O) C1-C12Alkyl, -C (═ O) OC1-C12Alkyl, -OC (═ O) OC1-C12Alkyl, -C (═ O) N (R)11)-C1-C12Alkyl, -N (R)11)C(＝O)-C1-C12An alkyl group; -OC (═ O) N (R)11)-C1-C12Alkyl, -C (═ O) -aryl, -C (═ O) -heteroaryl, -OC (═ O) -aryl, -C (═ O) O-aryl, -OC (═ O) -heteroaryl, -C (═ O) O-aryl, -C (═ O) O-heteroaryl, -C (═ O) N (R) (═ O) O-heteroaryl11) -aryl, -C (═ O) N (R)11) -heteroaryl, -N (R)11) C (O) -aryl, -N (R)11)2C (O) -aryl, -N (R)11) C (O) -heteroaryl and S (O)2N(R11) -an aryl group;
each R11Independently selected from H and C1-C6An alkyl group;
each R12Independently selected from H and C1-C6An alkyl group;
optionally, R3And R6Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R3And R6When taken together, O is at R3Bonding at the position;
optionally, R3aAnd R6aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R3aAnd R6aWhen taken together, O is at R3aBonding at the position;
optionally, R2And R3Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R2And R3When taken together, O is at R3Bonding at the position;
optionally, R2aAnd R3aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R2aAnd R3aWhen taken together, O is at R3aBonding at the position;
optionally, R4And R3Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R4And R3When taken together, O is at R3Bonding at the position;
optionally, R4aAnd R3aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical,C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R4aAnd R3aWhen taken together, O is at R3aBonding at the position;
optionally, R5And R6Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5And R6When taken together, O is at R5Bonding at the position;
optionally, R5aAnd R6aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5aAnd R6aWhen taken together, O is at R5aBonding at the position;
optionally, R5And R7Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5And R7When taken together, O is at R5Bonding at the position;
optionally, R5aAnd R7aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5aAnd R7aWhen taken together, O is at R5aBonding at the position;
optionally, the step of (a) is carried out,R8and R9Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, and
optionally, R8aAnd R9aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6An alkynylene group which is a substituent of a heterocyclic ring,
L1is a joint;
R115is that
Figure FDA0002340450690000281
Figure FDA0002340450690000291
-C(＝O)-、-ON＝***、-S-、-NHC(＝O)CH2-***、-S(＝O)2CH2CH2-***、-(CH2)2S(＝O)2CH2CH2-***、-NHS(＝O)2CH2CH2-**、-NHC(＝O)CH2CH2-***、-CH2NHCH2CH2-***、-NHCH2CH2-***、
Figure FDA0002340450690000292
Figure FDA0002340450690000293
Figure FDA0002340450690000294
Wherein indicates the point of attachment to Ab;
R13is H or methyl;
R14is H, -CH3Or phenyl;
each R110Independently selected from H, C1-C6Alkyl, F, Cl, and-OH;
each R111Independently selected from H, C1-C6Alkyl radical F, Cl, -NH2、-OCH3、-OCH2CH3、-N(CH3)2、-CN、-NO2and-OH;
each R112Independently selected from H, C1-6Alkyl, fluoro, benzyloxy substituted by-C (═ O) OH, benzyl substituted by-C (═ O) OH, C substituted by-C (═ O) OH1-4Alkoxy and C substituted by-C (═ O) OH1-4An alkyl group;
ab is an antibody or functional fragment thereof; and is
y is 1, 2, 3,4,5, 6, 7,8, 9 or 10.
38. The immunoconjugate according to any one of the preceding claims, comprising a structure selected from:
Figure FDA0002340450690000301
Figure FDA0002340450690000311
Figure FDA0002340450690000321
Figure FDA0002340450690000341
Figure FDA0002340450690000351
Figure FDA0002340450690000361
Figure FDA0002340450690000371
Figure FDA0002340450690000381
Figure FDA0002340450690000391
Figure FDA0002340450690000401
Figure FDA0002340450690000411
Figure FDA0002340450690000431
Figure FDA0002340450690000451
Figure FDA0002340450690000461
Figure FDA0002340450690000471
Figure FDA0002340450690000481
Figure FDA0002340450690000491
Figure FDA0002340450690000501
Figure FDA0002340450690000522
and
Figure FDA0002340450690000523
39. the immunoconjugate of any one of the preceding claims, wherein the immunoconjugate has anti-tumor activity in vivo.
40. A pharmaceutical composition comprising the immunoconjugate of any one of the preceding claims, and a pharmaceutically acceptable excipient.
41. A composition comprising an immunoconjugate according to any one of the preceding claims in combination with one or more additional therapeutic agents.
42. The composition of claim 41, wherein the additional therapeutic agent is selected from the group consisting of: an inhibitor of a co-inhibitory molecule, an activator of a co-stimulatory molecule, a cytokine, an agent that reduces Cytokine Release Syndrome (CRS), chemotherapy, targeted anti-cancer therapy, an oncolytic drug, a cytotoxic agent, an immune-based therapy, a vaccine, or a cell therapy.
43. The composition of claim 41, wherein the additional therapeutic agent is an inhibitor of a co-inhibitory molecule, an activator of a co-stimulatory molecule, or a cytokine, wherein:
(i) the co-inhibitory molecule is selected from programmed death-1 (PD-1), programmed death-ligand 1(PD-L1), lymphocyte activation gene-3 (LAG-3), or T cell immunoglobulin domain and mucin domain 3(TIM-3),
(ii) the co-stimulatory molecule is glucocorticoid-induced TNFR-related protein (GITR), and
(iii) the cytokine is IL-15 complexed with a soluble form of IL-15 receptor α (IL-15 Ra).
44. A method of treating cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of the immunoconjugate of any one of claims 1-39, the pharmaceutical composition of claim 40, or the composition of claims 41-43.
45. Use of the immunoconjugate of any one of claims 1-39, the pharmaceutical composition of claim 40, or the composition of claims 41-43 for treating cancer in a subject in need thereof.
46. The immunoconjugate according to any one of claims 1 to 39, pharmaceutical composition according to claim 40, or composition according to claims 41 to 43, for use in the treatment of cancer.
47. Use of the immunoconjugate of any one of claims 1-39, the pharmaceutical composition of claim 40, or the composition of claims 41-43 in the manufacture of a medicament for treating cancer in a subject in need thereof.
48. The method of claim 43, the use of claim 44 or 46, or the immunoconjugate of claim 45, wherein the cancer is selected from sarcoma, adenocarcinoma, blastoma, carcinoma, liver cancer, lung cancer, non-small cell lung cancer, breast cancer, lymphoma, colon cancer, kidney cancer, urothelial cancer, prostate cancer, pharyngeal cancer, rectal cancer, renal cell cancer, small intestine cancer, esophageal cancer, melanoma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, colorectal cancer, anal region cancer, peritoneal cancer, stomach cancer, esophageal cancer, salivary gland cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulval cancer, penile cancer, glioblastoma, cervical cancer, Hodgkin's lymphoma, cervical cancer, Non-hodgkin's lymphoma, esophageal cancer, small bowel cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, cancer of the urethra, cancer of the penis, chronic or acute leukemia (including acute myelogenous leukemia), chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, childhood solid tumors, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, central nervous system tumors (CNS), primary CNS lymphoma, tumor angiogenesis, spinal cord axis tumors, brain stem glioma, pituitary adenoma, kaposi's sarcoma, neuroendocrine tumors (including carcinoid tumors, gastrinoma, and islet cell carcinoma), mesothelioma, schwannoma (including acoustic neuroma), meningioma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, Environmentally induced cancers (including asbestos-induced cancers), leukemias, lymphomas, Acute Myelogenous Leukemia (AML), Acute Lymphocytic Leukemia (ALL), Chronic Myelogenous Leukemia (CML), Chronic Lymphocytic Leukemia (CLL), myelodysplastic syndrome, B-cell acute lymphocytic leukemia ("BALL"), T-cell acute lymphocytic leukemia ("TALL"), B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell tumors, Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small-cell-or large-cell follicular lymphoma, malignant lymphoproliferative disorders, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia, myelodysplastic syndrome, plasmacytic lymphoma, myeloblastosis, Plasmacytoid dendritic cell tumors, and Waldenstrom's macroglobulinemia.
49. The method of claim 43, the use of claim 44 or 45, or the immunoconjugate of claim 45, wherein said immunoconjugate is administered to said subject intravenously, intratumorally, or subcutaneously.
50. The immunoconjugate according to any one of claims 1 to 39, the pharmaceutical composition according to claim 40, or the composition according to claims 41 to 43, for use as a medicament.
51. A method of making the immunoconjugate of any one of claims 1-38, the method comprising the steps of:
a) reacting D and L to form (L- (D)m(ii) a And is
b) Make (L- (D)mAnd Ab to form an immunoconjugate Ab- (L- (D)m)n(formula (I)).
52. A compound having a structure selected from formula (A), formula (B), formula (C), formula (D), formula (E) or formula (F), or a stereoisomer or pharmaceutically acceptable salt thereof,
Figure FDA0002340450690000551
wherein:
each G1Is independently selected from
Figure FDA0002340450690000561
Wherein indicates and-CR8R9-an attachment point of;
XAis C (═ O) -, -C (═ S) -, or-C (═ NR) -11) -, and each Z1Is NR12；
XBIs C, and each Z2Is N;
G2is that
Figure FDA0002340450690000562
Wherein indicates and-CR8aR9a-an attachment point of;
XCis C (═ O) -, -C (═ S) -, or-C (═ NR) -11) -, and each Z3Is NR12；
XDIs C, and each Z4Is N;
Y1is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
Y2is-O-, -S- (O) -, -SO2-、-CH2-or-CF2-；
Y3Is OH, O-、OR10、N(R10)2、SR10、SeH、Se-、BH3SH or S-；
Y4Is OH, O-、OR10、N(R10)2、SR10、SeH、Se-、BH3SH or S-；
Y5is-CH2-, -NH-, -O-or-S;
Y6is-CH2-, -NH-, -O-or-S;
Y7is O or S;
Y8is O or S;
Y9is-CH2-, -NH-, -O-or-S;
Y10is-CH2-, -NH-, -O-or-S;
Y11is-O-、-S-、-S(＝O)-、-SO2-、-CH2-or-CF2-；
q is 1, 2 or 3;
R1is a partially saturated or aromatic monocyclic heterocyclic group or a partially saturated or aromatic fused bicyclic heterocyclic group comprising from 5 to 10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatom is independently selected from O, N or S, or a tautomer thereof, wherein R is1Is substituted with 0,1, 2, 3 or 4 substituents independently selected from-NHL1R15、F、Cl、Br、OH、SH、NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl), and-N (C)3-C8Cycloalkyl radicals2；
R1aIs a partially saturated or aromatic monocyclic heterocyclic group or a partially saturated or aromatic fused bicyclic heterocyclic group comprising from 5 to 10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatom is independently selected from O, N or S, or a tautomer thereof, wherein R is1aIs substituted with 0,1, 2, 3 or 4 substituents independently selected from-NHL1R15、F、Cl、Br、OH、SH、NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxyalkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH、-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl), and-N (C)3-C8Cycloalkyl radicals2；
R1bIs a partially saturated or aromatic monocyclic heterocyclic group or a partially saturated or aromatic fused bicyclic heterocyclic group comprising from 5 to 10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatom is independently selected from O, N or S, or a tautomer thereof, wherein R is1bIs substituted with 0,1, 2, 3 or 4 substituents independently selected from-NHL1R15、F、Cl、Br、OH、SH、NH2、D、CD3、C1-C6Alkyl radical, C1-C6Alkoxyalkyl group, C1-C6Hydroxyalkyl radical, C3-C8Cycloalkyl, 3 to 6 membered heterocyclyl with 1 to 2 heteroatoms independently selected from O, N and S, -O (C)1-C6Alkyl), -O (C)3-C8Cycloalkyl), -S (C)1-C6Alkyl), -S (C)1-C6Aminoalkyl), -S (C)1-C6Hydroxy radicalAlkyl), -S (C)3-C8Cycloalkyl), -NH (C)1-C6Alkyl), -NH (C)3-C8Cycloalkyl), -N (C)1-C6Alkyl radical)2、-N(C1-C6Alkyl) (C3-C8Cycloalkyl), -CN, -P (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-(CH2)1-10C(＝O)OH、-CH＝CH(CH2)1-10C(＝O)OH,-NHC(O)(C1-C6Alkyl), -NHC (O) (C)3-C8Cycloalkyl), -NHC (O) (phenyl) and-N (C)3-C8Cycloalkyl radicals2；
Each R2Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and OC (O) C2-C6Alkynyl, wherein R2of-OC (O) O phenyl and R2C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R3Independently selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3of-OC (O) O phenyl and R3C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R4Independently selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R4of-OC (O) O phenyl and R4C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN or N3；
Each R5Independently selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5of-OC (O) O phenyl and R5C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN or N3；
Each R6Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R6of-OC (O) O phenyl and R6C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R7Independently selected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C) ((C)C2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R7of-OC (O) O phenyl and R7C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN or N3；
Each R8Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R8of-OC (O) O phenyl and R8C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R9Independently selected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R9of-OC (O) O phenyl and R9C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R2aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R2aof-OC (O) O phenyl and R2aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3
R3aSelected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R3aof-OC (O) O phenyl and R3aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R4aSelected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R4aof-OC (O) O phenyl and R4aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R5aSelected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R5aof-OC (O) O phenyl and R5aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R6aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R6aof-OC (O) O phenyl and R6aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R7aSelected from the group consisting of: -OL1R15、H、-OH、F、Cl、Br、I、D、CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R7aof-OC (O) O phenyl and R7aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R8aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R8aof-OC (O) O phenyl and R8C of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
R9aSelected from the group consisting of: H. -OH, F, Cl, Br, I, D, CD3、CN、N3、C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OP (═ O) (OH)2、-O(CH2)1-10C(＝O)OH、-O(CH2)1-10P(＝O)(OH)2-OC (O) Ophenyl, -OC (O) OC1-C6Alkyl, -OC(O)OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) phenyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6Alkynyl, wherein R9aof-OC (O) O phenyl and R9aC of (A)1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Haloalkyl, C2-C6Haloalkenyl, C2-C6Haloalkynyl, -O (C)1-C6Alkyl), -O (C)2-C6Alkenyl), -O (C)2-C6Alkynyl), -OC (O) OC1-C6Alkyl, -OC (O) OC2-C6Alkenyl, -OC (O) OC2-C6Alkynyl, -OC (O) C1-C6Alkyl, -OC (O) C2-C6Alkenyl and-OC (O) C2-C6C of alkynyl1-C6Alkyl radical, C2-C6Alkenyl and C2-C6Alkynyl is substituted with 0,1, 2 or 3 substituents independently selected from F, Cl, Br, I, OH, CN and N3；
Each R10Independently selected from the group consisting of: H. c1-C12Alkyl radical, C1-C6Heteroalkyl, - (CH)2CH2O)nCH2CH2C(＝O)OC1-C6Alkyl radicals and
Figure FDA0002340450690000651
wherein R is10C of (A)1-C12Alkyl and C1-C6The heteroalkyl is substituted with 0,1, 2, or 3 substituents independently selected from-OH, C1-C12Alkoxy, -S-C (═ O) C1-C6Alkyl, halo, -CN, C1-C12Alkyl, -O-aryl, -O-heteroaryl, -O-cycloalkyl, oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl, -OC (O) OC1-C6Alkyl and C (O) OC1-C6Alkyl radicals, each of which being an alkyl radicalCycloalkyl, heterocyclyl, aryl and heteroaryl are substituted with 0,1, 2 or 3 substituents independently selected from C1-C12Alkyl, O-C1-C12Alkyl radical, C1-C12Heteroalkyl, halo, CN, OH, oxo, aryl, heteroaryl, O-aryl, O-heteroaryl, -C (═ O) C1-C12Alkyl, -OC (═ O) C1-C12Alkyl, -C (═ O) OC1-C12Alkyl, -OC (═ O) OC1-C12Alkyl, -C (═ O) N (R)11)-C1-C12Alkyl, -N (R)11)C(＝O)-C1-C12An alkyl group; -OC (═ O) N (R)11)-C1-C12Alkyl, -C (═ O) -aryl, -C (═ O) -heteroaryl, -OC (═ O) -aryl, -C (═ O) O-aryl, -OC (═ O) -heteroaryl, -C (═ O) O-aryl, -C (═ O) O-heteroaryl, -C (═ O) N (R) (═ O) O-heteroaryl11) -aryl, -C (═ O) N (R)11) -heteroaryl, -N (R)11) C (O) -aryl, -N (R)11)2C (O) -aryl, -N (R)11) C (O) -heteroaryl and S (O)2N(R11) -an aryl group;
each R11Independently selected from H and C1-C6An alkyl group;
each R12Independently selected from H and C1-C6An alkyl group;
optionally, R3And R6Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R3And R6When taken together, O is at R3Bonding at the position;
optionally, R3aAnd R6aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene radical toWhen R is3aAnd R6aWhen taken together, O is at R3aBonding at the position;
optionally, R2And R3Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R2And R3When taken together, O is at R3Bonding at the position;
optionally, R2aAnd R3aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R2aAnd R3aWhen taken together, O is at R3aBonding at the position;
optionally, R4And R3Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R4And R3When taken together, O is at R3Bonding at the position;
optionally, R4aAnd R3aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R4aAnd R3aWhen taken together, O is at R3aBonding at the position;
optionally, R5And R6Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene group,-O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5And R6When taken together, O is at R5Bonding at the position;
optionally, R5aAnd R6aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5aAnd R6aWhen taken together, O is at R5aBonding at the position;
optionally, R5And R7Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5And R7When taken together, O is at R5Bonding at the position;
optionally, R5aAnd R7aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6Alkynylene, -O-C1-C6Alkylene, -O-C2-C6Alkenylene, -O-C2-C6Alkynylene such that when R5aAnd R7aWhen taken together, O is at R5aBonding at the position;
optionally, R8And R9Are joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6An alkynylene group; and is
Optionally, R8aAnd R9aAre joined together to form C1-C6Alkylene radical, C2-C6Alkenylene radical, C2-C6An alkynylene group which is a substituent of a heterocyclic ring,
L1is-C (═ O) O (CH)2)mNR11C(＝O)(CH2)m-**；-C(＝O)O(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；
-C(＝O)OC(R12)2(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；
-C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)mC(＝O)-**；
-C(＝O)O(CH2)mNR11C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；-C(＝O)O(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)(CH2)mNR11C(＝O)X2C(＝O)(CH2)m-**；
-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)(CH2)m-**,
-C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-**,
-C(＝O)O(CH2)mX6C(＝O)(CH2)m-**,
-C(＝O)O(CH2)mX6C(＝O)(CH2)mO(CH2)m-**,
-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)(CH2)m-**,
-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)(CH2)mO(CH2)m-**,
-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)(CH2)mO(CH2)mC(＝O)-**,
-C(＝O)O(CH2)mX6C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**，
-C(＝O)X4C(＝O)X6(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**,
-C(＝O)(CH2)mX6C(＝O)X1X2C(＝O)(CH2)m-**,
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O))X5C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mNR11((CH2)mO)n(CH2)m-**；-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-**；-C(＝O)O(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)m-**；-C(＝O)O(CH2)mNR11(CH2)m-**；
-C(＝O)O(CH2)mNR11(CH2)mC(＝O)X2X1C(＝O)-**；
-C(＝O)O(CH2)mX3(CH2)m-**；-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)m-**,-C(＝O)O((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)O(CH2)mNR11C(＝O(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)nX3(CH2)m-**；-C(＝O)O((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)O((CH2)mO)n(CH2)mC(＝O)NR11(CH2)m-**；-C(＝O)O(CH2)mC(R12)2-**；
-C(＝O)OCH2)mC(R12)2SS(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)O(CH2)mC(＝O)NR11(CH2)m-**；-C(＝O)(CH2)m-**；-C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)(CH2)mNR11(CH2)m-**；-C(＝O)(CH2)mNR11(CH2)mC(＝O)X2X1C(＝O)-**；
-C(＝O)(CH2)mX3(CH2)m-**；-C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；-C(＝O)(CH2)mNR11C(＝O(CH2)mX3(CH2)m-**；-(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-(CH2)m(CHOH)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；-C(＝O)((CH2)mO)nX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；-C(＝O)((CH2)mO)n(CH2)mC(＝O)NR11(CH2)m-**；-C(＝O)(CH2)mC(R12)2-**；-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O))X5C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mNR11((CH2)mO)n(CH2)m-**；-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)m-**；-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-**；-C(＝O)(CH2)mC(R12)2SS(CH2)mNR11C(＝O)(CH2)m-**；-C(＝O)(CH2)mC(＝O)NR11(CH2)m-**；
-C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)X1X2C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)X1X2C(＝O)(CH2)mX3(CH2)m-**；-C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)X1X2C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)X1X2C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)X1X2(CH2)mX3(CH2)m-**；-C(＝O)X1X2((CH2)mO)n(CH2)m-**；
-C(＝O)X1X2((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)X1X2((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)X1X2((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)X1X2(CH2)mNR11((CH2)mO)n(CH2)m-**；-C(＝O)X1X2C(＝O)(CH2)mNR11((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)m-**；-C(＝O)NR11(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)O(CH2)m-**；-C(＝O)NR11(CH2)mNR11C(＝O)X1X2-**；-C(＝O)NR11(CH2)mNR11C(＝O)X5-；-C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mX5(CH2)m-**；-C(＝O)X1C(＝O)NR11(CH2)mX5(CH2)m-**；-C(＝O)X6C(＝O)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)NR11(CH2)mNR11C(＝O)(CH2)m-**；-C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)mC(＝O)-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5(CH2)mNR11((CH2)mO)n(CH2)m-**；-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11((CH2)mO)n(CH2)mX3(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5(CH2)m-**；-C(＝O)NR11(CH2)mNR11C(＝O)X5C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)X5(CH2)mX3(CH2)m-**；-C(＝O)X1C(＝O)NR11(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)X1C(＝O)NR11(CH2)mX3(CH2)m-**；-C(＝O)NR11(CH2)mNR11C(＝O)(CH2)m-**；
-C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mX3(CH2)m-**；-C(＝O)NR11(CH2)mNR11C(＝O)-**；
-C(＝O)X1X2(CH2)m-**；-C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)X1X2(CH2)mX3(CH2)m-**；-C(＝O)NR11(CH2)mX3(CH2)m-**；-C(＝O)NR11((CH2)mO)n(CH2)mX3(CH2)m-**；-C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)m-**；
-C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)X1C(＝O)(CH2)mNR11C(＝O)(CH2)m-; and
-C(＝O)X1C(＝O)(CH2)mNR11C(＝O)((CH2)mO)n(CH2)m-**；
wherein indicates with R15The attachment point of (a);
R15is that
Figure FDA0002340450690000741
-ONH2、-NH2、
Figure FDA0002340450690000742
Figure FDA0002340450690000743
-N3、
Figure FDA0002340450690000744
-SH、-SR12、-SSR17、-S(＝O)2(CH＝CH2)、-(CH2)2S(＝O)2(CH＝CH2)、-NHS(＝O)2(CH＝CH2)、-NHC(＝O)CH2Br、-NHC(＝O)CH2I、-C(O)NHNH2、
Figure FDA0002340450690000746
Figure FDA0002340450690000747
Figure FDA0002340450690000751
X1Is that
Figure FDA0002340450690000752
Wherein indicates with X2The attachment point of (a);
X2is selected from
Figure FDA0002340450690000753
Figure FDA0002340450690000762
Wherein indicates with X1The attachment point of (a);
X3is that
Figure FDA0002340450690000763
X4is-O (CH)2)nSSC(R12)2(CH2)n-or- (CH)2)nC(R12)2SS(CH2)nO-；
X5Is that
Figure FDA0002340450690000764
Wherein indicates the direction towards the drug moiety;
X6is that
Figure FDA0002340450690000765
Or, wherein indicates a direction towards the drug moiety;
R17is 2-pyridyl or 4-pyridyl;
each R11Independently selected from H and C1-C6An alkyl group;
each R12Independently selected from H and C1-C6An alkyl group;
each m is independently selected from 1, 2, 3,4,5, 6, 7,8, 9, and 10; and is
Each n is independently selected from 1, 2, 3,4,5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18;
each R110Independently selected from H, C1-C6Alkyl, F, Cl, and-OH;
each R111Independently selected from H, C1-C6Alkyl radical F, Cl, -NH2、-OCH3、-OCH2CH3、-N(CH3)2、-CN、-NO2and-OH;
each R112Independently selected from H, C1-6Alkyl, fluoro, benzyloxy substituted by-C (═ O) OH, benzyl substituted by-C (═ O) OH, C substituted by-C (═ O) OH1-4Alkoxy and C substituted by-C (═ O) OH1-4An alkyl group;
and with the proviso that R1、R1aOr R1bIs at least one-NHL1R15Substituted, or R3、R4、R5、R7、R3a、R4a、R5aOr R7ais-OL1R15。
53. The compound of claim 52, wherein:
L1is-C (═ O) O (CH)2)mNR11C(＝O)(CH2)m-**；-C(＝O)O(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；-C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)OC(R12)2(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)O(CH2)mNR8C(＝O)X1X2C(＝O)(CH2)mO(CH2)m-**；-C(＝O)O(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)mO(CH2)mC(＝O)-**；-C(＝O)O(CH2)mNR11C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；-C(＝O)O(CH2)mNR11C(＝O)X5C(＝O)(CH2)mNR11C(＝O)(CH2)m-**；-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)((CH2)mO)n(CH2)m-**；-(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-(CH2)m(CHOH)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m**；-C(＝O)X6C(＝O)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)X4C(＝O)NR11(CH2)mNR11C(＝O)(CH2)mO(CH2)m-**；-C(＝O)(CH2)mNR11C(＝O)X1X2C(＝O)(CH2)m-**；-C(＝O)O(CH2)mX6C(＝O)X1X2C(＝O)(CH2)m-, or-C (═ O) (CH)2)mNR11C(＝O)((CH2)mO)n(CH2)m-**，
Wherein indicates with R15The attachment point of (a).
54. A compound according to claim 52 or claim 53, selected from:
Figure FDA0002340450690000771
Figure FDA0002340450690000781
Figure FDA0002340450690000791
Figure FDA0002340450690000801
Figure FDA0002340450690000811
Figure FDA0002340450690000821
Figure FDA0002340450690000831
55. a compound according to claim 52 or claim 53, selected from:
Figure FDA0002340450690000832
Figure FDA0002340450690000851
56. a compound according to claim 52 or claim 53, selected from:
Figure FDA0002340450690000852
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