CN113905767A

CN113905767A - Traceless linkers and protein conjugates thereof

Info

Publication number: CN113905767A
Application number: CN202080019317.3A
Authority: CN
Inventors: A·韩
Original assignee: Regeneron Pharmaceuticals Inc
Current assignee: Regeneron Pharmaceuticals Inc
Priority date: 2019-01-08
Filing date: 2020-01-08
Publication date: 2022-01-07
Also published as: CO2021010315A2; WO2020146541A3; CA3125998A1; EP3908323A2; MX2021008114A; MA59295A1; BR112021013464A2; KR20210114008A; WO2020146541A2; AU2020205662A1; IL284673A; MA53772B1; SG11202107212QA; JP2022517767A; MA53772A1; CL2021001790A1

Abstract

The invention provides compounds, compounds comprising traceless linkers, protein conjugates thereof, and compositions thereof. The invention also provides methods for treating, and/or controlling the symptoms of, diseases, disorders, and conditions associated with inflammatory and autoimmune diseases further associated with glucocorticoid receptor, glucocorticoid binding, and/or glucocorticoid receptor signaling, comprising administering the compounds or payloads via scarless linker-payloads, and protein conjugates thereof.

Description

Traceless linkers and protein conjugates thereof

Cross Reference to Related Applications

This application claims and is entitled U.S. provisional application No. 62/872,229 filed on 7/9/2019; U.S. provisional application No. 62/937,721 filed on 19/11/2019; PCT patent application No. PCT/US2019/012786, entitled "Steroids and Antibody Conjugates therapeutics" filed on 8.1.2019; and U.S. patent application No. 16/243,020, entitled "sterides and Antibody Conjugates therapeutics, also filed on 8.1.2019. The contents of each of the priority patent applications are hereby incorporated by reference in their entirety and for all purposes in the present invention.

Technical Field

The present invention provides novel traceless linkers and protein conjugates thereof, as well as methods for treating a variety of diseases, disorders, and conditions, comprising administering a compound or payload via a traceless linker-payload, and protein conjugates thereof.

Background

Antibody-drug conjugates (ADCs) are antibodies that are covalently linked to a biologically active small molecule drug, commonly referred to as a payload, and thus can combine the targeting specificity of the antibody with the mode of action and potency of the small molecule drug. The therapeutic effects of ADC have been tested in the treatment of cancerAnd is the main focus of ongoing research.

(bentruximab VEdotin) and

(ado-trastuzumab emtansine conjugate (ado-trastuzumab emtansine)) are ADCs approved for the treatment of certain cancer types, and several others are currently in clinical development.

Glucocorticoids (GCs) are small molecule steroids that bind to the Glucocorticoid Receptor (GR) and are useful in anti-inflammatory and immunosuppressive therapy. However, glucocorticoid therapy is compromised by toxicity to most organ systems due to the ubiquitous expression of glucocorticoid receptor in many cell types. Thus, there is a need for new glucocorticoids and new therapies that minimize the side effects caused by glucocorticoid administration, particularly those caused by activation of glucocorticoid receptors in non-target cells. The present invention provides a solution to the above-mentioned needs and other unmet needs in the art to which the present invention pertains. The present disclosure includes antibody-drug conjugates comprising a glucocorticoid payload.

Liver X Receptors (LXRs) include LXR α and LXR β, which are ligand-dependent transcription factors that control the expression of genes involved in cholesterol, lipid and glucose homeostasis, inflammation, and innate immunity. LXR α is highly expressed in liver, intestine, adipose tissue, and differentiated macrophages; while LXR β is ubiquitously expressed. LXRs have a variety of biological functions, including: (i) stimulating the expression of cholesterol transporters (e.g., ABCA1 and ABCG1), both ABCA1 and ABCG1 mediating cellular cholesterol efflux; and (ii) down-regulating macrophage inflammatory gene expression by inhibiting NF-kB activation. LXRs are also associated with atherosclerosis, proliferative diseases, neurodegenerative diseases and inflammation. The development of ADCs comprising LXR modulators will allow target-specific modulation of LXR, thereby avoiding side effects caused by off-target modulation of LXR. In addition, such ADCs would provide improved modulation of biological targets, improved bioavailability, and improved therapeutic window. Thus, there is a continuing need for small molecule ADCs that use LXR modulators to effectively treat, for example, metabolic diseases.

The linker covalently links the payload moiety (e.g., a small molecule therapeutic agent of an ADC) to its antibody. One significant challenge in linker design is to find moieties that can keep the payload stably attached to the antibody during patient storage, formulation, administration, and plasma circulation, but allow for efficient release when the antibody binds its target, allowing for facile coupling to the payload under synthetic conditions, and allowing for release of the intended payload without changing structure. There is a continuing need for linkers having these and other attributes.

Summary of the invention

The present invention provides novel traceless linkers, and protein conjugates thereof, as well as methods for treating a variety of diseases, disorders, and conditions, comprising administering a compound or payload via a traceless linker-payload, and protein conjugates thereof. The invention includes a linker that is attached to a hydroxyl group of a payload and that allows the payload to release its intact hydroxyl group under appropriate conditions.

The present invention provides methods for treating a subject, e.g., inflammatory and autoimmune diseases, or controlling the symptoms of any disease, disorder or condition associated with glucocorticoid receptor, glucocorticoid binding, and/or glucocorticoid receptor signaling; and/or dyslipidemia, metabolic disease, inflammation, or neurodegenerative disease.

In one embodiment, the present invention provides a compound having the structure shown in formula I:

or a pharmaceutically acceptable salt thereof, wherein R^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, alkylene, or heteroalkyleneWherein when R is^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R ³To form a heterocyclic group of 3, 4, 5, 6, 7, or 8 atoms; r²Is H, alkylene, heteroalkylene, or an amino acid side chain, wherein when R is²When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r³Is H, alkyl, alkylene, or heteroalkylene, wherein when R is³When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R^1aOr R²To form said 3, 4, 5, 6, 7, or 8 atom heterocyclyl; r⁴Is H or alkyl; r⁵Is O, NR⁶Or S; r⁶Is H, or alkyl; d is an acyl group, or a residue of a biologically active compound comprising a hydroxyl group, an amino group, or a thiol; and n is 0, 1, 2, 3, 4, 5, or 6.

or a pharmaceutically acceptable salt thereof, wherein R^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, alkylene, or heteroalkylene, wherein when R is^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r ²Is H, alkylene, heteroalkylene, or an amino acid side chain, wherein when R is²When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r³Is H, alkyl, alkylene, or heteroalkylene, wherein when R is³When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R^1aOr R²To form the said4. A heterocyclic group consisting of 5 or 6 atoms; r⁴Is H or alkyl; r⁵Is O, NR⁶Or S; r⁶Is H, or alkyl; d is an acyl group, or a residue of a biologically active compound comprising a hydroxyl group, an amino group, or a thiol; and n is 0, 1, 2, 3, 4, or 5.

In another embodiment, the invention provides a linker-payload compound having the structure shown in formula II:

or a pharmaceutically acceptable salt thereof, wherein L is a linker comprising a moiety that reacts with the antibody or antigen-binding fragment thereof; r^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, alkylene, or heteroalkylene, wherein when R is^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R ³To form a heterocyclic group of 3, 4, 5, 6, 7, or 8 atoms; r²Is H, alkylene, heteroalkylene, or an amino acid side chain, wherein when R is²When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r³Is H, alkyl, alkylene, or heteroalkylene, wherein when R is³When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R^1aOr R²To form said 3, 4, 5, 6, 7, or 8 atom heterocyclyl; r⁴Is H or alkyl; r⁵Is O, NR⁶Or S; r⁶Is H, or alkyl; d is an acyl group, or a residue of a biologically active compound comprising a hydroxyl group, an amino group, or a thiol; and n is 0, 1, 2, 3, 4, 5, or 6.

In another embodiment, the invention provides a linker-payload having the structure shown in formula II:

or a pharmaceutically acceptable salt thereof, wherein L is a linker comprising a moiety that reacts with the antibody or antigen-binding fragment thereof; r^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, alkylene, or heteroalkylene, wherein when R is ^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r²Is H, alkylene, heteroalkylene, or an amino acid side chain, wherein when R is²When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r³Is H, alkyl, alkylene, or heteroalkylene, wherein when R is³When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R^1aOr R²To form said heterocyclic group of 4, 5, or 6 atoms; r⁴Is H or alkyl; r⁵Is O, NR⁶Or S; r⁶Is H, or alkyl; d is an acyl group, or a residue of a biologically active compound comprising a hydroxyl group, an amino group, or a thiol; and n is 0, 1, 2, 3, 4, 5, or 6.

In another embodiment, the present invention provides a compound having the structure shown in formula III:

wherein L is a linker; BA is a binder; r^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, alkylene, or heteroalkylene, wherein when R is^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R ³To form a heterocyclic group of 3, 4, 5, 6, 7, or 8 atoms; r²Is H, alkylene, heteroalkylene, orAmino acid side chain, wherein when R²When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r³Is H, alkyl, alkylene, or heteroalkylene, wherein when R is³When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R^1aOr R²To form said 3, 4, 5, 6, 7, or 8 atom heterocyclyl; r⁴Is H or alkyl; r⁵Is O, NR⁶Or S; r⁶Is H, or alkyl; d is the residue of a biologically active compound comprising a hydroxyl group, an amino group, or a thiol; n is 0, 1, 2, 3, 4, 5, or 6; and k is an integer from 1 to 30.

wherein L is a linker; BA is a binder; r^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, alkylene, or heteroalkylene, wherein when R is^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R ³To form a heterocyclic group of 3, 4, 5, 6, 7, or 8 atoms; r²Is H, alkylene, heteroalkylene, or an amino acid side chain, wherein when R is²When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r³Is H, alkyl, alkylene, or heteroalkylene, wherein when R is³When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R^1aOr R²To form said 3, 4, 5, 6, 7, or 8 atom heterocyclyl; r⁴Is H or alkyl; r⁵Is O, NR⁶Or S; r⁶Is H, or alkyl; d is an antiinflammatory compound containing a hydroxyl group, an amino group, or a thiol groupA residue of a biologically active compound; n is 0, 1, 2, 3, 4, 5, or 6; and k is an integer from 1 to 30.

wherein L is a linker comprising PAB or PABC; BA is a binder; r^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, alkylene, or heteroalkylene, wherein when R is^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R ³To form a heterocyclic group of 3, 4, 5, 6, 7, or 8 atoms; r²Is H, alkylene, heteroalkylene, or an amino acid side chain, wherein when R is²When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r³Is H, alkyl, alkylene, or heteroalkylene, wherein when R is³When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R^1aOr R²To form said 3, 4, 5, 6, 7, or 8 atom heterocyclyl; r⁴Is H or alkyl; r⁵Is O, NR⁶Or S; r⁶Is H, or alkyl; d is the residue of a biologically active compound comprising a hydroxyl group, an amino group, or a thiol; n is 0, 1, 2, 3, 4, 5, or 6; and k is an integer from 1 to 30.

wherein L is a linker; BA is a binder; r^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroAryl, alkylene, or heteroalkylene, wherein when R is^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R ³To form a heterocyclic group of 3, 4, 5, 6, 7, or 8 atoms; r²Is H, alkylene, heteroalkylene, or an amino acid side chain, wherein when R is²When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r³Is H, alkyl, alkylene, or heteroalkylene, wherein when R is³When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R^1aOr R²To form said 3, 4, 5, 6, 7, or 8 atom heterocyclyl; r⁴Is H or alkyl; r⁵Is O, NR⁶Or S; r⁶Is H, or alkyl; d is the residue of a biologically active compound comprising a hydroxyl group, an amino group, or a thiol; n is 0, 1, 2, 3, 4, 5, or 6; wherein the coupling of L to BA is selected from the group consisting of: click chemistry residues, amide residues, and residues comprising two cysteine residues of a single BA chemically bonded to L; and k is an integer from 1 to 30.

wherein L is a linker; BA is a binder; r^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, alkylene, or heteroalkylene, wherein when R is ^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r²Is H, alkylene, heteroalkylene, or an amino acid side chain, wherein when R is²When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms；R³Is H, alkyl, alkylene, or heteroalkylene, wherein when R is³When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R^1aOr R²To form said heterocyclic group of 4, 5, or 6 atoms; r⁴Is H or alkyl; r⁵Is O, NR⁶Or S; r⁶Is H, or alkyl; d is the residue of a biologically active compound comprising a hydroxyl group, an amino group, or a thiol; n is 0, 1, 2, 3, 4, 5, or 6; and k is an integer from 1 to 30.

In another embodiment, the present invention provides a method for treating a disease, disorder or condition associated with glucocorticoid receptor signaling in a subject, the method comprising administering to the subject an effective amount of a compound, linker-payload, antibody-drug conjugate, pharmaceutical composition, and/or a combination thereof, as described herein.

In another embodiment, the present invention provides a method for treating dyslipidemia, a metabolic disease, inflammation, or a neurodegenerative disease in a subject, the method comprising administering to the subject an effective amount of a compound, a linker-payload, an antibody-drug conjugate, a pharmaceutical composition, and/or a combination thereof, as described herein.

In another embodiment, the present invention provides a method for treating dyslipidemia in a subject, the method comprising administering to the subject an effective amount of a compound, a linker-payload, an antibody-drug conjugate, a pharmaceutical composition, and/or a combination thereof, as described herein.

In another embodiment, the present invention provides a method for treating a metabolic disease in a subject, the method comprising administering to the subject an effective amount of a compound, a linker-payload, an antibody-drug conjugate, a pharmaceutical composition, and/or a combination thereof, as described herein.

In another embodiment, the present invention provides a method for treating inflammation in a subject, the method comprising administering to the subject an effective amount of a compound, a linker-payload, an antibody-drug conjugate, a pharmaceutical composition, and/or a combination thereof, as described herein.

In another embodiment, the present invention provides a method for treating a neurodegenerative disease in a subject, the method comprising administering to the subject an effective amount of a compound, a linker-payload, an antibody-drug conjugate, a pharmaceutical composition, and/or a combination thereof, as described herein.

Brief description of the drawings

Figures 1-9 show synthetic chemistry schemes for payloads, prodrugs, traceless linkers, traceless linker-payloads, and protein conjugates thereof.

Detailed Description

Definition of

When referring to the compounds provided by the present invention, the following terms have the following meanings, unless otherwise specified. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In the event that there are multiple definitions of terms provided herein, those definitions shall control unless otherwise indicated.

As used herein, "alkyl" refers to a monovalent and saturated hydrocarbyl moiety. Alkyl groups are optionally substituted and may be straight chain, branched or cyclic (i.e., cycloalkyl). Alkyl groups include, but are not limited to, those having 1-20 carbon atoms, i.e., C _1-20An alkyl group; 1 to 12 carbon atoms, i.e. C_1-12An alkyl group; 1 to 8 carbon atoms, i.e. C_1-8An alkyl group; 1 to 6 carbon atoms, i.e. C_1-6An alkyl group; and 1 to 3 carbon atoms, i.e. C_1-3Those of alkyl groups. Examples of alkyl group moieties include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl group moieties, hexyl group moieties, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Pentyl group moieties include, but are not limited to, n-pentyl and isopentyl. Hexyl moieties include, but are not limited to, n-hexyl.

As used herein, "alkylene" refers to a divalent alkyl group. Unless otherwise specified, alkylene groups include, but are not limited to, 1 to 20 carbon atoms. Alkylene radicalThe groups are optionally substituted as described herein for alkyl. In some embodiments, the alkylene group is unsubstituted. Examples of alkylene moieties include-CH₂-、-CH₂CH₂-、-CH₂CH₂CH₂-、-CH₂CH₂CH₂CH₂-and the like.

As used herein, "heteroalkylene" refers to a divalent alkyl group in which one or more carbon atoms are replaced with a heteroatom. Unless otherwise specified, heteroalkylene groups include, but are not limited to, a total of 1 to 20 atoms (i.e., carbon and heteroatoms). The heteroalkylene group is optionally substituted as described herein for alkyl. In some embodiments, the heteroalkylene group is unsubstituted. In some embodiments, the heteroatoms encompassed in the heteroalkylene moiety include O, N, S (i.e., including sulfoxides, sulfites, sulfates, and sulfones), Si and P (i.e., including phosphites and phosphates), and/or combinations thereof. Non-limiting exemplary embodiments of the heteroalkylene moiety include-CH ₂O-、-CH₂OCH₂-、-CH₂OCH₂CH₂-、-CH₂CH₂CH₂OCH₂-and the like; -CH₂NR-、-CH₂NRCH₂-、-CH₂NRCH₂CH₂-、-CH₂CH₂CH₂NRCH₂-and the like; and-CH₂S-、-CH₂SCH₂-、-CH₂SCH₂CH₂-、-CH₂CH₂CH₂SCH₂-and the like.

The name of an amino acid or amino acid residue is intended to encompass the L form of an amino acid, the D form of an amino acid, or a racemic mixture thereof, without specifying its stereochemistry.

"haloalkyl" as used herein refers to an alkyl group as defined above, wherein said alkyl group includes at least one substituent selected from halogen, such as fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). Examples of haloalkyl groups include, but are not limited to, -CF₃、–CH₂CF₃、–CCl₂F、–CHF₂and-CCl₃。

"alkenyl" as used herein refers to a monovalent hydrocarbyl radical moiety comprising at least two carbon atoms and one or more non-aromatic carbon-carbon double bonds. Alkenyl groups are optionally substituted and may be straight chain, branched or cyclic. Alkenyl groups include, but are not limited to, those having 2-20 carbon atoms, i.e., C_2-20An alkenyl group; 2 to 12 carbon atoms, i.e. C_2-12An alkenyl group; 2 to 8 carbon atoms, i.e. C_2-8An alkenyl group; 2 to 6 carbon atoms, i.e. C_2-6An alkenyl group; and 2 to 4 carbon atoms, i.e. C_2-4Those of alkenyl. Examples of alkenyl moieties include, but are not limited to, ethenyl, propenyl, butenyl, and cyclohexenyl.

As used herein, "alkynyl" refers to a monovalent hydrocarbyl radical moiety comprising at least two carbon atoms and one or more carbon-carbon triple bonds. Alkynyl groups are optionally substituted and may be straight chain, branched or cyclic. Alkynyl groups include, but are not limited to, those having 2-20 carbon atoms, i.e., C _2-20An alkynyl group; 2 to 12 carbon atoms, i.e. C_2-12An alkynyl group; 2 to 8 carbon atoms, i.e. C_2-8An alkynyl group; 2 to 6 carbon atoms, i.e. C_2-6An alkynyl group; and 2 to 4 carbon atoms, i.e. C_2-4Those of alkynyl. Examples of alkynyl moieties include, but are not limited to, ethynyl, propynyl, and butynyl.

As used herein, "alkoxy" refers to a monovalent and saturated hydrocarbyl moiety wherein the hydrocarbon comprises a single bond to an oxygen atom, and wherein the radical is located on an oxygen atom, such as ethoxy CH₃CH₂-O. Alkoxy substituents are attached to the compounds they are substituted for through the oxygen atom of the alkoxy substituent. Alkoxy groups are optionally substituted and may be straight chain, branched or cyclic, i.e. cycloalkoxy. Alkoxy groups include, but are not limited to, those having 1-20 carbon atoms, i.e., C_1-20An alkoxy group; 1 to 12 carbon atoms, i.e. C_1-12An alkoxy group; 1 to 8 carbon atoms, i.e. C_1-8An alkoxy group; 1 to 6 carbon atoms, i.e. C_1-6An alkoxy group; and 1 to 3 carbon atoms, i.e. C_1-3Those of alkoxy groups. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-propoxyButoxy, sec-butoxy, tert-butoxy, isobutoxy, pentyloxy radical moiety, hexyloxy radical moiety, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy.

"haloalkoxy" as used herein refers to an alkoxy group as defined above, wherein the alkoxy group includes at least one substituent selected from halogen, such as F, Cl, Br or I.

As used herein, "aryl" refers to a monovalent radical moiety that is a radical of an aromatic compound in which the ring atoms are all carbon atoms. Aryl is optionally substituted and may be monocyclic or polycyclic, for example bicyclic or tricyclic. Examples of aryl moieties include, but are not limited to, moieties having 6 to 20 ring carbon atoms, i.e., C_6-20An aryl group; 6 to 15 ring carbon atoms, i.e. C_6-15Aryl, and 6 to 10 ring carbon atoms, i.e. C_6-10Those of aryl groups. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl, phenanthrenyl, and pyrenyl.

As used herein, "arylalkyl" or "aralkyl" refers to a monovalent radical moiety of an alkyl compound radical, wherein the alkyl compound is substituted with an aromatic substituent, i.e., the aromatic compound includes a single bond to an alkyl group, and wherein the radical is located on the alkyl group. The aralkyl group is attached to the chemical structure shown through the alkyl group. An aralkyl group can be represented by the following structure, for example,

Wherein B is an aromatic moiety, such as aryl or phenyl. Aralkyl groups are optionally substituted, i.e. the aryl group and/or the alkyl group may be substituted as described herein. Examples of aralkyl groups include, but are not limited to, benzyl.

As used herein, "alkylaryl" refers to a monovalent radical moiety of an aryl compound radical wherein the aryl compound is substituted with an alkyl substituent, i.e., the aryl compound includes a single bond to an alkyl group wherein the radical is located on the aryl group. Alkylaryl radicalGroups are attached to the chemical structure shown through the aryl group. The alkylaryl group can be represented by the following structure, for example,

wherein B is an aromatic moiety, such as phenyl. Alkylaryl is optionally substituted, i.e. the aryl group and/or the alkyl group may be substituted as described herein. Examples of alkylaryl groups include, but are not limited to, toluyl.

As used herein, "aryloxy/aryloxy" refers to a monovalent radical moiety of an aromatic compound radical, wherein the ring atoms are all carbon atoms, and wherein the ring is substituted with an oxy group, i.e., the aromatic compound includes a single bond attached to an oxygen atom, and wherein the radical is located on an oxygen atom, such as phenoxy

The aryloxy substituents are attached to the compound they are substituted for through this oxygen atom. The aryloxy group is optionally substituted. Aryloxy groups include, but are not limited to, those having from 6 to 20 ring carbon atoms, i.e., C_6-20An aryloxy group; 6 to 15 ring carbon atoms, i.e. C_6-15Aryloxy group, and 6 to 10 ring carbon atoms, i.e. C_6-10Those of aryloxy. Examples of aryloxy moieties include, but are not limited to, phenoxy, naphthoxy, and anthracenoxy.

As used herein, "arylene" refers to a divalent radical moiety of an aromatic compound in which the ring atoms are carbon atoms only. The arylene group is optionally substituted, and may be monocyclic or polycyclic, e.g., bicyclic or tricyclic. Examples of arylene moiety include, but are not limited to, moieties having 6 to 20 ring carbon atoms, i.e., C_6-20An arylene group; 6 to 15 ring carbon atoms, i.e. C_6-15An arylene group; and 6 to 10 ring carbon atoms, i.e. C_6-10Those of arylene groups.

As used herein, "heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced with a heteroatom. "Heteroalkenyl" as used herein refers to alkenyl groups in which one or more carbon atoms are replaced by a heteroatom. "Heteroalkynyl" as used herein refers to alkynyl groups in which one or more carbon atoms are replaced by a heteroatom. Suitable heteroatoms include, but are not limited to, nitrogen, oxygen, and sulfur atoms. Heteroalkyl, heteroalkenyl, and heteroalkynyl are all optionally substituted. Examples of heteroalkyl moiety include, but are not limited to, aminoalkyl, sulfonylalkyl, sulfinylalkyl. Examples of heteroalkyl moiety also include, but are not limited to, methylamino, methanesulfonyl, and methylsulfinyl.

As used herein, "heteroaryl" refers to a monovalent radical moiety of an aromatic compound radical in which the ring atoms contain carbon atoms and at least one oxygen, sulfur, nitrogen, or phosphorus atom. Examples of heteroaryl group moieties include, but are not limited to, those having 5 to 20 ring atoms, 5 to 15 ring atoms, and 5 to 10 ring atoms. Heteroaryl is optionally substituted.

As used herein, "heteroarylene" refers to a divalent heteroaryl group in which one or more ring atoms of the aromatic ring are replaced with an oxygen, sulfur, nitrogen, or phosphorus atom. The heteroarylene group is optionally substituted.

As used herein, "heterocycloalkyl" or "heterocyclyl" refers to a cycloalkyl group in which one or more carbon atoms are replaced by a heteroatom. Suitable heteroatoms include, but are not limited to, nitrogen, oxygen, and sulfur atoms (i.e., including sulfoxides and sulfones). Heterocycloalkyl is optionally substituted. The heterocycloalkyl or heterocyclyl group is optionally substituted. Examples of heterocycloalkyl and heterocyclyl moieties include, but are not limited to, morpholinyl, piperidinyl, tetrahydropyranyl, pyrrolidinyl, aziridinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, dioxolanyl, dithiolane, tetrahydropyranyl (oxanyl), or tetrahydrothiopyranyl (thianyl).

As used herein, "Lewis acid" refers to a molecule or ion that accepts a lone pair of electrons. The lewis acids used in the process of the present invention are those other than protons. Lewis acids include, but are not limited to, non-metallic acids, hard lewis acids, and soft lewis acids. Lewis acids include, but are not limited toLewis acids of aluminum, boron, iron, tin, titanium, magnesium, copper, antimony, phosphorus, silver, ytterbium, scandium, nickel, and zinc. Exemplary lewis acids include, but are not limited to: AlBr₃，AlCl₃，BCl₃Boron trichloride methyl sulfide, BF₃Boron trifluoride methyl ether complex, boron trifluoride methyl sulfide, boron trifluoride tetrahydrofuran, dicyclohexylboron trifluoromethanesulfonate, iron (III) bromide, iron (III) chloride, tin (IV) chloride, titanium (IV) chloride, isopropyl titanium (IV) chloride, Cu (OTf)₂，CuCl₂，CuBr₂Zinc chloride, alkylaluminum halides (R)_nAlX_3-nWherein R is a hydrocarbon group, Zn (OTf)₂，ZnCl₂，Yb(OTf)₃，Sc(OTf)₃，MgBr₂，NiCl₂，Sn(OTf)₂，Ni(OTf)₂And Mg (OTf)₂。

As used herein, "N-containing heterocycloalkyl" refers to a cycloalkyl group in which one or more carbon atoms are replaced by a heteroatom, and in which at least one of the replacing heteroatoms is a nitrogen atom. Suitable heteroatoms include, but are not limited to, oxygen and sulfur atoms in addition to nitrogen atoms. The N-containing heterocycloalkyl group is optionally substituted. Examples of N-containing heterocycloalkyl group moieties include, but are not limited to, morpholinyl, piperidinyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, or thiazolidinyl.

As used herein, "optionally substituted" or "optionally substituted," when used to describe a moiety, such as optionally substituted alkyl, means that the moiety is optionally attached to one or more substituents. Examples of such substituents include, but are not limited to, halogen, cyano, nitro, amino, hydroxy, optionally substituted haloalkyl, aminoalkyl, hydroxyalkyl, azido, epoxy, optionally substituted heteroaryl, optionally substituted heterocycloalkyl,

wherein R is^A、R^BAnd R^CEach occurrence is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heteroaryl, or heterocycloalkyl, or R^AAnd R^BTogether with the atoms to which they are attached, form a saturated or unsaturated carbocyclic ring, wherein the ring is optionally substituted, and wherein one or more ring atoms are optionally replaced by heteroatoms. In certain embodiments, when a moiety is optionally substituted with an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl, or an optionally substituted saturated or unsaturated carbocyclic ring, the substituent on the optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or optionally substituted saturated or unsaturated carbocyclic ring, if they are substituted, is not substituted with a substituent further optionally substituted with another substituent. In some embodiments, when a group described herein is optionally substituted, the substituent attached to the group is unsubstituted, unless otherwise specified.

As used herein, a "binding agent" refers to any molecule, such as a protein, antibody, or fragment thereof, that is capable of specifically binding to a given binding partner (e.g., an antigen).

As used herein, "linker" refers to a divalent, trivalent, or multivalent moiety that covalently links or enables covalent linking (e.g., via a reactive group) of the binding agent to one or more compounds described herein (e.g., payload compounds and enhancers described herein).

As used herein, "amide synthesis conditions" refer to reaction conditions suitable to promote the formation of an amide, for example, by reacting a carboxylic acid, activated carboxylic acid, or acid halide with an amine. In some embodiments, "amide synthesis conditions" refer to reaction conditions suitable to promote formation of an amide bond between a carboxylic acid and an amine. In some of these embodiments, the carboxylic acid is first converted to an activated carboxylic acid, which is then reacted with an amine to form an amide. Suitable conditions for effecting amide formation include, but are not limited to, those utilizing reagents to effect the reaction between the carboxylic acid and the amine, including, but not limited to, Dicyclohexylcarbodiimide (DCC), Diisopropylcarbodiimide (DIC), (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy) trispyrrolidinylphosphonium hexafluorophosphate (PyBOP), (7-azobenzotriazol-1-yloxy) trispyrrolidinylphosphonium hexafluorophosphate (PyAOP), trispyrrolidinylphosphonium bromide hexafluorophosphate (PyBrOP), O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU), O- (benzotriazol-1-yl) -N, n, N ', N' -tetramethyluronium hexafluoroborate (TBTU), 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium 3-oxide Hexafluorophosphate (HATU), 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline (EEDQ), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), 2-chloro-1, 3-dimethylimidazolium hexafluorophosphate (CIP), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT), and Carbonyldiimidazole (CDI). In some embodiments, the carboxylic acid is first converted to an activated carboxylic acid ester, which is then treated with an amine to form an amide bond. In some embodiments, the carboxylic acid is treated with a reagent. The reagent activates the carboxylic acid by deprotonating the carboxylic acid, which then forms a product complex with the deprotonated carboxylic acid as a result of nucleophilic attack of the deprotonated carboxylic acid on the protonating reagent. For certain carboxylic acids, the activated carboxylic acid ester is more susceptible to nucleophilic attack by the amine than the carboxylic acid is to be converted to the activated ester. This causes amide bonds to form. Thus, the carboxylic acid is described as activated. Exemplary reagents include DCC and DIC.

"regioisomer" or "mixture of regioisomers" as used herein refers to a compound resulting from treatment of a suitable azide (e.g., -N) with a suitable alkyne compound₃Or PEG-N₃Derivatized antibody) or strain-promoted alkyne-azide cycloaddition products (SPAACs) (also known as click reactions). In certain embodiments, for example, regioisomers and mixtures of regioisomers are characterized by the click reaction product shown below:

in certain embodiments, more than one suitable azide and more than one suitable alkyne can be used in a product-generating synthesis scheme, where each pair of azide-alkynes can participate in one or more independent click reactions to generate a mixture of regioisomeric click reaction products. For example, the skilled artisan will recognize that a first suitable azide can be independently reacted with a first suitable alkyne and a second suitable azide can be independently reacted with a second suitable alkyne en route to the product, thereby generating four possible click-reaction regioisomers or a mixture of the four possible click-reaction regioisomers.

The term "residue" as used herein refers to the portion of a chemical group that remains after a chemical reaction in a compound. For example, the term "amino acid residue" or "N-alkyl amino acid residue" refers to the product of amide coupling or peptide coupling of an amino acid or N-alkyl amino acid with a suitable coupling partner; wherein, for example, water molecules are expelled after amide coupling or peptide coupling of amino acids or N-alkyl amino acids, thereby obtaining a product into which amino acid residues or N-alkyl amino acid residues are incorporated.

As used herein, a "therapeutically effective amount" refers to an amount of a compound (e.g., of a compound) sufficient to provide a therapeutic benefit when a patient is treating or controlling a disease or disorder, or delaying or minimizing one or more symptoms associated with a disease or disorder.

As used herein, "structural isomers" refers to compounds having the same molecular formula but differing in chemical structure due to the arrangement of the atoms. Exemplary configurational isomers include n-propyl and isopropyl; n-butyl, sec-butyl, and tert-butyl; and n-pentyl, isopentyl, and neopentyl, and the like.

Certain groups, molecules/group moieties, substituents, and atoms are described as having wavy lines intersecting bonds to indicate the atoms through which the groups, molecules/group moieties, substituents, atoms are attached. For example, a phenyl group substituted with a propyl group can be represented by:

has the following structure:

as used herein, the exemplary illustration of a substituent attached to a cyclic group (e.g., aromatic ring, heteroaromatic ring, fused ring, and saturated or unsaturated cycloalkyl or heterocycloalkyl) by a bond between ring atoms is intended to indicate that the cyclic group can be substituted with a substituent at any ring position of the cyclic group or on any ring of the fused ring group in accordance with the techniques set forth herein or disclosed immediately herein in relation to techniques known in the art, unless otherwise indicated. Such as, the group

Wherein the subscript q is an integer of from 0 to 4, and wherein the substituent R¹Positions of (a) are generally described, i.e. not directly connected to any vertex of the bonded wire structure, i.e. a particular ring carbon atom, including the following, wherein the substituent R¹Non-limiting examples of groups attached to a particular ring carbon atom:

the phrase "reactive linker" or the abbreviation "RL" as used herein refers to a monovalent group comprising a reactive group ("RG") and a spacer group ("SP"), e.g.

Wherein RG is the reactive group and SP is the spacer group. As described herein, a reactive linker may comprise more than one reactive group and more than one spacer group. The spacer groupA group is any divalent moiety that bridges a reactive group to another group, such as a payload (e.g., a biologically active compound). The active linker (RL), together with the payload attached thereto, constitutes an intermediate ("linker-payload" or LP) that can be used as a synthetic precursor for the preparation of the antibody conjugates described herein. The active connecting body contains a reactive group, which is a group or a group part capable of reacting with another group (such as antibodies, modified antibodies, or antigen binding fragments thereof, or enhancing groups) of the reactive part. The moiety resulting from the reaction of the reactive group with the antibody, modified antibody or antigen-binding fragment thereof, together with the linking group, constitutes the "binder linker" ("BL") moiety of the conjugate of the invention. In certain embodiments, the "active group" is a functional group or moiety (e.g., maleimide or N-hydroxysuccinimide (NHS) ester) that reacts with a cysteine or lysine residue of the antibody or antigen-binding fragment thereof. In certain embodiments, the "reactive group" is a functional group or moiety capable of undergoing click chemistry reactions (see, e.g., click chemistry, Huisgen proc.chem.soc.1961, Wang et al.j.am.chem.soc.2003, and Agard et al.j.am.chem.soc.2004). In some embodiments of the click chemistry reaction, the reactive group is an alkyne capable of 1, 3-cycloaddition with an azide. Such suitable reactive groups include, but are not limited to, strained alkynes, such as those suitable for strain-promoted alkyne-azide cycloaddition (SPAAC), cycloalkynes, such as cyclooctynes, benzocycloated alkynes, and alkynes capable of 1, 3-cycloaddition reactions with alkynes in the absence of a copper catalyst. Suitable alkynes also include, but are not limited to

(TMTH)；

(COMBO)；

(PYRROC); cyclooctyne

(OCT)；

(SNO-OCT type); azacyclooctynes

(DIMAC); dibenzoazacyclooctyne or

(DIBAC), dibenzocyclooctyne or

(DIBO), a diarylazacyclooctynone or

(BARAC), Cyclooctyne monofluoride

(MOFO); cyclooctyne difluoride or

(DIFO), substituted, e.g. fluorinated alkynes, nitrogen heterocyclic alkynes, bicyclo [6.1.0]Nonene or

(BCN, where R is alkyl, alkoxy, or acyl), and derivatives thereof. Particularly useful alkynes include

Linker-payloads comprising such reactive groups can be used to couple antibodies that have been functionalized with azido groups. Such functionalized antibodies include antibodies functionalized with azido-polyethylene glycol groups. In certain embodiments, such functionalized antibodies are prepared by contacting a cell with a peptide in the presence of the enzyme transglutaminaseThe amino group and azido group are derivatized by treating an antibody having at least one glutamine residue (e.g., heavy chain Gln 295).

In some embodiments, the reactive group is an alkyne, e.g.

Which can be coupled to azides by click chemistry (e.g.

) To form click chemistry products, e.g.

In some embodiments, the group reacts with an azide on the modified antibody or antigen-binding fragment thereof. In some embodiments, the reactive group is an alkyne, e.g.

Which can be coupled to azides by click chemistry (e.g.

) To form click chemistry products, e.g.

In some embodiments, the reactive group is an alkyne, e.g.

Which can be coupled to azides by click chemistry (e.g.

) To form click chemistry products, e.g.

In some embodiments, the reactive group is a functional group, e.g.

Which react with cysteine residues on the antibody or antigen-binding fragment thereof to form a C-S bond therewith, e.g.

Where Ab refers to an antibody or antigen-binding fragment thereof and S refers to the S atom of a cysteine residue through which the functional group binds to Ab. In some embodiments, the reactive group is a functional group, e.g.

Which react with lysine residues on the antibody or antigen-binding fragment thereof to form amide bonds therewith, e.g.

Wherein Ab refers to an antibody or antigen-binding fragment thereof and NH refers to the NH atom of a lysine side chain residue through which the functional group is bound to Ab.

The phrase "biodegradable moiety" as used herein refers to a moiety that degrades in vivo into a non-toxic, biocompatible component that can be removed from the body by common biological processes. In some embodiments, the biodegradable moiety is completely or substantially degraded in vivo in about 90 days or less, about 60 days or less, or about 30 days or less, wherein the degree of degradation is based on the percent mass loss of the biodegradable moiety, wherein complete degradation corresponds to 100% mass loss. Exemplary biodegradable moieties include, but are not limited to, aliphatic polyesters such as poly (epsilon-caprolactone) (PCL), poly (3-hydroxybutyrate) (PHB), poly (glycolic acid) (PGA), poly (lactic acid) (PLA) and copolymers thereof with glycolic acid (i.e., poly (D, L-lactide-co-glycolide) (PLGA) (Vert M, Schwach G, Engel R and coudae J (1998) J Control Release 53(1-3):85-92, Jain R A (2000) Biomaterials 21(23): 2475-: 3181-: 1123-.

The phrase "binding agent linker," or "BL," as used herein, refers to any divalent, trivalent, or multivalent group or moiety that links, binds, or bonds a binding agent (e.g., an antibody or antigen-binding fragment thereof) to a payload compound (e.g., tubulysin) described herein, and optionally to one or more side chain compounds. In general, suitable binder linkers of the antibody conjugates described herein are those that are sufficiently stable to take advantage of the circulating half-life of the antibody conjugate, and at the same time are capable of releasing their payload following antigen-mediated internalization of the conjugate. The linker may be cleavable or non-cleavable. Cleavable linkers are linkers that are cleaved by intracellular metabolism after internalization, e.g., by hydrolysis, reduction, or enzymatic reaction. A non-cleavable linker is one that releases the attached payload by lysosomal degradation of the antibody upon internalization. Suitable linkers include, but are not limited to, acid-labile linkers, hydrolytically labile linkers, enzymatically cleavable linkers, reductively labile linkers, self-degradable (self-immolative) linkers, and non-cleavable linkers. Suitable linkers also include, but are not limited to, those that are or comprise peptides, glucosides, succinimide-thioethers, polyethylene glycol (PEG) units, hydrazones, maleimide (mal) -hexanoyl units, dipeptide units, valine-citrulline units, and p-aminobenzyloxycarbonyl (PABC) units, p-aminobenzyl (PAB) units. In some embodiments, the binding agent linker (BL) comprises a moiety formed from the reaction of an active group (RG) of an active linker (RL) with an active portion of a binding agent (e.g., an antibody, a modified antibody, or an antigen-binding fragment thereof).

In some embodiments, the BL comprises the following moiety:

wherein

Is a bond to the binding agent. In some embodiments, the BL comprises the following moiety:

wherein

wherein

wherein

Is a bond to the cysteine of the antibody or antigen-binding fragment thereof. In some embodiments, the BL comprises the following moiety:

wherein

Is a bond to the lysine of the antibody or antigen-binding fragment thereof.

As used herein, an "amino acid side chain" refers to a moiety of an additional chemical group on the same carbon that carries a primary or secondary amine and a carboxylic acid of an amino acid. As understood by those skilled in the art, there are 21 "standard" amino acids. Exemplary "standard" amino acids include, but are not limited to, alanine, serine, proline, arginine, and aspartic acid. Other amino acids include cysteine, selenocysteine, and glycine (e.g., whichWhere the additional chemical moiety on the same carbon bearing the primary amine and glycine carboxylic acid is hydrogen). Exemplary amino acid side chains include, but are not limited to, methyl (i.e., alanine), sec-butyl (i.e., isoleucine), isobutyl (i.e., leucine), -CH ₂CH₂SCH₃(i.e., methionine), -CH₂Ph (i.e. phenylalanine),

(i.e., tryptophan),

(i.e., tyrosine), isopropyl (i.e., valine), hydroxymethyl (i.e., serine), -CH (OH) CH₃(i.e., threonine), -CH₂C(O)NH₂(i.e., asparagine), -CH₂CH₂C(O)NH₂(i.e., glutamine), -CH₂SH (i.e. cysteine), -CH₂SeH (i.e., selenocysteine), -CH₂NH₂(i.e. glycine), propylene or-CH₂CH₂CH₂- (i.e. proline), -CH₂CH₂CH₂NHC(＝NH)NH₂(i.e., arginine),

(i.e., histidine), -CH₂CH₂CH₂CH₂NH₂(i.e., lysine), -CH₂COOH (i.e., aspartic acid), and-CH₂CH₂COOH (i.e., glutamic acid).

As used herein, "biologically active compound" refers to a compound, prodrug, or payload that elicits a biological response when a biological entity is administered. Exemplary biological responses include, but are not limited to, an increase or decrease in DNA or protein synthesis, an up-or down-regulation of signaling pathways, and an increase or decrease in cell proliferation, among others.

Compounds, prodrugs, or payloads

The invention provides a compound or payload. Without being bound by any particular theory of operation, the compounds include anti-inflammatory bioactive compounds, steroidsDerivatives, and/or LXR modulators, and derivatives thereof, such as prodrugs thereof. The terms or phrases "compound," "biologically active compound," "prodrug," and "payload" are used interchangeably throughout this invention. In certain embodiments, the biologically active compound (D) or residue thereof comprises a hydroxyl functional group (e.g., D-OH or D-O-R). In certain embodiments of the invention, for example and for convenience, R ⁵Represents hydroxyl, amino, and thiol functional groups within the biologically active compounds of the present invention, as understood by the skilled artisan, or a portion thereof, such as-O-, -N (R) -, or-S-. Alternatively, the skilled artisan will recognize that R⁵May be part of the biologically active compound (e.g., D) of the invention and may be used as a functional group for conjugation purposes. In one embodiment, the hydroxyl functional group is a primary hydroxyl moiety (e.g., D x-CH)₂OH or D-CH₂O-R; or D-C (O) CH₂OH or D-C (O) CH₂O-R). In another embodiment, the hydroxyl functional group is a secondary hydroxyl moiety (e.g., D-CH (OH) R or D-CH (O-R) R; or D-C (O) CH (R) (OH) or D-C (O) CH (R) (O-R)). In another embodiment, the hydroxyl functional group is a tertiary hydroxyl moiety (e.g., D x-C (R)₁)(R₂) (OH) or D-C (R)₁)(R₂) (O-R); or D-C (O) C (R)₁)(R₂) (OH) or D-C (O) C (R)₁)(R₂) (O-R)). The skilled person will appreciate that each functional group in the preceding sentence may be part of a biologically active compound D and is described in the general formula for the sake of clarity, convenience and/or emphasis. In another embodiment, D, which includes a hydroxyl functional group, is an aryl hydroxyl group or a phenolic hydroxyl group (e.g., D-Ar-OH, D-Ar-O-R). In one embodiment, the biologically active compound (D) comprising a hydroxyl functional group (D x-OH) is dexamethasone and the residue comprising a hydroxyl functional group is

Wherein

Refers to a linkage to a prodrug moiety (as shown in formula Ia and/or Ib), a linker and/or a binding agent, as described herein. In one embodiment, the biologically active compound comprising a hydroxyl functional group (D) is dexamethasone and the residue comprising a hydroxyl functional group is

Wherein

Refers to a linkage to a prodrug moiety (as shown in formula Ia and/or Ib), a linker and/or a binding agent, as described herein. In one embodiment, the biologically active compound (D) comprising a hydroxyl functional group (D x-OH) is budesonide, and the residue comprising a hydroxyl functional group is

Wherein

Refers to a linkage to a prodrug moiety (as shown in formula Ia and/or Ib), a linker and/or a binding agent, as described herein. In one embodiment, the biologically active compound (D) comprising a hydroxyl functional group is budesonide, and the residue comprising a hydroxyl functional group is

Wherein

Refers to a linkage to a prodrug moiety (as shown in formula Ia and/or Ib), a linker and/or a binding agent, as described herein. In one embodiment, the biologically active compound (D) comprising a hydroxyl function (D-OH) is 6, 11-2F-budesonide, and the residue comprising a hydroxyl function is

Wherein

Refers to a linkage to a prodrug moiety (as shown in formula Ia and/or Ib), a linker and/or a binding agent, as described herein. In one embodiment, the biologically active compound (D) comprising a hydroxyl functional group is 6, 11-2F-budesonide, and the residue comprising a hydroxyl functional group is

Wherein

Refers to a linkage to a prodrug moiety (as shown in formula Ia and/or Ib), a linker and/or a binding agent, as described herein. In one embodiment, the biologically active compound (D) comprising a hydroxyl functional group (D x-OH) is an LXR agonist and the residue comprising a hydroxyl functional group is

Wherein

Refers to a linkage to a prodrug moiety (as shown in formula Ia and/or Ib), a linker and/or a binding agent, as described herein. In one embodiment, the biologically active compound comprising a hydroxyl function (D) is an LXR agonist and the residue comprising a hydroxyl function is

Wherein

Refers to a linkage to a prodrug moiety (as shown in formula Ia and/or Ib), a linker and/or a binding agent, as described herein. In certain embodiments, the biologically active compound (D) or residue thereof comprises an amino functional group (e.g., D-NR)₂Or D x N (R) -R). In one embodiment, the amino functional group is a primary amine moiety (e.g., D-CH) ₂NR₂Or D-CH₂N (R) -R; or D-C (O) CH₂NR₂Or D-C (O) CH₂N (R) -R). In another embodiment, the amino functional group is part of a secondary amine group (e.g., D x-CH (NR)₂) R or D-CH (NR-R) R; or D-C (O) CH (R) (NR)₂) Or D — (o) ch (R) (NR-R)). In another embodiment, the amino functional group is a tertiary amine moiety (e.g., D x-C (R)₁)(R₂)(NR₂) Or D-C (R)₁)(R₂) (N (R) -R); or D-C (O) C (R)₁)(R₂)(NR₂) Or D-C (O) C (R)₁)(R₂) (N (R) -R)). In another embodiment, D comprising an amino functional group is an arylamine (e.g., D-Ar-NR)₂D-Ar-N (R) -R). In certain embodiments, the biologically active compound (D) or residue thereof comprises a thiol functional group (e.g., D-SH or D-S-R). In one embodiment, the thiol functional group is a primary thiol moiety (e.g., D x-CH)₂SH or D-CH₂S-R; or D-C (O) CH₂SH or D-C (O) CH₂S-R). In another embodiment, the thiol functional group is a secondary thiol moiety (e.g., D-CH (SH) R or D-CH (S-R) R; or D-C (O) CH (R) (SH) or D-C (O) CH (R) (S-R)). In another embodiment, the thiol functional group is a tertiary thiol moiety (e.g., D x-C (R)₁)(R₂) (SH) or D-C (R)₁)(R₂) (S-R); or D-C (O) C (R)₁)(R₂) (SH) or D-C (O) C (R) ₁)(R₂) (S-R)). In another embodiment, D, which includes a thiol functional group, is an aryl thiol or thiophenol (e.g., D-Ar-SH, D-Ar-S-R). In certain embodiments, D is a tetracyclic or pentacyclic steroid backbone structure, as understood by those skilled in the art. In certain embodiments, the compound may be delivered to the cell as part of a conjugate. In certain embodiments, the compounds are capable of any activity of a steroid, steroid derivative, LXR modulator, or derivative thereof at or in a target (e.g., a target cell). Certain compounds may have one or more additional activities.

In certain embodiments, the present invention provides compounds having the structure shown in formula Ia:

or a pharmaceutically acceptable salt thereof, wherein R^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, or alkylene, wherein when R is^1aWhen alkylene, the alkylene is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; r²Is H, or an amino acid side chain; r³Is H, alkyl, or alkylene, wherein when R is³When alkylene, the alkylene is further bonded to R ^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group, or a residue of a biologically active compound comprising a hydroxyl group; and n is 0, 1, 2, 3, 4, or 5.

In certain embodiments, the present invention provides compounds having the structure of formula Iaa:

or a pharmaceutically acceptable salt thereof, wherein R^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, alkylene, or heteroalkylene, wherein when R is^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r²Is H, alkylene, heteroalkylene, or an amino acid side chain, wherein when R is²When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r³Is H, alkyl, alkylene, or heteroalkylene, wherein when R is³When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R^1aOr R²To form said heterocyclic group of 4, 5, or 6 atoms; r⁶Is H, or alkyl; d is an acyl group, or a biologically active compound containing an amino groupA residue of a sex compound; and n is 0, 1, 2, 3, 4, or 5.

In certain embodiments, the present invention provides compounds having the structure of formula Iaaa:

or a pharmaceutically acceptable salt thereof, wherein R^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, alkylene, or heteroalkylene, wherein when R is^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r²Is H, alkylene, heteroalkylene, or an amino acid side chain, wherein when R is²When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r³Is H, alkyl, alkylene, or heteroalkylene, wherein when R is³When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R^1aOr R²To form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group, or a residue of a thiol-containing biologically active compound; and n is 0, 1, 2, 3, 4, or 5.

In certain embodiments, the present invention provides compounds having the structure shown in formula Ib:

or a pharmaceutically acceptable salt thereof, wherein R ^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, or alkylene, wherein when R is^1aWhen alkylene, the alkylene is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; r²Is H, or an amino acid side chain; r³Is HAlkyl, or alkylene, wherein when R is³When alkylene, the alkylene is further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group, or a residue of a biologically active compound comprising a hydroxyl group; and n is 0, 1, 2, 3, 4, or 5.

In certain embodiments, the present invention provides compounds having the structure shown by formula Ibb:

or a pharmaceutically acceptable salt thereof, wherein R^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, alkylene, or heteroalkylene, wherein when R is^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r²Is H, alkylene, heteroalkylene, or an amino acid side chain, wherein when R is²When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R ³To form a heterocyclic group of 4, 5, or 6 atoms; r³Is H, alkyl, alkylene, or heteroalkylene, wherein when R is³When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R^1aOr R²To form said heterocyclic group of 4, 5, or 6 atoms; r⁶Is H, or alkyl; d is an acyl group, or a residue of a biologically active compound comprising an amino group; and n is 0, 1, 2, 3, 4, or 5.

In certain embodiments, the present invention provides compounds having the structure shown by formula Ibbb:

or a pharmaceutically acceptable salt thereof, wherein R^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl,Aryl, aralkyl, heteroaryl, alkylene, or heteroalkylene, wherein when R is^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r²Is H, alkylene, heteroalkylene, or an amino acid side chain, wherein when R is²When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r³Is H, alkyl, alkylene, or heteroalkylene, wherein when R is ³When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R^1aOr R²To form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group, or a residue of a thiol-containing biologically active compound; and n is 0, 1, 2, 3, 4, or 5.

The following embodiments of formula I and/or formula Ib are contemplated, wherein in any one or more of the preceding embodiments, the biologically active compound comprises a hydroxyl group; or in residue D of the biologically active compound, in certain embodiments, through the residue of a hydroxyl group (i.e., the bond to O). In one embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r ³Is H; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is H; d is H; and n is 0. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodimentTable, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r ²Is an amino acid side chain; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To

form

4,5. Or a heterocyclic group consisting of 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 0. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To

form

4, 5, or 6 atomsA heterocyclic group of (a); and R^1bIs an aryl group; r ²Is H; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 0. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r ³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs alkyleneWherein said alkylene is further connected to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group;d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 0. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r ²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded toR³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 0. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r ³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said 4, 5, or 6A heterocyclic group of atoms; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 0. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R ^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H;and n is 0. In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r ³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is H; d is an acyl group; and n is 0. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs H; r ²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 0. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 0. In any of the embodiments in this paragraph, R ⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; in another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R ^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodimentTable, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 0. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded toR³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 0. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 0. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic ring of 4, 5, or 6 atomsA group; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r ³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 0. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyneA group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R ^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 0. In another embodiment, R ^1aIs H, and R^1bIs H; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkyneA group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs H; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 0. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R ^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is aminoAn acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 0. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R ^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs HAnd R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r ²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is biological activityA residue of a sex compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R ^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To

form

4,5. Or a heterocyclic group consisting of 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form4. A heterocyclic group consisting of 5 or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r ³Is an alkyl group; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 0. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 0. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an aralkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is alkylene, said alkylene being further linked To R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 0. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r ²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 0. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R ^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 0. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs H;R²is H; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 1. In another embodiment, R ^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 1. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R ^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is H; and n is 1. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R ^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 1. In another implementationScheme, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 1. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said 4, 5, or 6 atomic compositionA heterocyclic group of (a); d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 1. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R ^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is aAn alkyl group, said alkylene group being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 1. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 1. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r ²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 1. In another embodiment, R ^1aIs H, and R^1bIs H; r²Is H; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is an acyl group; and n is 1. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is H; d is an acyl group; and n is 1. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is H; d is an acyl group; and n is 1. At another placeEmbodiments, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r ³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 1. In any of the embodiments in this paragraph, R⁴Is H. In any of this paragraphIn embodiments, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r ³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To

form

4, 5,Or a heterocyclic group consisting of 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R ^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is an acyl group(ii) a And n is 1. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group(ii) a D is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r ³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 1. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms;and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 1. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R ^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 1. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 1. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To

form

4,5. Or a heterocyclic group consisting of 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 1. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 1. In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 1. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R ^1aIs H, and R^1bIs aralkyl；R²Is H; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic ring of 4, 5, or 6 atomsA group; and R^1bIs an aralkyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 1. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R ^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein the alkylene groupRadicals being further bound to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs H; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 1. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R ^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is furtherIs linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R ⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodimentTable, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R ^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms;and R^1bIs H; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 1. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an aryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 1. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs H; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acidA side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r ³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R ^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 1. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is alkylene, saidAlkylene is further attached to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 1. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r ²Is H; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group;R²is H; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is H; and n is 2. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R ⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 2. In another implementationScheme, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r ²Is an amino acid side chain; r³Is H; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is H; and n is 2. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs H; r²Is H; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 2. In any of the embodiments in this paragraph, R ⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bondedTo R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs H; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form said heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 2. In any of the embodiments in this paragraph, R ⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs a heteroaryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 2. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 2. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 2. In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R ^1bIs an aryl group; r²Is H; r³Is H; dIs an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is H; d is an acyl group; and n is 2. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is H; d is an acyl group;and n is 2. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r ³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a composition of 4, 5, or 6 atomsA heterocyclic group; and R^1bIs an alkyl group; r ²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r ²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 2. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs a compound of formula (I) wherein the compound is H,and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R ^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs alkylene, whereinSaid alkylene group being further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r ³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r ³Is an alkyl group; d is an acyl group; and n is 2. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is acylA group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 2. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r ³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 2.In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 2. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r ³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 2. In any of the embodiments in this paragraph, R ⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 2. In another embodiment, R^1aIs H, and R^1bIs H; r ²Is H; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs H; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 2. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R ^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 2. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is an alkyl group; d is biological activityA residue of a sex compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R ^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To

form

4, 5,Or a heterocyclic group consisting of 6 atoms; and R^1bIs an alkoxy group; r ²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkaneA group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r ³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R ^1aIs alkyleneWherein said alkylene is further connected to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkylene radical, said alkylene radicalRadicals being further bound to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 2. In any of the embodiments in this paragraph, R ⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 2. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H;R³is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded toR^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 2. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 2. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 2. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodimentTable, R^1aIs H, and R^1bIs H; r²Is H; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is H; and n is 3. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is H; d is H; and n is 3. In another embodimentEmbodiment (I) R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an aryl group; r²Is H; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 3. In another embodiment, R ^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 3. In any of the embodiments in this paragraph, R ⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R ^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To

form

4, 5, or 6 atom compositions A heterocyclic group of (a); and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is H; and n is 3. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs alkenyl；R²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 3. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an alkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 3. In another embodiment, R^1aIs alkylene, whereinSaid alkylene group being further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 3. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R ^1aTo form said 4, 5, or 6A heterocyclic group consisting of one atom; d is H; and n is 3. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 3. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H;and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r ²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 3. In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is an acyl group; and n is 3. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment，R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r ²Is H; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r ³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 3. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is aminoAn acid side chain; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R ^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H；R³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 3. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To

form

4, 5, or 6 atomsA sub-group of heterocyclic groups; and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r ³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R ^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To

form

4, 5, or 6 atom compositionsA heterocyclic group of (a); and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 3. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms(ii) a And R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 3. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R ^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To

form

4, 5,Or a heterocyclic group consisting of 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 3. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R ⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkaneAn oxy group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 3. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said 4, 5, or 6 atomic compositionA heterocyclic group; d is an acyl group; and n is 3. In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 3. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r ³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 3. At another placeEmbodiments, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R ^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 3. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs H, and R ^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodimentTable, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 3. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R ^1aIs H, and R^1bIs H; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is biological activityA residue of a sex compound; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group or a mixture of alkylene groups,wherein the alkylene is further connected to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R ^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is the amino acid sideA chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; dIs the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r ³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said 4, 5, or A heterocyclic group consisting of 6 atoms; d is the residue of a biologically active compound; and n is 3. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R ^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain;R³is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 3. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 3. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 3. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is H; d is H; and n is 4. In another embodiment, R ^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is H; d is H; and n is 4. In another implementationScheme, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r ³Is H; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 4. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is H; in another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is H; d isH; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r ²Is an amino acid side chain; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is H; and n is 4. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R ^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is H; andn is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r ²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 4. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To

form

4,5. Or a heterocyclic group consisting of 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an alkenyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 4. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R ^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo formA heterocyclic group consisting of said 4, 5, or 6 atoms; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R ^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form 4, 5Or a heterocyclic group consisting of 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 4. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r ³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r ²Is H; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is an acyl group; and n is 4. In another embodiment, R ^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 4. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain;R³is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs H; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyneA group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 4. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r ²Is H; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 4. In thatIn another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To

form

4,5. Or a heterocyclic group consisting of 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r ³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 4. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 4. In another embodiment，R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 4. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an aryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 4. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 4. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r ²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is H; d is a residue of a biologically active compoundA group; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r ²Is H; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is H;d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an alkynyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 4. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r ³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 4. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein the alkylene groupRadicals being further bound to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r ²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d isA residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To

form

4,5. Or a heterocyclic group consisting of 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R ^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs H, andR^1bis a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In thatIn another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r ³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an alkoxy group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said 4, 5,Or a heterocyclic group consisting of 6 atoms; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 4. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an aryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is alkylene, said alkylene being further Step (a) is connected to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 4. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said 4,5. Or a heterocyclic group consisting of 6 atoms; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 4. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 4. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r ³Is H; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is H; d is H; and n is 5. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs H, and R ^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is ammoniaAn amino acid side chain; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 5. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is H; and n is 5. In another embodiment, R ^1aIs H, and R^1bIs H; r²Is H; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d isH; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkaneA group; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is H; and n is 5. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R ^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To

form

4, 5, or 6 atomsA heterocyclic group of (a); and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is H; and n is 5. In another embodiment, R^1aIs alkylene, wherein the alkyleneAlkyl is further attached to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 5. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R ⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r ²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs aryl radical；R²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 5. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 5. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R ^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is H; and n is 5. In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is H; d is an acyl group; and n is 5. In another embodiment, R ^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is H; d is an acyl group; and n is 5. In this paragraphIn any embodiment of (1), R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an alkynyl group; r²Is H; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r ³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is acylA group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r ²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 5. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is an acyl group(ii) a And n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs H; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 5. In any of the embodiments in this paragraph, R ⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs HAnd R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R ^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is an acyl group; and n is 5. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r ³Is an alkyl group; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an alkenyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 5. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is alkyleneThe alkylene group is further connected to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 5. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radicalRadicals being further bound to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R ^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group; and n is 5. In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R ^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is H; d is a residue of a biologically active compound(ii) a And n is 5. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 5. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r ²Is H; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodimentTable, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an aralkyl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs H, and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r ³Is H; d is the residue of a biologically active compound; and n is 5. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r ²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound;and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is H; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs H, and R^1bIs H; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R ^1aIs H, and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs H, and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d isA residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an alkenyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs alkyleneWherein said alkylene is further connected to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs H, and R^1bIs H; r ²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs H, and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs H, and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R ^1aIs H, and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acidA side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkyl group; d is the residue of a biologically active compound; and n is 5. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R ^1bIs an alkenyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is H; r³Is alkylene, said alkylene being further linkedTo R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R ^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs H; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is biological activity A residue of a sex compound; and n is 5. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R⁴Is an alkyl group.

In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkoxy group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkenyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an alkynyl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 5. In another embodiment, R ^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs an aralkyl group; r²Is an amino acid side chain; r³Is alkylene, saidAlkyl is further attached to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 5. In another embodiment, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; and R^1bIs a heteroaryl group; r²Is an amino acid side chain; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound; and n is 5. In any of the embodiments in this paragraph, R⁴Is H. In any of the embodiments in this paragraph, R ⁴Is an alkyl group.

In certain embodiments of formulas I and/or Ib, R^1aAnd R^1bEach is H. In another embodiment of formula I and/or Ib, n is 2. In another embodiment of formula I and/or Ib, n is 2, and R²Is H or methyl. In another embodiment of formula I and/or Ib, n is 2, R²Is H or methyl, R³Is H, and D is the residue of a biologically active compound comprising a hydroxyl group. In another embodiment of formula I and/or Ib, the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof. In certain embodiments of this paragraph, all diastereomers are contemplated. For example, in one embodiment, the stereochemistry of the acetal is undefined or racemic. As a further example, in one embodiment, the stereochemistry at the acetal is (R) -. As a further example, in one embodiment, the stereochemistry at the acetal is (S) -. As advance intoAs an example of a step, in one embodiment, the stereochemistry at the acetal is in excess of (R) -over (S) -. As a further example, in one embodiment the stereochemistry at the acetal is an excess of (S) -over (R) -.

In certain embodiments of formulas I and/or Ib, R ^1aAnd R^1bEach is H. In another embodiment of formula I and/or Ib, n is 1. In another embodiment of formula I and/or Ib, R²Is H, methyl, or-CH₂Ph. In another embodiment of formula I and/or Ib, R³Is H. In another embodiment of formula I and/or Ib, D is the residue of a biologically active compound comprising a hydroxyl group. In another embodiment of formula I and/or Ib, the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof. In certain embodiments of this paragraph, all diastereomers are contemplated. For example, in one embodiment, the stereochemistry at the acetal is undefined or racemic. As a further example, in one embodiment, the stereochemistry at the acetal is (R) -. As a further example, in one embodiment, the stereochemistry at the acetal is (S) -. As a further example, in one embodiment the stereochemistry at the acetal is an excess of (R) -over (S) -. As a further example, in one embodiment the stereochemistry at the acetal is an excess of (S) -over (R) -.

In certain embodiments of formulas I and/or Ib, R^1aAnd R^1bEach is H. In another embodiment of formula I and/or Ib, n is 1. In another embodiment of formula I and/or Ib, R ²Is H or methyl. In another embodiment of formula I and/or IbIn, R³Is an alkyl group. In another embodiment of formula I and/or Ib, D is the residue of a biologically active compound comprising a hydroxyl group. In another embodiment of formula I and/or Ib, the compound is selected from the group consisting of:

In certain embodiments of formula I, R^1aIs alkyl or aralkyl, and R^1bIs H. In another embodiment of formula I, n is 1. In another embodiment of formula I, R²Is H. In another embodiment of formula I, R ³Is H. In another embodiment of formula I, D is the residue of a biologically active compound comprising a hydroxyl group. In another embodiment of formula I, the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof. In certain embodiments of this paragraph, all diastereomers are contemplated. For example, in one embodiment, the stereochemistry at the hemiaminylether (or hemiaminal, or N-acyl-N, O-acetal, where each name of this functional group is used interchangeably herein) is undefined or racemic. As a further example, in one embodiment the stereochemistry at the half amine ether is (R) -. As a further example, in one embodiment the stereochemistry at the half amine ether is (S) -. As a further example, in one embodiment the stereochemistry at the half amine ether is (R) -excess over (S) -. As a further example, in one embodiment the stereochemistry at the half amine ether is (S) -excess over (R) -. For example, in one embodiment, the stereochemistry at the acetal is undefined or racemic. As a further example, in one embodiment, the stereochemistry at the acetal is (R) -. As a further example, in one embodiment, the stereochemistry at the acetal is (S) -. As a further example, in one embodiment the stereochemistry at the acetal is an excess of (R) -over (S) -. As a further example, in one embodiment the stereochemistry at the acetal is an excess of (S) -over (R) -.

In certain embodiments of formula I, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; r^1bIs H; and R³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms. Useful 4-atom heterocyclic groups include, but are not limited to, optionally substituted aziridines. Useful 5-atom heterocyclic groups include, but are not limited to, optionally substituted pyrrolidines. In an exemplary embodiment, the optionally substituted pyrrolidine is indoline or indolinyl. Useful 6-atom heterocyclic groups include, but are not limited to, optionally substituted piperidines. In an exemplary embodiment, the optionally substituted piperidine is tetrahydroquinoline or tetrahydroquinolinyl. In another embodiment of formula I, n is 1. In another embodiment of formula I, R²Is H. In another embodiment of formula I, D is the residue of a biologically active compound comprising a hydroxyl group. In another embodiment of formula I, the compound is selected from the group consisting of:

In certain embodiments, other compounds, prodrugs, payloads, or biologically active compounds comprising a hydroxyl group are contemplated. Exemplary compounds, prodrugs or payloads contemplated include, but are not limited to,

in certain embodiments of this paragraph, all diastereomers are contemplated. For example, in one embodiment, the stereochemistry at the acetal is undefined or racemic. As a further example, in one embodiment, the stereochemistry at the acetal is (R) -. As a further example, in one embodiment, the stereochemistry at the acetal is (S) -. As a further example, in one embodiment the stereochemistry at the acetal is an excess of (R) -over (S) -. As a further example, in one embodiment the stereochemistry at the acetal is an excess of (S) -over (R) -.

In certain embodiments of formulas I and/or Ib, R^1aAnd R^1bEach is H. In another embodiment of formula I and/or Ib, n is 1. In another embodiment of formula I and/or Ib, R²Is an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 6 atoms; and R³Is an alkylene group, wherein said alkylene group is further bonded to R ²To form said 6-atom heterocyclic group. In another embodiment of formula I and/or Ib, D is the residue of a biologically active compound comprising a hydroxyl group. In another embodiment of formula I and/or Ib, the compound is

Binding agents

Suitable binding agents for any of the conjugates provided herein include, but are not limited to, antibodies, lymphokines (e.g., IL-2 or IL-3), hormones (e.g., insulin and glucocorticoids), growth factors (e.g., EGF, transferrin, and fibronectin type III), viral receptors, interleukins, or any other cell-or peptide-binding molecule or species. Binding agents also include, but are not limited to, ankyrin repeat proteins and interferons.

In some embodiments, the binding agent is an antibody or antigen-binding fragment thereof. The antibody may be in any form known to those skilled in the art. The term "antibody" as used herein refers to any antigen binding molecule or molecular complex comprising at least one Complementarity Determining Region (CDR) that specifically binds to or interacts with a particular antigen. The term "antibody" includes immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, as well as multimers thereof (e.g., IgM). Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or V)_H) And a heavy chain constant region. The heavy chain constant region comprises three domains, C _H1、C _H2 and C _H3. Each light chain comprises a light chain variable region (abbreviated as LCVR or V herein)_L) And a light chain constant region. The light chain constant region comprises a domain (C)_L1). The V is_HRegion and V_LThe regions may be further subdivided into regions of hypervariability, termed Complementarity Determining Regions (CDRs), interspersed with regions that are more conserved, termed Framework Regions (FRs). Each V_HAnd V_LEach consisting of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR 4. In various embodiments of the invention, the FR of the antibody (or antigen-binding portion thereof) suitable for use in the compounds of the invention may be identical to human germline sequences, or may be naturally occurring, or artificially modified. Amino acid consensus sequences can be defined based on a side-by-side analysis of two or more CDRs. The term "antibody" as used herein also includes antigen-binding fragments of intact antibody molecules. The term "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, as used herein includes any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Antigen-binding fragments of antibodies may be, for example, prepared using any suitable standard technique, e.g., involving manipulation and expression of encoding antibody variants Proteolytic digestion or recombinant genetic engineering of the DNA of the domains and optionally of the constant domains, derived from the whole antibody molecule. Such DNA is known and/or readily obtained, for example, from commercial sources, DNA libraries (including, for example, phage-antibody libraries), or may be synthetically derived. DNA can be sequenced and manipulated chemically or by using molecular biology techniques, e.g., to arrange one or more variable and/or constant domains into the appropriate configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc. Non-limiting examples of antigen-binding fragments include: (i) a Fab fragment; (ii) a F (ab')2 fragment; (iii) (ii) a fragment of Fd; (iv) (iv) an Fv fragment; (v) single chain fv (scFv) molecules; (vi) a dAb fragment; and (vii) the minimal recognition unit consisting of amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated CDR, such as the CDR3 peptide) or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, divalent nanobodies, etc.), Small Modular Immunopharmaceuticals (SMIPs), and shark variable IgNAR domains are also encompassed within the expression "antigen binding fragment" as used herein. Antigen-binding fragments of antibodies typically comprise at least one variable domain. The variable domain may be of any size or amino acid composition, and typically comprises at least one CDR that is adjacent to or in-frame with one or more framework sequences. In a region having a sum of V _LDomain-related V_HIn an antigen-binding fragment of a domain, the V_HAnd V_LThe domains may be positioned relative to each other in any suitable arrangement. For example, the variable region may be dimeric and contain V_H-V_H、V_H-V_LOr V_L-V_LA dimer. Alternatively, the antigen-binding fragment of the antibody may comprise a monomeric V_HOr V_LA domain. In certain embodiments, an antigen-binding fragment of an antibody may comprise at least one variable domain, which variable domainCovalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that can be found within antigen-binding fragments of antibodies of the invention include: (i) v_H-C _H1；(ii)V_H-C _H2；(iii)V_H-C _H3；(iv)V_H-C_H1-C _H2；(v)V_H-C_H1-C_H2-C _H3；(vi)V_H-C_H2-C _H3；(vii)V_H-C_L；(viii)V_L-C _H1；(ix)V_L-C _H2；(x)V_L-C _H3；(xi)V_L-C_H1-C _H2；(xii)V_L-C_H1-C_H2-C _H3；(xiii)V_L-C_H2-C _H3; and (xiv) V_L-C_L. In any configuration of the variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be directly linked to each other or may be linked by a complete or partial hinge or linker region. The hinge region can be comprised of at least 2 (e.g., 5, 10, 15, 20, 40, 60, or more) amino acids that result in flexible or semi-flexible connections between adjacent variable and/or constant domains in a single polypeptide molecule. As with intact antibody molecules, antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies typically comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, can be adapted for use in the context of an antigen-binding fragment of an antibody of the invention using routine techniques available in the art. In certain embodiments of the invention, the antibody of the invention is a human antibody. The term "human antibody" as used herein is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the invention may include ammonia that is not encoded by human germline immunoglobulin sequences Amino acid residues (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example, in the CDRs, particularly in CDR 3. 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 onto human framework sequences. The term "human antibody" does not include naturally occurring molecules that normally exist in naturally occurring, unmodified organisms without modification or human intervention/manipulation. In some embodiments, the antibodies of the invention can be recombinant human antibodies. The term "recombinant human antibody" as used herein is intended to include all human antibodies that have been prepared, expressed, produced or isolated by recombinant means, such as antibodies expressed using recombinant expression vectors transfected into host cells (described further below); antibodies isolated from libraries of recombinant, combinatorial human antibodies (described further below); antibodies isolated from animals (e.g., mice) that are transgenic for human immunoglobulin genes (see, e.g., Taylor et al (1992) Nucl. acids Res.20: 6287-6295); or by any other method involving splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when animals with transgenic human Ig sequences are used, in vivo somatic mutagenesis) and thus the V of the recombinant antibody _HRegion and V_LThe amino acid sequence of the region is derived from human germline V_HAnd V_LSequences related to and not naturally found in the germline repertoire of human antibodies in vivo. Human antibodies can exist in two forms associated with hinge heterogeneity. In one form, the immunoglobulin molecule comprises a stable four-chain construct of about 150-160kDa, wherein the dimers are linked together by interchain heavy chain disulfide bonds. In the second form, the dimers are not linked by interchain disulfide bonds and form a molecule of about 75-80kDa, consisting of covalently coupled light and heavy chains (half-antibodies). Even after affinity purification, thisThese forms are also extremely difficult to separate. The frequency of occurrence of the second form in the various intact IgG isotypes is due to, but not limited to, structural differences associated with the hinge region isotype of the antibody. Single amino acid substitutions in the hinge region of the human IgG4 hinge can significantly reduce the appearance of the second form (Angal et al (1993) Molecular Immunology 30:105) to levels typically observed with the human IgG1 hinge. The present disclosure includes in the hinge region, C_HRegion 2 or C _H3, which may be desired, e.g., in production, to increase the yield of the desired antibody form. The antibody of the invention may be an isolated antibody. An "isolated antibody" as used herein refers to an antibody that has been identified and isolated and/or recovered from at least one component of its natural environment. For example, for the purposes of the present invention, an antibody that has been isolated or removed from at least one component of an organism or from a tissue or cell in which the antibody naturally occurs or is naturally produced is an "isolated antibody". Isolated antibodies also include in situ antibodies within recombinant cells. An isolated antibody is an antibody that has been subjected to at least one purification or isolation step. According to certain embodiments, the isolated antibody may be substantially free of other cellular material and/or chemicals. The antibodies used in the invention may comprise one or more amino acid substitutions, insertions and/or deletions in the framework and/or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequences from which the antibodies were derived. Such mutations can be readily determined by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases. The present invention includes antibodies and antigen-binding fragments thereof derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and/or CDR regions are mutated to the corresponding residue of the germline sequence from which the antibody is derived, or to the corresponding residue of another human germline sequence, or to conservative amino acid substitutions of the corresponding germline residue (such sequence changes are collectively referred to herein as "germline mutations"). One of ordinary skill in the art can readily generate a number of antibodies and antigen junctions starting from the heavy and light chain variable region sequences disclosed herein A synthetic fragment, the antibody and antigen-binding fragment comprising one or more individual germline mutations or a combination thereof. In certain embodiments, V_HAnd/or V_LAll framework and/or CDR residues within the domain are mutated back to the residues found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues are mutated back to the original germline sequence, e.g., mutated residues found only within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or mutated residues found only in CDR1, CDR2, or CDR 3. In other embodiments, one or more framework and/or CDR residues are mutated to the corresponding residues of a different germline sequence (i.e., a germline sequence that is different from the germline sequence from the antibody originally derived). Furthermore, the antibodies of the invention may comprise any combination of two or more germline mutations within the framework and/or CDR regions, e.g., wherein certain individual residues are mutated to the corresponding residues of a particular germline sequence, while certain other residues that differ from the original germline sequence remain or are mutated to the corresponding residues of a different germline sequence. Once obtained, antibodies and antigen-binding fragments containing one or more germline mutations can be readily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, and the like. Antibodies and antigen-binding fragments obtained in this general manner are included in the present invention. Antibodies useful with the compounds of the invention also include antibodies comprising variants of any of the HCVR, LCVR and/or CDR amino acid sequences disclosed herein with one or more conservative substitutions. The term "epitope" refers to an antigenic determinant that interacts with a specific antigen binding site, called a paratope, in the variable region of an antibody molecule. A single antigen may have more than one epitope. Thus, different antibodies may bind to different regions on an antigen and may have different biological effects. Epitopes can be conformational or linear. Conformational epitopes are produced by spatially juxtaposed amino acids of different segments of a linear polypeptide chain. Linear epitopes are produced by adjacent amino acid residues in a polypeptide chain. In certain embodiments, epitopes may include carbohydrates, phosphoryls, or sulfonyls on antigens A radical moiety of the generic class.

In certain embodiments, the antibody comprises a light chain. In certain embodiments, the light chain is a kappa light chain. In certain embodiments, the light chain is a lambda light chain. In certain embodiments, the antibody comprises a heavy chain. In some embodiments, the heavy chain is IgA. In some embodiments, the heavy chain is IgD. In some embodiments, the heavy chain is IgE. In some embodiments, the heavy chain is IgG. In some embodiments, the heavy chain is IgM. In some embodiments, the heavy chain is IgG 1. In some embodiments, the heavy chain is IgG 2. In some embodiments, the heavy chain is IgG 3. In some embodiments, the heavy chain is IgG 4. In some embodiments, the heavy chain is IgA 1. In some embodiments, the heavy chain is IgA 2.

In some embodiments, the antibody is an antibody fragment. In some embodiments, the antibody fragment is an Fv fragment. In some embodiments, the antibody fragment is a Fab fragment. In some embodiments, the antibody fragment is F (ab')₂And (3) fragment. In some embodiments, the antibody fragment is a Fab' fragment. In some embodiments, the antibody fragment is a scfv (sfv) fragment. In some embodiments, the antibody fragment is a scFv-Fc fragment.

In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a polyclonal antibody. In some embodiments, the antibody is a bispecific antibody comprising a first antigen-binding domain (also referred to herein as "D1") and a second antigen-binding domain (also referred to herein as "D2").

The expression "antigen binding domain" as used herein refers to any peptide, polypeptide, nucleic acid molecule, scaffold-type molecule, peptide display molecule, or polypeptide-containing construct capable of specifically binding a specific antigen of interest (e.g., PRLR or STEAP 2). The term "specifically binds" or the like as used herein refers to the formation of a complex of an antigen binding domain and a specific antigen characterized by a dissociation constant (K)_D) Is 1 μ M or less and does not bind other unrelated antigens under general test conditions. "irrelevant antibodyThe "are proteins, peptides or polypeptides having less than 95% amino acid identity to each other.

Exemplary classes of antigen-binding domains that can be used in the context of the present invention include classes of antibodies, classes of antigen-binding portions of antibodies, peptides that specifically interact with a particular antigen (e.g., peptibodies), classes of receptor molecules that specifically interact with a particular antigen, classes of proteins that comprise a ligand-binding portion of a receptor that specifically binds a particular antigen, classes of antigen-binding scaffolds (e.g., darpins classes, HEAT repeats, ARM repeats, delta tetrapeptide repeats, and other naturally occurring repeat protein-based scaffolds, etc.) [ see, e.g., Boersma and Pluckthun,2011, curr.

Methods of determining whether two molecules specifically bind to each other are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, antigen binding domains used in the context of the present invention include binding to a particular antigen (e.g., a target molecule [ T [)]Or internalizing effector protein [ E]) Or a part thereof, as determined in a surface plasmon resonance assay, the K of which_DLess than about 1 μ M, less than about 500nM, less than about 250nM, less than about 125nM, less than about 60nM, less than about 30nM, less than about 10nM, less than about 5nM, less than about 2nM, less than about 1nM, less than about 500pM, less than about 400pM, less than about 300pM, less than about 200pM, less than about 100pM, less than about 90pM, less than about 80pM, less than about 70pM, less than about 60pM, less than about 50pM, less than about 40pM, less than about 30pM, less than about 20pM, less than about 10pM, less than about 5pM, less than about 4pM, less than about 2pM, less than about 1pM, less than about 0.5pM, less than about 0.2pM, less than about 0.1pM, or less than about 0.05 pM.

In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a human antibody.

In some embodiments, the antibody is an anti-PSMA, anti-PRLR, anti-MUC 16, anti-HER 2, or anti-EGFRvIII, or anti-STEAP 2 antibody. In some embodiments, the antibody is an anti-PRLR or anti-HER 2 antibody. In some embodiments, the antibody or antigen-binding fragment thereof is anti-STEAP 2. In some embodiments, the antibody or antigen-binding fragment thereof is anti-PRLR.

The antibody may have binding specificity for any antigen deemed suitable by one of skill in the art. In certain embodiments, the antigen is a transmembrane molecule (e.g., receptor). In one embodiment, the antigen is expressed on a tumor. In some embodiments, the binding agent interacts with or binds to a tumor antigen, including antigens specific for one type of tumor or antigens that are shared, overexpressed, or modified on a particular type of tumor. In one embodiment, the antigen is expressed on a solid tumor. Exemplary antigens include, but are not limited to, lipoproteins; alpha 1-antitrypsin; cytotoxic T lymphocyte-associated antigens (CTLA), such as CTLA-4; vascular Endothelial Growth Factor (VEGF); receptors for hormones or growth factors; protein a or protein D; fibroblast growth factor receptor 2(FGFR2), EpCAM, GD3, FLT3, PSMA, PSCA, MUC1, MUC16, STEAP2, CEA, TENB2, EphA receptor class, EphB receptor class, folate receptor, FOLRI, mesothelin, teratoma-derived growth factor antigen C-terminus (cripto), α ν β 6(alphavbeta6), integrins, VEGF, VEGFR, EGFR, transferrin receptor, IRTA1, IRTA2, IRTA3, IRTA4, IRTA 5; CD proteins, such as CD2, CD3, CD4, CD5, CD6, CD8, CD11, CD14, CD19, CD20, CD21, CD22, CD25, CD26, CD28, CD30, CD33, CD36, CD37, CD38, CD40, CD44, CD52, CD55, CD56, CD59, CD70, CD79, CD80, CD81, CD103, CD105, CD134, CD137, CD138, CDI52, or antibodies that bind to one or more tumor-associated antigens or cell surface receptors, which are disclosed in U.S. patent publication No. 2008/0171040 or U.S. patent publication No. 2008/0305044, each of which is incorporated herein by reference in its entirety; erythropoietin; osteoinductive factors; (ii) immunotoxins; bone Morphogenetic Protein (BMP); a class of T cell receptors; surface membrane proteins; integrins such as CDlla, CDllb, CDllc, CD18, ICAM, VLA-4 and VCAM; tumor-associated antigens, such as AFP, ALK, B7H, BAGE proteins, beta-catenin, -abl, BRCA, BORIS, CA (carbonic anhydrase IX), caspase-8, CD123, CDK, CEA, CLEC12, c-kit, cMET, CTLA, cyclin-B, CYP1B, EGFR, EGFRvIII, endoglin, Epcam, EphA, ErbB/Her, ETV-AML, Fra-1, FOLR, GAGE proteins, GD, GloboH, glypican-3, GM, gp100, Her, HLA/B-raf, HLA/EBNA, HLA/k-ras, HLA/MAGE-A, hTLG, IGF1, MARR, LMP, MAGE proteins, T-1, mesothelin, ML-MUIAP, MUC-MUCA, MUCA 125, MUERT-125, MUBR, MUERT-125, MUE-125, MUERT-A, MULR-1, and GAGE proteins, NY-BR62, NY-BR85, NY-ESO1, OX40, p15, p53, PAP, PAX3, PAX5, PCTA-1, PDGFR- α, PDGFR- β, PDGF-A, PDGF-B, PDGF-C, PDGF-D, PLAC1, PRLR, PRAME, PSCA, PSGR, PSMA (FOLH1), RAGE proteins, Ras, RGS5, Rho, SART-1, SART-3, Steap-1 (transmembrane epithelial antigen-1 of the prostate), Steap-2, STn, survivin, TAG-72, TGF- β, TMPRSS2, Tn, TNFRSF17, TRP-1, TRP-2, tyrosinase, and urolysin-3 (uropla-3), as well as fragments of any of the foregoing polypeptides; cell surface expressed antigens; MUC 16; c-MET; molecular classes, such as class A scavenger receptors including scavenger receptor A (SR-A), and other membrane protein classes, such as B7 family-related members including V-set and Ig domain 4-containing (VSIG4), colony stimulating factor 1 receptor (CSF1R), asialoglycoprotein receptor (ASGPR), and amyloid betA precursor-like protein 2 (APLP-2); macrophage receptors with collagen structure (MARCO), scavenger receptors with C-type lectins (SRCL), and scavenger receptor A-5(SCARA5), COLEC12, class B macrophage scavenger receptors including CD36, LIMPII, SRBI, SRBII, class D scavenger receptor CD68, and lysosomal membrane glycoprotein (LAMP), class E scavenger receptors including lectin-like oxidized low density lipoprotein receptor 1LOX-1 and Dectin-1, class F scavenger receptors including endothelial cell-I (SREC-I) and SREC-II and scavenger receptors expressed by a variety of Epidermal Growth Factor (EGF) -like domains (MEGF)10, class G scavenger receptor CXC chemokine ligand 16(CXCL16), class H scavenger receptors including Fasciclin (EGF), EGF-like, nuclear lamin-like and scavenger receptor-1 (FEEL-1) and receptor-2 (EL-2) containing linker domains, class I scavenger receptor CD163, and class J scavenger receptors for advanced glycation end products (RAGE), other C-type lectin superfamily members (including DEC205, CD206, Dectin-2, minicle, DC-SIGN, and DNGR-1), and other membrane protein classes (e.g., B7 family related members, including V-set and Ig domain 4-containing (VSIG 4)); AXL, BAFFR, BCMA, BCR-list components (BCR-list components), BDCA, BDCA, BTLA, BTNL, BTNL, BTNL, BTNL, C10orf, CCR, CCR, CCR, CCR, CCR, CD168, CD177, CD209, CD226, CD248, CD274, CD276, CD300, CD, CD, CD, CD, CD62, CD, CD, CD79, CD79, CD, CD90.2, CD, CLEC12, CLEC7, CLEC9, CR, CR, CRTAM, HVRB, OSEM, IFR, IL10R, DLL, DR, FAP, FCamR, FCMR's, Fire, GITR, HER, GIHHLA, HLA class II, HVEM, IFR, IL10R, MAG 12, MAG, SARL 12, SAIL 17R, IL17, IL23, IL17R, IL23, IL17, IL23, IL-R, IL-R, IL-R, and IL-R, NKp30, NKp46, PDCD1, PROKR1, PVR, PVRIG, PVRL2, PVRL3, RELT, SIGIRR, Siglec-1 (sialic acid binding immunoglobulin-like lectin-1), Siglec-10, Siglec-5, Siglec-6, Siglec-7, Siglec-8, Siglec-9, SIRPA, TACI, TCR-list components/assoc (TCR-list components/assoc), PTCRA, TCRb, CD3z, TEK, TGFBR1, TGFBR2, TGFBR3, TIGIT, TLR2, TLR4, TNF- α, TROY, TSLPR, TYRO, vldllr, and vt 1. In some embodiments, the binding agent is adalimumab (adalimumab) or infliximab (infliximab). In some embodiments, the binding agent is alemtuzumab (alemtuzumab), muromab (muromonab), rituximab (rituximab), tosituzumab (tosituzumab), or agonistic antibodies (where immune stimulation may be part of the intended mechanism of action). In some embodiments, the antigen is PRLR or HER 2. In some embodiments, the antigen is STEAP 2. In some embodiments, the antigen is human STEAP 2. In some embodiments, the MAGE protein is selected from the group consisting of MAGE-1, MAGE-2, MAGE-3, MAGE-4, MAGE-6, and MAGE-12. In some embodiments, the GAGE protein is selected from GAGE-1 and GAGE-2.

Exemplary antigens also include, but are not limited to, BCMA, SLAMF7, GPNMB, MSR1, and UPK 3A. Exemplary antigens also include, but are not limited to, MUC16, STEAP2, and HER 2.

In some embodiments, the antigen comprises MUC 16. In some embodiments, the antigen comprises STEAP 2. In some embodiments, the antigen comprises PSMA. In some embodiments, the antigen comprises MSR 1. In some embodiments, the antigen comprises HER 2. In some embodiments, the antigen is prolactin receptor (PRLR) or Prostate Specific Membrane Antigen (PSMA). In some embodiments, the antigen is MUC 16. In some embodiments, the antigen comprises PSMA. In some embodiments, the antigen is HER 2. In some embodiments, the antigen is STEAP 2. In some embodiments, the antigen is MSR 1.

In certain embodiments, the antibody comprises a glutamine residue at one or more heavy chain positions numbered 295 in the EU numbering system. In the present invention, this position is referred to as glutamine 295, or as Gln295, or as Q295. The skilled artisan will recognize that it is a conserved glutamine residue in the wild-type sequence of many antibodies. In other useful embodiments, the antibody can be designed to contain glutamine residues. In certain embodiments, the antibody comprises one or more N297Q mutations. Techniques for modifying antibody sequences to include glutamine residues are within the skill of those in the art (see, e.g., Ausubel et al current protocol.

In some embodiments, the antibody or antigen-binding fragment thereof coupled to the linker-payload or payload can be an antibody that targets STEAP 2. Suitable anti-STEAP antibodies or antigen-binding fragments thereof include, for example, those of international publication No. WO 2018/058001 a1, including those comprising the amino acid sequences disclosed in table 1 of page 75 therein. In some embodiments, the anti-STEAP 2 antibody is H1H7814N of WO 2018/058001 a1, which comprises the CDRs of H1M7814N in the same publication. In some embodiments, the anti-STEAP 2 antibody comprises: a heavy chain complementarity determining region (HCDR) -1 comprising SEQ ID NO: 2; HCDR2 comprising SEQ ID NO: 3; HCDR3 comprising SEQ ID NO: 4; a light chain complementarity determining region (LCDR) -1 comprising SEQ ID NO: 6; LCDR2 comprising SEQ ID NO: 7; and LCDR3 comprising SEQ ID NO: 8. in some embodiments, the anti-STEAP 2 antibody comprises: comprises the amino acid sequence of SEQ ID NO: 1 and a Heavy Chain Variable Region (HCVR) comprising SEQ ID NO: 5 Light Chain Variable Region (LCVR). In any of the preceding embodiments, an anti-STEAP 2 antibody can be prepared by site-directed mutagenesis to insert glutamine residues at sites that do not result in loss of antibody function or binding. For example, in any one of the preceding embodiments, the anti-STEAP 2 antibody can comprise an Asn297Gln (N297Q) mutation. Such antibodies with the N297Q mutation may also comprise in their variable region one or more additional naturally occurring glutamine residues that are accessible to transglutaminase and thus capable of conjugation to a payload or linker-payload (table a). In certain embodiments, the antibody or antigen-binding fragment thereof comprises SEQ ID NO: 1 (HCDR1, HCDR2, and HCDR 3); and SEQ ID NO: 5 (LCDR1, LCDR2, and LCDR 3). In certain embodiments, the antibody or antigen-binding fragment thereof comprises SEQ ID NO: 1, HCVR amino acid sequence; and SEQ ID NO: 5. International publication No. WO 2018/058001A 1 is hereby incorporated by reference in its entirety.

In some embodiments, the antibody or antigen-binding fragment thereof coupled to the linker-payload or payload can be an antibody that targets the human prolactin receptor (PRLR). Suitable anti-PRLR antibodies or antigen-binding fragments thereof include, for example, those of international publication No. WO 2015/026907 a1, including those comprising the amino acid sequences disclosed in table 1 of table 36 therein. In some embodiments, the anti-PRLR antibody is H1H6958N2 of WO 2015/026907 a1, which comprises the CDRs of H2M6958N2 in the same publication. The expression "PRLR" includes both monomeric and multimeric PRLR molecules, such as those described in WO 2015/026907 a 1. In some embodiments, the anti-PRLR antibody comprises: a heavy chain complementarity determining region (HCDR) -1 comprising SEQ ID NO: 10; HCDR2 comprising SEQ ID NO: 11; HCDR3 comprising SEQ ID NO: 12; a light chain complementarity determining region (LCDR) -1 comprising SEQ ID NO: 14; LCDR2 comprising SEQ ID NO: 15; and LCDR3 comprising SEQ ID NO: 16. in some embodiments, the anti-PRLR antibody comprises: comprises the amino acid sequence of SEQ ID NO: 9 and a Heavy Chain Variable Region (HCVR) comprising SEQ ID NO: 13 Light Chain Variable Region (LCVR). In any of the preceding embodiments, the anti-PRLR antibody can be prepared by site-directed mutagenesis to insert a glutamine residue at a site without causing loss of antibody function or binding. For example, in any of the preceding embodiments, the anti-PRLR antibody can comprise an Asn297Gln (N297Q) mutation. Such antibodies with the N297Q mutation may also comprise in their variable region one or more additional naturally occurring glutamine residues that are accessible to transglutaminase and thus capable of conjugation to a payload or linker-payload (table a). In certain embodiments, the antibody or antigen-binding fragment thereof comprises SEQ ID NO: 9 (HCDR1, HCDR2 and HCDR 3); and SEQ ID NO: 13 (LCDR1, LCDR2, and LCDR3) in the Light Chain Variable Region (LCVR) amino acid sequence. In certain embodiments, the antibody or antigen-binding fragment thereof comprises SEQ ID NO: 9, HCVR amino acid sequence; and SEQ ID NO: 13, LCVR amino acid sequence. International publication No. WO 2015/026907A 1 is hereby incorporated by reference in its entirety.

Table a. sequences of exemplary antibodies H1H7814N (anti STEAP2) and H1H6958N2 (anti PRLR)

The invention provides an antibody or antigen-binding fragment thereof that specifically binds STEAP2, comprising an HCVR comprising an amino acid sequence selected from any of the HCVR amino acid sequences listed in table a, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds STEAP2, comprising a LCVR comprising an amino acid sequence selected from any of the LCVR amino acid sequences set forth in table a, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds STEAP2, comprising an HCVR and LCVR amino acid sequence pair (HCVR/LCVR) comprising any one of the HCVR amino acid sequences listed in table a paired with any one of the LCVR amino acid sequences listed in table a. According to certain embodiments, the invention provides an antibody or antigen-binding fragment thereof comprising an HCVR/LCVR amino acid sequence pair contained within any one of the exemplary anti-STEAP 2 antibodies listed in table a. In certain embodiments, the HCVR/LCVR amino acid sequence pair is selected from the group consisting of 250/258; as described in international publication number WO 2018/058001 a1, the contents of which are incorporated herein by reference in their entirety.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds STEAP2, comprising a heavy chain CDR1(HCDRl) comprising an amino acid sequence selected from any of the HCDRl amino acid sequences listed in table a, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds STEAP2, comprising a heavy chain CDR2(HCDR2) and said heavy chain CDR2(HCDR2) comprising an amino acid sequence selected from any of the HCDR2 amino acid sequences listed in table a, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds STEAP2, comprising a heavy chain CDR3(HCDR3) and said heavy chain CDR3(HCDR3) comprising an amino acid sequence selected from any of the HCDR3 amino acid sequences listed in table a, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds STEAP2, comprising light chain CDR1(LCDRl) comprising an amino acid sequence selected from any of the LCDRl amino acid sequences listed in table a, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds STEAP2, comprising a light chain CDR2(LCDR2) that comprises an amino acid sequence selected from any of the LCDR2 amino acid sequences listed in table a, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds STEAP2, comprising a light chain CDR3(LCDR3) that comprises an amino acid sequence selected from any of the LCDR3 amino acid sequences listed in table a, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds STEAP2, comprising an HCDR3 and LCDR3 amino acid sequence pair (HCDR3/LCDR3), said HCDR3 and LCDR3 amino acid sequence pair (HCDR3/LCDR3) comprising any one of the HCDR3 amino acid sequences listed in table a paired with any one of the LCDR3 amino acid sequences listed in table a. According to certain embodiments, the invention provides an antibody or antigen-binding fragment thereof comprising an HCDR3/LCDR3 amino acid sequence pair, said HCDR3/LCDR3 amino acid sequence pair being comprised within any one of the exemplary anti-STEAP 2 antibodies listed in table a. In certain embodiments, the HCDR3/LCDR3 amino acid sequence pair is selected from the group consisting of 256/254; as described in international publication number WO 2018/058001 a1, the contents of which are incorporated herein by reference in their entirety.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds STEAP2, comprising a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained within any one of the exemplary anti-STEAP 2 antibodies listed in table a. In certain embodiments, the collection of HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequences is selected from the group consisting of: 252, 254, 260, 262, 264; as described in international publication number WO 2018/058001 a1, the contents of which are incorporated herein by reference in their entirety.

In related embodiments, the invention also provides an antibody or antigen-binding fragment thereof that specifically binds STEAP2, comprising a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained within the HCVR/LCVR amino acid sequence pair defined by any one of the exemplary anti-STEAP 2 antibodies listed in table a. For example, the invention includes an antibody or antigen-binding fragment thereof that specifically binds STEAP2, comprising the HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequence set, the HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequence set being comprised within an HCVR/LCVR amino acid sequence pair selected from the group consisting of 250/258; as described in international publication number WO 2018/058001 a1, the contents of which are incorporated herein by reference in their entirety. Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs within particular HCVR and/or LCVR amino acid sequences disclosed herein. Exemplary conventions or conventions that may be used to identify CDR boundaries include, for example, Kabat definition, cauchy (Chothia) definition, and AbM definition. Generally, the Kabat (Kabat) definition is based on sequence variability, the cauchy (Chothia) definition is based on the position of the structural loop (loop) region, and the AbM definition is a compromise between the Kabat (Kabat) and cauchy (Chothia) approaches. See, e.g., Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et Al, J.mol.biol.273:927-948 (1997); and Martin et al, Proc.Natl.Acad.Sci.USA 86: 9268-. Public databases can also be used to identify CDR sequences within antibodies.

The invention provides an antibody or antigen-binding fragment thereof that specifically binds PRLR, comprising an HCVR comprising an amino acid sequence selected from any one of the HCVR amino acid sequences set forth in table a, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds PRLR, comprising an LCVR comprising an amino acid sequence selected from any of the LCVR amino acid sequences set forth in table a, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds PRLR, comprising an HCVR and LCVR amino acid sequence pair (HCVR/LCVR) comprising any one of the HCVR amino acid sequences listed in table a paired with any one of the LCVR amino acid sequences listed in table a. According to certain embodiments, the invention provides an antibody or antigen-binding fragment thereof comprising an HCVR/LCVR amino acid sequence pair contained within any one of the exemplary anti-PRLR antibodies listed in table a. In certain embodiments, the HCVR/LCVR amino acid sequence pair is selected from the group consisting of 18/26, 66/74, 274/282, 290/298, and 370/378; as described in international publication number WO 2015/026907 a1, the contents of which are incorporated herein by reference in their entirety.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds PRLR comprising a heavy chain CDR1(HCDRl) comprising an amino acid sequence selected from any of the HCDRl amino acid sequences listed in table a, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds PRLR comprising a heavy chain CDR2(HCDR2), said heavy chain CDR2(HCDR2) comprising an amino acid sequence selected from any of the HCDR2 amino acid sequences listed in table a, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds PRLR comprising a heavy chain CDR3(HCDR3), said heavy chain CDR3(HCDR3) comprising an amino acid sequence selected from any of the HCDR3 amino acid sequences listed in table a, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds PRLR comprising a light chain CDR1(LCDRl) comprising an amino acid sequence selected from any of the LCDRl amino acid sequences listed in table a, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds PRLR comprising a light chain CDR2(LCDR2), said light chain CDR2(LCDR2) comprising an amino acid sequence selected from any of the LCDR2 amino acid sequences listed in table a, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds PRLR comprising a light chain CDR3(LCDR3), said light chain CDR3(LCDR3) comprising an amino acid sequence selected from any of the LCDR3 amino acid sequences listed in table a, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds PRLR comprising an HCDR3 and LCDR3 amino acid sequence pair (HCDR3/LCDR3) comprising any one of the HCDR3 amino acid sequences listed in table a paired with any one of the LCDR3 amino acid sequences listed in table a, and an HCDR3 and LCDR3 amino acid sequence pair (HCDR3/LCDR 3). According to certain embodiments, the invention provides an antibody or antigen-binding fragment thereof comprising an HCDR3/LCDR3 amino acid sequence pair, said HCDR3/LCDR3 amino acid sequence pair being comprised within any one of the exemplary anti-PRLR antibodies listed in table a. In certain embodiments, the HCDR3/LCDR3 amino acid sequence pair is selected from the group consisting of 24/32, 72/80, 280/288, 296/304, and 376/384; as described in international publication number WO 2015/026907 a1, the contents of which are incorporated herein by reference in their entirety.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds PRLR comprising a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained within any one of the exemplary anti-PRLR antibodies listed in table a. In certain embodiments, the collection of HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequences is selected from the group consisting of: 20-22-24-28-30-32, 68-70-72-76-78-80, 276-; as described in international publication number WO 2015/026907 a1, the contents of which are incorporated herein by reference in their entirety.

In related embodiments, the invention also provides an antibody or antigen-binding fragment thereof that specifically binds PRLR comprising a collection of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained within the HCVR/LCVR amino acid sequence pair defined by any of the exemplary anti-PRLR antibodies listed in table a. For example, the invention includes an antibody or antigen-binding fragment thereof that specifically binds PRLR comprising the HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequence set, the HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequence set being contained within an HCVR/LCVR amino acid sequence pair selected from the group consisting of 18/26, 66/74, 274/282, 290/298, and 370/378; as described in international publication number WO 2015/026907 a1, the contents of which are incorporated herein by reference in their entirety. Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs within particular HCVR and/or LCVR amino acid sequences disclosed herein. Exemplary conventions or conventions that may be used to identify CDR boundaries include, for example, Kabat definition, cauchy (Chothia) definition, and AbM definition. Generally, the Kabat (Kabat) definition is based on sequence variability, the cauchy (Chothia) definition is based on the position of the structural loop (loop) region, and the AbM definition is a compromise between the Kabat (Kabat) and cauchy (Chothia) approaches. See, e.g., Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et Al, J.mol.biol.273:927-948 (1997); and Martin et al, Proc.Natl.Acad.Sci.USA 86: 9268-. Public databases can also be used to identify CDR sequences within antibodies.

In any of the compound or conjugate embodiments provided, BA is an antibody or antigen-binding fragment thereof that binds PRLR. In any of the compound or conjugate embodiments provided, BA is an antibody or antigen-binding fragment thereof and is conjugated through at least one Q295 residue. In any of the compound or conjugate embodiments provided, BA is an antibody or antigen-binding fragment thereof and is conjugated via two Q295 residues. In any of the compound or conjugate embodiments provided, BA is the N297Q antibody or antigen binding fragment thereof. In any of the compound or conjugate embodiments provided, BA is an N297Q antibody or antigen binding fragment thereof, and is conjugated via at least one Q295 residue and at least one Q297 residue. In any of the compound or conjugate embodiments provided, BA is an N297Q antibody or antigen binding fragment thereof, and is coupled via two Q295 residues and two Q297 residues. In a particular embodiment, the numbering is according to the EU numbering system.

In any of the embodiments above, BA is an anti-MSR 1 antibody. In certain embodiments, BA is the MSR1 antibody H1H 21234N. In certain embodiments, BA is the anti-MSR 1 antibody H1H21234N N297Q. In certain embodiments, BA is an anti-MSR 1 antibody comprising an amino acid sequence according to SEQ ID NO: 19 and an HCVR according to SEQ ID NO: 27 LCVR. In certain embodiments, BA is an anti-MSR 1 antibody comprising amino acid sequences according to SEQ ID NOs: 21. SEQ ID NO: 23. SEQ ID NO: 25. SEQ ID NO: 29. SEQ ID NO: 31 and SEQ ID NO: 33 of 1, 2, 3, 4, 5 or 6 of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR 3. In certain embodiments, the HCVR is a HCVR consisting of SEQ ID NO: 18 encoding. In certain embodiments, the LCVR is a polypeptide consisting of SEQ ID NO: and 26, coding. In certain embodiments, 1, 2, 3, 4, 5, or 6 of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are encoded by the polynucleotide sequence of SEQ ID NO: 20. SEQ ID NO: 22. SEQ ID NO: 24. SEQ ID NO: 28. SEQ ID NO: 30 and SEQ ID NO: and (4) encoding by 32. N297Q indicates that one or more residues 297 are mutated from asparagine (N) to glutamine (Q). In certain embodiments, each residue 297 is separately mutated to Q. In a preferred embodiment, the numbering is according to the EU numbering system. In certain embodiments of this paragraph, the drug: antibody Ratio (DAR) is 1 to 4. In certain embodiments, the DAR is 1, 2, 3 or 4. In certain embodiments, the DAR is 2. In certain embodiments, the DAR is 4.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds MSR1, comprising an HCVR comprising an amino acid sequence selected from any of the HCVR amino acid sequences set forth in table B, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds MSR1, comprising an LCVR comprising an amino acid sequence selected from any of the LCVR amino acid sequences set forth in table B, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds MSR1, comprising an HCVR and LCVR amino acid sequence pair (HCVR/LCVR) comprising any one of the HCVR amino acid sequences listed in table B paired with any one of the LCVR amino acid sequences listed in table B. According to certain embodiments, the invention provides an antibody or antigen-binding fragment thereof comprising an HCVR/LCVR amino acid sequence pair contained within any one of the exemplary anti-MSR 1 antibodies listed in table B. In certain embodiments, the HCVR/LCVR amino acid sequence pair is selected from the group consisting of 2/10, 23/42, 50/58, 90/98, and 282/290; as described in international publication number WO 2019/217597 a1, the contents of which are incorporated herein by reference in their entirety.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds MSR1, comprising a heavy chain CDR1(HCDRl) comprising an amino acid sequence selected from any of the HCDRl amino acid sequences listed in table B, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds MSR1, comprising a heavy chain CDR2(HCDR2) and said heavy chain CDR2(HCDR2) comprises an amino acid sequence selected from any of the HCDR2 amino acid sequences listed in table B, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds MSR1, comprising a heavy chain CDR3(HCDR3) and said heavy chain CDR3(HCDR3) comprises an amino acid sequence selected from any of the HCDR3 amino acid sequences listed in table B, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds MSR1, comprising light chain CDR1(LCDRl) comprising an amino acid sequence selected from any of the LCDRl amino acid sequences listed in table B, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds MSR1, comprising light chain CDR2(LCDR2) and light chain CDR2(LCDR2) comprising an amino acid sequence selected from any of the amino acid sequences of LCDR2 listed in table B, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds MSR1, comprising light chain CDR3(LCDR3) and light chain CDR3(LCDR3) comprising an amino acid sequence selected from any of the amino acid sequences of LCDR3 listed in table B, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity thereto.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds MSR1, comprising an HCDR3 and LCDR3 amino acid sequence pair (HCDR3/LCDR3), said HCDR3 and LCDR3 amino acid sequence pair (HCDR3/LCDR3) comprising any one of the HCDR3 amino acid sequences listed in table B paired with any one of the LCDR3 amino acid sequences listed in table B. According to certain embodiments, the invention provides an antibody or antigen-binding fragment thereof comprising an HCDR3/LCDR3 amino acid sequence pair, said HCDR3/LCDR3 amino acid sequence pair being comprised within any one of the exemplary anti-MSR 1 antibodies listed in table B. In certain embodiments, the HCDR3/LCDR3 amino acid sequence pair is selected from the group consisting of 8/16, 40/48, 56/64; 96/104, and 288/296; as described in international publication number WO 2019/217591 a1, the contents of which are incorporated herein by reference in their entirety.

The invention also provides an antibody or antigen-binding fragment thereof that specifically binds MSR1, comprising a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained within any one of the exemplary anti-MSR 1 antibodies listed in table B. In certain embodiments, the collection of HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequences is selected from the group consisting of: 4-6-8-12-14-16, 36-38-40-44-46-48, 52-54-56-60-62-64, 92-94-96-100, 102-296, and 284-286-288-292-294-296; as described in international publication number WO 2019/217591 a1, the contents of which are incorporated herein by reference in their entirety.

In related embodiments, the invention also provides an antibody or antigen-binding fragment thereof that specifically binds MSR1, comprising a collection of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained within the HCVR/LCVR amino acid sequence pair defined by any one of the exemplary anti-PRLR antibodies listed in table B. For example, the invention includes an antibody or antigen-binding fragment thereof that specifically binds MSR1, comprising the HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequence set, the HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequence set being comprised within an HCVR/LCVR amino acid sequence pair selected from the group consisting of 2/10, 23/42, 50/58, 90/98, and 282/290; as described in international publication number WO 2019/217591 a1, the contents of which are incorporated herein by reference in their entirety. Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs within particular HCVR and/or LCVR amino acid sequences disclosed herein. Exemplary conventions or conventions that may be used to identify CDR boundaries include, for example, Kabat definition, cauchy (Chothia) definition, and AbM definition. Generally, the Kabat (Kabat) definition is based on sequence variability, the cauchy (Chothia) definition is based on the position of the structural loop (loop) region, and the AbM definition is a compromise between the Kabat (Kabat) and cauchy (Chothia) approaches. See, e.g., Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et Al, J.mol.biol.273:927-948 (1997); and Martin et al, Proc.Natl.Acad.Sci.USA 86: 9268-. Public databases can also be used to identify CDR sequences within antibodies.

Table b. sequences of exemplary anti-MSR 1 antibodies

The binding agent linker can be linked to the binding agent (e.g., an antibody or antigen binding molecule) by attachment at a specific amino acid within the antibody or antigen binding molecule. Exemplary amino acid attachments that can be used in the context of this embodiment of the invention include, for example, lysine (see, e.g., U.S. Pat. No. 5,208,020; U.S. Pat. No. 2010/0129314; Hollander et al, Bioconjugate chem.,2008,19: 358-361; WO 2005/089808; U.S. Pat. No. 5,714,586; U.S. Pat. No. 2013/0101546; and U.S. Pat. No. 2012/0585592); cysteine (see, e.g., US 2007/0258987; WO 2013/055993; WO 2013/055990; WO 2013/053873; WO 2013/053872; WO 2011/130598; US 2013/0101546; and US 7,750,116); selenocysteine (see, e.g., WO 2008/122039; and Hofer et al, Proc. Natl. Acad. Sci., USA,2008,105: 12451-; formylglycine (see, e.g., Carrico et al, nat. chem. biol.,2007,3: 321-; unnatural amino acids (see, e.g., WO 2013/068874, and WO 2012/166559), and acidic amino acids (see, e.g., WO 2012/05982). Linkers can also be coupled to antigen binding proteins by attachment to carbohydrates (see, e.g., US 2008/0305497, WO 2014/065661, and Ryan et al, Food & Agriculture immune, 2001,13: 127-.

In some embodiments, the binding agent is an antibody or antigen binding molecule, and the antibody is linked to the linker by a lysine residue. In some embodiments, the antibody or antigen binding molecule is linked to the linker through a cysteine residue.

Linkers can also be coupled to one or more glutamine residues by transglutaminase-based chemical enzymatic coupling (see, e.g., Dennler et al, Bioconjugate chem.2014,25, 569-. For example, one or more glutamine residues of an antibody can be conjugated to a primary amine compound in the presence of transglutaminase. Primary amine-based compounds include, for example, payloads or linker-payloads that directly provide antibody drug conjugates via transglutaminase-mediated conjugation. Primary amine-based compounds also include linkers and spacer groups functionalized with reactive groups, which can then be reacted with further compounds to synthesize antibody drug conjugates. Antibodies comprising glutamine residues can be isolated from natural sources or engineered to comprise one or more glutamine residues. Techniques for engineering glutamine residues into antibody polypeptide chains (glutaminyl-modified antibodies or antigen-binding molecules) are within the skill of those in the art. In certain embodiments, the antibody is aglycosylated.

In certain embodiments, the antibody or glutaminyl modified antibody or antigen binding molecule comprises at least one glutamine residue in at least one polypeptide chain sequence. In certain embodiments, the antibody or glutaminyl modified antibody or antigen binding molecule comprises two heavy chain polypeptides, each of which has one Gln295 or Q295 residue. In further embodiments, the antibody or glutaminyl modified antibody or antigen binding molecule comprises one or more glutamine residues at a site other than heavy chain 295. The invention includes antibodies of this section having the N297Q mutation described herein.

Primary amine compound

In certain embodiments, the primary amine-based compound useful for transglutaminase-mediated coupling of glutamine-containing antibodies (or antigen-binding compounds) can be any primary amine compound that the ordinarily skilled artisan would find useful. Typically, the primary amine compound has the formula H₂N-R, wherein R can be any group compatible with the antibody and reaction conditions. In certain embodiments, R is alkyl, substituted alkyl, heteroalkyl, or substituted heteroalkyl.

In some embodiments, the primary amine compound comprises a reactive group or a protected reactive group. Useful reactive groups include azides, alkynes, cycloalkynes, thiols, alcohols, ketones, aldehydes, carboxylic acids, esters, amides, hydrazides, anilines, and amines. In certain embodiments, the reactive group is selected from the group consisting of azide, alkyne, thiol, cycloalkyne, aldehyde, and carboxyl.

In certain embodiments, the primary amine compound has the formula H₂N-LL-X, wherein LL is a divalent spacer group and X is a reactive group or a protected reactive group. In a particular embodiment, LL is a divalent polyethylene glycol (PEG) group. In certain embodiments, X is selected from the group consisting of-SH, -N₃Alkyne, aldehyde and tetrazole. In a particular embodiment, X is-N₃。

In certain embodiments, the primary amine compound is a structure having one of the following general formulas:

H₂N-(CH₂)_n-X；

H₂N-(CH₂CH₂O)_n-(CH₂)_p-X；

H₂N-(CH₂)_n-N(H)C(O)-(CH₂)_m-X；

H₂N-(CH₂CH₂O)_n-N(H)C(O)-(CH₂CH₂O)_m-(CH₂)_p-X；

H₂N-(CH₂)_n-C(O)N(H)-(CH₂)_m-X；

H₂N-(CH₂CH₂O)_n-C(O)N(H)-(CH₂CH₂O)_m-(CH₂)_p-X；

H₂N-(CH₂)_n-N(H)C(O)-(CH₂CH₂O)_m-(CH₂)_p-X；

H₂N-(CH₂CH₂O)_n-N(H)C(O)-(CH₂)_m-X；

H₂N-(CH₂)_n-C(O)N(H)-(CH₂CH₂O)_m-(CH₂)_p-X; and

H₂N-(CH₂CH₂O)_n-C(O)N(H)-(CH₂)_m-X；

wherein n is an integer selected from 1 to 12;

m is an integer selected from 0 to 12;

p is an integer selected from 0 to 2;

and X is selected from the group consisting of: -SH, -N₃-C ≡ CH, -C (O) H, tetrazole, and one of:

Any of the alkyl or alkylene groups described hereinbefore (i.e. -CH)₂-) groups are all arbitraryLocation selecting quilt such as C_1-8Alkyl, methyl formyl, or-SO₃And H is substituted. In certain embodiments, the alkyl groups are both unsubstituted.

In certain embodiments, the primary amine compound is selected from the group consisting of:

in particular embodiments, the primary amine compound is:

exemplary conditions for the above reaction are provided in the following examples.

Connecting body

In certain embodiments, the linker L moiety of the conjugates of the invention is a moiety, such as a divalent moiety, that covalently links the binding agent to the payload compound of the invention. In other embodiments, linker L is a trivalent or multivalent moiety that covalently links the binding agent to the payload compound described herein. Suitable linkers can be found in, for example, Antibody-Drug Conjugates and Immunotoxins; phillips, g.l., ed.; springer Verlag, New York, 2013; Antibody-Drug Conjugates; ducry, l., ed; humana Press, 2013; Antibody-Drug Conjugates; wang, j., Shen, w. -c., and Zaro, j.l., eds.; springer International Publishing,2015, the contents of each of which are incorporated by reference in their entirety. In certain embodiments, the linker L portion of the linker-payload of the invention is a moiety covalently attached to the payload compound of the invention, which is capable of divalent attachment and covalent attachment of a binding agent to the payload compound of the invention. In other embodiments, the linker-payload linker L moiety of the invention is a moiety covalently attached to the payload compound of the invention that is capable of acting as a trivalent or multivalent moiety to attach a binding agent to the payload compound of the invention. Payload compounds include compounds of formulas I, Ib, Ibb, and Ibbb, above, and the residue following attachment or incorporation of linker L is a linker-payload compound. The linker-payload can be further linked to a binding agent, such as an antibody or antigen-binding fragment thereof, to form an antibody-drug conjugate. One skilled in the art will recognize that certain functional groups of the payload group moiety facilitate attachment to the linker and/or binding agent. For example, in certain embodiments, no linker is present and the payload is directly linked to the binding agent. In certain embodiments, the prodrug or payload comprises a hydroxyl, amine, or thiol functional group capable of binding to a peptide residue within the binding agent.

In certain embodiments, the linker is stable under physiological conditions. In certain embodiments, the linker is cleavable, e.g., capable of releasing at least the payload moiety in the presence of an enzyme or at a particular pH range or pH value. In some embodiments, the linker comprises an enzyme cleavable group moiety. Exemplary enzymatically cleavable moiety groups include, but are not limited to, peptide bonds, ester bonds, hydrazones, and disulfide bonds. In some embodiments, the linker comprises a cathepsin-cleavable linker. In some embodiments, the linker comprises a moiety that is stable at certain pH values and cleavable at other pH values to release a payload moiety. For example, in certain embodiments, the linker is stable at physiological pH and is capable of releasing the payload moiety at local pH in the vicinity of the target.

In some embodiments, the linker comprises a non-cleavable group moiety. In some embodiments, the non-cleavable linker is derived from maleimide. In some embodiments, the non-cleavable linker is derived from an ester. In some embodiments, the non-cleavable linker is derived from an N-hydroxysuccinimide ester. In some embodiments, the compound is not The cleaved linker is derived from

Or a residue thereof. In some embodiments, the non-cleavable linker-payload residue is

Or a regioisomer thereof. In some embodiments, the non-cleavable linker is derived from

Or a regioisomer thereof. In one embodiment, the linker is maleimide cyclohexanecarboxylate or 4- (N-maleimidomethyl) cyclohexanecarboxylic acid (MCC), wherein the payload can be added to either end of the MCC linker. In another embodiment, the linker is

Wherein the payload can be added to either end of this linker. In certain embodiments, the linker is a self-stabilizing maleimide. In an exemplary embodiment, the self-stabilizing maleimide linker is

Wherein the bond to the payload by the amide nitrogen may be a bond directly to the payload; or a bond to the payload via the amide nitrogen, as shown in the structural formula, encompassing the remainder of the linker. In another exemplary embodiment, the self-stabilizing linker is represented by

Wherein the bond to the payload by the amide nitrogen may be a bond directly to the payload; orThe bond to the payload by the amide nitrogen, as shown in the structural formula, encompasses the remainder of the linker. Without being bound by any particular theory, the self-stabilizing linker comprises a moiety that stabilizes a bond attached to the binding agent by the self-stabilizing linker. For example, in some embodiments, when the bond linked by the binder to the self-stabilizing linker is a C — S bond (e.g., after michael addition of the binder cysteine to the self-stabilizing maleimide linker), the self-stabilizing linker mitigates reverse michael addition. More specifically, in the self-stabilizing maleimide (or succinimide) linker shown, the aminomethyl functionality promotes rapid hydrolysis of the succinimide michael addition product to provide

Wherein the bond to the payload by the amide nitrogen may be a bond directly to the payload; or a bond to the payload via the amide nitrogen, as shown in structural formula, encompassing the remainder of the linker; thus, sensitivity to reverse michael addition is reduced. Those skilled in the art will appreciate that the self-stabilizing maleimide is linked to a moiety other than aminomethyl of the in vivo stabilizing conjugate. In the above-described structure, the first and second electrodes are formed on the substrate,

Representing a bond to a binding agent. In the described structure, the first and second electrodes, in some embodiments,

representing click chemistry residues resulting from, for example, the reaction of a binding agent having an azide or alkyne functionality with a linker-payload having a complementary alkyne or azide functionality. In the described structure, in other embodiments,

denotes a divalent sulfide which results from the reaction of, for example, one or more binder cysteines with one or more linkers or linker-payloads having maleimide functionality via a Michael addition reaction. In the described structure, in other embodiments,

refers to amide bonds resulting from, for example, the reaction of one or more binding agents lysine with one or more linkers or linker-payloads having activated or unactivated carboxyl functional groups, as understood by those skilled in the art. In one embodiment of the process of the present invention,

refers to amide bonds resulting from, for example, the reaction of one or more binding agents lysine with one or more linkers or linker-payloads having an activated carboxyl functional group, as understood by those skilled in the art.

In some embodiments, suitable linkers include, but are not limited to, those that chemically bond to two cysteine residues of a single binding agent (e.g., an antibody). Such linkers can be used to mimic the disulfide bond of the antibody that is disrupted by the coupling process.

In some embodiments, the linker comprises one or more amino acids. Suitable amino acids include natural, non-natural, standard, non-standard, proteinogenic, non-proteinogenic, and L-or D-form alpha-amino acids. In some embodiments, the linker comprises alanine, valine, glycine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or citrulline, or a derivative thereof, or any combination thereof (e.g., dipeptides, tripeptides, oligopeptides, polypeptides, etc.). In certain embodiments, one or more side chains of the amino acid are attached to a side chain group as described below. In some embodiments, the linker is a peptide comprising or consisting of the following amino acids: valine and citrulline (e.g., bivalent-Val-Cit-or bivalent-VCit-). In some embodiments, the linker is a peptide comprising or consisting of the following amino acids: alanine and alanine, or divalent-AA-. In some embodiments, the linker is a peptide comprising or consisting of the following amino acids: glutamic acid and alanine, or-EA-. In some embodiments, the linker is a peptide comprising or consisting of the following amino acids: glutamic acid and glycine, or-EG-. In some embodiments, the linker is a peptide comprising or consisting of the following amino acids: glycine and glycine, or-GG-. In some embodiments, the linker is a peptide comprising or consisting of the following amino acids: glutamine, valine and citrulline, or-Q-V-Cit-or-QVCit-. In some embodiments, the linker is a peptide comprising or consisting of the following amino acids: glutamic acid, valine and citrulline, or-E-V-Cit-or-EVCit-. In some embodiments, the linker is a peptide comprising or consisting of the following amino acids: -GGGGS-. In some embodiments, the linker is a peptide comprising or consisting of the following amino acids: -GGGGG-. In some embodiments, the linker is a peptide comprising or consisting of the following amino acids: -GGGGK-. In some embodiments, the linker is a peptide comprising or consisting of the following amino acids: -GFGG-. In some embodiments, the linker is a peptide comprising or consisting of the following amino acids: lysine, valine and citrulline, or-KVCit-. In some embodiments, the linker is a peptide comprising or consisting of the following amino acids: -KVA-. In some embodiments, the linker is a peptide comprising or consisting of the following amino acids: -VA-. As will be understood by those skilled in the art, in any of the embodiments in this paragraph, and throughout this disclosure, standard three-letter or one-letter amino acid designations are used. Exemplary single letter amino acid names include, G for glycine, K for lysine, S for serine, V for valine, a for alanine, and F for phenylalanine.

In some embodiments, the linker comprises a self-degrading (self-immolative) group. The self-degrading group may be any such group known to the skilled person. In a particular embodiment, the self-degrading group is p-aminobenzyl (PAB) or a derivative thereof. Useful derivatives include p-aminobenzyloxycarbonyl (PABC). One skilled in the art will recognize that the self-degrading group is capable of undergoing a chemical reaction that releases the remaining atoms of the linker from the payload.

In some embodiments, the linker is:

wherein:

SP¹is a spacer group;

SP²is a spacer group;

is one or more bonds linked to the binding agent;

is one or more keys connected to the payload;

each AA is an amino acid residue; and

n is an integer from 0 to 10.

SP¹The spacer group is a (AA)_nMoieties or residues are attached to the Binder (BA) or to a radical moiety attached to a reactive group residue attached to BA. Suitable SP¹Spacer groups include, but are not limited to, those containing alkylene groups or polyethers or both alkylene and polyethers. The end of the spacer group, e.g. the moiety to which the spacer group is attached to said BA or AA, may be a moiety derived from a reactive group moiety used for the purpose of coupling the antibody or AA to the spacer group during chemical synthesis of the conjugate. In certain embodiments, n is 1, 2, 3, or 4. In a particular embodiment, n is 2. In a particular embodiment, n is 3. In a particular embodiment And n is 4. In a particular embodiment, when n is 0, then (AA)_nIs a bond.

In some embodiments, SP¹The spacer group comprises an alkylene group. In some embodiments, SP¹The spacer group comprising C_5-7An alkylene group. In some embodiments, SP¹The spacer group comprises a polyether. In some embodiments, SP¹The spacer group comprises an ethylene oxide containing polymer, such as polyethylene glycol.

In some embodiments, SP¹The spacer group is:

wherein:

RG' is the active group residue after the active group RG reacts with the binding agent;

is a bond to the binding agent;

is and (AA)_nA linked bond, wherein n is an integer from 0 to 10; and

b is an integer from 2 to 8.

The reactive group RG can be any reactive group known to those skilled in the art that is capable of being linked to a binding agent to form one or more bonds. The reactive group RG is included in its structure that is capable of reacting with a binding agent (e.g., reacting with an antibody at a cysteine or lysine residue or an azide group portion of the antibody, e.g., with PEG-N at one or more glutamine residues₃Functionalized antibody) to form a moiety of the compound of formula III. After coupling with the binding agent, the reactive group becomes a reactive group residue (RG'). Exemplary reactive groups include, but are not limited to, those containing haloacetyl groups capable of reacting with a binding agent, isothiocyanates, succinimides, N-hydroxysuccinimides, or equines Those reactive groups of the imide moiety.

In certain embodiments, reactive groups include, but are not limited to, alkynes. In certain embodiments, the alkyne is an alkyne, such as a strained alkyne, capable of 1, 3-cycloaddition with an azide in the absence of a copper catalyst. Strained alkynes are suitable for strain-promoted alkyne-azide cycloaddition (SPAAC) and include cycloalkynes, such as cyclooctynes, and benzocycloated alkynes. Suitable alkynes include, but are not limited to, dibenzoazacyclooctyne or

(DIBAC); dibenzocyclooctyne or

(DIBO); diaryl azacyclooctynone or

(BARAC); cyclooctyne difluoride or

Or

(DIFO); substituted, e.g. fluorinated alkynes, aza-cycloalkynes, bicyclo [6.1.0]Nonene or

(BCN); and derivatives thereof. Particularly useful alkynes include

In certain embodiments, the binding agent is directly linked to RG'. In certain embodiments, the binding agent is through a spacer group such as SP⁴(located in

And RG ') to RG'. In particular embodiments, the binding agent is through SP⁴(e.g., a PEG spacer group) is indirectly attached to RG'. As discussed in detail below, in certain embodiments, the binding agent is prepared by functionalization with one or more azide groups. Each azido group is individually capable of reacting with RG to form RG'. In particular embodiments, the binding agent employs-PEG-N linked to a glutamine residue ₃And (4) derivation. The invention provides an exemplary-N₃Derivatized binding agents, methods of making them, and methods of their use in reactions with RG. In certain embodiments, RG is an alkyne suitable for participating in a 1, 3-cycloaddition, and RG' is a regioisomeric 1,2, 3-triazolyl moiety formed by the reaction of RG with an azido-functionalized binding agent. As a further example, in certain embodiments RG' is linked to a binding agent, e.g.

As shown, or a mixture of regioisomers. Each of R and R' has the definitions or is as exemplified herein.

SP²Spacer groups, when present, are (AA)_nThe moiety is attached to a payload moiety. Suitable spacer groups include, but are not limited to, those described above as SP¹Those of spacer groups. Other suitable SPs²Spacer groups include, but are not limited to, those comprising alkylene groups or polyethers or both alkylene and polyethers. SP²The end of the spacer group (e.g., the portion of the spacer group directly attached to the payload or AA) can be a moiety derived from a reactive group moiety used to couple the payload or AA to the SP during chemical synthesis of the conjugate²The purpose of the spacer coupling. In some embodiments, SP ²The end of the spacer group (e.g., SP directly attached to the payload or AA)²Part of a spacer group) may be the residue of a reactive group moiety used to attach a payload or AA to a spacer group during chemical synthesis of the conjugateThe purpose of the group coupling.

In some embodiments, SP²A spacer group, when present, selected from the group consisting of: -NH- (p-C)₆H₄)-CH₂–、–NH-(p-C₆H₄)-CH₂OC (O) -, amino acids, dipeptides, tripeptides, oligopeptides, -O-, -N (H) -, and,

And any combination thereof. In certain embodiments, each

Respectively, a key connected to said payload, and each

Are respectively and (AA)_nA linked key.

In the above formulae, each (AA)_nRespectively an amino acid, or optionally a p-aminobenzyloxycarbonyl residue (PABC),

if a PABC is present, in certain embodiments, it is preferred that only one PABC be present. In certain embodiments, if a PABC residue is present, then the linkage is to (AA)_nThe terminal AA in the group is located proximal to the payload. If it is not

If present, then only

Are present. In certain embodiments, the

The residue, if present, is attached to the payload through the benzyloxycarbonyl moiety and no AA is present. Suitable amino acids for each AA include natural, non-natural, standard, non-standard, proteinogenic, non-proteinogenic, and L-or D-form alpha-amino acids. In some embodiments, the AA comprises alanine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or citrulline, derivatives thereof, or any combination thereof (e.g., dipeptides, tripeptides, oligopeptides, and the like). In certain embodiments, one or more side chains of the amino acid are attached to a side chain group as described below. In some embodiments, n is 2. In some embodiments, the (AA) _nIs valine-citrulline. In some embodiments, (AA)_nIs citrulline-valine. In some embodiments, (AA)_nIs valine-alanine. In some embodiments, (AA)_nIs alanine-valine. In some embodiments, (AA)_nIs valine-glycine. In some embodiments, (AA)_nIs glycine-valine. In some embodiments, n is 3. In some embodiments, the (AA)_nIs valine-citrulline-PABC. In some embodiments, (AA)_nIs citrulline-valine-PABC. In some embodiments, (AA)_nIs glutamic acid-valine-citrulline. In some embodiments, (AA)_nIs glutamine-valine-citrulline. In some embodiments, (AA)_nIs lysine-valine-alanine. In some embodiments, (AA)_nIs lysine-valine-citrulline. In some embodiments, n is 4. In some embodiments, (AA)_nIs glutamic acid-valine-citrulline-PABC. In some embodiments, (AA)_nIs glutamine-valine-citrulline-PABC. The skilled artisan will recognize that PABC is the residue of a p-aminobenzyloxycarbonyl group having the structure:

the PABC residues have been shown to assist in cleavage of certain linkers in vitro and in vivo. The skilled artisan will recognize that PAB is p-aminobenzyl or-NH- (p-C) ₆H₄)-CH₂A divalent residue of (A-A).

In some embodiments, the linker is:

wherein:

each one of

Each a bond to the binding agent;

each one of

Each a key connected to the payload;

each R⁹Are respectively-CH₃Or- (CH)₂)₃N(H)C(O)NH₂(ii) a And

each A is-O-, -NH-,

wherein ZZ is H, alkylene, heteroalkylene, or a side chain of an amino acid as discussed elsewhere herein. As discussed above, the bond attached to the binding agent mayEither directly or via a spacer group. In certain embodiments, the bond attached to the binding agent is a glutamine residue attached to the binding agent via a PEG spacer group.

In some embodiments, the linker is:

wherein:

each one of

Each a bond to the binding agent;

each one of

Each a key connected to the payload;

each R⁹Are respectively-CH₃Or- (CH)₂)₃N(H)C(O)NH₂(ii) a And

each A is independently-O-, -N (H) -,

wherein ZZ is H, alkylene, heteroalkylene, or a side chain of an amino acid as discussed elsewhere herein. As discussed above, the bond to the binding agent may be direct or via a spacer. In certain embodiments, the bond attached to the binding agent is a glutamine residue attached to the binding agent via a PEG spacer group.

In any of the above embodiments, the (AA)_nThe groups may be modified with one or more reinforcing groups. Advantageously, the reinforcing group may be attached to (AA)_nThe side chain of any amino acid in (a). Useful amino acids for attachment of the enhancing group include lysine, asparagine, aspartic acid, glutamine, glutamic acid, and citrulline. The attachment to the enhancing group may be a direct attachment to the amino acid side chain, or the attachment may be indirect via a spacer and/or a reactive group. Useful spacer and reactive groups include any of the above groups. The reinforcing group may be any group which the skilled person would consider useful. For example, the enhancing group can be any group that confers a beneficial effect on the compound, prodrug, payload, linker-payload, or antibody conjugate, including but not limited to biological, biochemical, synthetic, solubilizing, imaging, detecting, and reactivity/activity aspects, and the like. In certain embodiments, the reinforcing group is a hydrophilic group. In certain embodiments, the enhancing group is a cyclodextrin. In certain embodiments, the enhancing group is an alkyl sulfonic acid, heteroalkyl sulfonic acid, alkylene sulfonic acid, heteroalkylene taurine, heteroalkylene phosphoric acid or phosphate, heteroalkylene amine (e.g., quaternary amine), or heteroalkylene sugar. In certain embodiments, sugars include, but are not limited to, monosaccharides, disaccharides, and polysaccharides. Exemplary monosaccharides include glucose, ribose, deoxyribose, xylose, arabinose, mannose, galactose, fructose, and the like. In certain embodiments, the sugar comprises a sugar acid such as glucuronic acid, further comprising a coupled form such as glucuronic acids (i.e., via glucuronidation). Exemplary disaccharides include maltose, sucrose, lactose, lactulose, trehalose, and the like. Exemplary polysaccharides include amylose, amylopectin, glycogen, inulin, cellulose and the like. The cyclodextrin may be any cyclodextrin known to the skilled person. In certain embodiments, the cyclodextrin is an alpha-cyclodextrin, beta-cyclodextrin, or gamma-cyclodextrin, or a mixture thereof. In certain embodiments, the cyclodextrin is an a-cyclodextrin. In certain embodiments, the cyclodextrin is β -cyclodextrin. In certain embodiments, the cyclodextrin is gamma-cyclodextrin. In certain embodiments, the enhancing group can improve the solubility of the remainder of the conjugate. In certain embodiments, the alkyl sulfonic acid, heteroalkyl group The sulfonic acid, alkylene sulfonic acid, or heteroalkylene sulfonic acid is substituted or unsubstituted. In certain embodiments, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂)_1-5SO₃H，–(CH₂)_n–NH-(CH₂)_1-5SO₃H，–(CH₂)_n–C(O)NH-(CH₂)_1-5SO₃H，–(CH₂CH₂O)_m–C(O)NH-(CH₂)_1-5SO₃H，–(CH₂)_n–N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂，–(CH₂)_n–C(O)N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂Or is- (CH)₂CH₂O)_m–C(O)N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂Wherein n is 1, 2, 3, 4, or 5, and m is 1, 2, 3, 4, or 5. In one embodiment, the alkyl, or alkylene, sulfonic acid is- (CH)₂)_1-5SO₃H. In another embodiment, the heteroalkylsulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂)_n–NH-(CH₂)_1-5SO₃H, wherein n is 1, 2, 3, 4, or 5. In another embodiment, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂)_n–C(O)NH-(CH₂)_1- ₅SO₃H, wherein n is 1, 2, 3, 4, or 5. In another embodiment, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂CH₂O)_m–C(O)NH-(CH₂)_1-5SO₃H, wherein m is 1, 2, 3, 4, or 5. In another embodiment, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂)_n–N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂Wherein n is 1, 2, 3, 4Or 5. In another embodiment, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂)_n–C(O)N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂Wherein n is 1, 2, 3, 4, or 5. In another embodiment, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH) ₂CH₂O)_m–C(O)N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂Wherein m is 1, 2, 3, 4, or 5. In some embodiments, the linker is:

wherein:

SP¹is a spacer group;

SP²is a spacer group;

SP³is a spacer group, attached to (AA)_nAA of (1);

is one or more bonds linked to the binding agent;

is one or more keys connected to the payload;

is one or more bonds linked to the enhancing group EG;

each AA is an amino acid; and

n is an integer from 1 to 10.

As discussed above, the bond to the binding agent may be direct, or via a spacer. In certain embodiments, the bond attached to the binding agent is a glutamine residue attached to the binding agent via a PEG spacer group.

SP¹The spacer group has the definition as described above. SP²The spacer group has the definition as described above. Each (AA)_nThe groups each have the definitions as described above.

SP³The spacer group is a (AA)_nMoiety to a reinforcing group (EG). Suitable SP³Spacer groups include, but are not limited to, those comprising alkylene groups or polyethers, or both alkylene groups and polyethers. SP³The end of the spacer group (i.e., SP directly attached to the reinforcing group or AA)³Part of a spacer group) may be a moiety derived from a reactive group moiety used to reinforce groups or AA and SP during chemical synthesis of the conjugate ³The purpose of the spacer coupling. In some embodiments, SP³The end of the spacer group (i.e., the portion of the spacer group directly attached to the enhancing group or AA) may be the residue of a reactive group moiety that is used for the purpose of coupling the enhancing group or AA to the spacer group during chemical synthesis of the conjugate. In certain embodiments, SP³Is a spacer group, attached to (AA)_nOne and only one AA. In certain embodiments, SP³The spacer group is attached to (AA)_nThe side chain of a lysine residue of (a).

In some embodiments, SP³The spacer group is:

wherein:

RG' is the active group residue after the reaction of the active group RG and the enhancer EG;

is a bond to the enhancer;

is and (AA)_nA linked key;

a is an integer from 2 to 8; and

n is an integer from 1 to 4.

The reactive group RG may be any reactive group known to the person skilled in the art that is capable of linking to an enhancer to form one or more bonds. The reactive group RG is a group moiety that comprises in its structure a moiety capable of reacting with a reinforcing group to form a compound of formula II or III. After coupling with the reinforcing group, the reactive group becomes a reactive group residue (RG'). The reactive group RG can be any of the reactive groups described above. Exemplary reactive groups include, but are not limited to, those comprising haloacetyl, isothiocyanate, succinimide, N-hydroxysuccinimide, or maleimide moieties capable of reacting with the binding agent.

In certain embodiments, reactive groups include, but are not limited to, alkynes. In certain embodiments, the alkyne is an alkyne, such as a strained alkyne, capable of 1, 3-cycloaddition with an azide in the absence of a copper catalyst. Strained alkynes are those suitable for strain-promoted alkyne-azide cycloaddition (SPAAC), cycloalkynes, such as cyclooctynes, and benzocyclized alkynes. Suitable alkynes include, but are not limited to, dibenzoazacyclooctyne or

(DIBAC), dibenzocyclooctyne or

(DIBO), a diarylazacyclooctynone or

(BARAC), difluorocyclooctyne or

Or

(DIFO) takingSubstituted, e.g. fluorinated alkynes, aza-cycloalkynes, bicyclo [6.1.0]Nonene or

(BCN), and derivatives thereof. Particularly useful alkynes include

In some embodiments, the linker is:

wherein:

PEG is-NH-PEG 4-C (O) -;

SP²is a spacer group;

SP³is a spacer group, attached to (AA)_nAA of (1);

is one or more bonds linked to the binding agent;

is one or more keys connected to the payload;

is one or more bonds linked to the enhancing group EG;

Each AA is an amino acid residue; and

n is an integer from 1 to 10.

In certain embodiments, the linker is:

or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, or a regioisomer thereof, or a mixture of regioisomers thereof, wherein:

each one of

Each a bond to the binding agent;

each one of

Each a key connected to the payload;

each one of

Each a bond to the enhancer;

each R⁹Are respectively-CH₃Or- (CH)₂)₃N(H)C(O)NH₂(ii) a And

each A is independently-O-, -N (H) -,

wherein ZZ is H, alkylene, heteroalkylene, or a side chain of an amino acid as discussed elsewhere herein. In certain embodiments, the 1, 3-cycloaddition or SPAAC regioisomer, or mixture of regioisomers, is derived from PEG-N treated with a suitable alkyne₃Derivatizing the antibody. For example, in one embodiment, the linker is:

or a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof, or a regioisomer thereof, or a mixture of regioisomers thereof. As another example, in one embodiment, the linker is:

Or a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof, or a regioisomer thereof, or a mixture of regioisomers thereof. As another example, the linker is:

or a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof, or a regioisomer thereof, or a mixture of regioisomers thereof. As discussed above, the bond to the binding agent may be direct, or via a spacer. In certain embodiments, the bond attached to the binding agent is a glutamine residue attached to the binding agent via a PEG spacer group. In certain embodiments, the enhancer is a hydrophilic group. In certain embodiments, the enhancer is a cyclodextrin. In certain embodiments, the reinforcing group is an alkylsulfonic acid, a heteroalkylsulfonic acid, an alkylenesulfonic acid, a heteroalkylenesulfonic acid, a heteroalkyleneA taurine radical, a heteroalkylene phosphoric acid or phosphate radical, a heteroalkylene amine (e.g., a quaternary amine), or a heteroalkylene sugar. In certain embodiments, sugars include, but are not limited to, monosaccharides, disaccharides, and polysaccharides. Exemplary monosaccharides include glucose, ribose, deoxyribose, xylose, arabinose, mannose, galactose, fructose, and the like. In certain embodiments, the sugar comprises a sugar acid such as glucuronic acid, further comprising a coupled form such as glucuronic acids (i.e., via glucuronidation). Exemplary disaccharides include maltose, sucrose, lactose, lactulose, trehalose, and the like. Exemplary polysaccharides include amylose, amylopectin, glycogen, inulin, cellulose and the like. The cyclodextrin may be any cyclodextrin known to the skilled person. In certain embodiments, the cyclodextrin is an alpha-cyclodextrin, beta-cyclodextrin, or gamma-cyclodextrin, or a mixture thereof. In certain embodiments, the cyclodextrin is an a-cyclodextrin. In certain embodiments, the cyclodextrin is β -cyclodextrin. In certain embodiments, the cyclodextrin is gamma-cyclodextrin. In certain embodiments, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH) ₂)_1-5SO₃H，–(CH₂)_n–NH-(CH₂)_1-5SO₃H，–(CH₂)_n–C(O)NH-(CH₂)_1-5SO₃H，–(CH₂CH₂O)_m–C(O)NH-(CH₂)_1-5SO₃H，–(CH₂)_n–N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂，–(CH₂)_n–C(O)N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂Or is- (CH)₂CH₂O)_m–C(O)N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂Wherein n is 1, 2, 3, 4, or 5, and m is 1, 2, 3, 4, or 5. In one embodiment, the alkyl, or alkylene, sulfonic acid is- (CH)₂)_1-5SO₃H. In another embodiment, the heteroalkylsulfonic acid, or heteroalkylenesulfonic acid, is–(CH₂)_n–NH-(CH₂)_1-5SO₃H, wherein n is 1, 2, 3, 4, or 5. In another embodiment, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂)_n–C(O)NH-(CH₂)_1- ₅SO₃H, wherein n is 1, 2, 3, 4, or 5. In another embodiment, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂CH₂O)_m–C(O)NH-(CH₂)_1-5SO₃H, wherein m is 1, 2, 3, 4, or 5. In another embodiment, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂)_n–N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂Wherein n is 1, 2, 3, 4, or 5. In another embodiment, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂)_n–C(O)N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂Wherein n is 1, 2, 3, 4, or 5. In another embodiment, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂CH₂O)_m–C(O)N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂Wherein m is 1, 2, 3, 4, or 5.

In some embodiments, the linker is:

each one of

Are respectively provided withIs a bond to the binding agent;

each one of

Each a bond to the enhancer;

each one of

Each a key connected to the payload;

each R⁹Are respectively-CH₃Or- (CH)₂)₃N(H)C(O)NH₂(ii) a And

each A is independently-O-, -N (H) -,

wherein ZZ is H, alkylene, heteroalkylene, or a side chain of an amino acid as discussed elsewhere herein. As discussed above, the bond to the binding agent may be direct or via a spacer. In certain embodiments, the bond attached to the binding agent is a glutamine residue attached to the binding agent via a PEG spacer group. In certain embodiments, the enhancer is a hydrophilic group. In certain embodiments, the enhancer is a cyclodextrin. In certain embodiments, the enhancing group is an alkyl sulfonic acid, heteroalkyl sulfonic acid, alkylene sulfonic acid, heteroalkylene taurine, heteroalkylene phosphoric acid or phosphate, heteroalkylene amine (e.g., quaternary amine), or heteroalkylene sugar. In certain embodiments, sugars include, but are not limited to, monosaccharides, disaccharides, and polysaccharides. Exemplary monosaccharides include glucose, ribose, deoxyribose, xylose, arabinose, mannose, galactose, fructose, and the like. In certain embodiments, the sugar comprises a sugar acid such as glucuronic acid, further comprising a coupled form such as glucuronic acids (i.e., via glucuronidation). Exemplary disaccharides include maltose, sucrose, lactose, lactulose, trehalose, and the like. Exemplary polysaccharides include amylose, amylopectin Amylose, glycogen, inulin, cellulose and the like. The cyclodextrin may be any cyclodextrin known to the skilled person. In certain embodiments, the cyclodextrin is an alpha-cyclodextrin, beta-cyclodextrin, or gamma-cyclodextrin, or a mixture thereof. In certain embodiments, the cyclodextrin is an a-cyclodextrin. In certain embodiments, the cyclodextrin is β -cyclodextrin. In certain embodiments, the cyclodextrin is gamma-cyclodextrin. In certain embodiments, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂)_1-5SO₃H，–(CH₂)_n–NH-(CH₂)_1-5SO₃H，–(CH₂)_n–C(O)NH-(CH₂)_1-5SO₃H，–(CH₂CH₂O)_m–C(O)NH-(CH₂)_1-5SO₃H，–(CH₂)_n–N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂，–(CH₂)_n–C(O)N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂Or is- (CH)₂CH₂O)_m–C(O)N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂Wherein n is 1, 2, 3, 4, or 5, and m is 1, 2, 3, 4, or 5. In one embodiment, the alkyl, or alkylene, sulfonic acid is- (CH)₂)_1-5SO₃H. In another embodiment, the heteroalkylsulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂)_n–NH-(CH₂)_1-5SO₃H, wherein n is 1, 2, 3, 4, or 5. In another embodiment, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂)_n–C(O)NH-(CH₂)_1- ₅SO₃H, wherein n is 1, 2, 3, 4, or 5. In another embodiment, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH) ₂CH₂O)_m–C(O)NH-(CH₂)_1-5SO₃H, wherein m is 1, 2, 3, 4, or 5. In another embodiment, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂)_n–N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂Wherein n is 1, 2, 3, 4, or 5. In another embodiment, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂)_n–C(O)N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂Wherein n is 1, 2, 3, 4, or 5. In another embodiment, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂CH₂O)_m–C(O)N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂Wherein m is 1, 2, 3, 4, or 5.

In some embodiments, the linker is:

each one of

Each a bond to the binding agent;

each one of

Each a key connected to the payload;

R⁹is-CH₃Or- (CH)₂)₃N(H)C(O)NH₂(ii) a And

a is-O-, -N (H) -,

In some embodiments, the linker is:

each one of

Each a bond to the binding agent;

each one of

Each a key connected to the payload;

R⁹is-CH₃Or- (CH)₂)₃N(H)C(O)NH₂(ii) a And

a is-O-, -N (H) -,

wherein ZZ is H, alkylene, heteroalkylene, or a side chain of an amino acid as discussed elsewhere herein. As discussed above, a bond attached to the binding agentMay be directly attached or attached via a spacer group. In certain embodiments, the bond attached to the binding agent is a glutamine residue attached to the binding agent via a PEG spacer group.

In some embodiments, the linker is:

each one of

Each a bond to the binding agent;

each one of

Each a key connected to the payload;

each one of

Each is a bond to the reinforcing group;

each R⁹Are respectively-CH ₃Or- (CH)₂)₃N(H)C(O)NH₂(ii) a And

each A is independently-O-, -N (H) -,

wherein ZZ is H, alkylene, heteroalkylene, or a side chain of an amino acid as discussed elsewhere herein. As discussed above, the bond to the binding agent may be direct or via a spacer. In certain embodiments, the bond attached to the binding agent is a glutamine residue attached to the binding agent via a PEG spacer groupAnd (4) a base. In certain embodiments, the enhancer is a hydrophilic group. In certain embodiments, the enhancer is a cyclodextrin. In certain embodiments, the enhancing group is an alkyl sulfonic acid, heteroalkyl sulfonic acid, alkylene sulfonic acid, heteroalkylene taurine, heteroalkylene phosphoric acid or phosphate, heteroalkylene amine (e.g., quaternary amine), or heteroalkylene sugar. In certain embodiments, sugars include, but are not limited to, monosaccharides, disaccharides, and polysaccharides. Exemplary monosaccharides include glucose, ribose, deoxyribose, xylose, arabinose, mannose, galactose, fructose, and the like. In certain embodiments, the sugar comprises a sugar acid such as glucuronic acid, further comprising a coupled form such as glucuronic acids (i.e., via glucuronidation). Exemplary disaccharides include maltose, sucrose, lactose, lactulose, trehalose, and the like. Exemplary polysaccharides include amylose, amylopectin, glycogen, inulin, cellulose and the like. The cyclodextrin may be any cyclodextrin known to the skilled person. In certain embodiments, the cyclodextrin is an alpha-cyclodextrin, beta-cyclodextrin, or gamma-cyclodextrin, or a mixture thereof. In certain embodiments, the cyclodextrin is an a-cyclodextrin. In certain embodiments, the cyclodextrin is β -cyclodextrin. In certain embodiments, the cyclodextrin is gamma-cyclodextrin. In certain embodiments, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH) ₂)_1-5SO₃H，–(CH₂)_n–NH-(CH₂)_1-5SO₃H，–(CH₂)_n–C(O)NH-(CH₂)_1- ₅SO₃H，–(CH₂CH₂O)_m–C(O)NH-(CH₂)_1-5SO₃H，–(CH₂)_n–N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂，–(CH₂)_n–C(O)N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂Or is- (CH)₂CH₂O)_m–C(O)N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂Wherein n is 1, 2, 3, 4, or 5, and m is 1, 2, 3, 4, or 5. In one embodiment, the alkyl, or alkylene, sulfonic acid is- (CH)₂)_1-5SO₃H. In another embodiment, the heteroalkylsulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂)_n–NH-(CH₂)_1- ₅SO₃H, wherein n is 1, 2, 3, 4, or 5. In another embodiment, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂)_n–C(O)NH-(CH₂)_1-5SO₃H, wherein n is 1, 2, 3, 4, or 5. In another embodiment, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂CH₂O)_m–C(O)NH-(CH₂)_1- ₅SO₃H, wherein m is 1, 2, 3, 4, or 5. In another embodiment, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂)_n–N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂Wherein n is 1, 2, 3, 4, or 5. In another embodiment, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂)_n–C(O)N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂Wherein n is 1, 2, 3, 4, or 5. In another embodiment, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂CH₂O)_m–C(O)N((CH₂)_1-5C(O)NH(CH₂)_1- ₅SO₃H)₂Wherein m is 1, 2, 3, 4, or 5.

In some embodiments, the linker is:

each one of

Each a bond to the binding agent;

each one of

Each a key connected to the payload;

each R⁹Are respectively-CH₃Or- (CH)₂)₃N(H)C(O)NH₂(ii) a And

each A is independently-O-, -N (H) -,

wherein ZZ is H, alkylene, heteroalkylene, or a side chain of an amino acid as discussed elsewhere herein. As discussed above, the bond to the binding agent may be direct or via a spacer. In certain embodiments, the bond attached to the binding agent is a glutamine residue attached to the binding agent via a PEG spacer group. In certain embodiments, the enhancer is a hydrophilic group. In certain embodiments, the enhancer is a cyclodextrin. In certain embodiments, the enhancing group is an alkyl sulfonic acid, heteroalkyl sulfonic acid, alkylene sulfonic acid, heteroalkylene taurine, heteroalkylene phosphoric acid or phosphate, heteroalkylene amine (e.g., quaternary amine), or heteroalkylene sugar. In certain embodiments, sugars include, but are not limited to, monosaccharides, disaccharides, and polysaccharides. Exemplary monosaccharides include glucose, ribose, deoxyribose, xylose, arabinose, mannose, galactose, fructose, and the like. In certain embodiments, the sugar comprises a sugar acid such as glucuronic acid, further comprising a coupled form such as glucuronic acids (i.e., via glucuronidation). Exemplary disaccharides include maltose, sucrose, lactose Lactulose, trehalose, and the like. Exemplary polysaccharides include amylose, amylopectin, glycogen, inulin, cellulose and the like. The cyclodextrin may be any cyclodextrin known to the skilled person. In certain embodiments, the cyclodextrin is an alpha-cyclodextrin, beta-cyclodextrin, or gamma-cyclodextrin, or a mixture thereof. In certain embodiments, the cyclodextrin is an a-cyclodextrin. In certain embodiments, the cyclodextrin is β -cyclodextrin. In certain embodiments, the cyclodextrin is gamma-cyclodextrin. In certain embodiments, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂)_1-5SO₃H，–(CH₂)_n–NH-(CH₂)_1-5SO₃H，–(CH₂)_n–C(O)NH-(CH₂)_1- ₅SO₃H，–(CH₂CH₂O)_m–C(O)NH-(CH₂)_1-5SO₃H，–(CH₂)_n–N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂，–(CH₂)_n–C(O)N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂Or is- (CH)₂CH₂O)_m–C(O)N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂Wherein n is 1, 2, 3, 4, or 5, and m is 1, 2, 3, 4, or 5. In one embodiment, the alkyl, or alkylene, sulfonic acid is- (CH)₂)_1-5SO₃H. In another embodiment, the heteroalkylsulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂)_n–NH-(CH₂)_1- ₅SO₃H, wherein n is 1, 2, 3, 4, or 5. In another embodiment, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂)_n–C(O)NH-(CH₂)_1-5SO₃H, wherein n is 1, 2, 3, 4, or 5. In another embodiment, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH) ₂CH₂O)_m–C(O)NH-(CH₂)_1- ₅SO₃H, wherein m is 1, 2, 3, 4, or 5. In another embodiment, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂)_n–N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂Wherein n is 1, 2, 3, 4, or 5. In another embodiment, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂)_n–C(O)N((CH₂)_1-5C(O)NH(CH₂)_1-5SO₃H)₂Wherein n is 1, 2, 3, 4, or 5. In another embodiment, the alkylsulfonic acid, heteroalkylsulfonic acid, alkylenesulfonic acid, or heteroalkylenesulfonic acid is- (CH)₂CH₂O)_m–C(O)N((CH₂)_1-5C(O)NH(CH₂)_1- ₅SO₃H)₂Wherein m is 1, 2, 3, 4, or 5.

In some embodiments, the linker is:

each one of

Each a bond to the binding agent;

each one of

Each a key connected to the payload;

R⁹is-CH₃Or- (CH)₂)₃N(H)C(O)NH₂(ii) a And

a is-O-, -N (H) -,

In some embodiments, the linker is:

each one of

Each a bond to the binding agent;

each one of

Each a key connected to the payload;

R⁹is-CH₃Or- (CH)₂)₃N(H)C(O)NH₂(ii) a And

a is-O-, -N (H) -,

wherein ZZ is H, alkylene, heteroalkylene,Or the side chain of an amino acid as discussed elsewhere in the invention. As discussed above, the bond to the binding agent may be direct or via a spacer. In certain embodiments, the bond attached to the binding agent is a glutamine residue attached to the binding agent via a PEG spacer group.

Linker-payload

In certain embodiments, linker-payloads include any particular compound, prodrug, or payload comprised by any one or more of formulas I, Ia, Iaaa, Ib, Ibb, and Ibbb described above that is linked to a linker, wherein the linker of the invention includes a moiety that is reactive with an antibody or antigen-binding fragment thereof described herein. In certain embodiments, the linker is attached to the primary or secondary nitrogen in any one or more of formulas I, Ia, Iaa, Iaaa, Ib, Ibb, Ibbb, or IV. In one embodiment of formula II, when D is the residue of a biologically active compound comprising a hydroxyl group, an amino group or a thiol, then said biologically active compound or residue thereof is an anti-inflammatory biologically active compound or residue thereof. In another embodiment of formula II, the anti-inflammatory biologically active compound is a steroid or a residue thereof. In another embodiment of formula II, the anti-inflammatory biologically active compound is an LXR agonist or a residue thereof. In one embodiment, the linker-payload has a structure represented by formula IIa:

Or a pharmaceutically acceptable salt thereof, wherein L is a linker comprising a moiety that reacts with the antibody or antigen-binding fragment thereof; r^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, or alkylene, wherein when R is^1aWhen alkylene, the alkylene is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; r²Is H, or an amino acid side chain; r³Is H, alkyl, or alkylene, wherein when R is³Is alkyleneWhen said alkylene is further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group, or a residue of a biologically active compound comprising a hydroxyl group; and n is 0, 1, 2, 3, 4, 5, or 6. In another embodiment, the linker-payload has the structure of formula IIaa:

or a pharmaceutically acceptable salt thereof, wherein L is a linker comprising a moiety that reacts with the antibody or antigen-binding fragment thereof; r^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, alkylene, or heteroalkylene, wherein when R is^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R ³To form a heterocyclic group of 4, 5, or 6 atoms; r²Is H, alkylene, heteroalkylene, or an amino acid side chain, wherein when R is²When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r³Is H, alkyl, alkylene, or heteroalkylene, wherein when R is³When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R^1aOr R²To form said heterocyclic group of 4, 5, or 6 atoms; r⁶Is H, or alkyl; d is an acyl group, or a residue of a biologically active compound comprising a hydroxyl group, an amino group, or a thiol; and n is 0, 1, 2, 3, 4, or 5. In another embodiment, the linker-payload has the structure of formula IIaaa:

or a pharmaceutically acceptable salt thereof, wherein L is a linker comprising a moiety that reacts with the antibody or antigen-binding fragment thereof; r^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, alkylene, or heteroalkylene, wherein when R is^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R ³To form a heterocyclic group of 4, 5, or 6 atoms; r²Is H, alkylene, heteroalkylene, or an amino acid side chain, wherein when R is²When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r³Is H, alkyl, alkylene, or heteroalkylene, wherein when R is³When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R^1aOr R²To form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group, or a residue of a biologically active compound comprising a hydroxyl group, an amino group, or a thiol; and n is 0, 1, 2, 3, 4, or 5. In another embodiment, the linker-payload has a structure according to formula IIb:

or a pharmaceutically acceptable salt thereof, wherein L is a linker comprising a moiety that reacts with the antibody or antigen-binding fragment thereof; r^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, or alkylene, wherein when R is^1aWhen alkylene, the alkylene is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; r²Is H, or an amino acid side chain; r ³Is H, alkyl, or alkylene, wherein when R is³When alkylene, the alkylene is further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group, or a residue of a biologically active compound comprising a hydroxyl group; and n is 0, 1, 2, 3, 4, 5, or 6. In another embodiment, the linker-payload has the structure of formula IIbb:

or a pharmaceutically acceptable salt thereof, wherein L is a linker comprising a moiety that reacts with the antibody or antigen-binding fragment thereof; r^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, alkylene, or heteroalkylene, wherein when R is^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r²Is H, alkylene, heteroalkylene, or an amino acid side chain, wherein when R is²When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r³Is H, alkyl, alkylene, or heteroalkylene, wherein when R is³When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R ^1aOr R²To form said heterocyclic group of 4, 5, or 6 atoms; r⁶Is H, or alkyl; d is an acyl group, or a residue of a biologically active compound comprising a hydroxyl group, an amino group, or a thiol; and n is 0, 1, 2, 3, 4, or 5. In another embodiment, the linker-payload has the structure of formula IIbbb:

or a pharmaceutically acceptable salt thereof, wherein L is a linker comprising a moiety that reacts with the antibody or antigen-binding fragment thereof; r^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, alkylene, or heteroalkylene, wherein when R is^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms；R²Is H, alkylene, heteroalkylene, or an amino acid side chain, wherein when R is²When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r³Is H, alkyl, alkylene, or heteroalkylene, wherein when R is³When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R ^1aOr R²To form said heterocyclic group of 4, 5, or 6 atoms; d is an acyl group, or a residue of a biologically active compound comprising a hydroxyl group, an amino group, or a thiol; and n is 0, 1, 2, 3, 4, or 5. In any of the above embodiments of IIa, IIaa, IIaaa, IIb, IIbb, and IIbbb, the linker further comprises

In one embodiment, the linker-payload has a structure according to formula IV:

or a pharmaceutically acceptable salt thereof, wherein R^1a、R^1b、R²、R³D and n are as described in any of the embodiments of the present disclosure, and wherein SP¹And SP²When present, are spacer groups, wherein SP¹Further comprising a moiety reactive with the antibody or antigen-binding fragment thereof; each AA is an amino acid; and p is an integer from 1 to 10. In one embodiment, the linker-payload has the structure of formula IVa:

or a pharmaceutically acceptable salt thereof, wherein R^1a、R^1b、R²、R³D and n are as described in any of the embodiments of the present disclosure, and wherein SP¹When present, is a spacer group, wherein SP¹Further comprising antibodiesOr an antigen binding fragment thereof; each AA is an amino acid; and p is an integer from 1 to 10. In certain embodiments of formula IV or formula IVa, R ^1aAnd R^1bAre all H; r²Is H or methyl; r³Is H; and n is 2. In another embodiment of formula IV or formula IVa, D is H. In another embodiment of formula IV or formula IVa, D is the residue of a biologically active compound comprising a hydroxyl group. In another embodiment of formula IV or formula IVa, the linker-payload is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof. In certain embodiments of this paragraph, all diastereomers are contemplated. For example, in one embodiment, the stereochemistry at the acetal is undefined or racemic. As a further example, in one embodiment, the stereochemistry at the acetal is (R) -. As a further example, in one embodiment, the stereochemistry at the acetal is (S) -. As a further example, in one embodiment the stereochemistry at the acetal is an excess of (R) -over (S) -. As a further example, in one embodiment the stereochemistry at the acetal is an excess of (S) -over (R) -. In any of the embodiments in this paragraph, p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In any of the embodiments in this paragraph, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

In certain embodiments of formula IV or formula IVa, R^1aAnd R^1bAre all H; r²Is H, methyl, or-CH₂Ph；R³Is H, or alkyl; and n is 1. In another embodiment of formula IV or formula IVa, D is H. In another embodiment of formula IV or formula IVa, D is the residue of a biologically active compound comprising a hydroxyl group. In another embodiment of formula IV or formula IVa, the linker-payload is selected from the group consisting of:

In certain embodiments of formula IV or formula IVa, R^1aAnd R^1bAre all H; r²Is H; r³Is an alkyl group; and n is 1. In another embodiment of formula IV or formula IVa, D is H. In another embodiment of formula IV or formula IVa, D is the residue of a biologically active compound comprising a hydroxyl group. In another embodiment of formula IV or formula IVa, the linker-payload has the structure

In certain embodiments of formula IV or formula IVa, R^1aIs alkyl or aralkyl; r^1bIs H; r²Is H; r³Is H; and n is 1. In another embodiment of formula IV or formula IVa, D is H. In another embodiment of formula IV or formula IVa, D is the residue of a biologically active compound comprising a hydroxyl group. In another embodiment of formula IV or formula IVa, the linker-payload is selected from the group consisting of:

In certain embodiments of formula IV or formula IVa, R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; r^1bIs H; r²Is H; r³Is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; and n is 1. In another embodiment of formula IV or formula IVa, D is H. In another embodiment of formula IV or formula IVa, D is the residue of a biologically active compound comprising a hydroxyl group. In another embodiment of formula IV or formula IVa, the linker-payload is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof. In another embodiment of formula IV or formula IVa, the linker-payload has the structure

In certain embodiments of formula IV or formula IVa, R^1aAnd R^1bAre all H; r²Is H; r³Is H; and n is 1. In another embodiment of formula IV or formula IVa, D is H. In another embodiment of formula IV or formula IVa, D is the residue of a biologically active compound comprising a hydroxyl group. In another embodiment of formula IV or formula IVa, the linker-payload is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof. In certain embodiments of this paragraph, all diastereomers are contemplated.

In certain embodiments of formula IV or formula IVa, R^1aAnd R^1bAre all H; r²Is H, or-CH₂Ph；R³Is H; and n is 4. In another embodiment of formula IV or formula IVa, D is H. In another embodiment of formula IV or formula IVa, D is the residue of a biologically active compound comprising a hydroxyl group. In another embodiment of formula IV or formula IVa, the linker-payload is selected from the group consisting of:

In certain embodiments of formula IV or formula IVa, R^1aAnd R^1bAre all H; r²Is H, or-CH₂OH；R³Is H; and n is 6. In another embodiment of formula IV or formula IVa, D is H. In another embodiment of formula IV or formula IVa, D is the residue of a biologically active compound comprising a hydroxyl group. In another embodiment of formula IV or formula IVa, the linker-payload has the structure:

In certain embodiments of formula IV or formula IVa, R^1aAnd R^1bAre all H; r²Is an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 6 atoms; r³Is an alkylene group, wherein said alkylene group is further bonded to R²To form a heterocyclic group of 6 atoms; and n is 1. In another embodiment of formula IV or formula IVa, D is H. In another embodiment of formula IV or formula IVa, D is the residue of a biologically active compound comprising a hydroxyl group. In another embodiment of formula IV or formula IVa, the linker-payload has the structure:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, other linker-payloads are also contemplated. In certain embodiments of formula IIb, R ^1aAnd R^1bAre all H; r³Is H; and n is 0. In another embodiment of formula IIb, D is H. In another embodiment of formula IIb, D is the residue of a biologically active compound comprising a hydroxyl group. In certain embodiments of formula IV or formula IVa, R^1aAnd R^1bAre all H; r²Is H; r³Is an alkyl group; r⁴Is an alkyl group; and n is 1. In another embodiment of formula IV or formula IVa, D is H. In another embodiment of formula IV or formula IVa, D is the residue of a biologically active compound comprising a hydroxyl group. Exemplary such linker-payloads contemplated include, but are not limited to,

conjugate/antibody-drug conjugate (ADC)

The invention provides antibodies or antigen binding fragments thereof, wherein the antibodies are conjugated to one or more compounds of formula I, Ia, Iaaa, Ib, Ibb, Ibbb, II, IIa, Iaaa, IIb, IIbb, IIbbb, and/or IV, as described herein. In one embodiment of formula III, D is the residue of an anti-inflammatory biologically active compound comprising a hydroxyl group, an amino group or a thiol. In another embodiment of formula III, the anti-inflammatory bioactive compound is a steroid or a residue thereof. In another embodiment of formula III, the anti-inflammatory biologically active compound is an LXR agonist or a residue thereof.

The invention provides a conjugate shown in a formula IIIa:

wherein L is a linker; BA is a binder; r^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, or alkylene, wherein when R is^1aWhen alkylene, the alkylene is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; r²Is H, or an amino acid side chain; r³Is H, alkyl, or alkylene, wherein when R is³When alkylene, the alkylene is further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound comprising a hydroxyl group; n is 0, 1, 2, 3, 4, 5, or 6; and k is an integer from 1 to 30. In another embodiment, the invention provides a conjugate of formula IIIaa:

wherein L is a linker; BA is a binder; r^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, alkylene, or heteroalkylene, wherein when R is^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r²Is H, alkylene, heteroalkylene, or an amino acid side chain, wherein when R is ²When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r³Is H, alkyl, alkylene, or heteroalkylene, wherein when R is³When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R^1aOr R²To form said heterocyclic group of 4, 5, or 6 atoms; r⁶Is H, or alkyl; d is the residue of a biologically active compound comprising a hydroxyl group, an amino group, or a thiol; n is 0, 1, 2, 3, 4, or 5; and k is an integer from 1 to 30. In another embodiment, the invention provides a conjugate of formula IIIaaa:

wherein L is a linker; BA is a binder; r^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, alkylene, or heteroalkylene, wherein when R is^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r²Is H, alkylene, heteroalkylene, or an amino acid side chain, wherein when R is²When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R ³To form a heterocyclic group of 4, 5, or 6 atoms; r³Is H, alkyl, alkylene, or heteroalkylene, wherein when R is³When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R^1aOr R²To form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound comprising a hydroxyl group, an amino group, or a thiol; n is 0, 1, 2, 3, 4, or 5; and k is an integer from 1 to 30. The invention also provides a conjugate shown in a formula IIIb:

wherein L is a linker; BA is a binder; r^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, or alkylene, wherein when R is^1aWhen alkylene, the alkylene is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms; r²Is H, or an amino acid side chain; r³Is H, alkyl, or alkylene, wherein when R is³When alkylene, the alkylene is further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound comprising a hydroxyl group; n is 0, 1, 2, 3, 4, 5, or 6; and k is an integer from 1 to 30. In another embodiment, the invention provides a conjugate of formula IIIbb:

Wherein L is a linker; BA is a binder; r^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, alkylene, or heteroalkylene, wherein when R is^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r²Is H, alkylene, heteroalkylene, or an amino acid side chain, wherein when R is²When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r³Is H, alkyl, alkylene, or heteroalkylene, wherein when R is³When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R^1aOr R²To form said heterocyclic group of 4, 5, or 6 atoms; r⁶Is H, or alkyl; d is the residue of a biologically active compound comprising a hydroxyl group, an amino group, or a thiol; n is 0, 1, 2, 3, 4, or 5; and k is an integer from 1 to 30. In addition toIn one embodiment, the invention provides a conjugate of formula IIIbbb:

wherein L is a linker; BA is a binder; r^1aAnd R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, alkylene, or heteroalkylene, wherein when R is ^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r²Is H, alkylene, heteroalkylene, or an amino acid side chain, wherein when R is²When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms; r³Is H, alkyl, alkylene, or heteroalkylene, wherein when R is³When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R^1aOr R²To form said heterocyclic group of 4, 5, or 6 atoms; d is the residue of a biologically active compound comprising a hydroxyl group, an amino group, or a thiol; n is 0, 1, 2, 3, 4, or 5; and k is an integer from 1 to 30. The invention also provides a conjugate shown as the formula V:

wherein BA and R^1a、R^1b、R²、R³D, n and k are as described in any of the embodiments of the present disclosure, and wherein SP¹And SP²When present, are spacer groups, wherein SP¹Further comprising a moiety reactive with the antibody or antigen-binding fragment thereof; each AA is an amino acid; and p is an integer from 1 to 10. In certain embodiments of formula V, the binding agent is according to formula H ₂N-LL-X, wherein LL is selected from the group consisting ofA divalent linker:

a divalent polyethylene glycol (PEG) group;

–(CH₂)_n–；

–(CH₂CH₂O)_n-(CH₂)_p–；

–(CH₂)_n-N(H)C(O)-(CH₂)_m–；

–(CH₂CH₂O)_n-N(H)C(O)-(CH₂CH₂O)_m-(CH₂)_p–；

–(CH₂)_n-C(O)N(H)-(CH₂)_m–；

–(CH₂CH₂O)_n-C(O)N(H)-(CH₂CH₂O)_m-(CH₂)_p–；

–(CH₂)_n-N(H)C(O)-(CH₂CH₂O)_m-(CH₂)_p–；

–(CH₂CH₂O)_n-N(H)C(O)-(CH₂)_m–；

–(CH₂)_n-C(O)N(H)-(CH₂CH₂O)_m-(CH₂)_p-; and

–(CH₂CH₂O)_n-C(O)N(H)-(CH₂)_m–，

wherein

n is an integer selected from 1 to 12;

m is an integer selected from 0 to 12;

p is an integer selected from 0 to 2; and

x is selected from the group consisting of: -SH, -N₃-C.ident.CH, -C (O) H, tetrazole,

In another embodiment of formula V, the binding agent is an antibody modified with a primary amine, orThe primary amines have the following structures:

in another embodiment of formula V, the compound is selected from the group consisting of:

wherein k is 1, 2, 3, or 4. In certain embodiments of this paragraph, all diastereomers are contemplated. For example, in one embodiment, the stereochemistry at the hemiaminylether (or hemiaminal, or N-acyl-N, O-acetal, where each name of this functional group is used interchangeably herein) is undefined or racemic. As a further example, in one embodiment the stereochemistry at the half amine ether is (R) -. As a further example, in one embodiment the stereochemistry at the half amine ether is (S) -. As a further example, in one embodiment the stereochemistry at the half amine ether is (R) -excess over (S) -. As a further example, in one embodiment the stereochemistry at the half amine ether is (S) -excess over (R) -. For example, in one embodiment, the stereochemistry at the acetal is undefined or racemic. As a further example, in one embodiment, the stereochemistry at the acetal is (R) -. As a further example, in one embodiment, the stereochemistry at the acetal is (S) -. As a further example, in one embodiment the stereochemistry at the acetal is an excess of (R) -over (S) -. As a further example, in one embodiment the stereochemistry at the acetal is an excess of (S) -over (R) -. In any of the embodiments in this paragraph, p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In certain embodiments, formula III, IIIa, IIIaa, IIIaaa, IIIb, IIIbb, IIIbbb, and/or V is an antibody-drug conjugate comprising an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof is conjugated to a compound of formula I, Ia, Iaa, Iaaa, Ib, Ibb, Ibbb, II, IIa, IIaa, IIaaa, IIb, IIbb, and/or IIbbb. In another embodiment of formulae III, IIIa, IIIaa, IIIaaa, IIIb, IIIbb, IIIbbb, and/or V, the antibody-drug conjugate is selected from the group consisting of:

in certain embodiments of this paragraph, all diastereomers are contemplated. For example, in one embodiment, the stereochemistry at the hemiaminylether (or hemiaminal, or N-acyl-N, O-acetal, where each name of this functional group is used interchangeably herein) is undefined or racemic. As a further example, in one embodiment the stereochemistry at the half amine ether is (R) -. As a further example, in one embodiment the stereochemistry at the half amine ether is (S) -. As a further example, in one embodiment the stereochemistry at the half amine ether is (R) -excess over (S) -. As a further example, in one embodiment the stereochemistry at the half amine ether is (S) -excess over (R) -. For example, in one embodiment, the stereochemistry at the acetal is undefined or racemic. As a further example, in one embodiment, the stereochemistry at the acetal is (R) -. As a further example, in one embodiment, the stereochemistry at the acetal is (S) -. As a further example, in one embodiment the stereochemistry at the acetal is an excess of (R) -over (S) -. As a further example, in one embodiment the stereochemistry at the acetal is an excess of (S) -over (R) -.

In one embodiment of formula III, IIIa, IIIaa, IIIaaa, IIIb, IIIbb or IIIbbb, BA is an antibody or antigen binding fragment thereof. In another embodiment of formula III, IIIa, IIIaa, IIIaaa, IIIb, IIIbb or IIIbbb, BA is a transglutaminase modified antibody or antigen binding fragment thereof comprising at least one glutamine residue for conjugation. In another embodiment of formula III, IIIa, IIIaa, IIIaaa, IIIb, IIIbb or IIIbbb, BA is a transglutaminase modified antibody or antigen binding fragment thereof comprising at least two glutamine residues for conjugation. In another embodiment of formula III, IIIa, IIIaa, IIIaaa, IIIb, IIIbb or IIIbbb, BA is a transglutaminase modified antibody or antigen binding fragment thereof comprising at least four glutamine residues for conjugation. In another embodiment of formula III, IIIa, IIIaa, IIIaaa, IIIb, IIIbb or IIIbbb, BA is a transglutaminase modified antibody or antigen binding fragment thereof, wherein the coupling is at two Q295 residues; and k is 2. In another embodiment of formula III, IIIa, IIIaa, IIIaaa, IIIb, IIIbb or IIIbbb, BA is a transglutaminase modified antibody or antigen binding fragment thereof, wherein the coupling is at two Q295 residues and two N297Q residues; and k is 4.

In certain embodiments, other antibody-drug conjugates are also contemplated. Exemplary antibody-drug conjugates contemplated include but are not limited to,

or mixtures thereof;

or mixtures thereof;

or mixtures thereof. In any of the embodiments in this paragraph, z or k is 1, 2, 3, or 4.

Methods of making compounds, prodrugs, or payloads and linker-payloads

The compounds provided herein may be prepared, isolated or obtained by any method apparent to those skilled in the art. Exemplary methods of preparation are described in detail in the examples below. In certain embodiments, the compounds provided herein can generally be prepared according to synthesis schemes A-H, J and K. In the following exemplary preparation scheme, R^1a、R^1b、R²、R³、R⁴D and n are as described in the context of the formula of the invention.

Scheme a. exemplary preparation scheme

In scheme a, the amino acid is oxidatively decarboxylated, followed by substitution with a payload (HO — D). The payload derivative is then subjected to further peptide homologation.

Scheme b. exemplary preparation scheme

In scheme B, the amino acid derivative is subjected to oxidative decarboxylation, followed by coupling with a payload (HO-D).

Scheme c. exemplary preparation scheme

In scheme C, linker-payloads were assembled using p-nitrophenyl carbonate.

Scheme d. exemplary preparation scheme

Scheme D also shows the synthesis of an alternative linker-payload. Dipeptide derivatives are homologated under peptide coupling conditions and then deprotected. Coupling of the tripeptide with N-hydroxysuccinimide ester affords the benzyl alcohol shown. Benzyl alcohol is converted to p-nitrophenyl carbonate, which is treated with a payload that provides a penultimate linker-payload. The final hydrolysis provides the linker-payload shown.

Scheme e. exemplary preparation scheme

Scheme E shows another linker-payload synthesis. The tripeptide derivative is coupled with an N-hydroxysuccinimide ester and provides the carboxylic acid as shown in the scheme. The carboxylic acid is activated and coupled to the payload.

Scheme f. exemplary preparation scheme

Other linker-payloads were synthesized according to scheme F. The protected pentapeptide is coupled to a payload under peptide coupling conditions and then deprotected. Subsequent coupling of the peptide to a carboxylic acid provides the linker-payload shown.

Scheme g. exemplary preparation scheme

Still other linker-payloads were synthesized according to scheme G. The payload is coupled with an N-hydroxysuccinimide ester.

Scheme h. exemplary preparation scheme

In scheme H, the synthesis of multiple linker-payloads is shown. The payload is coupled to a protected p-nitrophenyl carbonate and then deprotected. Peptide homologation provides linker-payload intermediates that terminate with (R) -or (S) -amino acids. These terminal amino acids were coupled with N-hydroxysuccinimide esters derived from the corresponding carboxylic acids to provide the linker-payloads shown.

Scheme j. exemplary preparation scheme

Scheme J illustrates a general coupling method of the linker-payload to an antibody or antigen binding fragment thereof. The antibody or antigen-binding fragment thereof is modified via transglutaminase to incorporate a terminal azide for participation in a click chemistry reaction with an alkyne. Thus, a suitable linker-payload is conjugated to an antibody or antigen-binding fragment thereof.

Conjugates of the invention can be synthesized by coupling a linker-payload of the invention to a binding agent (e.g., an antibody) under standard coupling conditions (see, e.g., Doronina et al nature Biotechnology 2003,21,7,778, which is incorporated herein by reference in its entirety). When the binding agent is an antibody, the antibody may be coupled to the linker-payload through one or more cysteine or lysine residues of the antibody. The linker-payload can be conjugated to the cysteine residue, for example, by subjecting the antibody to a reducing agent (e.g., dithiothreitol) to cleave the disulfide bond of the antibody, purifying the reduced antibody, e.g., by gel filtration, and then treating the antibody with a linker-payload containing a suitable reactive group moiety (e.g., a maleimide group). Suitable solvents include, but are not limited to, water, DMA, DMF, and DMSO. A linker-payload containing a reactive group such as an activated ester or acid halide group can be coupled to a lysine residue of the antibody. Suitable solvents include, but are not limited to, water, DMA, DMF, and DMSO. The conjugate can be purified using known protein techniques, including, for example, volume exclusion chromatography (size exclusion chromatography), dialysis, and ultrafiltration/diafiltration.

Binding agents, such as antibodies, may also be conjugated by click chemistry. In some embodiments of the click chemistry reaction, the linker-payload comprises a reactive group capable of regioisomeric 1, 3-cycloaddition reactions with azides, such as an alkyne. Such suitable reactive groups are described above. The antibodies include one or more azide groups. Such antibodies include antibodies functionalized with, for example, azido-polyethylene glycol groups. In certain embodiments, such functionalized antibodies are derived by treating an antibody having at least one glutamine residue (e.g., heavy chain Gln295) with a primary amine compound in the presence of the enzyme transglutaminase. In certain embodiments, such functionalized antibodies are derived by treating an antibody having at least one glutamine residue (e.g., heavy chain Gln297) with a primary amine compound in the presence of the enzyme transglutaminase. Such antibodies include Asn297Gln (N297Q) mutant. In certain embodiments, such functionalized antibodies are derived by treating an antibody having at least two glutamine residues (e.g., heavy chain Gln295 and heavy chain Gln297) with a primary amine compound in the presence of the enzyme transglutaminase. Such antibodies include Asn297Gln (N297Q) mutant. In certain embodiments, the antibody has two heavy chains as described in this paragraph for a total of two or a total of four glutamine residues.

In certain embodiments, the antibody comprises two glutamine residues, one in each heavy chain. In particular embodiments, the antibody comprises Q295 residues in each heavy chain. In further embodiments, the antibody comprises 1, 2, 3, 4, 5, 6, 7, 8, or more glutamine residues. These glutamine residues can be located in the heavy chain, in the light chain, or in both the heavy and light chains. These glutamine residues can be wild-type residues, or engineered residues. The antibodies can be prepared according to standard techniques.

Those skilled in the art will recognize that antibodies are typically glycosylated at residue N297 near residue Q295 in the heavy chain sequence. Glycosylation at residue N297 can interfere with transglutaminase at residue Q295 (Dennler et al, supra). Thus, in an advantageous embodiment, the antibody is not glycosylated. In certain embodiments, the antibody is deglycosylated or aglycosylated. In a particular embodiment, the antibody heavy chain has the N297 mutation. In other words, the antibody is mutated to no longer have an asparagine residue at position 297. In particular embodiments, the antibody heavy chain has the N297Q mutation. Such antibodies can be prepared by site-directed mutagenesis to remove or disable the glycosylation sequence or by site-directed mutagenesis to insert glutamine residues at any site interfering with glycosylation or any other interfering structure. Such antibodies may also be isolated from natural or artificial sources.

The antibody that does not interfere with glycosylation is then reacted with or treated with a primary amine compound. In certain embodiments, the aglycosylated antibody is reacted with or treated with a primary amine compound to produce a glutaminyl-modified antibody. In certain embodiments, the deglycosylated antibody is reacted with or treated with a primary amine compound to produce a glutaminyl-modified antibody.

The primary amine may be any primary amine capable of forming a covalent bond with a glutamine residue in the presence of transglutaminase. Useful primary amines are described below. The transglutaminase may be any transglutaminase considered suitable by the person skilled in the art. In certain embodiments, the transglutaminase is an enzyme that catalyzes the formation of isopeptide bonds between free amine groups on primary amine compounds and acyl groups on the side chains of glutamine residues. Transglutaminase is also known as protein-glutamine-gamma-glutamyltransferase. In a particular embodiment, the transglutaminase is classified as EC 2.3.2.13. The transglutaminase may be from any source deemed suitable. In certain embodiments, the transglutaminase is a microorganism. Useful transglutaminases have been isolated from streptoverticillium mobaraense (Streptomyces mobaraense), Streptomyces cinnamomi (Streptomyces cinnamoneum), Streptomyces griseus (Streptomyces griseo-carreum), Streptomyces lavendulae (Streptomyces lavendulae) and Bacillus subtilis (Bacillus subtilis). Non-microbial transglutaminase enzymes may also be used, including mammalian transglutaminase enzymes. In certain embodiments, the transglutaminase can be produced by any technique or obtained from any source deemed suitable by one skilled in the art. In a particular embodiment, the transglutaminase is obtained from a commercial source.

In particular embodiments, the primary amine compound comprises a reactive group capable of further reaction after transglutaminase amination. In such embodiments, the glutaminyl-modified antibody can be reacted with or treated with an active payload compound, or an active linker-payload compound to form an antibody-payload conjugate. In certain embodiments, the primary amine compound comprises an azide.

In certain embodiments, a glutaminyl modified antibody is reacted with or treated with an active linker-payload to form an antibody-payload conjugate. The reaction may be carried out under conditions deemed appropriate by the person skilled in the art. In certain embodiments, a glutaminyl-modified antibody is contacted with an active linker-payload compound under conditions suitable for formation of a bond between the glutaminyl-modified antibody and the linker-payload compound. Suitable reaction conditions are well known to those skilled in the art. Exemplary reactions are provided in the following examples. Accordingly, the present invention provides a method of preparing an antibody-drug conjugate comprising contacting a binding agent according to the present invention with a linker-payload also according to the present invention.

Pharmaceutical compositions and methods of treatment

The present invention provides methods of treating and preventing a disease, condition, or disorder comprising administering a therapeutically or prophylactically effective amount of one or more of the presently disclosed compounds, e.g., one or more compounds of the presently provided formula. Diseases, disorders and/or conditions include, but are not limited to, those associated with the antigens listed in the present invention.

The compounds of the present invention may be administered alone or in combination with one or more additional therapeutic agents. One or more additional therapeutic agents may be administered prior to, concurrently with, or shortly after administration of the compounds of the present invention. The invention also includes pharmaceutical compositions comprising any of the compounds described herein in combination with one or more additional therapeutic agents, as well as methods of treatment comprising administering such combinations to a subject in need thereof.

Suitable additional therapeutic agents include, but are not limited to: a second glucocorticoid, a steroid, an LXR modulator, a therapeutic agent for inflammation, an autoimmune therapeutic agent, a hormone, a biologic, or a monoclonal antibody. Suitable therapeutic agents also include, but are not limited to, any pharmaceutically acceptable salts, acids or derivatives of the compounds of the present invention. The compounds of the present invention may also be administered in combination and/or co-formulated with antivirals, antibiotics, analgesics, corticosteroids, steroids, oxygen, antioxidants, COX inhibitors, cardioprotectants, metal chelators, IFN- γ and/or NSAIDs.

In some embodiments of the methods of the invention, multiple doses of the compound of the invention (or a pharmaceutical composition comprising a combination of the compound of the invention and any additional therapeutic agent mentioned herein) may be administered to a subject over a defined course of time. The method according to this embodiment of the present disclosure comprises sequentially administering multiple doses of the compound of the present disclosure to a subject. As used herein, "sequentially administering" refers to administering each dose of a compound to a subject at different time points, e.g., on different days separated by predetermined intervals (e.g., hours, days, weeks, or months). The invention encompasses methods comprising sequentially administering to a patient a single initial dose of a compound of the invention, followed by one or more secondary doses of the compound, and optionally followed by one or more tertiary doses of the compound.

The terms "initial dose", "secondary dose", and "tertiary dose" refer to the time sequence of administration of the compounds of the present invention. Thus, an "initial dose" is a dose administered at the beginning of a treatment regimen (also referred to as a "baseline dose"); "Secondary dose" is the dose administered after administration of the initial dose; and "three doses" are the doses administered after the administration of the two doses. The initial, secondary and tertiary doses may all contain the same amount of a compound of the invention, but may generally differ from one another in terms of frequency of administration. In certain embodiments, the amounts of the compounds contained in the initial, secondary, and/or tertiary doses are varied from one another (e.g., adjusted up or down as appropriate) over the course of treatment. In certain embodiments, at the beginning of a treatment regimen, two or more (e.g., 2, 3, 4, or 5) doses are administered as a "loading dose" followed by subsequent doses (e.g., a "maintenance dose") that are administered in a less frequent manner.

In certain exemplary embodiments of the invention, each secondary and/or tertiary dose is administered for 1 to 26 weeks (e.g., 1) following the preceding dose¹/₂、2、2 ¹/₂、3、3 ¹/₂、4、4 ¹/₂、5、5 ¹/₂、6、6 ¹/₂、7、7 ¹/₂、8、8 ¹/₂、9、9 ¹/₂、10、10 ¹/₂、11、11 ¹/₂、12、12 ¹/₂、13、13 ¹/₂、14、14 ¹/₂、15、15 ¹/₂、16、16 ¹/₂、17、17 ¹/₂、18、18 ¹/₂、19、19 ¹/₂、20、20 ¹/₂、21、21 ¹/₂、22、22 ¹/₂、23、23 ¹/₂、24、24 ¹/₂、25、25 ¹/₂、26、26 ¹/₂Or more). The phrase "immediately following the preceding dose" as used herein refers to a dose of a compound of the present invention administered to a patient in a sequence of multiple administrations, immediately prior to administration of the next dose, in which sequence no intervening doses are present.

The method of this embodiment of the invention may comprise administering any number of secondary and/or tertiary doses of a compound of the invention to the patient. For example, in certain embodiments, only a single, secondary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) secondary doses are administered to the patient. Likewise, in certain embodiments, only a single three-dose is administered to the patient. In other embodiments, the patient is administered two or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) three doses. The dosing regimen may be carried out indefinitely over the lifetime of the particular subject, or until such treatment is no longer therapeutically necessary or advantageous.

In embodiments involving multiple secondary doses, each secondary dose may be administered/dosed at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient for 1 to 2 weeks or 1 to 2 months following the aforementioned dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose may be administered/dosed at the same frequency as the other tertiary doses. For example, each of the three doses may be administered to the patient for 2 to 12 weeks following the preceding dose. In certain embodiments of the invention, the frequency of administration of the secondary and/or tertiary doses to the patient may vary over the course of the treatment regimen. The frequency of administration can also be adjusted by the physician during the course of treatment, according to the needs of the individual patient after clinical examination.

The invention includes dosing regimens in which 2 to 6 loading doses are administered to the patient at a first frequency (e.g., once per week, once every two weeks, once every three weeks, once per month, once every two months, etc.), followed by two or more maintenance doses administered to the patient in a less frequent manner. For example, if the loading dose is administered at a frequency of once a month according to this embodiment of the invention, the maintenance dose may be administered once every 6 weeks, once every two months, once every three months, etc.

The present invention includes pharmaceutical compositions of the compounds, and/or conjugates of the invention (e.g., compounds of formulae I, Ia, Iaaa, Ib, Ibb, II, IIa, IIaa, IIaaa, IIb, IIbb, IIbbb, III, IIIa, IIIaa, IIIaaa, IIIb, IIIbb, IIIbbb, IV, and/or V), e.g., compositions comprising a compound of the invention, salts, stereoisomers, regioisomers, polymorphs thereof, and pharmaceutically acceptable carriers, diluents, and/or adjuvants. Examples of suitable carriers, diluents and adjuvants include, but are not limited to: buffers for maintaining the pH of the appropriate composition (e.g., citrate buffer, succinate buffer, acetate buffer, phosphate buffer, lactate buffer, oxalate buffer, etc.), carrier proteins (such as human serum albumin), saline, polyols (e.g., trehalose, sucrose, xylitol, sorbitol, etc.), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylate, etc.), antimicrobials, and antioxidants. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of any one of formulas I, Ia, Iaa, Iaaa, Ib, Ibb, Ibbb, II, IIa, IIaa, IIaaa, IIb, IIbb, IIbbb, III, IIIa, IIIaa, IIIaaa, IIIb, IIIbb, IIIbbb, IV, and/or V, and a pharmaceutically acceptable adjuvant, carrier, or diluent.

In some embodiments, the present invention provides methods of treating a disease, disorder, or condition comprising administering to a patient suffering from the disorder a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.

In some embodiments, the present invention provides methods of treating a disease, disorder, or condition comprising administering to a patient having the disorder a therapeutically effective amount of a compound of formula I, Ia, Iaaa, Ib, Ibb, Ibbb, II, IIa, IIaa, IIaaa, IIb, IIbb, IIbbb, III, IIIa, IIIaa, IIIaaa, IIIb, IIIbb, IIIbbb, IV, and/or V, or a pharmaceutical composition thereof.

In some embodiments, the present invention provides methods of treating a disease, disorder or condition associated with a glucocorticoid receptor, comprising administering to a patient suffering from the disease, disorder or condition a compound of formula I, Ia, Iaa, Iaaa, Ib, Ibb, Ibbb, II, IIa, IIaa, IIaaa, IIb, IIbb, IIbbb, III, IIIa, IIIaa, IIIaaa, IIIb, IIIbb, IIIbbb, IV, and/or V, and combinations thereof.

The present invention includes methods of preventing certain diseases or disorders comprising administering a therapeutically effective amount of one or more of the compounds disclosed herein (i.e., prophylactic use). Examples include, but are not limited to, prevention of CD3 bispecific cytokine release syndrome, as well as adoptive cell therapy (e.g., CAR T cells), systemic IL-2 administration, graft versus host disease, and postoperative nausea and vomiting. Examples also include, but are not limited to, therapeutic antibody classes such as alemtuzumab (alemtuzumab), muromab (muromonab), rituximab (rituximab), tosituzumab (tosituzumab), and agonistic antibody classes, where immune stimulation may be part of the intended mechanism of action.

In some embodiments, the disease, disorder or condition is an allergic state, including but not limited to asthma, atopic dermatitis, contact dermatitis, drug allergies, allergic rhinitis, perennial or seasonal allergic rhinitis, and seropathy; skin diseases including but not limited to cutaneous pruritus, seborrheic dermatitis, neurodermatitis, bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, and severe erythema multiforme (Stevens-Johnson syndrome); endocrine disorders, including but not limited to primary or secondary adrenocortical insufficiency, congenital adrenal hyperplasia, hypercalcemia associated with cancer, and non-suppurative thyroiditis; gastrointestinal disorders; hematologic disorders including, but not limited to, acquired (autoimmune) hemolytic anemia, congenital (erythroid) dysplastic anemia (Diamond-Blackfan anemia), adult idiopathic thrombocytopenic purpura, pure red cell aplasia, and secondary thrombocytopenia; trichinosis; tubercular meningitis with or about to block the subarachnoid space; neoplastic diseases including, but not limited to, leukemia and lymphoma; neurological disorders including, but not limited to, acute exacerbations of multiple sclerosis, cerebral edema associated with primary or metastatic brain tumors, craniotomy, or head injury; ophthalmic diseases including, but not limited to, sympathetic ophthalmia, temporal arteritis, uveitis, and ocular inflammation unresponsive to topical corticosteroids; kidney diseases, including but not limited to induction of idiopathic nephrotic syndrome or diuresis or proteinuria remission by lupus erythematosus; respiratory diseases including, but not limited to, beryllium poisoning, fulminant or disseminated tuberculosis when used in conjunction with appropriate anti-tubercular chemotherapy, idiopathic eosinophilic pneumonia, symptomatic sarcoidosis; and rheumatic diseases including, but not limited to, adjuvant therapy for short-term administration of acute gouty arthritis, acute rheumatic cardioitis, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, including juvenile rheumatoid arthritis (which perpetrates acute attacks or exacerbations to the patient), and for the treatment of dermatomyositis, polymyositis, and systemic lupus erythematosus.

In some embodiments, the invention provides methods for treating a disease, disorder or condition selected from the group consisting of autoimmune diseases, allergies (allergies), arthritis, asthma, respiratory disorders, blood diseases, cancer, collagen diseases, connective tissue diseases, skin diseases, eye diseases, endocrine problems, immune diseases, inflammatory diseases, intestinal diseases, gastrointestinal diseases, neurological diseases, organ transplantation disorders, rheumatoid diseases, skin diseases, swelling disorders, wound healing disorders, and combinations thereof, comprising administering a steroid payload or a conjugate thereof as described herein.

In some embodiments, the autoimmune disease is selected from multiple sclerosis, autoimmune hepatitis, herpes zoster, systemic lupus erythematosus (i.e., lupus), myasthenia gravis, duchenne muscular dystrophy, and sarcoidosis. In some embodiments, the respiratory disorder is selected from asthma, chronic respiratory disease, chronic obstructive pulmonary disease, bronchitis, and acute bronchitis. In some embodiments, the cancer is selected from leukemia, lymphocytic leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, hodgkin's lymphoma, non-hodgkin's lymphoma (NHL), and multiple myeloma. In some embodiments, the collagen disease is systemic lupus erythematosus. In some embodiments, the ocular disease is keratitis. In some embodiments, the endocrine problem is selected from the group consisting of Addison's Disease, adrenal insufficiency, adrenal cortex and congenital adrenal hyperplasia. In some embodiments, the inflammatory disease is selected from post-cataract inflammation, joint inflammation, immune inflammation, tendon inflammation, bursitis, epicondylitis, Crohn's disease, inflammatory bowel disease, fatty pneumonitis thyroiditis, urticaria, pericarditis, nephrotic syndrome, and uveitis. In some embodiments, the intestinal disease is selected from ulcerative colitis, crohn's disease, and inflammatory bowel disease. In some embodiments, the rheumatoid disease is selected from rheumatoid arthritis, polymyalgia rheumatica, psoriatic arthritis, ankylosing spondylitis, and systemic lupus erythematosus. In some embodiments, the skin disorder is selected from psoriasis, eczema, and rash caused by exposure to poison ivy. In some embodiments, the neurological disease is chronic inflammatory demyelinating polyradiculoneuropathy.

In some embodiments, a compound described herein is administered to a patient to treat acute inflammatory events including, but not limited to, shock, cerebral edema, and graft-versus-host disease. In some embodiments, the compounds of the present invention are administered to treat lympholysis, including but not limited to those associated with hematological malignancies, such as leukemias, lymphomas, and myelomas.

In some embodiments, the present invention provides a method for reducing inflammation in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a steroid of the invention or a conjugate thereof. In some embodiments, the present invention provides a method for modulating the immune system in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a steroid of the present invention or a conjugate thereof. In some embodiments, the present invention provides a method for modulating cortisol levels in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a steroid according to the present invention or a conjugate thereof. In some embodiments, the present invention provides a method of reducing lymphocyte migration in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a steroid of the invention or a conjugate thereof. In some embodiments, the present invention provides a method of treating hypercalcemia caused by cancer, Meniere's disease, migraine, cluster headache, severe aphthous ulcer, laryngitis, severe tuberculosis, Herxheimer response to syphilis, decompensated heart failure, allergic rhinitis, or nasal polyps comprising administering to a subject in need thereof a steroid payload as described herein or a conjugate thereof. In some embodiments, the compounds disclosed herein are useful for treating inflammatory bowel disease, crohn's disease, or ulcerative colitis. In some embodiments, the disease, disorder, or condition is a chronic inflammatory disease, including but not limited to asthma, skin infections, and eye infections. In some embodiments, the compounds of the invention are used for immunosuppression in patients undergoing organ transplantation.

In some embodiments, the steroid payloads and conjugates thereof described herein are administered to a patient to treat neurological disorders associated with GR signaling, including but not limited to psychiatric disorders such as schizophrenia, drug addiction, post-traumatic stress disorder (PTSD), and mood disorders, drug abuse, stress and anxiety. In some embodiments, the steroid payloads of the present invention and conjugates thereof are administered to a patient to treat diseases of the visual system, including, but not limited to, ocular inflammation (e.g., conjunctivitis, keratitis, uveitis), macular edema, and macular degeneration. In some embodiments, the steroid payloads of the present invention and conjugates thereof are administered to a patient to treat cardiovascular disease. In some embodiments, the steroid payloads and conjugates thereof described herein are administered to a patient to treat a disorder of glucose and/or liver metabolism. In some embodiments, the steroid payloads of the present invention and conjugates thereof are administered to a patient to treat a musculoskeletal system disease. In some embodiments, the steroid payloads, and conjugates thereof, described herein are administered to a patient to treat skin inflammatory disorders, such as eczema and psoriasis.

The protein conjugates of the present invention provide a means for targeted delivery of their steroid payloads to specific cell or organ systems, thereby reducing or preventing side effects resulting from administration of free unconjugated steroid payload. Examples of such potential side effects to be reduced or prevented include dexamethasone at approval

Those side effects listed in the drug label, the entire contents of which are incorporated herein by reference. In some embodiments, the side effect to be reduced or prevented is selected from the group consisting of elevated blood pressure; sodium retention; water/fluid retention (edema, angioedema, pulmonary edema); increased potassium excretion; reversible hypothalamic-pituitary adrenal (HPA) axis suppression; potential corticosteroid deficiency following withdrawal; susceptibility to infection; exacerbation of systemic fungal infection; the severity of chickenpox in pediatric and adult patients worsens; the severity of measles in pediatric and adult patients worsens; subcapsular cataract; glaucoma, which may damage the optic nerve; increased establishment of secondary ocular infections due to bacteria, fungi or viruses; increased new onset of optic neuritis; kaposi's sarcoma; secondary adrenal insufficiency caused by drugs; an increased risk of perforation when active or latent peptic ulcers, diverticulitis, fresh enteroanastomosis, and non-specific ulcerative colitis are present; peritoneal irritation following perforation of the gastrointestinal tract; a reduction in bone formation; increased bone resorption; inhibiting osteoblast function; inhibiting bone growth in pediatric patients; osteoporosis development at any age; acute myopathy (which may involve the eye and respiratory muscles and may lead to quadriplegia); an increase in creatinine kinase; confusion including euphoria and insomnia Mood swings, character changes and major depressive to tandard psychotic manifestations; current emotional instability or a psychotic tendency to worsen; an elevated intraocular pressure; bradycardia; cardiac arrest; arrhythmia; enlargement of the heart; a collapse of the circulation system; congestive heart failure; fat embolism; hypertension; hypertrophic cardiomyopathy of premature infants; myocardial rupture following recent myocardial infarction; syncope; tachycardia is treated; thromboembolism; thrombophlebitis; vasculitis; acne; allergic dermatitis; squamous xeroderma; ecchymosis and petechiae; erythema; poor healing of the wound surface; increased sweating; rash; stripes; inhibiting a response to a skin test; fragile skin; thinning scalp hair; urticaria; impaired carbohydrate and glucose tolerance; development of cushing's state; hyperglycemia; diabetes mellitus; hirsutism; excessive hair; the increased demand for insulin or oral hypoglycemic agents in diabetic patients (insulin resistance); potential diabetic manifestations; menoxenia; secondary adrenal cortex and pituitary gland unresponsiveness (particularly during periods of stress; e.g., during trauma, surgery or disease); inhibiting growth in pediatric patients; congestive heart failure in susceptible patients; retention of body fluids; low potassium alkalosis; potassium loss; sodium retention; abdominal distension; elevated serum liver enzyme levels (usually reversible upon withdrawal); hepatomegaly; appetite increase; nausea; pancreatitis; peptic ulcers with possible perforation and bleeding; small and large bowel perforation (particularly in patients with inflammatory bowel disease); ulcerative esophagitis; protein catabolism leads to negative nitrogen balance; aseptic necrosis of femoral head and humeral head; a decrease in muscle mass; muscle weakness; osteoporosis; pathological fractures of long bones; steroid myopathy; tendon rupture; vertebral compression fracture; twitching; depression; emotional instability; euphoria; headache; increased intracranial pressure, usually with papilloma (pseudobrain tumor) following withdrawal; insomnia; mood swings; neuritis; neuropathy; paresthesia; a character change; a psychiatric disorder; vertigo; the eyeball is protruded; glaucoma, and glaucoma; an elevated intraocular pressure; subcapsular cataract; abnormal fat deposition; decreased resistance to infection; burping; increased or decreased motility and number of sperm; discomfort; moon face; and weight gain; and those associated with drug-drug interactions And (4) acting. In some embodiments, the side effect to be reduced or prevented is a side effect associated with a drug-drug interaction. In some embodiments, the side effects to be reduced or prevented are associated with drug-drug interactions with aminoglutethimide using corticosteroids, including reduction of side effects interacting with the following drugs and inhibition of the adrenal glands: (ii) corticosteroids; amphotericin B injectable and potassium depleting drugs, including hypokalemia, cardiac augmentation and the development of congestive heart failure; antibiotic, including corticosteroid, clearance is significantly reduced; anticholinesterases, including severe weakness in patients with myasthenia gravis; oral anticoagulant drugs, including inhibition of warfarin response; antidiabetic agents, including increasing blood glucose concentration; antituberculous drugs, including lowering serum levels of isoniazid; cholestyramine, including increasing the clearance of corticosteroids; cyclosporine, including increasing the activity of cyclosporine and corticosteroids, and the incidence of convulsions; dexamethasone inhibition test (DST) interference, including false negative results in patients treated with indomethacin; digitosides, including an increased risk of arrhythmia due to hypokalemia; ephedrine, which includes enhancing metabolic clearance of corticosteroids, results in reduced blood levels and reduced physiological activity; estrogens, including oral contraceptives, including reduced hepatic metabolism of certain corticosteroids and associated increases in their effects; liver enzyme inducers, inhibitors and substrates (drugs that induce cytochrome P4503 a4(CYP 3a4) enzyme activity, such as barbiturates, phenytoin, carbamazepine, rifampicin), including enhancing metabolism of corticosteroids; drugs that inhibit CYP 3a4 (e.g., ketoconazole, macrolide antibiotics such as erythromycin), including the potential to increase plasma concentrations of corticosteroids; drugs metabolized by CYP 3a4 (e.g., indinavir, erythromycin), including increased clearance thereof, resulting in decreased plasma concentrations; ketoconazole, including some corticosteroids, reduces metabolism by up to 60%, resulting in an increased risk of corticosteroid side effects, and inhibits adrenal corticosteroid synthesis, possibly resulting in adrenal insufficiency during corticosteroid withdrawal; non-steroidal anti-inflammatory drugs (NSAIDs) S), including increased risk of gastrointestinal side effects and increased clearance of salicylic acid; phenytoin, including increasing or decreasing phenytoin levels, alters seizure control; skin test agents, including inhibition of response to skin tests; thalidomide, including toxic epidermal necrolysis; and vaccine classes, including attenuated responses to toxoids and live or inactivated vaccines, due to inhibition of antibody responses contained in attenuated live vaccines or enhancement of replication of certain organisms. Accordingly, the present invention provides a method of treating a disease, disorder or condition associated with a glucocorticoid receptor, comprising administering to a patient suffering from the disease, disorder or condition a conjugate of formulae I, Ia, Iaaa, Ib, Ibb, Ibbb, II, IIa, IIaa, IIaaa, IIb, IIbb, IIbbb, III, IIIa, IIIaa, IIIaaa, IIIb, IIIbb, IIIbbb, IV, and/or V, wherein side effects associated with administration of a free steroid payload of the conjugate are reduced. In addition, the present invention provides a method of delivering a compound of formula I, Ia, Iaa, Iaaa, Ib, Ibb, Ibbb, II, IIa, IIaa, IIaaa, IIb, IIbb, IIbbb, III, IIIa, IIIaa, IIIaaa, IIIb, IIIbb, IIIbbb, IV, and/or V to a cell comprising contacting the cell with a protein conjugate of a compound of formula I, Ia, Iaa, Iaaa, Ib, Ibb, Ibbb, II, IIa, IIaa, IIaaa, iiab, IIb, IIbb, IIbbb, III, IIIa, IIIaa, IIIaaa, IIIb, IIIbb, IIIbbb, IV, and/or V, wherein the protein conjugate comprises an antibody or antigen binding fragment thereof that binds to a surface antigen of the cell.

In some embodiments, the invention provides methods of treating a disease, disorder or condition selected from the group consisting of an immune disease, an autoimmune disease, inflammation, asthma, or inflammatory bowel disease, crohn's disease, ulcerative colitis.

In some embodiments, the invention provides methods of treating a disease, disorder or condition by targeting an antigen (e.g., an antigen that expresses the surface of a cell), wherein steroid administration can achieve a therapeutic benefit, comprising administering a conjugate described herein. In some embodiments, the antigen is AXL, BAFFR, BCMA, BCR-list components (BCR-list components), BDCA, BDCA, BTLA, BTNL2BTNL, BTNL, BTNL, C10orf, CCR, CCR, CCR, CCR, CCR, CD, CD11, CD137, CD138, CD168, CD177, CD, CD, CD, CD209, CD209, CD226, CD248, CD, CD, CD, CD274, CD276, CD, CD, CD, CD, CD300, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD62, CD, CD, CD, CD79, CD, CD, CD, CD, CD90.2, CD, CLEC12, CLEC12, CLEC7, CLEC9, CR, CSF, CTLA, CD1, CD, CD, CD, CD, CD79, CD79, CD, CD, CD, CD, CD, CD, CD, CD, CD, CD90.2, CD, CD 12, CLEC12, CLEC12, CLEC, CRIL 17, CRLRR, CRIL-R, CRIL-13, CRIL-LRE, CRIL-13, CRIL-IL-13, CRIL-IL-LRR, CRIL-LR, CRIL-IL-13, CRIL-LR, CRIL-13, CRIL-LR, CRIL-IL-LRR, CRIL-LR, CRR, CRIL-13, CRIL-LR, CRIL-IL-13, CRIL-IL-13, CRIL-LR, CRR, CRIL-13, CRIL-IL-13, CRIL-IL 23, CRIL-LR, CRIL-IL 23, CRIL 23, CRLR, CRIL-IL-LR, CRIL-13, CRIL-IL 23, CRIL-IL 23, CRIL-IL 23, CRIL-IL 23, CRIL-IL 23, CRIL-IL 23, CRIL-IL 23, CRIL-IL 23, CRIL, IL2Rg, IL31R, IL36R, IL3RA, IL4R, IL6R, IL5R, IL7R, IL9R, Integrins (Integrins), LAG3, LIFR, MAG/Siglec-4 (sialic acid binding immunoglobulin-like lectin-4), MMR, MSR1, NCR3LG1, NKG2D, NKp30, NKp46, PDCD1, PROKR1, PVR, PVRIG, PVRL 1, PVRL 1, RELT, SIGIRR, Siglec-1 (sialic acid binding immunoglobulin-like lectin-1), Siglec-10, Siglec-5, Siglec-6, Siglec-7, Siglec-8, Sig-9, SIRPA, SLF 1, TACI, TCR-group/TCOLC-5, TCOLOCS-6, TCOLC-7, TCOLC-8, TCPR-9, TCPA, SLF 1, TCLR 1, TCTROCR 1, TCLR 1, TCTROCR 1, TCLR 1, TCR 36LR 1, TCR 1, TCTROCR 1, TCTRTCR 1, TCR 1, TCTROCR 1, TCR 36LR 1, TCR 1, TCR 1, TCR 36R 1, TCR 36R, TCR 36R 1, TCR 1, TCR 36R, TCR 36R 1, TCR, and TCR, and TCR 36R, TCR 36R. In some embodiments, the antigen is IL 2R- γ.

In some embodiments, the invention provides methods for treating a disease, disorder or condition selected from an immune disease, an autoimmune disease, an inflammatory disease, a skin disease, or a gastrointestinal disease.

In some embodiments, the disease is crohn's disease, ulcerative colitis, Cushing's syndrome, adrenal insufficiency, or congenital adrenal cortical hyperplasia.

In some embodiments, the disease is inflammation, asthma, or inflammatory bowel disease.

In some embodiments, the disease is an autoimmune disease selected from multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, psoriasis, or eczema.

In some embodiments, the present invention provides methods for reducing or ameliorating a side effect of chemotherapy, wherein the method comprises administering to a patient suffering from the disorder a therapeutically effective amount of a compound or composition described herein.

In some embodiments, the present invention provides methods for reducing or ameliorating a side effect of an immunosuppressive therapy, wherein the method comprises administering to a patient suffering from the condition a therapeutically effective amount of a compound or composition described herein.

In some embodiments, the present invention provides methods for treating cancer, wherein the methods comprise administering to a patient having the disorder a therapeutically effective amount of a compound or composition of the present invention. In some embodiments, the cancer is selected from acute lymphocytic leukemia, chronic lymphocytic leukemia, hodgkin's lymphoma, non-hodgkin's lymphoma (NHL), or multiple myeloma, among others.

In some embodiments, the invention provides methods for treating or preventing any disease, disorder, or condition that is responsive to modulation of LXR signaling. In some embodiments, the disease or disorder is associated with LXR function, LXR polymorphism, LXR agonist activity, or LXR antagonist activity. In some embodiments, the present invention provides methods of treating or preventing a disease, disorder, or condition selected from the group consisting of: proliferative diseases, neurodegenerative diseases, immunological diseases, autoimmune diseases, inflammatory diseases, skin diseases, metabolic diseases, cardiovascular diseases and gastrointestinal diseases.

The proliferative disease may be any proliferative disease known to the skilled person. In certain embodiments, the proliferative disease includes, but is not limited to, an oncological disease, wherein the oncological disease may be any cancer disease known to the skilled artisan. In certain embodiments, the present invention provides methods of treating or preventing melanoma. In certain embodiments, the present invention provides methods of treating or preventing metastatic melanoma. In certain embodiments, the present invention provides methods of treating or preventing lung cancer. In certain embodiments, the present invention provides methods of treating or preventing EGFR-tyrosine kinase inhibitor resistant lung cancer. In certain embodiments, the present invention provides methods of treating or preventing oral cancer. In certain embodiments, the present invention provides methods of treating or preventing oral squamous cell carcinoma. In certain embodiments, the present invention provides methods of treating or preventing prostate cancer. In certain embodiments, the present invention provides methods of treating or preventing hodgkin's lymphoma. In certain embodiments, the present invention provides methods of treating or preventing breast cancer.

The neurodegenerative disease can be any neurodegenerative disease known to the skilled person. In certain embodiments, the present invention provides methods of treating or preventing alzheimer's disease. In certain embodiments, the present invention provides methods of treating or preventing parkinson's disease. In certain embodiments, the invention provides methods of treating or preventing huntington's disease. In certain embodiments, the present invention provides methods of treating or preventing amyotrophic lateral sclerosis. In certain embodiments, the invention provides methods of treating or preventing myelin gene expression. In certain embodiments, the invention provides methods of treating or preventing myelinated and remyelinated conditions, diseases or disorders.

The immune disease may be any immune disease known to the skilled person. In certain embodiments, the invention provides methods of treating or preventing inflammatory bowel disease. In certain embodiments, the present invention provides methods of treating or preventing ulcerative colitis. In certain embodiments, the present invention provides methods of treating or preventing crohn's disease.

The inflammatory disease may be any inflammatory disease known to the skilled person. In certain embodiments, the present invention provides methods of treating or preventing arthritis. In certain embodiments, the present invention provides methods for treating or preventing rheumatoid arthritis.

The metabolic disease may be any metabolic disease known to the skilled person. In certain embodiments, the metabolic disease is dyslipidemia. The dyslipidemia can be any dyslipidemia known to those skilled in the art. In certain embodiments, the dyslipidemia is selected from the group consisting of: hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipoproteinemia, HDL deficiency, ApoA-I deficiency, and cardiovascular diseases such as coronary artery disease (including, for example, the treatment and prevention of angina pectoris, myocardial infarction, and sudden cardiac death); atherosclerosis (including, for example, the treatment and prevention of atherosclerosis); and restenosis (including, for example, the prevention or treatment of atherosclerotic plaques formed as a result of medical procedures such as balloon angioplasty). In certain embodiments, the present invention provides methods for treating or preventing diabetes.

The cardiovascular disease may be any cardiovascular disease known to the skilled person. In certain embodiments, the invention provides methods of treating or preventing atherosclerosis. In certain embodiments, the present invention provides methods of treating or preventing atherosclerosis that results from aberrant macrophage processing. In certain embodiments, the present invention provides methods of treating or preventing atherosclerosis derived from the formation of oxidized low density lipoprotein (oxLDL), wherein macrophages are unable to process oxidized low density lipoprotein (oxLDL). In certain embodiments, the present invention provides methods of treating or preventing ischemic heart disease. In certain embodiments, the present invention provides methods of treating or preventing stroke. In certain embodiments, the present invention provides methods of treating or preventing hypertensive heart disease. In certain embodiments, the present invention provides methods of treating or preventing an aortic aneurysm. In certain embodiments, the present invention provides methods of treating or preventing endocarditis. In certain embodiments, the present invention provides methods of treating or preventing peripheral arterial disease. In certain embodiments, the present invention provides methods of treating or preventing any of the diseases provided in this paragraph.

In some embodiments, the invention provides methods of modulating nuclear receptor function. By way of non-limiting example, the function may be selected from the group consisting of expression/secretion of inflammatory mediators (e.g., cytokines, chemokines), cholesterol regulation, cholesterol uptake, cholesterol efflux, cholesterol oxidation, migration, chemotaxis, apoptosis and necrosis, inflammatory activity, lipid regulation, apoptosis, migration, chemotaxis, gene transcription, and protein expression.

Examples

The invention provides novel steroid and LXR modulator compounds, prodrugs or payloads, protein conjugates thereof, and methods of treating diseases, disorders, and conditions comprising administering the steroid and the LXR modulator compounds, prodrugs or payloads and conjugates.

TABLE 1 list of hydroxy-glucocorticoid receptor agonists

TABLE 2 a.N-C-O-steroid prodrug List

TABLE 2 properties of N-C-O-steroid prodrugs

TABLE 3A. linker-N-C-O-steroid prodrug List

TABLE 3b Properties of linker-N-C-O-glucocorticoids

1. All linker-payloads were tested in HPLC using method B; for compounds containing two chiral centers, two representative peaks were observed by LCMS.

TABLE 3C cleavage of linker-N-C-O-glucocorticoids

TABLE 3d structural formula of quenched linker-N-C-O-glucocorticoids

Acronyms

Synthesis of drug/payload D-OH

Dexamethasone I and budesonide II are commercially available steroid drugs (D x-OH). 6, 11-2F-budesonide III is reported in WO 2018/213077A 1. LXR agonist IV was synthesized from LXR agonist 7(LXR agonist 7 is reported in WO 2018/213077 a1 and WO 2018/213082 a1) as shown below.

(1S,4aS,10aR) -N- [ (1S,4aS,10aR) -6- (2-hydroxyacetamido) -1,4 a-dimethyl-1, 2,3,4,4a,9,10,10 a-octahydrophenanthrene-1-carbonyl ] -6-hydroxy-1, 4 a-dimethyl-1, 2,3,4,4a,9,10,10 a-octahydrophenanthrene-1-carboxamide (IV)

To a solution of 7(10mg, 19. mu. mol, see WO 2018213082A 1) in DMF (2mL) was added HATU (14mg, 38. mu. mol) and DIPEA (9.8mg, 76. mu. mol) at room temperature. The mixture was stirred at room temperature for 15 minutes, then glycolic acid (1.7mg, 23. mu. mol) was added. The reaction mixture was stirred at room temperature for 2 hours, monitored by LCMS. The resulting mixture was directly purified by preparative HPLC to give compound IV (5.7mg, 51% yield) as a white solid. ESI M/z 587(M +1)⁺。¹H NMR(400MHz,DMSO_d6)δ9.46(s,1H),9.00(s,1H),8.11(s,1H),7.59(d,J＝1.8Hz,1H),7.49(dd,J＝8.3,1.8Hz,1H),6.96(d,J＝8.3Hz,1H),6.82(d,J＝8.3Hz,1H),6.63(d,J＝2.3Hz,1H),6.50(dd,J＝8.3,2.3Hz,1H),5.64(t,J＝5.9Hz,1H),3.94(d,J＝5.9Hz,2H),2.93-2.66(m,4H),2.37-2.06(m,6H),2.03-1.75(m,4H),1.68-1.50(m,4H),1.28(s,3H),1.27(s,3H),1.36-1.20(m,2H),1.20-1.08(m,2H),1.00(s,3H),0.99(s,3H)ppm。

In addition to the payload PII-9 shown in fig. 2 and 2A; and payload PII-10 shown in fig. 2, most of the payloads are synthesized according to fig. 1. Intermediates 5a and 6a were synthesized as described in WO 2015/155998 a 1.

FIG. 1 starting dipeptides 3a-3h

3a:Fmoc-Gly-Gly-OH,CAS:35665-38-4

3b:Fmoc-Ala-Gly-OH,CAS:116747-54-7

3c:Fmoc-Phe-Gly-OH,CAS:169624-67-3

3d:Fmoc-Gly-Abu-OH,CAS:2171191-91-4

3e:Fmoc-Gly-Phe-OH,CAS:117370-45-3

3f:Fmoc-Gly-Sar-OH,CAS:1499188-24-7

3g and 3j Fmoc-Gly-Pro-OH, CAS:212651-48-4

3g1:Fmoc-Ala-Sar-OH,CAS:2171221-36-4

3h1 Fmoc- (R, S) -3-amino-1-carboxymethyl-valerolactam, CAS:209163-25-7

3i Fmoc-Gly-2-azetidinecarboxylic acid, 2171729-15-8

1- (2- { [ (9H-Fluoren-9-ylmethoxy) carbonyl ] amino } acetyl) piperidine-2-carboxylic acid (3H, Fmoc-Gly-Pip-OH)

To a mixture of pipecolic acid (0.59g, 4.6mmol) and Fmoc-Gly-OSu (1.80g, 4.6mmol) in DMF (10mL) was added DIPEA (1.8g, 14mmol) and the mixture was stirred at room temperature for 2 h, monitored by LCMS. The resulting mixture was directly purified by preparative HPLC to give compound 3h (1.0g, 53% yield) as a white solid. ESI M/z 409(M +1)⁺。¹H NMR(400MHz,DMSO_d6)δ7.89(d,J＝7.6Hz,2H),7.73(d,J＝7.2Hz,2H),7.42(t,J＝7.2Hz,2H),7.35-7.29(m,3H),4.32-4.21(m,4H),4.03-3.95(m,1H),3.67-3.61(m,1H),2.78-2.73(m,2H),2.23-2.14(m,1H),1.61-1.59(m,2H),1.50-1.25(m,4H)ppm。

Synthesis of intermediate 4

General procedure A for intermediate 4

To a mixture of peptide 3(1.0 equiv) in THF (30mL/g3) and toluene (10mL/g3) was added pyridine (1.2 equiv.) and lead tetraacetate (1.2 equiv.). The resulting mixture was stirred at 80 ℃ for 5 hours, monitored by LCMS. After cooling to room temperature, the mixture was filtered through celite and the filtrate was concentrated in vacuo or diluted directly with ethyl acetate. The organic solution was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-10% ethyl acetate in petroleum ether) to give compound 4 (67-67% yield) as a white solid.

General procedure B for intermediate 4

To a mixture of peptide 3(1.0 equiv) in dry DMF (2mL/g 3) was added lead tetraacetate (1.2 equiv). The resulting mixture was stirred at room temperature for 5-30 minutes, monitored by LCMS. The resulting mixture was filtered through celite, and the filtrate was diluted with ethyl acetate, then washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-10% ethyl acetate in petroleum ether) to give compound 4 (48-78% yield) as a white solid.

Table 3e. with different R¹Results of intermediate 4 of substituents

The acetate was easily hydrolyzed during the purification process.

TABLE 4 Synthesis summary of intermediate 4

1. Acetates are easily hydrolyzed and contaminated with alcohol.

2. Yield of alcohol 4J.

(2- (((9H-fluoren-9-yl) methoxy) carbonylamino) acetamido) methyl acetate (4a) (CAS:1599440-06-8)

Compound 4a (3.0g, 67% yield) was obtained as a white solid following general procedure A for intermediate 4 or the synthetic procedure reported in Tetrahedron 74(2018) 1951-1956. ESI M/z 391(M +23)⁺。

[ (2S) -2- { [ (9H-fluoren-9-ylmethoxy) carbonyl ] amino } propionamido ] methyl acetate (4b)

Following general procedure B for intermediate 4, compound 4B (30mg, 78% yield) was obtained as a white solid. ESI M/z 405(M +23) ⁺。

[ (2S) -2- { [ (9H-fluoren-9-ylmethoxy) carbonyl ] amino } -3-phenylpropionamino ] methyl acetate (4c)

Following general procedure B for intermediate 4, compound 4c (0.31g, 30% yield) was obtained as a white solid. ESI M/z:481(M +23)⁺。¹H NMR(400MHz,DMSO_d6)δ9.14(t,J＝6.8Hz,1H),7.88(d,J＝7.6Hz,2H),7.73-7.70(m,1H),7.64(t,J＝8.8Hz,2H),7.43-7.39(m,2H),7.34-7.24(m,6H),7.22-7.17(m,1H),5.12(dd,J＝7.2,2.8Hz,2H),4.31-4.26(m,1H),4.19-4.11(m,3H),3.01-2.94(m,1H),2.84-2.78(m,1H),2.00(s,3H)ppm。

1- (2- { [ (9H-fluoren-9-ylmethoxy) carbonyl ] amino } acetamido) propyl acetate (4d)

Following general procedure B of intermediate 4, crude compound 4d (0.35g) was obtained and used in the next step without purification. ESI M/z:419(M +23)⁺。

1- (2- { [ (9H-fluoren-9-ylmethoxy) carbonyl ] amino } acetamido) -2-phenylethyl acetate (4e)

Following general procedure B for intermediate 4, compound 4e (0.30g, 48% yield) was obtained as a white solid. ESI M/z:481(M +23)⁺。

(2- { [ (9H-fluoren-9-ylmethoxy) carbonyl ] amino } -N-methylacetamido) methyl acetate (4f)

Following general procedure B of intermediate 4, crude compound 4f (0.40g, 19% yield) was obtained as a white solid, which was contaminated with the hydrolysate alcohol after purification. The mixture was used in the next step without further purification. ESI M/z 405(M +23)⁺。

[ (2S) -2- { [ (9H-fluoren-9-ylmethoxy) carbonyl ] amino } -N-methylpropionamido ] methyl acetate (4g)

Following general procedure B for intermediate 4, crude compound 4g (0.44g, 53% yield) was obtained as a white solid after purification by preparative HPLC. ESI M/z:419(M +23) ⁺。

(3- { [ (9H-Fluoren-9-ylmethoxy) carbonyl ] amino } -2-oxopiperidin-1-yl) methyl acetate (4H)

Following general procedure B for intermediate 4, crude compound was obtained 4h (0.10g, 15% yield) as a white solid. ESI M/z 431(M +23)⁺。

1- (2- { [ (9H-fluoren-9-ylmethoxy) carbonyl ] amino } acetyl) azetidin-2-yl acetate (4i)

Following general procedure B of intermediate 4, crude compound 4i (0.18g, 47% yield) was obtained as a white solid. ESI M/z 395(M +1)⁺。

9H-fluoren-9-ylmethyl N- [2- (2-hydroxypyrrolidin-1-yl) -2-oxoethyl ] carbamate (4J)

Following general procedure B of intermediate 4, crude compound 4J (50mg, 53% yield) was obtained as a white solid. The acetate intermediate was not obtained. ESI M/z 389(M +23)⁺。¹H NMR(400MHz,DMSO_d6)δ7.90(d,J＝7.4Hz,2H),7.73(d,J＝7.5Hz,2H),7.47-7.37(m,3H),7.33(t,J＝7.3Hz,2H),5.86(br s,1H),5.48(d,J＝4.0Hz,0.25H),5.39(d,J＝4.0Hz,0.75H),4.33-4.18(m,3H),3.96(d,J＝6.0Hz,1.5H),3.75(d,J＝6.0Hz,0.5H),3.59-3.33(m,1H),3.22-3.11(m,1H),2.00-1.59(m,4H)ppm。

Synthesis of intermediate 5a and payloads PI, PII-1, PII-2, PII-3, PII-6, PII-7, PII-8, PII-11, PII-12, PII-13, and PIII-1 (FIG. 1)

General method of payload A

A mixture of compound 4(1 equivalent), the corresponding alcohol (HO-D or benzyl glycolate) (1 equivalent) and PPTS (0.1 equivalent) in DCM (40mL/g alcohol) was added to a 10mL sealed tube. The mixture was sealed and stirred at 50 ℃ overnight, monitored by LCMS. The resulting mixture was concentrated in vacuo and the residue was directly purified by preparative HPLC to afford Fmoc-P or intermediate 5 a. Fmoc-P was dissolved in DMF (40 mM). Piperidine (4 equivalents) was added to the resulting solution and the mixture was stirred at room temperature for 1 hour until Fmoc removal was complete, as monitored by LCMS. The reaction mixture was directly purified by preparative HPLC to give payload P (4.1-28% yield) as a white solid.

General method of payload B

To a solution of compound 4(1.0 eq) and the corresponding alcohol (HO-D) (1.0 eq) in THF (0.25M) at 0 ℃ was added potassium tert-butoxide (2.0 eq). The mixture was stirred at room temperature for 3 hours until the concentration of Fmoc-P remained unchanged as monitored by LCMS (neither compound 4 nor alcohol was completely consumed). The reaction mixture was diluted with ethyl acetate and carefully quenched with water at 0 ℃. The aqueous layer was extracted with ethyl acetate and chloroform. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (25-70% ethyl acetate in petroleum ether) to give Fmoc-P (containing payload P), which was dissolved in DMF (40 mM). Piperidine (4 equivalents) was added to the resulting solution and the mixture was stirred at room temperature for 2 hours until Fmoc removal was complete as monitored by LCMS. The reaction mixture was directly purified by preparative HPLC to give payload P (6.7-28% yield) as a white solid.

TABLE 5 conditions for general payload Synthesis procedure

2-amino group-N- ({2- [ (1R,2S,10S,11S,13R,14R,15S,17S) -1-fluoro-14, 17-dihydroxy-2, 13, 15-trimethyl-5-oxotetracyclo [8.7.0.0 ]²,⁷.0¹¹,¹⁵]Heptadecan-3, 6-dien-14-yl]-2-oxoethoxy } methyl) acetamide, TFA salt (PI)

Following general procedure a for payload, starting from compound 4a and dexamethasone, the payload PI (0.26g, 18% yield) was obtained as a white solid (TFA salt). ESI M/z 501(M +23)⁺。¹H NMR(400MHz,DMSO_d6)δ9.14(t,J＝6.5Hz,1H),8.02(s,3H),7.30(d,J＝10.2Hz,1H),6.23(dd,J＝10.2,2.0Hz,1H),6.02(s,1H),5.29(d,J＝2.0Hz,1H),5.00(s,1H),4.68-4.52(m,3H),4.17(d,J＝18.4Hz,1H),4.17-4.11(m,1H),3.60(s,2H),2.99-2.83(m,1H),2.70-2.56(m,1H),2.44-2.27(m,2H),2.17-2.03(m,2H),1.83-1.71(m,1H),1.62(q,J＝11.1Hz,1H),1.49(s,3H),1.47-1.29(m,2H),1.15-0.99(m,1H),0.87(s,3H),0.79(d,J＝7.2Hz,3H)ppm。

2-amino-N- ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclo [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) acetamide (PII-1)

Following general procedure B for payload, starting from compound 4a and budesonide, payload PII-1(50mg, 28% yield) was obtained as a white solid. ESI M/z 517(M +1)⁺。¹H NMR(400MHz,CDCl₃)δ8.08-8.04(m,1H),7.30(d,J＝10.4Hz,1H),6.25(d,J＝10.4Hz,1H),6.02(s,1H),5.20-5.18(m,1H),4.95-4.60(m,3H),4.60-4.25(m,3H),3.42(s,2H),3.25(br s,2H),2.57-2.54(m,1H),2.35-2.32(m,1H),2.22-2.00(m,2H),2.00-1.50(m,7H),1.46(s,3H),1.46-1.25(m,2H),1.15-1.00(m,2H),1.00-0.80(m,6H)ppm。

(2S) -2-amino-N- ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclo [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) propanamide TFA salt (PII-2)

Following general procedure B for payload, starting from compound 4B and budesonide, the payload PII-2(6.0mg, 6.7% yield) was obtained as a white solid (TFA salt). ESI M/z:531(M +1)⁺。¹H NMR(400MHz,DMSO_d6) δ 9.12 to 8.92(m,1H),7.33(d, J ═ 10.1Hz,1H),6.59(br s,2H),6.17(dd, J ═ 10.1 and 1.6Hz,1H)),5.92(s,1H),5.17(t, J ═ 4.7Hz,0.3H),5.03(d, J ═ 7.2Hz,0.3H),4.78(d, J ═ 3.2Hz,1H),4.72(d, J ═ 4.2Hz,0.7H),4.70 to 4.54(m,3H),4.49(d, J ═ 18.6Hz,0.7H),4.30(s,1H),4.23(d, J ═ 18.8Hz,0.7H), 4.17.68 (d, J ═ 18.6Hz,0.7H), 1.30 (s,1H),4.23(d, J ═ 18.8, 0.7H), 4.68 (d, J ═ 1H), 1.1H), 1H, 1.1H, 1H, 1.68 (d, 1.1H), 1H), 1.1H, 1.1.1.1H, 1H, 25(m, 1H), 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 1, 2H, 1, 2H, 1H, 2H, 1H, etc., 1H) 1.27(d, J ═ 7.0Hz,3H),1.15-0.91(m,2H),0.86(t, J ═ 7.4Hz,3H),0.81(s,3H) ppm.

(2S) -2-amino-N- ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclo [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) -3-phenylpropionamide TFA salt (PII-3)

Following general procedure B for payload, starting from compound 4c and budesonide, the payload PII-3(84mg, 21% yield) was obtained as a white solid (TFA salt). ESI M/z 607(M +1)⁺。¹H NMR(400MHz,DMSO_d6)δ8.73(t,J＝6.2Hz,1H),7.40-7.13(m,6H),6.17(d,J＝10.1Hz,1H),5.92(s,1H),5.17(t,J＝4.7Hz,0.4H),5.03(d,J＝7.1Hz,0.4H),4.77(s,1H),4.73(d,J＝4.1Hz,0.6H),4.68-4.53(m,2.8H),4.49(d,J＝2.4Hz,0.4H),4.44(s,0.4H),4.31(br s,1H),4.18(d,J＝8.4Hz,0.6H),4.13(d,J＝8.1Hz,0.4H),3.52-3.36(m,1H),3.02-2.85(m,1H),2.70-2.55(m,1H),2.36-2.22(m,1H),2.16-1.92(m,3H),1.88-1.64(m,4H),1.63-1.48(m,4H),1.48-1.40(m,1H),1.381(s,1.8H),1.376(s,1.2H),1.36-1.23(m,2H),1.18-0.91(m,2H),0.90-0.75(m,6H)ppm。

2-amino-N- { [ ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclo [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } acetamide (PII-4)

To a solution of compound PII-1(52mg, 0.10mmol) in DMF (2.0mL) at RT was added DIPEA (40mg, 0.31mmol), Fmoc-glycine (30mg, 0.10mmol) and HATU (50mg, 0.13mmol), respectively. The reaction mixture was stirred at room temperature for 2 hours, monitored by LCMS. Piperidine (43mg, 0.50mmol) was then added to the solution and the mixture was stirred at room temperature for 1 hour until Fmoc was removed, monitored by LCMS. The mixture was directly purified by reverse phase flash chromatography (0-100% acetonitrile in aqueous ammonium bicarbonate (0.08%)) to afford compound PII-4(50mg, 91% yield) as a white solid. ESI M/z:574(M +1) ⁺。¹H NMR(500MHz,DMSO_d6) δ 8.71(t, J ═ 6.7Hz,0.5H),8.70(t, J ═ 6.7Hz,0.5H),8.20(br s,1H),7.314(d, J ═ 10Hz,0.5H),7.307(d, J ═ 10Hz,0.5H),6.17(dd, J ═ 10 and 3.2Hz,0.5H),6.16(dd, J ═ 10 and 1.7Hz,0.5H),5.92(s,1H),5.17(t, J ═ 4.8Hz,0.5H),5.03(d, J ═ 7.3Hz,0.5H),4.81(s,1H),4.72(d, J ═ 4.4, 0.5H),4.62-4.56 (d, 2.5H), 4.5H, 4.52 (d, 2.5H), 4.5H, 2.5H, 18.5H, 2H, 5H, 18.5H, 5H, 18.5H, 6.5H, 5H, 18.5H, 5H, 18.5H, 2H, 5H, 18.5H, 2H, 18.5H, 2H, 5H, 18.5H, 2H, 5H, 2H, 18.5H, 2H, and so as H, 1H) 2.11-1.95(m,2.5H),1.77-1.70(m,2.5H),1.60-1.39 (m),5H),1.383(s,0.5H),1.377(s,0.5H),1.36-1.23(m,4H),1.11-0.92(m,2H),0.87-0.80(m,7H)ppm。

(2S) -2- [ (2S) -2-aminopropionylamino group]-N- ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclo [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) propanamide, TFA salt (PII-5)

The payload PII-5(10mg, 44% yield, TFA salt) was obtained from PII-2 and Fmoc-alanine following a similar procedure as for PII-4. ESI M/z 602.2(M +1)⁺。¹H NMR(400MHz,DMSO_d6) δ 8.85(t, J ═ 6.2Hz,0.6H),8.84(t, J ═ 5.8Hz,0.4H),8.46(s,1H),7.321(d, J ═ 10.1Hz,0.6H),7.320(br s,3H),7.313(d, J ═ 10.1Hz,0.4H),6.170(dd, J ═ 10.1 and 1.6Hz,0.6H),6.166(dd, J ═ 10.1 and 1.6Hz,0.4H),5.92(s,1H),5.17(t, J ═ 4.8Hz,0.4H),5.03(d, J ═ 7.2Hz,0.4H),4.764(s,0.4H),4.756(s,0.6H), 4.73-4H (t, 4.62, 4H), 5.7.7, 7.2H, 0.4H), 3.7H (d, 3.7H, 7H, 3.7H, 7H, 3.7H, 3.4H, 7H, 3.7H, 7H, 3H, 3.4H, 3H, 7H, 3H, 4H, 7H, 3H, 7H, 4H, 7H, 3H, 3.7H, 3H, 7H, 4H, 7H, 3H, 7H, 4H, 3H, 7H, 3H, 7H, 3H, 7H, 4H, 3H, 4H, 3H, 7H, 3H, 1H) 2.14-1.91(m,2H),1.83-1.47(m,7H),1.382(s,1.8H),1.377(s,1.2H),1.46-1.31(m,1H),1.31-1.22(m,6H),1.15-0.90(m,2H),0.90-0.76(m,6H) ppm.

2-amino-N- (1- {2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclo [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } propyl) acetamide (PII-6)

Following general procedure A for payload, starting from compound 4d and budesonide, payload PII-6(40mg, 4.1% yield) was obtainedAs a white solid. ESI:567.2(M +23)⁺。¹H NMR(400MHz,DMSO_d6) δ 8.20 to 8.10(m,1H),7.34 to 7.29(m,1H),6.16(dd, J ═ 10 and 1.6Hz,1H),5.92(s,1H),5.15(t, J ═ 4.8Hz,0.4H),5.10 to 4.95(m,1.8H),4.83 to 4.40(m,2.8H),4.29(br s,1H),4.28 to 4.05(m,1H),3.13(d, J ═ 7.9Hz,2H),2.60 to 2.50(m,1H),2.36 to 2.22(m,1H),2.14 to 1.87(m,3H),1.81 to 1.62(m,4H),1.62 to 1.44(m,5H),1.38 (m,1H), 0.13 to 1H, 1.90 (m,1H), 0.9 to 4H).

2-amino-N- (1- {2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclo [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } -2-phenylethyl) acetamide (PII-7)

Following general procedure B for payload, starting from compound 4e and budesonide, the payload PII-7 was obtained (80mg, 29% yield) as a white solid. ESI M/z:629(M +23) ⁺。¹H NMR(400MHz,DMSO_d6)δ8.45-8.26(m,1H),7.35-7.23(m,5H),7.22-7.16(m,1H),6.16(dd,J＝10.2,1.9Hz,1H),5.91(s,1H),5.37-5.23(m,1H),5.17-5.12(m,0.5H),5.08(s,0.5H),5.02(d,J＝7.6Hz,0.5H),4.78(dd,J＝9.6,3.6Hz,0.5H),4.74-4.68(m,0.5H),4.60-4.46(m,1.5H),4.31-4.11(m,2H),3.13-3.01(m,3H),2.93-2.84(m,1H),2.33-2.23(m,1H),2.12-1.92(m,2H),1.79-1.39(m,7H),1.38(s,1.5H),1.37(s,1.5H),1.35-1.22(m,2H),1.14-0.89(m,3H),0.88-0.75(m,6H)ppm。

2-amino-N- ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclo [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) -N-methylacetamide (PII-8)

Following general procedure a for payload, starting from compound 4f and budesonide, payload PII-8(64mg, 12% yield) was obtained as a white solid. ESI M/z:531(M +1)⁺。¹H NMR(500MHz,DMSO_d6)δ7.35-7.23(m,1H),6.20-6.13(d,J＝10Hz,1H),5.92(s,1H),5.20-4.44(m,6H),4.33-4.08(m,2H),3.441(s,0.5H),3.436(s,0.5H),3.37(s,1H),2.91(s,1.5H),2.895(s,0.75H),2.891(s,0.75H),2.57-2.52(m,1H),2.33-2.24(m,1H),2.13-1.65(m,6H),1.61-1.46(m,4H),1.45-1.41(m,1H),1.383(s,1.5H),1.377(s,1.5H),1.35-1.21(m,2H),1.14-0.91(m,2H),0.89-0.78(m,6H)ppm。

Temperature-variable NMR (T ═ 60 ℃) indicated the presence of rotamers.

(2S) -2-amino-N- ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclo [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) -N-methylpropanamide (PII-11)

Following general procedure a for payload, starting from compound 4g and budesonide, payload PII-11(0.13g, 23% yield) was obtained as a white solid. ESI M/z:545(M +1)⁺。¹H NMR(500MHz,DMSO_d6)δ7.31(d,J＝10,4Hz,1H),6.20-6.13(m,1H),5.92(s,1H),5.20-5.13(m,0.5H),5.08-5.01(m,0.5H),4.92-4.39(m,5H),4.34-4.07(m,2H),3.88-3.80(m,0.5H),3.76-3.69(m,0.5H),3.02(s,1.5H),2.88(s,1.5H),2.57-2.51(m,1H),2.33-2.25(m,1H),2.12-1.93(m,2H),1.83-1.67(m,4H),1.63-1.23(m,10H),1.12-1.06(m,3H),1.02-0.90(m,2H),0.89-0.78(m,6H)ppm。

3-amino-1- ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclo [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) piperidin-2-one (PII-12)

Following general procedure a for payload, starting from compound 4h and budesonide, payload PII-12(19mg, 15% yield) was obtained as a white solid. ESI M/z:557(M +1) ⁺。¹H NMR(400MHz,DMSO_d6)δ7.33-7.30(m,1H),6.17(d,J＝10Hz,1H),5.92(s,1H),5.20-4.97(m,2H),4.92-4.48(m,5H),4.32-4.12(m,2H),3.27-3.17(m,2H),2.33-2.24(m,1H),2.12-1.92(m,6H),1.82-1.69(m,4H),1.61-1.24(m,12H),0.99-0.92(m,1H),0.87-0.81(m,6H)ppm。

(1S,2S,4R,8S,9S,11S,12S,13R) -8- (2- { [1- (2-Aminoacetyl) pyrrolidin-2-yl]Oxy } acetyl) -11-hydroxy-9, 13-dimethyl-6-propyl-5, 7-dioxa-pentacyclic [10.8.0.0²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosane-14, 17-dien-16-one (PII-9) (FIG. 2A)

To a solution of compound 4J (0.40g, 1.1mmol) in DCM (15mL) was added chlorotrimethylsilane (TMSCl) (0.35g, 3.3 mmol). The mixture was stirred at room temperature for 3 hours, monitored by LCMS. Volatiles were removed and the residue was redissolved in DCM (6 mL). To the resulting solution was added budesonide (0.94g, 2.2mmol) and DIPEA (0.28g, 2.2 mmol). The mixture was stirred at room temperature for 1 hour, monitored by LCMS. The resulting mixture was concentrated in vacuo and the residue was purified by reverse phase chromatography (0-100% acetonitrile in aqueous ammonium bicarbonate (0.05%)) to give Fmoc-P-GCII-9(ESI M/z:801(M +23)⁺) It was dissolved in DMF (3 mL). Piperidine (0.12g, 1.4mmol) was added to the resulting solution and the mixture was stirred at room temperature for 1 hour until Fmoc had been completely removed by LCMS. The reaction solution was directly purified by preparative HPLC to give the payload PII-9(0.10g, 17% yield) as a white solid. ESI M/z 579(M +23)⁺。¹H NMR(400MHz,DMSO_d6)δ7.34-7.29(m,1H),6.16(dd, J ═ 10.4 and 1.6Hz,1H),5.92(s,1H),5.52-4.99(m,2.3H),4.81-4.47(m,3H),4.35-4.15(m,1.7H),3.47-3.36(m,2H),3.27-3.21(m,2H),2.30-2.28(m,1H),2.09-1.88(m,4.7H),1.84-1.66(m,5.7H),1.61-1.42(m,4.6H),1.38(s,3H),1.38-1.25(m,3H),1.00-0.91(m,2H),0.88-0.77(m,6H) ppm.

(1S,2S,4R,8S,9S,11S,12S,13R) -8- (2- { [1- (2-aminoacetyl) azetidin-2-yl]Oxy } acetyl) -11-hydroxy-9, 13-dimethyl-6-propyl-5, 7-dioxa-pentacyclic [10.8.0.0²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosane-14, 17-dien-16-one (PII-13)

Following general procedure a for payload, starting from compound 4i and budesonide, payload PII-13(30mg, 7% yield) was obtained as a white solid. ESI M/z:543(M +1)⁺。¹H NMR(400MHz,DMSO_d6)δ8.35(br s,1H),8.05(br s,1H),7.40-7.35(m,1H),6.20-6.15(m,1H),5.95(s,1H),5.20-5.15(m,0.55H),5.05-5.00(m,0.55H),4.80-4.60(m,3H),4.40-4.20(m,2.45H),3.80-3.20(m,6.45H),3.20(s,2H),2.25-2.20(m,1H),2.05-1.95(m,2H),1.80-1.30(m,13H),1.20-1.00(m,2H),0.90-0.85(m,6H)ppm。

(2S) -2-amino-N- ({2- [ (1S,2S,4R,8S,9S,11S,12R,13S,19S) -12, 19-difluoro-11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclo [10.8.0.0 ]²,⁹.0⁴,8.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) propanamide (PIII-5)

Following general procedure a for payload, starting from compound 4b and drug III, payload PIII-5(90mg, 61% yield) was obtained as a white solid. ESI M/z 567(M +1)⁺。

2-amino-N- ({2- [ (1S,2S,4R,8S,9S,11S,12R,13S,19S) -12, 19-difluoro-11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxa-pentacyclic [10.8.0.0²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) acetamide (PIII-1)

Following general procedure a for payload, starting from compound 4a and drug/payload III, payload PIII-1(0.26g, 23% yield) was obtained as a white solid. ESI M/z:553(M +1) ⁺。¹H NMR(400MHz,DMSO_d6)δ8.75(t,J＝5.9Hz,1H),7.27(d,J＝10.2Hz,1H),6.30(dd,J＝10.2,1.7Hz,1H),6.11(s,1H),5.73-5.49(m,2H),5.19(t,J＝4.9Hz,0.25H),5.08(d,J＝7.1Hz,0.25H),4.75(s,0.75H),4.69-4.63(m,3.75H),4.26(d,J＝18.9Hz,1H),4.23-4.13(m,1H),3.17(s,2H),3.00(br s,2H),2.69-2.54(m,1H),2.30-2.18(m,1H),2.08-1.92(m,2H),1.83-1.21(m,8H),1.48(s,3H),0.86(t,J＝7.4Hz,3H),0.81(s,3H)ppm。

2-amino-N- { [ ({2- [ (1S,2S,4R,8S,9S,11S,12R,13S,19S) -12, 19-difluoro-11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclic [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } acetamide (PIII-4)

To a solution of compound PIII-1(55mg, 0.10mmol) in DMF (2.0mL) at RT was added DIPEA (40mg, 0.31mmol), Fmoc-glycine (30mg, 0.10mmol) and HATU (50mg, 0.13mmol), respectively. The reaction mixture was stirred at room temperature for 2 hours, monitored by LCMS. Piperidine (43mg, 0.50mmol) was then added to the solution and the mixture was stirred at room temperature for 1 hour until Fmoc was removed, monitored by LCMS. The mixture was subjected to reverse phase flash chromatography (0-100% acetonitrile in aqueous ammonium bicarbonate (0.08%)) until the mixture was purifiedFollowed by purification to give compound PIII-4(50mg, 82% yield) as a white solid. ESI M/z 610(M +1)⁺。¹H NMR(400MHz,DMSO_d6)δ8.71(t,J＝6.8Hz,1H),8.21(br s,1H),7.27(d,J＝10.2Hz,1H),6.30(dd,J＝10.2,1.9Hz,1H),6.11(s,1H),5.72-5.54(m,2H),4.78-4.74(m,1H),4.64(t,J＝4.1Hz,1H),4.61(d,J＝6.8Hz,2H),4.49(d,J＝18.9Hz,1H),4.23(d,J＝18.9Hz,1H),4.21-4.16(m,1H),3.74(s,2H),3.16(s,2H),2.71-2.56(m,1H),2.30-2.20(m,1H),2.04-1.96(m,2H),1.70(d,J＝13.7Hz,1H),1.61-1.52(m,4H),1.49(s,3H),1.44-1.27(m,4H),0.86(t,J＝7.4Hz,3H),0.81(s,3H)ppm。

(1S,4aS,10aR) -N- [ (1S,4aS,10aR) -6- {2- [ (2-Aminoacetamido) methoxy ] acetamido } -1,4 a-dimethyl-1, 2,3,4,4a,9,10,10 a-octahydrophenanthrene-1-carbonyl ] -6-hydroxy-1, 4 a-dimethyl-1, 2,3,4,4a,9,10,10 a-octahydrophenanthrene-1-carboxamide (PIV)

To a solution of LXR agonist 7(63mg, 0.12mmol, see WO 2018/213082 a1) in DMF (5mL) at room temperature was added HATU (79mg, 0.21mmol) and DIPEA (54mg, 0.44mmol), the mixture was stirred at room temperature for 15 min, then intermediate 6a (42mg, 0.11mmol) was added. The reaction mixture was stirred at room temperature for 4 hours, monitored by LCMS. Piperidine (0.2mL) was added to the mixture and the reaction mixture was stirred at room temperature for 1 hour until Fmoc removal was complete, as monitored by LCMS. The mixture was directly purified by preparative HPLC to give the payload PIV (34mg, 47% yield) as a white solid. ESI M/z 673(M +1) ⁺。¹H NMR(400MHz,DMSO_d6)δ9.54(s,1H),8.99(s,1H),8.85(br s,1H),8.11(s,1H),7.59(d,J＝1.5Hz,1H),7.45(dd,J＝8.4,1.5Hz,1H),6.97(d,J＝8.4Hz,1H),6.82(d,J＝8.4Hz,1H),6.63(d,J＝2.2Hz,1H),6.50(dd,J＝8.4,2.2Hz,1H),4.66(d,J＝1.6Hz,2H),4.00(s,2H),3.14(s,2H),2.94-2.64(m,4H),2.35-2.32(m,1H),2.32-2.22(m,2H),2.22-2.09(m,4H),1.95-1.78(m,4H),1.68-1.52(m,4H),1.36-1.28(m,2H),1.28(s,3H),1.27(s,3H),1.20-1.09(m,2H),1.01(s,3H),0.99(s,3H)ppm。

Synthesis of payloads PII-9 and PII-10 in FIG. 2

The payloads PII-9 and PII-10 were synthesized according to FIG. 2 and the following procedure.

9H-fluoren-9-ylmethyl N- [2- (2-hydroxypyrrolidin-1-yl) -2-oxoethyl ] carbamate (4G)

Following general procedure B of intermediate 4, crude compound 4G (50mg, 53% yield) was obtained as a white solid. The acetate intermediate was not obtained. ESI M/z 389(M +23)⁺。¹H NMR(400MHz,DMSO_d6)δ7.90(d,J＝7.4Hz,2H),7.73(d,J＝7.5Hz,2H),7.47-7.37(m,3H),7.33(t,J＝7.3Hz,2H),5.86(br s,1H),5.48(d,J＝4.0Hz,0.25H),5.39(d,J＝4.0Hz,0.75H),4.33-4.18(m,3H),3.96(d,J＝6.0Hz,1.5H),3.75(d,J＝6.0Hz,0.5H),3.59-3.33(m,1H),3.22-3.11(m,1H),2.00-1.59(m,4H)ppm。

9H-fluoren-9-ylmethyl N- [2- (2-hydroxypiperidin-1-yl) -2-oxoethyl ] carbamate (4H)

Following general procedure B of intermediate 4, after preparative HPLC, compound 4H (40mg, 31% yield) was obtained as a white solid. The acetate intermediate was not obtained. ESI M/z:403(M +23)⁺。

(1S,2S,4R,8S,9S,11S,12S,13R) -8- (2- { [1- (2-Aminoacetyl) pyrrolidin-2-yl]Oxy } acetyl) -11-hydroxy-9, 13-dimethyl-6-propyl-5, 7-dioxa-pentacyclic [10.8.0.0²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosane-14, 17-dien-16-one (PII-9)

To a solution of compound 4G (0.40G, 1.1mmol) in DCM (15mL) was added trimethylChlorosilane (TMS-Cl) (0.35g, 3.3 mmol). The mixture was stirred at room temperature for 3 hours until the alcohol was consumed as monitored by LCMS. The volatiles were removed and the residue was redissolved in DCM (6 mL). To the resulting solution was added budesonide (0.94g, 2.2mmol) and DIPEA (0.28g, 2.2 mmol). The mixture was stirred at room temperature for 1 hour, monitored by LCMS. The resulting mixture was concentrated in vacuo and the residue was purified by reverse phase chromatography (0-100% acetonitrile in aqueous ammonium bicarbonate (0.05%)) to give Fmoc-P-GCII-9(ESI M/z:801(M +23) ⁺) It was dissolved in DMF (3 mL). Piperidine (0.12g, 1.4mmol) was added to the resulting solution and the mixture was stirred at room temperature for 1 hour until Fmoc had been completely removed by LCMS. The reaction solution was directly purified by preparative HPLC to give the payload PII-9(0.10g, 17% yield) as a white solid. ESI M/z 579(M +23)⁺。¹H NMR(400MHz,DMSO_d6) δ 7.34-7.29(m,1H),6.16(dd, J ═ 10.4 and 1.6Hz,1H),5.92(s,1H),5.52-4.99(m,2.3H),4.81-4.47(m,3H),4.35-4.15(m,1.7H),3.47-3.36(m,2H),3.27-3.21(m,2H),2.30-2.28(m,1H),2.09-1.88(m,4.7H),1.84-1.66(m,5.7H),1.61-1.42(m,4.6H),1.38(s,3H),1.38-1.25(m,3H),1.00-0.91(m,2H),0.88-0.77(m, 6H).

(1S,2S,4R,8S,9S,11S,12S,13R) -8- (2- { [1- (2-Aminoacetyl) piperidin-2-yl]Oxy } acetyl) -11-hydroxy-9, 13-dimethyl-6-propyl-5, 7-dioxa-pentacyclic [10.8.0.0²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosane-14, 17-dien-16-one (PII-10)

Following a similar procedure as for PII-9, the payload PII-10(0.10g, 20% yield) was obtained as a white solid. ESI M/z 593(M +23)⁺。

Benzyl 2- { [1- (2- { [ (9H-fluoren-9-ylmethoxy) carbonyl ] amino } acetyl) pyrrolidin-2-yl ] oxy } acetate (5b)

To a solution of compound 4J (0.30g, 0.82mmol) in DCM (25mL) was added chlorotrimethylsilane (TMSCl) (0.27g, 2.5 mmol). The reaction mixture was stirred at room temperature for 3 hours, monitored by LCMS. The resulting mixture was concentrated in vacuo and the residue was diluted with DCM (25 mL). To the resulting solution was added benzyl glycolate (0.27g, 1.6mmol) and DIPEA (0.21g, 1.6mmol), and the reaction mixture was stirred at room temperature for 1 hour, monitored by LCMS. The resulting mixture was concentrated in vacuo and the residue was purified by reverse phase flash chromatography (0-100% acetonitrile in aqueous ammonium bicarbonate (0.05%)) to afford compound 5b (0.11g, 25% yield, purity >99 percent; 50mg, 75% purity) as a white solid. ESI M/z 537.3(M + Na)⁺。¹H NMR(400MHz,DMSO_d6)δ7.91-7.89(m,2H),7.74-7.69(m,2H),7.63-7.48(m,1H),7.42-7.25(m,9H),5.51-5.09(m,2H),4.35-4.21(m,5H),4.00-3.77(m,2H),3.52-3.38(m,2H),3.30-3.18(m,1H),2.19-1.64(m,4H)ppm。

2- { [1- (2- { [ (9H-fluoren-9-ylmethoxy) carbonyl ] amino } acetyl) pyrrolidin-2-yl ] oxy } acetic acid (6b)

To a solution of compound 5b (89mg, 0.17mmol) in methanol (3mL) and THF (7mL) under nitrogen was added wet palladium on charcoal (10% Pd, 20 mg). The mixture was degassed, purged with hydrogen, and stirred at room temperature under a hydrogen balloon for 2 hours, monitored by LCMS. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by reverse phase flash chromatography (0-100% acetonitrile in aqueous ammonium bicarbonate (0.05%)) to afford compound 6b (36mg, 49% yield) as a white solid. ESI M/z 447.1(M + Na)⁺。

Linker-payload synthesis

Synthesis of linker-payload L1-P- #

Linker-payloads L1-PI, L1-PII-1, L1-PII-2, L1-PII-3, L1-PII-4, L1-PII-5, L1-PII-6, L1-PII-7, L1-PII-8, L1-PII-11, L1-PII-12, L1-PII-9, L1-PIII-1, L19-PIII-1, and L1-PIII-4 were synthesized according to FIG. 3 and the following procedures; linker-payloads L8-PII-1 and L2-PIII-1 were synthesized according to FIG. 4 and the following procedure. Intermediate L-3b was synthesized according to WO 2018/089373. Linkers vcPAB (CAS:1497404-26-8), L-1a (CAS:1427004-19-0), and L-1b (CAS:2101206-50-0) and L-1c (CAS:1702356-19-1) are all commercially available.

Synthesis of intermediate L-3a (FIG. 3)

N- [ (1S) -1- { [ (1S) -4- (carbamoylamino) -1- { [4- (hydroxymethyl) phenyl ] carbamoyl } butyl ] carbamoyl } -2-methylpropyl ] -1- [2- (cycloocta-2-yn-1-yloxy) acetamido ] -3,6,9, 12-tetraoxapentadecane-15-amide (L-2a)

To a solution of compound L-1a (0.17g, 0.33mmol) in DMF (10mL) was added DIPEA (0.13g, 1.0mmol) and vcPAB (0.13g, 0.34mmol) in that order, and the reaction mixture was stirred at room temperature for 1 hour and monitored by LCMS. The resulting mixture was directly purified by reverse phase flash chromatography (0-80% aqueous acetonitrile) to give compound L-2a (0.18g, 70% yield) as a colorless oil. ESI M/z 791.3(M + H)⁺。¹H NMR(400MHz,DMSO_d6)δ9.91(s,1H),8.11(d,J＝8.4Hz,1H),7.89(d,J＝8.8Hz,1H),7.61(t,J＝5.6Hz,1H),7.55(d,J＝8.4Hz,2H),7.23(d,J＝8.4Hz,2H),5.98(t,J＝5.6Hz,1H),5.42(s,2H),5.10(br s,1H),),4.43(s,2H),4.39-4.37(m,1H),4.30-4.21(m,2H),3.87(d,J＝14.8Hz,1H),3.75(d,J＝14.8Hz,1H),3.62-3.58(m,2H),3.50-3.46(m,12H),3.43(t,J＝6.0Hz,2H),3.27-3.22(m,2H),3.06-2.92(m,2H),2.41-2.32(m,2H),2.26-2.05(m,3H),1.99-1.66(m,6H),1.62-1.55(m,3H),1.44-1.35(m,3H),0.89(d,J＝6.8Hz,3H),0.83(d,J＝6.8Hz,3H)ppm。

{4- [ (2S) -5- (carbamoylamino) -2- [ (2S) -2- {1- [2- (cycloocta-2-yn-1-yloxy) acetamido ] -3,6,9, 12-tetraoxapentadecane-15-amido } -3-methylbutanamido ] pentanamido ] phenyl } methyl 4-nitrophenyl carbonate (L-3a)

A suspension of compound L-2a (80mg, 0.10mmol), DMAP (12mg, 0.10mmol) and DIPEA (26mg, 0.20mmol) in dry DMF (5mL) was stirred at room temperature for 10 minutes, then bis (4-nitrophenyl) carbonate (61mg, 0.20mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, monitored by LCMS. The resulting mixture was directly purified by reverse phase flash chromatography (0-80% acetonitrile in water) to give compound L-3a (53mg, 55% yield) as a white solid. ESI M/z 956.3(M + H) ⁺。

General procedure for vcPAB linker-payload L1-PI, L1-PII-1, L1-PII-2, L1-PII-3, L1-PII-4, L1-PII-5, L1-PII-6, L1-PII-7, L1-PII-8, L1-PII-11, L1-PII-12, L1-PII-9, L1-PIII-1, L19-PIII-1 and L1-PIII-4 (FIG. 3)

To a solution of payload (1.0 equiv) in DMF (5-10mM) were added compounds L-3a, L-3b (1.0 equiv), HOBt (0-0.05 equiv) and DIPEA (2.0 equiv) and the mixture was stirred at room temperature overnight, monitored by LCMS. The resulting mixture was directly purified by preparative HPLC to give vcPAB linker-payload L1-PI, L1-PII-1, L1-PII-2, L1-PII-3, L1-PII-4, L1-PII-5, L1-PII-6, L1-PII-7, L1-PII-8, L1-PII-11, L1-PII-12, L1-PII-9, L1-PIII-1, L19-PIII-1 and L1-PIII-4 (11-68% yield; see Table 3) all as white solids.

{4- [ (2S) -2- [ (2S) -2- [1- (4- { 2-Azotricyclo [10.4.0.0 ]⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -3,6,9, 12-tetraoxapentadecane-15-carboxamide]-3-methylbutanamido group]-5- (carbamoylamino) pentanamide]Phenyl } methyl N- { [ ({2- [ (1R,2S,10S,11S,13R,14R,15S,17S) -1-fluoro-14, 17-dihydroxy-2, 13, 15-trimethyl-5-oxotetracyclo [8.7.0.0 ] ²,⁷.0¹¹,¹⁵]Hexadeca-3, 6-dien-14-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamate (L1-PI)

Following the general procedure for vcPAB linker-payload, starting from payload PI and compound L-3b, linker-payload L1-PI (8.2mg, 17% yield) was obtained as a white solid. ESI M/z:710(M/2+1)⁺。¹H NMR(400MHz,DMSO_d6)δ10.01(s,1H),8.72(t,J＝6.7Hz,1H),8.14(d,J＝7.1Hz,1H),7.89(d,J＝8.0Hz,1H),7.78(t,J＝5.6Hz,1H),7.68(d,J＝8.0Hz,1H),7.65-7.54(m,3H),7.54-7.42(m,4H),7.42-7.21(m,6H),6.22(d,J＝10.0Hz,1H),6.05-5.96(m,2H),5.43(s,2H),5.26(s,1H),5.06-4.90(m,4H),4.63-4.48(m,3H),4.44-4.31(m,1H),4.27-4.08(m,3H),3.66-3.54(m,4H),3.52-3.35(m,12H),3.33-3.24(m,2H),3.14-2.84(m,4H),2.70-2.53(m,2H),2.48-1.88(m,10H),1.82-1.53(m,4H),1.48(s,3H),1.47-1.27(m,4H),1.23(s,2H),1.10-1.00(m,1H),0.87(s,3H),0.86(d,J＝6.5Hz,3H),0.82(d,J＝6.7Hz,3H),0.78(d,J＝7.2Hz,3H)ppm。

{4- [ (2S) -2- [ (2S) -2- [1- (4- { 2-Azotricyclo [10.4.0.0 ]⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -3,6,9, 12-tetraoxapentadecane-15-carboxamide]-3-methylbutanamido group]-5- (carbamoylamino) pentanamide]Phenyl } methyl N- { [ ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclo [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamate (L1-PII-1)

Following the general procedure for vcPAB linker-payload, starting from payload PII-1 and compound L-3b, linker-payload L1-PII-1(5.0mg, 11% yield) was obtained as a white solid. ESI M/z 729(M/2+1)⁺。¹H NMR(400MHz,DMSO_d6)δ10.00(s,1H),8.70-8.60(m,1H),8.20-8.10(m,1H),7.90-7.50(m,5H),7.50-7.20(m,10H),6.15-6.10(m,1H),6.05-6.00(m,1H),5.95(s,1H),5.50(s,2H),5.05-5.00(m,3H),4.80-4.30(m,8H),3.60-3.55(m,4H),3.50-3.45(m,14H),3.40-3.30(m,4H),3.10-2.80(m,4H),2.60-2.55(m,1H),2.40-2.20(m,5H),2.00-1.90(m,4H),1.80-1.60(m,4H),1.60-1.50(m,5H),1.40-1.30(m,8H),1.00-0.80(m,14H)ppm。

{4- [ (2S) -2- [ (2S) -2- [1- (4- { 2-Azotricyclo [10.4.0.0 ]⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -3,6,9, 12-tetraoxapentadecane-15-carboxamide ]-3-methylbutanamido group]-5- (carbamoylamino) pentanamide]Phenyl } methyl N- [ ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxa-pentacyclo [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamoyl) methyl]Carbamate (L1-PII-2)

Following the general procedure for vcPAB linker-payload, starting from payload PII-2 and compound L-3b, linker-payload L1-PII-2(1.0mg, 18% yield) was obtained as a white solid. ESI M/z 1041 (M-Bud)⁺,736(M/2+1)⁺,521[(M–Bud)/2]⁺。¹H NMR(400MHz,DMSO_d6)δ9.95(s,1H),8.60-8.55(m,1H),8.00(d,J＝10.0Hz,1H),7.75-7.70(d,J＝6.4Hz,1H),7.65-7.20(m,15H),6.05-6.00(m,1H),5.90-5.85(m,1H),5.80(s,1H),5.30(s,2H),5.10-4.60(m,4H),4.55-4.10(m,11H),3.90-3.85(m,2H),3.50-3.45(m,4H),3.40-3.30(m,14H),3.20-3.15(m,2H),3.00-2.80(m,3H),2.50-2.45(m,2H),2.30-2.10(m,3H),2.00-1.80(m,4H),1.75-1.50(m,4H),1.45-1.25(m,5H),1.20-1.05(m,6H),1.05-1.00(m,3H),0.85-0.75(m,12H)ppm。

{4- [ (2S) -2- [ (2S) -2- [1- (4- { 2-Azotricyclo [10.4.0.0 ]⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -3,6,9, 12-tetraoxapentadecane-15-carboxamide]-3-methylbutanamido group]-5- (carbamoylamino) pentanamide]Phenyl } methyl N- { [ (1- {2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclic [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } propyl) carbamoyl]Methyl } carbamate (L1-PII-3)

Following the general procedure for vcPAB linker-payload, starting from payload PII-3 and compound L-3b, linker-payload L1-PII-3(0.10g, 47% yield) was obtained as a white solid. ESI M/z 774(M/2+1) ⁺,1116.5(M–Bud)⁺,558.9[(M-Bud)/2]⁺。¹H NMR(400MHz,DMSO_d6)δ9.96(s,1H),8.93-8.91(m,1H),8.11(d,J＝7.2Hz,1H),7.87(d,J＝8.4Hz,1H),7.75(t,J＝4.8Hz,1H),7.69-7.45(m,9H),7.39-7.26(m,9H),7.24-7.16(m,3H),6.16(d,J＝10.0Hz,1H),5.97-5.92(m,2H),5.41(s,2H),5.17-5.01(m,2H),4.91-4.82(m,2H),4.73-4.54(m,5H),4.49-4.13(m,6H),3.62-3.57(m,3H),3.47-3.45(m,13H),3.11-2.92(m,5H),2.78-2.72(m,1H),2.40-2.20(m,4H),2.07-1.94(m,3H),1.80-1.67(m,4H),1.60-1.51(m,4H),1.43-1.24(m,9H),0.99-0.82(m,15H)ppm。

{4- [ (2S) -2- [ (2S) -2- [1- (4- { 2-Azotricyclo [10.4.0.0 ]⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -3,6,9, 12-tetraoxapentadecane-15-carboxamide]-3-methylbutanamido group]-5- (carbamoylamino) pentanamide]Phenyl } methyl N- [ ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxa-pentacyclo [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamoyl) methyl]Carbamate (L1-PII-4)

Following the general procedure for vcPAB linker-payload, starting from payload PII-4 and compound L-3b, linker-payload L1-PII-4(45mg, 68% yield) was obtained as a white solid. ESI M/z 757.5(M/2+1)⁺。¹H NMR(400MHz,DMSO_d6)δ9.99(s,1H),8.69-8.65(m,1H),8.23-8.20(m,1H),8.13(d,J＝7.0Hz,1H),7.87(d,J＝8.5Hz,1H),7.76(t,J＝6.0Hz,1H),7.68-7.67(m,1H),7.62-7.58(m,3H),7.51-7.42(m,4H),7.39-7.28(m,6H),6.17-6.15(m,1H),5.97(t,J＝6.0Hz,1H),5.91(s,1H),5.41(s,2H),5.16(t,J＝5.5Hz,0.5H),5.04-5.01(m,1.5H),4.96(s,2H),4.73-4.71(m,1.5H),4.61-4.58(m,2.5H),4.49(t,J＝19.0Hz,1H),4.40-4.35(m,1H),4.30-4.28(m,1H),4.24-4.14(m,2H),3.72(d,J＝5.5Hz,2H),3.67(d,J＝6.0Hz,2H),3.62-3.56(m,3H),3.47-3.45(m,10H),3.44-3.43(m,2H),3.31-3.28(m,3H),3.10-3.05(m,2H),3.04-3.00(m,1H),2.97-2.90(m,1H),2.60-2.54(m,1H),2.47-2.44(m,1H),2.39-2.34(m,1H),2.30-2.20(m,2H),2.08-1.94(m,4H),1.78-1.66(m,4H),1.59-1.49(m,5H),1.45-1.39(m,2H),1.37(d,J＝3.0Hz,3H),1.35-1.30(m,2H),1.28-1.21(m,2H),0.99-0.91(m,1H),0.86-0.80(m,12H)ppm。

{4- [ (2S) -2- [ (2S) -2- [1- (4- { 2-Azotricyclo [10.4.0.0 ]⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -3,6,9, 12-tetraoxapentadecane-15-carboxamide]-3-methylbutanamido group]-5- (carbamoylamino) pentanamide]Phenyl } methyl N- [ ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxa-pentacyclo [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl ]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamoyl) methyl]Carbamate (L1-PII-5)

Following the general procedure for vcPAB linker-payloads, starting from payload PII-5 and compound L-3b, linker-payload L1-PII-5(4mg, 25% yield) was obtained as whiteA colored solid. ESI M/z 771.5(M/2+1)⁺,556.3[(M–Bud)]⁺。¹H NMR(400MHz,DMSO_d6)δ9.99(s,1H),8.79-8.63(m,1H),8.13(d,J＝7.4Hz,1H),8.04(d,J＝7.2Hz,1H),7.88(d,J＝8.6Hz,1H),7.77(t,J＝5.6Hz,1H),7.71-7.54(m,4H),7.54-7.42(m,3H),7.42-7.21(m,7H),6.16(d,J＝10.1Hz,1H),5.99(t,J＝5.5Hz,1H),5.92(s,1H),5.42(s,2H),5.24-4.87(m,4H),4.80-4.00(m,11H),3.66-3.54(m,3H),3.53-3.41(m,12H),3.32-3.27(m,2H),3.13-2.87(m,4H),2.68-2.45(m,2H),2.42-2.17(m,4H),2.08(s,1H),2.05-1.90(m,4H),1.83-1.64(m,4H),1.64-1.39(m,7H),1.377(s,1.8H),1.371(s,1.2H),1.36-1.26(m,2H),1.23(d,J＝7.0Hz,3H),1.19(d,J＝7.0Hz,3H),1.12-0.89(m,2H),1.12-0.91(m,12H)ppm。

{4- [ (2S) -2- [ (2S) -2- [1- (4- { 2-Azotricyclo [10.4.0.0 ]⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -3,6,9, 12-tetraoxapentadecane-15-carboxamide]-3-methylbutanamido group]-5- (carbamoylamino) pentanamide]Phenyl } methyl N- { [ (1- {2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclic [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³ _, ¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } propyl) carbamoyl]Methyl } carbamate (L1-PII-6)

Following the general procedure for vcPAB linker-payload, starting from payload PII-6 and compound L-3b, linker-payload L1-PII-6(20mg, 50% yield) was obtained as a white solid. ESI M/z 1055(M-Bud)⁺,528[(M-Bud)/2]⁺，¹H NMR(500MHz,DMSO_d6)δ9.98(s,1H),8.31-8.19(m,1H),8.11(d,J＝7.4Hz,1H),7.86(d,J＝8.6Hz,1H),7.75(t,J＝5.6Hz,1H),7.68(d,J＝7.2Hz,1H),7.63-7.55(m,3H),7.52-7.43(m,3H),7.43-7.32(m,3H),7.32-7.21(m,4H),6.15(d,J＝10.0Hz,1H),5.97(t,J＝5.6Hz,1H),5.91(s,1H),5.40(s,2H),5.20-4.88(m,5H),4.75-4.08(m,7H),3.70-3.53(m,5H),3.51-3.40(m,12H),3.30-3.27(m,2H),3.13-2.89(m,4H),2.65-2.53(m,1H),2.47-2.43(m,1H),2.41-2.18(m,4H),2.04-1.97(m,4H),1.80-1.64(m,5H),1.63-1.47(m,6H),1.47-1.21(m,8H),1.11-0.90(m,2H),0.89-0.76(m,15H)ppm。

{4- [ (2S) -2- [ (2S) -2- [1- (4- { 2-Azotricyclo [10.4.0.0 ]⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -3,6,9, 12-tetraoxapentadecane-15-carboxamide ]-3-methylbutanamido group]-5- (carbamoylamino) pentanamide]Phenyl } methyl N- { [ (1- {2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclic [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } -2-phenylethyl) carbamoyl]Methyl } carbamate (L1-PII-7)

Following the general procedure for vcPAB linker-payload, starting from payload PII-7 and compound L-3b, linker-payload L1-PII-7(25mg, 33% yield) was obtained as a white solid. ESI M/z 1116.5 (M-Bud)⁺。¹H NMR(500MHz,DMSO_d6)δ9.98(s,1H),8.46(d,J＝9.7Hz,1H),8.12(d,J＝8.3Hz,1H),7.87(d,J＝8.9Hz,1H),7.75(t,J＝5.6Hz,1H),7.68(d,J＝7.8Hz,1H),7.64-7.55(m,3H),7.53-7.42(m,3H),7.41-7.31(m,3H),7.31-7.14(m,9H),6.14(d,J＝9.6Hz,1H),5.97(br s,1H),5.91(s,1H),5.41(s,2H),5.31-5.21(m,1H),5.18-5.11(m,0.5H),5.05-5.00(m,1.5H),4.99-4.89(m,2H),4.76-4.63(m,1H),4.59-4.47(m,2H),4.38(m,1H),4.31-4.13(m,3H),3.67-3.54(m,3H),3.51-3.40(m,12H),3.33-3.25(m,2H),3.13-2.83(m,6H),2.65-2.54(m,1H),2.41-2.18(m,5H),2.10-1.91(m,4H),1.80-1.64(m,4H),1.63-1.20(m,15H),1.11-0.89(m,2H),0.88-0.76(m,12H)ppm。

{4- [ (2S) -2- [ (2S) -2- [1- (4- { 2-Azotricyclo [10.4.0.0 ]⁴,⁹]Hexadeca-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -3,6,9, 12-tetraoxapentadecane-15-amideBase of]-3-methylbutanamido group]-5- (carbamoylamino) pentanamide]Phenyl } methyl N- { [ ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclo [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) (methyl) carbamoyl]Methyl } carbamate (L1-PII-8)

Following the general procedure for vcPAB linker-payload, starting from payload PII-8 and compound L-3b, linker-payload L1-PII-8(60mg, 44% yield) was obtained as a white solid. ESI M/z:736(M/2+1) ⁺。¹H NMR(500MHz,DMSO_d6)δ10.00(s,1H),8.14(d,J＝7.5Hz,1H),7.89(d,J＝8.5Hz,1H),7.76(d,J＝5.9Hz,1H),7.68(d,J＝7.1Hz,1H),7.64-7.54(m,3H),7.52-7.42(m,3H),7.40-7.18(m,5H),6.19-6.12(m,1H),6.00(t,J＝5.1Hz,1H),5.92(s,1H),5.41(s,2H),5.20-5.13(m,0.5H),5.08-4.99(m,1.5H),4.96(s,2H),4.85-4.08(m,10H),4.02-3.95(m,1H),3.92-3.85(m,1H),3.64-3.54(m,3H),3.51-3.40(m,12H),3.33-3.27(m,2H),2.91-2.86(m,5H),2.90(s,2H),2.65-2.53(m,1H),2.47-2.42(m,1H),2.41-2.32(m,1H),2.32-2.19(m,2H),2.13-1.91(m,4H),1.81-1.65(m,5H),1.63-1.47(m,5H),1.46-1.40(m,2H),1.38(s,3H),1.36-1.21(m,4H),1.15-0.90(m,2H),0.89-0.77(m,12H)ppm。

{4- [ (2S) -2- [ (2S) -2- [1- (4- { 2-Azotricyclo [10.4.0.0 ]⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -3,6,9, 12-tetraoxapentadecane-15-carboxamide]-3-methylbutanamido group]-5- (carbamoylamino) pentanamide]Phenyl } methyl N- [ (1S) -1- [ ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxa-pentacyclic [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) (methyl) carbamoyl]Ethyl radical]Carbamate (L1-PII-11)

Following the general procedure for vcPAB linker-payload, starting from payload PII-11 and compound L-3b, linker-payload L1-PII-11(50mg, 61% yield) was obtained as a white solid. ESI M/z 743(M/2+1)⁺。¹H NMR(400MHz,DMSO_d6)δ9.98(s,1H),8.12(d,J＝7.6Hz,1H),7.87(d,J＝8.4Hz,1H),7.76(t,J＝5.6Hz,1H),7.80-7.74(m,1H),7.71-7.66(m,1H),7.64-7.54(m,3H),7.53-7.43(m,3H),7.40-7.24(m,6H),6.15(d,J＝13.2Hz,1H),5.97(t,J＝5.6Hz,1H),5.92(s,1H),5.41(s,2H),5.20-4.83(m,5H),4.78-4.68(m,2H),4.67-4.50(m,2H),4.49-4.34(m,2H),4.33-4.12(m,3H),3.67-3.55(m,3H),3.52-3.41(m,12H),3.31-3.27(m,2H),3.12-2.84(m,7H),2.62-2.53(m,2H),2.47-2.43(m,1H),2.41-2.34(m,1H),2.33-2.19(m,2H),2.11-1.91(m,4H),1.82-1.67(m,4H),1.63-1.49(m,4H),1.47-1.40(m,2H),1.39-1.35(m,3H),1.25-1.15(m,4H),1.01-0.89(m,2H),0.89-0.79(m,12H)ppm。

{4- [ (2S) -2- [ (2S) -2- [1- (4- { 2-Azotricyclo [10.4.0.0 ]⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -3,6,9, 12-tetraoxapentadecane-15-carboxamide]-3-methylbutanamido group]-5- (carbamoylamino) pentanamide]Phenyl } methyl N- [1- ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclo [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl ]-2-oxoethoxy } methyl) -2-oxopiperidin-3-yl]Carbamate (L1-PII-12)

Following the general procedure for vcPAB-linker-payload, starting from payload PII-12 and compound L-3b, linker-payload L1-PII-12(5.0mg, 19% yield) was obtained as a white solid. ESI M/z 749(M/2+1)⁺。¹H NMR(400MHz,DMSO_d6)δ9.99(s,1H),8.11(d,J＝7.0Hz,1H),7.87(d,J＝8.5Hz,1H),7.79-7.74(m,1H),7.69-7.67(m,1H),7.63-7.58(m,3H),7.51-7.25(m,9H),6.17-6.14(m,1H),6.00-5.97(m,1H),5.92(s,1H),5.41(s,2H),5.33-5.15(m,1H),5.04-5.01(m,1H),4.95-4.47(m,7H),4.40-4.18(m,4H),4.00-3.93(m,1H),3.62-3.56(m,3H),3.47-3.42(m,11H),3.32-3.26(m,5H),3.12-2.93(m,4H),2.62-2.55(m,1H),2.50-2.20(m,4H),2.02-1.68(m,13H),1.60-1.28(m,14H),0.99-0.90(m,2H),0.86-0.81(m,12H)ppm。

{4- [ (2S) -2- [ (2S) -2- [1- (4- { 2-Azotricyclo [10.4.0.0 ]⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -3,6,9, 12-tetraoxapentadecane-15-carboxamide]-3-methylbutanamido group]-5- (carbamoylamino) pentanamide]Phenyl } methyl N- [2- (2- {2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxa-pentacyclic [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } pyrrolidin-1-yl) -2-oxoethyl]Carbamate (L1-PII-9)

Following the general procedure for vcPAB linker-payload, starting from payload PII-9 and compound L-3b, linker-payload L1-PII-9(42mg, 44% yield) was obtained as a white solid. ESI M/z 1066(M-Bud)⁺,534[(M-Bud)/2]⁺。¹H NMR(500MHz,DMSO_d6)δ10.04(s,1H),8.20(d,J＝7.8Hz,1H),7.93(d,J＝7.6Hz,1H),7.76(t,J＝5.7Hz,1H),7.68(d,J＝7.5Hz,1H),7.64-7.56(m,3H),7.53-7.43(m,3H),7.40-7.23(m,7H),6.18-6.16(m,1H),6.03-6.02(m,1H),5.92(s,1H),5.42(s,2H),5.32(s,1H),5.04-4.94(m,4H),4.74-4.50(m,4H),4.38-4.37(m,1H),4.29-4.21(m,3H),3.79-3.78(m,1H),3.62-3.55(m,3H),3.47-3.45(m,12H),3.31-3.19(m,2H),3.10-2.93(m,4H),2.64-2.54(m,1H),2.48-2.45(m,1H),2.40-2.20(m,2H),2.11-1.88(m,7H),1.85-1.64(m,7H),1.60-1.40(m,8H),1.38(s,3H),1.36-1.19(m,4H),1.00-0.91(m,2H),0.89-0.75(m,12H)ppm。

{4- [ (2S) -2- [ (2S) -2- [1- (4- { 2-Azotricyclo [10.4.0.0 ]⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -3,6,9, 12-tetraoxapentadecane-15-carboxamide ]-3-methylbutanamido group]-5- (carbamoylamino) pentanamide]Phenyl } methyl N- [2- (2- {2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxa-pentacyclic [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } piperidin-1-yl) -2-oxoethyl]Carbamate (L1-PII-10)

Following the general procedure for vcPAB linker-payload, starting from payload PII-10 and compound L-3b, linker-payload L1-PII-10(50mg, 50% yield) was obtained as a white solid. ESI M/z 1080(M-Bud)⁺,541[(M-Bud)/2]⁺。

{4- [ (2S) -2- [ (2S) -2- [1- (4- { 2-Azotricyclo [10.4.0.0 ]⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -3,6,9, 12-tetraoxapentadecane-15-carboxamide]-3-methylbutanamido group]-5- (carbamoylamino) pentanamide]Phenyl } methyl N- { [ ({2- [ (1S,2S,4R,8S,9S,11S,12R,13S,19S) -12, 19-difluoro-11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxa-pentacyclic [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamate (L1-PIII-1)

Following the general procedure for vcPAB linker-payloads, starting from payload PIII-1 and compound L-3b, linker-payload L1-PIII-1(23mg, 58% yield) was obtained as A white solid. ESI M/z 747(M/2+1)⁺。¹H NMR(400MHz,DMSO_d6)δ10.08(s,1H),8.83-8.71(m,1H),8.15(d,J＝6.6Hz,1H),7.89(d,J＝8.7Hz,1H),7.78(t,J＝5.4Hz,1H),7.68(d,J＝7.7Hz,1H),7.65-7.55(m,3H),7.52-7.44(m,4H),7.41-7.22(m,6H),6.29(d,J＝10.2Hz,1H),6.11(s,1H),5.99(t,J＝5.0Hz,1H),5.73-5.36(m,4H),5.22-4.93(m,3H),4.78-4.45(m,4H),4.42-4.33(m,1H),4.28-4.14(m,3H),3.67-3.54(m,5H),3.52-3.41(m,12H),3.29(t,J＝5.9Hz,2H),3.18-2.89(m,4H),2.72-2.42(m,3H),2.42-2.18(m,4H),2.10-1.89(m,4H),1.82-1.65(m,3H),1.63-1.51(m,4H),1.48(s,3H),1.47-1.19(m,6H),0.90-0.75(m,12H)ppm。

{4- [ (2S) -2- [ (2S) -2-amino-3-methylbutanamide]-5- (carbamoylamino) pentanamide]Phenyl } methyl N- { [ ({2- [ (1S,2S,4R,8S,9S,11S,12R,13S,19S) -12, 19-difluoro-11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxa-pentacyclic [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl carbamate

To a solution of Fmoc-vcPAB-PNP (L-4) (60mg, 78. mu. mol) in DMF (2mL) was added the payload PIII-1(44mg, 80. mu. mol) and DIPEA (31mg, 0.24mmol), and the mixture was stirred at room temperature for 2 h, monitored by LCMS. Piperidine (34mg, 0.40mmol) was added to the resulting mixture and the mixture was stirred at room temperature for 1 hour until Fmoc removal was complete, as monitored by LCMS. The reaction mixture was directly purified by reverse phase flash chromatography (0-100% acetonitrile in aqueous ammonium bicarbonate (0.05%)) to afford compound L-5(45mg, 60% yield) as a yellow solid. ESI M/z:958(M +1)⁺。

(1R,8S,9R) -bicyclo [6.1.0]Non-4-yn-9-ylmethyl N- (14- { [ (1S) -1- { [ (1S) -4- (carbamoylamino) -1- [ (4- { [ ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12R,13S,19S) -12, 19-difluoro-11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclic [10.8.0.0 ] ²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamoyl) oxy]Methyl } phenyl) carbamoyl]Butyl radical]Carbamoyl } -2-methylpropyl radical]Carbamoyl } -3,6,9, 12-tetraoxatetradecan-1-yl) carbamate (L19-PIII-1)

To a solution of compound L-5(30mg, 31. mu. mol) in DMF (2mL) was added compound L-1c (34mg, 63. mu. mol) and DIPEA (12mg, 93. mu. mol), and the reaction mixture was stirred at room temperature for 2 hours, monitored by LCMS. The resulting mixture was directly purified by reverse phase flash chromatography (0-100% acetonitrile in aqueous ammonium bicarbonate (0.05%)) to afford linker-payload L19-PIII-1(8.0mg, 14% yield) as a white solid. ESI M/z:691(M/2+1)⁺。¹H NMR(400MHz,DMSO_d6) δ 10.00(s,1H),8.75(t, J ═ 6.8Hz,1H),8.14(d, J ═ 7.6Hz,1H),7.89(d, J ═ 8.4Hz,1H),7.60(d, J ═ 8.4Hz,2H),7.47(t, J ═ 6.0Hz,1H),7.31-7.25(m,3H),7.12-7.09(m,1H),6.29(dd, J ═ 10.4 and 1.6Hz,1H),6.11(s,1H),5.99-5.97(m,1H),5.72-5.56(m,1H),5.48-5.46(m,1H),5.42(s,2H),4.96(s,2H), 4.76.76-5.56 (m, 4.19-5.56 (m,1H),5.48-5.46(m,1H),5.42(s,2H),4.96(s,2H), 4.76.76-4.67 (m, 4.19H), 4.19-5 (m, 3.67, 3.19H), 3.27 (m, 3.19-3.27, 3.19H), 3.27H), 3.41-3.38(m,2H),3.14-3.09(m,2H),3.05-2.92(m,2H),2.43-2.33(m,1H),2.27-2.13(m,7H),2.07-1.94(m,3H),1.72-1.69(m,2H),1.59-1.22(m,17H),0.87-0.82(m,15H) ppm.

{4- [ (2S) -2- [ (2S) -2- [1- (4- { 2-Azotricyclo [10.4.0.0 ]⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -3,6,9, 12-tetraoxapentadecane-15-carboxamide]-3-methylbutanamido group]-5- (carbamoylamino) pentanamide]Phenyl } methyl N- [ ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12R,13S,19S) -12, 19-difluoro-11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclic [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methylYl) carbamoyl radical]Methyl } carbamoyl) methyl]Carbamate (L1-PIII-4)

Following the general procedure for vcPAB linker-payload, starting from payload PIII-4 and compound L-3b, linker-payload L1-PIII-4(30mg, 43% yield) was obtained as a white solid. ESI M/z:775(M/2+1)⁺。¹H NMR(400MHz,DMSO_d6)δ10.00(s,1H),8.71-8.64(m,1H),8.26-8.20(m,1H),8.13(d,J＝7.0Hz,1H),7.88(d,J＝8.8Hz,1H),7.79-7.73(m,1H),7.68(d,J＝7.5Hz,1H),7.64-7.57(m,3H),7.53-7.43(m,4H),7.39-7.33(m,2H),7.32-7.25(m,4H),6.29(d,J＝8.5Hz,1H),6.11(s,1H),6.01-5.95(m,1H),5.72-5.66(m,0.5H),5.60-5.53(m,0.5H),5.48(s,1H),5.42(s,2H),5.03(d,J＝14.1Hz,1H),4.96(s,2H),4.75(s,1H),4.67-4.57(m,3H),4.50(d,J＝18.7Hz,1H),4.41-4.34(m,1H),4.28-4.17(m,3H),3.72(d,J＝5.3Hz,2H),3.67(d,J＝5.8Hz,2H),3.64-3.56(m,3H),3.52-3.41(m,13H),3.31-3.28(m,2H),3.12-2.93(m,4H),2.63-2.57(m,1H),2.41-2.36(m,1H),2.28-2.20(m,2H),2.06-1.93(m,4H),1.80-1.65(m,3H),1.62-1.51(m,4H),1.48(s,3H),1.47-1.20(m,7H),0.95-0.75(m,12H)ppm。

{4- [ (2S) -2- [ (2S) -2- [1- (4- { 2-Azotricyclo [10.4.0.0 ]⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -3,6,9, 12-tetraoxapentadecane-15-carboxamide]-3-methylbutanamido group]-5- (carbamoylamino) pentanamide]Phenyl } methyl N- ({ [ ({ [ (4bS,8S,8aR) -8- { [ (1S,4aS,10aR) -6-hydroxy-1, 4 a-dimethyl-1, 2,3,4,4a,9,10,10 a-octahydrophenanthrene-1-carbonyl ]Carbamoyl } -4b, 8-dimethyl-4 b,5,6,7,8,8a,9, 10-octahydrophenanthren-3-yl]Carbamoyl } methoxy) methyl]Carbamoyl } methyl) carbamate (L1-PIV)

PIV from payload and compounding following the general procedure for vcPAB-linker-payloadStarting with the substance L-3b, the linker-payload L1-PIV (20mg, 53% yield) was obtained as a white solid. ESI M/z:807(M/2+1)⁺。¹H NMR(400MHz,DMSO_d6)δ10.00(s,1H),9.53(s,1H),8.99(s,1H),8.92-8.83(m,1H),8.19-8.07(m,2H),7.88(d,J＝8.1Hz,1H),7.77(t,J＝5.6Hz,1H),7.68(d,J＝6.0Hz,1H),7.64-7.56(m,4H),7.53-7.25(m,9H),6.96(d,J＝8.5Hz,1H),6.81(d,J＝8.3Hz,1H),6.63(s,1H),6.50(d,J＝7.9Hz,1H),6.02-5.94(m,1H),5.42(s,2H),5.02(d,J＝14Hz,1H),4.95(s,2H),4.65(d,J＝6.5Hz,2H),4.43-4.32(m,1H),4.26-4.19(m,1H),4.00(s,2H),3.70-3.54(m,5H),3.50-3.41(m,12H),3.31-3.26(m,1H),3.13-2.54(m,8H),2.41-2.08(m,11H),2.06-1.52(m,14H),1.47-1.08(m,12H),1.00(s,3H),0.98(s,3H),0.86(d,J＝6.8Hz,3H),0.82(d,J＝6.8Hz,3H)ppm。

Synthesis of linker-payload L2-PIII-1

Linker-payloads L8-PII-1 and L2-PIII-1 were synthesized according to FIG. 4 and the following procedure.

Methyl (4S) -4-amino-4- { [ (1S) -1- { [ (1S) -4- (carbamoylamino) -1- { [4- (hydroxymethyl) phenyl ] carbamoyl } butyl ] carbamoyl } -2-methylpropyl ] carbamoyl } butanoate (L-7)

To a solution of compound L-6(26mg, 0.10mmol) in DMF (1mL) was added HATU (38mg, 0.10mmol) and DIPEA (26mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 10 min, then vcPAB (38mg, 0.10mmol) was added. The mixture was stirred at room temperature for 16 hours, monitored by LCMS. The resulting mixture was subjected to preparative HPLC to give impure Boc-L-7(ESI M/z:623(M +1)⁺) It was dissolved in DCM (3 mL). To the resulting solution was added TFA (0.3mL) and the reaction mixture was stirred at RT for 4 hours until complete Boc removal by LCMS. The mixture was concentrated in vacuo and the residue was dissolved in methanol (2 mL). After stirring overnight at room temperature, the mixture was concentrated in vacuo. The residue was purified by preparative HPLC to give compound L-7(23mg, 43% yield) as a colorless oil. ESI M/z 523(M +1) ⁺。

(4S) -methyl 4- { [ (1S) -1- { [ (1S) -4- (carbamoylamino) -1- { [4- (hydroxymethyl) phenyl ] carbamoyl } butyl ] carbamoyl } -2-methylpropyl ] carbamoyl } -4- {1- [2- (cycloocta-2-yn-1-yloxy) acetamido ] -3,6,9, 12-tetraoxapentadecane-15-amido } butanoate (L-8a)

To a solution of compound L-7(0.10g, 0.19mmol) in DMF (5mL) were added compound L-1a (0.10mg, 0.19mmol) and DIPEA (49mg, 0.38mmol) and the reaction mixture was stirred at room temperature for 4 h, monitored by LCMS. The resulting mixture was directly purified by preparative HPLC to give compound L-8a (0.11g, 63% yield) as a white solid. ESI M/z:934(M +1)⁺。

(4S) -4- { [ (1S) -1- { [ (1S) -4- (carbamoylamino) -1- [ (4- { [ ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclic [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamoyl) oxy]Methyl } phenyl) carbamoyl]Butyl radical]Carbamoyl } -2-methylpropyl radical]Carbamoyl } -4- {1- [2- (cycloocta-2-yn-1-yloxy) acetamido]-

methyl

3,6,9, 12-tetraoxapentadecane-15-amido } butanoate (L-10a)

To a solution of compound L-8a (0.10g, 0.11mmol) in DMF (3mL) was added 4-nitrophenyl chloroformate (24mg, 0.12mmol) and DIPEA (70mg, 54 mmol). The reaction mixture was stirred at room temperature for 4 hours, monitored by LCMS. The solution containing compound L-9a was used directly in the next step. ESI M/z 550.5(M/2+1) ⁺. To this solution (0.50mL) was added PII-1(9.5mg, 18. mu. mol) and DIPEA (4.7mg, 36. mu. mol). The reaction mixture was stirred at room temperature for 4 hours, monitored by LCMS. The mixture was purified by preparative HPLC to give compound L-10a (14mg, 76% yield) as a white solid. ESI M/z:1499(M +23)⁺。

(4S) -4- { [ (1S) -1- { [ (1S) -4- (carbamoylamino) -1- [ (4- { [ ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclic [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamoyl) oxy]Methyl } phenyl) carbamoyl]Butyl radical]Carbamoyl } -2-methylpropyl radical]Carbamoyl } -4- {1- [2- (cycloocta-2-yn-1-yloxy) acetamido]-3,6,9, 12-tetraoxapentadecane-15-amido } butyric acid (L8-PII-1)

To a solution of compound L-10a (30mg, 20. mu. mol) in dioxane (0.6mL) and water (0.2mL) was added lithium hydroxide (3.0mg, 0.12mmol) and the reaction mixture was stirred at room temperature for 18 h, monitored by LCMS. The residue was purified by preparative HPLC to give L8-PII-1(24mg, 75% yield) as a white solid. ESI M/z:1463(M +1)⁺。¹H NMR(400MHz,DMSO_d6)δ10.03(s,1H),8.74(d,J＝4.8Hz,1H),8.22(s,1H),8.09(d,J＝8.0Hz,1H),7.75(d,J＝8.5Hz,1H),7.59(d,J＝8.3Hz,3H),7.46(t,J＝6.1Hz,1H),7.30(dd,J＝11.4,6.0Hz,3H),6.16(d,J＝10.1Hz,1H),5.92(s,1H),5.46-5.31(m,2H),5.17-4.96(m,3H),4.71-4.58(m,4H),4.53-4.44(m,1H),4.40-4.25(m,4H),4.20(m,2H),3.87(d,J＝14.8Hz,1H),3.75(d,J＝14.7Hz,1H),3.64-3.56(m,4H),3.42(t,J＝6.0Hz,3H),3.25(m,3H),3.14-2.84(m,3H),2.44-1.80(m,18H),1.80-1.67(m,6H),1.63-1.40(m,10H),1.40-1.32(m,6H),1.28-1.22(m,6H),0.96(m,2H),0.90-0.75(m,14H)ppm。

(4S) -4- [1- (4- { 2-Azotricyclo [10.4.0.0 ] ⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -3,6,9, 12-tetraoxapentadecane-15-carboxamide]-4- { [ (1S) -1- { [ (1S) -4- (carbamoylamino) -1- { [4- (hydroxymethyl)Radical) phenyl]Carbamoyl } butyl group]Carbamoyl } -2-methylpropyl radical]Carbamoyl } butanoic acid methyl ester (L-8b)

Following a similar procedure to L-8a except substituting L-1a with L-1b gave compound L-8b (70mg, 47% yield) as a white solid. ESI M/z:529(M/2+1)⁺。

(4S) -4- [1- (4- { 2-Azotricyclo [10.4.0.0 ]⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -3,6,9, 12-tetraoxapentadecane-15-carboxamide]-4- { [ (1S) -1- { [ (1S) -4- (carbamoylamino) -1- [ (4- { [ ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12R,13S,19S) -12, 19-difluoro-11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxa-pentacyclic [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamoyl) oxy]Methyl } phenyl) carbamoyl]Butyl radical]Carbamoyl } -2-methylpropyl radical]Carbamoyl } butanoic acid methyl ester (L-10b)

To a solution of compound L-8b (7.0mg, 6.6. mu. mol) in DMF (0.5mL) was added 4-nitrophenyl chloroformate (1.3mg, 6.7. mu. mol) and DIPEA (1.7mg, 13. mu. mol). The reaction mixture was stirred at room temperature for 4 hours, monitored by LCMS. The solution containing compound L-9b was used in the next step without purification. ESI M/z:612(M/2+1) ⁺. To this solution (2.4. mu. mol (calculated)) was added PIII-1(1.4mg, 2.4. mu. mol) and DIPEA (0.6mg, 4.8. mu. mol). The reaction mixture was stirred at room temperature for 4 hours, monitored by LCMS. The mixture was purified by preparative HPLC to give compound L-10b (3mg, 76% yield) as a white solid. ESI M/z 819(M/2+1)⁺。

(4S) -4- [1- (4- { 2-Azotricyclo [10.4.0.0 ]⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -3,6,9, 12-tetraoxapentadecane-15-carboxamide]-4- { [ (1S) -1- { [ (1S) -4- (carbamoylamino) -1- [ (4- { [ ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12R,13S,19S) -12, 19-difluoro-11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxa-pentacyclic [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamoyl) oxy]Methyl } phenyl) carbamoyl]Butyl radical]Carbamoyl } -2-methylpropyl radical]Carbamoyl } butyric acid (L2-PIII-1)

To a solution of compound L-10b (9mg, 5.5. mu. mol) in dioxane (0.6mL) and water (0.2mL) was added lithium hydroxide (0.42mg, 16.7. mu. mol). The reaction mixture was stirred at room temperature for 4 hours, monitored by LCMS. Volatiles were removed in vacuo and the residue was purified by preparative HPLC to give linker-payload L2-PIII-1(3mg, 32% yield) as a white solid. ESI M/z:812(M/2+1) ⁺。¹H NMR(400MHz,DMSO_d6)δ10.20(s,1H),8.70-8.60(m,1H),8.55-8.50(m,1H),8.20-8.10(m,1H),7.90-7.20(m,13H),6.15-6.10(m,1H),6.05(s,1H),5.80-5.50(m,4H),5.10-4.95(m,3H),4.80(s,1H),4.75-4.50(m,4H),4.40-4.10(m,5H),3.60-3.55(m,26H),3.50-3.25(m,6H),3.10-2.80(m,4H),2.60-2.50(m,3H),2.40-2.20(m,5H),2.05-1.95(m,3H),1.90-1.20(m,15H),0.90-0.80(m,8H)ppm。

Synthesis of linker-payloads L4-PI, L9-PII-1, L10-PII-1, L11-PII-2, L12-PII-2, L13-PII-1, L14-PII-1, L3-PIII-1, L9-PIII-1, L12-PIII-5, L13-PIII-1, L4-PIII-1 and L14-PIV

Linker-payloads L4-PI, L9-PII-1, L10-PII-1, L11-PII-2, L12-PII-2, L13-PII-1, L14-PII-1, L3-PIII-1, L9-PIII-1, L12-PIII-5, L13-PIII-1, L4-PIII-1, and L14-PIV were synthesized according to FIG. 5 and the following procedures.

Synthesis of intermediate L-12a-g

(2S) -2- {2- [2- (4- { 2-Azotricyclo [10.4.0.0 ]⁴,⁹]Hexadeca-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanoylamino) acetamido]Acetamido } -3-phenylpropionic acid (L-12a)

To a solution of compound L-1e (0.28g, 0.69mmol) and peptide L-11a (Gly-Gly-Phe-OH, 0.19g, 0.69mmol) in DMF (10mL) was added DIPEA (0.37mL, 2.1mmol), and the reaction mixture was stirred at room temperature for 1 hour and monitored by LCMS. The resulting mixture was directly purified by reverse phase flash chromatography (0-100% acetonitrile in aqueous ammonium bicarbonate (10mM)) to give compound L-12a (0.31g, 78% yield) as a white solid. ESI M/z 567.0(M + H)⁺。

2- {2- [2- (Cyclooct-2-yn-1-yloxy) acetamido ] acetamido } acetic acid (L-12b)

Following a similar procedure to L-12a, except substituting Gly-Gly-OH (L-11b) for Gly-Gly-Phe-OH and L-1d for L-1e, intermediate L-12b (36mg, 60% yield) was obtained as a white solid. ESI M/z 297.2(M +1)⁺。

(2S) -2- [ (2S) -2- [2- (cycloocta-2-yn-1-yloxy) acetamido ] propionamido ] propanoic acid (L-12c)

Following a similar procedure to L-12a, except substituting Ala-Ala-OH (L-11c) for Gly-Gly-Phe-OH and L-1d for L-1e, intermediate L-12c (35mg, 91% yield) was obtained as a white solid. ESI M/z 325.3(M +1)⁺。

(2R) -2- [ (2S) -2- [2- (cycloocta-2-yn-1-yloxy) acetamido ] propionamido ] propanoic acid (L-12d)

Following a similar procedure to L-12a, except substituting Ala- (D) -Ala-OH (L-11D) for Gly-Gly-Phe-OH and L-1D for L-1e, intermediate L-12D (38mg, 64% yield) was obtained as a white solid. ESI M/z 325.2(M +1)⁺。

2- (2- {2- [2- (cycloocta-2-yn-1-yloxy) acetamido ] acetamido } acetamido) acetic acid (L-12e)

To a suspension of peptide L-11e (Gly-Gly-Gly-OH, 0.34g, 1.8mmol) in DMF (13mL) was added a solution of L-1d (0.50g, 1.8mmol) in THF (6mL) and DIPEA (0.69g, 5.4mmol), and the cloudy mixture was stirred at room temperature for 20 hours. The mixture was filtered, the clear filtrate was concentrated in vacuo, and the residue was purified by reverse phase flash chromatography (0-20% aqueous acetonitrile) to give compound L-12e (0.13g, 21% yield) as a white solid. ESI M/z 354.2(M + H) ⁺。¹H NMR(400MHz,DMSO_d6)δ12.6(s,1H),8.20(t,J＝5.6Hz,1H),8.15(t,J＝6.0Hz,1H),7.82(t,J＝5.6Hz,1H),4.35-4.31(m,1H),3.94(d,J＝14.8Hz,1H),3.83-3.73(m,7H),2.29-2.06(m,3H),1.99-1.93(m,1H),1.91-1.71(m,3H),1.63-1.56(m,2H),1.46-1.37(m,1H)ppm。

(2S) -2- (2- {2- [1- (4- { 2-Azotricyclo [10.4.0.0 ]⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -3,6,9, 12-tetraoxapentadecane-15-carboxamide]Acetamido } acetamido) -3-phenylpropionic acid (L-12f)

Following a similar procedure to L-12a, except substituting compound L-1b for L-1e, intermediate L-12f (15mg, 51% yield) was obtained as a white solid. ESI M/z:408.2(M/2+1)⁺。

2- [2- (Cyclooct-2-yn-1-yloxy) acetamido ] acetic acid (L-12g)

Following a similar procedure to L-12a, except substituting glycine for Gly-Gly-Phe-OH and L-1d for L-1e, intermediate L-12g (0.10g, 61% yield) was obtained as a colorless oil. ESI M/z:240.2(M +1)⁺。

(2S) -2- [2- (cycloocta-2-yn-1-yloxy) acetamido ] -3-hydroxypropionic acid (L-12h)

Following a similar procedure to L-12a, except substituting serine for Gly-Gly-Phe-OH and L-1d for L-1e, intermediate L-12h (90mg, 93% yield) was obtained as a yellow oil. ESI M/z 270.3(M +1)⁺。

(2S) -2- [2- (cycloocta-2-yn-1-yloxy) acetamido ] -6- { [ (9H-fluoren-9-ylmethoxy) carbonyl ] amino } hexanoic acid (L-12i)

Following a similar procedure to L-12a, except substituting H-Lys (Fmoc) -OH for Gly-Gly-Phe-OH and L-1d for L-1e, intermediate L-12i (30mg, 78% yield) was obtained as a white solid. ESI M/z 533.1(M +1) ⁺。

Peptide linker-general method of payload (FIG. 5)

To a mixture of intermediate L-12(1.0 equiv.) in DMF or DCM (25mM) was added HATU, EDCI or HOSu (1.5 equiv.) and DIPEA (3.0 equiv.), the reaction mixture was stirred at room temperature for 2h, then the corresponding payload (1.0 equiv.), HOBt and DIPEA in DMF was added. The reaction mixture was stirred at room temperature for 2-20 hours, monitored by LCMS. The reaction mixture was directly purified by preparative HPLC to give the peptide linker-payload (22-56% yield) as a white solid.

4- { 2-Aza-tricyclo [10.4.0.0⁴,⁹]Hexadeca-1 (12),4(9),5,7,13, 15-hexaen-10-yne-2-

Yl } -N- { [ ({ [ (1S) -1- ({ [ ({2- [ (1R,2S,10S,11S,13R,14R,15S,17S) -1-fluoro-14, 17-dihydroxy-2, 13, 15-trimethyl-5-oxotetracyclo [8.7.0.0 ]²,⁷.0¹¹,¹⁵]Heptadeca-3, 6-dien-14-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamoyl) -2-phenylethyl]Carbamoyl } methyl) carbamoyl]Methyl } -4-oxobutanamide (L4-PI)

Following the general procedure for peptide linker-payloads, linker-payload L4-PI (13mg, 30% yield) was obtained from L-12a and PI as a white solid. ESI M/z 606.0 (M-M)_NHCH2DEX)⁺,635.1(M–M_Dex+H)⁺。¹H NMR(400MHz,DMSO_d6)δ8.60-8.55(m,1H),8.35-8.27(m,1H),8.20-7.95(m,3H),7.71-7.63(m,1H),7.59(dd,J＝6.7,1.8Hz,1H),7.52-7.47(m,1H),7.47-7.43(m,1H),7.39-7.31(m,2H),7.30-7.28(m,1H),7.26-7.22(m,3H),7.19-7.15(m,1H),6.24-6.16(m,1H),6.01(s,1H),5.28-5.26(m,1H),5.01(d,J＝13.2Hz,2H),4.60-4.53(m,2H),4.52-4.44(m,1H),4.21-4.10(m,2H),3.78-3.66(m,3H),3.64-3.57(m,3H),3.10-3.00(m,2H),2.96-2.87(m,2H),2.83-2.75(m,2H),2.69-2.58(m,3H),2.37-2.23(m,3H),2.17-2.03(m,3H),1.84-1.73(m,2H),1.66-1.55(m,1H),1.53-1.45(m,3H),1.38-1.30(m,1H),1.27-1.22(m,1H),1.16-1.01(m,2H),0.87(s,3H),0.78(d,J＝7.2Hz,3H)ppm。¹⁹F NMR(376MHz,DMSO_d6)δ-164.47ppm。

2- (cyclooct-2-yn-1-yloxy) -N- [ ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclo [10.8.0.0 ] ²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamoyl) methyl]Acetamide (L9-PII-1)

Following the general procedure for peptide linker-payloads, starting from L-12g and PII-1, after purification by preparative HPLC (5-95% acetonitrile in formic acid in water (0.01%)), the linker-payload L9-PII-1 was obtained as a white solid (20mg, 56% yield). ESI M/z 308.1 (M-M)_bud+H)⁺,738.3(M+H)⁺。¹H NMR(500MHz,DMSO_d6)δ8.68-8.64(m,1H),8.29-8.26(m,1H),7.85(s,1H),7.34-7.31(m,1H),6.16(d,J＝10.0Hz,1H),5.92(s,1H),5.18-5.02(m,1H),4.72-4.45(m,5H),4.33-4.14(m,3H),3.96-3.72(m,6H),2.31-1.71(m,13H),1.62-1.49(m,6H),1.43-1.25(m,7H),1.01-0.92(m,2H),0.87-0.81(m,6H)ppm。

2- (cyclooct-2-yn-1-yloxy) -N- ({ [ ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclo [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamoyl) methyl]Carbamoyl } methyl) acetamide (L10-PII-1)

Following the general procedure for peptide linker-payloads, starting from L-12b and PII-1, after purification by preparative HPLC (5-95% acetonitrile in formic acid in water (0.01%)), the linker-payload L10-PII-1 was obtained as a white solid (20mg, 54% yield). ESI M/z 365.1 (M-M)_bud+H)⁺,795.3(M+H)⁺。¹H NMR(500MHz,DMSO_d6)δ8.69-8.63(m,1H),8.24-8.19(m,2H),7.86-7.83(m,1H),7.33-7.31(m,1H),6.17(d,J＝10.5Hz,1H),5.92(s,1H),5.18-5.03(m,1H),4.75-4.46(m,5H),4.35-4.15(m,3H),3.95-3.71(m,8H),2.31-1.70(m,13H),1.65-1.53(m,6H),1.48-1.24(m,7H),1.04-0.81(m,8H)ppm。

(2S) -2- [ (2S) -2- [ (2S) -2- [2- (cycloocta-2-yn-1-yloxy) acetamido]Propionamido group]Propionamido group]-N- ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclo [10.8.0.0 ] ²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) propanamide (L11-PII-2)

Following the general procedure for peptide linker-payloads, starting from L-12c and PII-2, after purification by preparative HPLC (5-95% acetonitrile in aqueous ammonium bicarbonate (10mM)), the linker-payload L11-PII-2 was obtained (3.0mg, 22% yield) as a white solid. ESI M/z 407.3 (M-M)_bud+H)⁺,859.5(M+Na)⁺。¹H NMR(400MHz,MeOH_d4)δ7.47(dd,J＝10.4,3.6Hz,1H),6.29-6.26(m,1H),6.03(s,1H),5.36(t,J＝4.4Hz,1H),5.22-5.14(m,1H),4.80-4.73(m,2H),4.65-4.48(m,2H),4.46-4.25(m,6H),4.10-3.90(m,2H),2.71-2.63(m,1H),2.42-2.37(m,1H),2.30-2.03(m,7H),1.98-1.80(m,5H),1.73-1.60(m,6H),1.51(s,3H),1.44-1.38(m,10H),1.24-1.23(m,2H),0.97-0.90(m,7H)ppm。

(2S) -2- [ (2R) -2- [ (2S) -2- [2- (cycloocta-2-yn-1-yloxy) acetamido]Propionamido group]Propionamido group]-N- ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclo [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) propanamide (L12-PII-2)

Following the general procedure for peptide linker-payloads, starting from L-12d and PII-2, the linker-payload L was obtained after purification by preparative HPLC (5-95% acetonitrile in ammonium bicarbonate in water (10mM))12-PII-2(3.5mg, 22% yield) was a white solid. ESI M/z 407.3 (M-M)_bud+H)⁺,859.5(M+Na)⁺。¹H NMR(400MHz,MeOH_d4)δ7.47(dd,J＝10.4,3.6Hz,1H),6.30-6.25(m,1H),6.03(s,1H),5.36(t,J＝4.4Hz,1H),5.23-5.12(m,1H),4.84-4.70(m,2H),4.66-4.48(m,2H),4.45-4.24(m,6H),4.06-3.89(m,2H),2.72-2.61(m,1H),2.43-2.35(m,1H),2.30-2.01(m,7H),1.98-1.80(m,5H),1.75-1.58(m,6H),1.51(s,3H),1.44-1.38(m,10H),1.36-1.27(m,2H),0.98-0.88(m,7H)ppm。

2- (cyclooct-2-yn-1-yloxy) -N- { [ ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclic [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl ]Methyl } carbamoyl) methyl]Carbamoyl } methyl) carbamoyl]Methyl } acetamide (L13-PII-1)

Following the general procedure for peptide linker-payloads, starting from L-12e and PII-1, after purification by preparative HPLC (5-95% acetonitrile in ammonia (10mM)) the linker-payload L13-PII-1(14mg, 16% yield) was obtained as a white solid. ESI M/z:422.3 (M-M)_bud+H)⁺,874.5(M+Na)⁺。¹H NMR(500MHz,DMSO_d6)δ8.68-8.63(m,1H),8.22-8.14(m,3H),7.84-7.82(m,1H),7.33-7.30(m,1H),6.18-6.16(m,1H),5.92(s,1H),5.18-5.16(m,0.5H),5.04-5.02(m,0.5H),4.73-4.45(m,5H),4.33-4.14(m,3H),3.95-3.71(m,10H),2.36-1.69(m,12H),1.62-1.50(m,6H),1.44-1.23(m,8H),1.01-0.81(m,8H)ppm。

4- { 2-Aza-tricyclo [10.4.0.0⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -N- { [ ({ [ (1S) -1- ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclic [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Twenty-fourAlk-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamoyl) -2-phenylethyl]Carbamoyl } methyl) carbamoyl]Methyl } -4-oxobutanamide (L14-PII-1)

Following the general procedure for peptide linker-payloads, starting from L-12a and PII-1, after purification by preparative HPLC (5-95% acetonitrile in aqueous ammonium bicarbonate (10mM)), the linker-payload L14-PII-1 was obtained (0.22g, 64% yield) as a white solid. ESI M/z 606.0 (M-M)_NHCH2Bud)⁺,635.0(M–M_Bud+H)⁺。¹H NMR(400MHz,DMSO_d6)δ8.63-8.53(m,1H),8.33-8.28(m,1H),8.20-7.97(m,3H),7.70-7.63(m,1H),7.61-7.57(m,1H),7.51-7.43(m,3H),7.39-7.33(m,2H),7.32-7.30(m,1H),7.29-7.26(m,1H),7.25-7.23(m,4H),7.20-7.16(m,1H),6.19-6.11(m,1H),5.92(s,1H),5.16(t,J＝4.8Hz,0.5H),5.03(d,J＝5.2Hz,1H),4.99(s,0.5H),4.73-4.72(m,2H),4.64-4.56(m,3H),4.51-4.46(m,2H),4.29(s,1H),4.19(t,J＝18.5Hz,1H),3.79-3.68(m,3H),3.62-3.57(m,3H),3.57-3.52(m,1H),3.07(dd,J＝13.7,4.0Hz,1H),2.83-2.77(m,1H),2.71-2.60(m,1H),2.36-2.24(m,2H),2.13-2.04(m,2H),2.02-1.93(m,1H),1.84-1.81(m,0.5H),1.80-1.73(m,2H),1.72-1.68(m,0.5H),1.63-1.57(m,1H),1.57-1.47(m,3H),1.44-1.39(m,1H),1.38-1.37(m,3H),1.34-1.23(m,2H),1.01-0.89(m,2H),0.88-0.80(m,6H)ppm。

1- (4- { 2-Azotricyclo [10.4.0.0 ]⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -N- { [ ({ [ (1S) -1- ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12R,13S,19S) -12, 19-difluoro-11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclic [10.8.0.0 ] ²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamoyl) -2-phenylethyl]Carbamoyl } methyl) carbamoyl]Methyl } -3,6,9, 12-tetraoxapentadecane-15-amide (L3-PIII-1)

To a solution of compound L-12f (60mg, 74. mu. mol) in DCM (6mL) were added HOSu (19mg, 0.16mmol) and EDCI (31mg, 0.16mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (40mL) and washed with water (20mL) and brine (20 mL). The organic solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was then dissolved in dry DMF (2 mL). DIPEA (45mg, 0.35mmol) and PIII-1(48mg, 88. mu. mol) were added to the resulting solution, and the mixture was stirred at room temperature for 2 hours, which was monitored by LCMS. The reaction mixture was directly purified by preparative HPLC to give L3-PIII-1(5mg, 4% yield) as a white solid. ESI M/z 882.3 (M-Bud)⁺。¹H NMR(400MHz,DMSO_d6)δ8.65-8.56(m,1H),8.32-8.30(m,1H),8.20-7.97(m,3H),7.79-7.72(m,1H),7.71-7.66(m,1H),7.65-7.61(m,1H),7.53-7.46(m,3H),7.42-7.28(m,3H),7.27-7.20(m,5H),7.19-7.14(m,1H),6.31-6.25(m,1H),6.10(s,1H),5.72-5.48(m,2H),5.49-5.48(m,1H),5.09-4.98(m,1H),4.68-4.48(m,4H),4.30-4.17(m,2H),3.78-3.65(m,5H),3.64-3.56(m,4H),3.54-3.39(m,12H),3.31-3.27(m,2H),3.11-3.01(m,3H),2.84-2.77(m,1H),2.71-2.56(m,2H),2.42-2.36(m,2H),2.29-2.17(m,2H),2.08-1.95(m,3H),1.83-1.67(m,2H),1.62-1.24(m,10H),0.91-0.75(m,6H)ppm。

2- (cyclooct-2-yn-1-yloxy) -N- [ ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12R,13S,19S) -12, 19-difluoro-11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclo [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamoyl) methyl ]Acetamide (L9-PIII-1)

Following the general procedure for the peptide linker-payload, starting from L-12g and PIII-1, preparative HPLC (5-95% acetonitrile in ammonium bicarbonate in water)(10mM)) was purified to give linker-payload L9-PIII-1(13mg, 31% yield) as a white solid. ESI M/z 774.3(M + H)⁺,308.1(M–M_III+H)⁺。¹H NMR(400MHz,DMSO_d6)δ8.66(t,J＝6.7Hz,1H),8.27(t,J＝5.8Hz,1H),7.86(t,J＝5.6Hz,1H),7.27(dd,J＝10.3,0.8Hz,1H),6.30(dd,J＝10.2,1.8Hz,1H),6.11(s,1H),5.73-5.53(m,1H),5.47(d,J＝2.6Hz,1H),4.78-4.73(m,1H),4.65(t,J＝4.1Hz,1H),4.62-4.56(m,2H),4.53-4.45(m,1H),4.35-4.29(m,1H),4.27-4.16(m,2H),3.97-3.69(m,6H),2.69-2.54(m,1H),2.30-2.14(m,3H),2.13-1.81(m,5H),1.80-1.68(m,3H),1.61-1.51(m,5H),1.49(s,3H),1.45-1.29(m,4H),1.24(s,1H),0.86(t,J＝7.4Hz,3H),0.81(s,3H)ppm。

(2S) -2- [ (2R) -2- [ (2S) -2- [2- (cycloocta-2-yn-1-yloxy) acetamido]Propionamido group]Propionamido group]-N- ({2- [ (1S,2S,4R,8S,9S,11S,12R,13S,19S) -12, 19-difluoro-11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclic [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) propanamide (L12-PIII-5)

Following the general procedure for peptide linker-payloads, starting from L-12d and PIII-5, after purification by preparative HPLC (5-95% acetonitrile in aqueous ammonium bicarbonate (10mM)), the linker-payload L12-PIII-5(3.5mg, 21% yield) was obtained as a white solid. ESI M/z 895.5(M + Na)⁺,407.3(M–M_III+H)⁺。H NMR(400MHz,MeOH_d4)δ7.40-7.32(m,1H),6.37-6.34(m,1H),6.32(s,1H),5.64-5.47(m,1H),5.37-5.35(m,1H),4.80-4.73(m,2H),4.69-4.66(m,1H),4.57-4.50(m,1H),4.41-4.25(m,6H),4.10-3.90(m,2H),2.74-2.57(m,1H),2.37-2.29(m,1H),2.26-2.21(m,5H),2.09-2.01(m,2H),1.98-1.76(m,4H),1.72-1.60(m,6H),1.59(s,3H),1.46-1.38(m,10H),1.35-1.33(m,1H),0.97-0.90(m,7H)ppm。

2- (Cyclooct-2-yn-1-yloxy) -N- { [ ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12R,13S,19S) -12, 19-difluoro-11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxa-pentacyclic [10.8.0.0²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl ]Methyl } carbamoyl) methyl]Carbamoyl } methyl) carbamoyl]Methyl } acetamide (L13-PIII-1)

Following the general procedure for peptide linker-payloads, starting from L-12e and PIII-1, after purification by preparative HPLC (5-95% acetonitrile in aqueous ammonium bicarbonate (10mM)), the linker-payload L13-PIII-1(8mg, 17% yield) was obtained as a white solid. ESI M/z 888.4(M + H)⁺,422.1(M–M_III+H)⁺。¹H NMR(400MHz,DMSO_d6)δ8.73-8.63(m,1H),8.24-8.17(m,2H),7.85(t,J＝5.2Hz,1H),7.27(d,J＝9.6Hz,1H),6.29(dd,J＝10.4,1.6Hz,1H),6.11(s,1H),5.74-5.47(m,2H),4.77-4.73(m,1H),4.66-4.54(m,3H),4.53-4.44(m,1H),4.35-4.29(m,1H),4.28-4.15(m,2H),3.97-3.90(m,1H),3.84-3.69(m,8H),3.30(s,1H),2.69-2.54(m,1H),2.35-2.14(m,3H),2.12-1.91(m,4H),1.90-1.66(m,4H),1.61-1.51(m,5H),1.49(s,3H),1.45-1.20(m,5H),0.96-0.92(m,1H),0.89-0.79(m,6H)ppm。

4- { 2-Aza-tricyclo [10.4.0.0⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -N- { [ ({ [ (1S) -1- ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12R,13S,19S) -12, 19-difluoro-11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclic [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamoyl) -2-phenylethyl]Carbamoyl } methyl) carbamoyl]Methyl } -4-oxobutanamide (L4-PIII-1)

Following the general procedure for peptide linker-payloads, starting from L-12a and PIII-1, after purification by preparative HPLC (5-95% acetonitrile in aqueous ammonium bicarbonate (10mM)), the linker-payload L4-PIII-1(23mg, 25% yield) was obtained as a white solid. ESI M/z 1124.5(M + Na)⁺。¹H NMR(400MHz,DMSO_d6)δ8.65-8.56(m,1H),8.32-8.30(m,1H),7.97-8.20(m,3H),7.72-7.62(m,1H),7.60-7.56(m,1H),7.52-7.43(m,3H),7.40-7.28(m,4H),7.27-7.20(m,5H),7.19-7.14(m,1H),6.31-6.25(m,1H),6.10(s,1H),5.72-5.52(m,1H),5.49-5.48(m,1H),5.05-4.98(m,1H),4.68-4.48(m,4H),4.74(s,1H),4.62-4.44(m,4H),4.30-4.17(m,2H),3.78-3.65(m,3H),3.05-3.01(m,1H),2.83-2.72(m,1H),2.71-2.56(m,2H),2.34-2.24(m,2H),2.12-1.95(m,3H),1.83-1.67(m,2H),1.65-1.51(m,4H),1.47(s,3H),1.46-1.22(m,3H),0.86-0.78(m,6H)ppm。

(1S,4aS,10aR) -N- [ (1S,4aS,10aR) -6- [2- ({2- [ (2S) -2- {2- [2- (4- { 2-azatricyclo [10.4.0.0 ] ⁴,⁹]Hexadeca-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanoylamino) acetamido]Acetylamino } -3-phenylpropionamido]Acetamido } methoxy) acetamido]1,4 a-dimethyl-1, 2,3,4,4a,9,10,10 a-octahydrophenanthrene-1-carbonyl]-6-hydroxy-1, 4 a-dimethyl-1, 2,3,4,4a,9,10,10 a-octahydrophenanthrene-1-carboxamide (L14-PIV)

Following the general procedure for peptide linker-payloads, starting from L-12a and PIV, after purification by preparative HPLC (5-95% acetonitrile in aqueous ammonium bicarbonate (10mM)), the linker-payload L14-PIV was obtained (8.4mg, 46% yield) as a white solid. ESI M/z 635 (M-M)_IV+H)⁺。¹H NMR(400MHz,DMSO_d6) δ 9.53(s,1H),8.99(s,1H),8.70(d, J ═ 5.2Hz,1H),8.36(d, J ═ 5.0Hz,1H),8.20-7.96(m,4H),7.69-7.62(m,1H),7.61-7.56(m,2H),7.51-7.39(m,4H),7.38-7.32(m,2H),7.31-7.20(m,5H),7.19-7.13(m,1H),6.95(d, J ═ 8.7Hz,1H),6.82(d, J ═ 8.2Hz,1H),6.63(d, J ═ 2.2Hz,1H),6.50(dd, 8.2 and 2, 1H), 6.9.64 (dd, 9.2H, 1H), 6.9.9, 6.13H, 1H, and 1H), and 1H, 6.13 (dd, 8.2 and J ═ 2H), and J ═ 6.2H),4.51-4.43(m,1H),4.00(s,2H),3.80-3.66(m,3H),3.62-3.56(m,3H),3.08-2.99(m,1H),2.91-2.59(m,7H),2.34-2.23(m,3H),2.20-2.10(m,4H),2.08-2.00(m,1H),1.95-1.72(m,5H),1.67-1.51(m,4H),1.27(s,3H),1.27(s,3H),1.25-1.22(m,2H),1.17-1.08(m,2H),0.99(s,3H),0.98(s,3H)ppm。

Synthesis of linker-payloads L15-PII-1, L16-PII-1 and L5-PIII-1 (FIG. 6)

Linker-payloads L15-PII-1, L16-PII-1 and L5-PIII-1 were synthesized according to FIG. 6 and the following procedures.

2-amino-N- ({ [ ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxa-pentacyclic [10.8.0.0 ] ²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamoyl) methyl]Carbamoyl } methyl) acetamide (L-14a)

To a mixture of Fmoc-Gly-Gly-Gly-OH (L-11g, 41mg, 0.10mmol) in DMF (4.0mL) was added HATU (38mg, 0.10mmol) and DIPEA (39mg, 0.30mmol), the mixture was stirred at room temperature for 15 min, then compound PII-1(50mg, 97. mu. mol) was added. The resulting mixture was stirred at room temperature for 1 hour, monitored by LCMS. The reaction mixture was directly purified by reverse phase flash chromatography (0-100% acetonitrile in ammonium bicarbonate in water (10mM)) to give compound L-13a (36mg, ESI M/z:932.1(M + Na)⁺) As a white solid, which was then dissolved in DMF (2 mL). Piperidine (17mg, 0.20mmol) was added to the resulting solution and the mixture was stirred at room temperature for 2 hours until Fmoc removal was complete, as monitored by LCMS. The resulting mixture was directly purified by preparative HPLC (5-95% acetonitrile in aqueous ammonium bicarbonate (10mM)) to give compound L-14a (26mg, 39% yield) as a white solid. ESI M/z 688.2(M + H)⁺。

(2S) -2- [2- (cycloocta-2-yn-1-yloxy) acetamido]-3-hydroxy-N- { [ ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy- 9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxa-pentacyclic [10.8.0.0²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamoyl) methyl]Carbamoyl } methyl) carbamoyl]Methyl } propionamide (L15-PII-1)

To a solution of compound L-12h (50mg, 0.19mmol) in DMF (4.0mL) was added HOSu (40mg, 0.38mmol) and EDCI (70mg, 0.38mmol), and the mixture was stirred at room temperature for 12h until L-12h was completely depleted. The reaction mixture was directly purified by reverse phase flash chromatography (0-100% acetonitrile in water) to give the active ester. The active ester (9.0mg, crude) was added to a mixture of compound L-14a (15mg, 22. mu. mol) and DIPEA (9.0mg, 70. mu. mol) in DMF (2mL) and the reaction mixture was stirred at room temperature for 30 min and monitored by LCMS. The resulting mixture was directly purified by preparative HPLC (5-95% acetonitrile in ammonium bicarbonate (10mM)) to give linker-payload L15-PII-1(11mg, 14% yield from L-14 a) as a white solid. ESI M/z 509.1 (M-M)_Bud+H)⁺；961.4(M+Na)⁺。¹H NMR(400MHz,DMSO_d6)δ8.80-8.65(m,1H),8.41-8.06(m,3H),7.37-7.27(m,1H),6.17(d,J＝9.6Hz,1H),5.92(s,1H),5.20-5.01(m,1H),4.84-4.43(m,5H),4.37-4.26(m,2H),4.25-4.14(m,1H),3.97-3.80(m,1H),3.79-3.55(m,8H),3.24-3.16(m,1H),3.02-2.90(m,1H),2.43-2.38(m,1H),2.34-2.27(m,2H),2.24-2.05(m,3H),2.03-1.93(m,2H),1.86-1.67(m,4H),1.63-1.47(m,5H),1.45-1.20(m,8H),0.98-0.90(m,5H),0.89-0.78(m,6H)ppm。

(2S) -6-amino-2- [2- (cycloocta-2-yn-1-yloxy) acetamido]-N- { [ ({ [ ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclic [10.8.0.0 ] ²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamoyl) methyl]Amino groupFormyl } methyl) carbamoyl]Methyl hexanoamide (L16-PII-1)

HOSu (11mg, 94. mu. mol) and EDCI (18mg, 94. mu. mol) were added to a solution of L-12i (25mg, 47. mu. mol) in DMF (2.0ml), and the reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was directly purified by reverse phase flash chromatography (0-100% aqueous acetonitrile) to give the active ester (17 mg). The active ester (12mg, 18. mu. mol) was added to a solution of compound L-14a (12mg, 17. mu. mol) in DMF (2.0mL) followed by DIPEA (6.6mg, 51. mu. mol). The reaction mixture was then stirred at room temperature for 1 hour, monitored by LCMS. The resulting mixture was separated by reverse phase flash chromatography (0-100% acetonitrile in aqueous ammonium bicarbonate (10mM)) to yield Fmoc-L16-PII-1(11mg) as a white solid, which was dissolved in DMF (2.0 mL). Piperidine (4.3mg, 51. mu. mol) was added to the resulting solution and the mixture was stirred at room temperature for 1 hour until Fmoc was completely removed, monitored by LCMS. The resulting mixture was directly purified by reverse phase flash chromatography (0-100% acetonitrile in ammonium bicarbonate (10mM)) to give linker-payload L16-PII-1(12mg, 76% yield from L-14 a) as a white solid. ESI M/z 490.9(M/2+ H) ⁺,980.7(M+H)⁺。¹H NMR(400MHz,DMSO_d6)δ8.80-8.73(m,1H),8.49-8.41(m,2H),8.33-8.28(m,1H),8.27-8.21(m,1H),7.74(dd,J＝14.0,7.9Hz,1H),7.32(dd,J＝10.1,2.7Hz,1H),6.19-6.16(m,1H),5.93(s,1H),5.18-5.16(m,0.5H),5.03(d,J＝7.4Hz,0.5H),4.85(s,1H),4.72(d,J＝4.2Hz,0.5H),4.65-4.53(m,3H),4.51-4.44(m,1H),4.38-4.28(m,3H),4.24(s,0.5H),4.19-4.15(m,1H),3.95-3.92(m,1H),3.85-3.81(m,1H),3.76-3.71(m,6H),2.76-2.68(m,2H),2.35-2.25(m,2H),2.25-2.15(m,2H),2.15-1.83(m,7H),1.82-1.64(m,6H),1.64-1.46(m,8H),1.45-1.23(m,9H),1.17-1.06(m,1H),1.02-0.91(m,2H),0.90-0.75(m,6H)ppm。

(2S) -2-amino-N- [ ({ [ ({ [ ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12R,13S,19S) -12, 19-difluoro-11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclic [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamoyl) methyl]Carbamoyl } methyl) carbamoyl]Methyl } carbamoyl) methyl]-3-hydroxypropionamide (L-14b)

To a solution of the payload PIII-1(0.20g, 0.36mmol) and the peptide Fmoc-Ser-Gly-Gly-Gly-GlyL-11h (0.20g, 0.36mmol) in DMF (4mL) was added HATU (0.21g, 0.55mmol) and DIPEA (0.14g, 1.1mmol), and the mixture was stirred at room temperature overnight, monitored by LCMS. The reaction mixture was purified by preparative HPLC to give L-13b (0.16g, ESI M/z:624 (M-M)_III+H)⁺) This was dissolved in DMF (2 mL). Piperidine (42mg, 0.50mmol) was added to the resulting solution and the mixture was stirred at room temperature for 1 hour until Fmoc had been completely removed by LCMS. The reaction mixture was purified by preparative HPLC to give compound L-14b (98mg, 77% yield) as a white solid. ESI M/z:868(M +1)⁺。

4- { 2-Aza-tricyclo [10.4.0.0⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -N- [ (1S) -1- { [ ({ [ ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12R,13S,19S) -12, 19-difluoro-11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclic [10.8.0.0 ] ²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamoyl) methyl]Carbamoyl } methyl) carbamoyl]Methyl } carbamoyl) methyl]Carbamoyl } -2-hydroxyethyl]-4-oxobutanamide (L5-PIII-1)

To a solution of compound L-14b (0.11g, 0.13mmol) in DMF (4mL) were added compound L-1e (39mg, 0.13mmol), HATU (72mg, 0.19mmol) and DIPEA (49mg, 0.38mmol) and the mixture was stirred overnightThe mixture was stirred at room temperature for 3 hours, monitored by LCMS. The resulting mixture was directly purified by preparative HPLC to give linker-payload L5-PIII-1(35mg, 24% yield) as a white solid. ESI M/z 1177(M +23)⁺。¹H NMR(400MHz,DMSO_d6) δ 8.66(t, J ═ 6.4Hz,1H),8.24-7.93(m,6H),7.71-7.66(m,1H),7.61(t, J ═ 6.0Hz,1H),7.54-7.43(m,3H),7.41-7.24(m,4H),6.30(dd, J ═ 10 and 2.0Hz,1H),6.11(s,1H),5.74-5.46(m,2H),5.08-4.97(m,1H),4.94-4.84(m,1H),4.78-4.73(m,1H),4.67-4.57(m,3H),4.54-4.46(m,1H),4.39-4.11(m,3H),3.83-3.67(m, 3H), 3.67-4.67 (m,3H), 3.67-4.47-2.47 (m,1H), 1H), 1.39-4.51 (m,1H), 4H) 1.481(s,3H),1.44-1.20(m,4H),0.95(d, J ═ 6.4Hz,1H),0.86-0.78(m,6H) ppm.

Synthesis of linker-payloads L7-PII-1, L17-PII1, L6-PII-9 and L6-PII-13

Linker-payloads L6-PII-9 and L7-PII-1 were synthesized according to FIG. 7 and the following procedure.

General procedure for pH sensitive linker-payloads

To a mixture of compounds L1-a, L1-b, L1-d, L1-e (1.0 equiv.) in DMF (25mM) was added the payload PII-1, PII-9 or PII-13(1.0 equiv.) and DIPEA (3.0 equiv.), and the reaction mixture was stirred at room temperature for 2 hours, monitored by LCMS. The resulting mixture was directly purified by preparative HPLC to give linker-payloads L7-PII-1, L17-PII1, L6-PII-9 or L6-PII-13 (19-51% yield) as white solids.

1- [2- (cycloocta-2-yn-1-yloxy) acetamido group]-N- { [ ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclic [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } -3,6,9, 12-tetraoxapentadecane-15-amide (L17-PII-1)

Sensitivity according to pHGeneral procedure for sex linker-payloads from L-1a and PII-1, linker-payload L17-PII-1(30mg, 22% yield) was obtained as a white solid. ESI M/z 498.3 (M-M)_Bud+H)⁺,950.6(M+Na)⁺。¹H NMR(400MHz,DMSO_d6)δ8.73-8.59(m,1H),8.27-8.15(m,1H),7.60(t,J＝6.0Hz,1H),7.31(dd,J＝10.0,2.4Hz,1H),6.21-6.11(m,1H),5.92(s,1H),5.20-5.00(m,1H),4.80-4.56(m,4H),4.54-4.43(m,1H),4.34-4.10(m,3H),3.90-3.83(m,1H),3.79-3.66(m,3H),3.61(t,J＝6.4Hz,2H),3.54-3.46(m,12H),3.42(t,J＝6.0Hz,2H),3.28-3.19(m,2H),2.41(t,J＝6.4Hz,2H),2.34-2.15(m,3H),2.14-2.01(m,2H),2.00-1.83(m,3H),1.81-1.72(m,4H),1.64-1.46(m,6H),1.45-1.20(m,8H),1.14-0.90(m,2H),0.89-0.76(m,6H)ppm。

1- (4- { 2-Azotricyclo [10.4.0.0 ]⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -N- [2- (2- {2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclic [10.8.0.0 ] ²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } pyrrolidin-1-yl) -2-oxoethyl]-3,6,9, 12-tetraoxapentadecane-15-amide (L6-PII-9)

Following the general procedure for pH sensitive linker-payload, linker-payload L6-PII-9(30mg, 15% yield) was obtained as a white solid from L-1b and PII-9. ESI M/z 661.5 (M-M)_Bud+H)⁺。¹H NMR(400MHz,DMSO_d6)δ8.11-8.02(m,1H),7.77(t,J＝5.2Hz,1H),7.69-7.67(m,1H),7.63-7.61(m,1H),7.52-7.43(m,3H),7.40-7.27(m,4H),6.18-6.15(m,1H),5.92(s,1H),5.44-5.30(m,1H),5.18-5.00(m,2H),4.85-4.48(m,3H),4.33-4.17(m,2H),4.00-3.83(m,1H),3.63-3.53(m,3H),3.48-3.45(m,13H),3.31-3.20(m,2H),3.12-3.03(m,2H),2.62-2.54(m,1H),2.45-2.37(m,2H),2.32-2.20(m,2H),2.10-1.89(m,6H),1.86-1.67(m,6H),1.60-1.42(m,4H),1.38-1.23(m,7H),1.03-0.92(m,2H),0.87-0.81(m,6H)ppm。

1- (4- { 2-Azotricyclo [10.4.0.0 ]⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -N- [2- (2- {2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclic [10.8.0.0 ]²,⁹.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } azetidin-1-yl) -2-oxoethyl]-3,6,9, 12-tetraoxapentadecane-15-amide (L6-PII-13)

Following the general procedure for pH sensitive linker-payload, linker-payload L6-PII-13(20mg, 19% yield) was obtained as a white solid from L-1b and PII-13. ESI M/z:539.1(M/2+ H)⁺。¹H NMR(400MHz,DMSO_d6)δ8.20(s,1H),7.90-7.25(m,9H),6.25-6.20(m,1H),5.95(s,1H),5.20(s,1H),5.10-5.00(m,1H),4.80-4.50(m,4H),4.25-4.20(m,3H),3.70-3.60(m,3H),3.40-3.30(m,9H),3.20-3.15(m,3H),3.20-3.00(m,3H),2.55-2.50(m,1H),2.40-2.20(m,4H),2.00-1.80(m,3H),1.80-1.75(m,5H),1.75-1.50(m,4H),1.45-1.25(m,9H),1.20-1.05(m,3H),0.85-0.75(m,8H)ppm。

4- { 2-Aza-tricyclo [10.4.0.0⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -N- { [ ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclo [10.8.0.0 ]^2,9.0⁴,⁸.0^13,18]Eicosan-14, 17-dien-8-yl ]-2-oxoethoxy } methyl) carbamoyl]Methyl } -4-oxobutanamide (L7-PII-1)

Following the general procedure for pH sensitive linker-payload, linker-payload L7-PII-1(30mg, 50% yield) was obtained as a white solid from L-1e and PII-1。ESI m/z:804(M+1)⁺。¹H NMR(400MHz,DMSO_d6)δ8.62-8.53(m,1H),8.23-8.11(m,1H),7.69-7.61(m,2H),7.54-7.44(m,3H),7.43-7.26(m,4H),6.20-6.13(m,1H),5.92(s,1H),5.20-5.00(m,2H),4.76-4.40(m,5H),4.32-4.10(m,2H),3.69-3.53(m,3H),2.70-2.60(m,1H),2.35-2.24(m,2H),2.14-1.93(m,3H),1.80-1.70(m,3H),1.62-1.46(m,4H),1.42-1.20(m,7H),1.14-0.90(m,2H),0.87-0.75(m,6H)ppm。

Synthesis of chiral linker-payload containing (R) -Glu and (S) -Glu in L2-PIII-1 (FIG. 8)

{4- [ (2S) -2- [ (2S) -2-amino-3-methylbutanamide]-5- (carbamoylamino) pentanamide]Phenyl } methyl N- { [ ({2- [ (1S,2S,4R,8S,9S,11S,12R,13S,19S) -12, 19-difluoro-11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxa-pentacyclic [10.8.0.0 ]^2,9.0^4,8.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamate (103-8b)

To a solution of crude compound 103b in DMF at room temperature was added Fmoc-vcPAB-PNP (11d), DMAP and DIPEA (50mg, 0.39 mmol). The mixture was stirred at room temperature for 3 hours until most of the starting material was consumed, monitored by LCMS. Piperidine was then added to the reaction mixture. After stirring the reaction at room temperature for 1 hour, Fmoc was completely removed according to LCMS. The reaction mixture was directly purified by preparative HPLC (method B) to give compound 103-8B (28mg, 20% yield) as a white solid. ESI M/z:480(M/2+ H) ⁺。

(4S) -4-amino-4- { [ (1S) -1- { [ (1S) -4- (carbamoylamino) -1- [ (4- { [ ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12R,13S,19S) -12, 19-difluoro-11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclic [10.8.0.0 ]²,⁹.0^4,8.0^13,18]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamoyl) oxy]Methyl } phenyl) carbamoyl]Butyl radical]Carbamoyl }-2-methylpropyl]Carbamoyl } butanoic acid (103-9a)

To a solution of the compound Boc-L-Glu (OTBU) -OH (0.15g, 0.50mmol) in DMF (5mL) was added HATU (0.19g, 0.50mmol) and DIPEA (0.13g, 1.0 mmol). The reaction mixture was stirred at room temperature for 10 minutes, then compound 103-8b (0.48g, 0.50mmol) was added to the reaction mixture. The reaction mixture was then stirred at room temperature for 3 hours until 103-8b had been completely consumed according to LCMS. The mixture was extracted with EtOAc, and the combined organic solutions were washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was dissolved in DCM (10 mL). To the resulting solution was added TFA (2mL) and the reaction mixture was stirred at room temperature for 3 hours, monitored by LCMS. The reaction mixture was concentrated and the residue was directly purified by preparative HPLC (method B) to give compound 103-9a (0.41g, 75% yield) as a white solid. ESI M/z 536.8(M/2+ H) ⁺。

(4R) -4-amino-4- { [ (1S) -1- { [ (1S) -4- (carbamoylamino) -1- [ (4- { [ ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12R,13S,19S) -12, 19-difluoro-11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclic [10.8.0.0 ]^2,9.0^4,8.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamoyl) oxy]Methyl } phenyl) carbamoyl]Butyl radical]Carbamoyl } -2-methylpropyl radical]Carbamoyl } butanoic acid (103-9b)

Following a similar procedure to 103-9a except substituting Boc-D-Glu (OTBU) -OH for Boc-L-Glu (OTBU) -OH, compound 103-9b (0.40g, 74% yield) was obtained as a white solid. ESI M/z 536.8(M/2+ H)⁺。

2, 5-dioxopyrrolidin-1-yl 1- (4- { 2-azatricyclo [10.4.0.0 ]⁴,⁹]Hexadecane-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -3,6,9, 12-tetraoxapentadecane-15-oic acid ester (5-1c)

To a solution of commercial compound 5c (160mg, 0.290mmol) in DCM (20mL) were added HOSu (73.3mg, 0.637mmol) and EDCI (122mg, 0.637mmol), and the mixture was stirred at room temperature for 24 h, monitored by LCMS. The reaction mixture was diluted with DCM (50mL), and the organic layer was washed with water (50mL) and brine, over anhydrous Na₂SO₄Drying and concentration in vacuo afforded compound 5-1c (159mg, 84% yield) as a colorless oil, which was used without purification. ESI M/z 650(M + H) ⁺。

2, 5-dioxopyrrolidin-1-yl-1- [ ({ endo-bicyclo [6.1.0] non-4-yn-9-ylmethoxy } carbonyl) amino ] -3,6,9, 12-tetraoxapentadecane-15-oic acid ester (5-1d)

Following a similar procedure to 5-1c, except substituting 5c with 5d, compound 5-1d (150mg, 54% yield) was obtained as a colorless oil, which was used without further purification. ESI M/z 539(M + H)⁺。

(4S) -4- [1- (4- { 2-Azotricyclo [10.4.0.0 ]^4,9]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -3,6,9, 12-tetraoxapentadecane-15-carboxamide]-4- { [ (1S) -1- { [ (1S) -4- (carbamoylamino) -1- [ (4- { [ ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12R,13S,19S) -12, 19-difluoro-11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxa-pentacyclic [10.8.0.0 ]^2,9.0^4, ⁸.0^13,18]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamoyl) oxy]Methyl } phenyl) carbamoyl]Butyl radical]Carbamoyl } -2-methylpropyl radical]Carbamoyl } butyric acid (L2-PIII-1)

To a solution of compound 103-9a (57mg, 53. mu. mol) in DMF (1mL) was added compound 5-1c (36mg, 56. mu. mol) and DIPEA (27mg, 0.21 mmol). The reaction mixture was stirred at room temperature for 4 hours, monitored by LCMS. The resulting mixture was then directly purified by preparative HPLC (method B) to give compound L2-PIII-1(12mg, 15% yield) as a white solid. ESI M/z 811.4(M/2+ H) ⁺。

(4R) -4- [1- (4- { 2-Azotricyclo [10.4.0.0 ]⁴,⁹]Hexadec-1 (12),4(9),5,7,13, 15-hexaen-10-yn-2-yl } -4-oxobutanamido) -3,6,9, 12-tetraoxapentadecane-15-carboxamide]-4- { [ (1S) -1- { [ (1S) -4- (carbamoylamino) -1- [ (4- { [ ({ [ ({2- [ (1S,2S,4R,8S,9S,11S,12R,13S,19S) -12, 19-difluoro-11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxa-pentacyclic [10.8.0.0 ]²,⁹.0⁴,⁸.0^13,18]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamoyl) oxy]Methyl } phenyl) carbamoyl]Butyl radical]Carbamoyl } -2-methylpropyl radical]Carbamoyl } butanoic acid (LP19)

Following a similar procedure to L2-PIII-1, except substituting 103-9a with 103-9b, compound LP19(14mg, 17% yield) was obtained as a white solid. ESI M/z 811.4(M/2+ H)⁺。

Synthesis of glucose linker-payload L18-PII-1 (FIG. 8B)

N- (2-aminoethyl) -2- (cycloocta-2-yn-1-yloxy) acetamide (L-15)

To a solution of ethylenediamine (0.71g, 12mmol) in DMF (2.0mL) was added DIPEA (0.30g, 2.4mmol) and the compound slowlyL-1d (0.33g, 1.2mmol) in DMF (3.0mL) and the mixture was stirred at room temperature for 30 min and monitored by LCMS. The resulting mixture was purified by reverse phase flash chromatography (0-100% acetonitrile in aqueous ammonium bicarbonate (0.8mM)) to give compound L-15(0.18g, 68% yield) as a colorless oil. ESI M/z 225.2(M + H) ⁺。¹H NMR(400MHz,DMSO_d6)δ7.74-7.63(m,1H),4.28(t,J＝5.8Hz,1H),3.88-3.73(m,2H),3.11-3.00(m,4H),2.58(t,J＝6.4Hz,2H),2.27-2.06(m,3H),1.94-1.71(m,4H),1.66-1.54(m,2H),1.45-1.33(m,1H)ppm。

(2S,3S,4S,5R,6S) -3,4, 5-Tris (acetoxy) -6- [2- ({2- [2- (cycloocta-2-yn-1-yloxy) acetamido ] ethyl } carbamoyl) -4- (hydroxymethyl) phenoxy ] tetrahydropyran-2-carboxylic acid methyl ester (L-17a)

To a mixture of compound L-16a (synthesized according to WO 2018/182341A 1) (0.11g, 0.23mmol) and HATU (96mg, 0.25mmol) in dry DMF (4mL) was added compound L-15(51mg, 0.23mmol) and DIPEA (89mg, 0.69mmol), and the reaction mixture was stirred at room temperature for 2 hours until L-16a was completely consumed, monitored by LCMS. The resulting mixture was directly purified by reverse phase flash chromatography (0-100% acetonitrile in TFA (0.01%)) to afford compound L-17a (0.14g, 90% yield) as a white solid. ESI M/z 691.4(M + H)⁺。¹H NMR(400MHz,CDCl₃)δ8.06-8.04(m,1H),7.64-7.59(m,1H),7.50-7.47(m,1H),7.22-7.18(m,1H),7.01-6.98(m,1H),5.44-5.28(m,5H),4.68(s,2H),4.30-4.21(m,2H),4.10-4.06(m,1H),3.93-3.88(m,1H),3.75(s,3H),3.67-3.48(m,2H),2.21-2.07(m,15H),1.93-1.79(m,3H),1.70-1.38(m,3H)ppm。

[ (2R,3R,4S,5R,6S) -3,4, 5-tris (acetoxy) -6- [2- ({2- [2- (cycloocta-2-yn-1-yloxy) acetamido ] ethyl } carbamoyl) -4- (hydroxymethyl) phenoxy ] tetrahydropyran-2-yl ] methyl acetate (L-17b)

Following a similar procedure to L-17a except substituting L-16a with L-16b gave compound L-17b (0.10g, 80% yield) as a white solid. ESI M/z 705.3(M + H)⁺。

(2S,3S,4S,5R,6S) -3,4, 5-Tris (acetoxy) -6- [2- ({2- [2- (cycloocta-2-yn-1-yloxy) acetamido ] ethyl } carbamoyl) -4- { [ (4-nitrophenoxycarbonyl) oxy ] methyl } phenoxy ] tetrahydropyran-2-carboxylic acid methyl ester (L-18a)

To a solution of compound L-17a (0.14g, 0.20mmol) in DMF (2.0mL) at 0 deg.C under nitrogen was added bis (4-nitrophenyl) carbonate (55mg, 0.18mmol) and DIPEA (26mg, 0.20 mmol). The reaction mixture was stirred at 0 ℃ for 30 minutes and then at room temperature for 3 hours. The reaction mixture was diluted with water (10mL) and then extracted with ethyl acetate (20 mL. times.3). The combined organic solutions were washed with brine (10mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (40-60% ethyl acetate in petroleum ether) to give compound L-18a (85mg, 49% yield) as a colorless oil. ESI M/z 856.0(M + H)⁺。

[ (2R,3R,4S,5R,6S) -3,4, 5-tris (acetoxy) -6- [2- ({2- [2- (cyclooct-2-yn-1-yloxy) acetamido ] ethyl } carbamoyl) -4- { [ (4-nitrophenoxycarbonyl) oxy ] methyl } phenoxy ] tetrahydropyran-2-yl ] methyl acetate (L-18b)

Following a similar procedure to L-18a, except substituting L-17a with L-17b, compound L-18b (62mg, 50% yield) was obtained as a white solid. ESI M/z 870.3(M + H)⁺。

[ (2R,3R,4S,5R,6S) -3,4, 5-tris (acetoxy) -6- [2- ({2- [2- (cycloocta-2-yn-1-yloxy) acetamido-e]Ethyl } carbamoyl) -4- { [ ({ [ ({2- [ (1S) 2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclo [10.8.0.0^2,9.0^4,8.0^13,18]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamoyl) oxy]Methyl group } phenoxy group]Tetrahydropyran-2-yl]Methyl acetate (L-19a)

To a solution of compound L-18b (59mg, 68. mu. mol) in DMF (4.0mL) was added the payload PII-1(35mg, 68. mu. mol), HOBt (9.1mg, 68. mu. mol) and DIPEA (26mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was directly purified by reverse phase flash chromatography (0-100% acetonitrile in aqueous ammonium bicarbonate (10mM)) to give compound L-19a (25mg, 30% yield) as a white solid. ESI M/z 817.3 (M-M)_Bud+H)⁺。

[3- ({2- [2- (cycloocta-2-yn-1-yloxy) acetamido group]Ethyl } carbamoyl) -4- { [ (2S,3R,4S,5S,6R) -3,4, 5-trihydroxy-6- (hydroxymethyl) tetrahydropyran-2-yl]Oxy } phenyl]Methyl N- { [ ({2- [ (1S,2S,4R,8S,9S,11S,12S,13R) -11-hydroxy-9, 13-dimethyl-16-oxo-6-propyl-5, 7-dioxapentacyclic [10.8.0.0 ]^2,9.0⁴,⁸.0¹³,¹⁸]Eicosan-14, 17-dien-8-yl]-2-oxoethoxy } methyl) carbamoyl]Methyl } carbamate (L18-PII-1)

To a mixture of compound L-19a (20mg, 16. mu. mol) in methanol (2mL) was added aqueous lithium hydroxide (72mM, 2mL) and the mixture was stirred at 15 ℃ for 1 hour and monitored by LCMS. The reaction mixture was acidified to pH 3 to 4 by aqueous hydrochloric acid (1N) and then purified by preparative HPLC (5-95% acetonitrile in aqueous formic acid (0.1%)) to afford linker-payload L18-PII-1(10mg, 45% yield) as a white solid. ESI M/z 1101.6(M + Na) ⁺。¹H NMR(400MHz,DMSO_d6)δ8.85-8.78(m,1H),8.53-8.40(m,3H),7.85(s,1H),7.81-7.74(m,1H),7.64-7.53(m,1H),7.47-7.43(m,1H),7.36-7.30(m,2H),6.16(d,J＝10.0Hz,1H),5.92(s,1H),5.19-5.00(m,3H),4.90(d,J＝6.8Hz,1H),4.81-4.71(m,2H),4.64-4.46(m,4H),4.33-4.14(m,3H),3.90-3.73(m,3H),3.61(d,J＝5.6Hz,2H),3.55-3.50(m,2H),3.29-3.16(m,9H),2.38-1.82(m,10H),1.76-1.48(m,10H),1.38-1.24(m,7H),1.00-0.81(m,6H)ppm。

Example 1

This example illustrates a specific method for site-specific conjugation of alkyne-containing linker-payloads to antibodies.

In this example, the site-specific antibody-drug conjugate can be generated in two steps. In a first step, the azido group is attached to a moiety, e.g., azide-PEG₃The amine is linked to an antibody having glutamine (e.g., a Q-tag (Q-tag)) by Microbial Transglutaminase (MTG) (e.g., MTG EC 2.3.2.13, Zedira, Darmstadt, germany; see WO 2017/147542, which is incorporated herein in its entirety). A DAR 2 site-specific antibody-drug conjugate can be synthesized by attaching a linker moiety to the Q295 residue of an antibody having the N297D mutation. A DAR 4 site-specific antibody-drug conjugate can be synthesized by attaching a linker moiety to an antibody having the N297Q mutation. Both Q295 and Q297 glutamine were reacted with a linker moiety through MTG to provide a DAR of 4. The second step is through [2+3 ]]Cycloaddition, such as 1, 3-dipolar cycloaddition between azide and cyclooctyne (also known as copper-free click chemistry), attaches a linker-payload to the azido-functionalized antibody. See Baskin, j.m.; prescher, j.a.; laughlin, s.t.; agrard, n.j.; chang, p.v.; miller, i.a.; lo, a.; codelil, j.a.; bertozzi, c.r.pnas 2007,104(43), 16793-7, the entire contents of which are incorporated herein by reference in their entirety for all purposes. When the Reactive Group (RG) is part of a DIBAC group, through [2+3 ] ]The cycloaddition reaction is coupled to an azido-functionalized antibody. This method provides site-specific and stoichiometric conjugates.

Synthesis of 2DAR antibody-drug conjugates

Step 1: preparation of azido-functionalized antibodies.

In PBS (pH 6.5-8.0), an aglycosylated human antibody IgG (IgG1, IgG4, etc.) or human IgG1 isotype having N297Q mutation (EU numbering) is combined with 200 molar equivalents or more of azido-dPEG₃-amines (MW 218.26 g/mol). The resulting solution was mixed with MTG (EC2.3.2.13 from Darmstadt (Darmstadt) Zedira, Germany, or modern Pantry [ L #210115A ]]-ACTIVAT comprises Maltodextrin (Maltodextrin) from Japanese (Japan) Ajinomoto (Ajinomoto)) (25U/mL; 5U MTG/mg antibody) so that the final concentration of the antibody is 0.5-5mg/mL, and then the solution is incubated at 37 ℃ for 4-24 hours while gently shaking. The reaction was monitored by ESI-MS. After completion of the reaction, excess amine and MTG are removed by SEC or protein a column chromatography to produce the azido-functionalized antibody. This product was characterized by SDS-PAGE and ESI-MS. azido-dPEG₃Addition of amines to two sites of the antibody, resulting in 2DAR antibody-PEG₃Azide conjugate increases 204 Da.

Step 2: the azido-functionalized antibody is reacted with the linker-payload by click chemistry.

Functionalization of [2+3 ] between antibody and linker-payload-containing alkyne by azido]And (3) click reaction to prepare a site-specific antibody drug conjugate with human IgG (IgG1, IgG4 and the like). The detailed coupling procedure is as follows. The mAb-PEG₃–N₃(1-3mg/mL) in an aqueous medium (e.g., PBS containing 5% glycerol, HBS) containing ≧ 6 molar equivalents of LP dissolved in an appropriate organic solvent (e.g., DMSO, DMF, or DMA) (i.e., reaction mixture containing 5-20% organic solvent, v/v) at 24 ℃ to 37 ℃ for 6 hours. Reaction progress was monitored by ESI-MS in the absence of mAb-PEG₃–N₃Indicating that the coupling is complete. Excess LP and organic solvent were removed by elution with PBS by SEC or acidic buffer by protein a column chromatography followed by neutralization with Tris (pH 8.0). The final product was concentrated by ultracentrifugation and characterized by UV, SEC, SDS-PAGE and ESI-MS.

Synthesis of 4DAR antibody-drug conjugates

Step 1: preparation of azido-functionalized antibodies.

BupH of aglycosylated antibodies with human IgG1 isotype^TMThe solution (pH 7.6-7.8) is mixed with more than or equal to 200 molar equivalents of azido-dPEG ₃Amine (MW.218.26g/mol). The resulting solution was then mixed with transglutaminase (25U/mL; 5U MTG/mg antibody) to give a final concentration of 0.5-3 mg/mL, and the solution was incubated at 37 ℃ for 4-24 hours while gently shaking. The reaction was monitored by SDS-PAGE or ESI-MS. After completion of the reaction, excess amine and MTG were removed by volume exclusion chromatography (SEC) to generate the azido-functionalized antibody. This product was analyzed via SDS-PAGE and ESI-MS. azido-dPEG₃-amine addition to two sites of antibody (Q295 and Q297) such that the 4DAR aglycosylated antibody-PEG₃Azide conjugate increase 804 Da.

The mAb-PEG₃–N₃(1-3mg/mL) in an aqueous medium (e.g., PBS containing 5% glycerol, HBS) containing ≧ 6 molar equivalents of linker-payload dissolved in an appropriate organic solvent (e.g., DMSO, DMF, or DMA) (i.e., reaction mixture containing 5-20% organic solvent, v/v), incubated at 24 ℃ to 37 ℃ for 6 hours. Reaction progress was monitored by ESI-MS in the absence of mAb-PEG₃–N₃Indicating that the coupling is complete. Excess linker-payload and organic solvent were removed by elution with PBS by SEC or acidic buffer by protein a column chromatography followed by neutralization with Tris (pH 8.0). The purified conjugates were analyzed by SEC, SDS-PAGE and ESI-MS.

Example 2

This example illustrates a method for non-specific coupling of a drug to an antibody using a thiol-maleimide Michael addition reaction. Use was made of a mixture of Mol pharm.2015jun 1; a method similar to that described in 1863-71, by conjugation of the cysteine of the antibody in two steps, is described in (12), (6) and is incorporated herein by reference in its entirety.

Monoclonal antibodies (mAb, 10mg/ml in 50mM HEPES solution, 150mM NaCl) were reduced with 1mM dithiothreitol (0.006mg/mg antibody) or TCEP (equivalent to 2.5 moles antibody) at pH 7.5 at 37 ℃ for 30 minutes. The concentration of the antibody was calculated based on the absorbance at 280nm on nanodrop (thermofisher scientific) and using the extinction coefficient of the antibody. After gel filtration (G-25, pH 4.5 sodium acetate), a DMSO solution of linker-payload compound (10mg/mL) was added to the reduced antibody and the mixture was adjusted to pH 7.0 with 1M HEPES (pH 7.4). The reaction was allowed to react for 3-14 hours. The resulting conjugate was purified by SEC. The dar (uv) value is determined using the absorbance of the ncADC determined and the extinction coefficients of the antibody and linker-payload compound.

Example 3

Characterization of ADC

SDS-PAGE can be used to analyze the integrity and purity of the ADC.

In one of the methods, SDS-PAGE run conditions included unreduced and reduced samples (2-4 μ g) and a BenchMark prestained Protein Ladder (BenchMark Pre-stabilized Protein Ladder, Invitrogen, Cat. No. 10748-010; L #1671922.), with a loading per lane (1.0 mm. times.10 wells) of Novex 4-20% Tris-Glycine Gel (Glycine Gel), and run at 180V, 300mA for 80 minutes. Unreduced samples were prepared using Novex Tris-Glycine SDS buffer (2X, 2 fold) (Novex Tris-Glycine SDS buffer, Invitrogen, catalog number LC2676) and reduced samples were prepared using SDS sample buffer containing 10% 2 mercaptoethanol (2 fold).

The molecular weights of the antibody and ncADC were determined on SDS-PAGE under non-reducing and reducing conditions. Under non-reducing conditions, the mass change may not be significant because the percentage of mass change is relatively small. However, the mass of the heavy chain increased from the naked antibody to the azido-functionalized antibody to the ncADC conjugate. The cross-linked material may or may not be detectable.

The purity of the ADC was analyzed by volume exclusion chromatography (SEC).

To determine the purity of the antibody drug conjugate, volume exclusion chromatography was performed. Analytical SEC experiments were performed using a Waters 600 instrument on a Superdex 200(1.0x30cm) HR chromatography column at a flow rate of 0.80mL/min using PBS pH 7.4 and monitored at λ 280nm using a Waters 2998 PDA. The assay consisted of 200. mu.L PBS (pH 7.4) and 30-100. mu.L of the test sample. Preparative SEC purification was performed using an AKTA instrument from GE Healthcare eluting with PBSg pH 7.4 at a flow rate of 2mL/min on a Superdex 200PG (2.6X60cm) column and monitored at λ 280 nm.

Both the antibody and the ADC were analyzed by LC-ESI-MS for complete mass analysis, as further described below.

The intact mass of the ADC samples was determined by LC-ESI-MS to determine the drug-payload distribution curve and calculate the average DAR. Each test sample (20-50ng, 5 μ L) was loaded onto an Acquity UPLC Protein BEH C4 chromatography column (10K psi,

1.7 μm, 75 μm × 100 mm; directory number 186003810). After 3 min of desalting, the proteins were eluted and mass spectra were obtained by a Waters Synapt G2-Si mass spectrometer.

Example 4

General method for quenching linker-payloads

For model studies of the linker-payloads described herein, e.g., pH stability test, capB assay, chemical stability test, and plasma stability assay, a "quenched linker-payload" was synthesized as an alternative. DIPEA (5 equivalents) and azide (CD-N)₃Or taurine-PEG 4-azide; 3 equivalents) were added sequentially to a solution of linker-payload (2mg) in acetonitrile and water (v/v ═ 1, 0.4 mL). The reaction mixture was stirred at room temperature for 20 hours, monitored by LCMS. The reaction mixture was directly purified by preparative HPLC to give quenched linker-payload. For example, L1-PII-1, L1-PII-6, L1-PII-7, L1-PII-8 and L1-PII-9 all use taurine-PEG ₄-N₃Treatment to give the corresponding quenched linker-payload (Q1L1-PII- #); and L1-PII-1, L6-PII-1 and L7-PII-1 are all CD-N₃Treatment yielded the corresponding quenched linker-payloads (Q2L1-PII-1, Q2L6-PII-1, and Q2L 7-PII-1). All are quenchedThe extinct linker-payloads are listed in table 3d and/or table 6 below.

Q1 Ln-payload

Q2 Ln-payload

Table 6.

Table 6a.

Synthesis of Q2L1-PII-1

To a solution of L1-PII-1(5mg, 3.4. mu. mol) in DMF (1.0mL) was added the compound CD-N₃(7.0mg, 6.8. mu. mol). The reaction mixture was stirred at room temperature overnight, monitored by LCMS. The reaction mixture was directly purified by preparative HPLC to give compound Q2L1-PII-1(5mg, 60% yield) as a white solid. ESI M/z 819.0(M/3+ H)⁺。

pH stability of linker-payload in buffer

These compounds were not tested for pH stability due to poor solubility of both linker-payloads (< 0.02mg/mL DMSO in water (20%)). The quenched linker-payloads were all water soluble and used for pH stability testing.

Method for testing quenched linker-payload pH stability

To a DMSO (0.2-1.0mg/mL) solution of compound (payload or quenched linker-payload) was added the corresponding PBS buffer (V (buffer)/V (DMSO) ═ 5) to give test samples (

pH

3, 4, 5, 6, 7.4, and 8.5, or other specific pH). The test samples were incubated at room temperature for at least 3 days and monitored by LCMS (i.e., at 1 hour, 2 hours, 4 hours, 8 hours and day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9 and day 21 time points). The initial concentration of the sample was 0.2mg/mL (DMSO/buffer, v/v-1/5). The percentage of remaining compound at the corresponding time point is reported; all compounds were stable at pH 7.4 and pH 8.5 on day 7 with no budesonide released and less than 3% other impurities (data not shown in table 7). After 3 days, the payload and quenched linker-payload were mostly stable at pH >5.0, 6.0, 7.4 and 8.5. Under more acidic conditions, e.g. at pH 1.0, the payload or linker-payload is easily cleaved to release D x-OH. After 24 hours, some of the quenched linker-payload was cleaved at pH 4.0 and pH 3.0 to release budesonide. The results are shown in tables 7, 7a, 7b, 7c and 7 d.

TABLE 7 pH stability of quenched linker-payloads for Release of parent payloads

TABLE 7a chemical stability of quenched vcPAB-linker

*. LP: the percentage of linker-payload remaining after the corresponding time.

P: percentage of budesonide released from the linker-payload after incubation time.

TABLE 7b chemical stability of quenched linkers

*. LP: the percentage of linker-payload remaining after the corresponding time.

TABLE 7c chemical stability of linker-budesonide

*. LP: the percentage of linker-payload remaining after the corresponding time.

TABLE 7d chemical stability of glucose linker-budesonide

*. LP: the percentage of linker-payload remaining after the corresponding time.

Example 4a

Metabolic stability of human liver microsomes

The metabolic stability of payload PIII-1 incubated with human liver microsomes was evaluated and the results are shown in table 7e below.

Table 7e.

Example 5

Antibodies coupled to steroid payloads via the half-amine ether linkers of the invention are active in GR luciferase reporter assays in HEK293/GRLuc/MSR1 cells

Linker-payloads generated and coupled to anti-macrophage scavenger receptor 1(MSRl) antibodies (H1H 21234N-N297Q; HCVR SEQ ID NO: 19, LCVR SEQ ID NO: 27, N297Q) or non-binding isotype control antibodies(isotype control-N297Q) to generate the non-cytotoxic antibody drug conjugates (ncadcs) listed in table 8. Specifically, site-specific azido-functionalized N297Q mutant nonglycosylated antibody (e.g., targeting MSR1 and unconjugated control) conjugates are prepared by incubating an azido-functionalized glutaminyl-modified antibody in an aqueous medium (1 mg/mL in PBS, 5% glycerol in PBS, HBS) containing ≧ 6 molar equivalents of linker-payload (which is dissolved in a suitable organic solvent such as DMSO, DMF or DMA) such that the reaction mixture contains 10-20% organic solvent, v/v). The progress of the reaction was monitored by ESI-MS. The absence of azido functionalized antibody indicates that the coupling is complete. Excess linker-payload and organic solvent were removed by SEC (Waters, Superdex 200HR, 1.0x30cm, GE Healthcare, flow rate 0.7mL/min) eluting with pH 7.4 PBS. The purified conjugates were analyzed by UV-Vis, SEC and ESI-MS. All antibodies (Ab), azido-functionalized antibody (Ab-N) ₃) And antibody GC-steroid conjugates (Ab-LP) are summarized in Table 8a for all ESI-MS and DAR values.

TABLE 8 GR reporter Gene Activity of ncADC

TABLE 8A ESI-MS and DAR Listing of site-specific steroid-antibody conjugates

The activity of anti-MSR 1 ncADC was tested using MSR1 ADC steroid responsive luciferase reporter assay. To generate assay cell lines, HEK293 cells were co-transfected with pBind-GR (Promega, cat # E158A) and pGL4.35[ Luc2P/9xGAL4UAS/Hygro ] (Promega, cat # E137A) vectors. The pBind-GR vector expresses a fusion protein consisting of a GR ligand binding domain and a yeast Gal4DNA binding domain, which binds to the Gal4 Upstream Activation Sequence (UAS) in the luciferase expression vector, and induces luciferase expression after GR agonist binding. Cells were selected in G418+ hygromycin for at least 2 weeks and the resulting cell line was designated HEK 293/GRLuc. HEK293/GRLuc cells were then transduced with the human MSR1 lentiviral expression vector and 48 hours later the cells were sorted into MSR1 positive cells. The resulting cell line was designated HEK293/GRLuc/MSR 1.

For the assay test, cells were seeded at 20,000 cells/well in assay medium (DME high glucose supplemented with 10% FBS, 100 units/mL penicillin, 100ug/mL streptomycin, and 53ug/mL glutamine) in 96-well plates the day before assay. Three-fold serial dilutions of ncADC in assay buffer were added to the cells and held for 48 hours. The last well in the plate served as a blank, containing assay medium only, and was plotted as a continuation of the 3-fold serial dilution. Luciferase activity was measured using One-GloTM reagent (Promega, Cat. No. E6130). Relative Light Units (RLU) were determined on an Envision photometer (Perkinelmer) and EC was determined on a 10-point dose response curve (GraphPad Prism) using a four-parameter logistic equation ₅₀The value is obtained. The signal-to-noise ratio (S/N) was determined by taking the ratio of the highest RLU on the dose response curve to the RLU in untreated wells.

As shown in Table 8, the EC of anti-MSRl (H1H21234N-N297Q) ncADC in HEK293/GRLuc/MSR1 cells₅₀The values ranged from 85pM to 609pM, and the S/N values ranged from 96.4 to 268.8. EC of all isotype control ncADCs in HEK293/GRLuc/MSR1 cell line₅₀The values were all greater than 50nM, with S/N values ranging from 3.8 to 148.4. All anti-MSR 1ncADC ECs in HEK293/GRLuc cells₅₀The values were all greater than 41nM, with S/N values ranging from 5.4 to 25.5. Unconjugated anti-MSR 1 was inactive in any of the cell lines tested.

Example 6

Evaluation of the Activity of Compounds III and PIII-1 in the GR luciferase reporter assay in HEK293/GRLuc cells and HEK293/GRLuc/MSR1

To test the activity of the GR agonist payloads disclosed herein, a cell-based GR-responsive luciferase reporter assay was developed as described above.

For the assay, cells were seeded at 20,000 cells/well in 96-well plates (DME high glucose supplemented with 10% FBS, 100 units/ml penicillin, 100ug/ml streptomycin, and 53ug/ml glutamine) the day before the assay. Three-fold serial dilutions of free payload were prepared in 100% DMSO, transferred to fresh assay medium, and added to the cells for 48 hours. The final DMSO concentration was kept constant at 0.2% and the final concentration of free payload ranged from 100nM to 0.015 nM. The last well in the plate served as a blank containing assay medium and 0.2% DMSO only (untreated wells) and was plotted as a continuation of the 3-fold serial dilution. Luciferase Activity Using One-Glo ^TMThe reagent (Promega, catalog No. E6130) was used for the measurement. Relative Light Units (RLU) were determined on an Envision photometer (Perkinelmer) and EC was determined on a 10-point dose response curve (GraphPad Prism) using a four-parameter logistic equation₅₀The value is obtained. The signal-to-noise ratio (S/N) was determined by taking the ratio of the highest RLU on the dose response curve to the RLU in untreated wells. As shown in Table 8b, the EC of the payload in HEK293/GRLuc/MSR1 cells₅₀The values ranged from 54.5pM nM to 272pM, and the S/N values ranged from 138.1 to 179.3. Payload EC in HEK293/GRLuc cell line₅₀Values ranged from 19.7pM nM to 213pM, and S/N values ranged from 24.6 to 34.4.

Table 8 b: GR reporter Gene Activity of GR agonists

Example 7

Evaluation of payload release

To confirm release of the payload linked to the antibody via the half-amine ether linker, lysosomal cleavage assay experiments were performed. For the assay, ncADC was added to a freshly prepared lysosomal working solution containing 1-fold amount of catabolic buffer (Xenotech, cat # K5200) and 0.125mg/mL human hepatolysosomal protein (Xenotech, cat # h0610. l). 200 μ L of the resulting mixture was incubated with 1 μ M payload equivalent ncADC for 24 hours at 37 ℃ with gentle shaking. Aliquots of 20 μ L were taken at 0, 0.5, 1.0, 2.0, 4.0, 8.0 and 24 hours, respectively, and immediately transferred to plates containing 80 μ L of cold acetonitrile to inactivate lysosomal enzymes and precipitate proteins. After centrifugation at 2,000rpm for 5 minutes, an aliquot of the supernatant was diluted with an equal volume of water and then analyzed by LC-MS to determine the amount of precursor and payload released from ncADC.

As shown in Table 9, with the linker vcPAB-gly-NHCH₂The ncADC steroid conjugate of (H1H21234N-N297Q-L1-PIII-1) released 164nM of steroid III at the 24 hour time point. With a linker GGFG-NHCH₂The ncADC steroid conjugate of (H1H21234N-N297Q-L3-PIII-1) released 345nM of steroid III at the 24 hour time point.

Without being bound by any particular theory, under certain conditions, the payload ("payload precursor" or "prodrug") having the half amine ether linker residue is released first, followed by release of the final payload. As shown in Table 10, with the linker vcPAB-gly-NHCH₂The ncADC steroid conjugate of (H1H21234N-N297Q-L1-PIII-1) released 725nM of the bioactive steroid precursor PIII-1 at the 24 hour time point. With a linker GGFG-NHCH₂The ncADC steroid conjugate of (H1H21234N-N297Q-L3-PIII-1) released 4.3nM of the bioactive steroid precursor PIII-1 at the 24 hour time point.

Table 9: payload release

Table 10: payload precursor release

Example 8

Antibody-drug conjugates with anti-macrophage scavenger receptor 1(MSR1) antibody (H1H21234N-N297Q) or non-binding isotype control antibody (isotype control) were conjugated to the linker-payloads listed in table 11 and evaluated as described in example 5. H1H21234N-N297Q provided a 4DAR ADC. As shown in Table 11, EC against MSR1(H1H21234N-N297Q) ADC in HEK293/GRLuc/MSR1 cells ₅₀The values ranged from 636pM to 3.96nM, and the signal-to-noise ratio (S/N) values ranged from 120.1 to 280.3. EC of all isotype controls in HEK293/GRLuc/MSR1 cell line₅₀Value of all>35nM, S/N values ranging from 1.9 to 153.5. EC of all ADCs in HEK293/GRLuc cells₅₀Value of all>100nM, S/N values ranging from 1.0 to 16.8. Unconjugated anti-MSR 1 antibodies were inactive in any of the cell lines tested. Free payload (budesonide) was active in both cell lines, EC in HEK293/GRLuc and HEK293/GRLuc/MSR1 cell lines₅₀Values were 710pM and 1.19nM, respectively, and S/N values were 23.3 and 135.4, respectively.

TABLE 11 GR reporter Gene Activity of ADCs

Claims

1.A compound having the structure:

or a pharmaceutically acceptable salt thereof, wherein,

R^1aand R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl or arylAlkyl, heteroaryl, alkylene, or heteroalkylene, wherein when R is^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 3, 4, 5, 6, 7, or 8 atoms;

R²is H, alkylene, heteroalkylene, or an amino acid side chain, wherein when R is²When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R ³To form a heterocyclic group of 4, 5, or 6 atoms;

R³is H, alkyl, alkylene, or heteroalkylene, wherein when R is³When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R^1aOr R²To form said 3, 4, 5, 6, 7, or 8 atom heterocyclyl;

R⁴is H or alkyl;

R⁵is O, NR⁶Or S;

R⁶is H, or alkyl;

d is an acyl group, or a residue of a biologically active compound comprising a hydroxyl group, an amino group, or a thiol; and

n is 0, 1, 2, 3, 4, 5, or 6.

2. The compound of claim 1, having the structure:

or a pharmaceutically acceptable salt thereof, wherein,

R^1aand R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, alkylene, or heteroalkylene, wherein when R is^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms;

R²is H, alkyleneHetero alkyl, or amino acid side chain, wherein when R is²When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms;

R³Is H, alkyl, alkylene, or heteroalkylene, wherein when R is³When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R^1aOr R²To form said heterocyclic group of 4, 5, or 6 atoms;

R⁴is H or alkyl;

R⁵is O, NR⁶Or S;

R⁶is H, or alkyl;

n is 0, 1, 2, 3, 4, or 5.

3. The compound of claim 2, having the structure:

or a pharmaceutically acceptable salt thereof, wherein,

R^1aand R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, or alkylene, wherein when R is^1aWhen alkylene, the alkylene is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms;

R²is H, or an amino acid side chain;

R³is H, alkyl, or alkylene, wherein when R is³When alkylene, the alkylene is further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms;

d is an acyl group, or a residue of a biologically active compound comprising a hydroxyl group; and

n is 0, 1, 2, 3, 4, or 5.

4. The compound of claim 2, wherein the compound has the structure:

5. A compound according to any one of the preceding claims, wherein R^1aAnd R^1bEach is H.

6. A compound according to any one of the preceding claims, wherein n is 2.

7. A compound according to any one of the preceding claims, wherein n is 2, and R²Is H or methyl.

8. A compound according to any one of the preceding claims, wherein n is 2, R²Is H or methyl, R³Is H, and D is the residue of a biologically active compound comprising a hydroxyl group.

9. The compound of claim 8, wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 5, wherein n is 1.

11. The compound of claim 10, wherein R²Is H, methyl, or-CH₂Ph。

12. The compound of claim 11, wherein R³Is H.

13. The compound according to claim 12, wherein D is the residue of a biologically active compound comprising a hydroxyl group.

14. The compound of claim 13, wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 10, wherein R²Is H or methyl.

16. The compound of claim 15, wherein R³Is an alkyl group.

17. The compound according to claim 16, wherein D is the residue of a biologically active compound comprising a hydroxyl group.

18. The compound of claim 17, wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

19. The compound of claim 2, wherein R^1aIs alkyl or aralkyl, and R^1bIs H.

20. The compound of claim 19, wherein n is 1.

21. The compound of claim 20, wherein R²Is H.

22. The compound of claim 21, wherein R³Is H.

23. The compound according to claim 22, wherein D is the residue of a biologically active compound comprising a hydroxyl group.

24. The compound of claim 23, wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

25. The compound of claim 2, wherein R^1aIs an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms;

R^1bis H; and

R³is an alkylene radical, said alkylene radical being further bonded to R^1aTo form A heterocyclic group consisting of the above-mentioned 4, 5 or 6 atoms.

26. The compound of claim 25, wherein n is 1.

27. The compound of claim 26, wherein R²Is H.

28. The compound according to claim 27, wherein D is the residue of a biologically active compound comprising a hydroxyl group.

29. The compound of claim 28, wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

30. The compound of claim 10, wherein the compound is

31. The compound of claim 5, wherein the compound is selected from the group consisting of:

32. the compound of claim 10, wherein R²Is alkylene, wherein said alkylene is further connected toTo R³To form a heterocyclic group of 6 atoms; and

R³is an alkylene group, wherein said alkylene group is further bonded to R²To form said 6-atom heterocyclic group.

33. The compound according to claim 32, wherein D is the residue of a biologically active compound comprising a hydroxyl group.

34. The compound of claim 33, wherein the compound is

Or a pharmaceutically acceptable salt thereof.

35. A compound having the structure:

or a pharmaceutically acceptable salt thereof, wherein,

l is a linker comprising a moiety that reacts with the antibody or antigen-binding fragment thereof;

R^1aand R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, alkylene, or heteroalkylene, wherein when R is^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 3, 4, 5, 6, 7, or 8 atoms;

R²is H, alkylene, heteroalkylene, or an amino acid side chain, wherein when R is²When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms;

R³is H, alkyl, alkylene, or heteroalkyleneWherein when R is³When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R^1aOr R²To form said 3, 4, 5, 6, 7, or 8 atom heterocyclyl;

R⁴is H or alkyl;

R⁵is O, NR⁶Or S;

R⁶is H, or alkyl;

n is 0, 1, 2, 3, 4, 5, or 6.

36. The compound according to claim 35, wherein when D is a residue of a biologically active compound comprising a hydroxyl group, an amino group, or a thiol, then the biologically active compound or residue thereof is an anti-inflammatory biologically active compound or residue thereof.

37. The compound of claim 36, wherein the anti-inflammatory bioactive compound is a steroid or a residue thereof.

38. The compound of claim 36, wherein the anti-inflammatory biologically active compound is an LXR agonist or a residue thereof.

39. The compound of claim 35, having the structure:

or a pharmaceutically acceptable salt thereof, wherein,

R^1aand R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, alkylene, or heteroalkyleneAlkyl, wherein when R^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms;

R²is H, alkylene, heteroalkylene, or an amino acid side chain, wherein when R is ²When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms;

R⁴is H or alkyl;

R⁵is O, NR⁶Or S;

R⁶is H, or alkyl;

n is 0, 1, 2, 3, 4, 5, or 6.

40. The compound of claim 39, having the structure:

or a pharmaceutically acceptable salt thereof, wherein,

R²is H, or an amino acid side chain;

R³is H, alkyl, or alkylene, wherein when R is ³When alkylene, the alkylene is further bonded to R^1aTo form said heterocyclic group of 4, 5, or 6 atoms;

n is 0, 1, 2, 3, 4, 5, or 6.

41. The compound of claim 39, having the structure:

or a pharmaceutically acceptable salt thereof, wherein,

R²is H, or an amino acid side chain;

n is 0, 1, 2, 3, 4, 5, or 6.

42. The compound of any one of claims 35-41, wherein the linker further comprises

43. The compound of claim 39, wherein the compound is

Or a pharmaceutically acceptable salt thereof, wherein,

SP¹and SP²When present, are spacer groups, wherein SP¹Further comprising a moiety reactive with the antibody or antigen-binding fragment thereof; each AA is an amino acid; and

p is an integer from 1 to 10.

44. The compound of claim 43, wherein SP¹Comprising a reactive group (reactive group) comprising an alkyne.

45. The compound of claim 44, wherein the alkyne is capable of participating in a 1, 3-cycloaddition reaction.

46. The compound of claim 35, wherein the alkyne is capable of participating in a 1, 3-cycloaddition reaction with an azide to form a regioisomeric 1,2, 3-triazolyl moiety class, wherein the azide comprises an azido-functionalized binder.

47. The compound of claim 43, wherein SP²Included

48. The compound of claim 43, wherein SP²Included

And R²Is H or alkyl.

49. The compound of claim 46, wherein the alkyne is capable of participating in a 1, 3-cycloaddition reaction with an azide comprising an azido-functionalized binder to form a regioisomeric 1,2, 3-triazolyl moiety class, and SP ²Included

50. The compound of claim 46, wherein the alkyne is capable of participating in a 1, 3-cycloaddition reaction with an azide comprising an azido-functionalized binder, SP, to form a regioisomeric 1,2, 3-triazolyl moiety class²Included

And R²Is H or alkyl.

51. The compound of claim 43, wherein,

R^1aand R^1bAre all H;

R²is H or methyl;

R³is H; and

n is 2.

52. The compound according to claim 51, wherein D is the residue of a biologically active compound comprising a hydroxyl group.

53. The compound of claim 52, selected from the group consisting of:

or

A pharmaceutically acceptable salt thereof.

54. The compound of claim 43, wherein,

R^1aand R^1bAre all H;

R²is H, methyl, or-CH₂Ph；

R³Is H or alkyl; and

n is 1.

55. The compound according to claim 54, wherein D is the residue of a biologically active compound comprising a hydroxyl group.

56. The compound of claim 55, selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

57. The compound of claim 43, wherein,

R^1aand R^1bAre all H;

R²is H;

R³is an alkyl group; and

n is 1.

58. The compound according to claim 57, wherein D is the residue of a biologically active compound comprising a hydroxyl group.

59. The compound of claim 58, having the structure

Or a pharmaceutically acceptable salt thereof.

60. The compound of claim 43, wherein,

R^1ais alkyl or aralkyl;

R^1bis H;

R²is H;

R³is H; and

n is 1.

61. The compound according to claim 60, wherein D is the residue of a biologically active compound comprising a hydroxyl group.

62. The compound of claim 61, selected from the group consisting of:

or

A pharmaceutically acceptable salt thereof.

63. The compound of claim 43, wherein,

R^1ais an alkylene radical, said alkylene radical being further bonded to R³To form a heterocyclic group of 4, 5 or 6 atoms;

R^1bis H;

R²is H;

R³is an alkylene radical, said alkylene radical being further bonded to R^1aTo form said heterocyclic group of 4, 5 or 6 atoms; and

n is 1.

64. The compound according to claim 63, wherein D is the residue of a biologically active compound comprising a hydroxyl group.

65. The compound of claim 64, selected from the group consisting of:

or

A pharmaceutically acceptable salt thereof.

66. The compound of claim 64, having the structure

Or a pharmaceutically acceptable salt thereof.

67. The compound of claim 39, wherein,

R^1aand R^1bAre all H;

R²is H;

R³is H; and

n is 1.

68. The compound according to claim 67, wherein D is the residue of a biologically active compound comprising a hydroxyl group.

69. The compound of claim 68, having the structure:

or

A pharmaceutically acceptable salt thereof.

70. The compound of claim 39, wherein,

R^1aand R^1bAre all H;

R²is H or-CH₂Ph；

R³Is H; and

n is 4.

71. The compound according to claim 70, wherein D is the residue of a biologically active compound comprising a hydroxyl group.

72. The compound of claim 71, selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

73. The compound of claim 41, wherein,

R^1aand R^1bAre all H;

R³is H; and

n is 0.

74. The compound according to claim 73, wherein D is the residue of a biologically active compound comprising a hydroxyl group.

75. The compound of claim 74, selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

76. The compound of claim 57, wherein,

R^1aand R^1bAre all H;

R²is H;

R³is an alkyl group;

R⁴is an alkyl group; and

n is 1.

77. The compound according to claim 76, wherein D is the residue of a biologically active compound comprising a hydroxyl group.

78. The compound of claim 77, having the structure:

or a pharmaceutically acceptable salt thereof.

79. The compound of claim 39, wherein,

R^1aand R^1bAre all H;

R²is H or-CH₂OH；

R³Is H; and

n is 6.

80. The compound according to claim 79, wherein D is the residue of a biologically active compound comprising a hydroxyl group.

81. The compound of claim 80, having the structure:

or a pharmaceutically acceptable salt thereof.

82. The compound of claim 43, wherein,

R^1aand R^1bAre all H;

R²is an alkylene group, wherein said alkylene group is further bonded to R³To form a heterocyclic group of 6 atoms;

R³is an alkylene group, wherein said alkylene group is further bonded to R²To form said 6-atom heterocyclic group; and

n is 1.

83. The compound according to claim 82, wherein D is the residue of a biologically active compound comprising a hydroxyl group.

84. The compound of claim 83, wherein the compound is

Or a pharmaceutically acceptable salt thereof.

85. The compound of claim 53, wherein the compound is

Or a pharmaceutically acceptable salt thereof.

86. The compound of claim 53, wherein the compound is

Or a pharmaceutically acceptable salt thereof.

87. The compound of claim 65, wherein the compound is

Or a pharmaceutically acceptable salt thereof.

88. The compound of claim 56, wherein the compound is

Or a pharmaceutically acceptable salt thereof.

89. The compound of claim 56, wherein the compound is

Or a pharmaceutically acceptable salt thereof.

90. A compound having the structure:

wherein the content of the first and second substances,

l is a linker;

BA is a binder;

R³is H, alkyl, alkylene, or heteroalkylene, wherein when R is ³When it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R^1aOr R²To form said 3, 4, 5, 6, 7, or 8 atom heterocyclyl;

R⁴is H or alkyl;

R⁵is O, NR⁶Or S;

R⁶is H, or alkyl;

d is the residue of a biologically active compound comprising a hydroxyl group, an amino group, or a thiol;

n is 0, 1, 2, 3, 4, 5, or 6; and

k is an integer from 1 to 30.

91. The compound according to claim 90, wherein D is the residue of an anti-inflammatory biologically active compound comprising a hydroxyl group, an amino group, or a thiol.

92. The compound of claim 91, wherein the anti-inflammatory bioactive compound is a steroid or a residue thereof.

93. The compound of claim 91, wherein the anti-inflammatory biologically active compound is an LXR agonist or a residue thereof.

94. A compound having the structure:

wherein the content of the first and second substances,

l is a linker;

BA is a binder;

R⁴is H or alkyl;

R⁵is O, NR⁶Or S;

R⁶is H, or alkyl;

d is the residue of an anti-inflammatory biologically active compound comprising a hydroxyl group, an amino group, or a thiol;

n is 0, 1, 2, 3, 4, 5, or 6; and

k is an integer from 1 to 30.

95. The compound according to claim 94, wherein D is the residue of a steroid comprising a hydroxyl group, an amino group, or a thiol.

96. A compound having the structure:

wherein the content of the first and second substances,

l is a linker, said linker comprising

BA is a binder;

R^1aand R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, alkylene, or heteroalkylene, wherein when R is^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R ³To form a heterocyclic group of 3, 4, 5, 6, 7, or 8 atoms;

R⁴is H or alkyl;

R⁵is O, NR⁶Or S;

R⁶is H, or alkyl;

n is 0, 1, 2, 3, 4, 5, or 6; and

k is an integer from 1 to 30.

97. The compound of claim 96, wherein L is a group comprising

And R, and²is H.

98. A compound having the structure:

wherein the content of the first and second substances,

l is a linker;

BA is a binder;

R⁴is H or alkyl;

R⁵is O, NR⁶Or S;

R⁶is H, or alkyl;

n is 0, 1, 2, 3, 4, 5, or 6;

wherein the coupling of L to BA is selected from the group consisting of: click chemistry residues, amide residues, and residues comprising two cysteine residues of a single BA chemically bonded to L; and

k is an integer from 1 to 30.

99. The compound of claim 90, having the structure:

wherein the content of the first and second substances,

l is a linker;

BA is a binder;

R^1aand R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, alkylene, or heteroalkylene, wherein when R is ^1aWhen it is alkylene or heteroalkylene, said alkylene or heteroalkylene is further linked to R³To form a heterocyclic group of 4, 5, or 6 atoms;

R⁴is H or alkyl;

R⁵is O, NR⁶Or S;

R⁶is H, or alkyl;

n is 0, 1, 2, 3, 4, 5, or 6; and

k is an integer from 1 to 30.

100. The compound of claim 99, having the structure

Wherein the content of the first and second substances,

l is a linker;

BA is a binder;

R^1aand R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, or alkylene, wherein when R is^1aWhen alkylene, the alkylene is further bonded to R ³To form a heterocyclic group of 4, 5, or 6 atoms;

R²is H, or an amino acid side chain;

d is the residue of a biologically active compound comprising a hydroxyl group;

n is 0, 1, 2, 3, 4, 5, or 6; and

k is an integer from 1 to 30.

101. The compound of claim 99, having the structure:

wherein the content of the first and second substances,

l is a linker;

BA is a binder;

R^1aand R^1bEach independently is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, or aryleneAlkyl, wherein when R^1aWhen alkylene, the alkylene is further bonded to R³To form a heterocyclic group of 4, 5, or 6 atoms;

R²is H, or an amino acid side chain;

d is the residue of a biologically active compound comprising a hydroxyl group;

n is 0, 1, 2, 3, 4, 5, or 6; and

k is an integer from 1 to 30.

102. The compound of any of claims 90-101, wherein the linker comprises

103. The compound of claim 99, wherein the compound is

Wherein the content of the first and second substances,

SP¹and SP²When present, are spacer groups, wherein SP¹Further comprising a moiety reactive with the antibody or antigen-binding fragment thereof;

each AA is an amino acid; and

p is an integer from 1 to 10.

104. The compound of claim 103, wherein SP¹Comprising a reactive group comprising an alkyne.

105. The compound of claim 104, wherein the alkyne is capable of participating in a 1, 3-cycloaddition reaction.

106. The compound of claim 105, wherein the alkyne is capable of participating in a 1, 3-cycloaddition reaction with the binding agent, wherein the binding agent is an azido-functionalized binding agent.

107. The compound of claim 103, wherein SP²Included

108. The compound of claim 103, wherein SP²Included

And R²Is H or alkyl.

109. The compound of claim 106, wherein the alkyne can participate in a 1, 3-cycloaddition reaction with the binding agent, the binding agent is an azido-functionalized binding agent, and SP²Included

110. The compound of claim 106, wherein the alkyne can participate in a 1, 3-cycloaddition reaction with the binding agent which is an azido-functionalized binding agent, SP ²Included

And R²Is H or alkyl.

111. The compound of claim 103, wherein the binding agent is according to formula H₂A primary amine compound-modified antibody of N-LL-X, wherein LL is a divalent linker selected from the group consisting of:

a divalent polyethylene glycol (PEG) group;

–(CH₂)_n–；

–(CH₂CH₂O)_n-(CH₂)_p–；

–(CH₂)_n-N(H)C(O)-(CH₂)_m–；

–(CH₂CH₂O)_n-N(H)C(O)-(CH₂CH₂O)_m-(CH₂)_p–；

–(CH₂)_n-C(O)N(H)-(CH₂)_m–；

–(CH₂CH₂O)_n-C(O)N(H)-(CH₂CH₂O)_m-(CH₂)_p–；

–(CH₂)_n-N(H)C(O)-(CH₂CH₂O)_m-(CH₂)_p–；

–(CH₂CH₂O)_n-N(H)C(O)-(CH₂)_m–；

–(CH₂)_n-C(O)N(H)-(CH₂CH₂O)_m-(CH₂)_p-; and

–(CH₂CH₂O)_n-C(O)N(H)-(CH₂)_m–，

wherein

n is an integer selected from 1 to 12;

m is an integer selected from 0 to 12;

p is an integer selected from 0 to 2; and

112. The compound of claim 111, wherein the binding agent is an antibody modified with a primary amine, the primary amine having the structure:

113. the compound of claim 112, wherein the compound is selected from the group consisting of:

wherein k is 1, 2, 3, or 4.

114. The compound of claim 90, wherein the compound is selected from the group consisting of:

wherein z is 1, 2, 3, or 4.

115. An antibody-drug conjugate comprising an antibody, or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof is conjugated to the compound of claim 2 or 39.

116. The antibody-drug conjugate of claim 115, wherein the conjugated compound is selected from the group consisting of:

117. The compound of claim 99, wherein BA is an antibody, or antigen-binding fragment thereof.

118. The compound of claim 117, wherein BA is a transglutaminase modified antibody, or antigen-binding fragment thereof, comprising at least one glutamine residue for conjugation.

119. The compound of claim 117, wherein BA is a transglutaminase modified antibody, or antigen-binding fragment thereof, comprising at least two glutamine residues for conjugation.

120. The compound of claim 117, wherein BA is a transglutaminase modified antibody, or antigen-binding fragment thereof, comprising at least four glutamine residues for conjugation.

121. The compound of claim 120, wherein BA is a transglutaminase modified antibody, or antigen-binding fragment thereof, wherein conjugation is at two Q295 residues; and k is 2.

122. The compound of claim 120, wherein BA is a transglutaminase modified antibody, or antigen-binding fragment thereof, wherein conjugation is at two Q295 residues and two N297Q residues; and k is 4.

123. A pharmaceutical composition comprising a compound of any one of the preceding claims, and a pharmaceutically acceptable adjuvant, carrier, or diluent.

124. A method of treating a disease, disorder or condition associated with glucocorticoid receptor signaling in a subject, comprising administering to the subject an effective amount of a compound or pharmaceutical composition of any one of the preceding claims.

125. The method of claim 124, wherein the disease, disorder, or condition is an inflammatory disease, disorder, or condition.

126. The method of claim 124 or 125, wherein side effects associated with administering the unconjugated steroid payload of the compound are reduced.

127. A method of treating dyslipidemia, a metabolic disease, inflammation, or a neurodegenerative disease in a subject, comprising administering to the subject an effective amount of a compound or pharmaceutical composition of any of the preceding claims.

128. A method of treating dyslipidemia in a subject, comprising administering to the subject an effective amount of a compound or pharmaceutical composition according to any of the preceding claims.

129. A method of treating a metabolic disease in a subject, comprising administering to the subject an effective amount of a compound or pharmaceutical composition of any of the preceding claims.

130. A method of treating inflammation in a subject, comprising administering to the subject an effective amount of a compound or pharmaceutical composition of any one of the preceding claims.

131. A method of treating a neurodegenerative disease in a subject comprising administering to the subject an effective amount of a compound or pharmaceutical composition of any one of the preceding claims.

132. A method of making an antibody-drug conjugate comprising contacting a binding agent with the compound of claim 39.

133. The compound of claim 2, having the structure: