# US 2021/0277056 A1 · Compositions containing, methods involving, and uses of non-natural amino acid linked dolastatin derivatives

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- Number: US 2021/0277056 A1
- Document ID: US20210277056A1
- Status: Published application
- Kind: A1
- Application number: 17/142,169
- Filed: 2021-01-05
- Published: 2021-09-09
- Earliest claimed: 2011-05-27
- Assignees: Ambrx, Inc.
- Applicants: Ambrx, Inc.
- Inventors: Zhenwei MIAO; Kyle ATKINSON; Sandra BIROC; Timothy BUSS; Melissa NEAL; Vadim KRAYNOV; Robin MARSDEN; Jason PINKSTAFF; Lillian SKIDMORE; Ying SUN; Agnieszka SZYDLIK; Delia Ianina LOPEZ DE VALENTA
- Web page: https://patentgrep.com/patent/US20210277056A1

## CPC

- A61K 38/07: Tetrapeptides
- A61K 47/68031: {the drug being an auristatin}
- A61K 47/6817: {Toxins}
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6855: {the tumour determinant being from breast cancer cell}
- A61K 47/6861: {the tumour determinant being from kidney or bladder cancer cell}
- A61P 35/00: Antineoplastic agents
- C07D 207/08: with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07K 5/0205: {containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof}
- C07K 5/101: {the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu}
- C07K 5/06043: {Leu-amino acid}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

Disclosed herein are non-natural amino acids and dolastatin analogs that include at least one non-natural amino acid, and methods for making such non-natural amino acids and polypeptides. The dolastatin analogs can include a wide range of possible functionalities, but typically have at least one oxime, carbonyl, dicarbonyl, and/or hydroxylamine group. Also disclosed herein are non-natural amino acid dolastatin analogs that are further modified post-translationally, methods for effecting such modifications, and methods for purifying such dolastatin analogs. Typically, the modified dolastatin analogs include at least one oxime, carbonyl, dicarbonyl, and/or hydroxylamine group. Further disclosed are methods for using such non-natural amino acid dolastatin analogs and modified non-natural amino acid dolastatin analogs, including therapeutic, diagnostic, and other biotechnology use.

## Claims

### Claim 1

A compound, or salt thereof, comprising Formula (I):
wherein:
Z has the structure of:
R5 is H, COR8, C1-C6alkyl, or thiazole;
R8 is OH or —NH-(alkylene-O)n—NH2;
R6 is OH or H;
Ar is phenyl or pyridine;
R7 is C1-C6alkyl or hydrogen;
Y and V are each selected from the group consisting of an hydroxylamine, methyl, aldehyde, protected aldehyde, ketone, protected ketone, thioester, ester, dicarbonyl, hydrazine, amidine, imine, diamine, azide, keto-amine, keto-alkyne, alkyne, cycloalkyne, and ene-dione;
L is a linker selected from the group consisting of -alkylene-, -alkylene-C(O)—, -(alkylene-O)n-alkylene-, -(alkylene-O)n-alkylene-C(O)—,-(alkylene-O)n—(CH2)n′-NHC(O) (CH2)n″—C(Me)2-S—S—(CH2)n′″—NHC(O)n-(alkylene-O)n″″-alkylene-, -(alkylene-O)n-alkylene-W-, -alkylene-C(O)—W-, -(alkylene-O)n-alkylene-U-alkylene-C(O)—, and -(alkylene-O)n-alkylene-U-alkylene-;
W has the structure of:
U has the structure of:
or L is absent, Y is methyl, R5 is COR8, and R8 is —NH-(alkylene-O)n NH2; and
each n, n′, n″, n′″ and n″″ are independently integers greater than or equal to one.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R5 is thiazole.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R6 is H.

### Claim 4 (depends on 1)

The compound of claim 1, wherein Ar is phenyl.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R7 is methyl.

### Claim 6 (depends on 1)

The compound of claim 1, where n is an integer from 0 to 20.

### Claim 7 (depends on 1)

The compound of claim 1, where n is an integer from 0 to 10.

### Claim 8 (depends on 1)

The compound of claim 1, where n is an integer from 0 to 5.

### Claim 9 (depends on 1)

The compound of claim 1, wherein Y is cyclooctyne.

### Claim 10 (depends on 9)

The compound of claim 9, wherein the cyclooctyne has a structure of:
each R19 is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, ester, ether, thioether, aminoalkyl, halogen, alkyl ester, aryl ester, amide, aryl amide, alkyl halide, alkyl amine, alkyl sulfonic acid, alkyl nitro, thioester, sulfonyl ester, halosulfonyl, nitrile, alkyl nitrile, and nitro; and
q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11.

### Claim 11 (depends on 1)

The compound of claim 1, wherein Y is azide.

### Claim 12 (depends on 1)

The compound of claim 1, comprising Formula (II):

### Claim 13 (depends on 12)

The compound of claim 12, wherein L is -(alkylene-O)n-alkylene-.

### Claim 14 (depends on 13)

The compound of claim 13, wherein each alkylene is CH2CH2, n is equal to 3, and R7 is methyl.

### Claim 15 (depends on 12)

The compound of claim 12, wherein L is -alkylene-.

### Claim 16 (depends on 15)

The compound of claim 15, wherein each alkylene is —CH2CH2— and R7 is methyl or hydrogen.

### Claim 17 (depends on 12)

The compound of claim 12, wherein L is -(alkylene-O)n-alkylene C(O)—.

### Claim 18 (depends on 17)

The compound of claim 17, wherein each alkylene is —CH2CH2—, n is equal to 4, and R7 is methyl.

### Claim 19 (depends on 12)

The compound of claim 12, wherein L is -(alkylene-O)n—(CH2)n′—NHC(O)—(CH2)n″—C(Me)2-S—S—(CH2)n′″—NHC(O)-(alkylene-O)n″″-alkylene-.

### Claim 20 (depends on 19)

The compound of claim 19, wherein each alkylene is -CH2CH2-, n is equal to 1, n′ is equal to 2, n″ is equal to 1, n′″ is equal to 2, n″″ is equal to 4, and R7 is methyl.

### Claim 21

A compound, or salt thereof, comprising Formula (III), (IV), (V) or (VI):
wherein:
Z has the structure of:
R5 is H, COR8, C1-C6alkyl, or thiazole;
R8 is OH;
R6 is OH or H;
Ar is phenyl or pyridine;
R7 is C1-C6alkyl or hydrogen;
Y and V are each selected from the group consisting of an hydroxylamine, methyl, aldehyde, protected aldehyde, ketone, protected ketone, thioester, ester, dicarbonyl, hydrazine, amidine, imine, diamine, azide, keto-amine, keto-alkyne, alkyne, cycloalkyne, and ene-dione;
L1, L2, L3, and L4 are each linkers independently selected from the group consisting of a bond, -alkylene-, (alkylene-O)n-alkylene-J-, -alkylene′-J-(alkylene-O)n-alkylene-, -J-(alkylene-O)n-alkylene-, -(alkylene-O)n-alkylene-J-(alkylene-O)n′-alkylene-J′-, -(alkylene-O)n-alkylene-J-alkylene′-, -W-, -alkylene-W-, alkylene′-J-(alkylene-NMe)n-alkylene-W-, -J-(alkylene-NMe)n-alkylene-W-, -J-alkylene-NMe-alkylene′-NMe-alkylene″-W-, and -alkylene-J-alkylene′-NMe-alkylene″-NMe-alkylene′″-W-;
W has the structure of:
each J and J′ independently have the structure of:
and
each n and n′ are independently integers greater than or equal to one.

### Claim 22 (depends on 21)

The compound of claim 21, comprising Formula (VII):

### Claim 23 (depends on 22)

The compound of claim 22, wherein L1 is -(alkylene-O)n-alkylene-J-, L2 is -alkylene′-J′-(alkylene-O)n′ alkylene-, L3 is -J″-(alkylene-O)n″-alkylene-, alkylene is —CH2CH2-, alkylene′ is —(CH2)4—, n is 1, n′ and n″ are 3, J has the structure of
J′ and J″ have the structure of
and R7 is methyl.

### Claim 24 (depends on 22)

The compound of claim 22, comprising Formula (IV) wherein L1 is -J-(alkylene-O)n-alkylene, L2 is -(alkylene-O)n′-alkylene-J′-alkylene′-, L3 is -(alkylene-O)n″, alkylene-J″-, alkylene is —CH2CH2—, alkylene′ is —(CH2)4— n is 1, n′ and n″ are 4, and J, J′ and J″ have the structure of

### Claim 25

A compound comprising Formula (VIII) or (IX):
wherein:
A is optional, and when present is lower alkylene, substituted lower alkylene, lower cycloalkylene, substituted lower cycloalkylene, lower alkenylene, substituted lower alkenylene, alkynylene, lower heteroalkylene, substituted heteroalkylene, lower heterocycloalkylene, substituted lower heterocycloalkylene, arylene, substituted arylene, heteroarylene, substituted heteroarylene, alkarylene, substituted alkarylene, aralkylene, or substituted aralkylene;
B is optional, and when present is a linker selected from the group consisting of lower alkylene, substituted lower alkylene, lower alkenylene, substituted lower alkenylene, lower heteroalkylene, substituted lower heteroalkylene, —O—, —O-(alkylene or substituted alkylene)-, —S—, —S-(alkylene or substituted alkylene)-, —S(O)k— where k is 1, 2, or 3, —S(O)k(alkylene or substituted alkylene)-, —C(O)—, —C(O)-(alkylene or substituted alkylene)-, —C(S)—, —C(S)-(alkylene or substituted alkylene)-, —N(R′)—, —NR′-(alkylene or substituted alkylene)-, —C(O)N(R′)—, —CON(R′)-(alkylene or substituted alkylene)-, —CSN(R′)—, —CSN(R′)-(alkylene or substituted alkylene)-, —N(R′)CO-(alkylene or substituted alkylene)-, —N(R′)C(O)O—, —S(O)kN(R′), —N(R′)C(O)N(R′)—, —N(R′)C(S)N(R′), —N(R′)S(O)kN(R′)—, —N(R′)—N═, —C(R′)═N—, —C(R′)═N—N(R′)—, —C(R′)═N—N═, —C(R′)2—N═N—, and —C(R′)2—N(R′)—N(R′)—, where each R′ is independently H, alkyl, or substituted alkyl;
R is H, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl;
R1 is H, an amino protecting group, resin, at least one amino acid, polypeptide, or polynucleotide;
R2 is OH, an ester protecting group, resin, at least one amino acid, polypeptide, or polynucleotide;
R3 and R4 are each independently H, halogen, lower alkyl, or substituted lower alkyl, or R3 and R4 or two R3 groups optionally form a cycloalkyl or a heterocycloalkyl;
Z has the structure of:
R5 is H, COR8, C1-C6alkyl, or thiazole;
R8 is OH;
R6 is OH or H;
Ar is phenyl or pyridine;
R7 is C1-C6alkyl or hydrogen;
L is a linker selected from the group consisting of -alkylene-, -alkylene-C(O)—, -(alkylene-O)n-alkylene-, (alkylene-O)n-alkylene-C(O)—, -(alkylene -O)n—(CH2)n′-NHC(O)—(CH2)n″-C(Me)2-S-S-(CH2)n′″-NHC(O)-(alkylene-O)n″″-alkylene-, -(alkylene-O)n-alkylene-W-, -alkylene-C(O)—W-, -(alkylene-O)n-alkylene-U-alkylene-C(O)-, and -(alkylene-O)n-alkylene-U-alkylene-;
W has the structure of;
U has the structure of:
and
each n, n′, n″, n′″ and n″″ are independently integers greater than or equal to one;
or an active metabolite, or a pharmaceutically acceptable prodrug or solvate thereof.

### Claim 26 (depends on 25)

The compound of claim 25, wherein R1 is a polypeptide.

### Claim 27 (depends on 26)

The compound of claim 26, wherein the polypeptide is an antibody.

### Claim 28 (depends on 27)

The compound of claim 27, wherein the antibody is herceptin.

### Claim 29 (depends on 25)

The compound of claim 25, wherein R2 is a polypeptide.

### Claim 30 (depends on 29)

The compound of claim 29, wherein the polypeptide is an antibody.

### Claim 31 (depends on 30)

The compound of claim 30, wherein the antibody is herceptin.

### Claim 32

The compound, or salt thereof, comprising Formula (X), (XI), (XII) or (XIII):
wherein:
A is optional, and when present is lower alkylene, substituted lower alkylene, lower cycloalkylene, substituted lower cycloalkylene, lower alkenylene, substituted lower alkenylene, alkynylene, lower heteroalkylene, substituted heteroalkylene, lower heterocycloalkylene, substituted lower heterocycloalkylene, arylene, substituted arylene, heteroarylene, substituted heteroarylene, alkarylene, substituted alkarylene, aralkylene, or substituted aralkylene;
B is optional, and when present is a linker selected from the group consisting of lower alkylene, substituted lower alkylene, lower alkenylene, substituted lower alkenylene, lower heteroalkylene, substituted lower heteroalkylene, —O—, —O-(alkylene or substituted alkylene)-, —S—, —S-(alkylene or substituted alkylene)-, —S(O)k— where k is 1, 2, or 3, —S(O)k(alkylene or substituted alkylene)-, —C(O)—, —C(O)-(alkylene or substituted alkylene)-, —C(S)—, —C(S)-(alkylene or substituted alkylene)-, —N(R′)-, —NR′-(alkylene or substituted alkylene)-, —C(O)N(R′)—, —CON(R′)-(alkylene or substituted alkylene)-, —CSN(R′)—, —CSN(R′)-(alkylene or substituted alkylene)-, —N(R′)CO-(alkylene or substituted alkylene)-, —N(R′)C(O)O—, —S(O)kN(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(S)N(R′)—, —N(R′)S(O)kN(R′)—N(R′)—N═, -C(R′)═N—, -C(R′)═N—N(R′)—, -C(R′)═N-N═, -C(R′)2-N═N—, and —C(R′)2-N(R′)—N(R′)—, where each R′ is independently H, alkyl, or substituted alkyl;
R is H, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl;
R1 is H, an amino protecting group, resin, at least one amino acid, polypeptide, or polynucleotide;
R2 is OH, an ester protecting group, resin, at least one amino acid, polypeptide, or polynucleotide;
R3 and R4 are each independently H, halogen, lower alkyl, or substituted lower alkyl, or R3 and R4 or two R3 groups optionally form a cycloalkyl or a heterocycloalkyl;
Z has the structure of:
R5 is H, CO2H, C1-C6alkyl, or thiazole;
R6 is OH or H;
Ar is phenyl or pyridine;
R7 is C1-C6alkyl or hydrogen;
L1, L2, L3, and L4 are each linkers independently selected from the group consisting of a bond, -alkylene-, -(alkylene-O)n-alkylene-J-, -alkylene′-J-(alkylene-O)n-alkylene-, -J-(alkylene-O)n-alkylene-, -(alkylene-O)n-alkylene-J-(alkylene-O)n′-alkylene J′-, -(alkylene-O)n-alkylene-J-alkylene′-, -W-, -alkylene-W-, alkylene′-J-(alkylene-NMe)n-alkylene-W-, -J-(alkylene-NMe)n-alkylene-W-, -J-alkylene-NMe-alkylene′-NMe-alkylene″-W-, and alkylene-J-alkylene′-NMe-alkylene″-NMe-alkylene′″, -W-;
W has the structure of:
each J and J′ independently have the structure of;
and
each n and n′ are independently integers greater than or equal to one.

### Claim 33 (depends on 32)

The compound of claim 32, wherein R1 is a polypeptide.

### Claim 34 (depends on 33)

The compound of claim 33, wherein the polypeptide is an antibody.

### Claim 35 (depends on 34)

The compound of claim 34, wherein the antibody is herceptin.

### Claim 36 (depends on 32)

The compound of claim 32, wherein R2 is a polypeptide.

### Claim 37 (depends on 36)

The compound of claim 36, wherein the polypeptide is an antibody.

### Claim 38 (depends on 37)

The compound of claim 37, wherein the antibody is herceptin.

### Claim 39

A method for derivatizing a dolastatin analog comprising Formula (I), (III), (IV), (V), or (VI), the method comprising contacting the dolastatin analog with a reagent of Formula (XXXVII), wherein Formula (I), (III), (IV), (V), or (VI) correspond to:
wherein:
Z has the structure of:
R5 is H, COR8, C1-C6alkyl, or thiazole;
R8 is OH or —NH-(alkylene-O)n—NH2;
R6 is OH or H;
Ar is phenyl or pyridine;
R7 is C1-C6 alkyl or hydrogen;
Y is NH2—O— or methyl;
L, L1, L2, L3, and L4 are each linkers selected from the group consisting of a bond, -alkylene-, -alkylene-C(O)—, -(alkylene-O)n-alkylene-, -(alkylene-O)n-alkylene-C(O)—, -(alkylene-O)n—(CH2)n′-NHC(O)—(CH2)n″—C(Me)2-S-S-CH2)n′″-NHC(O)-(alkylene-O)n″″-alkylene-, -(alkylene-O)n-alkylene-W-, -alkylene-C(O)-W-, (alkylene-O)n-alkylene-J-, -alkylene′-J-(alkylene-O)n-alkylene-, -(alkylene-O)n-alkylene-J-alkylene′, -J-(alkylene-O)n-alkylene-, -(alkylene-O)n-alkylene-J-(alkylene-O)n′-alkylene-J′-, -W-, -alkylene-W-, alkylene′-J-(alkylene-NMe)n-alkylene-W-, and J-(alkylene-NMe)n-alkylene-W-, -(alkylene-O)n-alkylene-U-alkylene-C(O)-, -(alkylene-O)n-alkylene-U-alkylene-; -J-alkylene-NMe-alkylene′-NMe-alkylene″-W-, and -alkylene-J-alkylene′-NMe-alkylene″-NMe-alkylene′″-W-;
W has the structure of:
U has the structure of:
each J and J′ independently have the structure of:
or L is absent, Y is methyl, R5 is COR8, and R8 is —NH-(alkylene-O)n—NH2; and
each n, n′, n″, n′″ and n″″ are independently integers greater than or equal to one;
wherein Formula (XXXVII) corresponds to:
wherein:
A is optional, and when present is lower alkylene, substituted lower alkylene, lower alkenylene, substituted lower alkenylene, arylene, substituted arylene, heteroarylene, substituted heteroarylene, alkarylene, substituted alkarylene, aralkylene, or substituted aralkylene;
B is optional, and when present is a linker selected from the group consisting of lower alkylene, substituted lower alkylene, lower alkenylene, substituted lower alkenylene, —O—, —O-(alkylene or substituted alkylene)-, —S—, —S-(alkylene or substituted alkylene)-, —S(O)k— where k is 1, 2, or 3, —S(O)k(alkylene or substituted alkylene)-, —C(O)—, —C(O)-(alkylene or substituted alkylene)-, —C(S)—, —C(S)-(alkylene or substituted alkylene)-, —N(R′)—, —NR′-(alkylene or substituted alkylene)-, —C(O)N(R′)—, —CON(R′)-(alkylene or substituted alkylene)-, —CSN(R′)—, —CSN(R′)-(alkylene or substituted alkylene)-, —N(R′)CO-(alkylene or substituted alkylene)-, —N(R′)C(O)O—, —S(O)kN(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(S)N(R′)—, —N(R′)S(O)kN(R′)—, —N(R′)—N═, —C(R′)═N—, —C(R′)═N—N(R′)—, —C(R′)═N-N═, —C(R′)2-N═N—, and —C(R′)2-N(R′)—N(R′)—, where each R′ is independently H, alkyl, or substituted alkyl;
each R′ is independently H, alkyl, or substituted alkyl;
K is
R is H, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl;
R1 is H, an amino protecting group, resin, at least one amino acid, or polynucleotide;
R2 is OH, an ester protecting group, resin, at least one amino acid, or polynucleotide; and
R3 and R4 are each independently H, halogen, lower alkyl, or substituted lower alkyl, or R3 and R4 or two R3 groups optionally form a cycloalkyl or a heterocycloalkyl.

### Claim 40 (depends on 39)

The method of claim 39, wherein the derivatized dolastatin analog comprises at least one oxime containing amino acid having the structure of Formula (VIII), (IX), (X), (XI), (XII), or (XIII):

### Claim 41 (depends on 39)

The method of claim 39, wherein the dolastatin analog is contacted with the reagent of Formula (XXXVII) in aqueous solution under mildly acidic conditions.

### Claim 42

A compound comprising Formula (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), or (XXX):
wherein:
Z has the structure of:
R5 is H, CO2H, C1-C6alkyl, or thiazole;
R6 is OH or H;
Ar is phenyl or pyridine;
R1 is H, an amino protecting group, resin, at least one amino acid, polypeptide, or polynucleotide;
R2 is OH, an ester protecting group, resin, at least one amino acid, polypeptide, or polynucleotide;
R4 is H, halogen, lower alkyl, or substituted lower alkyl;
R7 is C1-C6alkyl or hydrogen;
L, L1, L2, L3, and L4 are each linkers selected from the group consisting of a bond, -alkylene-, -alkylene-C(O)—, -alkylene-J-, -(alkylene-O)n-alkylene-, -(alkylene-O)n-alkylene-C(O)—, -(alkylene-O)n-J-, -(alkylene-O)n-J-alkylene, -(alkylene-O)n—(CH2)n′—NHC(O)—(CH2)n″-C(Me)2-S-S-(CH2)n′″-NHC(O)-(alkylene-O)n″″-alkylene-, -(alkylene-O)n-alkylene-W-, -alkylene-C(O)—W-, -(alkylene-O)n-alkylene-J-, -alkylene′-J-(alkylene-O)n-alkylene-, -(alkylene-O)n-alkylene-J-alkylene′, -J-(alkylene-O)n-alkylene-, -(alkylene-O)n-alkylene-J-(alkylene-O)n′-alkylene-J′-, -W-, -alkylene-W-, alkylene′-J-(alkylene-NMe)n-alkylene-W-, -J-(alkylene-NMe)n-alkylene-W-, -(alkylene-O)n-alkylene-U-alkylene-C(O)-, -(alkylene-O)n-alkylene-U-alkylene-; -J-alkylene-NMe-alkylene′-NMe-alkylene″-W-, and -alkylene-J-alkylene′-NMe-alkylene″, -NMe-alkylene′″-W-;
W has the structure of:
U has the structure of:
each J and J′ independently have the structure of:
each n and n′ are independently integers greater than or equal to one; and
each R16 is independently selected from the group consisting of hydrogen, halogen, alkyl, NO2, CN, and substituted alkyl.

### Claim 43 (depends on 42)

The compound of claim 42, wherein R1 is a polypeptide.

### Claim 44 (depends on 43)

The compound of claim 43, wherein the polypeptide is an antibody.

### Claim 45 (depends on 44)

The compound of claim 44, wherein the antibody is herceptin.

### Claim 46 (depends on 42)

The compound of claim 42, wherein R2 is a polypeptide.

### Claim 47 (depends on 46)

The compound of claim 46, wherein the polypeptide is an antibody.

### Claim 48 (depends on 47)

The compound of claim 47, wherein the antibody is herceptin.

### Claim 49

A compound comprising Formula (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI):
wherein:
Z has the structure of:
R5 is H, CO2H, C1-C6alkyl, or thiazole;
R6 is OH or H;
Ar is phenyl or pyridine;
R1 is H, an amino protecting group, resin, at least one amino acid, polypeptide, or polynucleotide;
R2 is OH, an ester protecting group, resin, at least one amino acid, polypeptide, or polynucleotide;
R4 is H, halogen, lower alkyl, or substituted lower alkyl;
R7 is C1-C6alkyl or hydrogen;
L, L1, L2, L3, and L4 are each linkers selected from the group consisting of a bond, -alkylene-, -alkylene-C(O)—, -alkylene-J-, -(alkylene-O)n-alkylene-, -(alkylene-O)n-alkylene C(O)-, -(alkylene-O)n-J-, -(alkylene-O)n-J-alkylene, (alkylene-O)n-(CH2)n′ NHC(O)—(CH2)n″-C(Me)2-S—S—(CH2)n′″-NHC(O)-(alkylene-O)n″″-alkylene-, -(alkylene-O)n-alkylene-W-, -alkylene-C(O)-W-, -(alkylene-O)n-alkylene-J-, -alkylene′-J-(alkylene-O)n-alkylene-, -(alkylene-O)n-alkylene-J-alkylene′, -J-(alkylene-O)n-alkylene-, -(alkylene-O)n-alkylene-J-(alkylene-O)n′-alkylene-J′-, -W-, -alkylene-W-, alkylene′-J-(alkylene-NMe)n-alkylene W-, -J-(alkylene-NMe)n-alkylene-W-, -(alkylene-O)n-alkylene-U-alkylene-C(O)-, -(alkylene-O)n-alkylene-U-alkylene-; -J-alkylene-NMe-alkylene′-NMe-alkylene″-W-, and -alkylene-J-alkylene′-NMe-alkylene″-NMe-alkylene′″-W-;
U has the structure of:
each J and J′ independently have the structure of:
each n and n′ are independently integers greater than or equal to one;
D has the structure of:
each R17 is independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkylalkoxy, substituted alkylalkoxy, polyalkylene oxide, substituted polyalkylene oxide, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl, substituted aralkyl, -(alkylene or substituted alkylene)-ON(R″)2-(alkylene or substituted alkylene)-C(O)SR″, -(alkylene or substituted alkylene)-S-S-(aryl or substituted aryl), —C(O)R″, —C(O)2R″, or —C(O)N(R″)2, wherein each R″ is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl;
each Z1 is a bond, CR17R17, O, S, NR′, CR17R17—CR17R17, CR17R17-O, O—CR17R17, CR17R17—S, S—CR17R17, CR17R17—NR′, or NR′—CR17R17;
each R′ is H, alkyl, or substituted alkyl;
each Z2 is selected from the group consisting of a bond, —C(O)—, —C(S)—, optionally substituted C1-C3 alkylene, optionally substituted C1-C3 alkenylene, and optionally substituted heteroalkyl;
each Z3 are independently selected from the group consisting of a bond, optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted heteroalkyl, —O—, —S—, —C(O)—, —C(S)—, and —N(R′)—;
each T3 is a bond, C(R″)(R″), O, or S; with the proviso that when T3 is O or S, R″ cannot be halogen;
each R″ is H, halogen, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl;
m and p are 0, 1, 2, or 3, provided that at least one of m or p is not 0;
M2 is
where (a) indicates bonding to the B group and (b) indicates bonding to respective positions within the heterocycle group;
M3 is
where (a) indicates bonding to the B group and (b) indicates bonding to respective positions within the heterocycle group;
M4 is
where (a) indicates bonding to the B group and (b) indicates bonding to respective positions within the heterocycle group;
each R19 is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, ester, ether, thioether, aminoalkyl, halogen, alkyl ester, aryl ester, amide, aryl amide, alkyl halide, alkyl amine, alkyl sulfonic acid, alkyl nitro, thioester, sulfonyl ester, halosulfonyl, nitrile, alkyl nitrile, and nitro;
q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; and
each R16 is independently selected from the group consisting of hydrogen, halogen, alkyl, NO2-, CN, and substituted alkyl.

### Claim 50 (depends on 49)

The compound of claim 49, wherein R1 is a polypeptide.

### Claim 51 (depends on 50)

The compound of claim 50, wherein the polypeptide is an antibody.

### Claim 52 (depends on 51)

The compound of claim 51, wherein the antibody is herceptin.

### Claim 53 (depends on 49)

The compound of claim 49, wherein R2 is a polypeptide.

### Claim 54 (depends on 53)

The compound of claim 53, wherein the polypeptide is an antibody.

### Claim 55 (depends on 54)

The compound of claim 54, wherein the antibody is herceptin.

### Claim 56 (depends on 49)

The compound of claim 49, comprising Formula (XXXI-A):

### Claim 57 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56)

A pharmaceutical composition comprising a compound of any of claims 1-38 and 42-56 and a pharmaceutically acceptable carrier, excipient, or binder.