# US 11,993,625 B2 · Calicheamicin derivatives and antibody drug conjugates thereof

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- Number: US 11,993,625 B2
- Document ID: US11993625B2
- Status: Granted
- Kind: B2
- Application number: 16/477,290
- Filed: 2018-01-10
- Published: 2019-11-14
- Granted: 2024-05-28
- Earliest claimed: 2017-01-24
- Assignees: Pfizer Inc.
- Applicants: Pfizer Inc.
- Inventors: Omar Khaled Ahmad; Stephen Paul Brown; Kenneth John Dirico; Russell Dushin; Gary Frederick Filzen; Sujiet Puthenveetil; Pavel Strop; Chakrapani Subramanyam; Lawrence N. Tumey
- Web page: https://patentgrep.com/patent/US11993625B2

## CPC

- A61K 47/6867: {the tumour determinant being from a cell of a blood cancer}
- C07H 15/26: Acyclic or carbocyclic radicals, substituted by hetero rings
- A61K 47/6807: {the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense}
- A61P 35/00: Antineoplastic agents
- C07H 15/00: Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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)
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention is directed to novel calicheamicin derivatives useful as payloads in antibody-drug-conjugates (ADC's), and to payload-linker compounds and ADC compounds comprising the same; to pharmaceutical compositions comprising the same and to methods for using the same to treat pathological conditions such as cancer.

## Claims

### Claim 1

A compound of Formula (IIA):
or a pharmaceutically acceptable salt thereof,
wherein:
R3 is selected from the group consisting of —CH3, —CH2CH3, and —CH(CH3)2;
X is selected from the group consisting of:
(i) —CH3 optionally substituted by one R10;
(ii) —C2-C8alkyl optionally substituted by one R10;
(iii) —(C0-C6alkyl)-C3-C10 carbocyclyl,
wherein said C3-C10 carbocyclyl is optionally substituted by one R10;
(iv) —(C0-C6alkyl)-3 to 10 membered heterocyclyl,
wherein said 3 to 10 membered heterocyclyl is optionally substituted by one R10, and
wherein said 3 to 10 membered heterocyclyl comprises one, two or three heteroatoms independently selected from the group consisting of N, O and S;
(v) —(C0-C6alkyl)-phenyl,
wherein said phenyl is optionally substituted by one R10; and
(vi) —(C0-C6alkyl)-5 to 10 membered heteroaryl,
wherein said 5 to 10 membered heteroaryl is optionally substituted by one R10, and
wherein said 5 to 10 membered heteroaryl comprises one, two or three heteroatoms independently selected from the group consisting of N, O and S;
and which X is optionally further substituted by 1, 2, 3, 4, 5, 6, 7, or 8 G;
R10 is —R10a-R10b, wherein
R10a is either absent or —(CH2)n—, which R10a is optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 G;
R10b is selected from the group consisting of:
(i) —OH;
(ii) —CN;
(iii) —PO3H;
(iv) —CO2H;
(v) —CO2C1-C4alkyl,
wherein said C1-C4alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 E;
(vi) —CO—R11;
(vii) —NH—R11;
(viii) —N(C1-C4alkyl)-R11,
wherein said C1-C4alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 E;
(ix) —CONN—R11;
(x) —CON(C1-C4alkyl)-R11,
wherein said C1-C4alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 E;
(xi) —CONHNH—R11;
(xii) —CONHN(C1-C4alkyl)-R11,
wherein said C1-C4alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 E;
(xiii) —CON(C1-C4alkyl)NH—R11,
wherein said C1-C4alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 E;
(xiv) —CON(C1-C4alkyl)N(C1-C4alkyl)-R11,
wherein each said C1-C4alkyl is independently optionally substituted by 1, 2, 3, 4, 5, or 6 E;
(xv) —CON(R11)NH2;
(xvi) —CON(R11)NH(C1-C4alkyl),
wherein said C1-C4alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 E;
(xvii) —CON(R11)N(C1-C4alkyl)2,
wherein each said C1-C4alkyl is independently optionally substituted by 1, 2, 3, 4, 5, or 6 E;
(xviii) —CONHN═C(C1-C4alkyl)-C6H4-OC1-C4alkyl,
wherein each said C1-C4alkyl is independently optionally substituted by 1, 2, 3, 4, 5, or 6 E;
(xix) —CON(C1-C4alkyl)N═C(C1-C4alkyl)-C6H4-OC1-C4alkyl,
wherein each said C1-C4alkyl is independently optionally substituted by 1, 2, 3, 4, 5, or 6 E;
(xx) —N(R11)CO(C1-C4alkyl),
wherein said C1-C4alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 E;
(xxi) —CH(CO2H)NH—R11;
(xxii) —CH(CO2C1-C4alkyl)NH—R11,
wherein said C1-C4alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 E;
(xxiii) —CH(NH2)CO—R11;
(xxiv) —CH(NH(C1-C4alkyl))CO—R11,
wherein said C1-C4alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 E;
(xxv) —CH(N(C1-C4alkyl)2)CO—R11,
wherein each said C1-C4alkyl is independently optionally substituted by 1, 2, 3, 4, 5, or 6 E;
(xxvi) —CH(CO—R11)NH—R11; and
(xxvii) —CH(CO—R11)N(C1-C4alkyl)-R11,
wherein said C1-C4alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 E;
R11 is selected from the group consisting of —R11a-R11b—R11c and —R11d—R11e-R11f, wherein
R11a is either absent, or is selected from the group consisting of,
R11b is either absent, or is selected from the group consisting of
and AAr,
wherein AA is independently for each occurrence a natural amino acid or a non-natural amino acid;
R11c is either absent or is selected from the group consisting of —H, —C1-C4alkyl and -COC1-C4alkyl;
R11d is either absent or —(CH2)t—,
wherein R11d when present is optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 G;
R11e is either absent or selected from the group consisting of —O— and —NH—;
R11f is selected from the group consisting of C6-C12 aryl and 5 to 10 membered heteroaryl,
wherein said 5 to 10 membered heteroaryl comprises one, two or three heteroatoms independently selected from the group consisting of N, O and S, and
wherein R11f is optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 G;
n is 1, 2, 3, 4, 5, or 6;
r is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, or 20;
t is 1, 2, 3, 4, 5, or 6;
G is selected, independently for each occurrence, from the group consisting of —F, —Cl, —CN, —OH, —NH2, —NH—C1-C4alkyl, —N(C1-C4alkyl)2, —NO2, —CO2H, —C1-C4alkylOH, —C1-C4alkylNH2, —C1-C4alkoxy, ═O, —CO2C1-C4alkyl, —OC(O)C1-C4alkyl, —NHC(O)C1-C4alkyl, —C(O)NHC1-C4alkyl, and —C(O)N(C1-C4alkyl)2;
E is selected, independently for each occurrence, from the group consisting of —F, —Cl, —CN, —OH, —NH2, —NHCH3, —N(CH3)2, —NO2, —CO2H, —OCH3, —OCF3, and —CF3; and
L is -LB-LA:
wherein:
LA is selected from the group consisting of —NHR,
LB is —LB1—LB2—LB3 wherein:
LB1 is absent;
LB2 is either absent, or is selected from the group consisting of
LB3 is AA0-12, wherein AA is independently for each occurrence a natural amino acid or a non-natural amino acid; and
each R is independently selected from the group consisting of H, —C1-C20 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, halo, hydroxyl, alkoxy, —NH2, —NH(C1-C8 alkyl), —N(C1-C8 alkyl)2, —NO2, —C6-C14 aryl and —C6-C14 heteroaryl,
wherein two or more R optionally join to form a ring or rings, and
wherein said —C6-C14 aryl and —C6-C14 heteroaryl are optionally substituted with 1 to 5 substituents independently selected from —C1-C10 alkyl, —C1-C10 alkoxy, -halo, —C1-C10 alkylthio, -trifluoromethyl, —NH2, —NH(C1-C8 alkyl), —N(C1-C8 alkyl)2, —C1-C10 alkyl-N(C1-C8 alkyl)2, —C1-C3 alkylthio, —NO2 or —C1-C10 heterocyclyl, for each ring system in which R appears.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein LA is selected from the group consisting of:
—NH2;

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein LB2 is absent.

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein LB2 is

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein LB3 is absent.

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein LB3 is AA2, wherein AA is independently for each occurrence a natural amino acid or a non-natural amino acid.

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is H.

### Claim 8 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is

### Claim 9

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

### Claim 10 (depends on 1)

A pharmaceutical composition comprising an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, carrier, or excipient.

### Claim 11 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is:

### Claim 12 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is:

### Claim 13 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is:

### Claim 14 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is:

### Claim 15 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is:

### Claim 16 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is: