US Patent No. 9,138,486

CYTOTOXIC PEPTIDES AND ANTIBODY DRUG CONJUGATES THEREOF


Patent No. 9,138,486
Issue Date September 22, 2015
Title Cytotoxic Peptides And Antibody Drug Conjugates Thereof
Inventorship Matthew David Doroski, Mystic, CT (US)
Andreas Maderna, Stony Point, NY (US)
Chakrapani Subramanyam, South Glastonburty, CT (US)
Beth Vetelino, North Stonington, CT (US)
Russell George Dushin, Old Lyme, CT (US)
Pavel Strop, San Mateo, CA (US)
Edmund Idris Graziani, Chestnut Ridge, NY (US)
Assignee Pfizer Inc., New York, NY (US)

Claim of US Patent No. 9,138,486

1. A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of
the compound of formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein, independently for each occurrence,
W is

R1 is hydrogen, C1-C8 alkyl or C1-C8 haloalkyl;

R2 is hydrogen, C1-C8 alkyl or C1-C8 haloalkyl;

R3A and R3B are either of the following:

(i) R3A is hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C3-C8 carbocyclyl, C1-C10 heterocyclyl, aryl, heteroaralkyl, halogen or aralkyl; and R3B is C1-C8 alkyl, C1-C8 haloalkyl, C3-C8 carbocyclyl, C1-C10 heterocyclyl, aryl, heteroaralkyl, aralkyl or halogen; or

(ii) R3A and R3B taken together are C2-C8 alkylene or C1-C8 heteroalkylene;

R4A and R4B are either of the following:

(i) R4A is hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C3-C8 carbocyclyl, C1-C10 heterocyclyl, aryl, heteroaralkyl or aralkyl; and R4B is hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C3-C8 carbocyclyl, C1-C10 heterocyclyl, aryl, heteroaralkyl or aralkyl; or

(ii) R4A and R4B taken together are C2-C8 alkylene or C1-C8 heteroalkylene;

R5 is

C1-C10 heterocyclyl, C3-C8 carbocycly or C6-C14 aryl, optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of —C1-C8 alkyl, —C1-C8 alkyl-N(R?)2, —C1-C8 alkyl-C(O)R?, —C1-C8 alkyl-C(O)OR?—O—(C1-C8 alkyl), —C(O)R?, —OC(O)R?, —C(O)OR?, —C(O)N(R?)2, —NHC(O)R?, —S(O)2R?, —S(O)R?, —OH, halogen, —N3, —N(?)2, —CN, —NHC(?NH)NH2, —NHCONH2, —S(?O)2R? and —SR?, wherein each R? is independently selected from the group consisting of hydrogen, C1-C8 alkyl and unsubstituted aryl, or two R? can, together with the nitrogen to which they are attached, form a C1-C10 heterocyclyl; or R5 is
optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of C1-C8 alkyl, —C1-C8 alkyl-N(R?)2, —C1-C8 alkyl-C(O)R?, —C1-C8 alkyl-C(O)OR?, —O—(C1-C8 alkyl), —C(O)R?, —OC(O)R?, —C(O)OR?, —C(O)N(R?)2, —NHC(O)R?, —S(O)2R?, —S(O)R?, —OH, halogen, —N3, —N(R?)2, —CN, —NHC(?NH)NH2, —NHCONH2, —S(?O)2R?, —SR? and arylene-R?, wherein each R? is independently selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8heterocyclyl, C1-C10alkylene-C3-C8heterocyclyl and aryl, or two R? can, together with the nitrogen to which they are attached, form a C1-C10 heterocyclyl; R6 is hydrogen, —C1-C8 alkyl, —C2-C8 alkenyl, —C2-C8 alkynyl or —C1-C8 haloalkyl;
R12 is hydrogen, C1-C4 alkyl, C1-C10 heterocyclyl or C6-C14 aryl;

R13 is C1-C10 heterocyclyl; and

X is O or S;
provided that when R3A is hydrogen X is S.