Antiproliferative compounds and conjugates made therefrom
A compound capable of inhibiting cell proliferation, having a structure according to formula (I) wherein the variables in formula (I) are as defined in the specification. Such compounds are useful as anti-cancer agents, especially in antibody-drug conjugates.
1. A compound of formula (Ib)
wherein —X 20 —Ar 1 —X 21 — is selected from
and
W is selected from
wherein each R 34 is independently H, C 1 -C 3 alkyl, OH, Cl, F, CH 2 F, CHF 2 , CF 3 , O(C 1 -C 3 alkyl), O(CH 2 ) 2-4 OH, O(CH 2 ) 0-2 CHF 2 , C(═O)(C 1 -C 3 alkyl), C(═O)O(C 1 -C 3 alkyl), C(═O)NH 2 , C(═O)NH(C 1 -C 3 alkyl), C(═O)N(C 1 -C 3 alkyl) 2 , O(C 2 -C 4 alkenyl), NH 2 , NH(C 1 -C 3 alkyl), N(C 1 -C 3 alkyl) 2 , O(CH 2 ) 0-2 C 6 H 5 , CN, or NO 2 .
2. A compound having a structure of formula (IIa″)
wherein R 7 , R 8 , R 9 , and R 10 are independently H, C 1 -C 5 alkyl, C≡C(CH 2 ) 1-5 X 2 , OH, O(C 1 -C 5 alkyl), cyano, NO 2 , F, Cl, Br, O(CH 2 CH 2 O) 1-8 (C 1-3 alkyl), (CH 2 ) 0-5 X 2 , O(CH 2 ) 2-5 X 2 , 3- to 7-membered cycloalkyl or heterocycloakyl unsubstituted or substituted with (CH 2 ) 0-5 X 2 or O(CH 2 ) 2-5 X 2 phenyl unsubstituted or substituted with (CH 2 ) 0-5 X 2 or O(CH 2 ) 2-5 X 2 , 5- to 6-membered heteroaryl unsubstituted or substituted with (CH 2 ) 0-5 X 2 or O(CH 2 ) 2-5 X 2 ,
each X 2 is independently H, F, Cl, Br, OH, O(C 1 -C 3 alkyl), O(C 1 -C 3 alkylene), CO 2 H, N 3 , CN, NO 2 , CO 2 (C 1 -C 3 alkyl), NH 2 , NH(C 1 -C 5 alkyl), N(C 1 -C 5 alkyl)2, SH, CHO, N(CH 2 CH 2 ) 2 N(C 1 -C 3 alkyl), NHNH 2 , or C(═O)NHNH 2 ;
and each R 34 is independently H, C 1 -C 3 alkyl, OH, Cl, F, CH 2 F, CHF 2 , CF 3 , O(C 1 -C 3 alkyl), O(CH 2 ) 2-4 OH, O(CH 2 ) 0-2 CHF 2 , C(═O)(C 1 -C 3 alkyl), C(═O)O(C 1 -C 3 alkyl), C(═O)NH 2 , C(═O)NH(C 1 -C 3 alkyl), C(═O)N(C 1 -C 3 alkyl) 2 , O(C 2 -C 4 alkenyl), NH 2 , NH(C 1 -C 3 alkyl), N(C 1 -C 3 alkyl) 2 , O(CH 2 ) 0-2 C 6 H 5 , CN, or NO 2 .
3. A compound having a structure of formula (IIIc′)
wherein
R 15 , R 16 and R 17 are independently H, CH 3 , CH(CH 3 ) 2 , CH 2 CO 2 H, CH 2 CH 2 CO 2 H, CH 2 C(═O)NH 2 , CH 2 CH 2 C(═O)NH 2 , (CH 2 ) 4 NH 2 , (CH 2 ) 3 NHC(═NH)NH 2 or (CH 2 ) 3 NHC(═O)NH 2 ;
R 18 is
each R 33 is independently H, Cl, F, Br, C 1 -C 5 alkyl, O(C 1 -C 5 alkyl), OH, CN, NO 2 , NH(C═O)(C 1 -C 5 alkyl), N(C 1 -C 5 alkyl) 2 , or CF 3 ;
and
each R 36 is independently H, C 1 -C 3 alkyl, OH, Cl, F, CH 2 F, CHF 2 , CF 3 , O(C 1 -C 3 alkyl), O(CH 2 ) 2-4 OH, O(CH 2 ) 0-2 CHF 2 , C(═O)(C 1 -C 3 alkyl), C(═O)O(C 1 -C 3 alkyl), C(═O)NH 2 , C(═O)NH(C 1 -C 3 alkyl), C(═O)N(C 1 -C 3 alkyl) 2 , O(C 2 -C 4 alkenyl), O(CH 2 ) 0-2 C 6 H 5 , CN, or NO 2 .
4. A compound according to claim 3 , having a structure of formula (IIIc-01) or (IIIc-02):