Pyrrolobenzodiazepines and conjugates thereof

Patent metadata

Field	Value
Publication number	US-10526294-B2
Application number	US-201715630068-A
Country	US
Kind code	B2
Filing date	Jun 22, 2017
Priority date	Jun 24, 2016
Publication date	Jan 7, 2020
Grant date	Jan 7, 2020

Abstract

The present disclosure relates generally to derivatives of pyrrolobenzodiazepines and antibody-drug conjugates thereof and to methods of using these conjugates as therapeutics and/or diagnostics.

First claim

What is claimed is:

1. A compound of Formula (I),

or a tautomer thereof, or a pharmaceutically acceptable salt or solvate of the compound or the tautomer, wherein:
D is D1:

wherein the dotted line between C2 and C3 or between C2 and C1 in D1 indicates the presence of a single or double bond;
m is 0, 1 or 2;
when D is D1, the dotted line between C2 and C3 is a double bond, and m is 1, then R 1 is:
(i) C 6-10 aryl group, optionally substituted by one or more substituents selected from —OH, halo, —NO 2 , —CN, —N 3 , —OR 2 , —COOH, —COOR 2 , —COR 2 , —OCONR 13 R 14 , C 1-10 alkyl, C 3-10 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, a polyethylene glycol unit —(OCH 2 CH 2 ) r —OR a , 3- to 14-membered heterocycloalkyl, 5- to 12-membered heteroaryl, bis-oxy-C 1-3 alkylene, —NR 13 R 14 , —S(═O) 2 R 12 , —S(═O) 2 NR 13 R 14 , —SR 12 , —SO x M, —OSO x M, —NR 9 COR 19 , —NH(C═NH)NH 2 ;
(ii) C 1-5 alkyl;
(iii) C 3-6 cycloalkyl;

 or
(viii) halo; or
when D is D1, the dotted line between C2 and C3 is a single bond, and m is 1, then R 1 is:
(i) —OH, ═O, ═CH 2 , —CN, —R 2 , —OR 2 , halo, ═CH—R 6 , ═C(R 6 ) 2 , —O—SO 2 R 2 , —CO 2 R 2 , —COR 2 , —CHO, or —COOH; or

 or
when D is D1 and m is 2, then each R 1 independently is halo and either both R 1 are attached to the same carbon atom or one is attached to C2 and the other is attached to C3;
T is C 1-10 alkylene linker;
A is

 wherein the —NH group of A is connected to the —C(O)-T- moiety of Formula (I) and the C═O moiety of A is connected to E; and each

 independently is

E is E1, E2, E3, E4, E5 or E6:

G is —OH, —NH—(C 1-6 alkylene)-R 13a , G1, G2, G3 or G4:

 wherein the dotted line in G1 or G4 indicates the presence of a single or double bond;
each occurrence of R 2 and R 3 independently is an optionally substituted C 1-8 alkyl, optionally substituted C 2-8 alkenyl, optionally substituted C 2-8 alkynyl, optionally substituted C 3-8 cycloalkyl, optionally substituted 3- to 20-membered heterocycloalkyl, optionally substituted C 6-20 aryl or optionally substituted 5- to 20-membered heteroaryl, and, optionally in relation to the group NR 2 R 3 , R 2 and R 3 together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered heterocycloalkyl or an optionally substituted 5- or 6-membered heteroaryl;
R 4 , R 5 and R 7 are each independently —H, —R 2 , —OH, —OR 2 , —SH, —SR 2 , —NHR 2 , —NR 2 R 3 , —NO 2 , —SnMe 3 , halo or a polyethylene glycol unit —(OCH 2 CH 2 ) r —OR a ; or R 4 and R 7 together form bis-oxy-C 1-3 alkylene;
each R 6 independently is —H, —R 2 , —CO 2 R 2 , —COR 2 , —CHO, —CO 2 H, or halo;
each R 8 independently is —OH, halo, —NO 2 , —CN, —N 3 , —OR 2 , —COOH, —COOR 2 , —COR 2 , —OCONR 13 R 14 , —CONR 13 R 14 , —CO—NH—(C 1-6 alkylene)-R 13a , —OCO—NH—(C 1-6 alkylene)-R 13a , C 1-10 alkyl, C 3-10 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, a polyethylene glycol unit —(OCH 2 CH 2 ) r —OR a , 3- to 14-membered heterocycloalkyl, 5- to 12-membered heteroaryl, —S(═O) 2 R 12 , —S(═O) 2 NR 13 R 14 , —SR 12 , —SO x M, —OSO x M, —NR 9 COR 19 , —NH(C═NH)NH 2 or —R 20 —R 21 —NR 13 R 14 ; each R 9 independently is C 1-10 alkyl, C 3-10 cycloalkyl, C 2-10 alkenyl or C 2-10 alkynyl;
R 10 is —H or a nitrogen protecting group;
R 11 is -QR Q or —SO x M;
or R 10 and R 11 taken together with the nitrogen atom and carbon atom to which they are respectively attached, form a N═C double bond;
each R 12 independently is C 1-7 alkyl, 3- to 20-membered heterocycloalkyl, 5- to 20-membered heteroaryl, or C 6-20 aryl;
each occurrence of R 13 and R 14 are each independently H, C 1-10 alkyl, C 3-10 cycloalkyl, 3- to 20-membered heterocycloalkyl, 5- to 20-membered heteroaryl, or C 6-20 aryl;
each R 13a independently is —OH or —NR 13 R 14 ;
each R 19 independently is C 1-10 alkyl, C 3-10 cycloalkyl, C 2-10 alkenyl or C 2-10 alkynyl;
each R 20 independently is a bond, C 6-10 arylene, 3-14 membered heterocycloalkylene or 5- to 12-membered heteroarylene;
each R 21 independently is a bond or C 1-10 alkylene;
R 31 , R 32 and R 33 are each independently —H, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl or cyclopropyl, where the total number of carbon atoms in the R 1 group is no more than 5;
R 34 is —H, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, cyclopropyl, or phenyl wherein the phenyl is optionally substituted by one or more of halo, methyl, methoxy, pyridyl or thiophenyl;
one of R 35a and R 35b is —H and the other is a phenyl group optionally substituted with one or more of halo, methyl, methoxy, pyridyl or thiophenyl;
R 36a , R 36b , R 36c are each independently —H or C 1-2 alkyl;
R 36d is —OH, —SH, —COOH, —C(O)H, —N═C═O, —NHNH 2 , —CONHNH 2 ,

 or NHR N , where R N is —H or C 1-4 alkyl;
R 37a and R 37b are each independently is —H, —F, C 1-4 alkyl, C 2-3 alkenyl, wherein the alkyl and alkenyl groups are optionally substituted by C 1-4 alkyl amido or C 1-4 alkyl ester; or when one of R 37a and R 37b is —H, the other is —CN or a C 1-4 alkyl ester;
each X 1 independently is CR b , or N;
each Y 1 independently is NR a , O or S;
each Z 1 independently is CH, NR a , O or S;
X 2 is CH, CH 2 or N;
X 3 is CH or N;
X 4 independently is CR b , or N;
X 5 is NH, O or S;
Y 2 independently is NR a , O or S;
Z 2 is CH or N;
each R a independently is H or C 1-4 alkyl;
each R b independently is H, OH, C 1-4 alkyl, or C 1-4 alkoxyl;
Q is O, S or NH;
R Q is —H, optionally substituted C 1-7 alkyl, or —SO x M;
when Q is S or NH, then R Q is —H or optionally substituted C 1-7 alkyl; or
when Q is O, then R Q is —H or optionally substituted C 1-7 alkyl, or —SO x M;
each M independently is H or a monovalent pharmaceutically acceptable cation;
each r independently is an integer from 1 to 200;
s is 0, 1, 2 or 3;
t is 0, 1, or 2;
each x independently is 2 or 3; and
when G is G4, the dotted line indicates the presence of a double bond, X 3 is CH, and X 5 is O or S, then s is 2, 3, 4, 5 or 6; provided that
(i) when D is

 and s is 0, and T is —(CH 2 ) 3 or 4 —, then E is not E3 wherein X 4 is N, Y 2 is O or S, Z 2 is CH, t is 0, 1, or 2, and R 8 is fluoro;

Assignees

• Mersana Therapeutics Inc

Inventors

• Thomas Joshua D
• Yin Mao
• Yurkovetskiy Aleksandr V
• Conlon Patrick R
• Hilmy Ahmed
• Kelleher Eugene W
• Lowinger Timothy B
• Stevenson Cheri A
• Tang Shuyi

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/6883

  Polymer-drug antibody conjugates, e.g. mitomycin-dextran-Ab; DNA-polylysine-antibody complex or conjugate used for therapy · CPC title

• C12N15/111

  General methods applicable to biologically active non-coding nucleic acids · CPC title

• C07D243/14 Primary

  1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines · CPC title

• C07C2603/22

  containing only six-membered rings · CPC title