Pyrrolobenzodiazepines and conjugates thereof

Patent metadata

Field	Value
Publication number	US-10660901-B2
Application number	US-201816181867-A
Country	US
Kind code	B2
Filing date	Nov 6, 2018
Priority date	May 18, 2016
Publication date	May 26, 2020
Grant date	May 26, 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 D2:

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 —OH, —NH—(C 1-6 alkylene)-R 13a , E1, E2, E3, or E4:

wherein the dotted line in E1 or E4 indicates the presence of a single or double bond;
R 4 , R 5 and R 7 are each independently —H, —R 2 , —OH, —OR 2 , —SH, —SR 2 , —NH 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 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;
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 , C 1-10 alkyl, —CO—NH—(C 1-6 alkylene)-R 3a , 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, 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 ;
R 15 , R 16 , R 17 , and R 18 are each independently —H, —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 , 3-14 membered heterocycloalkyl, 5- to 12-membered heteroaryl, —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 , or —NH(C═NH)NH 2 ;
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;
each X 1 independently is CR b or N;
each Y 1 independently is CH, NR a , O or S, wherein when

then Y 1 is NR a , O, or S;
each Z 1 independently is CH, NR a , O or S, wherein when

then Z1 is NR a , O, or S;
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;
X 2 is CH, CH 2 , or N;
X 3 is CH or N;
X 4 is NH, O, or S;
Q is O, S, or NH;
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 1, 2, 3, 4, 5, or 6;
t is 0, 1, or 2;
each x independently is 2 or 3, and
when E is E4, the dotted line indicates the presence of a double bond, X 3 is CH, and X 4 is O or S, then s is 2, 3, 4, 5, or 6.

2. The compound of claim 1 , wherein T is C 2-6 alkylene linker.

3. The compound of claim 1 , wherein T is C 2-4 alkylene linker.

4. The compound of claim 1 , wherein T is propylene.

5. The compound of claim 1 , wherein the compound is of Formula (III):

or a tautomer thereof, or a pharmaceutically acceptable salt or solvate of the compound or the tautomer.

6. The compound of claim 1 , wherein each

independently is

7. The compound of claim 1 , wherein A is:

wherein each X 1 independently is CH or N.

8. The compound of claim 1 , wherein A is:

wherein each X 1 independently is CH or N.

9. The compound of claim 1 , wherein A is

wherein each X 1 independently is CH or N.

10. The compound of claim 1 , wherein E is:

11. The compound of claim 1 , wherein R 4 , R 5 and R 7 are each independently —H, —R 2 , —OH, —OR 2 , —SH, —SR 2 , —NH 2 , —NHR 2 , —NR 2 R 3 , —NO 2 , halo, or a polyethylene glycol unit —(OCH 2 CH 2 ) r —OR a .

12. The compound claim 1 , wherein R 4 and R 7 together form bis-oxy-C 1-3 alkylene.

13. The compound of claim 1 , wherein 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 , 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 , —NH(C═NH)NH 2 , or —R 20 —R 21 —NR 13 R 14 .

14. The compound of claim 1 , wherein each of R 20 and R 21 is a bond.

15. The compound of c

Assignees

• Mersana Therapeutics Inc

Inventors

• Yin Mao
• Thomas Joshua D
• Yurkovetskiy Aleksandr V
• Conlon Patrick R
• Du Bingfan
• Kelleher Eugene W
• Lowinger Timothy B
• Tang Shuyi

Classifications

• A61K47/6851

  the antibody targeting a determinant of a tumour cell · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/55 Primary

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title