Isoindolinone inhibitors of the MDM2-P53 interaction having anticancer activity

Patent metadata

Field	Value
Publication number	US-10526311-B2
Application number	US-201615763724-A
Country	US
Kind code	B2
Filing date	Sep 29, 2016
Priority date	Sep 29, 2015
Publication date	Jan 7, 2020
Grant date	Jan 7, 2020

Abstract

Also provided are pharmaceutical compositions containing the compounds of formula (I), processes for making the compounds and the medical uses of the compounds.

First claim

The invention claimed is:

1. A compound of formula (I):

or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein:
Het is pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, or an N-oxide thereof;
R 1 is attached to a carbon atom and is independently selected from hydroxy, halogen, nitro, nitrile, C 1-4 alkyl, haloC 1-4 alkyl, hydroxyC 1-4 alkyl, C 2-6 alkenyl, C 1-4 alkoxy, haloC 1-4 alkoxy, C 2-4 alkynyl, —O 0,1 —(CR x R y ) v —CO 2 H, —(CR x R y )v-CO 2 C 1-4 alkyl, —(CR x R y ) v —CON(C 1-4 alkyl) 2 , —P(═O)(R x ) 2 , —S(O) d —R x , —S(O) d -heterocyclic group with 3 to 6 ring members and —S(O) d —N(R) 2 ;
R 2 is selected from hydrogen, C 1-4 alkyl, C 2-6 alkenyl, hydroxyC 1-4 alkyl, —(CR x R y ) u —CO 2 H, —(CR x R y ) u —CO 2 C 1-4 alkyl, and —(CR x R y ) u —CONR x R y ;
s is selected from 0 and 1;
R 3 is hydrogen or -(A) t -(CR x R y ) q —X;
t is selected from 0 and 1;
q is selected from 0, 1 and 2;
wherein when R 3 is -(A) t -(CR x R y ) q —X then (i) at least one of s, t and q is other than 0 and (ii) when t is 0 then s is 1 and q is other than 0;
A is a C 3-6 cycloalkyl group or a heterocyclic group with 3 to 6 ring members, wherein the heterocyclic group comprises one or more heteroatoms selected from N, O, S and oxidised forms thereof;
X is selected from hydrogen, halogen, —CN, —OR 9 , —(CH 2 ) v —CO 2 H, —(CH 2 ) v —CO 2 C 1-4 alkyl, —S(O) d —R x , —C(═O)—C 1-4 alkyl, —S(O) d —N(H) e (C 1-4 alkyl) 2-e , —NR x R y , —NHSO 2 R x , —NR x COR y , and —C(═O)NR x R y ;
R 4 and R 5 are independently selected from halogen, nitrile, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy and haloC 1-4 alkoxy;
R 6 and R 7 are independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxy, hydroxyC 1-6 alkyl, —COOC 1-6 alkyl, —(CH 2 ) j —O—C 1-6 alkyl, —(CH 2 ) j —O-(hydroxyC 1-6 alkyl), —C 1-6 alkyl-NR x R y , —(CR x R y ) p —CONR x R y , —(CR x R y ) p —NRXCORy, —(CR x R y ) p —O—CH 2 —CONR x R y , heterocyclic group with 3 to 7 ring members, —CH 2 -heterocyclic group with 3 to 7 ring members, —CH 2 —O-heterocyclic group with 3 to 7 ring members, —CH 2 —NH-heterocyclic group with 3 to 7 ring members, —CH 2 —N(C 1-6 alkyl)-heterocyclic group with 3 to 7 ring members, —C(═O)NH-heterocyclic group with 3 to 7 ring members, C 3-8 cycloalkyl, —CH 2 —C 3-8 cycloalkyl, —CH 2 —O—C 3-8 cycloalkyl, and C 3-8 cycloalkenyl, wherein said cycloalkyl, cycloalkenyl or heterocyclic groups may be optionally substituted by one or more R z groups, and wherein in each instance the heterocyclic group comprises one or more heteroatoms selected from N, O, S and oxidised forms thereof;
or the R 6 and R 7 groups, together with the carbon atom to which they are attached, can join to form a C 3-6 cycloalkyl or heterocyclyl group with 3 to 6 ring members, wherein the heterocyclic group comprises one or more heteroatoms selected from N, O, S and oxidised forms thereof, and wherein said C 3-6 cycloalkyl and heterocyclyl groups may be optionally substituted by one or more R z groups;
R 8 and R 9 are independently selected from hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, —(CH 2 ) k —O—C 1-6 alkyl, —(CH 2 ) k —O-(hydroxyC 1-6 alkyl), hydroxyC 1-6 alkoxy, —(CH 2 ) k —CO 2 C 1-6 alkyl, —(CH 2 ) k —CO 2 H, —C 1-6 alkyl-N(H) e (C 1-4 alkyl) 2-e , —(CH 2 ) j —C 3-8 cycloalkyl and —(CH 2 ) j —C 3-8 cycloalkenyl;
R x and R y are independently selected from hydrogen, halogen, nitro, nitrile, C 1-6 alkyl, haloC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxy, hydroxyC 1-6 alkyl, C 1-6 alkoxy, —(CH 2 ) k —O—C 1-6 alkyl, hydroxyC 1-6 alkoxy, —COOC 1-6 alkyl, —N(H) e (C 1-4 alkyl) 2-e , —C 1-6 alkyl-N(H) e (C 1-4 alkyl) 2-e , —(CH 2 ) k —C(═O)N(H) e (C 1-4 alkyl) 2-e , C 3-8 cycloalkyl and C 3-8 cycloalkenyl;
or the R x and R y groups, together with the carbon or nitrogen atom to which they are attached, can join to form a C 3-6 cycloalkyl or saturated heterocyclyl group with 3 to 6 ring members which may be optionally fused to an aromatic heterocyclyl group of 3 to 5 ring members;
or when on a carbon atom the R x and R y groups can join together to form a=CH 2 group;
R z is independently selected from halogen, nitro, nitrile, C 1-6 alkyl, haloC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, ═O, hydroxy, hydroxyC 1-6 alkyl, C 1-6 alkoxy, —(CH 2 ) k —O—C 1-6 alkyl, hydroxyC 1-6 alkoxy, —C(═O)C 1-6 alkyl, —C(═O)C 1-6 alkyl-OH, —C(═O)C 1-6 alkyl-N(H) e (C 1-4 alkyl) 2-e , —C(═O)N(H) e (C 1-4 alkyl) 2-e , —(CH 2 )r-CO 2 C 1-6 alkyl, —(CH 2 )r-CO 2 H, —N(H) e (C 1 -4alkyl) 2-e , —C 1-6 alkyl-N(H) e (C 1-4 alkyl) 2-e , heterocyclyl group with 3 to 6 ring members, heterocyclyl group with 3 to 6 ring members substituted by —C(═O)C 1-4 alkyl, heterocyclyl group with 3 to 6 ring members substituted by —C(═O)OC 1-4 alkyl, heterocyclyl group with 3 to 6 ring members substituted by —C(═O)N(H) e (C 1-4 alkyl) 2-e , —C(═O)heterocyclyl group with 3 to 6 ring members, C 3-8 cycloalkyl and C 3-8 cycloalkenyl, wherein if R 7 is pyridine then R z is other than —NH 2 ;
a, j, d, e, n, r and p are independently selected from 0, 1 and 2;
k and m are independently selected from 1 and 2;
u is selected from 0, 1, 2 and 3; and
v and w are independently is selected from 0 and 1.

2. A compound according to claim 1 , wherein R 1 is halogen, hydroxy, nitrile, C 1-4 alkyl, C 2-4 alkynyl, or C 1-4 alkoxy.

3. A compound according to claim 1 , wherein R 2 is selected from hydrogen, C 1-4 alkyl, hydroxyC 1-4 alkyl and —(CR x R y ) u —CO 2 H.

4. A compound according to claim 1 , wherein R 3 is:
(i) -(A) t -(CR x R y ) q —X and A is a C 3-6 cycloalkyl group; or
(ii) H and s is 1.

5. A compound according to claim 1 , wherein s is 1.

6. A compound according to claim 1 , wherein X is hydrogen, halogen, —CN, —OR 9 , or —C(═O)NR x R y .

7. A compound according to claim 1 , wherein the compound is a compound of the formula

or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein L is CR 1 , CH or N.

8. A compound according to claim 1 , wherein a is 1 and R 4 is F and at the 4-position of the isoindolinone ring.

9. A compound according to claim 1 , wherein R 5 is chloro and m is 1 and the substituent R 5 is at the para-position of the phenyl group.

10. A compound according to claim 1 , wherein:
(i) R 7 is selected from a heterocyclic group with 3 to 7 ring members and a —CH 2 -heterocyclic group with 3 to 7 ring members, wherein said heterocyclic groups may be optionally substituted by one or more R z groups, and wherein in each instance the heterocyclic group comprises one or more heteroatoms selected from N, O, S and oxidised forms thereof; or
(ii) R 6 is methyl or ethyl.

11. A compound according to claim 1 , wherein Het is pyridinyl or pyrimidinyl.

12. A compound according to claim 1 , or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
(3R)-3-(4-chlorophenyl)-2-[(5-chloropyridin-2-yl)methyl]-4-fluoro-3-({1-[hydroxy( 2 H 2 )methyl]cyclopropyl}( 2 H 2 )methoxy)-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;
(3R)-3-(4-chlorophenyl)-2-[(5-chloropyridin-2-yl)methyl]-4-fluoro-6-(2-hydroxypropan-2-yl)-3-methoxy-2,3-dihydro-1H-isoindol-1-one;
6-{[(1R)-1-

Assignees

• Astex Therapeutics Ltd
• Cancer Research Tech Ltd

Inventors

• Chessari Gianni
• Howard Steven
• Buck Ildiko Maria
• Cons Benjamin David
• Johnson Christopher Norbert
• Holvey Rhian Sara
• Rees David Charles
• St Denis Jeffrey David
• Tamanini Emiliano
• Golding Bernard Thomas
• Hardcastle Ian Robert
• Cano Celine Florence
• Miller Duncan Charles
• Noble Martin Edward Mäntylä
• Griffin Roger John
• Osborne James Daniel
• Peach Joanne
• Lewis Arwel
• Hirst Kim Louise
• Whittaker Benjamin Paul
• Watson David Wyn
• Mitchell Dale Robert

Classifications

• C07B59/002

  Heterocyclic compounds · CPC title

• C07D487/08

  Bridged systems · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title