Isoindolinone inhibitors of the mdm2-p53 interaction having anticancer activity

Abstract

The invention provides a compound of formula (I): or tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein the various substituents are as defined in the claims. Also provided are pharmaceutical compositions containing the compounds of formula (I), processes for making the compounds and the medical uses of the compounds.

1 . A method for treating cancer selected from colon cancer, colorectal cancer, lung cancer, mesothelioma, breast cancer, osteosarcoma, fibrosarcoma, melanoma, liver cancer, leukemia, lymphoma, prostate cancer, liposarcoma, pancreatic cancer, ovarian cancer, gastric cancer, bladder cancer, epithelial cancer, multiple myeloma, soft tissue sarcoma, neuroblastoma, glioblastoma, a myeloproliferative disorder, a hematological malignancy, salivary gland cancer, and myelodysplastic syndrome,
 said method comprising administering to a patient 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 8 ) 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 )—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 —NR x COR y , —(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 ,-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 2-8 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 ,-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 1-4 alkyl) 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 is selected from 0 and 1.