US 12,077,526 B2
Isoindolinone inhibitors of the MDM2-P53 interaction and process for making them
Steven Howard, Cambridge (GB); Benjamin David Cons, Cambridge (GB); Jeffrey David St. Denis, Cambridge (GB); Rhian Sara Holvey, Cambridge (GB); Guillaume François Parra, Ste. Eulalie (FR); Kim Louise Hirst, Saffron Walden (GB); Isabelle Anne Lemasson, Cambridge (GB); David John Nash, Saffron Walden (GB); James Daniel Osborne, Cambridge (GB); Jonas Calleja Priede, Cambridge (GB); Nicholas Paul Richards, Haverhill (GB); Aaron Michael Dumas, Stevenage (GB); Brian Christopher Bishop, Harlow (GB); David Parry-Jones, Welwyn Garden (GB); Meenakshi Sundaram Shanmugham, London (GB); Darren James Dixon, Oxford (GB); and Matthew James Gaunt, Cambridge (GB)
Assigned to ASTEX THERAPEUTICS LIMITED, Cambridge (GB); and CANCER RESEARCH TECHNOLOGY LIMITED, London (GB)
Filed by ASTEX THERAPEUTICS LIMITED, Cambridge (GB); and CANCER RESEARCH TECHNOLOGY LIMITED, London (GB)
Filed on Jan. 25, 2023, as Appl. No. 18/159,452.
Application 18/159,452 is a division of application No. 16/498,207, granted, now 11,603,367, previously published as PCT/GB2018/050845, filed on Mar. 28, 2018.
Claims priority of application No. 1704965 (GB), filed on Mar. 28, 2017.
Prior Publication US 2023/0278989 A1, Sep. 7, 2023
Int. Cl. C07D 405/06 (2006.01)
CPC C07D 405/06 (2013.01) [C07B 2200/13 (2013.01)] 22 Claims
 
1. A process for preparing a 1-methoxyisoindoline of formula (1°):

OG Complex Work Unit Chemistry
or a tautomer or a solvate or a salt thereof,
the process comprising taking a compound of the formula (2°)

OG Complex Work Unit Chemistry
wherein cyc is phenyl or a heterocyclic group Het which is pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, or an N-oxide thereof;
R1 is independently selected from hydroxy, halogen, nitro, nitrile, C1-4alkyl, haloC1-4alkyl, hydroxyC1-4alkyl, C2-6alkenyl, C1-4alkoxy, haloC1-4alkoxy, C2-4alkynyl, —O0,1—(CRxRy)v—CO2H, —(CRxRy)v—CO2C1-4alkyl, —(CRxRy)v—CON(C1-4alkyl)2, —P(═O)(Rx)2, —S(O)d—Rx, —S(O)d-heterocyclic group with 3 to 6 ring members and —S(O)d—N(R8)2, wherein when cyc is Het then R1 is attached to a carbon atom;
R2 is selected from hydrogen, C1-4alkyl, C2-6alkenyl, hydroxyC1-4alkyl, —(CRxRy)u—CO2H, —(CRxRy)u—CONRxRy, —(CRxRy)u—CO2R10 wherein R10 is selected from C1-7 alkyl, C1-7 alkeneyl, C1-7 haloalkyl, triC1-7 alkylsilyl-C1-7alkyl, C5-20 aryl and C5-20 aryl-C1-7 alkyl;
R4 and R5 are independently selected from halogen, nitrile, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy and haloC1-4alkoxy;
Q is selected from —C(OH)R6R7, —C(═O)R7, halogen and —OTf;
R6 and R7 are independently selected from hydrogen, C1-6alkyl, haloC1-6alkyl, C2-6alkenyl, C2-6alkynyl, hydroxy, hydroxyC1-6alkyl, —COOC1-6alkyl, —(CH2)j—O—C1-6alkyl, —(CH2)j—O-(hydroxyC1-6alkyl), —C1-6alkyl-NRxRy, —(CRxRy)p—CONRxRy, —(CRxRy)p—NRxCORy, —(CRxRy)p—O—CH2—CONRxRy, heterocyclic group with 3 to 7 ring members, —CH2-heterocyclic group with 3 to 7 ring members, —CH2—O-heterocyclic group with 3 to 7 ring members, —CH2—NH-heterocyclic group with 3 to 7 ring members, —CH2—N(C1-6alkyl)-heterocyclic group with 3 to 7 ring members, —C(═O)NH-heterocyclic group with 3 to 7 ring members, C3-8cycloalkyl, —CH2—C3-8cycloalkyl, —CH2—O—C3-8cycloalkyl, and C3-8cycloalkenyl, wherein said cycloalkyl, cycloalkenyl or heterocyclic groups may be optionally substituted by one or more Rz groups, and wherein in each instance the heterocyclic group comprises one or more heteroatoms selected from N, O, S and oxidised forms thereof;
or, when Q is —C(OH)R6R7, the R6 and R7 groups, together with the carbon atom to which they are attached, can join to form a C3-6cycloalkyl 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 C3-6cycloalkyl and heterocyclyl groups may be optionally substituted by one or more Rz groups;
R8 is selected from hydrogen, C1-6alkyl, haloC1-6alkyl, hydroxyC1-6alkyl, —(CH2)k—O—C1-6alkyl, —(CH2)k—O-(hydroxyC1-6alkyl), hydroxyC1-6alkoxy, —(CH2)k—CO2C1-6alkyl, —(CH2)k—CO2H, —C1-6alkyl-N(H)e(C1-4alkyl)2-e, —(CH2)j—C3-8cycloalkyl and —(CH2)j—C3-8cycloalkenyl;
Rx and Ry are independently selected from hydrogen, halogen, nitro, nitrile, C1-6alkyl, haloC1-6alkyl, C2-6alkenyl, C2-6alkynyl, hydroxy, hydroxyC1-6alkyl, C1-6alkoxy, —(CH2)k—O—C1-6alkyl, hydroxyC1-6alkoxy,
—COOC1-6alkyl, —N(H)e(C1-4alkyl)2-e, —C1-6alkyl-N(H)e(C1-4alkyl)2-e, —(CH2)k—C(═O)N(H)e(C1-4alkyl)2-e, C3-8cycloalkyl and C3-8cycloalkenyl;
or the Rx and Ry groups, together with the carbon or nitrogen atom to which they are attached, can join to form a C3-6cycloalkyl 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 Rx and Ry groups can join together to form a ═CH2 group; Rz is independently selected from halogen, nitro, nitrile, C1-6alkyl, haloC1-6alkyl, C2-6alkenyl, C2-6alkynyl, ═O, hydroxy, hydroxyC1-6alkyl, C1-6alkoxy, —(CH2)—O—C1-6alkyl, hydroxyC1-6alkoxy, —C(═O)C1-6alkyl, C(═O)C1-6alkyl-OH, —C(═O)C1-6alkyl-N(H)e(C1-4alkyl)2-e, —C(═O)N(H)e(C1-4alkyl)2-e, —(CH2)r—CO2C1-6alkyl, —(CH2)r—CO2H, —N(H)e(C1-4alkyl)2-e, —C1-6alkyl-N(H)e(C1-4alkyl)2-e, heterocyclyl group with 3 to 6 ring members, heterocyclyl group with 3 to 6 ring members substituted by —C(═O)C1-4alkyl, heterocyclyl group with 3 to 6 ring members substituted by —C(═O)OC1-4alkyl, heterocyclyl group with 3 to 6 ring members substituted by —C(═O)N(H)e(C1-4alkyl)2-e, —C(═O)heterocyclyl group with 3 to 6 ring members, C3-8cycloalkyl and C3-8cycloalkenyl, wherein if R7 is pyridine then Rz is other than —NH2;
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;
and reacting the compound of formula (2°) with a methylating agent in the presence of a base.