US 11,236,047 B2Granted

Combination of isoindolinone derivatives with SGI-110

AssigneesAstex Therapeutics Limited, Cancer Research Technology Limited

InventorsGianni Chessari, John Francis Lyons

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Abstract

The invention provides a combination comprising: (i) a compound of formula (Io): or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein the various substituents are as defined in the claims; and (ii) a compound which is SGI-110 or a tautomer or a solvate or a pharmaceutically acceptable salt thereof. Also provided are pharmaceutical compositions containing the combinations and medical uses of the combinations.

Claims21

Dependent claims

A combination comprising:

(i) a compound of formula (Io):
or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein:
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, —(CRxR31)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, —(CRxR31)u—CO2H, —(CRxRy)u—CO2C1-4alkyl, and —(CRxRy)u—CONRxRy;
s is selected from 0 and 1;
R3 is hydrogen or -(A)t-(CRxRy)q—X;
t is selected from 0 and 1;
q is selected from 0, 1 and 2;
wherein when R3 is -(A)t-(CRxRy)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 C3-6cycloalkyl 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, —OR9, —(CH2)v—CO2H, —(CH2)v—CO2C1-4alkyl, —S(O)d—Rx, —C(═O)—C1-4alkyl, —S(O)d—N(H)e(C1-4alkyl)2−e, —NRxRy, —NHSO2Rx, —NRxCORy, and —C(═O)NRxRy;
R4 and R5 are independently selected from halogen, nitrile, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy and haloC1-4alkoxy;
R6 and R1 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 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 and R9 are independently 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, —C1-6 alkyl-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)k—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
(ii) a compound which is SGI-110
or a tautomer or a solvate or a pharmaceutically acceptable salt thereof.

25 more elements

A combination comprising:

(i) a compound selected from:
(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;
(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;
(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-(2-hydroxyethoxy)-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;
(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;
1-({[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carboxylic acid;
(3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-3-(2,3-dihydroxy-2-methylpropoxy)-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;
(3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;
(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(1,2-dihydroxypropan-2-yl)-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;
(3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-6-(2-hydroxy-1-methoxypropan-2-yl)-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;
(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-[1-(dimethylamino)-2-hydroxypropan-2-yl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;
(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid;
(3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-6-(1,2-dihydroxypropan-2-yl)-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;
(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-(3-hydroxy-3-methylbutoxy)-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;
(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-[(1H-pyrazol-4-yl)methoxy]-2,3-dihydro-1H-isoindol-1-one;
1-({[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carbonitrile;
N-{[1-({[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropyl]methyl}methanesulfonamide;
(3R)-3-(4-chlorophenyl)-2-[(4-ethynylphenyl)methyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;
(3R)-3-(4-chlorophenyl)-2-[(4-ethynylphenyl)methyl]-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;
(3R)-3-(4-chlorophenyl)-6-(1,2-dihydroxypropan-2-yl)-2-[(4-ethynylphenyl)methyl]-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;
4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-1-({1-[hydroxy(2H2)methyl]cyclopropyl}(2H2)methoxy)-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile;
4-{[(1R)-1-(4-chlorophenyl)-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile;
(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-[(3-methyl oxetan-3-yl)methoxy]-2,3-dihydro-1H-isoindol-1-one;
4-{[(1R)-1-(4-chlorophenyl)-5-(1,2-dihydroxypropan-2-yl)-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile;
(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-[(1-hydroxycyclopropyl)methoxy]-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;
2-{[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}-N,N-dimethylacetamide;
(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-{[1-(methoxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;
(3R)-3-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-{[1-(hydroxymethyl)cyclobutyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;
5-chloro-2-{[(1R)-1-(4-chlorophenyl)-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoic acid;
(3R)-2-{[4-chloro-2-(morpholine-4-sulfonyl)phenyl]methyl}-3-(4-chlorophenyl)-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;
1-({[(1R)-2-[(4-chloro-2-methanesulfonyl phenyl)methyl]-1-(4-chlorophenyl)-7-fluoro-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carboxamide;
(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-3-({1-[hydroxy(2H2)methyl]cyclopropyl}(2H2)methoxy)-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;
(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-(oxolan-3-yloxy)-2,3-dihydro-1H-isoindol-1-one;
(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-[(oxolan-3-yl)methoxy]-2,3-dihydro-1H-isoindol-1-one;
(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(oxan-4-yl)ethyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;
(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[2-hydroxy-1-(piperazin-1-yl)propan-2-yl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;
(3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-3-{[(3S,4R)-4-hydroxyoxolan-3-yl]oxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;
(3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-3-{[(3R,4S)-4-hydroxyoxolan-3-yl]oxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;
(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-methoxy-2,3-dihydro-1H-isoindol-1-one;
(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-({1-[hydroxy(2H2)methyl]cyclopropyl}(2H2)methoxy)-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;
(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-(3-hydroxypropoxy)-2,3-dihydro-1H-isoindol-1-one;
(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;
(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-(2,2-difluoro-3-hydroxypropoxy)-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;
(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-{[2-(hydroxymethyl)cyclobutyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;
(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-[2-hydroxy-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;
2-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-2-hydroxy-N,N-dimethylpropanamide;
2-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-2-hydroxy-N-methylpropanamide;
(3R)-2-{[4-chloro-2-(methylsulfanyl)phenyl]methyl}-3-(4-chlorophenyl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;
(3R)-2-[(4-chloro-2-methanesulfinylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;
(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-(2-hydroxy-1-methoxypropan-2-yl)-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;
(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-6-(1,2-dihydroxypropan-2-yl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;
(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[2-hydroxy-1-(4-methylpiperazin-1-yl)propan-2-yl]-3-[(3R)-oxolan-3-yl oxy]-2,3-dihydro-1H-isoindol-1-one;
(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[2-hydroxy-1-(4-methylpiperazin-1-yl)propan-2-yl]-3-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-1-one;
(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-(2-hydroxypropan-2-yl)-3-oxo-1-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]propanoic acid;
1-({[(1R)-2-{[4-chloro-2-(hydroxymethyl)phenyl]methyl}-1-(4-chlorophenyl)-7-fluoro-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carbonitrile;
1-({[(1R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-pyrazol-4-yl)ethyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carboxamide;
(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(1-methyl-1H-pyrazol-4-yl)ethyl]-3-[(1-hydroxycyclopropyl)methoxy]-2,3-dihydro-1H-isoindol-1-one;
(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[2-hydroxy-1-(4-methylpiperazin-1-yl)propan-2-yl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;
5-chloro-2-{[(1R)-1-(4-chlorophenyl)-1-[(1-cyanocyclopropyl)methoxy]-7-fluoro-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoic acid;
(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;
(3R)-2-{[4-chloro-2-(dimethylphosphoryl)phenyl]methyl}-3-(4-chlorophenyl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;
(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[hydroxy(oxan-4-yl)methyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;
1-({[(1R)-2-[(4-chloro-2-methanesulfonyl phenyl)methyl]-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(oxan-4-yl)ethyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carboxamide;
5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoic acid;
(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(oxan-4-yl)ethyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid;
4-[(1R)-1-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]-3-oxo-1-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]-2-hydroxyethyl]benzonitrile;
4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]-3-oxo-1-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]methyl}-3-(hydroxymethyl)benzonitrile;
4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile;
4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]-3-oxo-1-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile;
(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-(4-fluorooxan-4-yl)-1-hydroxyethyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid;
(4S)-4-(4-chlorophenyl)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-pyrazol-3-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol -2-yl]butanoic acid;
(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-(4-fluorooxan-4-yl)-1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid;
(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-5-(1-cyclobutyl -1-hydroxyethyl)-7-fluoro-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid;
(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid;
(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid;
(4S)-4-(4-chlorophenyl)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid;
(4S)-4-(4-chlorophenyl)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid;
(4S)-4-(4-Chlorophenyl)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluorooxan-4-yl)-1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid;
(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluorooxan-4-yl)-1-hydroxypropyl]-1-trideuteromethoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid;
(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-1-ethoxy-7-fluoro-5-[(1R)-1-(4-fluorooxan-4-yl)-1-hydroxypropyl]-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid;
(4S)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluorooxan-4-yl)-1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-4-(4-methoxyphenyl)butanoic acid;
(4S)-4-(4-chlorophenyl)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-{1-hydroxy-1-[trans-4-hydroxycyclohexyl]propyl}-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoic acid;
2-(5-chloro-2-{[1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluorooxan-4-yl)-1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenoxy)acetic acid;
5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoic acid;
5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoic acid;
5-chloro-2-{[(1R)-1-(4-chlorophenyl)-1-ethoxy-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoic acid;
2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluorooxan-4-yl)-1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}-5-methylbenzoic acid;
2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluorooxan-4-yl)-1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}-5-methoxybenzoic acid;
2-(5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenyl)-2-methylpropanoic acid;
2-(5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenyl)acetic acid;
2-(5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenyl)acetic acid;
(2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid;
(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-1-[(3-fluorooxetan-3-yl)methoxy]-5-(2-hydroxybutan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol -2-yl]propanoic acid;
(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(pyri din-2-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid;
(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-(4-fluoropiperidin-4-yl)-1-hydroxypropyl]-3-methoxy-2,3-dihydro-1H-isoindol-1-one;
4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(1-methylpiperidin-4-yl)propyl]-3-oxo-1-[ci s-3-hydroxycyclobutoxy]-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile;
(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-(4-fluoro-1-methylpiperidin-4-yl)-1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic acid;
tert-butyl 2-{4-[(1S)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}acetate;
tert-butyl 2-{4-[(1R)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}acetate;
2-{4-[(1S)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}acetic acid;
2-{4-[(1R)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}acetic acid;
methyl 3-{4-[(1S)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}propanoate;
and
3-{4-[(1S)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}propanoic acid;
or a tautomer, N-oxide, pharmaceutically acceptable salt or solvate thereof;
and
(ii) a compound which is SGI-110
or a tautomer or a solvate or a pharmaceutically acceptable salt thereof.

105 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/497,135Filed 28 Mar 2018
Priority: GB 170496628 Mar 2017
Published: US 2020/0207711 A12 Jul 2020
Granted: 1 Feb 2022
Term ends: Not estimatedThe source records don’t support an estimate.

Classification20 codes

C07D 209/46
Iso-indoles; Hydrogenated iso-indoles: with an oxygen atom in position 1
C07D 209/48
Iso-indoles; Hydrogenated iso-indoles: with oxygen atoms in positions 1 and 3, e.g. phthalimide
A61K 31/4035
Condensed with carbocyclic rings, e.g. carbazole: isoindoles, e.g. phthalimide
A61K 31/708
Containing purines, e.g. adenosine, adenylic acid: having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid

Family

US 2020/0207711 A1Pre-grant publication · published 2 Jul 2020
US 11,236,047 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A combination comprising:

(i) a compound of formula (Io):
or a tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein:
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, —(CRxR31)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, —(CRxR31)u—CO2H, —(CRxRy)u—CO2C1-4alkyl, and —(CRxRy)u—CONRxRy;
s is selected from 0 and 1;
R3 is hydrogen or -(A)t-(CRxRy)q—X;
t is selected from 0 and 1;
q is selected from 0, 1 and 2;
wherein when R3 is -(A)t-(CRxRy)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 C3-6cycloalkyl 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, —OR9, —(CH2)v—CO2H, —(CH2)v—CO2C1-4alkyl, —S(O)d—Rx, —C(═O)—C1-4alkyl, —S(O)d—N(H)e(C1-4alkyl)2−e, —NRxRy, —NHSO2Rx, —NRxCORy, and —C(═O)NRxRy;
R4 and R5 are independently selected from halogen, nitrile, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy and haloC1-4alkoxy;
R6 and R1 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 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 and R9 are independently 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, —C1-6 alkyl-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)k—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
(ii) a compound which is SGI-110
or a tautomer or a solvate or a pharmaceutically acceptable salt thereof.

25 more elements

Facts

Application

16/497,135Filed 28 Mar 2018

Priority

GB 170496628 Mar 2017

Published

US 2020/0207711 A12 Jul 2020

Granted

1 Feb 2022

Term ends

Not estimatedThe source records don’t support an estimate.

Classification20 codes

C07D 209/46
Iso-indoles; Hydrogenated iso-indoles: with an oxygen atom in position 1
C07D 209/48
Iso-indoles; Hydrogenated iso-indoles: with oxygen atoms in positions 1 and 3, e.g. phthalimide
A61K 31/4035
Condensed with carbocyclic rings, e.g. carbazole: isoindoles, e.g. phthalimide
A61K 31/708
Containing purines, e.g. adenosine, adenylic acid: having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid