3-(5-oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Derivatives and Uses thereof
AssigneeNovartis AG
InventorsSimone BONAZZI, Artiom CERNIJENKO, Jennifer Stroka COBB, Janetta DEWHURST, John Ryan KERRIGAN, Gary O'BRIEN, MooJe SUNG, Noel Marie-France THOMSEN, Pamela TING
Life of this patent
Estimating the term…
Abstract
The present disclosure relates to compounds of formula (I) and pharmaceutical compositions and their use in reducing Widely Interspaced Zinc Finger Motifs (WIZ) expression levels, or inducing fetal hemoglobin (HbF) expression, and in the treatment of inherited blood disorders (e.g., hemoglobinopathies, e.g., beta-hemoglobinopathies), such as sickle cell disease and beta-thalassemia.
Claims60
A compound of formula (I′) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:
- each R1 is independently selected from hydrogen, C1-C6alkyl, hydroxyl, halo, C1-C6haloalkyl, C1-C6haloalkoxyl, and C1-C6alkoxyl;
- or 2 R1 on the same carbon atom together with the same carbon atom to which they are attached form a C3-C8cycloalkyl;
- or 2 R1 on adjacent carbon atoms together with the adjacent carbon atoms to which they are attached form a C3-C8cycloalkyl;
- or 2 R1 on non-adjacent carbon atoms together with the non-adjacent carbon atoms to which they are attached form a bridging ring;
- R2 is selected from hydrogen, C3-C11cycloalkyl, 4- to 11-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O, and S, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C10alkyl, —SO2R6, —C(═O)—R2a, —C(═O)—O—R2a, and —C(═O)NR2bR2c,
- wherein the C3-C11cycloalkyl, 4- to 11-membered heterocyclyl, C2-C6alkynyl, and C1-C10alkyl are each independently substituted with 0-5 occurrences of R3;
- R2a is selected from C1-C6alkyl, and 4- to 6-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O, and S;
- R2b and R2c are each independently selected from hydrogen, and C1-C6alkyl;
- each R3 is independently selected from C1-C6alkoxyl, halo, C6-C10aryl, 5- to 10-membered heteroaryl comprising 1-4 heteroatoms independently selected from N, O, and S, 4- to 11-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O, and S, and C3-C8cycloalkyl, wherein the C6-C10aryl, 5- to 10-membered heteroaryl, 4- to 11-membered heterocyclyl, and C3-C8cycloalkyl are each independently substituted with 0-4 occurrences of R4;
- each R4 is independently selected from C1-C10alkyl, C1-C6alkoxyl, halo, and C3-C8cycloalkyl, wherein the C3-C8cycloalkyl is substituted with 0-3 occurrences of R5;
- each R5 is independently selected from —CN, C1-C6alkyl, C1-C6alkoxyl, hydroxyl, and C1-C6haloalkyl;
- R6 is selected from C3-C8cycloalkyl, C1-C6alkyl, a 4- to 6-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O and S, and C6-C10aryl;
- n is 0, 1, 2, 3, 4, or 5;
- and
- m is 0, 1 or 2;
- with the proviso that the compound of formula (I′) does not include 3-(1-oxo-5-(pyrrolidin-3-yloxy)isoindolin-2-yl)piperidine-2,6-dione.
A compound of formula (I″) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:
- each R1 is independently selected from hydrogen, C1-C6alkyl, hydroxyl, halo, C1-C6haloalkyl, C1-C6haloalkoxyl, and C1-C6alkoxyl;
- or 2 R1 on the same carbon atom together with the same carbon atom to which they are attached form a C3-C8cycloalkyl;
- or 2 R1 on adjacent carbon atoms together with the adjacent carbon atoms to which they are attached form a C3-C8cycloalkyl;
- or 2 R1 on non-adjacent carbon atoms together with the non-adjacent carbon atoms to which they are attached form a bridging ring;
- R2 is selected from hydrogen, C3-C11cycloalkyl, 4- to 11-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O, and S, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C10alkyl, —SO2R6, —C(═O)—R2a, —C(═O)—O—R2a, and —C(═O)NR2bR2c,
- wherein the C3-C11cycloalkyl, 4- to 11-membered heterocyclyl, C2-C6alkynyl, and C1-C10alkyl are each independently substituted with 0-5 occurrences of R3;
- R2a is selected from C1-C6alkyl, and 4- to 6-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O, and S;
- R2b and R2c are each independently selected from hydrogen, and C1-C6alkyl;
- each R3 is independently selected from C1-C6alkoxyl, halo, C6-C10aryl, 5- to 10-membered heteroaryl comprising 1-4 heteroatoms independently selected from N, O, and S, 4- to 11-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O, and S, and C3-C8cycloalkyl, wherein the C6-C10aryl, 5- to 10-membered heteroaryl, 4- to 11-membered heterocyclyl, and C3-C8cycloalkyl are each independently substituted with 0-4 occurrences of R4;
- each R4 is independently selected from C1-C10alkyl, C1-C6alkoxyl, halo, and C3-C8cycloalkyl, wherein the C3-C8cycloalkyl is substituted with 0-3 occurrences of R5;
- each R5 is independently selected from —CN, C1-C6alkyl, C1-C6alkoxyl, hydroxyl, and C1-C6haloalkyl;
- R6 is selected from C3-C8cycloalkyl, C1-C6alkyl, a 4- to 6-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O and S, and C6-C10aryl;
- n is 0, 1, 2, 3, 4, or 5;
- and
- m is 1 or 2.
A compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:
- each R1 is independently selected from hydrogen, C1-C6alkyl, hydroxyl, halo, C1-C6haloalkyl, C1-C6haloalkoxyl, and C1-C6alkoxyl;
- or 2 R1 on the same carbon atom together with the same carbon atom to which they are attached form a C3-C8cycloalkyl;
- or 2 R1 on adjacent carbon atoms together with the adjacent carbon atoms to which they are attached form a C3-C8cycloalkyl;
- or 2 R1 on non-adjacent carbon atoms together with the non-adjacent carbon atoms to which they are attached form a bridging ring;
- R2 is selected from hydrogen, C3-C11cycloalkyl, 4- to 11-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O, and S, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, and C1-C10alkyl,
- wherein the C3-C11cycloalkyl, 4- to 11-membered heterocyclyl, C2-C6alkynyl, and C1-C10alkyl are each independently substituted with 0-5 occurrences of R3;
- each R3 is independently selected from C1-C6alkoxyl, halo, C6-C10aryl, 5- to 10-membered heteroaryl comprising 1-4 heteroatoms independently selected from N, O, and S, 4- to 11-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O, and S, and C3-C8cycloalkyl, wherein the C6-C10aryl, 5- to 10-membered heteroaryl, 4- to 11-membered heterocyclyl, and C3-C8cycloalkyl are each independently substituted with 0-4 occurrences of R4;
- each R4 is independently selected from C1-C10alkyl, C1-C6alkoxyl, halo, and C3-C8cycloalkyl, wherein the C3-C8cycloalkyl is substituted with 0-3 occurrences of R5;
- each R5 is independently selected from —CN, C1-C6alkyl, C1-C6alkoxyl, hydroxyl, and C1-C6haloalkyl;
- n is 0, 1, 2, 3 or 4;
- and
- m is 0, 1 or 2;
- with the proviso that the compound of formula (I) does not include 3-(1-oxo-5-(pyrrolidin-3-yloxy)isoindolin-2-yl)piperidine-2,6-dione.
The compound of formula (I′), (I″), or (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein m is 1 or 2.
The compound of formula (I′), (I″) or (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:
- each R1 is independently selected from hydrogen, C1-C6alkyl, hydroxyl, fluoro, and C1-C6alkoxyl;
- or 2 R1 on the same carbon atom together with the same carbon atom to which they are attached form a C3-C6cycloalkyl;
- or 2 R1 on adjacent carbon atoms together with the adjacent carbon atoms to which they are attached form a C3-C6cycloalkyl;
- or 2 R1 on non-adjacent carbon atoms together with the non-adjacent carbon atoms to which they are attached form a C1-C2 alkylene bridging ring;
- R2 is selected from hydrogen, C3-C11cycloalkyl, 4- to 11-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O, and S, C2-C6alkynyl, and C1-C6alkyl,
- wherein the C3-C11cycloalkyl is substituted with 0-3 occurrences of R3, wherein the C1-C6alkyl is substituted with 0-1 occurrence of R3a, and wherein the C2-C6alkynyl is substituted with 0-1 occurrence of R3b;
- each R3 is independently selected from C1-C6alkoxyl, and fluoro;
- R3a is selected from 4- to 11-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O, and S, and C3-C8cycloalkyl, wherein the 4- to 11-membered heterocyclyl, and C3-C8cycloalkyl are each independently substituted with 0-3 occurrences of R4;
- R3b is C3-C8cycloalkyl;
- each R4 is independently selected from C1-C6alkyl, C1-C6alkoxyl, fluoro, and C3-C8cycloalkyl;
- n is 0, 1, 2 or 3;
- and
- m is 1.
The compound of formula (I′), (I″) or (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:
- each R1 is independently selected from hydrogen, C1-C6alkyl, hydroxyl, fluoro, and C1-C6alkoxyl;
- or 2 R1 on the same carbon atom together with the same carbon atom to which they are attached form a C3-C6cycloalkyl;
- R2 is selected from C3-C8cycloalkyl, 4- to 6-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O, and S, C2-C6alkynyl, and C1-C6alkyl,
- wherein the C3-C8cycloalkyl is substituted with 0-3 occurrences of R3, wherein the C1-C6alkyl is substituted with 0-1 occurrence of R3a, and wherein the C2-C6alkynyl is substituted with 0-1 occurrence of R3b;
- each R3 is independently selected from C1-C6alkoxyl, and fluoro;
- R3a is C3-C8cycloalkyl, wherein the C3-C8cycloalkyl is substituted with 0-3 occurrences of R4;
- R3b is C3-C8cycloalkyl;
- each R4 is independently selected from C1-C6alkyl, C1-C6alkoxyl, fluoro, and C3-C8cycloalkyl;
- n is 0, 1, 2 or 3;
- and
- m is 1.
The compound of formula (I′), (I″) or (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein formula (I) is formula (IA):
The compound of formula (I′), (I″) or (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein R2 is unsubstituted C1-C6alkyl or —(CH2)—R3, wherein R3 is defined according to any one of the preceding claims.
The compound of formula (I′), (I″) or (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein R2 is selected from unsubstituted C1-C6alkyl,
The compound of formula (I′), (I″) or (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein R2 is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, and t-butyl.
The compound of formula (I′), (I″) or (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein m is 1.
The compound of formula (I′), (I″) or (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein n is 0, 1, 2 or 3, for example, n is 1.
The compound of formula (I′), (I″) or (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein R1 is selected from C1-C6alkyl, hydroxyl, halo, and C1-C6alkoxyl;
- or 2 R1 on the same carbon atom together with the same carbon atom to which they are attached form a C3-C8cycloalkyl.
The compound of formula (I′), (I″) or (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein R1 is selected from C1-C4alkyl, C1-C4alkoxyl, and fluoro;
- or 2 R1 on the same carbon atom together with the same carbon atom to which they are attached form a C3-C6cycloalkyl.
The compound of formula (I′), (I″) or (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein each R3 is independently selected from 4- to 11-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O, and S, C3-C8cycloalkyl, and halo, wherein the 4- to 11-membered heterocyclyl, and C3-C8cycloalkyl are each independently substituted with 0-2 occurrences of R4;
- wherein each R4 is independently selected from C1-C6alkyl, C1-C6alkoxyl, halo, and C3-C8cycloalkyl.
The compound of formula (I′), (I″) or (I) according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein each R4 is independently selected from C1-C6alkyl, and fluoro.
A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.
A compound a compound of Formula (Y)
- wherein each R1 is independently selected from hydrogen, C1-C6alkyl, hydroxyl, halo, C1-C6haloalkyl, C1-C6haloalkoxyl, and C1-C6alkoxyl;
- or 2 R1 on the same carbon atom together with the same carbon atom to which they are attached form a C3-C8cycloalkyl;
- or 2 R1 on adjacent carbon atoms together with the adjacent carbon atoms to which they are attached form a C3-C8cycloalkyl;
- or 2 R1 on non-adjacent carbon atoms together with the non-adjacent carbon atoms to which they are attached form a bridging ring;
- n is 0, 1, 2, 3, 4, or 5;
- m is 0, 1 or 2;
- and
- each of PG1 and PG2 is independently a nitrogen protecting group.
Dependencies are inferred from the claim text.