Compounds and methods for modulating splicing
AssigneeRemix Therapeutics Inc.
InventorsDominic Reynolds, Michael W. Seiler, Anant A. Agrawal, Frederic Vaillancourt, Peter Smith, Sudeep Prajapati, Allen t. Hopper, Stepan Vyskocil, Benoit Moreau
Life of this patent
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Abstract
The present disclosure features compounds and related compositions that, inter alia, modulate nucleic acid splicing, e.g., splicing of a pre-mRNA, as well as methods of use thereof.
Claims96
A compound of Formula (I):
- or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:
- A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R1;
- L is absent, C1-C6-alkylene, C1-C6-heteroalkylene, C(O), or —C(O)N(RB)—, wherein each alkylene and heteroalkylene is optionally substituted with one or more R8;
- W, X, Z1, and Z2 are each independently C(R3) or N, wherein at least one of W and X is N;
- each R1 is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, C1-C6 heteroalkylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C1-C6 heteroalkylene-heteroaryl, halo, cyano, oxo, —ORA, —NRBRC, —NRBC(O)RD, —NO2, —C(O)NRBRC, —C(O)RD, —C(O)ORD, or —S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R4;
- or
- two R1 groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R4;
- R2 is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, —C(O)RD, or —ORA;
- wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R5;
- R3 is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, —C(O)RD, or —ORA;
- wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R5;
- each R4 is independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, —ORA, —NRBRC, —NRBC(O)RD, —NO2, —C(O)NRBRC, —C(O)RD, —C(O)ORD, or —S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6;
- each R5 is C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, —ORA, —NRBRC, —NRBC(O)RD, —NO2, —C(O)NRBRC, —C(O)RD, —C(O)ORD, or —S(O)xRD;
- each R6 is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or —ORA;
- each RA is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, —C(O)RD, or —S(O)xRD;
- each of RB and RC is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)RD, or —S(O)xRD;
- or
- RB and RC together with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R7;
- each RD is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl;
- each R7 and R8 is independently C1-C6-alkyl, halo, cyano, oxo, or —ORA1;
- each RA1 is hydrogen or C1-C6-alkyl;
- and
- x is 0, 1, or 2.
The compound of any one of the preceding claims, wherein one of A and B is independently a monocyclic heteroaryl or bicyclic heteroaryl, each of which is optionally substituted with one or more R1.
The compound of any one of the preceding claims, wherein one of A and B is independently a bicyclic heteroaryl optionally substituted with one or more R1.
The compound of any one of the preceding claims, wherein one of A and B is independently a nitrogen-containing heteroaryl optionally substituted with one or more R1.
The compound of any one of the preceding claims, wherein one of A and B is a 5-10 membered heteroaryl optionally substituted with one or more R1.
The compound of any one of the preceding claims, wherein one of A and B is independently selected from
- wherein each R1 is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, or —ORA, and each alkyl, heteroalkyl, and haloalkyl is optionally substituted with one or more R4.
The compound of any one of the preceding claims, wherein one of A and B is independently
- wherein each R1 is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, or —ORA, and each alkyl, heteroalkyl, and haloalkyl is optionally substituted with one or more R4.
The compound of any one of the preceding claims, wherein A is selected from
- wherein each R1a is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, or —ORA, and each alkyl, heteroalkyl, and haloalkyl is optionally substituted with one or more R4.
The compound of any one of the preceding claims, wherein one of A and B is independently selected from
The compound of any one of the preceding claims, wherein one of A and B is independently selected from
The compound of any one of the preceding claims, wherein one of A and B is independently selected from
The compound of any one of the preceding claims, wherein A is selected from
The compound of any one of the preceding claims, wherein B is selected from
The compound of any one of the preceding claims, wherein A selected from
The compound of any one of the preceding claims, wherein B selected from
The compound of any one of the preceding claims, wherein one of A and B is independently a monocyclic heterocyclyl or bicyclic heterocyclyl, each of which is optionally substituted with one or more R1.
The compound of any one of the preceding claims, wherein one of A and B is independently a nitrogen-containing heterocyclyl optionally substituted with one or more R1.
The compound of any one of the preceding claims, wherein one of A and B is independently a 4-8 membered heterocyclyl optionally substituted with one or more R1.
The compound of any one of the preceding claims, wherein one of A and B is independently selected from
The compound of any one of the preceding claims, wherein one of A and B is independently selected from
The compound of any one of the preceding claims, wherein one of A and B is
The compound of any one of the preceding claims, wherein A is selected from
The compound of any one of the preceding claims, wherein B is selected from
The compound of any one of the preceding claims, wherein A is selected from
The compound of any one of the preceding claims, wherein B is selected from
The compound of any one of the preceding claims, wherein X is N.
The compound of any one of the preceding claims, wherein W is N.
The compound of any one of the preceding claims, wherein both of W and X is independently N.
The compound of any one of the preceding claims, wherein Z1 is C(R3) (e.g., CH).
The compound of any one of the preceding claims, wherein Z1 is N.
The compound of any one of the preceding claims, wherein X is N and W, Z1, and Z2 are each independently C(R3).
The compound of any one of the preceding claims, wherein X and Z1 are each independently N, and W and Z2 are each independently C(R3).
The compound of any one of the preceding claims, wherein X and W are each independently N and Z1 is C(R3).
The compound of any one of the preceding claims, wherein each of W, X, and Z1 are each independently N, and Z1 is C(R3).
The compound of any one of the preceding claims, wherein R2 is hydrogen.
The compound of any one of the preceding claims, wherein R2 is C1-C6-alkyl, halo, or —ORA.
The compound of any one of the preceding claims, wherein R2 is —CH3, —Cl, —F, —OCH3, or
The compound of any one of the preceding claims, wherein L is absent or C1-C6-alkylene optionally substituted with one or more R8.
The compound of any one of the preceding claims, wherein L is absent.
The compound of the preceding claims, wherein:
- A and B are each independently selected from heteroaryl (e.g., bicyclic heteroaryl) optionally substituted with R1 and heterocyclyl (e.g., monocyclic heterocyclyl) optionally substituted with one or more R1;
- and
- m is 0 or 1;
- and
- R2 is C1-C6-alkyl, halo, or —ORA.
The compound of any one of the preceding claims, wherein when Z1 is N, B is bicyclic heteroaryl optionally substituted with one or more R1, wherein at least one R1 comprises an oxygen atom.
The compound of any one of the preceding claims, wherein the compound is selected from a compound listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.
A pharmaceutical composition comprising a compound of any one of the preceding claims and a pharmaceutically acceptable excipient.
Dependencies are inferred from the claim text.