Compounds and methods for modulating splicing
AssigneeRemix Therapeutics Inc.
InventorsDominic Reynolds, Benoît Moreau, Sudeep Prajapati, Stepan Vyskocil, Derek LaPlaca, Francois Brucelle
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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.
Claims101
A compound of Formula (I-c):
- or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:
- A is a nitrogen-containing heterocyclyl optionally substituted with one or more R1;
- B is a nitrogen-containing heteroaryl and optionally substituted with one or more R1;
- X, Y, and Z are each independently C(R3a), C(R3a)(R3b), N, N(R3c), S, or O, wherein at least one of X, Y, and Z is N, N(R3c), or O, and the bonds in the ring comprising X, Y, and Z may be single or double bonds as valency permits;
- 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, —SRE, or —S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R6;
- 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 R6;
- each R2 is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, —ORA, —NRBRC, —C(O)RD, or —C(O)ORD;
- R3a and R3b are each independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, —ORA, —NRBRC, —C(O)RD, or —C(O)ORD;
- or
- each of R3a and R3b, together with the carbon atom to which they are attached, form an oxo group;
- R3c is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, C1-C6 alkylene-cycloalkyl, heterocyclyl, C1-C6 alkylene-heterocyclyl, aryl, C1-C6 alkylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, or —C(O)RD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8;
- each R4 is independently hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, or C1-C6-haloalkyl;
- each R6 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, —SRE, or —S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R11;
- each R8 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, —SRE, or —S(O)xRD, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R12;
- each R11 is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or —ORA;
- each R12 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 haloalkyl, 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 RA1 is hydrogen or C1-C6-alkyl;
- m is 0, 1, or 2;
- and
- x is 0, 1, or 2.
The compound of any one of the preceding claims, wherein B is monocyclic heteroaryl optionally substituted with one or more R1.
The compound of any one of the preceding claims, wherein B is bicyclic heteroaryl optionally substituted with one or more R1.
The compound of any one of the preceding claims, wherein B is a 5-10 membered heteroaryl optionally substituted with one or more R1.
The compound of any one of the preceding claims, wherein B is a bicyclic nitrogen-containing heteroaryl containing at least two nitrogen atoms optionally substituted with one or more R1.
The compound of any one of the preceding claims, wherein B is selected from
- and 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 R7.
The compound of any one of the preceding claims, wherein B is
- and 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 R7.
The compound of any one of the preceding claims, wherein B is
- and 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 R7.
The compound of any one of the preceding claims, wherein B 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 B is selected from
The compound of any one of the preceding claims, wherein A is 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 A is a monocyclic nitrogen-containing heterocyclyl optionally substituted with one or more R1.
The compound of any one of the preceding claims, wherein A is a 4-8 membered heterocyclyl optionally substituted with one or more R1.
The compound of any one of the preceding claims, wherein A is 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 one of A and B is
The compound of any one of the preceding claims, wherein at least one of X, Y, and Z is N or N(R3c).
The compound of any one of the preceding claims, wherein one of X, Y, and Z is C(R3a) (e.g., CH), and the others of X, Y, and Z are each independently N or N(R3c).
The compound of any one of the preceding claims, wherein Z and Y are each independently N or N(R3c), and X is C(R3a) (e.g., CH).
The compound of any one of the preceding claims, wherein X is C(R3a) (e.g., CH), and Y and Z are each independently N or N(R3c).
The compound of any one of the preceding claims, wherein
- is selected from
The compound of any one of the preceding claims, wherein
The compound of any one of the preceding claims, wherein R3c is C1-C6-alkyl, C2-C6-alkenyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, C1-C6 alkylene-heterocyclyl, aryl, C1-C6 alkylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, heteroaryl, wherein each alkyl, alkylene, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8.
A compound of Formula (II-c):
- or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:
- A is a nitrogen-containing heterocyclyl optionally substituted with one or more R1;
- B is a nitrogen-containing heteroaryl and optionally substituted with one or more R1;
- M and P are each independently C(R2) or N;
- U and W are each independently C or N;
- X, Y, and Z are each independently C(R3a), C(R3a)(R3b), N, N(R3c), S, or O, wherein at least one of X, Y, and Z is N or N(R3c), and the bonds in the ring comprising U, W, X, Y, and Z may be single or double bonds as valency permits;
- 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 alkylene-heteroaryl, 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 R6;
- 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 R6;
- each R2 is independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, or —ORA,
- R3a and R3b are each independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, ORA, —NRBRC, —C(O)RD, or —C(O)ORD;
- or
- each of R3a and R3b, together with the carbon atom to which they are attached, form an oxo group;
- R3c is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, C1-C6 alkylene-cycloalkyl, heterocyclyl, C1-C6 alkylene-heterocyclyl, aryl, C1-C6 alkylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, or —C(O)RD, wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8;
- each R4 is independently hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, or C1-C6-haloalkyl;
- each R6 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, —NRBN(RB)(RC), —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 R11;
- each RA is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, —C(O)RD, or —S(O)xRD, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, and C1-C6 alkylene-heteroaryl is optionally substituted with one or more R7;
- 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, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl, —ORA, —C(O)NRBRC, —C(O)RD, —C(O)ORD, or —S(O)xRD, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, and C1-C6 alkylene-heteroaryl is optionally substituted with one or more R7;
- 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 is C1-C6-alkyl, halo, cyano, oxo, or —ORA1;
- each R11 is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or —ORA;
- 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 B is monocyclic heteroaryl optionally substituted with one or more R1.
The compound of any one of the preceding claims, wherein B is bicyclic heteroaryl optionally substituted with one or more R1.
The compound of any one of the preceding claims, wherein B is a 5-10 membered heteroaryl optionally substituted with one or more R1.
The compound of any one of the preceding claims, wherein B is a bicyclic nitrogen-containing heteroaryl containing at least two nitrogen atoms optionally substituted with one or more R1.
The compound of any one of the preceding claims, wherein B is selected from
- and 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 R7.
The compound of any one of the preceding claims, wherein B is
- and 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 R7.
The compound of any one of the preceding claims, wherein B is
- and 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 R7.
The compound of any one of the preceding claims, wherein B 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 B is
The compound of any one of the preceding claims, wherein A is 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 A is a monocyclic nitrogen-containing heterocyclyl optionally substituted with one or more R1.
The compound of any one of the preceding claims, wherein A is a 4-8 membered heterocyclyl optionally substituted with one or more R1.
The compound of any one of the preceding claims, wherein A is 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 one of A and B is
The compound of any one of the preceding claims, wherein each of M and P is independently C(R2) (e.g., CH).
The compound of any one of the preceding claims, wherein M is C(R2) (e.g., CH) and P is N.
The compound of any one of the preceding claims, wherein M is N and P is C(R2) (e.g., CH).
The compound of any one of the preceding claims, wherein each of U and W is independently C.
The compound of any one of the preceding claims, wherein U is C and W is N.
The compound of any one of the preceding claims, wherein U is N and W is C.
The compound of any one of the preceding claims, wherein one of X, Y, and Z is C(R3a) (e.g., CH), and the others of X, Y, and Z are each independently N, N(R3c), or S.
The compound of any one of the preceding claims, wherein two of X, Y, and Z are independently N or N(R3c).
The compound of any one of the preceding claims, wherein X and Y are each independently N or N(R3c), and Z is C(R3a) (e.g., CH).
The compound of any one of the preceding claims, wherein X is C(R3a) (e.g., CH), and Y and Z are each independently N or N(R3c).
The compound of any one of the preceding claims, wherein two of X, Y, and Z independently is C(R3a) (e.g., CH).
The compound of any one of the preceding claims, wherein
- is selected from
The compound of any one of the preceding claims, wherein the compound is selected from any one of the compounds shown 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.