Pyridazine derivatives for modulating nucleic acid splicing
AssigneeRemix Therapeutics Inc.
InventorsDominic Reynolds, Michael W. Seiler, Anant A. Agrawal, Frederic Vaillancourt, Allen T. Hopper, Peter Smith
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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.
Claims53
A compound of Formula (I-d):
- 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, —O—, —C(O)—, —N(R3)—, —N(R3)C(O)—, or —C(O)N(R3)—, wherein each alkylene and heteroalkylene is optionally substituted with one or more R4;
- M and P are each independently C(R2) or N;
- D, E, and F are each independently C(R5d), C(R5d)(R5e), N, N(R5f), S, or O, wherein the bonds between the atoms in the ring comprising D, E, and F may be a single bonds 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, C1-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, —SRE, or —S(O)xRD, wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R8;
- 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 R′;
- each R2 is independently hydrogen, halo, cyano, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, or —ORA;
- each R3 is independently hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl or heterocyclyl;
- wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R12;
- each R4 is C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, halo, cyano, oxo, —ORA, —NRBRC, —C(O)RD, or —C(O)ORD;
- R5d and R5c are each independently hydrogen, halo, or C1-C6 alkyl;
- or
- R5d and R5c are taken together to form an oxo group;
- R5f is hydrogen, halo, or C1-C6 alkyl;
- each R7 is independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, oxo, cyano, NRBC(O)RD, —C(O)NRBRC, —C(O)RD, or —SRE, wherein alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl are optionally substituted with one or more R9;
- or
- two R7 groups, together with the atoms to which they are attached (e.g., X or Y), form a 4-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R9;
- R8 and R9 are each 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 of 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, C1-C6 haloalkyl, 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, C1-C6-heteroalkyl, cycloalkyl, heterocyclyl, —ORA;
- 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 R10;
- each RD and RE 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 R10 is independently C1-C6-alkyl or halo;
- 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 deuterium, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or —ORA;
- n is 0, 1, 2, 3, or 4;
- and
- x is 0, 1, or 2.
The compound of any one of the preceding claims, wherein A is a nitrogen-containing heterocyclyl.
The compound of any one of the preceding claims, wherein A 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 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 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 L is —O— or —N(R3)—.
The compound of any one of the preceding claims, wherein L is —N(R3)— and R3 is hydrogen, C1-C6-alkyl, or cycloalkyl, wherein each alkyl and heteroalkyl are each optionally substituted with one or more R12.
The compound of any one of the preceding claims, wherein L is —N(CH3)— or —N(H)—.
The compound of any one of the preceding claims, wherein L is —N(CH3)—.
The compound of any one of the preceding claims, wherein
- is selected from
The compound of any one of the preceding claims, wherein
- 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 one of M and P is independently C(R2) (e.g., CH) and the other of M and P is independently N.
The compound of any one of the preceding claims, wherein M is CH and P is N.
The compound of any one of the preceding claims, wherein one of D, E, and F is independently N or N(R5f).
The compound of any one of the preceding claims, wherein two of D, E, and F is independently N or N(R5f).
The compound of any one of the preceding claims, wherein D is N, N(R5S), or S.
The compound of any one of the preceding claims, wherein D is N or N(R5S) (e.g., NH).
The compound of any one of the preceding claims, wherein each of D and E is independently N or N(R5S).
The compound of any one of the preceding claims, wherein F is C(R5d) or C(R5d)(R5e).
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.