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, Gulseher Sarah Sirin
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.
Claims183
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;
- W, X, Y, and Z are each independently C(R3a) or N, wherein at least one of W, X, Y, and Z is independently N;
- L1 is absent, C1-C6-alkylene, C1-C6-heteroalkylene, —O—, —C(O)—, —N(R4)—, —N(R4)C(O)—, or —C(O)N(R4)—, wherein each alkylene and heteroalkylene is optionally substituted with one or more R5;
- 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, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-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 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 is 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;
- each R4 is independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl;
- each R5 is independently hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, halo, cyano, oxo, —ORA, —NRBRC, —C(O)RD, or —C(O)ORD;
- 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 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, or —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 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;
- m is 0, 1, or 2;
- 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 N
- and 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 R7.
The compound of any one of the preceding claims, wherein one of A and B is independently
- 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 R7.
The compound of any one of the preceding claims, wherein A is selected from
- wherein each Ra 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 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
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 A is
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 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 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 L1 is absent, —N(R4)C(O)—, or —C(O)N(R4)—.
The compound of any one of the preceding claims, wherein L1 is —C(O)N(R4)—.
The compound of any one of the preceding claims, wherein W is N.
The compound of any one of the preceding claims, wherein at least two of W, X, Y, and Z is independently N.
The compound of any one of the preceding claims, wherein W and X are each independently N.
The compound of any one of the preceding claims, wherein R3a is C1-C6-alkyl or C1-C6-heteroalkyl.
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 compound of Formula (II):
- 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;
- M and P are each independently C(R2) or N, wherein at least one of M and P is independently N;
- W, X, Y, and Z are each independently C(R3) or N, wherein at least one of W, X, Y, and Z is N;
- each of L1 and L2 is independently absent, C1-C6-alkylene, C1-C6-heteroalkylene, —O—, —C(O)—, —N(R4)—, —N(R4)C(O)—, or —C(O)N(R4)—, wherein each alkylene and heteroalkylene is optionally substituted with one or more R5;
- 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, —ORA, —NRBRC, —NBC(O)RD, —NO2, —C(O)NRBRC, —C(O)ORD, or —S(O)xRD, or —C(O)RD;
- R3 is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, —ORA, —NRBRC, —NBC(O)RD, —NO2, —C(O)NRBRC, —C(O)ORD, or —S(O)xRD, or —C(O)RD;
- each R4 is independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl;
- each R5 is independently hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, halo, cyano, oxo, —ORA, —NRBRC, —C(O)RD, or —C(O)ORD;
- 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, 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;
- 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;
- 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 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 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 one of A and B is independently
- 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 R7.
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 R7.
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
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 A is
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 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 one of LC and L2 is independently absent, —N(R4)C(O)—, or —C(O)N(R4)—.
The compound of any one of the preceding claims, wherein each of L1 and L2 is independently absent, —N(R4)C(O)—, or —C(O)N(R4)—.
The compound of any one of the preceding claims, wherein each of L1 and L2 is independently absent.
The compound of any one of the preceding claims, wherein L1 is —C(O)N(R4)—.
The compound of any one of the preceding claims, wherein L2 is absent.
The compound of any one of the preceding claims, wherein L1 is —C(O)NH— and L2 is absent.
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 W is independently N.
The compound of any one of the preceding claims, wherein X is N.
The compound of any one of the preceding claims, wherein Y is N.
The compound of any one of the preceding claims, wherein Z is N.
The compound of any one of the preceding claims, wherein one of W and X is independently N.
The compound of any one of the preceding claims, wherein two of W, X, Y, and Z are independently N.
The compound of any one of the preceding claims, wherein
- is selected from N and N
The compound of any one of the preceding claims, wherein the compound is selected from any one of the compounds shown in Table 2 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.
The compound of any one of claims 1-118, or the pharmaceutical composition of claim 117, wherein the compound alters a target nucleic acid (e.g., an RNA, e.g., a pre-mRNA).
A method of forming a complex comprising a component of a spliceosome (e.g., a major spliceosome component or a minor spliceosome component), a nucleic acid (e.g., a DNA, RNA, e.g., a pre-mRNA), and a compound of Formula (I), (II), or (III), described herein:
- comprising contacting the nucleic acid (e.g., a DNA, RNA, e.g., a pre-mRNA) with a compound of Formula (I), (II), or (III).
A method of altering the conformation of a nucleic acid (e.g., a DNA, RNA, e.g., a pre-mRNA) comprising contacting the nucleic acid with a compound of Formula (I), (II), or (III) or a pharmaceutically acceptable salt or a composition thereof.
A method for treating a disease or disorder in a subject comprising administering to the subject a a compound of Formula (I), (II), or (III) or a pharmaceutically acceptable salt or a composition thereof.
A method of treating a proliferative disease in a subject comprising administering to the subject a compound of Formula (III) or a composition comprising a compound of Formula (III) and a pharmaceutically acceptable excipient, wherein the compound of Formula (III) is:
- 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;
- L2 is absent, C1-C6-alkylene, C1-C6-heteroalkylene, —O—, —C(O)—, —N(R3)—, —N(R3)C(O)—, or —C(O)N(R3)—, wherein alkylene and heteroalkylene are optionally substituted with one or more R4;
- 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, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R5;
- 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 R5;
- each R2 is independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, or —ORA;
- each R3 is independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl;
- each R4 is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, halo, cyano, oxo, —ORA, —NRBRC, —C(O)RD, or —C(O)ORD;
- each R5 is independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, —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 R7 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 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, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6-heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, —ORA, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl is optionally substituted with one or more R7;
- or
- RB and RC together with the nitrogen atom to which they are attached form a 3-7-membered heterocyclyl or heteroaryl, wherein each heterocyclyl or heteroaryl is optionally substituted with one or more R7;
- 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;
- m is 0, 1, or 2;
- and
- x is 0, 1, or 2.
The method 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 method 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 method of any one of the preceding claims, wherein one of A and B is independently selected from
The method of any one of the preceding claims, wherein one of A and B is independently selected from
The method of any one of the preceding claims, wherein A is selected from
The method of any one of the preceding claims, wherein B is selected from
The method of any one of the preceding claims, wherein each of A and B is independently heteroaryl or heterocyclyl, each of which is optionally substituted with one or more R1.
The method 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 method 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 method 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 method 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 method of any one of the preceding claims, wherein one of A and B is independently selected from RN
The method of any one of the preceding claims, wherein one of A and B is independently
- 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 R7.
The method of any one of the preceding claims, wherein one of A and B is independently is selected from
The method of any one of the preceding claims, wherein A is independently is selected from
The method of any one of the preceding claims, wherein B is independently is selected from
The method of any one of the preceding claims, wherein L2 is absent, C1-C6-alkylene, C1-C6-heteroalkylene, —N(R3)C(O)—, or —C(O)N(R3)—, wherein each alkylene and heteroalkylene is optionally substituted with one or more R4.
The method of any one of the preceding claims, wherein L2 is absent or —C(O)N(R3)—.
The method of any one of the preceding claims, wherein
- is selected from
- wherein each X is independently halo (e.g., fluoro, chloro, bromo, or iodo).
The method of any one of the preceding claims, wherein
- is
The method of any one of the preceding claims, wherein m is 1 and R2 is halo (e.g., fluoro).
The method of any one of the preceding claims, wherein the compound is selected from a compound listed in Table 3 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.
The method of any one of the preceding claims, wherein the proliferative disease is selected from a cancer, a benign neoplasm, or angiogenesis.
The method of any one of the preceding claims, wherein the proliferative disease is cancer.
A composition for use in treating a proliferative disease in a subject comprising administering to the subject a compound of Formula (III):
- 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;
- L2 is absent, C1-C6-alkylene, C1-C6-heteroalkylene, —O—, —C(O)—, —N(R3)—, —N(R3)C(O)—, or —C(O)N(R3)—, wherein alkylene and heteroalkylene are optionally substituted with one or more R4;
- 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, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R5;
- 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 R5;
- each R2 is independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, or —ORA;
- each R3 is independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl;
- each R4 is independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, halo, cyano, oxo, —ORA, —NRBRC, —C(O)RD, or —C(O)ORD;
- each R5 is independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, —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 R7 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 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, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6-heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, —ORA, wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl is optionally substituted with one or more R7;
- or
- RB and RC together with the nitrogen atom to which they are attached form a 3-7-membered heterocyclyl or heteroaryl, wherein each heterocyclyl or heteroaryl is optionally substituted with one or more R7;
- 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;
- m is 0, 1, or 2;
- and
- x is 0, 1, or 2.
Dependencies are inferred from the claim text.