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US 2025/0051344 A1Published application
Bifunctional selective degraders of smarca2 and therapeutic uses thereof
OwnerKatherine Keenan, Rishab N. Iyer +2inventors
InventorsKatherine Keenan, Rishab N. Iyer, Tim R. Kane, Jake C. Swartzel
Life of this patent
Estimating the term…
Abstract
The present disclosure provides bifunctional compounds as selective SMARCA2 degraders via ubiquitin proteosome pathway, and their therapeutic use for treating cancers.
Claims35
A compound having a structure represented by Formula (IA):
- or a stereoisomer, pharmaceutically acceptable salt thereof, wherein:
- R1 is hydrogen or C1-6 alkyl optionally substituted with 1 to 3 Ra;
- R2 is hydrogen, halo, hydroxyl, —O—Re, C1-6 alkyl optionally substituted with 1 to 3 Ra;
- R3 is hydrogen, —CN, C1-6 alkyl, C6-12 aryl, C3-12 cycloalkyl, 5-12 membered heteroaryl, each being optionally substituted with 1 to 3 Rd, or —O—Re;
- L comprises up to 8 linker segments represented by -L1-L2-L3-L4-L5-L6-L7-L8-, each L1, L2, L3, L4, L5, L6, L7, or L8, being independently:
- i) C3-12 cycloalkyl optionally substituted with 1-3 Rb;
- ii) C6-12 aryl optionally substituted with 1-3 Rb;
- iii) 4-12 membered heterocyclyl optionally substituted with 1-3 Rb;
- iv) 5-12 membered heteroaryl optionally substituted with 1-3 Rb;
- v) direct bond;
- vi) C1-12 alkylene chain optionally substituted with 1-3 Rb;
- or
- vii) —(CH2)m—C(O)—, —(CH2)m—C(O)O—, —(CH2)m—O—, —(CH2)m—N(Rc)—, —(CH2)m—S—, —(CH2)m—C(S)—, —(CH2)m—C(S)—O—, —(CH2)m—S(O)2—, —(CH2)m—S(O)═N—, —(CH2)m—S(O)2NH—, —(CH2)m—C(O)—N(Rc)—, —C(O)—N(Rc)—(CH2)m—, —(CH2)m—O—C(O)—N(Rc)—, —(CH2)m—O—C(O)—O—, or —NH—(CH2)m—C(O)—, wherein m is 0, 1, 2, 3, 4, 5 or 6;
- each Ra is independently halo, or —O—Rc;
- each Rb is independently oxo, imino, sulfoximino, halo, nitro, —CN, C1-6 alkyl, C2-6 alkenyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-12 aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclyl, —O—Rc, —C(O)—Rc, —C(O)O—Rc, —C(O)—N(Rc)(R), —N(Rc)(Rc), —N(Rc)C(O)—Rc, —N(Rc)C(O)O—Rc, —N(Rc)C(O)N(Rc)(Rc), —N(Rc)S(O)2(Rc), —NRcS(O)2N(Rc)(Rc), —N(Rc)S(O)2O(Rc), —OC(O)Rc, —OC(O)—N(Rc)(Rc), —Si(Rc)3, —S—Rc, —S(O)Rc, —S(O)(NH)Rc, —S(O)2Rc or —S(O)2N(Rc)(Rc), wherein each of C1-6 alkyl, C2-6 alkenyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-12 aryl, 5-12 membered heteroaryl, and 4-12 membered heterocyclyl may be optionally substituted with 1 to 3 Rd;
- each Rc is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C6-12 aryl or C1-6 haloalkyl, wherein C1-6 alkyl is optionally substituted with C1-3 alkoxy;
- each Rd is independently halo, —CN, —O—Rc, C1-6 alkyl, C6-12 aryl or C1-6 haloalkyl;
- Rc is C1-6 alkyl, C3-12 cycloalkyl, C6-12 aryl, 5-12 membered heteroaryl, each being optionally substituted with C1-6 alkyl or halo;
- W is —C(Rg)— or —N—;
- Y is direct bond, C1-4 alkylene chain, —C(O)—, —C(O)O—, —O—, —N(Rg)—, —S——C(S)—, —C(S)—O—, —O—C(O)O—, —C(O)—N(Rg)—, or —O—C(O)—N(Rg)—;
- B ring is C6-12 aryl, 5-12 membered heteroaryl, or 4-12 membered heterocyclyl, each being optionally substituted with 1 to 3 R3;
- Rg is hydrogen or C1-6 alkyl;
- and
- each Rj is independently halo, oxo, —CN, —O—Rc, C1-6 alkyl, or C1-6 haloalkyl.
21 more elements
A compound having a structure represented by Formula (I):
- or a stereoisomer, pharmaceutically acceptable salt thereof, wherein:
- R1 is hydrogen or C1-6 alkyl optionally substituted with 1 to 3 Ra;
- R2 is hydrogen, halo, hydroxyl, —O—Rc, C1-6 alkyl optionally substituted with 1 to 3 Ra;
- R3 is hydrogen, —CN, C1-6 alkyl, C6-12 aryl, C3-12 cycloalkyl, or 5-12 membered heteroaryl, each being optionally substituted with 1 to 3 Rd;
- L comprises up to 8 linker segments represented by -L1-L2-L3-L4-L5-L6-L7-L8-, each L1, L2, L3, L4, L5, L6, L7, or L8, being independently:
- i) C3-12 cycloalkyl optionally substituted with 1-3 Rb;
- ii) C6-12 aryl optionally substituted with 1-3 Rb;
- iii) 4-12 membered heterocyclyl optionally substituted with 1-3 Rb;
- iv) 5-12 membered heteroaryl optionally substituted with 1-3 Rb;
- v) direct bond;
- vi) C1-12 alkylene chain optionally substituted with 1-3 Rb;
- or
- vii) —(CH2)m—C(O)—, —(CH2)m—C(O)O—, —(CH2)m—O—, —(CH2)m—N(Rc)—, —(CH2)m—S—, —(CH2)m—C(S)—, —(CH2)m—C(S)—O—, —(CH2)m—S(O)2—, —(CH2)m—S(O)═N—, —(CH2)m—S(O)2NH—, —(CH2)m—C(O)—N(Rc)—, —C(O)—N(Rc)—(CH2)m—, —CH2)m—O—C(O)—N(Rc)—, —(CH2)m—O—C(O)—O—, or —NH—(CH2)m—C(O)—, wherein m is 0, 1, 2, 3, 4, 5 or 6;
- each Ra is independently halo, or —O—Rc;
- each Rb is independently oxo, imino, sulfoximino, halo, nitro, —CN, C1-6 alkyl, C2-6 alkenyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-12 aryl, 5-12 membered heteroaryl, 4-12 membered heterocyclyl, —O—R, —C(O)—Rc, —C(O)O—Rc, —C(O)—N(Rc)(Rc), —N(Rc)(Rc), —N(Rc)C(O)—Rc, —N(Rc)C(O)O—Rc, —N(Rc)C(O)N(Rc)(Rc), —N(Rc)S(O)2(Rc), —NRcS(O)2N(Rc)(Rc), —N(Rc)S(O)2O(Rc), —OC(O)Rc, —OC(O)—N(Rc)(Rc), —Si(Rc)3, —S—Rc, —S(O)Rc, —S(O)(NH)Rc, —S(O)2Rc or —S(O)2N(Rc)(Rc), wherein each of C1-6 alkyl, C2-6 alkenyl, C3-15 cycloalkyl, C1-8 haloalkyl, C6-12 aryl, 5-12 membered heteroaryl, and 4-12 membered heterocyclyl may be optionally substituted with 1 to 3 Rd;
- each Rc is independently hydrogen, C1-6 alkyl, or C1-6 haloalkyl;
- each Rd is independently halo, —CN, —O—Rc, C1-6 alkyl, C6-12 aryl or C1-6 haloalkyl;
- W is —C(Rg)— or —N—;
- Y is direct bond, C1-4 alkylene chain, —C(O)—, —C(O)O—, —O—, —N(Rg)—, —S——C(S)—, —C(S)—O—, —O—C(O)O—, —C(O)—N(Rg)—, or —O—C(O)—N(Rg)—;
- B ring is C6-12 aryl, 5-12 membered heteroaryl, or 4-12 membered heterocyclyl, each being optionally substituted with 1 to 3 Rj;
- Rg is hydrogen or C1-6 alkyl;
- and
- each Rj is independently halo, —CN, —O—Rc, C1-6 alkyl, or C1-6 haloalkyl.
20 more elements
-27. (canceled)
(canceled)
Dependencies are inferred from the claim text.