US 12,391,686 B2
Compounds and uses thereof
Sabine K. Ruppel, Cambridge, MA (US); Zhaoxia Yang, Belmont, MA (US); Jason T. Lowe, East Bridgewater, MA (US); Johannes H. Voigt, Cambridge, MA (US); Matthew Netherton, Cambridge, MA (US); and Francois Brucelle, Belmont, MA (US)
Assigned to FOGHORN THERAPEUTICS INC., Cambridge, MA (US)
Appl. No. 17/425,132
Filed by Foghorn Therapeutics Inc., Cambridge, MA (US)
PCT Filed Jan. 29, 2020, PCT No. PCT/US2020/015740
§ 371(c)(1), (2) Date Jul. 22, 2021,
PCT Pub. No. WO2020/160192, PCT Pub. Date Aug. 6, 2020.
Claims priority of provisional application 62/798,434, filed on Jan. 29, 2019.
Claims priority of provisional application 62/881,163, filed on Jul. 31, 2019.
Claims priority of provisional application 62/881,018, filed on Jul. 31, 2019.
Prior Publication US 2023/0077730 A1, Mar. 16, 2023
Int. Cl. C07D 471/04 (2006.01); A61K 31/4745 (2006.01); A61P 35/00 (2006.01); C07D 401/04 (2006.01); C07D 401/14 (2006.01); C07D 519/00 (2006.01)
CPC C07D 471/04 (2013.01) [A61P 35/00 (2018.01); C07D 401/14 (2013.01); C07D 519/00 (2013.01)] 22 Claims
 
1. A compound having the structure of Formula II:
A-L-B   Formula II,
wherein
L is a linker having the structure of Formula IV
A1-(B1)f—(C1)g—(B2)h-(D)-(B3)i—(C2)j—(B4)k-A2   Formula IV
wherein
A1 is a bond between the linker and A;
A2 is a bond between B and the linker;
each of B1, B2, B3, and B4 is, independently, optionally substituted C1-C2 alkyl, optionally substituted C1-C3 heteroalkyl, O, S, S (O)2, or NRN;
each RN is, independently, H, optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C2-6 heterocyclyl, optionally substituted C6-12 aryl, or optionally substituted C1-7 heteroalkyl;
each of C1 and C2 is, independently, carbonyl, thiocarbonyl, sulphonyl, or phosphoryl;
each of f, g, h, i, j, and k is, independently, 0 or 1; and
D is optionally substituted C1-10 alkyl, optionally substituted C2-10 alkenyl, optionally substituted C2-10 alkynyl, optionally substituted C2-6 heterocyclyl, optionally substituted C6-12 aryl, optionally substituted C2-C10 polyethylene glycol, or optionally substituted C1-10 heteroalkyl, or a chemical bond linking A1-(B1)f—(C1)g—(B2)h-to —(B3)i—(C2)j—(B4)k-A2;
B is a degradation moiety having the structure of Formula A

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wherein in
Y1 is

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RA5 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;
RA6 is H or optionally substituted C1-C6 alkyl; and RA7 is H or optionally substituted C1-C6 alkyl; or RA6 and RA7, together with the carbon atom to which each is bound, combine to form optionally substituted C3-C6 carbocyclyl or optionally substituted C2-C5 heterocyclyl; or RA6 and RA7, together with the carbon atom to which each is bound, combine to form optionally substituted C3-C6 carbocyclyl or optionally substituted C2-C5 heterocyclyl;
RA8 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl;
each of RA1, RA2, RA3, and RA4 is, independently, H, A2, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted-O—C3-C6 carbocyclyl, hydroxyl, mercapto, or optionally substituted amino; or RA1 and RA2, RA2 and RA3, and/or RA3 and RA4, together with the carbon atoms to which each is attached, combine to form

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is optionally substituted C6-C10 aryl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heteroaryl, or C2-C9 heterocyclyl, any of which is optionally substituted with A2,
wherein one of RA1, RA2, RA3, and RA4 is A2, or

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is substituted with A2; and
A has the structure of Formula III:

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wherein R1 is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted C3-C10 carbocyclyl;
Z1 is CR2 or N;
R2 is H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 carbocyclyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, or optionally substituted C2-C9 heteroaryl;
X1 is N or CH, and X2 is C—R7″; or X1 is C—R7″, and X2 is N or CH;
R7″ is

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optionally substituted C1-C6 alkoxy, optionally substituted amino, optionally substituted sulfone, optionally substituted sulfonamide, optionally substituted carbocyclyl having 3 to 6 atoms, or optionally substituted heterocyclyl having 3 to 6 atoms;
R7′ is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted C3-C10 carbocycylyl;
X3 is N or CH;
X4 is N or CH;
G″ is

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optionally substituted C3-C10 carbocyclyl, C2-C9 heterocyclyl, optionally substituted C6-C10 aryl, or optionally substituted C2-C9 heteroaryl;
G′ is optionally substituted C3-C10 carbocyclylene, C2-C9 heterocyclylene, optionally substituted C6-C10 arylene, or optionally substituted C2-C9 heteroarylene; and
A1 is a bond between A and the linker,
where G″ is

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or R7″ is

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or a pharmaceutically acceptable salt thereof,
wherein optionally substituted moieties when substituted comprise a substituent selected from alkyl, aryl, carbocyclyl, halogen, hydroxyl, heteroalkyl, heteroaryl, heterocyclyl, amino, azido, cyano, nitro, oxo, sulfonyl, or thiol.