US 12,329,821 B2
Degradation of bruton's tyrosine kinase (BTK) by conjugation of BTK inhibitors with E3 ligase ligand and methods of use
Nathanael S. Gray, Stanford, CA (US); Dennis Dobrovolsky, Toronto (CA); and Hai-Tsang Huang, Boston, MA (US)
Assigned to DANA-FARBER CANCER INSTITUTE, INC., Boston, MA (US)
Filed by DANA-FARBER CANCER INSTITUTE, INC., Boston, MA (US)
Filed on Jun. 27, 2023, as Appl. No. 18/214,825.
Application 18/214,825 is a division of application No. 17/123,955, filed on Dec. 16, 2020, granted, now 11,730,818.
Application 17/123,955 is a division of application No. 16/343,979, granted, now 10,925,967, issued on Feb. 23, 2021, previously published as PCT/US2017/063027, filed on Nov. 22, 2017.
Claims priority of provisional application 62/425,211, filed on Nov. 22, 2016.
Prior Publication US 2023/0338551 A1, Oct. 26, 2023
Int. Cl. C07D 487/04 (2006.01); A61K 31/427 (2006.01); A61K 31/454 (2006.01); A61K 31/497 (2006.01); A61K 47/54 (2017.01); A61K 47/55 (2017.01); C07D 401/14 (2006.01); C07D 409/14 (2006.01); C07D 417/14 (2006.01)
CPC A61K 47/55 (2017.08) [A61K 31/427 (2013.01); A61K 31/454 (2013.01); A61K 31/497 (2013.01); A61K 47/545 (2017.08); C07D 401/14 (2013.01); C07D 409/14 (2013.01); C07D 417/14 (2013.01); C07D 487/04 (2013.01)] 21 Claims
 
1. A bifunctional compound of Formula X:

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wherein:
the Targeting Ligand is of Formula-II:

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or a stereoisomer, wherein:
A is phenyl or 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S, wherein the phenyl or heteroaryl is optionally substituted with 1 to 3 R8;
B is phenyl or 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S, wherein the phenyl or heteroaryl is optionally substituted with 1 to 3 R9;
Y2 is NR10a or O;
Y3 is C(O)NR10b or NR10bC(O);
Y4 is NR5′ or, when B is bonded to Y4, N;
R5′ is H, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, or halogen;
each R5 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, or oxo;
R6 is H, (C1-C4) alkyl, or (C1-C4) haloalkyl;
each R7 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl, halogen, OH, or NH2;
each R8 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, NH2, or (C3-C6) cycloalkyl; or two R8 together with the atoms to which they are attached form a (C5-C7) cycloalkyl ring; or R8 and R10b together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R11;
each R9 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, or halogen;
R10a and R10b are each independently H, (C1-C4) alkyl, or (C1-C4) haloalkyl; or R8 and R10b together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl or heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 3 R11;
each R11 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2; and
o1 and o2 are each independently 0, 1, 2, or 3,
wherein the Targeting Ligand is bonded to the Linker via the

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 next to

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 in
the Linker is a group that covalently binds to the Targeting Ligand and the Degron; and
the Degron is of Formula D1 or D2:

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or a stereoisomer thereof, wherein:
Y is a bond, (CH2)1-6, (CH2)0-6—O, (CH2)0-6—C(O)NR26, (CH2)0-6—NR26C(O), (CH2)0-6—NH, or (CH2)0-6—NR27;
Z3 is C(O) or C(R28)2;
R26 is H or C1-C6 alkyl;
R27 is C1-C6 alkyl or C(O)—C1-C6 alkyl;
each R28 is independently H or C1-C3 alkyl;
each R29 is independently C1-C3 alkyl;
R30 is H, deuterium, C1-C3 alkyl, F, or Cl;
each R31 is independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy;
q is 0, 1, or 2; and
v is 0, 1, 2, or 3, and
each R32 is independently C1-C3 alkyl;
q′ is 0, 1, 2, 3 or 4; and
R33 is H or C1-C3 alkyl,
wherein the Degron is covalently bonded to the Linker via

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 or a stereoisomer or pharmaceutically acceptable salt thereof.