DEGRADATION OF BRUTON'S TYROSINE KINASE (BTK) BY CONJUGATION OF BTK INHIBITORS WITH E3 LIGASE LIGAND AND METHODS OF USEThe present application provides bifunctional compounds of Formula (X), or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, which act as protein degradation inducing moieties for Bruton's tyrosine kinase (BTK). The present application also relates to methods for the targeted degradation of BTK through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to BTK which can be utilized in the treatment of disorders modulated by BTK.A bifunctional compound of Formula X:wherein: the Targeting Ligand is capable of binding to BTK;the Linker is a group that covalently binds to the Targeting Ligand and the Degron; and the Degron is capable of binding to a ubiquitin ligase. 2. The bifunctional compound of claim 1, wherein the Targeting Ligand is of Formula TL-I, TL-II, or TL-III:or an enantiomer, diastereomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein:X1 is O or NR3a; X2 is O oreach R1 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2;each R2 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, CN, OH, or NH2;R3a and R3b are each independently H, (C1-C4) alkyl, or (C1-C4) haloalkyl;each R4 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2;n1 and n2 are each independently 0, 1, or 2;n3 is 0, 1, 2, 3 or 4; andn4 is 1, 2, 3 or 4; or or an enantiomer, diastereomer, stereoisomer, or pharmaceutically acceptable salt thereof, 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; ando1 and o2 are each independently 0, 1, 2, or 3; oror an enantiomer, diastereomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein:Z is NR17 each R12 is independently H, (C1-C4) alkyl, or (C1-C4) haloalkyl;R13 is H, (C1-C4) alkyl, (C1-C4) haloalkyl, or CN;each R14 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, O-phenyl, OH, or NH2;R15 is H, (C1-C4) alkyl, halogen, or CN;each R16 is independently H, (C1-C4) alkyl, or (C1-C4) haloalkyl;R17 is H, (C1-C4) alkyl, or (C1-C4) haloalkyl;each R18 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, or oxo;s1 and s5 are each independently 0, 1, 2 or 3; ands2, s3, and s4 are each independently 0 or 1, wherein the Targeting Ligand is bonded to the Linker via the next to X2 in TL-I, 3. The bifunctional compound of claim 2, wherein the Targeting Ligand is of Formula TL-I. 4. The bifunctional compound of claim 3, wherein X1 is O. 5. The bifunctional compound of claim 3 or 4, wherein R1 is (C1-C4) alkoxy. 6. The bifunctional compound of any one of the preceding claims, wherein R2 is CN. 7. The bifunctional compound of any one of the preceding claims, wherein R3b is H. 8. The bifunctional compound of any one of the preceding claims, wherein R4 is (C1-C4) alkoxy or halogen. 9. The bifunctional compound of any one of the preceding claims, wherein n1 is 1. 10. The bifunctional compound of any one of the preceding claims, wherein n2 is 1. 11. The bifunctional compound of any one of the preceding claims, wherein n3 is 3. 12. The bifunctional compound of any one of the preceding claims, wherein n4 is 3. 13. The bifunctional compound of any one of the preceding claims, wherein n4 is 3. 14. The bifunctional compound of claim 2, wherein the Targeting Ligand is of Formula TL- II.
Ｅ3 리가아제 리간드와 브루톤 티로신 키나아제(ＢＴＫ) 억제제의 컨쥬게이션에 의한 ＢＴＫ의 분해 및 사용 방법본 출원은 브루톤 티로신 키나아제(BTK)에 대한 단백질 분해 유도 모이어티로서 작용하는 하기 화학식(X)의 이작용성 화합물, 또는 이의 거울상 이성질체, 부분입체 이성질체 또는 입체 이성질체, 또는 이의 약제학적으로 허용가능한 염, 수화물, 용매화물 또는 프로드러그를 제공한다. 본 출원은 또한 BTK에 결합할 수 있는 리간드에 유비퀴틴 리가아제-결합 모이어티를 연결하는 이작용성 화합물의 사용을 통한 BTK의 표적화된 분해 방법에 관한 것으로, 이것은 BTK에 의해 조절된 장애의 치료에 이용될 수 있다.화학식 X의 이작용성 화합물:식 중,표적화 리간드는 BTK에 결합할 수 있고;링커는 표적화 리간드 및 데그론(Degron)에 공유 결합하는 기이며;데그론은 유비퀴틴 리가아제에 결합할 수 있다.