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KR-20260062969-A - Tricyclic quinolone BCL6 bifunctional decomposer

KR20260062969AKR 20260062969 AKR20260062969 AKR 20260062969AKR-20260062969-A

Abstract

The present disclosure provides a compound of formula (I) (e.g., formula (I-1), formula (I-2), formula (I-a) (e.g., formula (I-a-1), (I-a-2), (I-a-3), or (I-a-4)), formula (I-b) (e.g., formula (I-b-1), (I-b-2), (I-b-3), or (I-b-4)), formula (I-c) (e.g., formula (I-c-1) or (I-c-2)), formula (I-d) (e.g., formula (I-d-1)), or formula (I-e) (e.g., formula (I-e-1) or (I-e-2))), formula (II), or formula (II-a) (e.g., formula (II-a-1)), or a pharmaceutically acceptable salt thereof, which induces the degradation of BCL6 protein. These compounds are useful, for example, for treating cancer in subjects (e.g., humans). The present disclosure also provides compositions containing the compounds provided herein, or pharmaceutically acceptable salts thereof, as well as methods of use and methods of preparation thereof.

Inventors

  • 오버그, 케빈 엠.
  • 한센, 조슈아 디.
  • 코레아, 매튜 디.
  • 마론, 타미 제이.
  • 맥닐, 매튜 에이치.
  • 나기, 마크 에이.
  • 슈라이허, 크리스틴 디.
  • 발리에르, 앤드류

Assignees

  • 트리라인 바이오사이언시스, 인크.

Dates

Publication Date
20260507
Application Date
20240830
Priority Date
20240401

Claims (20)

  1. Compound of the chemical formula ( Ib ) or a pharmaceutically acceptable salt thereof: Chemical formula ( Ib ) In the above formula, E 1 is CR 2a and; R 2a and R 2b are each independently selected from the group consisting of H and F; -( X 3 ) m3 - R 1 is a C 1-3 alkyl; X a is N and; R6 is F or Cl; m4 and m5 are independently 0, 1, or 2; Each of R a4 and R a5 is independently selected from the group consisting of F, CN, C 1-3 alkoxy, OH, and C 1-3 alkyl groups optionally substituted with 1 to 3 F; L A1 is CH 2 or CH RR L , and RG L is a C 1-3 alkyl selectively substituted with 1 to 3 RG c ; c1 is 0, 1, or 2; R Ya is selected from a group consisting of the following: (a) H; and (b) C 1-6 alkyl optionally substituted with 1 to 3 R c ; Each R Yb is independently selected from the group consisting of F and C 1-3 alkyl groups optionally substituted with 1 to 3 Fs; Each R c is independently selected from the group consisting of halo, cyano, OH, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -N R d R e , C(=O)C 1-6 alkyl, C(=O)OC 1-6 alkyl, C(=O)N( R f ) 2 , S(O) O-2 (C 1-6 alkyl), and S(O) O-2 (C 1-6 haloalkyl); Each R d and R e is independently selected from the group consisting of H, C(=O)C 1-6 alkyl, C(=O)C 1-6 haloalkyl, C(=O)OC 1-6 alkyl, C(=O)OC 1-6 haloalkyl, C(=O)N( R f ) 2 , S(O) 1-2 (C 1-6 alkyl), S(O) 1-2 (C 1-6 haloalkyl), S(O) 1-2 N( R f ) 2 , and C 1-6 alkyl optionally substituted with 1 to 3 R h ; Each Rf is independently selected from the group consisting of H and C 1-6 alkyls optionally substituted with 1 to 3 Rhs ; Each R h is independently selected from the group consisting of halo, cyano, OH, -(C O-3 alkylene)-C 1-6 alkoxy, -(C O-3 alkylene)-C 1-6 haloalkoxy, -(C O - 3 alkylene)-NH 2 , -(C O-3 alkylene)-N(H)(C 1-3 alkyl), and -(C O -3 alkylene)-N(C 1-3 alkyl) 2 .
  2. In paragraph 1, a compound to which one or more of (1), (3) or (5) apply: (1) R 2b is F; (3) Moiety Im; and/or (5) c1 is 2.
  3. In paragraph 1, a compound to which two or more of (1) to (4) apply: (1) m4 is 1 or 2; (2) m5 is 1 or 2; (3) L A1 is CH R L ; and/or (4) c1 is 1 or 2.
  4. In claim 1, the compound of formula ( Ib ) is a compound of formula ( Ib-1 ) or a pharmaceutically acceptable salt thereof, compound: Chemical formula ( Ib-1 ).
  5. In any one of paragraphs 1 through 4, R Ya is a C 1-3 alkyl (e.g., C 1-3 alkyl (e.g., methyl)) optionally substituted with 1 to 3 F groups, and A compound in which each R Yb is independently selected from the group consisting of F and C 1-3 alkyl groups optionally substituted with 1 to 3 Fs.
  6. A compound according to any one of paragraphs 1 to 5, wherein L A1 is CH 2 .
  7. A compound according to any one of claims 1 to 6, wherein m4 is 0 and m5 is 0.
  8. In any one of paragraphs 1 through 7, Moiety Phosphorus, compound.
  9. A compound according to any one of claims 1 to 6, wherein m4 is 1 or 2; m5 is 0, and each R a4 is independently selected from the group consisting of F, Me, and CF3 .
  10. In any one of paragraphs 1 through 6, or paragraph 9, Moiety or Phosphorus, compound.
  11. In any one of paragraphs 1 through 6, or paragraph 9, or paragraph 10, Moiety Phosphorus, compound.
  12. In Paragraph 11, Moiety or Phosphorus, compound.
  13. In claim 11 or 12, R a4 is a compound selected from the group consisting of F and Me.
  14. A compound according to any one of claims 1 to 6, wherein m4 is 0; m5 is 1 or 2, and each R a5 is independently selected from the group consisting of F, Me, and CF3 .
  15. In any one of paragraphs 1 through 14, Moiety , , , and A compound selected from the group consisting of
  16. In any one of paragraphs 1 through 15, Moiety , , and A compound selected from the group consisting of, wherein each R Yb is independently a C 1-3 alkyl selectively substituted with F or 1 to 3 F; and R Ya is a C 1-3 alkyl selectively substituted with 1 to 3 F (e.g., C 1-3 alkyl (e.g., methyl)).
  17. In any one of paragraphs 1 through 15, Moiety , , and A compound selected from the group consisting of
  18. In claim 1, a compound of the formula ( Ib-3 ) or a pharmaceutically acceptable salt thereof: Chemical formula ( Ib-3 ) In the above formula, E 1 is CR 2a and; R 2a and R 2b are each independently selected from the group consisting of H and F; m4 and m5 are independently 0, 1, or 2; Each of R a4 and R a5 is independently selected from the group consisting of F, CN, C 1-3 alkoxy, OH, and C 1-3 alkyl groups optionally substituted with 1 to 3 F; L A1 is CH 2 or CH RR L , and RG L is a C 1-3 alkyl selectively substituted with 1 to 3 RG c ; R Ya is selected from a group consisting of the following: (a) H; and (b) C 1-6 alkyl optionally substituted with 1 to 3 R c ; Each R Yb is independently selected from the group consisting of F and C 1-3 alkyl groups optionally substituted with 1 to 3 F.
  19. In paragraph 18, a compound of the formula ( Ib-4 ) or a pharmaceutically acceptable salt thereof: Chemical formula ( Ib-4 ).
  20. A compound according to paragraph 18 or 19, wherein R 2b is H.

Description

Tricyclic quinolone BCL6 bifunctional decomposer Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63/580,207, filed September 1, 2023; No. 63/607,009, filed December 6, 2023; No. 63/572,811, filed April 1, 2024; and No. 63/665,613, filed June 28, 2024, each incorporated herein by reference in its entirety. Sequence list The present application includes a list of sequences submitted electronically in XML format, the entirety of which is incorporated herein by reference. The name of the XML file created on August 26, 2024 is TLS-054WO_SL.xml and the size is 2,685 bytes. Technology field The present disclosure provides a compound of formula ( I ) (e.g., formula ( I-1 ), formula ( I-2 ), formula ( Ia ) (e.g., formula ( Ia-1 ), ( Ia-2 ), ( Ia-3 ), or ( Ia-4 )), formula ( Ib ) (e.g., formula ( Ib-1 ), ( Ib-2 ), ( Ib-3 ), or ( Ib-4 )), formula ( Ic ) (e.g., formula ( Ic-1 ) or ( Ic-2 )), formula ( Id ) (e.g., formula ( Id-1 )), or formula ( Ie ) (e.g., formula ( Ie-1 ) or ( Ie-2 ))), formula ( II ), or formula ( II-a ) (e.g., formula ( II-a-1 )), or a pharmaceutically acceptable salt thereof, which induces degradation of a BCL6 protein. These compounds are useful, for example, for treating cancer in subjects (e.g., humans). Additionally, the present disclosure relates to compositions containing compounds of formula ( I ) (e.g., formula ( I-1 ), formula ( I-2 ), formula ( Ia ) (e.g., formula ( Ia-1 ) , ( Ia-2 ), ( Ia-3), or (Ia-4 )), formula ( Ib ) (e.g., formula (Ib - 1 ), ( Ib-2 ), (Ib-3), or ( Ib-4 )), formula ( Ic ) (e.g., formula ( Ic-1 ) or ( Ic- 2 )), formula ( Id ) (e.g., formula (Id-1)), or formula ( Ie ) (e.g., formula ( Ie-1 ) or ( Ie-2 ))), formula ( II ), or formula ( II-a ) (e.g., formula ( II-a-1 )), or pharmaceutically acceptable salts thereof, as well as methods of use and methods of preparation thereof. Provides B-cell lymphoma 6 (BCL6) protein is a transcriptional repressor involved in the formation and maintenance of germinal centers (GCs) within lymphoid follicles. It regulates GC function and modulates the activity of signaling mediators during the maturation process of GC B cells. There are over 1,000 known or putative BCL6 target genes, including MYC , BCL2 , genes related to DNA damage response (e.g., ATR , TP53 ), and genes related to cell cycle checkpoint regulation (e.g., CDKN1A , CDKN1B ). BCL6 is expressed in cells in the dark zone of the GC, where somatic hypermutations can occur to generate high-affinity B-cell receptors. Overexpression of BCL6 or loss of regulation, for example, by translocation, can maintain BCL6's hypermutation-promoting function and neutralize its anti-tumor function. A compound of formula ( I ) or a pharmaceutically acceptable salt thereof is provided herein: Chemical formula ( I ) In the above formula E1 is CR 2a or N and; R2a and R 2b are independently selected from the group consisting of H, halo, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, and C 1-3 haloalkoxy; m3 is 0 or 1 and; X3is a C1-3 alkylene selectively substituted with 1 to 3 Rc ; R1 is selected from the group consisting of H, halo, and Rb1 ; Xa is selected from the group consisting of N and CR Xa ; R6andRXa are independently selected from the group consisting of H, halo, C1-2 alkyl , C1-2 haloalkyl, C1-2 alkoxy, CN, and C≡CH; L is -( L A ) n1 -, and in the above equation n1 is an integer from 1 to 5; Each LA is independently selected from the group consisting of L A1 , L A3 , and L A4 , and 0 to 2 of LA are L A1 ; 0 to 2 of LA are L A3 ; 1 to 3 of LA are L A4 , and Each LA1 is independently selected from the group consisting of CH 2 , CH RR L and C( RR ) 2 , and Each RL is independently selected from the group consisting of halo, cyano, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, -(C 0-3 alkylene)-(C 3-5 cycloalkyl), -(C 0-3 alkylene)-(4 to 6-membered heterocyclyl), and C 1-6 alkyl groups optionally substituted with 1 to 6 R c ; Each LA3 is independently selected from the group consisting of N( R d ), N( R b ), O, S(O) 0-2 and C(=O); Each LA4 is independently selected from a group consisting of: (a) C 3-15 cycloalkylene or 4 to 15-membered heterocyclylene, each optionally substituted with 1 to 6 substituents independently selected from the group consisting of R a and R b ; and (b) phenylene or 5 to 6-membered heteroarylene, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of R a and R b ; Ring C is , , and Selected from a group consisting of, where c1 is 0, 1, or 2; Each RYb is independently selected from the group consisting of R a and R b ; RYa is selected from the group consisting of H, R a , and R b ; yy represents the attachment point to L ; X is CH or N and; Each Ra is independently selected from a group consisting of: (a) Hallo; (b) Cyano; (c) OH; (d) Oxo; (e) C 1-6 alkoxy optionally substituted with 1 to 6 R c ; (f) N R d R e ; (g) C(=O)C 1-6 alkyl; (h) C(=O)OC 1-6 alkyl; (i) C(=O