Tricyclic quinolone BCL6 bifunctional degrader

Abstract

The present disclosure provides compounds of formula (I) (e.g., formula (I-aa) (e.g., formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), formula (I-a) (e.g., formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5), or (I-a-6)), formula (I-bb) (e.g., formula (I-bb-1) or (I-bb-2)), or formula (I-b) (e.g., formula (I-b-1) or (I-b-2))), or formula (II), or pharmaceutically acceptable salts thereof, which induce the degradation of the BCL6 protein. These compounds are useful, for example, in treating cancer in a subject (e.g., a human). The present disclosure also provides methods of using and making the compounds, as well as compositions containing the compounds provided herein.

Claims

1. Compound of formula (I-aa-2): or a pharmaceutically acceptable salt thereof, in the formula, X ａ is N or CH, R ６ is -F or -Cl, m3 is 1, X ３ is C １～３ It is alkylene and R １ H is, Ring C is, Selected from the group consisting of, where c1 is 0 or 1, and R Ｙ is selected from the group consisting of halo and C optionally substituted with 1 to 3 F １～３ alkyl, and R ａＮ is C １～３ alkyl yy represents the connection point with Z 4, L Ａ１ CH ２ CHMe, or CMe ２ And, Z １ and Z ２ CH, CR ａ４ Independently selected from the group consisting of , and N, Z ３ and Z ４ CH, CR ａ５ Independently selected from the group consisting of , and N, However, Z １ and Z ２ At least one of them is N, and Z ３ and Z ４ At least one of them is N, and Z ２ If Z is N, ３ is CH or CR ａ５ And, m4 and m5 are independently selected from the group consisting of 0, 1, and 2, and Each R ａ４ and R ａ５ is -F, CN, C １～３ C may be substituted with alkoxy, OH, and 1 to 3 F groups. １～３ Independently selected from the group consisting of alkyl groups, A compound of formula (I-aa-2) or a pharmaceutically acceptable salt thereof.

2. The compound is a compound of formula (I-a-2): or a pharmaceutically acceptable salt thereof, in the formula, X a is N or CH, R 6 is -F or -Cl, m3 is 1, X3 is C1-3 alkylene, and R1 is H. Ring C is, Selected from the group consisting of, yy represents the connection point with Z 4, L A1 is CH 2, CHMe, or CMe 2. Z1 and Z2 are independently selected from the group consisting of CH, CR a4, and N. Z3 and Z4 are independently selected from the group consisting of CH, CR a5, and N. However, if at least one of Z1 and Z2 is N, and at least one of Z3 and Z4 is N, then Z3 is CH or CR a5. m4 and m5 are independently selected from the group consisting of 0, 1, and 2, and Each R a4 and R a5 is independently selected from the group consisting of -F, CN, C1-3 alkoxy, OH, and C1-3 alkyl which may be substituted with 1-3 F atoms. The compound according to claim 1, which is a compound of formula (I-a-2) or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein Z1 is N and Z2 is CH or CR a4.

4. The compound according to claim 1, wherein Z1 is N, Z2 is CH or CR a4, and Z3 is N.

5. The above The following is the part: Selected from the group consisting of, where bb represents a bond point with ring C, or the following: Selected from the group consisting of, where bb represents the bond point with ring C, The compound according to claim 1.

6. X ａ The compound according to claim 1, wherein is N.

7. X ａ The compound according to claim 1, wherein is CH.

8. The compound is as follows: The compound according to claim 1, which is selected from the group consisting of or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

10. A pharmaceutical composition according to claim 9 for use in the treatment of cancer.

11. The pharmaceutical composition according to claim 10, wherein the cancer is selected from the group consisting of blood cancer, breast cancer, gastrointestinal cancer, brain cancer, and lung cancer.

12. The pharmaceutical composition according to claim 11, wherein the hematological cancer is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), diffuse histiocytic lymphoma (DHL), intravascular large B-cell lymphoma (IVLBCL), small lymphocytic lymphoma (SLL), Burkitt lymphoma (BL), mantle cell lymphoma (MCL), peripheral T-cell lymphoma (PTCL), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or chronic myeloid leukemia (CML).

13. The pharmaceutical composition according to claim 10, for use in combination with an additional therapy or therapeutic agent.

14. The aforementioned additional therapy or therapeutic agent is a PI3K inhibitor, Abl inhibitor, BTK inhibitor, JAK inhibitor, BRaf inhibitor, MEK inhibitor, BCL-2 inhibitor, Bcl-X Ｌ The pharmaceutical composition according to claim 13, comprising an inhibitor, an XPO1 inhibitor, a Polycomb inhibitory complex 2 (PRC2) inhibitor, an immunomodulatory imide drug, an anti-CD19 therapy, an anti-CD20 therapy, an anti-CD3 therapy, chemotherapy, or a combination thereof.

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