Tetrahydroisoquinoline heterobifunctional BCL-XL degrader

Abstract

The present disclosure relates to BCL-X L compounds of formula (I) (e.g., (I-A) (e.g., (I-A-1), (I-A-2), or (I-A-3)), (I-B) (e.g., (I-B-1), (I-B-2), or (I-B-3)), (I-C), (I-D), (I-E) (e.g., (I-E-1), (I-E-2), or (I-E-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (I-F) (e.g., (I-F-1), (I-F-2), or (I-F-3)), (I-G), (I-Ga), (I-H) (e.g., (I-H-1), (I-H-2), or (I-H-3))), or formula (II) (e.g., (II-a)), or pharmaceutically acceptable salts thereof. These compounds are useful, for example, in treating cancer in a subject (e.g., a human). The present disclosure also provides compositions containing the compounds provided herein, as well as methods of using and making the same. TIFF2025517642000966.tif79128

Claims

1. Equation (I): A compound of or a pharmaceutically acceptable salt thereof, wherein the formula is Ring A is, In the equation, aa represents the connection point to L, The R a present on ring A is either methyl or CF3. R1 is C(O)OH or C(O)OC1-6 alkyl, Each R ２ , R ３ , R ４ , and R ５ are independently selected from the group consisting of halo, CN, C １～３ alkyl, C １～３ haloalkyl, C １～３ alkoxy, C １～３ haloalkoxy, OH, and NR ｄ R ｅ and the selection is made from the group m2 is 0, 1, or 2. m3 and m4 are independently 0, 1, 2, or 3. m5 is 0, 1, 2, 3, or 4. Ring C is, And in the formula, R aN is a C1-3 alkyl group. c1 is 0 or 1, and R a2 is selected from the group consisting of a halo and C1-3 alkyl which may be optionally substituted with 1-3 F atoms. yy represents the connection point to L, X is CH, C, or N. The aforementioned It is either a single bond or a double bond. L Ｃ It is a combination, Each R ｄ and R ｅ These are H and C(=O)C, independently of each other. １～６ Alkyl and C(=O)C １～６ Haloalkyl and C(=O)OC １～６ Alkyl and C(=O)OC １～６ Haloalkyl and C(=O)N(R) ｆ ) ２ And, S(O) １～２ (C １～６ Alkyl) and S(O) １～２ (C １～６ Haloalkyl) and S(O) １～２ N(R) ｆ ) ２ and 1 to 3 R ｈ C may be optionally replaced by １～６ Selected from the group consisting of alkyls, Each R ｆ H and 1 to 3 R ｈ C may be optionally replaced by １～６ Independently selected from the group consisting of alkyls, Each R ｇ R is independent of R ｈ , C １～３ Alkyl and C １～３ Selected from the group consisting of haloalkyls, Each R ｈ These are independently halo, cyano, -OH, and -C. １～６ Alkoxy, -C １～６ Haloalkoxy, -NH ２ , -N(H)(C １～３ Alkyl), and -N(C １～３ Alkyl) ２ Selected from the group consisting of, L is as follows: Selected from the group consisting of, The aforementioned compound or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein m2 is 0, m3 is 0, m4 is 0, and m5 is 0.

3. R ａＮ The compound according to claim 1, wherein is methyl.

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

5. The aforementioned part is, or That is, The compound according to claim 1.

6. 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.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

8. A pharmaceutical composition according to claim 7 for use in the treatment of cancer.

9. The pharmaceutical composition according to claim 8, wherein the treatment of cancer comprises administering an additional treatment or therapeutic agent.

10. The pharmaceutical composition according to claim 9, wherein the additional treatment or therapeutic agent is an ALK inhibitor, a BCL-2 inhibitor, a BCR-Abl inhibitor, a BRaf inhibitor, a CDK2 inhibitor, a CDK4 / 6 inhibitor, a CDK7 inhibitor, a CDK9 inhibitor, an EGFR inhibitor, an anti-EGFR antibody or an anti-EGFR antibody-drug conjugate, an ERK inhibitor, an FFFR1 inhibitor, an FFFR2 inhibitor, an FFFR3 inhibitor, an FFFR4 inhibitor, a HER2 inhibitor, an anti-HER2 antibody or an anti-HER2 antibody-drug conjugate, a JAK inhibitor, a KRas inhibitor, a MEK inhibitor, a MET inhibitor, a PARP inhibitor, an LSD1 inhibitor, a BET inhibitor, a telomerase inhibitor, a TORC1 / 2 inhibitor, chemotherapy, radiotherapy, or a combination thereof.

11. The pharmaceutical composition according to claim 8, wherein the cancer is breast cancer, colorectal cancer, bile duct cancer, gastrointestinal stromal tumor, pancreatic cancer, bladder cancer, kidney cancer, cervical cancer, ovarian cancer, uterine cancer, head and neck cancer, hematological cancer, lung cancer, skin cancer, or a combination thereof.

12. The pharmaceutical composition according to claim 11, wherein the blood cancer is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), small lymphocytic lymphoma (SLL), essential thrombocythemia, polycythemia vera, myelofibrosis, or a combination thereof.

13. The pharmaceutical composition according to claim 12, wherein the blood cancer is essential thrombocythemia, polycythemia vera, myelofibrosis, or a combination thereof.

14. The pharmaceutical composition according to claim 13, wherein the blood cancer has a JAK2 mutation.

15. The pharmaceutical composition according to claim 14, wherein the JAK2 mutation is JAK2 V617F.

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