Compounds and uses thereof
The present disclosure features compounds useful for the treatment of BAF complex-related disorders.
1. A compound having the structure:
wherein
A is
m is 0, 1, 2, or 3;
n is 1 or 2;
o is 0 or 1;
X is O, CH 2 , or NR 7 ;
X′ is N, CH, or CR X , wherein R X is a halogen;
B is an optionally substituted 6-membered monocyclic heteroarylene or an optionally substituted 9- or 10-membered bicyclic heteroarylene;
L is a covalent bond, optionally substituted C 1 -C 3 alkylene, C 2 alkynylene, optionally substituted C 2 alkenylene, optionally substituted C 2 -C 3 heteroalkylene, optionally substituted C 3 -C 5 cycloalkylene, or optionally substituted 4- to 10-membered heterocyclylene;
C is optionally substituted 3- to 10-membered cycloalkyl; optionally substituted 6- to 10-membered aryl; optionally substituted 5- to 10-membered heteroaryl; or optionally substituted 5- to 10-membered heterocyclyl;
R 1 and R 7 are, independently, hydrogen or optionally substituted C 1 -C 6 alkyl;
each R 2 and R 3 is independently, hydrogen, optionally substituted C 1 -C 6 alkyl; or
optionally substituted C 1 -C 6 heteroalkyl;
R 4 is cyano, fluoro, hydroxy, or —CH 2 OH;
R 5 is C 1 -C 3 alkyl optionally substituted with one, two, three, four, five, six, or seven fluoro groups; and
R 6 is C 1 -C 3 alkyl optionally substituted with one, two, three, four, five, six, or seven fluoro groups,
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein R 1 is hydrogen.
3. The compound of claim 1 , wherein m is 1.
4. The compound of claim 1 , wherein R 3 is hydrogen.
5. The compound of claim 1 , wherein R 2 is hydrogen.
6. The compound of claim 1 , wherein R 2 is optionally substituted C 1 -C 6 alkyl.
7. The compound of claim 1 , wherein R 2 is optionally substituted C 1 -C 6 heteroalkyl.
8. The compound of claim 1 , wherein A is
9. The compound of claim 8 , wherein A is
10. The compound of claim 1 , wherein C is optionally substituted 3- to 10-membered cycloalkyl.
11. The compound of claim 1 , wherein C is optionally substituted 6- to 10-membered aryl.
12. The compound of claim 11 , wherein C is phenyl, 3-difluoromethyl-phenyl, 4-difluoromethylphenyl, 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 3,5-difluorophenyl, 3-difluoromethylphenyl, 2-methoxy-5-methyl-phenyl, 2-methoxy-4-chloro-phenyl, 3-cyano-phenyl, 3-fluoro-5-methoxy-phenyl, 3-fluoro-5-azetidinyl-phenyl, 3-azetidyl-phenyl, 4-azetidyl-2-methoxy-phenyl, 4-morpholin-4-yl-2-methoxy-phenyl, 4-tert-butyl-2-methoxy-phenyl, 4-azetidyl-phenyl, 2-methoxy-4-oxetan-3-yl-phenyl, 2-azetidin-2-one-1-yl-phenyl, 3-(3-difluoromethyloxetan-3-yl)-phenyl, 3-(3-methoxyoxetan-3-yl)-phenyl, 3-(N-methyl-N-acetamido)-phenyl, 3-cyclopropylphenyl, 3-(N-methylazetidin-3-yl)-phenyl, 3-(N-methyl-N′-piperazinyl)-phenyl, 3-fluoro-5-azetidyl-phenyl, 3-methyl ester-phenyl,
13. The compound of claim 1 , wherein C is optionally substituted 5- to 10-membered heteroaryl.
14. The compound of claim 13 , wherein C is
15. The compound of claim 13 , wherein C is
16. The compound of claim 1 , wherein C is optionally substituted 5- to 10-membered heterocyclyl.
17. The compound of claim 16 , wherein C is
or N-pyrrolidinyl.
18. The compound of claim 16 , wherein C is
19. The compound of claim 1 , wherein B is an optionally substituted 6-membered monocyclic heteroarylene.
20. The compound of claim 19 , wherein B has the structure:
wherein R a is hydrogen or fluoro;
R b is hydrogen, fluoro, or C 1 -C 3 alkyl; and
X a is N or CH.
21. The compound of claim 20 , wherein B is
22. The compound of claim 1 , wherein B has the structure:
wherein D is an optionally substituted 5- or 6-membered heteroaryl or optionally substituted 5- or 6-membered heterocyclyl.
23. The compound of claim 1 , wherein B is
24. The compound of claim 1 , wherein L is optionally substituted C 1 -C 3 alkylene.
25. The compound of claim 1 , wherein L is optionally substituted C 2 alkenylene.
26. The compound of claim 25 , wherein L is
27. The compound of claim 1 , wherein L is optionally substituted C 2 -C 3 heteroalkylene.
28. The compound of claim 1 , wherein L is optionally substituted C 3 -C 5 cycloalkylene.
29. The compound of claim 28 , wherein L is
30. The compound of claim 1 , wherein L is optionally substituted 4- to 10-membered heterocyclylene.
31. The compound of claim 30 , wherein L is
32. The compound of claim 1 , wherein the compound is any one of the following compounds
#
Compound
1
2
3
4
5
6
7
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10
11
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16
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31
32
33
34
35
36
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126
33. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
34. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of claim 1 .
35. The method of claim 34 , wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, small-cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, Adrenocortical carcinoma, appendiceal cancer, small bowel cancer, or penile cancer.
36. The method of claim 35 , wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, soft tissue sarcoma, or penile cancer.
37. The method of claim 36 , wherein the cancer is non-small cell lung cancer.
38. The method of claim 36 , wherein the cancer is soft tissue sarcoma.
39. A method of treating melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of claim 1 .
40. The method of claim 39 , wherein the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematologic cancer is metastatic.