BAF complex modulating compounds
The present disclosure features compounds useful for the treatment of BAF complex-related disorders.
1 . A compound having the structure:
wherein m is 1, 2, 3, or 4;
n is 0, 1, 2, 3, or 4;
R 1 combines with R 2 and the atoms to which they are attached to form a 5- to 7-membered ring;
each R 2 is, independently, halo, hydroxy, thiol, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted amino, or one R 2 combines with another R 2 and the atoms to which they are attached to form a 5- to 7-membered ring;
R 3 and R 5 are, independently, hydrogen or optionally substituted C 1 -C 6 alkyl;
R 4 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 1 -C 6 alkyl C 6 -C 10 aryl, or optionally substituted C 1 -C 6 alkyl C 2 -C 9 heteroaryl;
Het is 5- or 6-membered heterocycle;
R 6 is hydrogen, halo, cyano, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 heteroalkyl, carboxyl, optionally substituted amide, optionally substituted C 2 -C 9 heteroaryl, optionally substituted C 2 -C 9 heterocyclyl, or optionally substituted C 6 -C 10 aryl; and
R 7 is cyano, halo, optionally substituted C 1 -C 6 alkyl or optionally substituted C 1 -C 6 heteroalkyl,
or a pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 , wherein R 3 is hydrogen.
3 . The compound of claim 1 , wherein R 5 is hydrogen.
4 . The compound of claim 1 , wherein R 4 is hydrogen.
5 . The compound of claim 1 , wherein R 4 is optionally substituted C 1 -C 6 heteroalkyl.
6 . The compound of claim 5 , wherein R 4 is
7 . The compound of claim 1 , wherein R 4 is optionally substituted C 1 -C 6 alkyl.
8 . The compound of claim 7 , wherein R 4 is methyl.
9 . The compound of claim 1 , wherein Het is
10 . The compound of claim 1 , wherein Het is
11 . The compound of claim 1 , wherein R 1 is iso-propyl,
12 . The compound of claim 1 , wherein m is 1 or 2.
13 . The compound of claim 12 , wherein m is 1 or 2, and at least one R 2 is optionally substituted C 1 -C 6 alkyl or halo.
14 . The compound of claim 13 , wherein R 2 is methyl.
15 . The compound of claim 12 , wherein m is 1 or 2, and R 2 is optionally substituted C 1 -C 6 heteroalkyl.
16 . The compound of claim 15 , wherein R 2 is
17 . The compound of claim 12 , wherein m is 1 or 2 and R 2 is —NH 2 .
18 . The compound of claim 1 , wherein the compound has the structure of Formula Ia:
19 . The compound of claim 1 , wherein n is 0 or 1.
20 . The compound of claim 1 , wherein n is 1, and R 7 is cyano.
21 . The compound of claim 1 , wherein R 6 is hydrogen, cyano, or optionally substituted C 1 -C 6 heteroalkyl.
22 . The compound of claim 21 , wherein R 6 is
23 . The compound of claim 1 , wherein R 6 is carboxyl.
24 . The compound of claim 1 , wherein R 6 is optionally substituted C 2 -C 9 heteroaryl.
25 . The compound of claim 24 , wherein R 6 is
26 . The compound of claim 1 , wherein R 6 is optionally substituted C 2 -C 9 heterocyclyl.
27 . The compound of claim 26 , wherein R 6 is
28 . The compound of claim 1 , wherein R 6 is C 6 -C 10 aryl.
29 . The compound of claim 28 , wherein R 6 is 3,5-dicyano-phenyl, 3-hydroxymethyl-5-cyano-phenyl, 3-cyano-phenyl, 3-hydroxymethyl-5-trifluoromethyl-phenyl, 3-chloro-phenyl, 3,5-dichloro-phenyl, 3-aminomethyl-phenyl,
or 4-aminomethyl-phenyl.
30 . The compound of claim 1 , wherein the compound is any one of compounds
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Compound
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129
31 . A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.
32 . 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 .
33 . The method of claim 32 , 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.
34 . The method of claim 32 , 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, or penile cancer.
35 . The method of claim 32 , wherein the cancer is non-small cell lung cancer.
36 . The method of claim 32 , wherein the cancer is soft tissue sarcoma.
37 . 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 .
38 . The method of claim 37 , wherein the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematologic cancer is metastatic.
39 . The method of claim 37 , wherein the method further comprises administering to the subject an additional anticancer therapy, wherein the anticancer therapy is a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation.
40 . A method of reducing the level and/or activity of BRG1 and/or BRM in a melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematologic cancer cell, the method comprising contacting the cell with an effective amount a compound of claim 1 .