Macrocyclic compounds and methods of use
The present disclosure provides compounds useful for the inhibition of KRAS G12D, G12V, G12A, G12S, G13D, Q61H, Q61L or G12C. The compounds have a general Formula I′: wherein the variables of Formula I′ are defined herein. This disclosure also provides pharmaceutical compositions comprising the compounds, uses of the compounds, and compositions for treatment of, for example, cancer.
1 . A compound, wherein the compound is:
Compound
or
or a pharmaceutically acceptable salt thereof.
2 . A compound, wherein the compound is
or a pharmaceutically acceptable salt thereof.
3 . The compound or salt of claim 1 , wherein the compound is
4 . The compound or salt of claim 1 , wherein the compound is
5 . The compound or salt of claim 1 , wherein the compound is
6 . The compound or salt of claim 1 , wherein the compound is
7 . The compound or salt of claim 1 , wherein the compound is
8 . The compound or salt of claim 1 , wherein the compound is
9 . The compound or salt of claim 1 , wherein the compound is
10 . The compound or salt of claim 1 , wherein the compound is
11 . The compound or salt of claim 1 , wherein the compound is
12 . A compound, wherein the compound is:
Compound
or
or a pharmaceutically acceptable salt thereof.
13 . The compound or salt of claim 12 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
14 . The compound or salt of claim 12 , wherein the compound is
15 . The compound or salt of claim 12 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
16 . The compound or salt of claim 12 , wherein the compound is
17 . The compound or salt of claim 12 , wherein the compound is
18 . The compound or salt of claim 12 , wherein the compound is
19 . The compound or salt of claim 12 , wherein the compound is
20 . The compound or salt of claim 12 , wherein the compound is
21 . The compound or salt of claim 12 , wherein the compound is
22 . The compound or salt of claim 12 , wherein the compound is
23 . A pharmaceutical composition comprising the compound or salt according to claim 1 and a pharmaceutically acceptable excipient.
24 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound or salt according to claim 1 or a pharmaceutical composition according to claim 23 .
25 . The method according to claim 24 , wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelionma, thyroid cancer, leukemia, or melanoma.
26 . The method according to claim 24 , wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma.
27 . The method according to claim 26 , wherein the cancer is non-small cell lung cancer.
28 . The method according to claim 26 , wherein the cancer is colorectal cancer.
29 . The method according to claim 26 , wherein the cancer is pancreatic cancer.
30 . A pharmaceutical composition comprising the compound or salt according to claim 12 and a pharmaceutically acceptable excipient.
31 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound or salt according to claim 12 or a therapeutically effective amount of the pharmaceutical composition according to claim 30 .
32 . The method according to claim 31 , wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
33 . The method according to claim 31 , wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma.
34 . The method according to claim 33 , wherein the cancer is non-small cell lung cancer.
35 . The method according to claim 33 , wherein the cancer is colorectal cancer.
36 . The method according to claim 33 , wherein the cancer is pancreatic cancer.
37 . A pharmaceutical composition comprising the compound or salt according to claim 13 and a pharmaceutically acceptable excipient.
38 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound or salt according to claim 13 or a therapeutically effective amount of the pharmaceutical composition according to claim 37 .
39 . The method according to claim 38 , wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
40 . The method according to claim 38 , wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma.
41 . The method according to claim 40 , wherein the cancer is non-small cell lung cancer.
42 . The method according to claim 40 , wherein the cancer is colorectal cancer.
43 . The method according to claim 40 , wherein the cancer is pancreatic cancer.
44 . The method according to claim 41 , wherein the cancer is non-small cell lung cancer wherein one or more cells express a KRAS G12D, G12V, G12A, G12S, G13D, Q61H, Q61L or G12C mutant protein.
45 . The method according to claim 41 , wherein the cancer is non-small cell lung cancer wherein one or more cells express a KRAS G12D, G12V, G12A, G12S or G12C mutant protein.
46 . The method according to claim 45 , wherein the cancer is non-small cell lung cancer wherein one or more cells express a KRAS G12C mutant protein.
47 . The method according to claim 45 , wherein the cancer is non-small cell lung cancer wherein one or more cells express a KRAS G12D mutant protein.
48 . The method according to claim 45 , wherein the cancer is non-small cell lung cancer wherein one or more cells express a KRAS G12V mutant protein.
49 . The method according to claim 45 , wherein the cancer is non-small cell lung cancer wherein one or more cells express a KRAS G12A mutant protein.
50 . The method according to claim 42 , wherein the cancer is colorectal cancer wherein one or more cells express a KRAS G12D, G12V, G12A, G12S, G13D, Q61H, Q61L or G12C mutant protein.
51 . The method according to claim 42 , wherein the cancer is colorectal cancer wherein one or more cells express a KRAS G12D, G12V, G12A, G12S or G12C mutant protein.
52 . The method according to claim 51 , wherein the cancer is colorectal cancer wherein one or more cells express a KRAS G12D mutant protein.
53 . The method according to claim 51 , wherein the cancer is colorectal cancer wherein one or more cells express a KRAS G12V mutant protein.
54 . The method according to claim 51 , wherein the cancer is colorectal cancer wherein one or more cells express a KRAS G12A mutant protein.
55 . The method according to claim 51 , wherein the cancer is colorectal cancer wherein one or more cells express a KRAS G12C mutant protein.
56 . The method according to claim 43 , wherein the cancer is pancreatic cancer wherein one or more cells express a KRAS G12D, G12V, G12A, G12S, G13D, Q61H, Q61L or G12C mutant protein.
57 . The method according to claim 43 , wherein the cancer is pancreatic cancer wherein one or more cells express a KRAS G12D, G12V, G12A, G12S or G12C mutant protein.
58 . The method according to claim 57 , wherein the cancer is pancreatic cancer wherein one or more cells express a KRAS G12D mutant protein.
59 . The method according to claim 57 , wherein the cancer is pancreatic cancer wherein one or more cells express a KRAS G12V mutant protein.
60 . The method according to claim 57 , wherein the cancer is pancreatic cancer wherein one or more cells express a KRAS G12C mutant protein.
61 . The method according to claim 57 , wherein the cancer is pancreatic cancer wherein one or more cells express a KRAS G12A mutant protein.