Tricyclic triazolo compounds as DGK inhibitors
The present application provides tricyclic triazolo compounds that modulate the activity of diacylglycerol kinase (DGK), which are useful in the treatment of various diseases, including cancer.
1 . A compound, which is 4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine, or a pharmaceutically acceptable salt thereof.
2 . A pharmaceutical composition, comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
3 . The compound of claim 1 , which is 4-((2S,5R)-4-(bis(4-fluorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-1-(((R)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-e][1,2,4]triazolo[4,3-a]pyrimidine.
4 . A compound, which is 4-((2S,5R)-4-((3,3-difluorocyclobutyl)(4-(trifluoromethyl)phenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, or a pharmaceutically acceptable salt thereof.
5 . The compound of claim 4 , which is 4-((2S,5R)-4-((3,3-difluorocyclobutyl)(4-(trifluoromethyl)phenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine.
6 . A compound, which is 4-((2S,5R)-4-(bis(4-chlorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, or a pharmaceutically acceptable salt thereof.
7 . The compound of claim 6 , which is 4-((2S,5R)-4-(bis(4-chlorophenyl)methyl)-2,5-dimethylpiperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine.
8 . A compound, which is 4-((2S,5R)-2,5-dimethyl-4-((S)-2-methyl-1-(4-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, or a pharmaceutically acceptable salt thereof.
9 . The compound of claim 8 , which is 4-((2S,5R)-2,5-dimethyl-4-((S)-2-methyl-1-(4-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine.
10 . A compound, which is 4-((2S,5R)-2,5-dimethyl-4-((R)-2-methyl-1-(4-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine, or a pharmaceutically acceptable salt thereof.
11 . The compound of claim 10 , which is 4-((2S,5R)-2,5-dimethyl-4-((R)-2-methyl-1-(4-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-2-methyl-1-(((S)-tetrahydrofuran-2-yl)methyl)-1H-[1,2,4]triazolo[3,4-b]purine.
12 . A pharmaceutical composition, comprising a compound of claim 3 , and a pharmaceutically acceptable carrier.
13 . A pharmaceutical composition, comprising a compound of claim 4 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
14 . A pharmaceutical composition, comprising a compound of claim 5 , and a pharmaceutically acceptable carrier.
15 . A pharmaceutical composition, comprising a compound of claim 6 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
16 . A pharmaceutical composition, comprising a compound of claim 7 , and a pharmaceutically acceptable carrier.
17 . A pharmaceutical composition, comprising a compound of claim 8 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
18 . A pharmaceutical composition, comprising a compound of claim 9 , and a pharmaceutically acceptable carrier.
19 . A pharmaceutical composition, comprising a compound of claim 10 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
20 . A pharmaceutical composition, comprising a compound of claim 11 , and a pharmaceutically acceptable carrier.
21 . A method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from non-small cell lung cancer, bladder urothelial carcinoma, esophageal carcinoma, stomach adenocarcinoma, mesothelioma, liver hepatocellular carcinoma, diffuse large B cell lymphoma, kidney renal clear cell carcinoma, head and neck squamous cell carcinoma, cholangiocarcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, and melanoma.
22 . A method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of claim 3 , wherein the cancer is selected from non-small cell lung cancer, bladder urothelial carcinoma, esophageal carcinoma, stomach adenocarcinoma, mesothelioma, liver hepatocellular carcinoma, diffuse large B cell lymphoma, kidney renal clear cell carcinoma, head and neck squamous cell carcinoma, cholangiocarcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, and melanoma.
23 . A method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from non-small cell lung cancer, bladder urothelial carcinoma, esophageal carcinoma, stomach adenocarcinoma, mesothelioma, liver hepatocellular carcinoma, diffuse large B cell lymphoma, kidney renal clear cell carcinoma, head and neck squamous cell carcinoma, cholangiocarcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, and melanoma.
24 . A method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of claim 5 , wherein the cancer is selected from non-small cell lung cancer, bladder urothelial carcinoma, esophageal carcinoma, stomach adenocarcinoma, mesothelioma, liver hepatocellular carcinoma, diffuse large B cell lymphoma, kidney renal clear cell carcinoma, head and neck squamous cell carcinoma, cholangiocarcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, and melanoma.
25 . A method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from non-small cell lung cancer, bladder urothelial carcinoma, esophageal carcinoma, stomach adenocarcinoma, mesothelioma, liver hepatocellular carcinoma, diffuse large B cell lymphoma, kidney renal clear cell carcinoma, head and neck squamous cell carcinoma, cholangiocarcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, and melanoma.
26 . A method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of claim 7 , wherein the cancer is selected from non-small cell lung cancer, bladder urothelial carcinoma, esophageal carcinoma, stomach adenocarcinoma, mesothelioma, liver hepatocellular carcinoma, diffuse large B cell lymphoma, kidney renal clear cell carcinoma, head and neck squamous cell carcinoma, cholangiocarcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, and melanoma.
27 . A method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from non-small cell lung cancer, bladder urothelial carcinoma, esophageal carcinoma, stomach adenocarcinoma, mesothelioma, liver hepatocellular carcinoma, diffuse large B cell lymphoma, kidney renal clear cell carcinoma, head and neck squamous cell carcinoma, cholangiocarcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, and melanoma.
28 . A method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of claim 9 , wherein the cancer is selected from non-small cell lung cancer, bladder urothelial carcinoma, esophageal carcinoma, stomach adenocarcinoma, mesothelioma, liver hepatocellular carcinoma, diffuse large B cell lymphoma, kidney renal clear cell carcinoma, head and neck squamous cell carcinoma, cholangiocarcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, and melanoma.
29 . A method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from non-small cell lung cancer, bladder urothelial carcinoma, esophageal carcinoma, stomach adenocarcinoma, mesothelioma, liver hepatocellular carcinoma, diffuse large B cell lymphoma, kidney renal clear cell carcinoma, head and neck squamous cell carcinoma, cholangiocarcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, and melanoma.
30 . A method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of claim 11 , wherein the cancer is selected from non-small cell lung cancer, bladder urothelial carcinoma, esophageal carcinoma, stomach adenocarcinoma, mesothelioma, liver hepatocellular carcinoma, diffuse large B cell lymphoma, kidney renal clear cell carcinoma, head and neck squamous cell carcinoma, cholangiocarcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, and melanoma.
31 . The method of claim 21 , wherein the melanoma is metastatic melanoma.
32 . The method of claim 22 , wherein the melanoma is metastatic melanoma.
33 . The method of claim 23 , wherein the melanoma is metastatic melanoma.
34 . The method of claim 24 , wherein the melanoma is metastatic melanoma.
35 . The method of claim 25 , wherein the melanoma is metastatic melanoma.
36 . The method of claim 26 , wherein the melanoma is metastatic melanoma.
37 . The method of claim 27 , wherein the melanoma is metastatic melanoma.
38 . The method of claim 28 , wherein the melanoma is metastatic melanoma.
39 . The method of claim 29 , wherein the melanoma is metastatic melanoma.
40 . The method of claim 30 , wherein the melanoma is metastatic melanoma.