IP Library › Granted Patent US 12,692,276
Granted Patent B2
US 12,692,276 · App. 18/330,623 · Granted Jul 28, 2026

Tricyclic triazolo compounds as DGK inhibitors

Inventors: Joshua Hummel (Hockessin, DE); Liana Hie (Wilmington, DE); Jacob J. Lacharity (Chesterbrook, PA); Sharada Manns (Wilmington, DE); Ding-Quan Qian (Newark, DE); Xiaozhao Wang (Moorestown, NJ)
Assignee: Incyte Corporation
C07D513/14C07D487/14C07B2200/05
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,692,276
App. No.
18/330,623
Filed
Jun 7, 2023
Granted
Jul 28, 2026
Kind
B2
Art Unit
1625
USPC
514/267
Abstract

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.

Claims (40)

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.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 16, 2026
From: HUMMEL, JOSHUA; HIE, LIANA; LACHARITY, JACOB J.; LI, XIAOLEI; MANNS, SHARADA; QIAN, DING-QUAN; WANG, XIAOZHAO; WEI, BO; XU, MEIZHONG
To: INCYTE CORPORATION
Reel/Frame 076002/0872 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 17, 2024
From: HUMMEL, JOSHUA; HIE, LIANA; LACHARITY, JACOB J.; LI, XIAOLEI; MANNS, SHARADA; QIAN, DING-QUAN; WANG, XIAOZHAO; WEI, BO; XU, MEIZHONG
To: INCYTE CORPORATION
Reel/Frame 066147/0314 →
Continuity (3)
Provisional Application 63436248 · Dec 30, 2022
Provisional Application 63350244 · Jun 8, 2022
Related Publication 20230399342A1 · Dec 14, 2023
References Cited (185)
US 6833454B1 · Koppes et al. · 2004 [cited by applicant]
US 7381401B2 · Gajewski et al. · 2008 [cited by applicant]
US 7488802B2 · Collins et al. · 2009 [cited by applicant]
US 7943743B2 · Korman et al. · 2011 [cited by applicant]
US 8008449B2 · Korman et al. · 2011 [cited by applicant]
US 8168757B2 · Finnefrock et al. · 2012 [cited by applicant]
US 8217149B2 · Irving et al. · 2012 [cited by applicant]
US 8618288B2 · Dvorak et al. · 2013 [cited by applicant]
US 10087180B2 · Ford et al. · 2018 [cited by applicant]
US 10308644B2 · Wu et al. · 2019 [cited by applicant]
US 20070161072A1 · Prescott et al. · 2007 [cited by applicant]
US 20170145025A1 · Li et al. · 2017 [cited by applicant]
US 20170174671A1 · Wu et al. · 2017 [cited by applicant]
US 20170174679A1 · Lajkiewicz et al. · 2017 [cited by applicant]
US 20170320875A1 · Li et al. · 2017 [cited by applicant]
US 20170342060A1 · Lu et al. · 2017 [cited by applicant]
US 20170362253A1 · Xiao et al. · 2017 [cited by applicant]
US 20180016260A1 · Yu et al. · 2018 [cited by applicant]
US 20180028501A1 · Lindsley et al. · 2018 [cited by applicant]
US 20180057486A1 · Wu et al. · 2018 [cited by applicant]
US 20180177784A1 · Wu et al. · 2018 [cited by applicant]
US 20180177870A1 · Liu et al. · 2018 [cited by applicant]
US 20180179179A1 · Wu et al. · 2018 [cited by applicant]
US 20180179197A1 · Wu et al. · 2018 [cited by applicant]
US 20180179201A1 · Wu et al. · 2018 [cited by applicant]
US 20180179202A1 · Wu et al. · 2018 [cited by applicant]
US 20180273519A1 · Wu et al. · 2018 [cited by applicant]
US 20190040082A1 · Xiao et al. · 2019 [cited by applicant]
US 20190062345A1 · Xiao et al. · 2019 [cited by applicant]
US 20190071439A1 · Li et al. · 2019 [cited by applicant]
US 20190127467A1 · Shah et al. · 2019 [cited by applicant]
US 20190144439A1 · Wu et al. · 2019 [cited by applicant]
US 20190202824A1 · Wu et al. · 2019 [cited by applicant]
US 20190225601A1 · Wu et al. · 2019 [cited by applicant]
US 20190300524A1 · Wu et al. · 2019 [cited by applicant]
US 20190345170A1 · Wu et al. · 2019 [cited by applicant]
US 20240025900A1 · Hummel et al. · 2024 [cited by applicant]
US 20240034734A1 · Hummel et al. · 2024 [cited by applicant]
US 20240083898A1 · Hummel et al. · 2024 [cited by applicant]
US 20240217989A1 · Xiang et al. · 2024 [cited by applicant]
US 20240270739A1 · Xiang et al. · 2024 [cited by applicant]
US 20240374497A1 · Joyal · 2024 [cited by examiner]
US 20250066363A1 · Hummel et al. · 2025 [cited by applicant]
US 20250179083A1 · Hummel · 2025 [cited by examiner]
US 20250186450A1 · Ren et al. · 2025 [cited by applicant]
US 20260001880A1 · Hummel et al. · 2026 [cited by applicant]
CN 105315293A · 2016 [cited by applicant]
CN 109180686A · 2019 [cited by applicant]
CN 110643705A · 2020 [cited by applicant]
CN 111097048A · 2020 [cited by applicant]
CN 112300194A · 2021 [cited by applicant]
CN 113061132A · 2021 [cited by applicant]
CN 115463214A · 2022 [cited by applicant]
CN 116969943A · 2023 [cited by applicant]
EP 4083038A1 · 2022 [cited by applicant]
WO WO2001002398A1 · 2001 [cited by applicant]
WO WO2002000196A2 · 2002 [cited by applicant]
WO WO2002077177A2 · 2002 [cited by applicant]
WO WO2003042402A2 · 2003 [cited by applicant]
WO WO2004021984A2 · 2004 [cited by applicant]
WO WO2005121138A2 · 2005 [cited by applicant]
WO WO2007019083A1 · 2007 [cited by applicant]
WO WO2007109251A2 · 2007 [cited by applicant]
WO WO2008017161A1 · 2008 [cited by applicant]
WO WO2008148926A2 · 2008 [cited by applicant]
WO WO2008156712A1 · 2008 [cited by applicant]
WO WO2009017863A2 · 2009 [cited by applicant]
WO WO2007114239A1 · 2009 [cited by applicant]
WO WO2010036959A2 · 2010 [cited by applicant]
WO WO2010089411A2 · 2010 [cited by applicant]
WO WO2011066342A2 · 2011 [cited by applicant]
WO WO2011082400A2 · 2011 [cited by applicant]
WO WO2011143423A2 · 2011 [cited by applicant]
WO WO2011159877A2 · 2011 [cited by applicant]
WO WO2011161699A2 · 2011 [cited by applicant]
WO WO2012080727A2 · 2012 [cited by applicant]
WO WO2012080729A2 · 2012 [cited by applicant]
WO WO2012130780A1 · 2012 [cited by applicant]
WO WO2014096423A1 · 2014 [cited by applicant]
WO WO2015054572A1 · 2015 [cited by applicant]
WO WO2015095492A1 · 2015 [cited by applicant]
WO WO2015193167A1 · 2015 [cited by applicant]
WO WO2016044772A1 · 2016 [cited by applicant]
WO WO2018062954A1 · 2018 [cited by applicant]
WO WO2019005883A1 · 2019 [cited by applicant]
WO WO2019046795A1 · 2019 [cited by applicant]
WO WO2020006016A1 · 2020 [cited by applicant]
WO WO2020006018A1 · 2020 [cited by applicant]
WO WO2020110127A1 · 2020 [cited by applicant]
WO WO2020239123A1 · 2020 [cited by applicant]
WO WO2021013561A1 · 2021 [cited by applicant]
WO WO2021041588A1 · 2021 [cited by applicant]
WO WO2021052499A1 · 2021 [cited by applicant]
WO WO2021083167A1 · 2021 [cited by applicant]
WO WO2021105115A1 · 2021 [cited by applicant]
WO WO2021105116A1 · 2021 [cited by applicant]
WO WO2021105117A1 · 2021 [cited by applicant]
WO WO2021127554A1 · 2021 [cited by applicant]
WO WO2021130638A1 · 2021 [cited by applicant]
WO WO2021133748A1 · 2021 [cited by applicant]
WO WO2021133749A1 · 2021 [cited by applicant]
WO WO2021133750A1 · 2021 [cited by applicant]
WO WO2021133751A1 · 2021 [cited by applicant]
WO WO2021133752A1 · 2021 [cited by applicant]
WO WO2021219513A1 · 2021 [cited by applicant]
WO WO2021234607A1 · 2021 [cited by applicant]
WO WO2021132422A1 · 2021 [cited by applicant]
WO WO2021243421A1 · 2021 [cited by applicant]
WO WO2021258010A1 · 2021 [cited by applicant]
WO WO2022037630A1 · 2022 [cited by applicant]
WO WO2022076446A1 · 2022 [cited by applicant]
WO WO2022108980A1 · 2022 [cited by applicant]
WO WO2022114164A1 · 2022 [cited by applicant]
WO WO2022114812A1 · 2022 [cited by applicant]
WO WO2022133083A1 · 2022 [cited by applicant]
WO WO2022171745A1 · 2022 [cited by applicant]
WO WO2022187406A1 · 2022 [cited by applicant]
WO WO2022271650A1 · 2022 [cited by applicant]
WO WO2022271659A1 · 2022 [cited by applicant]
WO WO2022271677A1 · 2022 [cited by applicant]
WO WO2022271684A1 · 2022 [cited by applicant]
WO WO2023011456A1 · 2023 [cited by applicant]
WO WO2023125681A1 · 2023 [cited by applicant]
WO WO2023150186A1 · 2023 [cited by applicant]
WO WO2023165525A1 · 2023 [cited by applicant]
WO WO2023165528A1 · 2023 [cited by applicant]
WO WO2023184327A1 · 2023 [cited by applicant]
WO WO2024160277A1 · 2024 [cited by applicant]
Wichroski, Cancer Immunol Res vol. 13(9), Sep. 2025, 1342-1362. (Year: 2025). [cited by examiner]
Offringa, J Immunotherapy Cancer 2023, 11(suppl 1):A1-A1731, A1079. (Year: 2023). [cited by examiner]
Ikeda, Mol Cancer Ther, 24(6), Jun. 2025, 884-895. (Year: 2025). [cited by examiner]
Arranz-Nicolás et al., “Diacylglycerol kinase α inactivation is an integral component of the costimulatory pathway that amplifies TCR signals,” Cancer Immunology Immunotherapy, Jun. 2018, 67(6):965-980. [cited by applicant]
Atzrodt et al., “The renaissance of H/D exchange,” Angewandte Chemie International Edition English, Oct. 2007, 46(41):7744-7765. [cited by applicant]
Bennett et al., “Proposals for the classification of the myelodysplastic syndromes,” British Journal of Haematology, Jun. 1982, 51(2):189-199. [cited by applicant]
Blom et al., “Optimizing preparative LC/MS configurations and methods for parallel synthesis purification,” Journal of Combinatorial Chemistry, Sep. 2003, 5(5):670-683. [cited by applicant]
Blom et al., “Preparative LC-MS Purification: Improved Compound-Specific Method Optimization,” Journal of Combinatorial Chemistry, Nov. 2004, 6(6):874-883. [cited by applicant]
Blom, “Two-Pump at-Column-Dilution Configuration for Preparative Liquid Chromatography—Mass Spectrometry,” Journal of Combinatorial Chemistry, Jul. 2002, 4(4):295-301. [cited by applicant]
Cai et al., “Increased diacylglycerol kinase ζ expression in human metastatic colon cancer cells augments Rho GTPase activity and contributes to enhanced invasion,” BMC cancer, Mar. 19, 2014, 14:208. [cited by applicant]
Chen et al., “Diacylglycerol Kinases in T Cell Tolerance and Effector Function,” Frontiers in Cell and Development Biology, Nov. 10, 2016, 4:130. [cited by applicant]
Chen et al., “The diacylglycerol kinase α (DGKα)/Akt/NF-κB feedforward loop promotes esophageal squamous cell carcinoma (ESCC) progression via FAK-dependent and FAK-independent manner,” Oncogene, Apr. 2019, 38(14):2533-… [cited by applicant]
Chinchilla et al., “Recent advances in Sonogashira reactions,” Chemical Society Reviews, Oct. 2011, 40(10):5084-5121. [cited by applicant]
Cooke et al., “Overarching roles of diacylglycerol signaling in cancer development and antitumor immunity,” Science Signaling, Apr. 2022, 15(729):eabo0264. [cited by applicant]
Cordovilla et al., “The Stille reaction, 38 years later,” ACS Catalysis, May 2015, 5(5):3040-3053. [cited by applicant]
Eurasian Office Action in Eurasia Application No. 202493158, dated Apr. 15, 2025, 6 pages (with English translation). [cited by applicant]
Fu et al., “DGKA interacts with SRC/FAK to promote the metastasis of non-small cell lung cancer,” Cancer Letters, Apr. 2022, 532:215585. [cited by applicant]
Gonzalez et al., “Roles of the immune system in cancer: from tumor initiation to metastatic progression,” Genes & Development, Oct. 2018, 32(19-20):1267-1284. [cited by applicant]
Gu et al., “DGKζ exerts greater control than DGKα over CD8+ T cell activity and tumor inhibition,” Oncoimmunology, Jan. 2021, 10(1):1941566. [cited by applicant]
Haas et al., “Recent developments in Negishi cross-coupling reactions,” ACS Catalysis, Mar. 2016, 6(3):1540-1552. [cited by applicant]
Harabuchi et al. “Manipulation of diacylglycerol and ERK-mediated signaling differentially controls CD8+ T cell responses during chronic viral infection,” Frontiers in Immunology, Nov. 2022, 13:1032113. [cited by applicant]
Harris et al., “World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting—Airlie House, Virginia, Nov. 1997,” Journal of… [cited by applicant]
International Preliminary Report on Patentability in International Application No. PCT/US2023/024679, dated Dec. 10, 2024, 7 pages. [cited by applicant]
International Search Report and Written Opinion in International Appln. No. PCT/US2023/024679, mailed on Aug. 7, 2023, 13 pages. [cited by applicant]
Joshi et al., “Diacylglycerol kinases: regulated controllers of T cell activation, function, and development,” International Journal of Molecular Sciences, Mar. 2013, 14(4):6649-6673. [cited by applicant]
Jung et al., “CRISPR/Cas9-mediated knockout of DGK improves antitumor activities of human T cells,” Cancer Research, Aug. 2018, 78(16):4692-4703. [cited by applicant]
Kerekes et al., “Aurora kinase inhibitors based on the imidazo [1, 2-a] pyrazine core: fluorine and deuterium incorporation improve oral absorption and exposure,” Journal of Medicinal Chemistry, Jan. 2011, 54(1):201-210. [cited by applicant]
Kotha et al., “Recent applications of the Suzuki-Miyaura cross-coupling reaction in organic synthesis,” Tetrahedron, Nov. 2002, 58(48):9633-9695. [cited by applicant]
Krishna et al., “Regulation of lipid signaling by diacylglycerol kinases during T cell development and function,” Frontiers in Immunology, Jul. 2013, 4:178. [cited by applicant]
Mérida et al., “Diacylglycerol kinases in cancer,” Advances in Biological Regulation, Jan. 2017, 63:22-31. [cited by applicant]
Panama Office Action in Panama Application No. PI/2024/95245-01, dated Feb. 17, 2025, 2 pages (with English translation). [cited by applicant]
Prinz et al., “High DGK-α and disabled MAPK pathways cause dysfunction of human tumor-infiltrating CD8+ T cells that is reversible by pharmacologic intervention,” The Journal of Immunology, Jun. 15, 2012, 188(12):5990-6… [cited by applicant]
Rainero et al., “The diacylglycerol kinase α/atypical PKC/α1 integrin pathway in SDF-lα mammary carcinoma invasiveness,” PloS One, Jun. 2014, 9(6):e97144. [cited by applicant]
Remington's Pharmaceutical Sciences, 17th ed., 1985, p. 1418. [cited by applicant]
Riese et al., “Diacylglycerol kinases (DGKs): novel targets for improving T cell activity in cancer,” Frontiers in Cell and Developmental Biology, Oct. 2016, 4:108. [cited by applicant]
Riese et al., “Enhanced effector responses in activated CD8+ T cells deficient in diacylglycerol kinases,” Cancer Research, Jun. 2013, 73(12):3566-3577. [cited by applicant]
Ruffo et al., “Inhibition of diacylglycerol kinase α restores restimulation-induced cell death and reduces immunopathology in XLP-1” Science Translational Medicine, Jan. 2016, 8(321):321ra7. [cited by applicant]
Sakane et al., “New era of diacylglycerol kinase, phosphatidic acid and phosphatidic acid-binding protein,” International Journal of Molecular Sciences, Sep. 2020, 21(18):6794-6829. [cited by applicant]
Sharma et al., “Primary, adaptive, and acquired resistance to cancer immunotherapy,” Cell, Feb. 2017, 168(4):707-723. [cited by applicant]
Sharma et al., “The next decade of immune checkpoint therapy,” Cancer Discovery, Apr. 2021, 11(4):838-857. [cited by applicant]
Sitaram et al., “Beyond the cell surface: targeting intracellular negative regulators to enhance T cell anti-tumor activity,” International Journal of Molecular Sciences, Nov. 2019, 20(23):5821-5848. [cited by applicant]
Speiser et al., “Regulatory circuits of T cell function in cancer,” Nature Reviews Immunology, Oct. 2016, 16(10):599-611. [cited by applicant]
Surry et al., “Dialkylbiaryl Phosphines in Pd-Catalyzed Amination: A User's Guide,” Royal Society of Chemistry, 2011, 2(1):27-50. [cited by applicant]
Swerdlow et al., WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4 [cited by applicant]
Takeishi et al., “Diacylglycerol kinase alpha enhances hepatocellular carcinoma progression by activation of Ras-Raf-MEK-ERK pathway” Journal of Hepatology, Jul. 2012, 57(1):77-83. [cited by applicant]
Torres-Ayuso et al., “Diacylglycerol kinase α promotes 3D cancer cell growth and limits drug sensitivity through functional interaction with Src,” Oncotarget, Oct. 2014, 5(20):9710-9726. [cited by applicant]
Vardiman et al., “The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes,” Blood, Jul. 2009, 114(5):937-951. [cited by applicant]
Vardiman et al., “The World Health Organization (WHO) classification of the myeloid neoplasms,” Blood, Oct. 2002, 100(7):2292-2302. [cited by applicant]
Velnati et al., “Identification of a novel DGKα inhibitor for XLP-1 therapy by virtual screening,” European Journal of Medicinal Chemistry, Feb. 2019, 164:378-390. [cited by applicant]
Wesley et al., “Diacylglycerol Kinase ζ (DGKζ) and Casitas b-Lineage Proto-Oncogene b-deficient mice have similar functional outcomes in T Cells but DGKζ-deficient mice have increased T cell activation and tumor clearan… [cited by applicant]
Xu et al., “Design, synthesis and biological evaluation of deuterated nintedanib for improving pharmacokinetic properties,” Journal of Labelled Compounds and Radiopharmaceuticals, Jun. 2015, 58(7):308-312. [cited by applicant]
Yu et al., “DGKZ acts as a potential oncogene in osteosarcoma proliferation through its possible interaction with ERK1/2 and MYC pathway,” Frontiers in Oncology, Jan. 4, 2019, 8:655. [cited by applicant]
Eurasian Office Action in Eurasia Application No. 202493158, dated Nov. 13, 2025, 4 pages (with English translation). [cited by applicant]
European Office Action in Europe Application No. 23738298.1, dated Nov. 14, 2025, 6 pages. [cited by applicant]
Georgian Office Action in Georgia Application No. AP 2023 16670, dated Oct. 8, 2025, 8 pages (with English translation). [cited by applicant]
Noessner, “DGK-α: A Checkpoint in Cancer-Mediated Immuno-Inhibition and Target for Immunotherapy,” Frontiers in Cell and Developmental Biology, Mar. 3, 2017, 5(Article 16):7 pages. [cited by applicant]
Sadreddini et al., “Immune checkpoint blockade opens a new way to cancer immunotherapy,” Cellular Physiology, Jun. 2019, 234:8541-8549. [cited by applicant]