CN-117736207-B - Diacylglycerol kinase modulating compounds

Abstract

The present disclosure provides diacylglycerol kinase modulating compounds and pharmaceutical compositions thereof for use in the treatment of cancers, including solid tumors, and viral infections such as HIV or hepatitis b virus infections. The compounds may be used alone or in combination with other agents.

Inventors

• Ze Kuangming
• J.XU
• L. Rad
• L. PATEL
• M. GRAUPE
• Q.ZHU
• S. Holmbo
• Xiao Lin Zheye
• W. Watkins
• Y. Moyazami
• S.C.Yang
• New well really
• J.A. Dudley
• H. A. Weaver
• NAKAI RYOKO
• MATSUMOTO MASAKAZU
• C .puge
• E.Hu
• J. GUERRERO
• J. JACOBSON
• J. W. Medley

Assignees

• 卡尔那生物科学株式会社
• 吉利德科学公司

Dates

Publication Date

20260512

Application Date

20201218

Priority Date

20191224

Claims (10)

1. 1. A compound having the structure: TABLE 1A Compounds TABLE 1B Compounds TABLE 1C Compounds TABLE 1D Compounds TABLE 1H Compounds TABLE 1 Compounds TABLE 1J Compounds TABLE 2G Compounds TABLE 2J Compounds TABLE 2K Compounds TABLE 3 Compounds TABLE 3 Compounds TABLE 3 Compounds TABLE 3 Compounds J TABLE 3K Compounds Or a pharmaceutically acceptable salt thereof.
2. 2. A compound having the structure of the following formula, Or a pharmaceutically acceptable salt thereof.
3. 3. A compound having the structure of the following formula, Or a pharmaceutically acceptable salt thereof.
4. 4. A compound having the structure of the following formula, Or a pharmaceutically acceptable salt thereof.
5. 5. A compound having the structure of the following formula, Or a pharmaceutically acceptable salt thereof.
6. 6. A compound having the structure of the following formula, Or a pharmaceutically acceptable salt thereof.
7. 7. A compound having the structure of the following formula, Or a pharmaceutically acceptable salt thereof.
8. 8. A compound having the structure of the following formula, Or a pharmaceutically acceptable salt thereof.
9. 9. A compound having the structure of the following formula, Or a pharmaceutically acceptable salt thereof.
10. 10. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

Description

Diacylglycerol kinase modulating compounds The present application is a divisional application of the application patent application with the application date of 2020, 12/18, china application number 202080095556.7 (PCT International application number PCT/IB 2020/062229) and the name of "diacylglycerol kinase modulating compound". Cross Reference to Related Applications The present application claims priority from japanese application nos. 2019-232938, filed on 12 months of 2019, 24, and from japanese application nos. 2020-135810, filed on 8 months of 2020, 11, each of which is incorporated herein by reference in its entirety. Background Diacylglycerols (DAG) are known as the second messenger of signaling molecules and play an important role in cell proliferation, differentiation and/or metabolism (Carrasco, s., merida, i.trends biochem. Sci.2007,32,27-36). The intracellular concentration and localization of DAG are tightly controlled and diacylglycerol kinase (DGK) is one of the enzymes controlling them. DGK is an enzyme that synthesizes Phosphatidic Acid (PA) by transferring phosphoryl groups to DAG. Ten isozymes (α, β, γ, δ, ε, ζ, η, θ, iota, κ) are known (Joshi, r.p., koretzky, g.a. int.j.mol.sci.,2013,14,6649-6673). It is believed that each isozyme localizes and associates with a different protein and/or with a different cell type. DGK is reported to be involved in the pathogenesis of a variety of diseases including cancer, immune diseases, neurodegenerative diseases and diabetes (Sakane, f. Et al front. Cell dev. Biol.,2016,4,82.) Dgkα is a research target, including the study of possible cancer treatments. For example, as a result of knockdown caused by dgkα -targeted RNA interference, inhibitory activity on glioblastoma cell proliferation was reported (domiiguez, c.l. et al Cancer discover, 2013, 782-797). Inhibition of human colon cancer cell lines in three-dimensional cell cultures was also reported, and further inhibition of dgkα was reported in WO 2007/114239 by Torres-Ayuso, p. et al Oncotarget,2014,5,9710-9726, in a mouse model of dgkα knockdown inhibition. Thus, compounds having inhibitory activity against dgkα may be used in therapies such as the treatment of cancers in which dgkα is involved in its proliferation. In recent years, cancer immunotherapy has attracted attention as a potential cancer treatment. Immune checkpoint inhibitors such as anti-CTLA-4 (cytotoxic T lymphocyte antigen 4) antibodies, anti-PD-1 (programmed death receptor 1) antibodies, anti-PD-L1 (programmed death ligand 1) antibodies, and the like, can be administered, and anti-tumor immune responses can be boosted in patients. Some immune checkpoint inhibitors have been approved as medicine for anti-tumor therapy. However, the anti-tumor effect is generally limited to a few patients. In addition, some patients are resistant to inhibitors (Spranger, s., gajewski, T.F., nat.Rev.Cancer.,2018,18,139-147). Dgkα is expressed in T cells, mediates signaling of T Cell Receptors (TCRs), and is believed to play a role in T cell activation (Joshi et al, supra and Merida, i. et al, adv.biol. Regul.,2017,63,22-31.) dgkα expression may be increased when T cells are under immune non-responsive conditions such as allergy, and dgkα overexpression is reported to induce allergic conditions (Zha, y. et al, nat.immunol.,2006,7,1166-1173). In addition, T cell activation due to knockdown of DGK alpha in T cells by RNA interference has been reported (Avila-Flores, A. Et al Immunol. Cell. Biol.,2017,95,549-563.) therefore, compounds having an activity of controlling DGK alpha can be used for preventing and/or treating T cell-related diseases such as immune or inflammatory diseases. Recently, CAR (chimeric antigen receptor) T cell therapies have attracted attention as promising immune cancer therapies as well. DGK alpha-deficient CAR T cells have been reported to have high effector functions and anti-tumor effects on solid cancers (Riese, M.J. et al Cancer Res.,2013,73,3566-3577; jung, I.Y. et al Cancer Res.,2018,78,4692-4703). Thus, the use of compounds that have an inhibitory effect on dgkα can supplement CAR T cell therapy. However, there remains a need for dgkα inhibitors, for example, having desirable pharmaceutical and therapeutic properties. Disclosure of Invention In one embodiment, the present disclosure provides a compound of formula (I-1): or a pharmaceutically acceptable salt thereof, wherein R 1、R2、R3 and R 4 are independently a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a formyl group, a cyano group, an amino group, a nitro group, a nitroso group, an alkoxycarbonyl group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted alkylamino group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally