On June 2, 2022, Watanabe, Hideyuki; Kamikubo, Takashi; Kamikawa, Akio; Washio, Takuya; Seki, Yohei; Okuyama, Keiichiro; Ikeda, Osamu; Tomiyama, Hiroshi; Iwai, Yoshinori; Nakamura, Akihiko; Miyasaka, Kozo published a patent.Electric Literature of 1805937-67-0 The title of the patent was Preparation of heteroaryl carboxamide compounds as DGKζ (DGKzeta) inhibitors and anticancer agents. And the patent contained the following:
Heteroaryl carboxamide compounds including N-phenyl-1H-pyrazole-3-carboxamides, N-phenyl-2-oxo-1,2-dihydropyridine-3-carboxamides, and N-phenyloxazole-4-carboxamides represented by formula I [A = Q1, Q2, Q3, or Q4; B = Q5, Q6, Q7, or Q8; when R1 a = halo-C1-6 alkyl, B = Q5; R1a = pyridazinyl or halo-C1-6 alkyl; R1b = H or C1-6 alkyl; R2 = C3-5 cycloalkyl, C1-6 alkyloxy, halo-C1-6 alkyl, halo, or Ph; R3 = each (un)substituted Ph, C3-8 cycloalkyl, or pyridyl, or 5- or 6-membered partially unsaturated heterocyclyl containing 1-4 heteroatoms selected from O, S, and N atoms; R4 = H or F; R6 = -L2-(CH2)2NRaRb, or piperidinyl; L1 = a singe bond, O, or NH; L2 = a single bond, O, or CH2; X = CH2 or NMe; Y = CH or N; Ra = H or Me; Rb = H, Me, Et, cyclopropyl, or (CH2)2OMe; m = 1, 2, or 3] or salts thereof are prepared The compounds I or salts thereof have a DGKζ (DGKzeta) inhibiting activity and are useful as active ingredients for pharmaceutical compositions for treating cancer associated with the activation of an immunocyte or cancer having resistance to an anti-PD-1 antibody/anti-PD-L1 antibody therapy. Thus, [[(2R)-4-[6-amino-3-(2-fluorophenoxy)-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl]methyl](methyl)carbamic acid tert-Bu ester was condensed with 1-(pyridazin-4-yl)-1H-pyrazole-3-carboxylic acid using HATU in the presence of diisopropylethylamine in DMF at 50° for 12 h to give [[(2R)-4-[3-(2-fluorophenoxy)-6-[[[1-(pyridazin-4-yl)-1H-pyrazol-3-yl]carbonyl]amino]-2-(trifluoromethyl)phenyl]-1-methylpiperazin-2-yl]methyl](methyl)carbamic acid tert-Bu ester which was treated with CF3CO2H in CH2Cl2 at room temperature for 4 h followed by purification using silica gel chromatog. (CHCl3/MeOH/aqueous ammonia solution) to give N-[4-(2-fluorophenoxy)-2-[(3S)-4-methyl-3-[(methylamino)methyl]piperazin-1-yl]-3-(trifluoromethyl)phenyl]-1-(pyridazin-4-yl)-1H-pyrazole-3-carboxamide (II). II, II monobutanedioate, and compound (III) showed IC50 of 10, 3.2, 0.42 nM, resp., against human recombinant DGKζ (DGKzeta). The experimental process involved the reaction of 2-Bromo-4-fluoro-1-nitro-3-(trifluoromethyl)benzene(cas: 1805937-67-0).Electric Literature of 1805937-67-0
The Article related to antibody immunotherapy resistant cancer treatment, heteroaryl carboxamide preparation dgkzeta inhibitor anticancer, phenylpyrazolecarboxamide phenyloxodihydropyridinecarboxamide phenyloxazolecarboxamide preparation dgkzeta inhibitor anticancer and other aspects.Electric Literature of 1805937-67-0
Referemce:
Bromide – Wikipedia,
bromide – Wiktionary