Glycinamide compounds containing alkynyl thiazolylcarbonyl, preparation methods and applications thereof

Abstract

The embodiments of the present application relate to a glycine amide compound containing an alkynyl thiazolylcarbonyl group, its preparation method and application, belonging to the technical field of pharmaceutical chemistry. A glycine amide compound containing an alkynyl thiazolylcarbonyl group according to the embodiments of the present application, wherein the compound is a compound represented by formula I, a pharmaceutically acceptable salt of the compound represented by formula I, a hydrate of the compound represented by formula I, a solvate of the compound represented by formula I, an optical isomer of the compound represented by formula I or a derivative of the compound represented by formula I. The glycine amide compound containing an alkynyl thiazolylcarbonyl group provided by the embodiments of the present application has a significant inhibitory effect on glutathione peroxidase 4 (GPX4) activity.

Description

Technical Field

[0001] The embodiments of the present application relate to the technical field of medicinal chemistry, and in particular to a glycine amide compound containing an alkynyl thiazolyl group, a preparation method thereof, and an application thereof. Background Art

[0002] Malignant tumors are one of the major diseases in the world and pose a serious threat to human health and life. Although the current medical quality has been significantly improved, there is still a lack of effective countermeasures to treat cancer. In 2020, there were 19.29 million newly diagnosed cancer cases and 9.96 million cancer deaths globally.

[0003] GPX4 is a member of the glutathione peroxidase family and is an enzyme containing a selenium cysteine core. Different from other members of this family, GPX4 is the only peroxidase that can catalyze the reduction of lipid peroxides. Inhibition of GPX4 activity will directly lead to the obstruction of intracellular LPO clearance, thereby inducing ferroptosis. Therefore, inhibiting the activity of GPX4 is the most effective way to induce ferroptosis. Under the condition that glutathione (GSH) is used as a coenzyme, GPX4 can biologically reduce various LPOs (such as PE-AA-OOH and PE-ADA-OOH) generated intracellularly to normal lipids. GPX4 is highly expressed in various tumors such as fibrosarcoma, lymphoma, breast cancer, lung cancer, and renal cancer, and is related to tumor MDR. Research shows that inhibiting GPX4 activity will block the intracellular lipid peroxide metabolism and induce ferroptosis to overcome tumor MDR.

[0004] Currently, the research on ferroptosis inducers is still in the early stage. Although multiple compounds have been found to have GPX4 inhibitor activity and ferroptosis induction activity, such as RSL-3, Erastin, and ML-210, etc., their structures are single, and there are problems such as insufficient ferroptosis induction activity, lack of selectivity, and poor drug-likeness. No ferroptosis inducer has entered clinical trials yet. Summary of the Invention

[0005] In view of this, the embodiments of the present application provide a glycine amide compound containing an alkynyl thiazolyl group, a preparation method thereof, and an application thereof. Through experiments, it is proved that this kind of compound has a significant inhibitory effect on glutathione peroxidase 4 (GPX4) activity, and can block the intracellular lipid peroxide metabolism by inhibiting GPX4, so that toxic lipid peroxides such as LPO (PE-AA-OOH and PE-ADA-OOH) accumulate, inducing cells to undergo ferroptosis. In addition, GPX4 is highly expressed in various tumors such as fibrosarcoma, lymphoma, breast cancer, lung cancer, and renal cancer. The ferroptosis induced by this kind of compound effectively kills tumor cells, providing more optional drugs for patients, and can effectively overcome the defects existing in the above-mentioned prior art.

[0006] In the first aspect of the embodiments of the present application, a glycine amide compound containing an alkynyl thiazolylcarbonyl group is provided. The compound is a compound represented by formula I, a pharmaceutically acceptable salt of the compound represented by formula I, a hydrate of the compound represented by formula I, a solvate of the compound represented by formula I, an optical isomer of the compound represented by formula I, or a derivative of the compound represented by formula I. The structure of formula I is shown as follows:

[0007]

[0008] In the formula, R1 is selected from allyl, C1-6 alkyl, cycloalkyl, substituted or unsubstituted benzyl, phenethyl, phenethyl with 1-2 substituents, substituted or unsubstituted aromatic ring, and haloalkyl;

[0009] R2 is selected from a nitrogen-containing aromatic heterocycle, a saturated nitrogen-containing heterocycle, or 1-3 identical or different R3 substituents;

[0010] R3 is selected from hydrogen, hydroxy, alkoxy, halogen, C1-6 alkylamino, cyano, C1-6 alkyl, and haloalkyl;

[0011] Cyl is selected from a five-membered aromatic heterocycle, a six-membered aromatic heterocycle, a benzo five-membered heterocycle, a benzo six-membered heterocycle, a pyrido six-membered heterocycle, a pyrido five-membered heterocycle, a heterocyclic ring, naphthalene, anthracene, C1-6 alkyl, and cycloalkyl.

[0012] In some embodiments that may include the above embodiments, R1 is selected from allyl, tert-butyl, cycloalkyl, benzyl, substituted or unsubstituted aromatic ring, phenethyl, phenethyl with 1-2 substituents, substituted or unsubstituted aromatic ring, and haloalkyl;

[0013] R2 is selected from a five-membered nitrogen-containing aromatic heterocycle, a saturated nitrogen-containing heterocycle, or 1-3 identical or different R3 substituents;

[0014] R3 is selected from hydrogen, alkoxy, halogen, C 1-6 alkylamino, cyano, C 1-6 alkyl, and haloalkyl;

[0015] Cyl is selected from a five-membered aromatic heterocycle, a six-membered aromatic heterocycle, a benzo five-membered heterocycle, a benzo six-membered heterocycle, naphthalene, and cycloalkyl.

[0016] In some embodiments that may include the above embodiments, Cyl is selected from any of the following structures:

[0017]

[0018] In some embodiments that may include the above embodiments, the compound is selected from N-(1-(benzo[b]thiophen-3-yl)-2-oxo-2-(phenethylamino)ethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide, N-(1-(benzo[b]thiophen-3-yl)-2-((4-fluorophenethyl)amino)-2-oxoethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide, N-(1-(benzo[b]thiophen-3-yl)-2-(tert-butylamino)-2-oxoethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide, N-(1-(benzo[b]thiophen-3-yl)-2-(cyclohexylamino)-2-oxoethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide, N-(1-(benzo[b]thiophen-3-yl)-2-(benzylamino)-2-oxoethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide, N-(1-(benzo[b]thiophen-3-yl)-2-(tert-butylamino)-2-oxoethyl)-2-ethynyl-N-(4-(piperazin-1-yl)phenyl)thiazole-4-carboxamide, N-(4-(1H-imidazol-1-yl)phenyl)-N-(1-(benzothiophen-3-yl)-2-(tert-butylamino)-2-oxoethyl)-2-ethynylthiazole-4-carboxamide, N-(4-(1H-pyrazol-1-yl)phenyl)-N-(1-(benzo[b]thiophen-3-yl)-2-(tert-butylamino)-2-oxoethyl)-2-ethynylthiazole-4-carboxamide, N-(4-(1H-1,2,4-triazol-1-yl)phenyl)-N-(1-(benzothiophen-3-yl)-2-(tert-butylamino)-2-oxoethyl)-2-ethynylthiazole-4-carboxamide, N-(1-(benzo[b]thiophen-3-yl)-2-(tert-butylamino)-2-oxoethyl)-2-ethynyl-N-(4-fluorophenyl)thiazole-4-carboxamide, N-(1-(benzo[b]thiophen-3-yl)-2-(tert-butylamino)-2-oxoethyl)-2-ethynyl-N-(3-fluorophenyl)thiazole-4-carboxamide, N-(1-(benzo[b]thiophen-3-yl)-2-(tert-butylamino)-2-oxoethyl)-N-(2,6-difluorophenyl)-2-ethynylthiazole-4-carboxamide, N-(1-(benzo[b]thiophen-3-yl)-2-(tert-butylamino)-2-oxoethyl)-2-ethynyl-N-(4-(trifluoromethyl)phenyl)thiazole-4-carboxamide, N-(2-(tert-butylamino)-1-cyclohexyl-2-oxoethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide, N-(2-(tert-butylamino)-1-(5,6-dihydro-2H-pyran-3-yl)-2-oxoethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide, N-(2-(tert-butylamino)-2-oxo-1-(pyrimidin-4-yl)ethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide, N-(2-(tert-butylamino)-1-(1H-imidazol-4-yl)-2-oxoethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide, N-(2-(tert-butylamino)-2-oxo-1-(thiazol-5-yl)ethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide, N-(2-(tert-butylamino)-2-oxo-1-(1H-pyrrol-2-yl)ethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide, N-(2-(tert-butylamino)-2-oxo-1-(thiophen-3-yl)ethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide, N-(2-(tert-butylamino)-2-oxo-1-(thiophen-2-yl)ethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide, N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide, N-(2-(tert-butylamino)-2-oxo-1-(1H-pyrazol-3-yl)ethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide, N-(2-(tert-butylamino)-1-(naphthalen-2-yl)-2-oxoethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide, and N-(2-(tert-butylamino)-1-(1H-indol-3-yl)-2-oxoethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide.,

[0019] In the second aspect of the embodiments of the present application, a preparation method of the above-mentioned glycine amide compounds containing an alkynyl thiazolylcarbonyl group is further provided, including the step of obtaining the compound shown in Formula I according to the following reaction formula:

[0020]

[0021] That is: Dissolve Compound 1 and Compound 4 in 0.6 mL of methanol, stir for 15 minutes, then add Compound 2 and Compound 3, carry out the reaction, the reaction time is 8 - 10 h, and perform post-treatment to obtain the target compound.

[0022] Preferably, the post-treatment includes the following steps: After the reaction is completed, concentrate under reduced pressure, separate by preparative thin layer chromatography to obtain the target compound.

[0023] In the third aspect of the embodiments of the present application, a pharmaceutical composition is further provided, which comprises the alkynyl thiazolylformyl glycinamide compound as described above and one or more pharmaceutically acceptable adjuvants or excipients.

[0024] In the fourth aspect of the embodiments of the present application, the application of the alkynyl thiazolylformyl glycinamide compound as described above in the preparation of a ferroptosis inducer is further provided.

[0025] In the fifth aspect of the embodiments of the present application, the application of the alkynyl thiazolylformyl glycinamide compound as described above in the preparation of an anti-tumor drug is further provided.

[0026] In some embodiments that may include the above embodiments, the tumor is a ferroptotic tumor, specifically including fibrosarcoma, lymphoma, breast cancer, lung cancer, and renal cancer.

[0027] In some embodiments that may include the above embodiments, the compound induces ferroptosis by inhibiting GPX4, thereby inhibiting the survival of tumor cells and achieving an anti-tumor effect.

[0028] Compared with the prior art, the embodiments of the present application have the following beneficial effects:

[0029] The alkynyl thiazolylformyl glycinamide compound of the embodiments of the present application has a significant inhibitory effect on the activity of glutathione peroxidase 4 (GPX4), can block the intracellular lipid peroxide metabolism by inhibiting GPX4, cause the accumulation of toxic lipid peroxides such as LPO (PE-AA-OOH and PE-ADA-OOH, etc.), and induce ferroptosis in cells; in addition, GPX4 is highly expressed in various tumors such as fibrosarcoma, lymphoma, breast cancer, lung cancer, and renal cancer, and the ferroptosis induced by this type of compound effectively kills tumor cells, providing more optional drugs for patients. Detailed implementation manners

[0030] To make the objectives, technical solutions, and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be clearly and completely described below. Obviously, the described embodiments are some, but not all, of the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present application.

[0031] In the following examples and comparative examples, unless otherwise specified, all raw materials can be obtained through commercial purchase or conventional methods.

[0032] In the embodiments of the present application, the term "substituted" means that one or more hydrogen atoms in the group are independently replaced by the corresponding number of substituents.

[0033] In the embodiments of the present application, excipients or adjuvants are substances that have been reasonably evaluated in terms of safety and are included in pharmaceutical preparations in addition to the active ingredient. They can be gum arabic, syrup, lanolin, starch, magnesium chloride, cyclodextrin, sebacic acid, dextrin, pharmaceutical calcium sulfate, glycerol, mannitol, sorbitol, inositol, thiol, tromethamine, phenol, m-cresol, benzyl alcohol, parabens, methyl paraben, tert-butanol, benzalkonium chloride, chlorobutanol, thimerosal, etc.

[0034] In the embodiments of the present application, an optical isomer is a type of stereoisomer, also known as an enantiomer, enantiomorph, optical isomer, mirror image isomer, enantiomeric isomer or chiral isomer, which cannot be completely overlapped with its stereoisomer mirror image.

[0035] In the embodiments of the present application, derivatives of the compound of general formula I as prodrugs mean that they may have weak activity or even no activity by themselves, but after administration, they are converted into the corresponding bioactive form under physiological conditions (such as by metabolism, solvolysis or other means).

[0036] The chemical structures of the embodiments of the present application were confirmed by 1H-NMR and 13C-NMR. Flash column chromatography was carried out on silica gel H (10 - 40 μM).

[0037] Example 1

[0038] N-(1-(Benzo[b]thiophen-3-yl)-2-oxo-2-(phenethylamino)ethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide The preparation process is as follows:

[0039] Preparation of the target compound: Dissolve 3-benzo[b]thiophenecarboxaldehyde and 4-(oxazol-5-yl)aniline in 0.6 mL of methanol. After stirring for 15 minutes, add 2-(ethynyl)thiazole-4-carboxylic acid and compound phenethyl isocyanide, and carry out the reaction for 8 - 10 hours. After post-treatment, the compound of Example 1 is obtained with a yield of 95%.

[0040] 1 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.34 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.84–7.74 (m, 2H), 7.53 (s, 1H), 7.50–7.33 (m, 3H), 7.30–7.13 (m, 9H), 6.75 (s, 1H), 4.84 (s, 1H), 3.68–3.47 (m, 1H), 2.78 (t, J = 6.4 Hz, 2H).

[0041] 13 C NMR(101MHz, DMSO) δ 168.66, 163.05, 151.80, 149.92, 149.67, 145.68, 139.40, 139.35, 138.95, 138.03, 130.45, 129.47, 128.88, 128.69, 128.26, 126.03, 125.84, 124.61, 124.51, 123.06, 122.90, 122.35, 121.46, 117.35, 86.32, 75.78, 57.65, 40.38, 34.88。

[0042] Example 2

[0043] N-(1-(Benzo[b]thiophen-3-yl)-2-((4-fluorophenethyl)amino)-2-oxoethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide The synthesis route of the example of this application is the same as that of Example 1.

[0044] 1 H NMR(400MHz, DMSO-d6) δ 8.46(s, 1H), 8.34(s, 1H), 7.90(d, J = 8.0Hz, 1H), 7.85–7.74(m, 2H), 7.53(s, 1H), 7.50–7.33(m, 3H), 7.29–7.22(m, 4H), 7.18(s, 1H), 7.05(t, J = 8.8Hz, 2H), 6.73(s, 1H), 4.84(s, 1H), 3.61–3.46(m, 1H), 2.76(t, J = 7.0Hz, 2H)。

[0045] 13 C NMR(101MHz, DMSO) δ 168.72, 163.05, 161.99, 159.59, 151.82, 149.91, 149.67, 145.68, 139.40, 138.96, 138.02, 135.49, 135.46, 130.51, 130.43, 129.46, 128.88, 126.06, 125.85, 124.63, 124.53, 123.06, 122.93, 122.37, 121.48, 114.98, 114.78, 86.32, 75.78, 57.66, 54.88, 33.95。

[0046] Example 3

[0047] N-(1-(Benzo[b]thiophen-3-yl)-2-(tert-butylamino)-2-oxoethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide The synthetic route of the application example is the same as that of Example 1.

[0048] 1 H NMR(400MHz,DMSO-d6)δ8.33(s,1H),8.04(s,1H),7.89(d,J=8.0Hz,1H),7.82(d,J=7.8Hz,1H),7.75(s,1H),7.54–7.43(m,3H),7.41–7.20(m,5H),6.72(s,1H),4.84(s,1H),1.31(s,9H).

[0049] 13 C NMR(101MHz,DMSO)δ168.15,163.01,151.77,150.04,149.71,145.67,139.53,138.97,138.15,130.52,130.35,128.18,125.86,125.73,124.58,124.40,122.97,122.85,122.29,121.68,86.29,75.80,59.72,50.55,50.55,28.40,14.06.

[0050] Example 4

[0051] N-(1-(Benzo[b]thiophen-3-yl)-2-(cyclohexylamino)-2-oxoethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide The synthetic route of the application example is the same as that of Example 1.

[0052] 1 H NMR(400MHz,DMSO-d6)δ8.34(s,1H),8.28(d,J=6.0Hz,1H),7.90(d,J=8.0Hz,1H),7.83(d,J=7.9Hz,1H),7.76(s,1H),7.55–7.16(m,8H),6.74(s,1H),4.85(s,1H),3.76–3.63(m,1H),1.83–1.49(m,5H),1.37–1.00(m,5H).

[0053] 1313C NMR (101 MHz, DMSO) δ 167.74, 163.08, 151.79, 149.98, 149.69, 145.69, 139.44, 138.99, 138.11, 130.52, 129.92, 128.57, 125.92, 125.79, 124.61, 124.49, 122.98, 122.90, 122.33, 121.52, 86.33, 75.78, 57.63, 48.05, 32.16, 32.12, 25.15, 24.53, 24.42。

[0054] Example 5

[0055] N-(1-(Benzo[b]thiophen-3-yl)-2-(benzylamino)-2-oxoethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide The synthetic route of the application example is the same as that of Example 1.

[0056] 1 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.34 (s, 1H), 8.00–7.71 (m, 3H), 7.59–7.13 (m, 13H), 6.83 (s, 1H), 4.84 (s, 1H), 4.43 (s, 2H).

[0057] 13 13C NMR (101 MHz, DMSO) δ 168.94, 163.09, 151.81, 149.88, 149.68, 145.69, 139.39, 138.99, 138.06, 130.57, 129.44, 128.93, 128.23, 127.34, 126.81, 126.11, 125.91, 124.65, 124.54, 123.10, 122.92, 122.39, 121.55, 86.33, 75.78, 57.78, 42.55。

[0058] Example 6

[0059] N-(1-(Benzo[b]thiophen-3-yl)-2-(tert-butylamino)-2-oxoethyl)-2-ethynyl-N-(4-(piperazin-1-yl)phenyl)thiazole-4-carboxamide The synthetic route of the application example is the same as that of Example 1.

[0060] 1313C NMR (101 MHz, DMSO) δ 168.22, 150.36, 149.70, 138.96, 138.42, 130.82, 129.96, 127.75, 124.46, 124.29, 122.82, 121.67, 113.39, 86.17, 75.93, 54.89, 50.46, 50.38, 48.03, 47.17, 44.87, 31.14, 29.82, 28.42。

[0061] Example 7

[0062] N-(4-(1H-Imidazol-1-yl)phenyl)-N-(1-(benzo[b]thiophen-3-yl)-2-(tert-butylamino)-2-oxoethyl)-2-ethynylthiazole-4-carboxamide The synthetic route of the application example is the same as that of Example 1.

[0063] 1 1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 8.06 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.78 (s, 1H), 7.60 (s, 1H), 7.49 (t, J = 7.2 Hz, 1H), 7.38 (t, J = 7.3 Hz, 1H), 7.32 (s, 1H), 7.26 (s, 2H), 7.01 (s, 1H), 6.72 (s, 1H), 4.85 (s, 1H), 1.31 (s, 9H).

[0064] 13 13C NMR (101 MHz, DMSO) δ 168.21, 150.01, 139.03, 138.20, 137.69, 135.15, 135.07, 131.34, 130.44, 129.90, 128.20, 126.01, 124.64, 124.47, 122.92, 121.69, 118.19, 117.34, 86.31, 75.81, 54.88, 50.56, 28.41.

[0065] Example 8

[0066] N-(4-(1H-Pyrazol-1-yl)phenyl)-N-(1-(benzo[b]thiophen-3-yl)-2-(tert-butylamino)-2-oxoethyl)-2-ethynylthiazole-4-carboxamide The synthetic route of the application example is the same as that of Example 1.

[0067] 11H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 2.5 Hz, 1H), 8.05 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.64 (s, 1H), 7.52–7.29 (m, 5H), 6.72 (s, 1H), 6.52–6.39 (m, 1H), 4.84 (s, 1H), 1.32 (s, 9H).

[0068] 13 13C NMR (101 MHz, DMSO) δ 168.21, 163.06, 150.06, 145.65, 140.96, 138.98, 138.19, 137.91, 137.11, 131.01, 130.92, 130.42, 128.15, 127.47, 125.71, 124.58, 124.41, 122.86, 121.69, 116.66, 107.93, 86.30, 75.83, 57.93, 54.87, 50.54, 28.41.

[0069] Example 9

[0070] N-(4-(1H-1,2,4-Triazol-1-yl)phenyl)-N-(1-(benzothiophen-3-yl)-2-(tert-butylamino)-2-oxoethyl)-2-ethynylthiazole-4-carboxamide The synthetic route of the application example is the same as that of Example 1.

[0071] 1 1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.07 (s, 1H), 7.96–7.80 (m, 5H), 7.57–7.32 (m, 6H), 6.74 (s, 1H), 4.84 (s, 1H), 1.32 (s, 9H).

[0072] 13 13C NMR (101 MHz, DMSO) δ 168.18, 162.99, 149.93, 145.74, 139.44, 139.02, 138.12, 134.83, 134.42, 131.26, 130.29, 128.31, 126.28, 124.64, 124.47, 122.90, 122.76, 121.69, 121.63, 118.49, 113.80, 86.34, 75.79, 58.01, 50.58, 28.40.

[0073] Example 10

[0074] N-(1-(Benzo[b]thiophen-3-yl)-2-(tert-butylamino)-2-oxoethyl)-2-ethynyl-N-(4-fluorophenyl)thiazole-4-carboxamide The synthetic route of the application example is the same as that of Example 1.

[0075] 1 H NMR(400MHz,DMSO-d6)δ8.04(s,1H),7.91(d,J=7.6Hz,1H),7.83–7.70(m,2H),7.47(t,J=6.7Hz,1H),7.38(d,J=7.1Hz,1H),7.29(s,1H),6.67(s,4H),4.86(s,1H),1.30(s,9H).

[0076] 13 C NMR(101MHz,DMSO)δ168.21,163.03,161.73,159.30,150.06,138.99,138.13,135.64,130.40,128.13,125.87,124.59,124.39,122.85,121.68,114.16,113.94,86.24,75.80,57.86,50.53,28.40.

[0077] Example 11

[0078] N-(1-(Benzo[b]thiophen-3-yl)-2-(tert-butylamino)-2-oxoethyl)-2-ethynyl-N-(3-fluorophenyl)thiazole-4-carboxamide The synthetic route of the application example is the same as that of Example 1.

[0079] 1 H NMR(400MHz,DMSO-d6)δ8.07(s,1H),7.96–7.74(m,3H),7.46(t,J=7.4Hz,1H),7.41–7.29(m,2H),6.93–6.74(m,3H),6.71(s,1H),4.87(s,1H),1.31(s,9H).

[0080] 1313C NMR (101 MHz, DMSO) δ 168.64, 163.41, 160.00, 150.42, 146.17, 141.55, 141.45, 139.47, 138.58, 130.69, 129.09, 129.00, 128.70, 126.64, 125.09, 124.87, 123.33, 122.18, 114.53, 114.32, 86.79, 76.28, 51.08, 28.89。

[0081] Example 12

[0082] N-(1-(Benzo[b]thiophen-3-yl)-2-(tert-butylamino)-2-oxoethyl)-N-(2,6-difluorophenyl)-2-ethynylthiazole-4-carboxamide The synthetic route of the application example is the same as that of Example 1.

[0083] 1 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 8.01 (s, 1H), 7.90 (s, 2H), 7.64 (s, 1H), 7.43–7.28 (m, 3H), 7.14 (t, 2H), 6.84 (t, J = 8.0 Hz, 2H), 6.65 (t, J = 8.2 Hz, 2H), 6.56 (s, 1H), 4.82 (s, 1H), 1.22 (s, 9H).

[0084] 13 13C NMR (101 MHz, DMSO) δ 166.34, 163.14, 149.20, 145.76, 138.96, 138.30, 130.33, 129.66, 127.60, 127.51, 124.34, 123.92, 122.67, 121.74, 111.23, 111.01, 110.88, 110.68, 86.29, 75.62, 57.56, 50.34, 28.16。

[0085] Example 13

[0086] N-(1-(Benzo[b]thiophen-3-yl)-2-(tert-butylamino)-2-oxoethyl)-2-ethynyl-N-(4-(trifluoromethyl)phenyl)thiazole-4-carboxamide The synthetic route of the application example is the same as that of Example 1.

[0087] 11H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.96 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.46 (t, J = 7.4 Hz, 1H), 7.41–7.22 (m, 6H), 6.75 (s, 1H), 4.85 (s, 1H), 1.30 (s, 9H).

[0088] 13 13C NMR (101 MHz, DMSO) δ 168.05, 162.80, 149.79, 145.72, 143.30, 139.02, 138.00, 130.57, 130.16, 128.36, 127.31, 126.99, 126.93, 125.23, 124.66, 124.46, 124.32, 122.88, 122.53, 121.64, 86.25, 75.64, 58.18, 50.59, 28.37.

[0089] Example 14

[0090] N-(2-(tert-Butylamino)-1-cyclohexyl-2-oxoethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide The synthetic route of the application example is the same as that of Example 1.

[0091] 1 1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.78 (d, J = 8.5 Hz, 2H), 7.67 (s, 1H), 7.59 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 7.3 Hz, 2H), 4.87 (d, J = 14.2 Hz, 2H), 1.94 (s, 1H), 1.84 (s, 1H), 1.69 (s, 2H), 1.59 (s, 2H), 1.20 (s, 9H), 1.11 (s, 5H).

[0092] 13 13C NMR (101 MHz, DMSO) δ 167.58, 163.49, 151.94, 150.48, 149.86, 145.60, 139.93, 130.24, 126.12, 125.28, 123.80, 122.44, 86.36, 75.77, 65.47, 50.37, 36.86, 29.40, 28.27, 25.95, 25.37.

[0093] Example 15

[0094] N-(2-(tert-Butylamino)-1-(5,6-dihydro-2H-pyran-3-yl)-2-oxoethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide The synthetic route of the application example is the same as that of Example 1.

[0095] 1 H NMR(400MHz,DMSO-d6)δ8.42(s,1H),7.78(s,1H),7.68(d,J=8.8Hz,2H),7.58(d,J=8.1Hz,2H),7.43(s,2H),5.73(s,1H),5.47(s,1H),4.85(s,1H),3.77(q,J=15.6Hz,2H),3.39(t,1H),3.20(t,1H),1.97(d,J=10.8Hz,1H),1.80(d,J=16.9Hz,1H),1.26(s,9H).

[0096] 13 C NMR(101MHz,DMSO)δ167.71,162.86,151.89,150.20,149.94,145.58,139.74,131.87,131.16,127.11,126.04,125.58,123.34,122.40,86.24,75.83,66.35,62.69,62.43,50.36,28.37,24.84.

[0097] Example 16

[0098] N-(2-(tert-Butylamino)-2-oxo-1-(pyrimidin-4-yl)ethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide The synthetic route of the application example is the same as that of Example 1.

[0099] 1 H NMR(400MHz,DMSO-d6)δ9.15(s,1H),8.73(d,J=5.2Hz,1H),8.40(s,1H),8.22(s,1H),7.82(s,1H),7.64(s,2H),7.53(d,J=8.2Hz,4H),7.35(d,J=8.2Hz,2H),6.28(s,1H),4.86(s,1H),1.10(s,9H).

[0100] 1313C NMR (101 MHz, DMSO) δ 165.17, 164.74, 162.77, 157.97, 157.23, 151.96, 149.78, 149.68, 145.84, 140.18, 130.48, 126.33, 126.18, 123.69, 122.49, 120.99, 86.44, 75.81, 66.55, 50.61, 28.04。

[0101] Example 17

[0102] N-(2-(tert-Butylamino)-1-(1H-imidazol-4-yl)-2-oxoethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide The synthetic route of the application example is the same as that of Example 1.

[0103] 1 1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.38 (s, 1H), 8.04 (s, 1H), 7.73 (s, 1H), 7.60 (s, 1H), 7.56 (s, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.16 (s, 2H), 6.76 (s, 1H), 6.11 (s, 1H), 4.84 (s, 1H), 1.26 (s, 9H).

[0104] 13 13C NMR (101 MHz, DMSO) δ 167.85, 162.55, 151.81, 150.42, 149.94, 145.57, 140.64, 135.16, 135.07, 130.64, 125.56, 123.24, 122.21, 116.27, 86.23, 75.86, 60.04, 54.88, 50.28, 28.35。

[0105] Example 18

[0106] N-(2-(tert-Butylamino)-2-oxo-1-(thiazol-5-yl)ethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide The synthetic route of the application example is the same as that of Example 1.

[0107] 11H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.40 (s, 1H), 8.01 (s, 1H), 7.80 (d, J = 3.6 Hz, 2H), 7.64 (s, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.22 (s, 2H), 6.55 (s, 1H), 4.84 (s, 1H), 1.25 (s, 9H).

[0108] 13 13C NMR (101 MHz, DMSO) δ 167.29, 162.41, 156.22, 151.96, 149.74, 149.72, 145.67, 144.71, 139.30, 132.08, 131.34, 126.40, 126.23, 123.63, 122.59, 86.34, 75.75, 57.50, 50.64, 28.20.

[0109] Example 19

[0110] N-(2-(tert-Butylamino)-2-oxo-1-(1H-pyrrol-2-yl)ethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide The synthetic route of the application example is the same as that of Example 1.

[0111] 1 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.37 (s, 1H), 7.75 (s, 1H), 7.59 (d, J = 10.9 Hz, 2H), 7.38 (d, J = 7.9 Hz, 2H), 7.15 (s, 2H), 6.56 (s, 1H), 6.22 (s, 1H), 5.71 (d, J = 14.1 Hz, 2H), 4.84 (s, 1H), 1.29 (s, 9H).

[0112] 13 13C NMR (101 MHz, DMSO) δ 168.03, 162.41, 151.74, 150.41, 150.00, 145.52, 140.29, 130.74, 125.54, 125.33, 124.57, 123.04, 122.14, 118.40, 109.47, 107.26, 86.17, 75.88, 59.01, 50.36, 28.43.

[0113] Example 20

[0114] N-(2-(tert-Butylamino)-2-oxo-1-(thiophen-3-yl)ethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide The synthetic route of the application example is the same as that of Example 1.

[0115] 1 H NMR(400MHz,DMSO-d6)δ8.38(s,1H),7.82(s,1H),7.70(s,1H),7.60(s,1H),7.40(d,J=7.7Hz,2H),7.25(q,4H),6.78(d,J=3.8Hz,1H),6.26(s,1H),4.84(s,1H),1.27(s,9H).

[0116] 13 C NMR(101MHz,DMSO)δ168.54,162.56,151.83,150.22,149.85,145.55,139.96,135.57,131.20,128.79,126.12,125.77,125.67,125.56,123.24,122.32,86.23,75.84,60.10,50.41,28.39.

[0117] Example 21

[0118] N-(2-(tert-Butylamino)-2-oxo-1-(thiophen-2-yl)ethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide The synthetic route of the application example is the same as that of Example 1.

[0119] 1 H NMR(400MHz,DMSO-d6)δ8.39(s,1H),7.92(s,1H),7.74(s,1H),7.61(s,1H),7.43(d,J=7.7Hz,2H),7.38(d,J=4.2Hz,1H),7.21(s,2H),6.93(s,1H),6.85(s,1H),6.45(s,1H),4.84(s,1H),1.27(s,9H).

[0120] 1313C NMR (101 MHz, DMSO) δ 167.78, 162.47, 151.87, 150.00, 149.82, 145.60, 139.58, 136.87, 131.29, 129.48, 127.77, 126.31, 126.04, 125.79, 123.31, 122.41, 86.27, 75.79, 59.63, 50.51, 28.29。

[0121] Example 22

[0122] N-(2-(tert-Butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide The synthetic route of the application example is the same as that of Example 1.

[0123] 1 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 2H), 8.34–8.30 (m, 1H), 7.97 (s, 1H), 7.77 (s, 1H), 7.59 (s, 1H), 7.44 (dd, J = 22.0, 7.3 Hz, 4H), 7.23–7.13 (m, 2H), 6.27 (s, 1H), 4.84 (s, 1H), 1.25 (s, 9H).

[0124] 13 13C NMR (101 MHz, DMSO) δ 167.80, 162.64, 151.90, 151.02, 149.99, 149.68, 148.77, 145.61, 139.59, 137.29, 131.59, 131.11, 126.04, 125.92, 123.52, 123.01, 122.50, 86.27, 75.80, 62.40, 50.52, 28.31。

[0125] Example 23

[0126] N-(2-(tert-Butylamino)-2-oxo-1-(1H-pyrazol-3-yl)ethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide The synthetic route of the application example is the same as that of Example 1.

[0127] 11H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 8.38 (s, 1H), 7.85 (s, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.42 (d, J = 8.1 Hz, 3H), 7.18 (s, 2H), 6.24 (s, 1H), 5.87 (s, 1H), 4.85 (s, 1H), 1.26 (s, 9H).

[0128] 13 13C NMR (101 MHz, DMSO) δ 167.76, 162.50, 151.82, 150.22, 149.91, 145.62, 140.39, 130.82, 128.89, 125.76, 125.64, 123.33, 122.28, 105.55, 86.23, 75.86, 59.76, 50.40, 48.59, 28.39.

[0129] Example 24

[0130] N-(2-(tert-Butylamino)-1-(naphthalen-2-yl)-2-oxoethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide

[0131] N-(2-(tert-Butylamino)-1-(1H-indol-3-yl)-2-oxoethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide The synthetic route of the application example is the same as that of Example 1.

[0132] 1 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.94 (s, 1H), 7.85–7.65 (m, 6H), 7.50 (s, 1H), 7.48–7.42 (m, 2H), 7.36–7.20 (m, 4H), 6.44 (s, 1H), 4.84 (s, 1H), 1.28 (s, 9H).

[0133] 13 13C NMR (101 MHz, DMSO) δ 168.53, 162.86, 151.77, 150.22, 149.68, 145.60, 139.87, 132.86, 132.39, 132.13, 131.49, 129.38, 127.82, 127.62, 127.37, 127.25, 126.36, 126.21, 125.76, 125.60, 123.23, 122.34, 86.25, 75.85, 64.59, 50.49, 28.42.

[0134] Example 25

[0135] N-(2-(tert-Butylamino)-1-(1H-indol-3-yl)-2-oxoethyl)-2-ethynyl-N-(4-(oxazol-5-yl)phenyl)thiazole-4-carboxamide The synthetic route of the application example is the same as that of Example 1.

[0136] 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.33(s,1H),7.78–7.66(m,2H),7.51(s,2H),7.26(d,J=7.5Hz,3H),7.02(dq,J=16.4,6.6Hz,3H),6.94(s,1H),6.56(s,1H),4.84(s,1H),1.29(s,9H).

[0137] 13 C NMR(101MHz,DMSO)δ169.71,163.32,152.21,151.05,150.34,146.03,140.64,136.16,131.33,127.36,126.65,126.00,125.77,123.33,122.64,121.77,119.45,118.83,112.00,109.38,86.69,76.37,57.70,50.84,28.96.

[0138] Application Example

[0139] Table 1 shows the growth inhibition activity of some examples of this application against tumor cells HT1080 and the selectivity data for inducing ferroptosis. In the table: "A" indicates IC50≤100nM, and "B" indicates 100nM<IC50≤500nM.

[0140] Table 1

[0141] Compound <![CDATA[IC 50 > Compound <![CDATA[IC 50 > Example 1 A Example 14 B Example 2 A Example 15 B Example 3 A Example 16 B Example 4 A Example 17 B Example 5 A Example 18 B Example 6 B Example 19 B Example 7 B Example 20 B Example 8 A Example 21 B Example 9 B Example 22 B Example 10 A Example 23 B Example 11 B Example 24 A Example 12 A Example 25 B Example 13 A

[0142] The study on the inhibitory activity of compounds against the growth of tumor cells HT1080 showed that lipophilic antioxidants, such as Ferrostatin-1 (fer-1), could rescue cells from ferroptosis induced by GPX4 inhibition. Mesenchymal state GPX4-knockout cells could survive in the presence of fer-1, but in the absence of fer-1, these cells would undergo ferroptosis. In addition, ferroptosis induced by GPX4 inhibitors could also be blocked by other small molecules, such as the lipid ROS scavenger Liproxstatin, the iron chelator DFO, etc. Therefore, the ability of GPX4 inhibitors to induce ferroptotic cell death could be indicated by the reversal of the addition of fer-1.

[0143] Table 2 shows the inhibitory activity data of some compounds against the growth of tumor cells HT1080.

[0144] Table 2

[0145]

[0146] As shown in Table 2, the inhibitory activity of some compounds of this application was significantly weakened in the presence of fer-1, so it was an effective GPX4 inhibitor.

[0147] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present application, rather than to limit it; although the present application has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A glycine amide compound containing an alkynyl thiazolylcarbonyl group, characterized in that The compound is selected from one of the following structures: 。 2. A pharmaceutical composition comprising the glycine amide compound containing an alkynyl thiazolylcarbonyl group according to claim 1 and one or more pharmaceutically acceptable excipients.

3. Use of the glycine amide compound containing an alkynyl thiazolylcarbonyl group according to claim 1 in the preparation of a drug for treating fibrosarcoma.

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