CN115197167B - 1,2, 4-thiadiazolidine-3, 5-dione compound, and preparation method and application thereof - Google Patents

1,2, 4-thiadiazolidine-3, 5-dione compound, and preparation method and application thereof Download PDF

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CN115197167B
CN115197167B CN202210861070.0A CN202210861070A CN115197167B CN 115197167 B CN115197167 B CN 115197167B CN 202210861070 A CN202210861070 A CN 202210861070A CN 115197167 B CN115197167 B CN 115197167B
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synthesis
compound
benzyl
thiadiazolidine
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CN115197167A (en
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杨鹏
肖易倍
谢逸石
邝文彬
汪大伟
郝海平
王丽萍
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China Pharmaceutical University
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    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
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    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract

The invention discloses a 1,2, 4-thiadiazolidine-3, 5-dione compound, and a preparation method and application thereof, and belongs to the technical field of pharmaceutical chemistry. The invention also discloses a method for treating PTPN2 mediated diseases by using the 1,2, 4-thiadiazolidine-3, 5-dione derivative, which is a compound with a structure shown as a general formula (I) or pharmaceutically acceptable salt thereofThe application in medicines. The compounds disclosed in the invention have remarkable activity on PTPN2 phosphatase, and most of the synthesized compounds have IC (integrated circuit) on PTPN2 phosphatase 50 The value is kept at mu M level, the compound preparation has important influence on the occurrence and development of tumors and immune response, can be used in combination with immunosuppressants to treat related immune diseases, can be developed into antitumor drugs with high activity, good selectivity and small toxic and side effects, and has the characteristics of novel skeleton, strong plasticity and great future transformation potential.

Description

1,2, 4-thiadiazolidine-3, 5-dione compound, and preparation method and application thereof
Technical Field
The invention belongs to the field of medicinal chemistry, relates to a 1,2, 4-thiadiazolidine-3, 5-dione derivative, and in particular relates to a compound shown as a formula (I) or pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof and application thereof in treating PTPN2 mediated diseases.
Background
PTPNs are important mediators of numerous signaling pathway activities involved in the primary cellular processes of cell growth, proliferation and differentiation. PTPN2 is a widely expressed cytoplasmic tyrosine phosphatase. PTPN2 is dephosphorylated by different tyrosine phosphorylated JAK/STAT proteins (e.g., STAT1 or JAK 1), thereby down regulating the JAK/STAT signaling pathway. In addition to STAT1, PTPN2 is also able to dephosphorylate STAT3 and STAT5 and negatively regulate their activation. JAK/STAT pathways play a critical role in the cancer process, and aberrant activation of STAT signals is involved in the development of many cancers.
PTP1B is one of the most important members of the PTPN family, playing an important role in a variety of cellular functions. To date, PTP1B has been reported to be involved in the development of various diseases such as diabetes, cancer and cardiovascular diseases. PTP1B is highly homologous to PTPN2, so there are many selective inhibitors of PTP1B that have inhibitory activity on PTPN 2. However, these compounds lack selectivity for PTPN2, leading to greater potential toxic side effects; meanwhile, the structure contains a plurality of carboxyl groups, phosphate groups, ortho-dicarbonyl groups and other groups with larger polarity, and the patent medicine property of the compound is still to be optimized. To date, no PTPN2 selective small molecule inhibitors have been reported. Therefore, the small molecule inhibitor of PTPN2 can provide an important theoretical basis for developing anti-tumor drugs with anti-tumor activity, good selectivity and small toxic and side effects.
Disclosure of Invention
The invention aims to: the technical problem to be solved by the invention is to develop a small molecular inhibitor with PTPN2 inhibitory activity by taking 1,2, 4-thiadiazolidine-3, 5-dione as a mother nucleus.
The invention also solves the technical problem of providing the application of the 1,2, 4-thiadiazolidine-3, 5-dione derivative in medicines for treating PTPN2 mediated diseases.
The technical scheme is as follows: in order to solve the technical problems, the invention provides the following technical scheme:
1,2, 4-thiadiazolidine-3, 5-dione derivative or pharmaceutically acceptable salt thereof, wherein the 1,2, 4-thiadiazolidine-3, 5-dione derivative is a compound with a structure shown as a general formula (I) or pharmaceutically acceptable salt thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
m=1 to 4; y is O or S;
R 1 selected from halogen,Wherein:
l is a covalent bond (i.e., is absent) or O;
r is C 6 ～C 10 A 4-to 7-membered heteroaromatic ring having 1 to 3 heteroatoms selected from N, O or a 4-to 7-membered heterocyclic ring having 1 to 3 heteroatoms selected from N, O;
R a 、R b each independently selected from hydrogen, hydroxy, aldehyde, carbonyl, carboxyl, nitro, cyano, C 1 ～C 6 Alkyl, C 1 ～C 6 Carboxyalkyl, C 1 ～C 6 Alkylcarbonyl, C 1 ～C 6 Alkylsulfonyl, C 3 ～C 8 Cycloalkyl carbonyl, C 6 ～C 10 C substituted by a 4-to 7-membered heterocyclic ring having 1-3 heteroatoms selected from N, O, aryl having 1-3 heteroatoms selected from N, O 1 ～C 6 An alkyl group;
or R is a 、R b Together with the atoms to which they are attached, form an optionally substituted 4-to 7-membered monocyclic heterocyclic group, the heteroatom being selected from O or N; the substituents being selected from hydrogen, hydroxy, aldehyde, carboxyl, carbonyl, nitro, cyano or C 1 ～C 6 An alkyl group;
R c 、R d each independently selected from hydrogen, hydroxy, aldehyde, carbonyl, carboxyl, nitro, cyano, and optionally substituted C 1 ～C 6 Alkyl or optionally substituted C 6 ～C 10 Aryl of (a); the substituents are selected from hydrogen, hydroxy, aldehyde, carboxyl, carbonyl, nitro, cyano, C 6 ～C 10 Or a 4-to 7-membered heteroaromatic ring having 1 to 3 heteroatoms selected from N, O.
In some examples, Y is O.
In some examples, R is C 6 ～C 10 Or an aryl group having 1 to 3 heteroatoms selected from N and O;
R a 、R b each independently selected from hydrogen, hydroxy, aldehyde, carbonyl, carboxyl, nitro, cyano, C 1 ～C 4 Alkyl, C 1 ～C 4 Carboxyalkyl, C 1 ～C 4 Alkylcarbonyl, C 1 ～C 4 Alkylsulfonyl, C 3 ～C 8 Cycloalkyl carbonyl, C 6 ～C 10 C substituted by a 4-to 7-membered heterocyclic ring having 1-3 heteroatoms selected from N and O 1 ～C 3 An alkyl group;
or R is a 、R b Together with the atoms to which they are attached, form an optionally substituted 4-to 7-membered monocyclic heterocyclic group, the heteroatom being selected from O or N; the substituents being selected from hydrogen, hydroxy, aldehyde, carboxyl, carbonyl, nitro, cyano or C 1 ～C 3 An alkyl group.
In some more specific examples of the present invention,
r is
R a 、R b Each independently selected from hydrogen, hydroxy, aldehyde, carbonyl, carboxyl, nitro, cyano, C 1 ～C 4 Alkyl, C 1 ～C 4 Carboxyalkyl, C 1 ～C 4 Alkylcarbonyl, C 1 ～C 4 Alkylsulfonyl, C 3 ～C 8 Cycloalkyl carbonyl, C 6 ～C 10 C substituted by a 4-to 7-membered heterocyclic ring having 1-3 heteroatoms selected from N and O 1 ～C 3 An alkyl group;
or R is a 、R b Together with the atoms to which they are attached, form an optionally substituted 4-to 7-membered monocyclic heterocyclic group, the heteroatom being selected from O or N; the substituents being selected from hydrogen, hydroxy, aldehyde, carboxyl, carbonyl, nitro, cyano or C 1 ～C 3 An alkyl group.
In some more specific examples, when R is notWhen R is a Is hydrogen.
In some examples, R c 、R d Each independently selected from hydrogen, hydroxy, aldehyde, carbonyl, carboxyl, nitro, cyano or optionally substituted C 1 ～C 4 An alkyl group; the substituents being selected from hydrogen, hydroxy, aldehyde, carboxyl, carbonyl, nitro, cyano or C 6 ～C 10 Aryl groups of (a). In some more specific examples, R c 、R d Each independently selected from hydrogen orOptionally substituted C 1 ～C 3 An alkyl group; the substituent is selected from hydrogen, hydroxy, aldehyde, carboxyl, carbonyl, nitro, cyano or benzene ring.
When m=1, R 1 Selected from phenyl;
when m=2, R 1 Selected from-Br, -NHR 2 、-NR 3 R 4 6-7 membered azacycloalkyl, alkylphenoxy, wherein 6-7 membered heterocycloalkyl is
Alkylphenoxy is-O-Ph-R 7 ；
When m=4, R 1 Selected from-Br, -NHR 8 、-NR 9 R 10 6-to 7-membered heterocycloalkyl, alkylphenoxy, where
6-7 membered heterocycloalkyl isThe alkylphenoxy group being
-O-Ph-R 12 。
Preferably, the method comprises the steps of,
when m=1, R 1 Selected from phenyl groups.
When m=2, R 1 Selected from-Br, -NHR 2 、-NR 3 R 4 6-7 membered azacycloalkyl, alkylphenoxy, wherein 6-7 membered heterocycloalkyl is
Alkylphenoxy is-O-Ph-R 7 ；
Wherein R is 2 Selected from-CH (CH) 3 )-C(O)OH、-CH(CH 2 Ph)-C(O)OH，
-NR 3 R 4 Selected from the group consisting of-N (CH 3) CH2C (O) OH,
R 5 Selected from-CH 2 -C(O)OH、-CH 2 CH 3 、-CH(CH 3 ) 2 、-C(O)CH 3 、
R 6 Selected from-CH 2 -C(O)OH，
-O-Ph-R 7 Selected from the group consisting of
When m=4, R 1 Selected from-Br, -NHR 8 、-NR 9 R 10 6-7 membered azacycloalkyl, alkylphenoxy, wherein 6-7 membered heterocycloalkyl is-O-Ph-R 12 ；
Wherein R is 8 Selected from-CH (CH) 3 )-C(O)OH、-CH(CH 2 Ph)-C(O)OH，
-NR 9 R 10 Selected from the group consisting of-N (CH 3) CH2C (O) OH,
-R 11 Selected from-CH 3 、-CH 2 CH 3 、-CH(CH 3 ) 2 、-C(O)CH 3 、
-O-Ph-R 12 Selected from the group consisting of
In some examples, the present application also provides compounds of the following specific structure:
the pharmaceutically acceptable salts of the invention are acid addition salts of the compounds of formula (I), wherein the acids used for forming the salts include inorganic acids and organic acids, and the inorganic acids include: hydrochloric acid, sulfuric acid, phosphoric acid and methanesulfonic acid, and the organic acids include acetic acid, trifluoroacetic acid, propionic acid, butyric acid, maleic acid, p-toluenesulfonic acid, malic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid, digluconic acid, aspartic acid and tartaric acid.
Preferably, the pharmaceutically acceptable salt described in the present invention is the hydrochloride or trifluoroacetate salt.
The invention also discloses a preparation method of the compound of the general formula (I):
wherein Y, m, R 1 Is defined as before.
The invention also discloses a medicinal composition which comprises the compound of the general formula (I) or pharmaceutically acceptable salt or isomer thereof and a pharmaceutically acceptable carrier.
Pharmaceutically acceptable carrier refers to excipients or diluents that do not cause significant irritation to the organism and do not interfere with the biological activity and properties of the compound being administered. The excipient comprises binding agent, filler, disintegrating agent, lubricant, antiseptic, antioxidant, correctant, aromatic, cosolvent, emulsifier, solubilizer, osmotic pressure regulator, colorant, etc., and the diluent comprises physiological saline, starch, dextrin, sucrose, lactose, etc.
A method of treating a PTPN2 mediated disease comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a PTPN2 mediated disease is within the scope of the invention.
In some embodiments of the invention, the PTPN2 mediated disease is selected from diseases mediated by modulation of the JAK/STAT signaling pathway.
In some embodiments of the invention, the PTPN2 mediated disease comprises cancer, inflammation, infection, immune disease, organ transplantation, viral disease, diabetes, cardiovascular disease, or metabolic disease.
In some embodiments of the invention, the cancer includes, but is not limited to: lung cancer, head and neck cancer, breast cancer, prostate cancer, esophageal cancer, rectal cancer, colon cancer, nasopharyngeal cancer, uterine cancer, pancreatic cancer, lymphoma, leukemia, osteosarcoma, melanoma, renal cancer, gastric cancer, liver cancer, bladder cancer, thyroid cancer or carcinoma of large intestine. More specifically Acute Myeloid Leukemia (AML).
In some embodiments of the invention, the cancer is selected from the group consisting of first line cancer.
In a preferred embodiment of the invention, the disease is selected from the group consisting of PTPN2 mediated diseases selected from pancreatic cancer.
The terms used in the present invention generally have the following meanings unless specifically indicated.
The term "[ CH" as described herein 2 ] 1-4 "means that the moiety has 1 to 4 carbon atoms.
The term "halogen" is fluorine, chlorine, bromine or iodine.
The term "C 1-6 Alkyl "refers to saturated straight and branched chain hydrocarbon groups having 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.
The term "heterocycloalkyl" refers to cycloalkanes having 1 or more non-C heteroatoms such as N, O, S, including but not limited to tetrahydropyrrole, piperidine, morpholine, piperazine, pyrazine, N-methylpiperazine, N-ethylpiperazine, and the like.
The term "C (O)" denotes a carbonyl group, in particular a carbon-oxygen double bond.
The term "C (O) O" denotes an ester group, specifically a carbon-oxygen double bond plus one carbon-oxygen single bond.
The term "C 1 ～C 6 Carboxyalkyl "means C substituted with carboxyl 1 ～C 6 Is a hydrocarbon group.
The term "C 1 ～C 6 Alkylcarbonyl "refers to-C (O) -R ', wherein R' is C 1 ～C 6 An alkyl group.
The term "C 1 ～C 6 Alkylsulfonyl "means-S (O) 2 -R ', wherein R' is C 1 ～C 6 An alkyl group.
The term "C 3 ～C 8 Cycloalkylcarbonyl "refers to-C (O) -R", where R "is C 3 ～C 8 Cycloalkyl groups.
The beneficial effects are that:
the compound disclosed by the invention has obvious activity on PTPN2 phosphatase, and the synthesized compound IC 50 The value is maintained at mu M level, and can be used for treating tumor development and immune response, and can also be used in combination with immunosuppressant for treating related immune diseases The compound is developed into an antitumor drug with high activity, good selectivity and small toxic and side effects, and has the characteristics of novel skeleton, strong plasticity and great future transformation potential.
Drawings
FIG. 1 is a study of Compound X-18. (a) weight change in each group of mice; (B) Weight change of heart, liver, spleen, lung, kidney of each group of mice;
FIG. 2 shows the in vivo activity of Compound X-18. (a) change in body weight of the mouse; (B) And (C) changes in fluorescence intensity in mice at day 1 and day 9 of administration; ns is no significant difference, p <0.01.
Detailed Description
The following examples facilitate a better understanding of the present invention, but are not intended to limit the same. The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the examples described below, unless otherwise specified, were purchased from conventional biochemical reagent stores. The present application will be described in detail with reference to specific examples.
Example 1: synthesis of intermediate K-1
4-benzyl-2- (2-bromoethyl) -1,2, 4-thiadiazolidine-3, 5-dione
The synthetic route is as follows:
step 1.1 Synthesis of 1-bromo-2-isocyanatoethane (1 b) and 4-benzyl-2- (2-bromoethyl) -1,2, 4-thiadiazolidine-3, 5-dione (K-1)
2-Bromoethylamine hydrobromide (20 g,1.0 eq), pyridine (32 mL) was added to a three-necked flask and protected with nitrogen, cold-bathed to below-15℃and then dichloromethane (150 mL) was added. Triphosgene (13 g,0.5 eq) was dissolved in dichloromethane (100 mL) and added slowly dropwise to the three-necked flask reaction system, maintaining the temperature at no more than 0℃and addingAfter completion of stirring for 4-6 hours, the reaction was monitored by TLC plates and the cold bath was stopped when the starting material was essentially complete. The reaction solution was washed twice with 0.5M diluted hydrochloric acid, the aqueous solution was washed twice with dichloromethane, the organic layers were combined, washed twice with saturated brine, dried, and concentrated under reduced pressure to give a yellow transparent oily substance, which was directly taken to the next step. The yellow oily substance was dissolved in tetrahydrofuran (400 mL), isothiocyanate (16 g,1.0 eq) was added, cooled to 0 ℃, then sulfonyl chloride (15 g,1.0 eq) was slowly added dropwise, warmed to room temperature, stirred overnight, and the next day the reaction was left to stir in air for 30 minutes. After the reaction, two products were monitored by TLC plate, the more polar product was K-1, and after concentration by distillation under reduced pressure, column chromatography gave Compound K-1 (12.1 g, 57% yield). 1 H NMR(400MHz,CDCl 3 )δ7.45–7.43(m,2H),7.38–7.29(m,3H),4.84(s,2H),4.03–3.99(m,2H),3.55–3.52(m,2H)。
1. Synthesis of Compound X-1-X-41
Example 2:2- (2- (1, 4-diaza-1-yl) ethyl) -4-benzyl-1, 2, 4-thiadiazolidine-3, 5-dione (X-1)
The synthetic route is as follows:
step 1 Synthesis of tert-butyl 4- (2- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) ethyl) -1, 4-diazine-1-carboxylate (2 a)
Compound K-1 (300 mg,1.0 eq), t-butyl 1, 4-diazacycloheptane-1-carboxylate (195 mg,1.03 eq) was dissolved in a closed glass tube filled with acetonitrile (5 mL), followed by addition of potassium carbonate (399 mg,2.5 eq) and reaction was monitored by TLC at 80℃for 3-4 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate 3 times, and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by a flash silica gel column to give compound 2a in a yellow oily liquid yield of 42%. MS [ (MS)ESI)m/z 435.5[M+H] + .
Step 2.Synthesis of 2- (2- (1, 4-diaza-1-yl) ethyl) -4-benzyl-1, 2, 4-thiadiazolidine-3, 5-dione (X-1)
The tert-butyl ester was removed from the reaction 2a in a mixed solution of trifluoroacetic acid (10 ml/mmol) and dichloromethane (10 ml/mmol) for 3 hours. After the reaction was monitored by TLC, concentrated under reduced pressure and purified by flash column on silica gel to give compound (X-1) as a white solid in 90% yield. 1 H NMR(400MHz,DMSO-d 6 )δ7.36–7.30(m,5H),4.73(s,2H),4.46(s,1H),4.06–4.02(m,2H),3.80–3.61(m,4H),3.38–3.17(m,6H),2.17(s,2H),1.23(s,1H).
Example 3:2- (4- (2- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) ethyl) -1, 4-diaza-1-yl) acetic acid (X-2)
The synthetic route is as follows:
step 1.Synthesis of tert-butyl 2- (4- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) ethyl) -1, 4-diaza-1-yl) acetate (2 b)
X-1 (1.0 eq) and t-butyl bromoacetate (1.0 eq) were dissolved in tetrahydrofuran, then triethylamine (2.5 eq) was added to the reaction solution and reacted at 65℃for 2 hours, and the reaction was monitored by TLC. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, dried over anhydrous sodium sulfate, and purified by a rapid silica gel column to give compound 2b as a colorless oily liquid in 83% yield. MS (ESI) m/z 449.5[ M+H ]] + .
Step 2.Synthesis of 2- (4- (2- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) ethyl) -1, 4-diaza-1-yl) acetic acid (X-2)
Intermediate 2b was freed from tert-butyl ester in a mixed solution of trifluoroacetic acid (10 ml/mmol) and dichloromethane (10 ml/mmol) for 3 hours. After the completion of the reaction, the reaction mixture was monitored by TLC, concentrated under reduced pressure, and purified by a rapid silica gel columnCompound (X-2) was obtained as a white solid in 90% yield. 1 H NMR(400MHz,DMSO-d 6 )δ7.38–7.22(m,3H),4.73(s,1H),4.05(t,J＝6.9Hz,1H),3.78(s,2H),3.43(t,J＝7.0Hz,1H),3.36(d,J＝6.4Hz,1H),2.25(s,1H),1.24(d,J＝3.7Hz,1H).
Example 4: 4-benzyl-2- (2- (piperazin-1-yl) ethyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-3)
The synthetic route is as follows:
step 1 Synthesis of tert-butyl 4- (2- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) ethyl) piperazine-1-carboxylate (2 c)
Compound K-1 (300 mg,1.0 eq) was dissolved in a closed glass tube containing acetonitrile (5 mL), followed by addition of potassium carbonate (329 mg,2.5 eq) and reaction was carried out at 80℃for 3-4 hours, followed by TLC monitoring. After the reaction was completed, the reaction solution was extracted with ethyl acetate 3 times, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by a flash silica gel column to give compound 2a in a yellow oily liquid yield of 51%. MS (ESI) m/z 421.5[ M+H ] ] + .
Step 2.Synthesis of 4-benzyl-2- (2- (piperazin-1-yl) ethyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-4)
Intermediate 2c was freed from tert-butyl ester in a mixed solution of trifluoroacetic acid (10 ml/mmol) and dichloromethane (10 ml/mmol) for 3 hours. After the reaction was monitored by TLC, concentrated under reduced pressure and purified by flash column on silica gel to give compound (X-3) as a white solid in 90% yield. 1 H NMR(400MHz,DMSO-d 6 )δ7.38–7.29(m,5H),4.74(s,2H),3.74(t,J＝5.4Hz,2H),3.08(t,J＝4.9Hz,4H),2.67–2.64(m,4H),2.60(d,J＝5.4Hz,2H).
Example 5: synthesis of 2- (4- (2- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) ethyl) piperazin-1-yl) acetic acid (X-4)
The synthetic route is as follows:
reference to the synthesis of compound (X-2), intermediate 2d and compound X-4 were obtained. The yield of compound X-4 was 30% as a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ7.38–7.28(m,5H),4.75(s,2H),3.90–3.74(m,4H),3.53(s,2H),2.83(t,J＝41.7Hz,8H).
Example 6: synthesis of (2- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) ethyl) -L-alanine (X-5)
The synthetic route is as follows:
step 1 Synthesis of tert-butyl (2- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) ethyl) -L-alanine ester (3 a)
Compound K-1 (300 mg,1.0 eq), L-alanine tert-butyl ester hydrochloride (182 mg,1.05 eq) was dissolved in a closed glass tube containing acetonitrile (5 mL), then anhydrous potassium carbonate (399 mg,2.5 eq) was added and reacted at 80℃for 3-4 hours, followed by TLC monitoring the reaction. After the reaction was completed, the reaction solution was extracted with ethyl acetate 3 times, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by a flash silica gel column to give compound 2a in the form of a yellow oily liquid with a yield of 60%, colorless transparent oily liquid. MS (ESI) m/z 380.4[ M+H ] ] + .
Synthesis of (2- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) ethyl) -L-alanine (X-5)
The tert-butyl ester was removed from the reaction 3a in a mixed solution of trifluoroacetic acid (10 ml/mmol) and dichloromethane (10 ml/mmol) for 3 hours. After the reaction was monitored by TLC, concentrated under reduced pressure and purified by flash column on silica gel to give compound (X-5) as a white solid in 90% yield. 1 H NMR(400MHz,DMSO-d 6 )δ7.36–7.28(m,5H),3.82–3.59(m,3H),3.21(d,J＝7.0Hz,1H),2.95–2.68(m,2H),1.19(d,J＝7.0Hz,3H).
Example 7: synthesis of N- (2- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) ethyl) -N-methylglycine (X-6)
The synthetic route is as follows:
step 1 Synthesis of tert-butyl N- (2- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) ethyl) -N-methylglycine ester (4 a)
Referring to the synthesis of intermediate 3a from step 1 of example 6, the yield was 73% as a colorless oily liquid. MS (ESI) m/z 380.4[ M+H ]] + .
Synthesis of N- (2- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) ethyl) -N-methylglycine (X-6)
With reference to the synthesis of compound X-5, step 2, example 6, the yield was 90% as a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ12.30(s,1H),7.33(dt,J＝22.1,7.5Hz,5H),4.74(s,2H),3.70(t,J＝5.4Hz,2H),2.79(t,J＝5.4Hz,2H),2.35(s,3H).
Example 8: synthesis of (2- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) ethyl) -L-phenylalanine (X-7)
The synthetic route is as follows:
step 1 Synthesis of tert-butyl (2- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) ethyl) -L-phenylalanine ester (5 a)
Referring to the synthesis of intermediate 3a of step 1, example 6, the yield was 51% as a colorless oily liquid. MS (ESI) m/z 456.5[ M+H ]] + .
Synthesis of (2- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) ethyl) -L-phenylalanine (X-7)
With reference to the synthesis of compound X-5, step 2, example 6, the yield was 90% as a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ7.36–7.16(m,10H),4.70(s,2H),3.76–3.45(m,4H),2.92–2.86(m,2H),2.78(dd,J＝13.5,7.4Hz,1H).
Example 9: synthesis of 4-benzyl-2- (2- (4-ethylpiperazin-1-yl) ethyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-8)
The synthetic route is as follows:
step 1.Synthesis of 4-benzyl-2- (2- (4-ethylpiperazin-1-yl) ethyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-9)
Compound K-1 (300 mg,1.0 eq) and N-ethylpiperazine (116 mg,1.05 eq) were dissolved in a closed glass tube containing 1, 4-dioxane (5 mL) and DIPEA (307 mg,2.5 eq) was added and reacted at 100℃for 3-4 hours, followed by TLC monitoring the reaction. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by flash column chromatography (DCM: meoh=94:6) to give compound X-8 as a white solid in 67% yield. 1 H NMR(300MHz,DMSO-d 6 )δ7.39–7.29(m,3H),4.74(s,1H),3.52(s,1H),3.11(s,1H),1.25(d,J＝7.3Hz,2H),1.22(d,J＝4.8Hz,1H).
Example 10: synthesis of 4-benzyl-2- (2- (4-isopropylpiperazin-1-yl) ethyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-9)
The synthetic route is as follows:
step 1.Synthesis of 4-benzyl-2- (2- (4-isopropylpiperazin-1-yl) ethyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-9)
The synthesis method of the reference compound (X-8) replaces N-ethylpiperazine with N-isopropylpiperazine. Yield 68%, white solid. 1 H NMR(400MHz,DMSO-d 6 )δ7.38–7.28(m,5H),4.73(s,2H),4.11(s,2H),4.03(d,J＝7.1Hz,1H),3.98(s,2H),3.64(s,2H),3.50(d,J＝8.7Hz,2H),1.29(d,J＝6.6Hz,6H).
EXAMPLE 11 Synthesis of 2- (2- (4-acetylpiperazin-1-yl) ethyl) -4-benzyl-1, 2, 4-thiadiazolidine-3, 5-dione hydrochloride (X-10)
The synthetic route is as follows:
step 1.Synthesis of 2- (2- (4-acetylpiperazin-1-yl) ethyl) -4-benzyl-1, 2, 4-thiadiazolidine-3, 5-dione (X-10) hydrochloride
The synthesis method of the reference compound (X-8) replaces N-ethylpiperazine with 1-acetylpiperazine. Yield 45%, white solid. 1 H NMR(400MHz,DMSO-d 6 )δ11.36(s,1H),7.38–7.29(m,5H),4.74(s,2H),4.08(s,2H),4.01(s,2H),3.56(d,J＝12.3Hz,3H),3.35(s,2H),3.08(d,J＝12.7Hz,2H),2.96(s,1H),2.04(s,3H).
EXAMPLE 12 Synthesis of 4-benzyl-2- (2- (4- (methylsulfonyl) piperazin-1-yl) ethyl) -1,2, 4-thiadiazolidine-3, 5-dione hydrochloride (X-11)
The synthetic route is as follows:
step 1.Synthesis of 4-benzyl-2- (2- (4- (methylsulfonyl) piperazin-1-yl) ethyl) -1,2, 4-thiadiazolidine-3, 5-dione hydrochloride (X-11)
The synthesis method of the reference compound (X-8) is to change N-ethylpiperazine into 1-methanesulfonylpiperazine. Yield 81%, white solid. 1 H NMR(300MHz,DMSO-d 6 )δ11.25(s,1H),7.34(dt,J＝8.8,4.2Hz,5H),4.74(s,2H),4.06–4.05(m,2H),3.67(s,2H),3.00(s,3H).
Example 13: synthesis of 4-benzyl-2- (2- (4-phenylpiperazin-1-yl) ethyl) -1,2, 4-thiadiazolidine-3, 5-dione hydrochloride (X-12)
The synthetic route is as follows:
step 1.Synthesis of 4-benzyl-2- (2- (4-phenylpiperazin-1-yl) ethyl) -1,2, 4-thiadiazolidine-3, 5-dione hydrochloride (X-12)
The synthesis method of the reference compound (X-8) is to change N-ethylpiperazine into N-phenylpiperazine.Yield 56%, white solid. 1 H NMR(300MHz,DMSO-d 6 )δ10.90(s,1H),7.37–7.24(m,7H),7.01(d,J＝8.1Hz,2H),6.87(t,J＝7.2Hz,1H),4.75(s,2H),4.06–4.00(m,8H),3.67(d,J＝10.7Hz,2H).
Example 14: synthesis of 2- (2- (4- (benzo [ d ] [1,3] dioxin-5-ylmethyl) piperazin-1-yl) ethyl) -4-benzyl-1, 2, 4-thiadiazolidine-3, 5-dione (X-13)
The synthetic route is as follows:
step 1.Synthesis of 2- (2- (4- (benzo [ d ] [1,3] dioxin-5-ylmethyl) piperazin-1-yl) ethyl) -4-benzyl-1, 2, 4-thiadiazolidine-3, 5-dione (X-13)
The synthesis method of the reference compound (X-8) is to change N-ethylpiperazine into 1-piperonyl piperazine. Yield 69%, white solid. 1 H NMR(300MHz,DMSO-d 6 )δ7.34(qd,J＝7.8,7.3,4.9Hz,5H),7.23(s,1H),7.06–6.98(m,2H),6.07(s,2H),4.74(s,2H),3.84(s,2H),3.22(d,J＝69.5Hz,6H),1.24(s,2H).
Example 15: synthesis of 2, 4-dibenzyl-3-thioxy-1, 2, 4-thiadiazolidin-5-one (X-14)
The synthetic route is as follows:
step 1 Synthesis of 1.1-bromo-2-isocyanatoethane (1 b) and 2, 4-dibenzyl-3-thioxy-1, 2, 4-thiadiazolidin-5-one (X-14)
Bromine 2-BromoethylamineThe acid salt (20 g,1.0 eq), pyridine (32 mL) was added to a three-necked flask and blanketed with nitrogen, cold-bathed to below-15 degrees, and then dichloromethane (150 mL) was added. Triphosgene (13 g,0.5 eq) was dissolved in dichloromethane (100 mL) and added slowly dropwise to the three-necked flask reaction system, maintaining the temperature no more than 0 ℃, stirring for 4-6 hours after addition, monitoring the reaction with TLC plates during which time the cold bath was stopped when the starting material was essentially complete. The reaction solution was washed twice with 0.5M diluted hydrochloric acid, the aqueous solution was washed twice with dichloromethane, the organic layers were combined, washed twice with saturated brine, dried, and concentrated under reduced pressure to give a yellow transparent oily substance, which was directly taken to the next step. The yellow oily substance was dissolved in tetrahydrofuran (400 mL), isothiocyanate (16 g,1.0 eq) was added, cooled to 0 ℃, then sulfonyl chloride (15 g,1.0 eq) was slowly added dropwise, warmed to room temperature, stirred overnight, and the next day the reaction was left to stir in air for 30 minutes. After the reaction was completed, two products were monitored by TLC plate and the less polar product was X-14, and after concentration by distillation under reduced pressure, column chromatography gave compound X-15 (7.2 g, yield 32%). 1 H NMR(400MHz,CDCl 3 )δ7.46–7.43(m,2H),7.33–7.26(m,8H),5.06(s,2H),4.52(s,2H)。
Example 16: synthesis of 4- (2- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) ethoxy) benzaldehyde (X-15)
The synthetic route is as follows:
step 1.Synthesis of 4- (2- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) ethoxy) benzaldehyde (X-16)
Compound K-1 (300 mg,1.0 eq), p-hydroxybenzaldehyde (122 mg,1.05 eq) was dissolved in acetonitrile (5-10 mL), followed by the addition of potassium carbonate (264 mg,2.0 eq) and reaction was monitored by TLC at 80℃for 3 hours. After the reaction, it was dried by spin-drying, extracting with ethyl acetate 3 times, and combining the organic layers, usingDrying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying with rapid silica gel column to obtain compound X-15 with yield of 31%. 1 HNMR(400MHz,DMSO-d 6 )δ9.98(s,1H),7.55–7.51(m,2H),7.45(q,J＝1.2Hz,1H),7.37–7.25(m,6H),4.76(s,2H),4.29(t,J＝4.9Hz,2H),4.06(dd,J＝5.4,4.4Hz,2H).
Example 17: 4-benzyl-2- (2- ((2, 2-dimethyl-4-oxo-4H-benzo [ d ] [1,3] dioxin-5-yl) oxy) ethyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-16)
The synthetic route is as follows:
step 1.5-hydroxy-2, 2-dimethyl-4H-benzo [ d ]][1,3]Synthesis of Dioxin-4-one (6 a) to a round bottom flask containing 2, 6-dihydroxybenzoic acid (8.00 g,51.9mmol,1.0 eq) and 4-dimethylaminopyridine (0.317 g,2.56mmol,0.05 eq) was added 35mL of dimethyl ether. Before acetone (4.88 mL,66.4mmol,1.28 eq) was added, the reaction solution was cooled to 0deg.C, and then thionyl chloride (4.84 mL, 66.44mmol,1.28 eq) was added to the reaction mixture. The reaction mixture was stirred at 0℃for 1 hour and at room temperature for 15 hours. The reaction solution was neutralized with 25 ml of saturated sodium bicarbonate solution, and then the mixture was extracted with three portions of 30 ml of diethyl ether. The combined organic layers were washed with brine, dried over MgSO4, and the solvent was removed under reduced pressure to give a crude orange solid. Silica gel chromatography and 1:4 ethyl acetate were used: hexane purified the solid to afford intermediate 6a in 89% yield. MS (ESI) m/z 195.3[ M+H ] ] + .
Step 2.Synthesis of 4-benzyl-2- (2- ((2, 2-dimethyl-4-oxo-4H-benzo [ d ] [1,3] dioxin-5-yl) oxy) ethyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-17)
Compound K-1 (1.0 eq), intermediate 6a (1.0 eq) was dissolved in acetonitrile (10 mL), followed by the addition of potassium carbonate (2.0 eq), reacted at 80℃for 3-4 hours, TThe LC monitors the reaction. After the reaction was completed, it was dried by spin-drying, extraction with ethyl acetate for 3 times, and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash column on silica gel to give the product X-16 in 71% yield. 1 H NMR(400MHz,CDCl 3 )δ7.43–7.38(m,3H),7.31(d,J＝2.4Hz,3H),6.60(d,J＝8.3Hz,1H),6.54(d,J＝8.4Hz,1H),4.82(s,2H),4.25(t,J＝4.7Hz,2H),4.13(t,J＝4.7Hz,2H),1.71(s,6H).
Example 18: synthesis of 2- (2- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) ethoxy) -6-hydroxybenzoic acid (X-17)
The synthetic route is as follows:
step 1.Synthesis of 2- (2- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) ethoxy) -6-hydroxybenzoic acid (X-17)
Compound X-16 was deprotected in a mixed solution of trifluoroacetic acid (10 ml/mmol) and water (2.5 ml/mmol), and reacted overnight at room temperature. After the reaction was monitored by TLC, concentrated under reduced pressure and purified by flash column chromatography (PE: ea=3:1) to give compound X-17 as a white solid in 85% yield. 1 H NMR(400MHz,CDCl 3 )δ12.33(s,1H),7.44–7.31(m,6H),6.73(d,J＝8.5Hz,1H),6.41(d,J＝8.3Hz,1H),4.83(s,2H),4.36(s,2H),4.13(s,2H).
Example 19: synthesis of 4-benzyl-2- (2- (4-nitrophenoxy) ethyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-18)
The synthetic route is as follows:
step 1.Synthesis of 4-benzyl-2- (2- (4-nitrophenoxy) ethyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-18)
The synthetic method of the reference compound X-15 is to replace parahydroxybenzaldehyde with paranitrophenol. Yield 31%, white solid. 1 H NMR(400MHz,CDCl 3 )δ8.20(d,J＝9.3Hz,2H),7.48–7.42(m,2H),7.37–7.32(m,3H),6.93(d,J＝9.3Hz,2H),4.84(s,2H),4.27(t,J＝4.9Hz,2H),4.09(t,J＝4.9Hz,2H).
Example 20: synthesis of 4-benzyl-2- (2- (4- (pyridin-2-yl) piperazin-1-yl) ethyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-19)
The synthetic route is as follows:
step 1.Synthesis of 4-benzyl-2- (2- (4- (pyridin-2-yl) piperazin-1-yl) ethyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-19)
Referring to the synthetic method of compound X-8, N-ethylpiperazine was replaced with 1- (2-pyridyl) piperazine to give product X-19 as a white solid in 67% yield. 1 H NMR(400MHz,DMSO-d 6 )δ8.13(dd,J＝5.9,1.8Hz,1H),8.00(t,J＝8.0Hz,1H),7.38–7.28(m,6H),7.00(t,J＝6.5Hz,1H),4.74(s,2H),4.53(s,2H),4.12(t,J＝6.1Hz,2H),3.39(s,2H),3.24(s,2H),2.51(d,J＝3.8Hz,5H).
Example 21: synthesis of (2- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) ethyl) -L-proline (X-20)
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The synthetic route is as follows:
step 1 Synthesis of tert-butyl (2- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) ethyl) -L-proline (7 a)
Compound X-1 (300 mg,1.0 eq), L-proline tert-butyl ester (172 mg,1.05 eq) was dissolved in a closed glass tube containing acetonitrile (5 mL), then anhydrous potassium carbonate (399 mg,2.5 eq) was added and reacted at 80℃for 3-4 hours, followed by TLC monitoring the reaction. After the reaction was completed, the reaction solution was extracted with ethyl acetate 3 times, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by a flash silica gel column to give compound 7a as a yellow oily liquid in a yield of 56%. MS (ESI) m/z 406.4[ M+H ] ] + .
Synthesis of (2- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) ethyl) -L-proline (X-20)
Intermediate 7a was removed of tert-butyl ester in a mixed solution of trifluoroacetic acid (10 ml/mmol) and dichloromethane (10 ml/mmol) for 3 hours. After the reaction was completed by TLC, it was concentrated under reduced pressure and purified by a rapid silica gel column to give compound (X-20) as a white solid in 89% yield. 1 H NMR(400MHz,DMSO-d 6 )δ7.39–7.29(m,5H),4.81–4.72(m,2H),4.19(dd,J＝14.7,7.2Hz,1H),3.88(d,J＝15.0Hz,1H),3.65(dd,J＝13.2,6.8Hz,2H),3.45–3.25(m,3H),2.40(dt,J＝8.7,5.9Hz,1H),2.04(dq,J＝9.3,5.2Hz,2H),1.94–1.91(m,1H).
Example 22: synthesis of 4-benzyl-2- (2- (4- (cyclopropylcarbonyl) piperazin-1-yl) ethyl) -1,2, 4-thiadiazolidine-3, 5-dione hydrochloride (X-21)
The synthetic route is as follows:
step 1.Synthesis of 4-benzyl-2- (2- (4- (cyclopropylcarbonyl) piperazin-1-yl) ethyl) -1,2, 4-thiadiazolidine-3, 5-dione hydrochloride (X-21)
Referring to the synthesis of compound X-8, N-ethylpiperazine was replaced with 1-cyclopropylpiperazine to give the product X-21 as a white solid in 68% yield. 1 H NMR(300MHz,DMSO-d 6 )δ11.15(s,1H),7.39–7.28(m,5H),4.75(s,2H),4.42(s,2H),4.07(s,2H),3.37(s,2H),2.02(dt,J＝10.7,4.1Hz,1H),0.75(d,J＝7.2Hz,4H).
Example 23: synthesis of 4-benzyl-2- (4-bromobutyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-22)
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The synthetic route is as follows:
step 1.Synthesis of 4-benzyl-2- (4-bromobutyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-22)
4-bromo-1-butylamine hydrobromic acid (20 g,1.0 eq), pyridine (32 mL) was added to a three-necked flask and protected with nitrogen, cold-bathed to below-15℃and then dichloromethane (150 mL) was added. Triphosgene (13 g,0.5 eq) was dissolved in dichloromethane (100 mL) and added slowly dropwise to the three-necked flask reaction system, maintaining the temperature no more than 0 ℃, stirring for 4-6 hours after addition, monitoring the reaction with TLC plates during which time the cold bath was stopped when the starting material was essentially complete. The reaction solution was washed twice with 0.5M diluted hydrochloric acid, the aqueous solution was washed twice with dichloromethane, the organic layers were combined, washed twice with saturated brine, dried, and concentrated under reduced pressure to give a yellow transparent oily substance, which was directly taken to the next step. The yellow oily substance was dissolved in tetrahydrofuran (400 mL), isothiocyanate (16 g,1.0 eq) was added, cooled to 0 ℃, then sulfonyl chloride (15 g,1.0 eq) was slowly added dropwise, warmed to room temperature, stirred overnight, and the next day the reaction was left to stir in air for 30 minutes. After the reaction is finished, two products are monitored by a TLC plate, and the product with larger polarity is X-22 Column chromatography after concentration by distillation under reduced pressure gave compound X-23 as a yellow oily liquid (11.1 g, yield 38%). 1 H NMR(400MHz,CDCl 3 )δ7.44–7.42(m,2H),7.35–7.30(m,3H),4.82(s,2H),3.66(t,J＝6.8Hz,2H),3.42(t,J＝6.3Hz,2H),1.92–1.85(m,2H),1.84–1.75(m,2H).
Example 24: synthesis of 4-benzyl-2- (4- (4-ethylpiperazin-1-yl) butyl) -1,2, 4-thiadiazolidin-3-one hydrochloride (X-23)
The synthetic route is as follows:
step 1.Synthesis of 4-benzyl-2- (4- (4-ethylpiperazin-1-yl) butyl) -1,2, 4-thiadiazolidin-3-one hydrochloride (X-23)
Compound X-22 (343 mg,1.0 eq) was dissolved in acetonitrile (5-10 mL) and potassium carbonate (345 mg,2.5 eq) was added and the reaction monitored by TLC at 80℃for 3 hours. After the reaction was completed, it was extracted 3 times with ethyl acetate and water, and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash silica gel column (DCM: meoh=94:6) to give compound X-23 in 60% yield. 1 H NMR(400MHz,DMSO-d 6 )δ11.69(s,1H),7.39–7.29(m,5H),4.76(s,2H),3.71(s,2H),3.66(t,J＝6.7Hz,2H),3.36(t,J＝7.2Hz,2H),1.81–1.58(m,4H),1.26(d,J＝7.2Hz,3H).
EXAMPLE 25 Synthesis of 4-benzyl-2- (4- (4-isopropylpiperazin-1-yl) butyl) -1,2, 4-thiadiazolidine-3, 5-dione hydrochloride (X-24)
The synthetic route is as follows:
step 1.Synthesis of 4-benzyl-2- (4- (4-isopropylpiperazin-1-yl) butyl) -1,2, 4-thiadiazolidine-3, 5-dione hydrochloride (X-24)
The synthesis of reference compound (X-23) was carried out by substituting N-ethylpiperazine for N-isopropylpiperazine in 67% yield as a white solid. 1 H NMR(300MHz,DMSO-d 6 )δ11.76(s,1H),7.40–7.28(m,5H),4.76(s,2H),3.66(t,J＝6.6Hz,5H),1.72(s,2H),1.68–1.61(m,2H),1.29(d,J＝6.5Hz,6H).
EXAMPLE 26 Synthesis of 2- (4- (4-acetylpiperazin-1-yl) butyl) -4-benzyl-1, 2, 4-thiadiazolidine-3, 5-dione (X-25)
The synthetic route is as follows:
step 1.Synthesis of 2- (4- (4-acetylpiperazin-1-yl) butyl) -4-benzyl-1, 2, 4-thiadiazolidine-3, 5-dione (X-25)
The synthesis of reference compound (X-23) was carried out by substituting N-ethylpiperazine for 1-acetylpiperazine in 38% yield as a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ7.36–7.28(m,5H),4.74(s,2H),4.16(dd,J＝169.3,14.1Hz,2H),3.64(t,J＝6.8Hz,2H),3.61–3.56(m,1H),3.39(d,J＝11.8Hz,2H),3.12(d,J＝14.5Hz,1H),3.08–3.04(m,2H),2.99–2.80(m,2H),2.03(s,3H),1.75–1.71(m,2H),1.63–1.59(m,2H).
EXAMPLE 27 Synthesis of 4-benzyl-2- (4- (methylsulfonyl) piperazin-1-yl) butyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-26)
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The synthetic route is as follows:
step 1.Synthesis of 4-benzyl-2- (4- (methylsulfonyl) piperazin-1-yl) butyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-26)
The synthesis of reference compound (X-23) was carried out by substituting N-ethylpiperazine for 1-methanesulfonylpiperazine in 69% yield as a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ7.38–7.28(m,3H),4.75(s,1H),3.63(t,J＝6.9Hz,1H),3.07(d,J＝6.5Hz,2H),2.86(s,2H),2.41(s,2H),2.36–2.29(m,1H),1.57(q,J＝7.2Hz,1H),1.44–1.39(m,1H).
EXAMPLE 28 Synthesis of 4-benzyl-2- (4- (4-phenylpiperazin-1-yl) butyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-27)
The synthetic route is as follows:
step 1.Synthesis of 4-benzyl-2- (4- (4-phenylpiperazin-1-yl) butyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-28)
The synthesis of reference compound (X-23) was carried out by substituting N-ethylpiperazine for N-phenylpiperazine in 48% yield as a white solid. 1 H NMR(400MHz,Chloroform-d)δ7.88(d,J＝7.4Hz,2H),7.58–7.49(m,3H),7.45–7.42(m,2H),7.38–7.31(m,3H),4.84(s,2H),4.74(t,J＝12.3Hz,2H),4.27(s,2H),3.71(t,J＝6.2Hz,2H),3.62(t,J＝15.2Hz,4H),3.24(s,2H),1.98(s,2H),1.84(d,J＝8.3Hz,2H).
EXAMPLE 29 Synthesis of 2- (4- (4- (benzo [ d ] [1,3] dioxin-5-ylmethyl) piperazin-1-yl) butyl) -4-benzyl-1, 2, 4-thiadiazolidine-3, 5-dione (X-28)
The synthetic route is as follows:
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step 1.Synthesis of 2- (4- (4- (benzo [ d ] [1,3] dioxin-5-ylmethyl) piperazin-1-yl) butyl) -4-benzyl-1, 2, 4-thiadiazolidine-3, 5-dione (X-28)
The synthesis method of the reference compound (X-23) was changed from N-ethylpiperazine to 1-piperonyl piperazine. Yield 69%, white solid. 1 H NMR(400MHz,DMSO-d 6 )δ7.38–7.27(m,6H),7.08(d,J＝8.0Hz,1H),6.99(d,J＝7.9Hz,1H),6.07(s,2H),4.75(s,2H),4.27(s,2H),3.64(t,J＝6.1Hz,4H),3.53(s,4H),3.37(s,2H),3.11(s,2H),1.69(s,2H),1.62(d,J＝7.3Hz,2H).
EXAMPLE 30 Synthesis of 4-benzyl-2- (4- (4- (pyridin-2-yl) piperazin-1-yl) butyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-29)
The synthetic route is as follows:
step 1.Synthesis of 4-benzyl-2- (4- (4- (pyridin-2-yl) piperazin-1-yl) butyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-29)
The synthesis method of the reference compound (X-23) is to change N-ethylpiperazine into 1- (2-pyridyl) piperazine. Yield 55%, white solid. 1 H NMR(400MHz,Chloroform-d)δ8.19(ddd,J＝4.9,2.1,0.9Hz,1H),7.46(ddd,J＝14.8,8.2,1.8Hz,3H),7.36–7.30(m,3H),6.65–6.60(m,2H),4.82(s,2H),3.67(t,J＝7.0Hz,2H),3.54–3.52(m,4H),2.53–2.50(m,4H),2.42–2.38(m,2H),1.73–1.66(m,2H),1.60–1.52(m,2H).
Example 31: synthesis of 4-benzyl-2- (4-morpholinobutyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-30)
The synthetic route is as follows:
step 1.Synthesis of 4-benzyl-2- (4-morpholinobutyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-30)
The synthesis method of the reference compound (X-23) changes N-ethylpiperazine into morpholine. Yield 58%, white solid. 1 H NMR(400MHz,Chloroform-d)δ7.45–7.42(m,2H),7.36–7.30(m,3H),4.82(s,2H),3.70–3.68(m,4H),3.65(t,J＝7.0Hz,2H),2.40(t,J＝4.7Hz,4H),2.36–2.32(m,2H),1.66(q,J＝7.3Hz,2H),1.51(ddd,J＝11.4,5.7,3.4Hz,2H).
Example 32: synthesis of 4-benzyl-2- (4- (4-methylpiperazin-1-yl) butyl) -1,2, 4-thiadiazolidine-3, 5-dione hydrochloride (X-31)
The synthetic route is as follows:
step 1.Synthesis of 4-benzyl-2- (4- (4-methylpiperazin-1-yl) butyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-31) hydrochloride
The synthesis method of the reference compound (X-23) was changed from N-ethylpiperazine to N-methylpiperazine. Yield 73%, white solid. 1 H NMR(300MHz,DMSO-d 6 )δ11.77(s,1H),7.40–7.28(m,5H),4.75(s,2H),3.66(t,J＝6.6Hz,4H),1.69(d,J＝9.9Hz,2H),1.64(d,J＝6.7Hz,2H).
Example 33: synthesis of 4-benzyl-2- (4- (4-nitrophenoxy) butyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-32)
The synthetic route is as follows:
step 1.Synthesis of 4-benzyl-2- (4- (4-nitrophenoxy) butyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-32)
Compound X-22 (343mg, 1.0 eq) was dissolved in acetonitrile (5-10 mL), followed by the addition of potassium carbonate (276 mg,2.0 eq) and reaction was monitored by TLC at 80℃for 3 hours. After the reaction was completed, it was dried by spin-drying, extraction with ethyl acetate was performed 3 times, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash column on silica gel to give compound X-32 in 46% yield. 1 HNMR(400MHz,CDCl 3 )δ8.26–8.15(m,2H),7.50–7.41(m,2H),7.36–7.30(m,3H),6.95–6.91(m,2H),4.83(s,2H),4.08(t,J＝5.5Hz,2H),3.73(t,J＝6.6Hz,2H),1.96–1.75(m,4H).
Example 34: synthesis of 4-benzyl-2- (4- ((2, 2-dimethyl-4-oxo-4H-benzo [ d ] [1,3] dioxin-5-yl) oxy) butyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-33)
The synthetic route is as follows:
step 1.5-hydroxy-2, 2-dimethyl-4H-benzo [ d ]][1,3]Synthesis of Dioxin-4-one (6 a) to a solution containing 2, 6-dihydroxybenzoic acid (8.00 g,51.9mmol,1.0 eq) and 4-Di To a round bottom flask of methylaminopyridine (0.317 g,2.56mmol,0.05 eq) was added 35mL of dimethyl ether. Before acetone (4.88 mL,66.4mmol,1.28 eq) was added, the reaction solution was cooled to 0deg.C, and then thionyl chloride (4.84 mL, 66.44mmol,1.28 eq) was added to the reaction mixture. The reaction mixture was stirred at 0℃for 1 hour and at room temperature for 15 hours. The reaction was neutralized with 25mL of saturated sodium bicarbonate solution, and then the mixture was extracted with three portions of 30 mL of diethyl ether. The combined organic layers were washed with brine, dried over MgSO4, and the solvent was removed under reduced pressure to give a crude orange solid. Silica gel chromatography and 1:4 ethyl acetate were used: hexane purified the solid to afford intermediate 6a in 89% yield. MS (ESI) m/z 195.3[ M+H ]] + .
Step 2.Synthesis of 4-benzyl-2- (4- ((2, 2-dimethyl-4-oxo-4H-benzo [ d ] [1,3] dioxin-5-yl) oxy) butyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-33)
Compound X-22 (1.0 eq), intermediate 6a (1.0 eq) was dissolved in acetonitrile (10 mL), followed by the addition of potassium carbonate (2.0 eq), and reacted at 80℃for 3-4 hours, with TLC monitoring the reaction. After the reaction was completed, it was dried by spin-drying, extraction with ethyl acetate for 3 times, and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash column on silica gel to give the product X-33 in 78% yield. 1 H NMR(400MHz,CDCl 3 )δ7.45–7.39(m,3H),7.37–7.29(m,3H),6.56(t,J＝8.9Hz,2H),4.82(s,2H),4.10(t,J＝5.6Hz,2H),3.77(t,J＝6.8Hz,2H),1.98–1.90(m,4H),1.70(s,6H).
Example 35: synthesis of 2- (4- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) butoxy) -6-hydroxybenzoic acid (X-34)
The synthetic route is as follows:
step 1.Synthesis of 2- (4- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) butoxy) -6-hydroxybenzoic acid (X-34)
The compound X-33 was used as a starting material, and the deprotection was carried out in a mixed solution of trifluoroacetic acid (10 ml/mmol) and water (2.5 ml/mmol), and reacted overnight at room temperature. After the reaction was monitored by TLC, concentrated under reduced pressure and purified by flash column chromatography (PE: ea=3:1) to give compound X-34 as a white solid in 90% yield. 1 HNMR(400MHz,CDCl 3 )δ12.13(s,1H),11.39(s,1H),7.55–7.22(m,6H),6.72(d,J＝8.5Hz,1H),6.45(d,J＝7.8Hz,1H),4.83(s,2H),4.27(t,J＝6.4Hz,2H),3.73(t,J＝6.7Hz,2H),2.01–1.92(m,2H),1.87–1.80(m,2H)
Example 36: synthesis of 4-benzyl-2- (4- (piperazin-1-yl) butyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-35)
The synthetic route is as follows:
step 1.Synthesis of tert-butyl 4- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) butyl) piperazine-1-carboxylate (8 a)
Compound X-22 (343mg, 1.0 eq) was dissolved in a closed glass tube containing acetonitrile (5 mL), followed by the addition of potassium carbonate (399 mg,2.5 eq) and the reaction was monitored by TLC at 80℃for 3-4 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate 3 times, and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by a rapid silica gel column to give intermediate 8a as a yellow oily liquid in 52% yield. MS (ESI) m/z 449.8[ M+H ] ] + .
Step 2.Synthesis of 4-benzyl-2- (4- (piperazin-1-yl) butyl) -1,2, 4-thiadiazolidine-3, 5-dione (X-35)
Intermediate 8a was removed of tert-butyl ester in a mixed solution of trifluoroacetic acid (10 ml/mmol) and dichloromethane (10 ml/mmol) for 3 hours. After the completion of the reaction, the reaction mixture was monitored by TLC, concentrated under reduced pressure, and subjected to a rapid silica gel columnPurification gave compound (X-35) as a white solid in 87% yield. 1 H NMR(400MHz,DMSO-d 6 )δ7.37–7.29(m,5H),4.76(s,2H),3.65(d,J＝6.4Hz,2H),3.47(s,2H),3.07–3.04(m,8H),1.74–1.62(m,4H).
Example 37: synthesis of (4- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) butyl) -L-alanine (X-36)
The synthetic route is as follows:
step 1 Synthesis of tert-butyl (4- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) butyl) -L-alanine ester (9 a)
Compound X-22 (343 mg,1 eq), L-alanine tert-butyl ester hydrochloride (191 mg,1.05 eq) was dissolved in a closed glass tube containing acetonitrile (5 mL), then anhydrous potassium carbonate (345 mg,2.5 eq) was added and reacted at 80℃for 3-4 hours, followed by TLC monitoring the reaction. After the reaction was completed, the reaction solution was extracted 3 times with ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by a rapid silica gel column (PE: ea=1:4) to obtain intermediate 9a as a yellow oily liquid in 73% yield. MS (ESI) m/z 408.4[ M+H ]] + .
Synthesis of (4- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) butyl) -L-alanine (X-36)
Intermediate 9a was freed from tert-butyl ester in a mixed solution of trifluoroacetic acid (10 ml/mmol) and dichloromethane (10 ml/mmol) for 4 hours. After the reaction was monitored by TLC, concentrated under reduced pressure and purified by flash column on silica gel to give compound (X-36) as a white solid in 87% yield. 1 H NMR(400MHz,DMSO-d 6 )δ7.38–7.28(m,5H),4.75(s,2H),3.62(d,J＝6.4Hz,2H),3.24(d,J＝7.7Hz,1H),2.82(d,J＝7.2Hz,2H),1.60(d,J＝6.0Hz,4H),1.27(d,J＝7.0Hz,3H).
Example 38: synthesis of (4- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) butyl) -L-proline (X-37)
The synthetic route is as follows:
step 1 Synthesis of tert-butyl (4- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) butyl) -L-proline (10 a)
Compound X-22 (343 mg,1 eq), L-proline tert-butyl ester (180 mg,1.05 eq) was dissolved in a closed glass tube containing acetonitrile (5 mL), then anhydrous potassium carbonate (345 mg,2.5 eq) was added and reacted at 80℃for 3-4 hours, followed by TLC monitoring the reaction. After the reaction was completed, the reaction solution was extracted with ethyl acetate 3 times, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by a flash silica gel column to give compound 10a as a yellow oily liquid in a yield of 56%. MS (ESI) m/z 434.5[ M+H ]] + .
Synthesis of (4- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) butyl) -L-proline (X-37)
Intermediate 10a was removed of tert-butyl ester in a mixed solution of trifluoroacetic acid (10 ml/mmol) and dichloromethane (10 ml/mmol) for 4 hours. After the reaction was completed by TLC, it was concentrated under reduced pressure and purified by flash column chromatography to give compound (X-37) as a white solid in 89% yield. 1 H NMR(300MHz,DMSO-d 6 )δ7.39–7.27(m,5H),4.75(s,2H),3.62(d,J＝6.7Hz,2H),3.51–3.43(m,2H),3.07–2.86(m,2H),2.77(td,J＝10.0,7.1Hz,1H),2.19–1.89(m,2H),1.89–1.67(m,2H),1.65–1.56(m,4H).
Example 39: synthesis of 4-benzyl-2- (4- (4- (cyclopropylcarbonyl) piperazin-1-yl) butyl) -1,2, 4-thiadiazolidine-3, 5-dione hydrochloride (X-38)
The synthetic route is as follows:
step 1.Synthesis of 4-benzyl-2- (4- (4- (cyclopropylcarbonyl) piperazin-1-yl) butyl) -1,2, 4-thiadiazolidine-3, 5-dione hydrochloride (X-38)
The synthesis of reference compound X-23 replaced N-ethylpiperazine with 1-cyclopropylpiperazine gave the product X-38 as a white solid in 68% yield. 1 H NMR(400MHz,DMSO-d 6 )δ10.81(s,1H),7.39–7.29(m,5H),4.76(s,2H),4.40(d,J＝14.2Hz,2H),3.66(t,J＝6.7Hz,2H),3.09(dd,J＝9.9,5.4Hz,4H),2.01(dd,J＝11.2,4.8Hz,1H),1.72(dd,J＝10.9,5.5Hz,2H),1.63(q,J＝7.1Hz,2H),0.75(d,J＝7.6Hz,4H).
Example 40: synthesis of N- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) butyl) -N-methylglycine (X-39)
The synthetic route is as follows:
step 1 Synthesis of tert-butyl N- (4- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) butyl) -N-methylglycine ester (11 a)
Compound X-22 (343 mg,1.0 eq), tert-butyl glycinate (138 mg,1.05 eq) was dissolved in a closed glass tube containing acetonitrile (5 mL) and then anhydrous potassium carbonate (345 mg,2.5 eq) was added and reacted at 80℃for 3-4 hours, followed by TLC monitoring the reaction. After the reaction was completed, the reaction solution was extracted 3 times with ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by a rapid silica gel column to give intermediate 11a in the form of a yellow oily liquid with a yield of 78%, a pale yellow oily liquid. MS (ESI) m/z 408.4[ M+H ] ] + .
Synthesis of N- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) butyl) -N-methylglycine (X-39)
Intermediate 11a was removed of tert-butyl ester in a mixed solution of trifluoroacetic acid (10 ml/mmol) and dichloromethane (10 ml/mmol) for 4 hours. After the reaction was completed by TLC, it was concentrated under reduced pressure and purified by flash column chromatography to give compound (X-39) as a white solid in 90% yield. 1 H NMR(400MHz,DMSO-d 6 )δ7.36–7.19(m,5H),4.19(d,J＝4.5Hz,2H),3.63(s,2H),3.32(s,2H),2.86(d,J＝8.4Hz,2H),2.59(s,3H),1.46(d,J＝7.6Hz,4H).
Example 41: synthesis of (2- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) ethyl) -L-phenylalanine (X-40)
The synthetic route is as follows:
step 1 Synthesis of tert-butyl (2- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) ethyl) -L-phenylalanine ester (12 a)
The procedure of reference example 40 shows that intermediate 11a is synthesized by substituting tert-butyl glycine for tert-butyl L-phenylalanine hydrochloride. Intermediate 12a was an oily liquid with a yield of 70%. MS (ESI) m/z 484.5[ M+H ]] + .
Synthesis of (2- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) ethyl) -L-phenylalanine (X-40)
Reference example 40, method of synthesis of compound X-39. The product (X-40) was a white solid in 85% yield. 1 H NMR(300MHz,DMSO-d 6 )δ7.39–7.18(m,10H),4.75(s,2H),3.60–3.55(m,2H),3.46(t,J＝6.4Hz,2H),3.07–2.89(m,3H),2.75–2.60(m,2H).
Example 42: synthesis of 2- (4- (1, 4-diaza-1-yl) butyl) -4-benzyl-1, 2, 4-thiadiazolidine-3, 5-dione (X-41)
The synthetic route is as follows:
step 1 Synthesis of tert-butyl 4- (4- (4-benzyl-3, 5-dioxo-1, 2, 4-thiadiazolidin-2-yl) butyl) -1, 4-diazine-1-carboxylate (13 a)
Compound X-22 (343 mg,1.0 eq), tert-butyl 1, 4-diazacycloheptane-1-carboxylate (210 mg,1.05 eq) was dissolved in a closed glass tube containing acetonitrile (5 mL), then potassium carbonate (345 mg,2.5 eq) was added and reacted at 80℃for 3-4 hours, followed by TLC monitoring the reaction. After the reaction was completed, the reaction solution was extracted with ethyl acetate 3 times, and the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by a rapid silica gel column to give intermediate 13a as a yellow oily liquid in a yield of 51%. MS (ESI) m/z 463.5[ M+H ]] + .
Step 2.Synthesis of 2- (4- (1, 4-diaza-1-yl) butyl) -4-benzyl-1, 2, 4-thiadiazolidine-3, 5-dione (X-41)
Intermediate 13a was removed from a mixed solution of trifluoroacetic acid (10 ml/mmol) and dichloromethane (10 ml/mmol) for 3-4 hours. After the reaction was completed by TLC, it was concentrated under reduced pressure and purified by flash column chromatography to give compound (X-41) as a white solid in 83% yield. 1 H NMR(300MHz,DMSO-d 6 )δ7.39–7.28(m,5H),4.75(s,2H),3.67–3.63(m,2H),3.45(s,4H),3.25(t,J＝5.4Hz,4H),3.05(s,2H),2.07(d,J＝5.8Hz,2H),1.62–1.60(m,4H).
2. Biological evaluation
(1) PTPN2 kinase activity analysis and test method
Evaluating the activity of the compound in inhibiting PTPN2 by using an established in vitro phosphatase activity detection method, and calculating IC 50 Values. The enzyme activity buffer of the reaction system was 50mM Tris (hydroxymethyl) aminomethane chloride (Tris-cl), pH 7.2, 10mM NaCl,10% glycerol,0.1% Bovine Serum Albumin (BSA), the reaction was performed in 96-well plates, and the total reaction system was 100. Mu.L, and divided into three groups, an experimental group, a negative control group and a positive control group. Sequentially adding 48 mu L of PTPN2 (obtained by artificial purification), 2 mu L of compound (dissolved in DMSO) into each hole of an experimental group, shaking and uniformly mixing for 30s, incubating at 37 ℃ for 15min, then adding 50 mu L of 50nM PNPP, shaking and uniformly mixing for 30s, incubating at 37 ℃ for 5min, then adding 100 mu L of 1M sodium hydroxide, measuring absorbance at 405nM wavelength by using an enzyme-labeling instrument, and obtaining an IC (integrated circuit) of each compound on enzyme activity by adopting log (inhibitor) vs. response-Variable slope of analytical software GraphPad Prism 50 Values.
The resulting IC 50 The values are shown in Table 1, and it can be seen that the synthesized compounds of the examples all have good inhibitory activity on PTPN 2.
TABLE 1 IC of example Compounds for PTPN2 phosphatase inhibitory Activity 50 Measurement value
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It can be seen from the table that the compounds of the present invention have very good inhibitory activity against PTPN2, of which compound 18 has the strongest inhibitory activity against PTPN2, which was further evaluated for in vivo activity.
(2) Compound acute toxicity assay
Test animals: ICR mice (supplied by Shanghai lycra laboratory animal limited liability company); 18-22g; a female; a total of 20.
Sample to be tested: examples X-18
Group dose setting: setting four groups in total, and setting a control group; 1000mg/kg group; 2500mg/kg group: 5000mg/kg group: gastric lavage drug, administration group each group was administered 1 time, control group was administered the same amount of vehicle, 5 mice each, and observation was performed for 14 days;
experimental results: as shown in fig. 1, no abnormalities were seen in the animals within 12 hours after dosing of each group of mice. No animal death was seen within 24 hours of dosing and no animal death was seen after day 14 of dosing. No other obvious anomalies were seen. There was no significant difference between the body weight of the 3 mice in the dosing group and the control group. There was no significant difference between the weights of heart, liver, spleen, lung and kidney of the 3 mice in the dosing group and the control group. Thus, the test drug was administered by gavage at 1000mg/kg,2500mg/kg,5000mg/kg without toxicity, and example X-19 was excellent in safety.
(3) Compound activity assay against Acute Myeloid Leukemia (AML)
Sample to be tested: implementation of X-18
The experimental method comprises the following steps: M-NSG mice were injected with MOLM13-Luciferase (5X 10) 5 ) Tumor cells, and a MOLM13-Luciferase transplantation tumor model is established. On day 2 post inoculation, animals were randomized into 2 groups of tumor-bearing mice by Flux values: control, compound (10 mg/kg), 5 per group. Intraperitoneal administration was started on day 3 after inoculation, once a day, for 10 consecutive days. Mice were daily recorded for body weight, tumor fluorescence changes were measured, and mice were sacrificed.
The experimental results show that: the mice lost significantly in weight on day 9, and the control group died on day 10, either in the control group or in the dosing group. We used small animal imaging to detect fluorescence intensity in mice on day 2 and day 9, as shown in figure 2, and on day 9, the in vivo fluorescence intensity was significantly lower in mice of the dosing group than in the blank group. Thus, the example X-18 human acute myeloid leukemia cell MOLM13-Luciferase transplanted tumor has remarkable inhibition effect.

Claims (7)

1. A compound represented by the general formula (I):
wherein m=2 or 4; y is O;
R 1 selected asWherein:
l is O;
r is
R a 、R b Each independently selected from hydrogen, hydroxy, aldehyde, carboxyl, nitro, C 1 ～C 6 Alkyl, C 1 ～C 6 Carboxyalkyl, C 1 ～C 6 An alkylcarbonyl group.
2. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: r is R a 、R b Each independently selected from hydrogen, hydroxy, aldehyde, carboxyl, nitro, C 1 ～C 4 Alkyl, C 1 ～C 4 Carboxyalkyl, C 1 ～C 4 An alkylcarbonyl group.
3. A compound selected from the following structures:
4. the preparation method of the compound shown in the general formula (I):
wherein Y, m, R 1 Is defined as in claim 1.
5. A pharmaceutical composition comprising a compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
6. Use of a compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a PTPN2 mediated disease.
7. The use according to claim 6, wherein the PTPN2 mediated disease is leukemia.
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