CN115197167A - 1,2,4-thiadiazolidine-3,5-diketone compound and preparation method and application thereof - Google Patents
1,2,4-thiadiazolidine-3,5-diketone compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a 1,2,4-thiadiazolidine-3,5-diketone compound and a preparation method and application thereof, belonging to the technical field of pharmaceutical chemistry. The invention relates to 1,2,4-thiadiazolidine-3,5-diketone derivative which is a compound with a structure shown as a general formula (I) or a pharmaceutically acceptable salt thereof, and also discloses an application of the 1,2,4-thiadiazolidine-3,5-diketone derivative in a medicine for treating PTPN2 mediated diseases. The compounds disclosed in the present invention have significant activity against PTPN2 phosphatase, and the IC of most synthetic compounds against PTPN2 phosphatase 50 The value is kept at the mu M level, has important influence on the generation and development of tumors and immune response, can be used together with an immunosuppressant 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 large potential for future modification.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and relates to a 1,2,4-thiadiazolidine-3,5-diketone derivative, in particular to a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, and application thereof in treating PTPN2 mediated diseases.
Background
PTPNs are important regulators of numerous signaling pathways involved in major cellular processes such as cell growth, proliferation and differentiation. PTPN2 is a widely expressed cytosolic tyrosine phosphatase. PTPN2 is dephosphorylated through JAK/STAT proteins (such as STAT1 or JAK 1) with different tyrosine phosphorylations, so that a JAK/STAT signal passage is negatively regulated and controlled. Besides STAT1, PTPN2 also dephosphorylates STAT3 and STAT5 and negatively regulates their activation. The JAK/STAT pathway plays a crucial role in cancer processes, and aberrant activation of STAT signals is implicated in the development of many cancers.
PTP1B is one of the most important members of the PTPN family, and plays an important role in a variety of cellular functions. PTP1B has been reported to be involved in the development of a variety of diseases including diabetes, cancer and cardiovascular disease. PTP1B is highly homologous to PTPN2, so that there are many selective inhibitors of PTP1B that have inhibitory activity against PTPN 2. However, these compounds lack selectivity for PTPN2, resulting in a large potential for toxic side effects; meanwhile, the structure comprises a plurality of groups such as carboxyl group, phosphate group, ortho-dicarbonyl group and the like with larger polarity, and the pharmaceutical property of the structure is also to be optimized. To date, selective small molecule inhibitors of PTPN2 have not been reported. Therefore, the discovery that the small-molecule inhibitor of PTPN2 can provide an important theoretical basis for developing antitumor drugs with antitumor activity, good selectivity and small toxic and side effects.
Disclosure of Invention
The invention aims to: the invention aims to solve the technical problem of developing a small molecule inhibitor which takes 1,2,4-thiadiazolidine-3,5-diketone as a parent nucleus and has PTPN2 inhibitory activity.
The invention also aims to solve the technical problem of providing the application of the 1,2,4-thiadiazolidine-3,5-diketone derivative in the preparation of medicaments 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:
a1,2,4-thiadiazolidine-3,5-dione derivative or a pharmaceutically acceptable salt thereof, wherein the 1,2,4-thiadiazolidine-3,5-dione derivative is a compound having a structure shown in a general formula (I):
wherein the content of the first and second substances,
m =1 to 4; y is O or S;
R 1 selected from halogen,
Wherein:
l is a covalent bond (i.e., absent) or O;
r is C 6 ～C 10 A 4-to 7-membered heteroaromatic ring having 1-3 heteroatoms selected from N, O or a 4-to 7-membered heterocyclic ring having 1-3 heteroatoms selected from N, O;
R a 、R b each independently selected from hydrogen, hydroxyl, aldehyde group, carbonyl, carboxyl, nitro, cyano and C 1 ～C 6 Alkyl radical, C 1 ～C 6 Carboxyalkyl, C 1 ～C 6 Alkyl carbonyl, C 1 ～C 6 Alkylsulfonyl radical, C 3 ～C 8 Cycloalkyl carbonyl group, C 6 ～C 10 Aryl of (a), a 4-to 7-membered heteroaromatic ring having 1-3 heteroatoms selected from N, O, a C substituted with a 4-to 7-membered heterocyclic ring having 1-3 heteroatoms selected from N, O 1 ～C 6 An alkyl group;
or R a 、R b Together with the atoms to which they are attached form an optionally substituted 4-7 membered monocyclic heterocyclyl, the heteroatom is selected from O or N; the substituent is selected from hydrogen, hydroxyl, aldehyde group, carboxyl, carbonyl, nitro, cyano or C 1 ～C 6 An alkyl group;
R c 、R d each independently selected from hydrogen, hydroxyl, aldehyde group, carbonyl, carboxyl, nitro, cyano, and optionally substituted C 1 ～C 6 Alkyl or optionally substituted C 6 ～C 10 Aryl of (a); the substituent is selected from hydrogen, hydroxyl, aldehyde group, carboxyl, carbonyl, nitro, cyano and C 6 ～C 10 Or a 4-to 7-membered heteroaromatic ring having 1-3 heteroatoms selected from N, O.
In some examples, Y is O.
In some examples, R is C 6 ～C 10 Or a 5-to 7-membered heterocyclic ring having 1 to 3 heteroatoms selected from N and O;
R a 、R b each independently selected from hydrogen, hydroxyl, aldehyde group, carbonyl, carboxyl, nitro, cyano and C 1 ～C 4 Alkyl radical, C 1 ～C 4 Carboxyalkyl, C 1 ～C 4 Alkylcarbonyl group, C 1 ～C 4 Alkylsulfonyl radical, C 3 ～C 8 Cycloalkyl carbonyl group, C 6 ～C 10 Aryl of (2), a 4-to 7-membered heteroaromatic ring having 1 to 3 heteroatoms selected from N and O, C substituted with a 4-to 7-membered heterocyclic ring having 1 to 3 heteroatoms selected from N and O 1 ～C 3 An alkyl group;
or R a 、R b Together with the atoms to which they are attached form an optionally substituted 4-7 membered monocyclic heterocyclyl, the heteroatom is selected from O or N; the substituent is selected from hydrogen, hydroxyl, aldehyde group, carboxyl, carbonyl, nitro, cyano or C 1 ～C 3 An alkyl group.
In some of the more specific examples,
r is
R a 、R b Each independently selected from hydrogen, hydroxyl, aldehyde group, carbonyl, carboxyl, nitro, cyano and C 1 ～C 4 Alkyl radical, C 1 ～C 4 Carboxyalkyl, C 1 ～C 4 Alkylcarbonyl group, C 1 ～C 4 Alkylsulfonyl radical, C 3 ～C 8 Cycloalkyl carbonyl group, C 6 ～C 10 Aryl of (2), a 4-to 7-membered heteroaromatic ring having 1 to 3 heteroatoms selected from N and O, C substituted with a 4-to 7-membered heterocyclic ring having 1 to 3 heteroatoms selected from N and O 1 ～C 3 An alkyl group;
or R a 、R b Together with the atoms to which they are attached form an optionally substituted 4-to 7-membered monocyclic heterocyclyl, the heteroatom being selected from O or N; the substituent is selected from hydrogen, hydroxyl, aldehyde group, carboxyl, carbonyl, nitro and cyanoOr C 1 ～C 3 An alkyl group.
In some more specific examples, when R is other than
When R is a Is hydrogen.
In some examples, R c 、R d Each independently selected from hydrogen, hydroxyl, aldehyde group, carbonyl, carboxyl, nitro, cyano or C which is optionally substituted 1 ～C 4 An alkyl group; the substituent is selected from hydrogen, hydroxyl, aldehyde group, carboxyl, carbonyl, nitro, cyano or C 6 ～C 10 Aryl group of (1). In some more specific examples, R c 、R d Each independently selected from hydrogen or optionally substituted C 1 ～C 3 An alkyl group; the substituent is selected from hydrogen, hydroxyl, aldehyde group, carboxyl, carbonyl, nitro, cyano or benzene ring.
When m =1, R 1 Is selected from phenyl;
when m =2, R 1 Selected from-Br, -NHR 2 、-NR 3 R 4 6-7 membered azacycloalkyl, alkylphenyloxy, wherein 6-7 membered heterocycloalkyl is
The alkylphenoxy group 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, wherein
6-to 7-membered heterocycloalkyl group
The alkylphenoxy radical is
-O-Ph-R 12 。
Preferably, the first and second electrodes are formed of a metal,
when m =1, R 1 Selected from phenyl.
When m =2, R 1 Selected from-Br, -NHR 2 、-NR 3 R 4 6-to 7-membered azacycloalkyl, alkylphenyloxy, wherein6-to 7-membered heterocycloalkyl is
The alkylphenoxy group is-O-Ph-R 7 ；
Wherein R is 2 Is 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 Is selected from-CH 2 -C(O)OH、-CH 2 CH 3 、-CH(CH 3 ) 2 、-C(O)CH 3 、
R 6 Is selected from-CH 2 -C(O)OH，
-O-Ph-R 7 Is selected from
When m =4, R 1 Selected from-Br, -NHR 8 、-NR 9 R 10 6-7 membered azacycloalkyl and alkylphenoxy, wherein 6-7 membered heterocycloalkyl is
-O-Ph-R 12 ；
Wherein R is 8 Is 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 Is selected from-CH 3 、-CH 2 CH 3 、-CH(CH 3 ) 2 、-C(O)CH 3 、
-O-Ph-R 12 Is selected from
In some examples, the present application also provides compounds of the following specific structures:
the pharmaceutically acceptable salt is an acid addition salt of a compound shown as a general formula (I), wherein the acid for forming the salt comprises an inorganic acid and an organic acid, and the inorganic acid comprises: 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 in the present invention is hydrochloride or trifluoroacetate.
The invention also discloses a preparation method of the compound with the general formula (I):
wherein Y, m, R 1 As defined above.
The invention also discloses a medicinal composition which comprises the compound shown in the general formula (I) or pharmaceutically acceptable salt or isomer thereof and a pharmaceutically acceptable carrier.
Pharmaceutically acceptable carriers refer 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 administered compound. The excipient comprises a binder, a filler, a disintegrating agent, a lubricant, a preservative, an antioxidant, a flavoring agent, an aromatic, a cosolvent, an emulsifier, a solubilizer, an osmotic pressure regulator, a coloring agent and the like, and the diluent comprises normal saline, starch, dextrin, sucrose, lactose and the like.
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 PTPN2 mediated diseases is within the scope of the present invention.
In some embodiments of the invention, the PTPN 2-mediated disease is selected from diseases mediated by modulation of the JAK/STAT signaling pathway.
In some embodiments of the invention, the PTPN 2-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 particularly Acute Myeloid Leukemia (AML).
In some embodiments of the invention, the cancer is selected from first line cancer.
In some preferred embodiments of the invention, the disease is selected from PTPN2 mediated diseases selected from pancreatic cancer.
The terms used in the present invention have the following meanings unless otherwise specified.
The term "[ CH ] as used 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 a cycloalkane having 1 or more heteroatoms other than C, 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, in particular a carbon-oxygen double bond plus one carbon-oxygen single bond.
The term "C 1 ～C 6 Carboxyalkyl "means C substituted by carboxy 1 ～C 6 Alkyl group of (1).
The term "C 1 ～C 6 Alkylcarbonyl "means-C (O) -R ', where 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" wherein R "is C 3 ～C 8 A cycloalkyl group.
Has the advantages that:
the compound disclosed by the invention has obvious activity on PTPN2 phosphatase, and the synthesized compound IC 50 The value is kept at the mu M level, can be used for having important influence on the generation and development of tumors and immune response, can also be used for treating related immune diseases by combining with an immunosuppressant, can be developed into antitumor drugs with high activity, good selectivity and small toxic and side effects, and has the characteristics of novel framework, strong plasticity and large potential for future modification.
Drawings
FIG. 1 is a study of Compound X-18. (a) weight change in each group of mice; (B) The weight change of the heart, liver, spleen, lung and kidney of each group of mice;
FIG. 2 shows the in vivo activity of compound X-18. (a) weight change in mice; (B) And (C) changes in fluorescence intensity in mice on days 1 and 9 of administration; ns is no significant difference, [ p ] 0.01.
Detailed Description
The following examples are intended to facilitate a better understanding of the invention, but are not intended to limit the invention thereto. The experimental procedures in the following examples are all conventional ones unless otherwise specified. The test materials used in the following examples were purchased from a conventional biochemical reagent store unless otherwise specified. 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 (20g, 1.0eq), pyridine (32 mL) was added to a three-necked flask and nitrogen-blanketed, cold-bathed to-15 ℃ or below, and dichloromethane (150 mL) was added. Triphosgene (13g, 0.5eq) was dissolved in dichloromethane (100 mL), slowly added dropwise to the reaction system in a three-necked flask, the temperature was kept at 0 ℃ or lower, and after the addition, the mixture was stirred for 4 to 6 hours, during which the reaction was monitored by a TLC plate, and when the reaction of the starting materials was substantially completed, the cooling bath was stopped. The reaction solution was washed twice with 0.5M dilute hydrochloric acid, the aqueous solution was washed twice with dichloromethane, the organic layers were combined, washed twice with saturated brine, dried, concentrated under reduced pressure to give a yellow transparent oily substance, which was directly put to the next step. The yellow oily substance was dissolved in tetrahydrofuran (400 mL), isothiocyanate (16g, 1.0eq) was added, and the mixture was cooled to 0 ℃ and then sulfuryl chloride (15g, 1.0eq) was slowly added dropwise, and the mixture was warmed to room temperature, stirred overnight, and the reaction was left to stir in the air for 30 minutes the next day. After the reaction was completed, two products were detected by TLC plate, the more polar product was K-1, and the compound K-1 was obtained by column chromatography after concentration by distillation under reduced pressure (12.1 g, yield 57%). 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-dioxy-1,2,4-thiadiazolidin-2-yl) ethyl) -1,4-diazane-1-carboxylate (2 a)
Compound K-1 (300mg, 1.0eq), 1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester (195mg, 1.03eq) was dissolved in a closed glass tube filled with acetonitrile (5 mL), followed by addition of potassium carbonate (329mg, 2.5eq) and reaction at 80 ℃ for 3-4 hours, and the reaction was monitored by TLC. After the reaction, 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 flash silica gel column to obtain compound 2a in 42% yield as a yellow oily liquid. MS (ESI) m/z 435.5[ 2 ] M + H] + .
Step 2.2 Synthesis of 2- (2- (1,4-diaza-1-yl) ethyl) -4-benzyl-1,2,4-thiadiazolidine-3,5-dione (X-1)
The reaction product 2a was treated with a mixed solution of trifluoroacetic acid (10 ml/mmol) and dichloromethane (10 ml/mmol) to remove tert-butyl ester for 3 hours. After the completion of the reaction was monitored by TLC, concentration under reduced pressure and purification by flash silica gel column gave compound (X-1) as a white solid with a yield of 90%. 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-dioxy-1,2,4-thiadiazolidin-2-yl) ethyl) -1,4-diaza-1-yl) acetic acid (X-2)
The synthetic route is as follows:
step 1.2 Synthesis of tert-butyl (4- (4-benzyl-3,5-dioxy-1,2,4-thiadiazolidin-2-yl) ethyl) -1,4-diaza-1-yl) acetate (2 b)
X-1 (1.0 eq) and tert-butyl bromoacetate (1.0 eq) were dissolved in tetrahydrofuran, triethylamine (2.5 eq) was added to the reaction mixture, the mixture was reacted at 65 ℃ for 2 hours, and the reaction was monitored by TLC. After the reaction, the reaction mixture was concentrated under reduced pressure, dried over anhydrous sodium sulfate, and purified by flash silica gel column to obtain compound 2b as a colorless oily liquid with a yield of 83%. MS (ESI) m/z 449.5[ 2 ] M + H] + .
Step 2.Synthesis of 2- (4- (2- (4-benzyl-3,5-dioxy-1,2,4-thiadiazolidin-2-yl) ethyl) -1,4-diaza-1-yl) acetic acid (X-2)
The intermediate 2b 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 was monitored by TLC, concentration under reduced pressure and purification by flash silica gel column gave compound (X-2) as a white solid with a yield of 90%. 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-dioxy-1,2,4-thiadiazolidin-2-yl) ethyl) piperazine-1-carboxylate (2 c)
Compound K-1 (300mg, 1.0 eq), piperazine-1-carboxylic acid tert-butyl ester (195mg, 1.03eq) was dissolved in a closed glass tube filled with acetonitrile (5 mL), followed by addition of potassium carbonate (329mg, 2.5eq) and reaction at 80 ℃ for 3-4 hours, and the reaction was monitored by TLC. After the reaction is finished, extracting the reaction liquid for 3 times by using ethyl acetate, combining organic layers, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by using a quick silica gel column to obtain a compound 2a which is yellow oily liquidThe yield was 51%. MS (ESI) m/z 421.5[ 2 ] M + H] + .
Step 2.4-benzyl-2- (2- (piperazin-1-yl) ethyl) -1,2,4-thiadiazolidine-3,5-dione (X-4) Synthesis
The intermediate 2c 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 was monitored by TLC, concentration under reduced pressure and purification by flash silica gel column gave compound (X-3) as a white solid with a yield of 90%. 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-dioxy-1,2,4-thiadiazolidin-2-yl) ethyl) piperazin-1-yl) acetic acid (X-4)
The synthetic route is as follows:
referring to the synthesis method of the compound (X-2), the intermediate 2d and the compound X-4 are 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-dioxy-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-dioxy-1,2,4-thiadiazolidin-2-yl) ethyl) -L-alanine ester (3 a)
Compound K-1 (300mg, 1.0eq), L-alanine tert-butyl ester hydrochloride (182mg, 1.05eq) was dissolved in a closed glass tube containing acetonitrile (5 mL), and anhydrous potassium carbonate (329mg, 2.5eq) was added thereto, followed by reaction at 80 ℃ for 3 to 4 hours, and the reaction was monitored by TLC. After the reaction, 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 flash silica gel column to obtain compound 2a as a yellow oily liquid with a yield of 60%, a colorless transparent oily liquid. MS (ESI) m/z 380.4[ 2 ] M + H] + .
The t-butyl ester was removed from the reaction product 3a in a mixed solution of trifluoroacetic acid (10 ml/mmol) and dichloromethane (10 ml/mmol) for 3 hours. After the completion of the reaction was monitored by TLC, concentration under reduced pressure and purification by flash silica gel column gave compound (X-5) as a white solid with a yield of 90%. 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-dioxy-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-dioxy-1,2,4-thiadiazolidin-2-yl) ethyl) -N-methylglycinate (4 a)
Referring to the procedure for the synthesis of intermediate 3a in step 1 of example 6, yield was 73%, colorless oily liquid. MS (ESI) m/z 380.4[ 2 ] M + H] + .
Synthesis of step 2.N- (2- (4-benzyl-3,5-dioxy-1,2,4-thiadiazolidin-2-yl) ethyl) -N-methylglycine (X-6)
Referring to the synthesis of compound X-5 of step 2 of 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-dioxy-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-dioxy-1,2,4-thiadiazolidin-2-yl) ethyl) -L-phenylalanine ester (5 a)
Referring to the procedure for the synthesis of intermediate 3a in step 1 of example 6, yield was 51% as a colorless oily liquid. MS (ESI) m/z 456.5[ 2 ], [ M + H ]] + .
Referring to the synthesis of compound X-5 of step 2 of 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 1.4 Synthesis of benzyl-2- (2- (4-ethylpiperazin-1-yl) ethyl) -1,2,4-thiadiazolidine-3,5-dione (X-9)
Compound K-1 (300mg, 1.0eq) and N-ethylpiperazine (116mg, 1.05eq) were dissolved in a closed glass tube containing 1,4-dioxane (5 mL), followed by addition of DIPEA (307mg, 2.5eq) and reaction at 100 ℃ for 3-4 hours, and the reaction was monitored by TLC. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by flash silica gel column (DCM: meOH = 94) to give compound X-8 as a white solid with a yield of 67%. 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 1.4-benzyl-2- (2- (4-isopropylpiperazin-1-yl) ethyl) -1,2,4-thiadiazolidine-3,5-dione (X-9) Synthesis
A synthesis method of reference compound (X-8) in which N-ethylpiperazine was replaced with N-isopropylpiperazine. Yield was 68% as a 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 1.2- (2- (4-acetylpiperazin-1-yl) ethyl) -4-benzyl-1,2,4-thiadiazolidine-3,5-dione (X-10) hydrochloride Synthesis
A synthesis method of the reference compound (X-8) in which N-ethylpiperazine was replaced with 1-acetylpiperazine. Yield 45% as a 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)
Referring to the synthesis method of the compound (X-8), N-ethylpiperazine was changed to 1-methanesulfonylpiperazine. Yield 81% as a 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 1.4-benzyl-2- (2- (4-phenylpiperazin-1-yl) ethyl) -1,2,4-thiadiazolidine-3,5-dione hydrochloride (X-12) Synthesis
A synthesis method of the reference compound (X-8) wherein N-ethylpiperazine is changed to N-phenylpiperazine. Yield was 56% as a 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 1.2- (2- (4- (benzo [ d ] [1,3] dioxin-5-ylmethyl) piperazin-1-yl) ethyl) -4-benzyl-1,2,4-thiadiazolidine-3,5-dione (X-13) Synthesis
A synthesis method of reference compound (X-8) wherein N-ethylpiperazine is changed to 1-piperonylpiperazine. Yield was 69% as a 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-sulfoxy-1,2,4-thiadiazolidin-5-one (X-14)
The synthetic route is as follows:
step 1. Step 1.1 Synthesis of bromo-2-isocyanatoethane (1 b) and 2,4-dibenzyl-3-sulfoxy-1,2,4-thiadiazolidin-5-one (X-14)
2-bromoethylamine hydrobromide (20g, 1.0eq), pyridine (32 mL) was added to a three-necked flask and nitrogen-blanketed, cold-bathed to-15 ℃ or below, and dichloromethane (150 mL) was added. Triphosgene (13g, 0.5eq) was dissolved in dichloromethane (100 mL), slowly added dropwise to the reaction system in a three-necked flask, the temperature was kept at 0 ℃ or lower, and after the addition, the mixture was stirred for 4 to 6 hours, during which the reaction was monitored by a TLC plate, and when the reaction of the starting materials was substantially completed, the cooling bath was stopped. The reaction solution was washed twice with 0.5M dilute hydrochloric acid, the aqueous solution was washed twice with dichloromethane, the organic layers were combined, washed twice with saturated brine, dried, concentrated under reduced pressure to give a yellow transparent oily substance, which was directly put to the next step. The yellow oily substance was dissolved in tetrahydrofuran (400 mL), isothiocyanate (16g, 1.0eq) was added, cooled to 0 ℃ and then sulfuryl chloride (15g, 1.0eq) was slowly added dropwise, warmed to room temperature, stirred overnight, and the reaction was left to stir in the air for 30 minutes the next day. After the reaction was completed, two products, X-14 which is a less polar product, were monitored by TLC plate, and concentrated by distillation under reduced pressure and subjected to column chromatography to obtain 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-dioxy-1,2,4-thiadiazolidin-2-yl) ethoxy) benzaldehyde (X-15)
The synthetic route is as follows:
step 1.4- (2- (4-benzyl-3,5-dioxy-1,2,4-thiadiazolidin-2-yl) ethoxy) benzaldehyde (X-16) Synthesis
Compound K-1 (300mg, 1.0eq), p-hydroxybenzaldehyde (122mg, 1.05eq) was dissolved in acetonitrile (5-10 mL), followed by addition of potassium carbonate (264mg, 2.0eq) and reaction at 80 ℃ for 3 hours, and the reaction was monitored by TLC. After the reaction, the product is spin-dried, extracted with ethyl acetate for 3 times, the organic layers are combined, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by a rapid silica gel column to obtain a compound X-15 with the 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 (8.00g, 51.9mmol, 1.0eq) and 4-dimethylaminopyridine (0.317g, 2.56mmol, 0.05eq) was added 35mL of dimethyl ether. The reaction was cooled to 0 ℃ before acetone (4.88ml, 66.4mmol, 1.28eq) was added, and thionyl chloride (4.84 ml, 66.44mmol, 1.28eq) was then added to the reaction mixture. The reaction mixture was stirred at 0 ℃ for 1 hour, in the chamberStirred at room temperature for 15 hours. The reaction solution was neutralized with 25ml of saturated sodium bicarbonate solution, and 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 was used: the solid was purified with hexane to afford intermediate 6a in 89% yield. MS (ESI) m/z 195.3[ 2 ], [ 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 addition of potassium carbonate (2.0 eq) and reaction at 80 ℃ for 3-4 hours, and the reaction was monitored by TLC. After the reaction is finished, spin-drying the product, extracting the product for 3 times by using ethyl acetate, combining organic layers, drying the organic layers by using anhydrous sodium sulfate, concentrating the organic layers under reduced pressure, and purifying the organic layers by using a quick silica gel column to obtain a product X-16 with the yield of 71%. 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-dioxy-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-dioxy-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 at room temperature overnight. After the completion of the reaction was monitored by TLC, the reaction mixture was concentrated under reduced pressure and purified by flash silica gel column (PE: EA = 3:1) to obtain a compoundSubstance X-17, white solid, yield 85%. 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 1.4-benzyl-2- (2- (4-nitrophenoxy) ethyl) -1,2,4-thiadiazolidine-3,5-dione (X-18) synthesis
The synthesis method of the reference compound X-15 is to replace p-nitrobenzaldehyde with p-nitrophenol. Yield was 31% as a 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 1.4-benzyl-2- (2- (4- (pyridin-2-yl) piperazin-1-yl) ethyl) -1,2,4-thiadiazolidine-3,5-dione (X-19) Synthesis
Synthesis of reference Compound X-8, substituting N-ethylpiperazine for 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-dioxy-1,2,4-thiadiazolidin-2-yl) ethyl) -L-proline (X-20)
The synthetic route is as follows:
step 1 Synthesis of tert-butyl (2- (4-benzyl-3,5-dioxy-1,2,4-thiadiazolidin-2-yl) ethyl) -L-proline (7 a)
Compound X-1 (300mg, 1.0 eq), L-proline tert-butyl ester (172mg, 1.05eq) was dissolved in a closed glass tube containing acetonitrile (5 mL), and anhydrous potassium carbonate (329mg, 2.5 eq) was added thereto, followed by reaction at 80 ℃ for 3 to 4 hours, and the reaction was monitored by TLC. After the reaction, 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 flash silica gel column to give compound 7a as a yellow oily liquid with a yield of 56%. MS (ESI) m/z 406.4[ 2 ], [ M + H ]] + .
The 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 completion of the reaction was monitored by TLC, concentration under reduced pressure and purification by flash silica gel column gave 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 1.4 Synthesis of 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-cyclopropylformylpiperazine 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)
The synthetic route is as follows:
step 1.4-benzyl-2- (4-bromobutyl) -1,2,4-thiadiazolidine-3,5-dione (X-22) Synthesis
4-bromo-1-butylamine hydrobromic acid (20g, 1.0eq), pyridine (32 mL) was charged into a three-necked flask and blanketed with nitrogen, cold-bathed to-15 ℃ or below, and dichloromethane (150 mL) was added. Triphosgene (13g, 0.5eq) was dissolved in dichloromethane (100 mL)Slowly dropping into a three-necked flask, keeping the temperature not higher than 0 ℃, stirring for 4-6 hours after the addition, monitoring the reaction by using a TLC plate during the period, and stopping the cold bath when the raw materials basically react. The reaction solution was washed twice with 0.5M dilute hydrochloric acid, the aqueous solution was washed twice with dichloromethane, the organic layers were combined, washed twice with saturated brine, dried, concentrated under reduced pressure to give a yellow transparent oily substance, which was directly put to the next step. The yellow oily material was dissolved in tetrahydrofuran (400 mL), isothiocyanate (1691, 1.0 eq) was added, cooled to 0 ℃, then sulfonyl chloride (15g, 1.0 eq) was slowly added dropwise, warmed to room temperature, stirred overnight, the next day the reaction was left to air stir for 30 minutes. After the reaction was completed, two products were detected by TLC plate, and the more polar product was X-22, which was concentrated by distillation under reduced pressure and subjected to column chromatography to give 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 1.4-benzyl-2- (4- (4-ethylpiperazin-1-yl) butyl) -1,2,4-thiadiazolidin-3-one hydrochloride (X-23) Synthesis
Compound X-22 (343mg, 1.0eq), N-ethylpiperazine (120mg, 1.05eq) was dissolved in acetonitrile (5-10 mL), followed by addition of potassium carbonate (345mg, 2.5eq), reaction at 80 ℃ for 3 hours, and the reaction was monitored by TLC. 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) to obtain a compound of formulaObject X-23, yield 60%. 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 1.4-benzyl-2- (4- (4-isopropylpiperazin-1-yl) butyl) -1,2,4-thiadiazolidine-3,5-dione hydrochloride (X-24) Synthesis
Referring to the synthesis method of the compound (X-23), N-ethylpiperazine was replaced with 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 1.2- (4- (4-acetylpiperazin-1-yl) butyl) -4-benzyl-1,2,4-thiadiazolidine-3,5-dione (X-25) Synthesis
Synthesis of reference Compound (X-23) by substitution of N-ethylpiperazine for N-ethylpiperazine1-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)
The synthetic route is as follows:
step 1.4 Synthesis of benzyl-2- (4- (methylsulfonyl) piperazin-1-yl) butyl) -1,2,4-thiadiazolidine-3,5-dione (X-26)
Referring to the synthesis method of the compound (X-23), N-ethylpiperazine was replaced with 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 1.4 Synthesis of benzyl-2- (4- (4-phenylpiperazin-1-yl) butyl) -1,2,4-thiadiazolidine-3,5-dione (X-28)
Referring to the synthesis method of the compound (X-23), N-ethylpiperazine was replaced by N-phenylpiperazine, yield 48%, 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:
step 1.2 Synthesis of 4- (4- (benzo [ d ] [1,3] dioxin-5-ylmethyl) piperazin-1-yl) butyl) -4-benzyl-1,2,4-thiadiazolidine-3,5-dione (X-28)
Referring to the synthesis method of the compound (X-23), N-ethylpiperazine was changed to 1-piperonylpiperazine. Yield was 69% as a 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)
A synthesis method of reference compound (X-23) wherein N-ethylpiperazine is changed to 1- (2-pyridyl) piperazine. Yield was 55% as a 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-morpholinylbutyl) -1,2,4-thiadiazolidine-3,5-dione (X-30)
The synthetic route is as follows:
step 1.4-benzyl-2- (4-morpholinebutyl) -1,2,4-thiadiazolidine-3,5-dione (X-30) Synthesis
A synthesis method of reference compound (X-23) wherein N-ethylpiperazine is changed to morpholine. Yield was 58% as a 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 1.4 Synthesis of benzyl-2- (4- (4-methylpiperazin-1-yl) butyl) -1,2,4-thiadiazolidine-3,5-dione (X-31) hydrochloride
A synthesis method of reference compound (X-23) wherein N-ethylpiperazine is changed to N-methylpiperazine. Yield was 73% as a 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 1.4-benzyl-2- (4- (4-nitrophenoxy) butyl) -1,2,4-thiadiazolidine-3,5-dione (X-32) synthesis
Compound X-22 (343mg, 1.0 eq), p-nitrophenol (139mg, 1.0 eq) was dissolved in acetonitrile (5-10 mL), followed by addition of potassium carbonate (276mg, 2.0 eq), reaction at 80 ℃ for 3 hours, and the reaction was monitored by TLC. After the reaction, the product was spin-dried, extracted with ethyl acetate 3 times, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash silica gel column to give compound X-32 with a yield of 46%. 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 round bottom flask containing 2,6-dihydroxybenzoic acid (8.00g, 51.9mmol, 1.0eq) and 4-dimethylaminopyridine (0.317g, 2.56mmol, 0.05eq) was added 35mL of dimethyl ether. The reaction was cooled to 0 ℃ before acetone (4.88ml, 66.4mmol, 1.28eq) was added, and thionyl chloride (4.84 ml, 66.44mmol, 1.28eq) was then 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 25mL of saturated sodium bicarbonate solution, and 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 was used: the solid was purified with hexane to afford intermediate 6a in 89% yield. MS (ESI) m/z 195.3[ 2 ] 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 addition of potassium carbonate (2.0 eq) and reaction at 80 ℃ for 3-4 hours, and the reaction was monitored by TLC. After the reaction is finished, spin-drying the product, extracting the product for 3 times by using ethyl acetate, combining organic layers, drying the organic layers by using anhydrous sodium sulfate, concentrating the dried organic layers under reduced pressure, and purifying the dried organic layers by using a quick silica gel column to obtain a product X-33 with the yield of 78%. 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-dioxy-1,2,4-thiadiazolidin-2-yl) butoxy) -6-hydroxybenzoic acid (X-34)
The synthetic route is as follows:
step 1.2- (4- (4-benzyl-3,5-dioxy-1,2,4-thiadiazolidin-2-yl) butoxy) -6-hydroxybenzoic acid Synthesis (X-34)
The compound X-33 was reacted with a deprotected compound in a mixed solution of trifluoroacetic acid (10 ml/mmol) and water (2.5 ml/mmol) at room temperature overnight. After the completion of the reaction was monitored by TLC, concentration under reduced pressure and flash silica gel column purification (PE: EA = 3:1) gave compound X-34 as a white solid with a yield of 90%. 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 4- (4-benzyl-3,5-dioxy-1,2,4-thiadiazolidin-2-yl) butyl) piperazine-1-carboxylic acid tert-butyl ester (8 a)
Compound X-22 (343mg, 1.0eq), piperazine-1-carboxylic acid tert-butyl ester (195 mg)1.05 eq) was dissolved in a closed glass tube containing acetonitrile (5 mL), followed by addition of potassium carbonate (329mg, 2.5eq) and reaction at 80 ℃ for 3-4 hours, with TLC monitoring of the reaction. After the reaction, 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 flash silica gel column to obtain intermediate 8a as a yellow oily liquid with a yield of 52%. MS (ESI) m/z 449.8[ 2 ], [ M + H ]] + .
Step 2.4-benzyl-2- (4- (piperazin-1-yl) butyl) -1,2,4-thiadiazolidine-3,5-dione (X-35) Synthesis
The 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 was monitored by TLC, concentration under reduced pressure and purification by flash silica gel column 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-dioxy-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-dioxy-1,2,4-thiadiazolidin-2-yl) butyl) -L-alanine ester (9 a)
Compound X-22 (343mg, 1eq), L-alanine tert-butyl ester hydrochloride (191mg, 1.05eq) was dissolved in a closed glass tube containing acetonitrile (5 mL), followed by addition of anhydrous potassium carbonate (345mg, 2.5eq) and reaction at 80 ℃ for 3 to 4 hours, and the reaction was monitored by TLC. After the reaction, 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 flash silica gel column (PE: EA = 1:4) to obtain intermediate 9a as a yellow oily liquid,the yield was 73%. MS (ESI) m/z 408.4[ 2 ] M + H] + .
The intermediate 9a 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 completion of the reaction was monitored by TLC, it was concentrated under reduced pressure and purified by flash silica gel column 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-dioxy-1,2,4-thiadiazolidin-2-yl) butyl) -L-proline (X-37)
The synthetic route is as follows:
step 1 Synthesis of t-butyl (4- (4-benzyl-3,5-dioxy-1,2,4-thiadiazolidin-2-yl) butyl) -L-proline (10 a)
Compound X-22 (343mg, 1eq), L-proline tert-butyl ester (180mg, 1.05eq) was dissolved in a closed glass tube containing acetonitrile (5 mL), followed by addition of anhydrous potassium carbonate (345mg, 2.5eq), reaction at 80 ℃ for 3 to 4 hours, and the reaction was monitored by TLC. After the reaction, 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 flash silica gel column to give compound 10a as a yellow oily liquid with a yield of 56%. MS (ESI) m/z 434.5[ 2 ] M + H] + .
Intermediate 10a was dissolved in a mixture of trifluoroacetic acid (10 ml/mmol) and dichloromethane (10 ml/mmol)The tert-butyl ester was removed from the solution for 4 hours. After completion of the reaction monitored by TLC, concentration under reduced pressure and purification by flash silica gel column gave 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 1.4 Synthesis of benzyl-2- (4- (4- (cyclopropylcarbonyl) piperazin-1-yl) butyl) -1,2,4-thiadiazolidine-3,5-dione hydrochloride (X-38)
Referring to the synthesis of compound X-23, N-ethylpiperazine was replaced with 1-cyclopropylformylpiperazine to give 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-dioxy-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-dioxy-1,2,4-thiadiazolidin-2-yl) butyl) -N-methylglycinate (11 a)
Compound X-22 (343mg, 1.0eq), tert-butyl glycinate (138mg, 1.05eq) was dissolved in a closed glass tube containing acetonitrile (5 mL), and then anhydrous potassium carbonate (345mg, 2.5eq) was added to conduct a reaction at 80 ℃ for 3 to 4 hours, and the reaction was monitored by TLC. After the reaction, 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 obtain intermediate 11a, which was 78% in yield as a yellow oily liquid and a pale yellow oily liquid. MS (ESI) m/z 408.4[ 2 ] M + H] + .
Synthesis of step 2.N- (4-benzyl-3,5-dioxy-1,2,4-thiadiazolidin-2-yl) butyl) -N-methylglycine (X-39)
The intermediate 11a was removed tert-butyl ester in a mixed solution of trifluoroacetic acid (10 ml/mmol) and dichloromethane (10 ml/mmol) for 4 hours. After the completion of the reaction was monitored by TLC, concentration under reduced pressure and purification by flash silica gel column gave compound (X-39) as a white solid with a yield of 90%. 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-dioxy-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-dioxy-1,2,4-thiadiazolidin-2-yl) ethyl) -L-phenylalanine ester (12 a)
Reference example 40 intermediate11a, the tert-butyl glycinate is changed into L-phenylalanine tert-butyl ester hydrochloride. Intermediate 12a was an oily liquid in 70% yield. MS (ESI) m/z 484.5[ 2 ] M + H] + .
Reference example 40 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-dioxy-1,2,4-thiadiazolidin-2-yl) butyl) -1,4-diazane-1-carboxylate (13 a)
Compound X-22 (343mg, 1.0eq), 1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester (210mg, 1.05eq) was dissolved in a closed glass tube containing acetonitrile (5 mL), followed by addition of potassium carbonate (345mg, 2.5eq), reaction at 80 ℃ for 3 to 4 hours, and the reaction was monitored by TLC. After the reaction, 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 flash silica gel column to give intermediate 13a as a yellow oily liquid with a yield of 51%. MS (ESI) m/z 463.5[ 2 ] M + H] + .
Step 2.2 Synthesis of 2- (4- (1,4-diaza-1-yl) butyl) -4-benzyl-1,2,4-thiadiazolidine-3,5-dione (X-41)
The intermediate 13a was dissolved in a mixed solution of trifluoroacetic acid (10 ml/mmol) and dichloromethane (10 ml/mmol)The tert-butyl ester is removed for 3-4 hours. After completion of the reaction monitored by TLC, concentration under reduced pressure and purification on flash silica gel column gave 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 for inhibiting PTPN2 by using an established in-vitro phosphatase activity detection method, and calculating IC 50 The value is obtained. The enzyme activity buffer of the reaction system was 50mM Tris-Cl, pH 7.2, 10mM NaCl,10% glycerol,0.1% Bovine Serum Albumin (BSA), and the reaction was carried out in a 96-well plate, and the total reaction system was 100. Mu.L, which was 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) and 2 mu L of compound (dissolved in DMSO) into each well of an experimental group, oscillating for 30s for mixing, incubating for 15min at 37 ℃, then adding 50 mu L of 50nM PNPP, oscillating for 30s for mixing, incubating for 5min at 37 ℃, then adding 100 mu L of 1M sodium hydroxide, measuring absorbance at 405nM by using a microplate reader, and fitting a dose-effect curve by using log (inhibitor) vs. response-Variable slope of GraphPad Prism of analysis software, thereby obtaining IC (integrated circuit) of each compound on enzyme activity 50 The value is obtained.
The resulting IC 50 The values are shown in table 1, and it can be seen that the synthesized example compounds all have better inhibitory activity on PTPN 2.
TABLE 1 IC of the compounds of the examples on the inhibitory activity of PTPN2 phosphatase 50 Measured value
As can be seen from the table, the compounds of the present invention showed very good inhibitory activity against PTPN2, with compound 18 having the strongest inhibitory activity against PTPN2, which was further evaluated for in vivo activity.
(2) Acute toxicity assay for compounds
The test animals were: ICR mice (provided by shanghai slek experimental animals, llc); 18-22g; a female; the number of the devices is 20.
And (3) testing a sample: example X-18
Group dose setting: four groups in total are set, and a control group is set; 1000mg/kg group; 2500mg/kg group: 5000mg/kg group: the gastric lavage drug is administrated 1 time per group in the administration group, 5 mice in each group with the same amount of menstruum are administrated in the control group, and the observation lasts for 14 days;
the experimental results are as follows: as shown in FIG. 1, no abnormality was observed in the animals within 12 hours after the administration of the drugs to the mice of each group. No animal death was observed within 24 hours of administration, and no animal death was observed after 14 days of administration. No other obvious abnormalities were observed. There was no significant difference between the body weight of the mice in the 3 administration groups and the control group. There was no significant difference between the weights of heart, liver, spleen, lung and kidney of the 3 mice of the administration group and the control group. Therefore, the tested drug is administrated by gavage at 1000mg/kg,2500mg/kg and 5000mg/kg without toxic reaction, and the safety of the example X-19 is good.
(3) Determination of Compound Activity against Acute Myeloid Leukemia (AML)
And (3) testing a sample: implementation of X-18
The experimental method comprises the following steps: M-NSG mouse tail vein injection MOLM13-Luciferase (5X 10) 5 ) And (3) tumor cells, and establishing a MOLM13-Luciferase transplanted tumor model. On day 2 post-inoculation, animals were randomized by Flux values into 2 groups of tumor-bearing mice: control group, compound group (10 mg/kg), 5 pieces per group. Intraperitoneal injection administration is carried out on the 3 rd day after inoculation, and is carried out once a day for 10 days continuously. The body weight of the mice, the change in tumor fluorescence and the death of the mice were recorded daily.
The experimental results show that: the mice lost weight significantly on day 9 and died on day 10 in both the control and dosing groups. We measured the fluorescence intensity of mice using animal imaging on day 2 and day 9, as shown in fig. 2, and at day 9, the fluorescence intensity in mice of the administered group was significantly lower than that of the blank group. Therefore, in example X-18, the growth of MOLM13-Luciferase transplanted tumor, which is a human acute myeloid leukemia cell, is significantly inhibited.
Claims (10)
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein the content of the first and second substances,
m =1 to 4; y is O or S;
R 1 selected from halogen,
Wherein:
l is a covalent bond (i.e., absent) or O;
r is C 6 ～C 10 Aryl of (a), a 4-to 7-membered heteroaromatic ring having 1-3 heteroatoms selected from N, O, or a 4-to 7-membered heterocyclic ring having 1-3 heteroatoms selected from N, O;
R a 、R b each independently selected from hydrogen, hydroxyl, aldehyde group, carbonyl, carboxyl, nitro, cyano and C 1 ～C 6 Alkyl radical, C 1 ～C 6 Carboxyalkyl, C 1 ～C 6 Alkylcarbonyl group, C 1 ～C 6 Alkylsulfonyl radical, C 3 ～C 8 Cycloalkyl carbonyl group, C 6 ～C 10 Aryl of (a), a 4-to 7-membered heteroaromatic ring having 1-3 heteroatoms selected from N, O, a C substituted with a 4-to 7-membered heterocyclic ring having 1-3 heteroatoms selected from N, O 1 ～C 6 An alkyl group;
or R a 、R b Together with the atoms to which they are attached form an optionally substituted 4-7 membered monocyclic heterocyclyl, the heteroatom is selected from O or N; the substituent is selected from hydrogen, hydroxyl, aldehyde group, carboxyl, carbonyl, nitro, cyano or C 1 ～C 6 An alkyl group;
R c 、R d each independently selected from hydrogen, hydroxyl, aldehyde group, carbonyl, carboxyl, nitro, cyano, and optionally substituted C 1 ～C 6 Alkyl or optionally substituted C 6 ～C 10 Aryl of (a); the substituent is selected from hydrogen, hydroxyl, aldehyde group, carboxyl, carbonyl, nitro, cyano and C 6 ～C 10 Or a 4-to 7-membered heteroaromatic ring having 1-3 heteroatoms selected from N, O.
2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: y is O.
3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein:
r is C 6 ～C 10 Or a 5-to 7-membered heterocyclic ring having 1 to 3 heteroatoms selected from N and O;
R a 、R b each independently selected from hydrogen, hydroxyl, aldehyde group, carbonyl, carboxyl, nitro, cyano and C 1 ～C 4 Alkyl radical, C 1 ～C 4 Carboxyalkyl, C 1 ～C 4 Alkylcarbonyl group, C 1 ～C 4 Alkylsulfonyl radical, C 3 ～C 8 Cycloalkyl carbonyl group, C 6 ～C 10 Aryl of (2), a 4-to 7-membered heteroaromatic ring having 1 to 3 heteroatoms selected from N and O, C substituted with a 4-to 7-membered heterocyclic ring having 1 to 3 heteroatoms selected from N and O 1 ～C 3 An alkyl group;
or R a 、R b Together with the atoms to which they are attached form an optionally substituted 4-to 7-membered monocyclic heterocyclyl, the heteroatom being selected from O or N; the substituent is selected from hydrogen, hydroxyl, aldehyde group, carboxyl, carbonyl, nitro, cyano or C 1 ～C 3 An alkyl group;
preferably, the first and second liquid crystal materials are,
r is
R a 、R b Each independently selected from hydrogen, hydroxyl, aldehyde group, carbonyl, carboxyl, nitro, cyano and C 1 ～C 4 Alkyl radical, C 1 ～C 4 Carboxyalkyl, C 1 ～C 4 Alkylcarbonyl group, C 1 ～C 4 Alkylsulfonyl radical, C 3 ～C 8 Cycloalkyl carbonyl group, C 6 ～C 10 Aryl of (2), a 4-to 7-membered heteroaromatic ring having 1 to 3 heteroatoms selected from N and O, C substituted with a 4-to 7-membered heterocyclic ring having 1 to 3 heteroatoms selected from N and O 1 ～C 3 An alkyl group;
or R a 、R b Together with the atoms to which they are attached form an optionally substituted 4-to 7-membered monocyclic heterocyclyl, the heteroatom being selected from O or N; the substituent is selected from hydrogen, hydroxyl, aldehyde group, carboxyl, carbonyl, nitro, cyano or C 1 ～C 3 An alkyl group;
more preferably, when R is other than
When R is a Is hydrogen.
4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: r c 、R d Each independently selected from hydrogen, hydroxyl, aldehyde group, carbonyl, carboxyl, nitro, cyano or C which is optionally substituted 1 ～C 4 An alkyl group; the substituent is selected from hydrogen, hydroxyl, aldehyde group, carboxyl, carbonyl, nitro, cyano or C 6 ～C 10 Aryl of (a); preferably, R c 、R d Each independently selected from hydrogen or optionally substituted C 1 ～C 3 An alkyl group; the substituent is selected from hydrogen, hydroxyl, aldehyde group, carboxyl, carbonyl, nitro, cyano or benzene ring.
5. The 1,2,4-thiadiazolidine-3,5-dione derivative of claim 1, wherein:
when m =1, R 1 Is selected from phenyl;
when m =2, R 1 Selected from-Br, -NHR 2 、-NR 3 R 4 6-7 membered azacycloalkyl, alkylphenyloxy, wherein 6-7 membered heterocycloalkyl is
The alkylphenoxy group is-O-Ph-R 7 ；
Wherein R is 2 Is 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 Is selected from-CH 2 -C(O)OH、-CH 2 CH 3 、-CH(CH 3 ) 2 、-C(O)CH 3 、
R 6 Is selected from-CH 2 -C(O)OH，
-O-Ph-R 7 Is selected from
When m =4, R 1 Selected from-Br, -NHR 8 、-NR 9 R 10 6-7 membered azacycloalkyl, alkylphenyloxy, wherein 6-7 membered heterocycloalkyl is
-O-Ph-R 12 ；
Wherein R is 8 Is 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 Is selected from-CH 3 、-CH 2 CH 3 、-CH(CH 3 ) 2 、-C(O)CH 3 、
-O-Ph-R 12 Is selected from
6. A compound selected from the following structures:
7. a process for the preparation of a compound of formula (I):
wherein Y, m, R 1 Is as defined in claim 1.
8. A pharmaceutical composition comprising a compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
9. Use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a PTPN2 mediated disease.
10. Use according to claim 9, wherein the PTPN2 mediated disease is selected from cancer, inflammation, infection, immunological disease, organ transplantation, viral disease, diabetes, cardiovascular disease or metabolic disease.
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