WO2018192535A1 - 噻唑衍生物在治疗非淋巴细胞性白血病中的应用 - Google Patents

噻唑衍生物在治疗非淋巴细胞性白血病中的应用 Download PDF

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WO2018192535A1
WO2018192535A1 PCT/CN2018/083596 CN2018083596W WO2018192535A1 WO 2018192535 A1 WO2018192535 A1 WO 2018192535A1 CN 2018083596 W CN2018083596 W CN 2018083596W WO 2018192535 A1 WO2018192535 A1 WO 2018192535A1
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nmr
alkyl
compound
optionally substituted
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李洪林
陈卓
赵振江
齐甜甜
杨婷媛
宋文琳
韩乐
孙德恒
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East China University of Science and Technology
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention relates to the field of medicinal chemistry; in particular, the present invention relates to a medicament for the preparation of a thiazole derivative for the treatment of leukemia and for the treatment of non-lymphocytic leukemia.
  • Acute leukemia is a malignant disease of abnormal hematopoietic stem cells, mainly due to its ability to lose further differentiation and maturation.
  • Acute myeloid leukemia (AML) is a manifestation of malignant proliferation of bone marrow hematopoietic stem cells. This abnormal stem cell ceases to function properly and continues to interfere with other normal hematopoietic systems, leading to infection, bleeding, and various tissue dysfunctions. If left untreated, the patient usually develops fatal injuries within a few weeks after diagnosis.
  • Acute myeloid leukemia is the second most common hematological malignancy and affects the elderly. The most important challenge is to improve the survival rate of patients over 65 years of age. Patients in this age group have higher morbidity and medicinal resistance than other patients.
  • Methods for treating AML include standard treatment, monoclonal antibody therapy, blockade signaling therapy, and epigenetic molecular mechanisms for treatment.
  • the traditional treatment method is based on the combination of anthracyclines and glucosinolates.
  • the common rule of use is (3+7) mode: daunorubicin is administered at a dose of 45 mg/m2 for 3 days, plus arabinose.
  • the sporoside was continuously injected for 7 days at a dose of 100-200 mg/m2. This method is used for young patients with a recovery rate of 60-70%, and the recovery rate for elderly patients is about 40%.
  • the object of the present invention is to provide a series of thiazole derivatives having excellent leukemia therapeutic activity, thereby laying a new material foundation for the development of drugs for treating non-lymphocytic leukemia.
  • the present invention provides the use of a compound of formula I for the manufacture of a medicament for the treatment of leukemia,
  • R a is selected from the group consisting of hydrogen, C 1 -C 3 alkyl,
  • R b is selected from the group consisting of: H, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, C 1 -C 3 alkylcarbonyl, optionally substituted benzoyl, carboxyl, aminocarbonyl, C 1 -C 6 alkoxycarbonyl, hydroxy, C 1 -C 6 alkoxy, optionally substituted C 6 -C 10 aryl or heteroaryl, amino, NR 6 R 7 ;
  • R 6 and R 7 are each independently selected from: H, or an optionally substituted carbonyl C 1 -C 3 alkyl group (preferably a C 1 -C 3 alkyl group or a C 3 -C 6 cycloalkyl substituted carbonyl group; most preferably a ring) Propyl substituted carbonyl);
  • R 2 is selected from the group consisting of: H, C 1 -C 10 alkyl or C 1 -C 10 haloalkyl, C 1 -C 10 alkoxy or C 1 -C 10 haloalkoxy, or hydroxy C 1 -C 6 alkyl Or a hydroxy C 1 -C 6 haloalkyl group;
  • R c is selected from: Ar or
  • R 3 is selected from the group consisting of: H, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, C 1 -C 6 alkoxycarbonyl, optionally substituted phenyl, C 1 -C 4 alkylcarbonyl, any a substituted benzoyl group, a C 1 -C 3 alkylcarboxy group, an amide group, an optionally substituted benzoyl group;
  • Ar is selected from the group consisting of: an optionally substituted C 6 -C 14 aryl group, an optionally substituted C 6 -C 14 heterocyclic group, an optionally substituted C 6 -C 14 arylcarbonyl group, an optionally substituted C 6 -C a 14 heterocyclylcarbonyl group, an optionally substituted C 6 -C 14 aryloxyalkylcarbonyl group;
  • R 1 is selected from the group consisting of: H, halogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;
  • R 5 is selected from the group consisting of: H, halogen, OH, NR 8 R 9 , C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy;
  • R 8 and R 9 are each independently selected from: H, or C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl;
  • R is selected from the group consisting of: aldehyde group CHO, carboxyl group COOH, C 1 -C 6 alkoxycarbonyl group;
  • A is selected from the group consisting of C 1 -C 6 alkyl groups (preferably C 1 -C 3 alkyl groups).
  • the leukemia includes, but is not limited to, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML, formerly known as acute non-lymphocytic leukemia), chronic myeloid leukemia, chronic lymphocytic leukemia; Acute myeloid leukemia is preferred.
  • ALL acute lymphocytic leukemia
  • AML acute myeloid leukemia
  • chronic myeloid leukemia chronic lymphocytic leukemia
  • chronic lymphocytic leukemia chronic lymphocytic leukemia
  • Acute myeloid leukemia is preferred.
  • the compound of Formula I has the structure of Formula Ia:
  • R 3 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl, optionally substituted phenyl, C 1 -C 4 alkylcarbonyl, optionally substituted benzoyl, C 1 - a C 3 alkylcarboxy group, an amide group, an optionally substituted benzoic acid group;
  • Ar, R b are as described above.
  • Ar has 0-5 substituents selected from the group consisting of: C 1 -C 10 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 4 alkoxy, optionally substituted phenyl, optionally substituted phenoxy, benzyloxy, CF 3, halogen.
  • R b is selected from the group consisting of: C 1 -C 6 alkyl, CF 3 , phenyl, acetyl, benzoyl, carboxyl, carbamoyl, C 1 -C 6 alkoxycarbonyl, amino More preferred are methyl, CF 3 or phenyl.
  • R 3 is selected from the group consisting of: C 1 -C 6 alkyl, phenyl, C 1 -C 3 alkylcarbonyl, optionally substituted benzoyl, carboxy, C 1 -C 6 alkoxy A carbonyl group, an amide group, an optionally substituted benzocarbamoyl group; preferably a C 1 -C 3 alkylcarbonyl group, a C 1 -C 3 alkoxycarbonyl group.
  • the compound of formula I is selected from the group consisting of compounds 1-100.
  • the compound of Formula I has the structure of Formula Ib:
  • R 4 is selected from the group consisting of: H, halogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy;
  • R, R 1 , R 2 , R 3 , R 5 are as described above.
  • the compound of Formula I has the structure of Formula Ic:
  • R 1 is selected from H, F, Cl, Br, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl;
  • R 2 is selected from H, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy, or hydroxy C 1 -C 3 alkyl or a hydroxy C 1 -C 3 haloalkyl group;
  • R 3 is from H, C 1 -C 3 alkyl or C 1-3 haloalkyl
  • R 4 is selected from H, F, Cl, Br, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy or C 1 -C 3 haloalkoxy;
  • R 5 is selected from the group consisting of H, F, Cl, Br, OH, NH 2 , OCH 3 .
  • R 1 is selected from the group consisting of H, C 1 -C 3 alkyl
  • R 2 is selected from C 1 -C 3 alkyl
  • R 3 is selected from H, C 1 -C 3 alkyl
  • R 4 is selected from H or Cl
  • R 5 is selected from H.
  • the compound of Formula I is selected from the group consisting of:
  • the compound of Formula I is selected from the group consisting of:
  • the invention provides a method of treating non-lymphocytic leukemia comprising administering a therapeutically effective amount of a compound of the first aspect of the invention to a patient in need of treatment for leukemia.
  • the leukemia includes, but is not limited to, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia, chronic lymphocytic leukemia, and the like; preferably non-lymphocytic leukemia, including However, it is not limited to: acute myeloid leukemia, chronic myeloid leukemia; more preferably acute myeloid leukemia.
  • ALL acute lymphocytic leukemia
  • AML acute myeloid leukemia
  • chronic myeloid leukemia chronic lymphocytic leukemia
  • chronic lymphocytic leukemia preferably non-lymphocytic leukemia
  • Leukemia as used herein has the meaning commonly understood by those skilled in the art, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML, formerly known as acute non-lymphocytic leukemia), chronic myeloid leukemia, chronic lymphoid. Cellular leukemia, etc.
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • chronic myeloid leukemia chronic lymphoid.
  • Cellular leukemia etc.
  • leukemia can also be classified into three types: granulocyte, lymphocyte and monocyte.
  • the leukemia described herein is a non-lymphocytic leukemia, ie, leukemia other than lymphocytic leukemia is excluded.
  • the non-lymphocytic leukemia described herein refers to acute myeloid leukemia, chronic myeloid leukemia; more preferably acute myeloid leukemia.
  • alkyl refers to a saturated branched or straight-chain alkyl group having a carbon chain length of from 1 to 10 carbon atoms, and preferred alkyl groups include from 2 to 8 carbon atoms, from 1 to 6, and from 1 to An alkyl group having 4 carbon atoms and 1-3 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, heptyl, and the like.
  • the alkyl group may be substituted by one or more substituents, for example by halogen or haloalkyl.
  • the alkyl group may be an alkyl group substituted with 1 to 4 fluorine atoms, or the alkyl group may be an alkyl group substituted with a fluoroalkyl group.
  • alkoxy refers to an oxy group substituted with an alkyl group.
  • Preferred alkoxy groups are alkoxy groups having from 1 to 6 carbon atoms, more preferably alkoxy groups having from 1 to 4 carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and the like.
  • the alkoxy group can be a substituted alkoxy group, for example, a halogen substituted alkoxy group. In a specific embodiment, a halogen-substituted C1-C3 alkoxy group is preferred.
  • halogen refers to fluoro, chloro, bromo and iodo.
  • the halogen is chlorine or fluorine; more preferably chlorine.
  • amino refers to a group of the formula "NR x R y ", wherein R x and R y may be independently selected from H or C 1 -C 3 alkyl or C 1 -C 3 haloalkyl. In specific embodiments herein described in the “amino” refers to NH 2.
  • carbonyl refers to a group represented by RC(O)-, wherein R may be lower alkyl or lower alkoxy, such as C 1 -C 6 or C 1 -C 3 alkyl or C 1 -C 6 or C 1 -C 3 alkoxy; it is also known to those skilled in the art that when R in the carbonyl group represented by RC(O)- is an alkoxy group, the group represented by RC(O)- is an ester group. For example, when R is an ethoxy group, RC(O)- is an ethyl ester group.
  • the present inventors have found that a series of thiazole derivatives have excellent activity in inhibiting non-lymphocytic leukemia cell lines, and these thiazole derivatives have even better inhibitory effects on non-lymphocytic leukemia cell lines than positive control drugs, thereby treating non-lymphatic drugs.
  • the development of drugs for cellular leukemia has laid a new material foundation.
  • LiOH.H 2 O (1.25 g, 29.7 mmol) was weighed and dissolved in 50 mL of water, and the ester (2.5 g, 13.5 mmol) synthesized in one step was added under stirring, and the temperature was raised to 90 ° C. The solid gradually dissolved as the reaction proceeded. After 1 h, the reaction was stopped, the pH of the reaction solution was adjusted to neutral neutral acidity with dilute hydrochloric acid, a large amount of solid was precipitated, suction filtration, and the filter cake was washed with water and dried to give a pale yellow solid (2.05 g, yield 96.6%).
  • Post-treatment method 1 Add saturated ammonium chloride solution to the reaction solution, the solution gradually becomes turbid and a large amount of solid appears. Add saturated ammonium chloride solution until no more solids appear. Filter the reaction solution. The filter cake is first saturated with chlorination. The ammonium aqueous solution is washed, washed with a saturated aqueous solution of sodium hydrogencarbonate, and the cake is dried to give the object compound 1-9, 12.
  • Post-treatment method 2 Saturate ammonium chloride solution is added dropwise to the reaction solution, and the solution gradually becomes turbid and a large amount of solid appears. The saturated ammonium chloride solution is added dropwise until solids no longer appear. The reaction solution is filtered, and the filter cake is first saturated with chlorination. The ammonium aqueous solution was washed with a saturated aqueous solution of sodium hydrogencarbonate, and the cake was dried.
  • Post-treatment method 3 a large amount of the solvent of the reaction liquid is removed under reduced pressure, and the mixture is extracted with ethyl acetate / saturated ammonium chloride. The obtained organic phase is dried over anhydrous sodium sulfate and then evaporated. Purification by silica gel column chromatography gave Compound 11.
  • LiOH.H 2 O (1.25 g, 29.7 mmol) was weighed and dissolved in 50 mL of water, and the ester (2.5 g, 13.5 mmol) synthesized in one step was added under stirring, and the temperature was raised to 90 ° C. The solid gradually dissolved as the reaction proceeded. After 1 h, the reaction was stopped, and the pH of the reaction solution was adjusted to neutral neutrality with dilute hydrochloric acid. A large amount of solid was precipitated, suction filtered, and the filter cake was washed with water and dried to give a pale yellow solid.
  • Synthetic Method Compound 13-18 was prepared in a similar manner to the procedure of Example 1. Among them, compounds 13-15, 18 are treated with post-treatment one, compound 16 is treated with post-treatment method 2, and compound 17 is treated with post-treatment method three.
  • the aromatic amine (8 mmol, 1 eq) was dissolved in 24 mL of acetone, and the weighed triethylenediamine (24 mmol, 3 eq) was added under stirring, and then 20 mL of carbon disulfide was added dropwise. A large amount of solid appeared, and the mixture was stirred at room temperature for 24 h.
  • the solution and the filter cake were washed with petroleum ether. After drying, the cake was dissolved in 50 mL of chloroform, and BTC (2.7 mmol, 0.33 eq) was weighed and dissolved in 30 mL of chloroform, and added dropwise to the reaction solution over 1 h, and stirred at room temperature. The solution was overnight. After completion of the reaction, the reaction mixture was filtered under suction, and the filter cake was washed with dichloromethane, and the obtained filtrate was directly applied to silica gel and dried, and then dried (PE eluted).
  • the NCS was dissolved in a small amount of methylene chloride, a large excess of ammonia water was added, and the mixture was stirred at 0 ° C for 3 hours.
  • the reaction mixture was filtered, the filter cake was washed with water, and the filter cake was dried to obtain thiourea, which was directly used for the next reaction.
  • the ⁇ -cyclodextrin (590 mg, 0.52 mmol) was dissolved in 10 mL of H 2 O, and the solution was warmed to 50 ° C until the ⁇ -cyclodextrin was completely dissolved to form a colorless transparent solution, and the corresponding acetoacetate B was added.
  • the ester was diluted with 0.5 mL of acetone and added dropwise to the ⁇ -cyclodextrin aqueous solution. After stirring, NBS (138.9 mg, 0.780 mmol) was added to the mixed solution, and after stirring for 1 h, aromatic thiourea (0.52 mmol) was added.
  • the o-carboxybenzaldehyde (66 mg, 0.44 mmol) was weighed into a 25 mL eggplant-shaped flask, and the decomposed product 1d (70 mg, 0.37 mmol) was added, 15 mL of ethanol was added, two drops of acetic acid were added as a catalyst, and the mixture was stirred at room temperature under argon atmosphere, TLC The reaction was traced until the conversion of the starting material was complete, and the mixture was filtered rapidly. The filter cake was washed with iced ethanol to give a bright yellow powdery solid 100 mg, yield 85%. Mp 196.8-197.5 ° C.
  • O-phthalaldehyde (105 mg, 0.78 mmol) was weighed into a 50 mL two-necked flask, dissolved in 15 mL of ethanol, and 1 d (75 mg, 0.39 mmol) was added to the solution. The mixture was stirred at room temperature under argon atmosphere, and a bright yellow precipitate appeared after about 10 min. TLC followed the reaction until the starting material was completely converted, suction filtered, and the filter cake was washed with ethanol and dried to give 25 mg of product.
  • Synthetic method was the same as 1c to give a milky yellow powdery solid, yield 80%.
  • the synthesis method was the same as 1d, and the yellow needle-like crystals were obtained in an amount of 1.3 g, and the yield was 48%.
  • the product of the previous step (1.0 g, 4.1 mmol) was weighed into a 50 mL two-necked flask, 20 mL of ethanol was added, and a new 80% hydrazine hydrate (0.6 mL, 12.3 mmol) was added. After heating under reflux for 24 h under argon atmosphere, the reaction was stopped. After standing overnight, suction filtration, and the obtained crude ethanol was recrystallized to obtain 200 mg of yellow needle crystals, yield 26%.
  • the synthesis method was the same as that of S1, and 100 mg of a yellowish powdery solid was obtained, yield 76%. Mp 215.9-216.0 ° C.
  • the synthesis method was the same as that of 4d, and the crude product was separated into a green needle-like solid by a thin layer of silica gel, and the yield was 46%.
  • the synthesis method was the same as that of S1 to obtain 60 mg of a pale yellow powdery solid, yield 80%. Mp 220.0-220.3 ° C.
  • 2-Chlorobenzophenone (1.0 g, 5.5 mmol) was weighed into a 50 mL single-mouth bottle, 5 mL of diethyl ether was added, 2 drops of glacial acetic acid were added dropwise with stirring, and liquid bromine (0.88 g, 5.5 mmol) of diethyl ether was added dropwise thereto under ice bath. solution was stirred at room temperature overnight, TLC the reaction was followed to complete conversion of starting material, the reaction solution was extracted 3 times with saturated NaHC03, extracted three times with saturated NaCl, dried over anhydrous NaSO 4, rotary evaporation to give 1.04g yellow liquid, yield 89%.
  • the synthesis method was the same as 1c, and the brown viscous liquid was 0.6 g, and the yield was 85%.
  • the synthesis method was the same as that of S1 to obtain a bright yellow powdery solid of 70 mg, yield 68%. Mp 223.9-223.9 ° C.
  • the synthesis method was the same as that of S1, and a yellowish powdery solid of 75 mg was obtained in a yield of 70%. Mp 211.6-212.8 ° C.
  • the synthesis method was the same as that of S1 to obtain a bright yellow powdery solid of 75 mg, yield 70%. Mp 221.6-222.5 ° C.
  • reaction solution was cooled to room temperature, filtered, and the filtrate was added to 200 mL of water, extracted with ethyl acetate three times, and the organic layer was washed three times with saturated aqueous NaCl solution and dried over anhydrous NaSO 4 The solvent was evaporated to give a brown brown oil.
  • the synthesis method was the same as that of 8d, and 190 mg of a brown needle-like solid was obtained, and the yield was 76%.
  • the synthesis method was the same as that of S8, yielding a yellow powdery solid 130 mg, yield 93%. Mp185.6-187.0 °C.
  • the synthesis method was the same as that of 8d to obtain 120 mg of a yellow powdery solid, yield 50%.
  • the synthesis method was the same as that of S8 to obtain 93 mg of a yellowish powdery solid, yield 46%. Mp 187.9-188.9 ° C.
  • the synthesis method was the same as that of 8d, and a brown solid 100 mg was obtained in a yield of 75%.
  • the synthesis method was the same as that of S8 to obtain 60 mg of a yellow powdery solid, yield 76%. Mp 203.3-204.1 ° C.
  • the synthesis method was the same as that of 8d, and a brown viscous solid 100 mg was obtained with a yield of 62%.
  • the synthesis method was the same as that of S8, yielding a yellow powdery solid 105 mg, yield 80%. Mp 170.5-170.6 ° C.
  • the synthesis method was the same as that of 8d, and a brown viscous solid of 120 mg was obtained, and the yield was 65%.
  • the synthesis method was the same as that of 8d, and a brown viscous solid of 105 mg was obtained in a yield of 50%.
  • the synthesis method was the same as that of S8 to obtain a yellow solid, 130 mg, yield 65%. Mp 99.9-100.1 ° C.
  • the synthesis method was the same as that of S7, yielding a yellow powdery solid 78mg, yield 85%. Mp 200.6-201.8 ° C.
  • the synthesis method was the same as that of S7 to obtain a yellow powdery solid, 80 mg, yield 69%. Mp 244.7-245.4 ° C.
  • the synthesis method was the same as that of S7 to obtain 100 mg of a yellow powdery solid, yield 72%. Mp 268.4-269.5 ° C.
  • the synthesis method was the same as that of S7, yielding 78 mg of a yellow powdery solid, yield 70%. Mp 208.8-209.8 ° C.
  • the synthesis method was the same as that of S7 to obtain 0.5 g of a yellow powdery solid, yield 60%. Mp 222.7-224.9 ° C.
  • the synthesis method was the same as that of S7 to obtain 50 mg of a yellowish powdery solid, yield 56%. Mp 209.3-210.7 ° C.
  • the synthesis method was the same as 20f, yielding 0.4 g of a white powdery solid, yield 26%.
  • the synthesis method was the same as 20h, yielding a white powdery solid, 0.36g, yield 60%.
  • the synthesis method was the same as that of S7 to obtain a yellow powdery solid 120 mg, yield 76%. Mp 231.3-232.5 ° C.
  • the synthesis method was the same as that of S7 to obtain a yellow powdery solid of 0.46 g, yield 70%. Mp 243.2-245.2 ° C.
  • the synthesis method was the same as 20f, yielding a pale yellow powdery solid, 68 mg, yield 15%.
  • the synthesis method was the same as that of 8d, 1.2g of brown needle-like solid, and the yield was 61%.
  • the synthesis method was the same as that of S8 to give a bright yellow powdery solid, 35 mg, yield 57%. Mp 236.2-237.1 ° C.
  • the present inventors examined the compounds of the present invention as well as positive control drugs such as buquina, anthracyclines (daunorubicin, demethoxydaunorubicin or mitoxantrone) and cytarabine against acute myeloid cells.
  • positive control drugs such as buquina, anthracyclines (daunorubicin, demethoxydaunorubicin or mitoxantrone) and cytarabine against acute myeloid cells.
  • the half inhibitory concentration of leukemia cell lines are examples of leukemia cell lines.
  • CCK8 reagent was purchased from Beyotime; THP-1, MV4-11, RS4-11, HL60 cells were purchased from ATCC, MOLM13, MOLM14, SIG-M5, AML2, AML3, AML5, U937, MONOMAC6 was purchased from DSMZ, Germany; culture medium was purchased from Hylcone, USA; fetal bovine serum was purchased from Gibco, USA; CO 2 incubator was purchased from Thermo Company, USA, model TM3111; biosafety cabinet was purchased from Heal Force; ultrapure water was purchased.
  • a single cell suspension was prepared with a medium containing 10% fetal bovine serum, and inoculated into a 96-well culture plate at a volume of 80,000/mL per well at a volume of 100 ⁇ L per well, and then the culture plate was transferred to a CO 2 incubator.
  • the medium was cultured for 24 hours at 37 ° C, 5% CO 2 and saturated humidity.
  • the desired inhibitor concentration and dilution gradient generally starting at 10 ⁇ M
  • dilute with the medium to obtain a gradient dilution of the compound, and add to the corresponding well of the 96-well plate. Beat evenly, incubate with cells, incubate in a cell culture incubator for 72 h.
  • survival rate (%) (OD dosing - OD blank ) / (OD control - OD blank ) x 100%, fitting IC 50 and inhibition curve.
  • the compound of the present invention has an inhibitory effect on the proliferation of AML cells, and is generally superior to the positive control drug, wherein the compound S7 inhibits the proliferation of AML cells even better than the positive control drug Brequinar.

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Abstract

本发明涉及式I所示噻唑衍生物作为白血病的治疗药物的应用。式I所示噻唑衍生物对白血病，包括急性淋巴细胞白血病(ALL)、急性髓细胞白血病(AML)、慢性粒细胞白血病、慢性淋巴细胞白血病等有明显的抑制作用。

Description

噻唑衍生物在治疗非淋巴细胞性白血病中的应用 技术领域
本发明涉及药物化学领域；具体地说，本发明涉及噻唑衍生物在制备治疗白血病中的药物以及在治疗非淋巴细胞性白血病中的应用。
背景技术
急性白血病是造血干细胞异常的恶性疾病，主要是其白血病细胞失去进一步分化和成熟的能力。急性骨髓性白血病(acute myeloid leukemia,AML)是骨髓造血干细胞恶性增殖的表现。这种异常的干细胞停止了正常工作，并不断干扰其他正常的造血系统，导致感染、出血和多种组织功能紊乱。如果不进行治疗，患者一般在确诊之后的几周时间内出现致命性伤害。急性骨髓性白血病为第二大常见的血液恶性肿瘤疾病，并主要影响老年人。最重要的挑战主要是提高超过65岁患者的生存率，这个年龄段的患者比其他患者存在更高的发病率和药物化学抵抗性。
治疗AML的方法有标准治疗、单克隆抗体治疗、阻断信号传递途径治疗和表观遗传分子机制进行治疗等一系列方法。传统的治疗方法是基于蒽环类药物加上阿糖孢苷联合使用，常见的使用规则是(3+7)模式：柔红霉素以45mg/m2的剂量给药3天，加上阿糖孢苷以100-200mg/m2的剂量连续注射7天。这种方法用于年轻患者恢复率达60-70％左右，年老患者恢复率达40％左右。
治疗AML的方法仍在不断地探索当中，运用一些较新的方案，比如药物靶向作用于信号通路成为了可行性方法，尤其是针对高风险难治愈性疾病。
因此，人们需要通过不断地临床试验探索出更新更好的药物。
发明内容
本发明的目的是提供一系列具备优异的白血病治疗活性的噻唑衍生物，从而为治疗非淋巴细胞性白血病的药物的开发奠定了新的物质基础。
在第一方面，本发明提供式I所示化合物在制备治疗白血病的药物中的用途，
Figure PCTCN2018083596-appb-000001
式中，
R a选自：氢、C 1-C 3烷基、
Figure PCTCN2018083596-appb-000002
R b选自：H、C 1-C 6烷基、卤素取代的C 1-C 6烷基、C 1-C 3烷基羰基、任选取代的苯甲酰基、羧基、氨基羰基、C 1-C 6烷氧基羰基、羟基、C 1-C 6烷氧基、任选取代的C 6-C 10芳基或杂芳基、氨基、NR 6R 7；
R 6和R 7各自独立选自：H、或任选取代的羰基C 1-C 3烷基(优选C 1-C 3烷基或C 3-C 6环烷基取代的羰基；最优选环丙基取代的羰基)；
R 2选自：H、C 1-C 10烷基或C 1-C 10卤代烷基、C 1-C 10烷氧基或C 1-C 10卤代烷氧基、或羟基C 1-C 6烷基或羟基C 1-C 6卤代烷基；
R c选自：Ar或
Figure PCTCN2018083596-appb-000003
R 3选自：H、C 1-C 6烷基或C 1-C 6卤代烷基、C 1-C 6烷氧基羰基、任选取代的苯基、C 1-C 4烷基羰基、任选取代的苯甲酰基、C 1-C 3烷基羧基、酰胺基、任选取代的苯胺甲酰基；
Ar选自：任选取代的C 6-C 14芳基、任选取代的C 6-C 14杂环基、任选取代的C 6-C 14芳基羰基、任选取代的C 6-C 14杂环基羰基、任选取代的C 6-C 14芳氧基烷基羰基；
R 1选自：H、卤素、C 1-C 6烷基或C 1-C 6卤代烷基；
R 5选自：H、卤素、OH、NR 8R 9、C 1-C 6烷氧基或C 1-C 6卤代烷氧基；
R 8和R 9各自独立选自：H、或C 1-C 3烷基、或C 1-C 3卤代烷基；
R选自：醛基CHO，羧基COOH，C 1-C 6烷氧基羰基；
A选自：C 1-C 6烷基(优选C 1-C 3烷基)。
在具体的实施方式中，所述白血病包括但不限于：急性淋巴细胞白血病(ALL)、急性髓细胞白血病(AML，以往称为急性非淋巴细胞白血病)、慢性粒细胞白血病、慢性淋巴细胞白血病；优选急性髓细胞白血病。
在具体的实施方式中，式I所示化合物具有式Ia所示结构：
Figure PCTCN2018083596-appb-000004
式中，
R 3选自：C 1-C 6烷基、C 1-C 6烷氧基羰基、任选取代的苯基、C 1-C 4烷基羰基、任选取代的苯甲酰基、C 1-C 3烷基羧基、酰胺基、任选取代的苯胺甲酰基；和
Ar、R b如上文所述。
在具体的实施方式中，Ar上具有0-5个取代基，所述取代基选自：C 1-C 10烷基、C 3-C 8环烷基、C 1-C 4烷氧基、任选取代的苯基、任选取代的苯氧基、苄氧基、CF 3、卤素。
在具体的实施方式中，R b选自：C 1-C 6烷基、CF 3、苯基、乙酰基、苯甲酰基、羧基、氨基甲酰基、C 1-C 6烷氧基羰基、氨基；更优选甲基、CF 3或苯基。
在具体的实施方式中，R 3选自：C 1-C 6烷基、苯基、C 1-C 3烷基羰基、任选取代的苯甲酰基、羧基、C 1-C 6烷氧基羰基、酰胺基、任选取代的苯胺甲酰基；优选C 1-C 3烷基羰基，C 1-C 3烷氧基羰基。
在具体的实施方式中，式I所示化合物选自化合物1-100。
在具体的实施方式中，式I所示化合物具有式Ib所示结构：
Figure PCTCN2018083596-appb-000005
式中，
R 4选自：H、卤素、C 1-C 6烷基或C 1-C 6卤代烷基、或C 1-C 6烷氧基或C 1-C 6卤代烷氧基；
m＝0～3的整数；
R、R 1、R 2、R 3、R 5如上文所述。
在具体的实施方式中，式I所示化合物具有式Ic所示结构：
Figure PCTCN2018083596-appb-000006
R 1选自H、F、Cl、Br、C 1-C 3烷基或C 1-C 3卤代烷基；
R 2选自H、C 1-C 6烷基或C 1-C 6卤代烷基、C 1-C 6烷氧基或C 1-C 6卤代烷氧基、或羟基C 1-C 3烷基或羟基C 1-C 3卤代烷基；
R 3自H、C 1-C 3烷基或C 1-3卤代烷基；
R 4选自H、F、Cl、Br、C 1-C 3烷基或C 1-C 3卤代烷基、C 1-C 3烷氧基或C 1-C 3卤代烷氧基；
R 5选自H、F、Cl、Br、OH、NH 2、OCH 3。
在具体的实施方式中，
R 1选自H、C 1-C 3烷基；
R 2选自C 1-C 3烷基；
R 3选自H、C 1-C 3烷基
R 4选自H或Cl；
R 5选自H。
在具体的实施方式中，式I所示化合物选自下组化合物：
Figure PCTCN2018083596-appb-000007
Figure PCTCN2018083596-appb-000008
Figure PCTCN2018083596-appb-000009
在具体的实施方式中，式I所示化合物选自下组化合物：
Figure PCTCN2018083596-appb-000010
在第二方面，本发明提供一种非淋巴细胞性白血病的治疗方法，包括将治疗有效量的本发明第一方面所述的化合物给予需要治疗白血病的患者。
在优选的实施方式中，所述白血病包括但不限于：急性淋巴细胞白血病(ALL)、急性髓细胞白血病(AML)、慢性粒细胞白血病、慢性淋巴细胞白血病等；优选非淋巴细胞性白血病，包括但不限于：急性髓细胞性白血病、慢性粒细胞性白血病；更优选急性髓细胞性白血病。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
发明人经过广泛而深入的研究，出乎意料地发现一系列噻唑衍生物，这些噻唑衍生物具备优异的抑制非淋巴细胞性白血病细胞系的活性，从而能够用于治疗非淋巴细胞性白血病的药物的开发。在此基础上完成了本发明。
白血病
本文所述的“白血病”具有本领域技术人员通常理解的含义，包括急性淋巴细胞白血病(ALL)、急性髓细胞白血病(AML，以往称为急性非淋巴细胞白血病)、慢性粒细胞白血病、慢性淋巴细胞白血病等。
根据增生细胞的类型，白血病也可分类为粒细胞性、淋巴细胞性和单核细胞性三类。在具体的实施方式中，本文所述的白血病是非淋巴细胞性白血病，即，排除淋巴细胞性白血病以外的白血病。在优选的实施方式中，本文所述的非淋巴细胞性白血病是指急性髓细胞性白血病、慢性粒细胞性白血病；更优选急性髓细胞性白血病。
术语定义
本文中涉及的基团具有本领域技术人员常规理解的含义；为清晰起见，对其中的一些基团定义如下：
在本文中，“烷基”指碳链长度为1-10个碳原子的饱和的支链或直链烷基，优选的烷基 包括长2-8个碳原子、1-6个、1-4个碳原子、1-3个碳原子不等的烷基。烷基的例子包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、庚基等。烷基可以被1个或多个取代基取代，例如被卤素或卤代烷基取代。例如，烷基可以是被1-4个氟原子取代的烷基，或者烷基可以是被氟代烷基取代的烷基。
在本文中，“烷氧基”指被烷基取代的氧基。优选的烷氧基是长1-6个碳原子的烷氧基，更优选为长1-4个碳原子的烷氧基。烷氧基的例子包括但不限于甲氧基、乙氧基、丙氧基等。在具体的实施方式中，烷氧基可以是取代的烷氧基，例如，卤素取代的烷氧基。在具体的实施方式中，优选卤素取代的C1-C3烷氧基。
在本文中，“卤素”指氟、氯、溴和碘。在优选的实施方式中，卤素是氯或氟；更优选氯。
在本文中，“氨基”指结构式为“NR xR y”的基团，其中，R x和R y可独立选自H或C 1-C 3烷基或C 1-C 3卤代烷基。在具体的实施方式中，本文所述的“氨基”是指NH 2。
在本文中，“羰基”是指RC(O)-所示的基团，其中R可以是低级烷基或低级烷氧基，例如C 1-C 6或C 1-C 3烷基或C 1-C 6或C 1-C 3烷氧基；本领域技术人员还知晓，当RC(O)-所示羰基中的R为烷氧基时，RC(O)-所示基团为酯基；例如当R为乙氧基时，RC(O)-为乙酯基。
本发明的优点：
本发明发现了一系列噻唑衍生物具备优异的抑制非淋巴细胞性白血病细胞系的活性，这些噻唑衍生物对于非淋巴细胞性白血病细胞系的抑制作用甚至优于阳性对照药物，从而为治疗非淋巴细胞性白血病的药物的开发奠定了新的物质基础。
以下结合具体实施案例对本发明的技术方案进一步描述，但以下实施案例不构成对本发明的限制，所有依据本发明的原理和技术手段采用的各种施用方法，均属于本发明范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
合成部分
实施例1：化合物1-12的合成通法：
Figure PCTCN2018083596-appb-000011
将氯代乙酰乙酸乙酯(9.52g，57.84mmol)溶解在100mL乙醇中，搅拌条件下加入硫代乙酰胺(4.8g，63.9mmol)，升温至回流温度，搅拌回流2h，待反应结束，将反应液减压除溶剂,得桔粉色固体9.80g，收率91.1％，直接用于下一步反应。
称取LiOH.H 2O(1.25g，29.7mmol)溶解在50mL水中，搅拌条件下加上一步反应合成的酯(2.5g，13.5mmol)，升温至90℃，随着反应进行，固体逐渐溶解，1h后停止反应，用稀盐酸调节反应液pH至中性偏酸性，有大量固体析出，抽滤，滤饼用水洗后，干燥，得淡 黄色固体2.05g，收率96.6％。
Figure PCTCN2018083596-appb-000012
称取噻唑酸(1.1eq)和HATU(1.2eq)溶解于7mL DMF中，搅拌均匀后，滴加8滴DIPEA，搅拌5min后，再加入芳胺类化合物(1eq)，室温条件下搅拌过夜，TLC跟踪反应。
后处理方法一:于反应液中滴加饱和氯化铵溶液，溶液逐渐变混浊出现大量固体，滴加饱和氯化铵溶液至不再出现固体，抽滤反应液，滤饼先用饱和氯化铵水溶液洗，再用饱和碳酸氢钠水溶液洗，干燥滤饼，即得目标化合物1-9，12。
后处理方法二:于反应液中滴加饱和氯化铵溶液，溶液逐渐变混浊出现大量固体，滴加饱和氯化铵溶液至不再出现固体，抽滤反应液，滤饼先用饱和氯化铵水溶液洗，再用饱和碳酸氢钠水溶液洗，干燥滤饼，干燥后得到的粗品再用硅胶柱层析分离，得到化合物10。
后处理方法三:减压除去反应液的大量溶剂，用乙酸乙酯/饱和氯化铵对其进行萃取，收集得到的有机相用无水硫酸钠干燥后减压除溶剂，得到的固体再进一步硅胶柱层析纯化，得到化合物11。
目标化合物谱图数据
N-(4-氯苯基)-2，4-二甲基噻唑-5-甲酰胺(化合物1)
Figure PCTCN2018083596-appb-000013
1H NMR(400MHz,CDCl 3):δ10.24(s,1H),7.70(d,J＝8.8Hz,2H),7.40(d,J＝8.8Hz,2H),2.66(s,3H),2.54(s,3H). 13C NMR(100MHz,CDCl 3):δ166.52,160.16,156.11,136.05,129.88,129.04,125.16,121.77,19.34,17.24.HRMS(ESI)calcd for C 12H 11ClN 2OS[M+H] +267.0359,found 267.0355。
N-[4-(三氟甲基)苯基]-2，4-二甲基-噻唑-5-甲酰胺(化合物2)
Figure PCTCN2018083596-appb-000014
1H NMR(400MHz,CDCl 3):δ7.69(d,J＝8.4Hz,2H),7.62(d,J＝8.8Hz,2H),7.51(s,1H),2.73(s,3H),2.72(s,3H). 13C NMR(100MHz,CDCl 3):δ166.91,160.25,156.50,140.58,126.30,126.26,126.22,124.97,119.97,19.28,17.22.HRMS(ESI)calcd for C 13H 11F 3N 2OS[M-H] +299.0466,found 299.0464。
N-(3-氟-4-甲基苯基)-2，4-二甲基噻唑-5-甲酰胺(化合物3)
Figure PCTCN2018083596-appb-000015
1H NMR(400MHz,CDCl 3):δ7.46(dd,J 1＝2.0Hz,J 2＝11.2Hz,1H),7.41(s,1H),7.15(t, J＝8.0Hz,1H),7.10(dd,J 1＝2.0Hz,J 2＝8.4Hz,1H),2.72(s,6H),2.26(d,J＝1.6Hz,3H). 13C NMR(100MHz,CDCl 3):δ166.43,162.25,160.09,159.83,155.99,136.54,136.43,131.40,131.33,125.25,121.26,121.08,115.62,115.59,107.93,107.66,19.31,17.20,14.13,14.10.HRMS(ESI)calcd for:C 13H 13FN 2OS[M+H] +265.0811,found 265.0805。
N-(4-溴-2-甲基苯基)-2,4-二甲基噻唑-5-甲酰胺(化合物4)
Figure PCTCN2018083596-appb-000016
1H NMR(400MHz,CDCl 3):δ7.80(d,J＝9.2Hz,1H),7.37-7.35(m,2H),7.21(s,1H),2.73(s,3H),2.71(s,3H),2.28(s,3H). 13C NMR(100MHz,CDCl 3):δ166.56,159.90,156.01,134.5133.28,131.12,129.88,125.44,124.47,118.40,19.45,17.68,17.41.HRMS(ESI)calcd for:C 13H 13BrN 2OS[M+H] +325.0010,found 325.0009。
N-(9-乙基-9H-咔唑-3-基)-2,4-二甲基噻唑-5-甲酰胺(化合物5)
Figure PCTCN2018083596-appb-000017
1H NMR(400MHz,CDCl 3):δ8.36(s,1H),8.10(d,J＝7.6Hz,1H),7.57-7.55(m,2H),7.52-7.49(m,1H),7.44-7.39(m,2H),7.25(t,J＝7.2Hz,1H),4.41-4.36(m,2H),2.78(s,3H),2.74(s,3H),1.45(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ166.02,160.33,155.50,140.45,137.52,129.10,125.98,123.03,122.70,120.69,120.07,118.87,113.59,108.61,108.52,37.59,19.35,17.32,13.82.HRMS(ESI)calcd for:C 20H 19N 3OS[M+H] +350.1327,found 350.1332。
N-(蒽-2-基)-2,4-二甲基噻唑-5-甲酰胺(化合物6)
Figure PCTCN2018083596-appb-000018
1H NMR(400MHz,DMSO-d 6):δ8.52(s,2H),8.48(s,1H),8.08-8.04(m,3H),7.70(dd,J 1＝1.6Hz,J 2＝9.2Hz,1H),7.50-7.47(m,2H),2.68(s,3H),2.59(s,3H). 13C NMR(100MHz,DMSO-d 6):δ166.37,160.84,155.11,136.26,132.16,131.90,131.09,129.20,129.15,128.55,128.23,126.34,126.14,126.09,125.74,125.58,122.13,116.04,19.35,17.42.HRMS(ESI)calcd for:C 20H 16N 2OS[M-H] +331.0905,found 331.0907。
N-(4-溴-3-(三氟甲基)苯基)-2,4-二甲基噻唑-5-甲酰胺(化合物7)
Figure PCTCN2018083596-appb-000019
1H NMR(400MHz,CDCl 3):δ8.76(d,J＝4.4Hz,1H),8.47(d,J＝8.4Hz,1H),7.50-7.47(m,1H),2.82(s,3H),2.80(s,3H). 13C NMR(100MHz,CDCl 3):δ166.88,160.13,157.10,136.91,135.53,130.84,130.53,124.45,124.36,123.89,121.17,119.65,119.60,119.54,119.48,114.59,19.44,17.37.HRMS(ESI)calcd for:C 13H 10BrF 3N 2OS[M-H] +376.9571,found 376.9572。
N-(3,5-二氯苯基)-2,4-二甲基噻唑-5-甲酰胺(化合物8)
Figure PCTCN2018083596-appb-000020
1H NMR(400MHz,CDCl 3):δ8.77(dd,J 1＝1.2Hz,J 2＝4.4Hz,1H),8.48(dd,J 1＝1.2Hz,J 2＝8.0Hz,1H),7.51-7.48(m,1H),2.83(s,3H),2.81(s,3H)。HRMS(ESI)calcd for:C 12H 10C l2N 2OS[M-H] +298.9813，found 298.9806。
2,4-二甲基-N-(4-吗啉苯基)噻唑-5-甲酰胺(化合物9)
Figure PCTCN2018083596-appb-000021
1H NMR(400MHz CDCl 3):δ9.86(s 1H)7.50(d J＝8.4Hz 2H)6.92(d J＝8.8Hz 2H)3.73(t,J＝4.4Hz,4H),3.06(t,J＝4.4Hz,4H),2.65(s,3H),2.52(s,3H). 13C NMR(100MHz,CDCl 3):δ166.02,160.33,155.50,140.45,137.52,129.10,125.98,123.03,122.70,120.69,120.07,118.87,113.59,108.61,108.52,37.59,19.35,17.32,13.82.HRMS(ESI)calcd for:C 16H 19N 3O 2S[M+H] +318.1276,found 318.1276。
2,4-二甲基-N–(萘-2-基)噻唑-5-甲酰胺(化合物10)
Figure PCTCN2018083596-appb-000022
1H NMR(400MHz,CDCl 3):δ8.26(s,1H),7.86-7.82(m,3H),7.64(s,1H),7.57–7.42(m,3H),2.78(s,3H),2.74(s,3H). 13C NMR(100MHz,CDCl 3):δ166.39,160.06,156.08,134.86,133.79,130.90,128.95,127.73,127.62,126.70,125.35,120.01,117.24,19.44,17.34.HRMS(ESI)calcd for:C 16H 14N 2OS[M+H] +283.0905,found 283.0900。
2,4-二甲基-N-苯基噻唑-5-甲酰胺(化合物11)
Figure PCTCN2018083596-appb-000023
1H NMR(400MHz,CDCl 3):δ7.57(d,J＝7.6Hz,2H),7.43(s,1H),7.39(t,J＝7.6Hz,2H),7.18(t,J＝7.2Hz,1H),2.75(s,3H),2.74(s,3H). 13C NMR(100MHz,CDCl 3):δ166.27,160.23,155.67,137.50,129.03,125.60,124.86,120.55,19.31,17.20.HRMS(ESI)calcd for:C 12H 12N 2OS[M+H] +233.0749,found 233.0745。
N-(二苯并(b,d)噻吩-2-基)-2,4-二甲基噻唑-5-甲酰胺(化合物12)
Figure PCTCN2018083596-appb-000024
HRMS(ESI)calcd for:C 18H 14N 2OS 2[M+H] +339.0626,found 339.0620。
实施例2：化合物13-18的合成通法：
Figure PCTCN2018083596-appb-000025
将甲酰胺(1eq)溶解于20mL甲苯中，搅拌条件下加入称量好得劳森试剂(0.25eq)，升温至100℃至劳森试剂全部溶解，TLC跟踪反应，待硫代反应结束，滴加氯代乙酰乙酸乙酯(0.6eq)，继续反应，TLC跟踪，反应结束后，减压除去大量甲苯溶剂，再用乙酸乙酯萃取，有机相用饱和食盐水洗，收集得到的有机相用无水硫酸钠干燥后减压除溶剂，得到黄色粗品，用硅胶柱层析进一步纯化(PE:EA＝8:1)。
称取LiOH.H 2O(1.25g，29.7mmol)溶解在50mL水中，搅拌条件下加上一步反应合成的酯(2.5g，13.5mmol)，升温至90℃，随着反应进行，固体逐渐溶解，1h后停止反应，用稀盐酸调节反应液pH至中性偏酸性，有大量固体析出，抽滤，滤饼用水洗后，干燥，得淡黄色固体。
Figure PCTCN2018083596-appb-000026
合成方法采用实例1流程类似的方法制备得到化合物13-18。其中化合物13-15，18采用后处理方一，化合物16采用后处理方法二，化合物17采用后处理方法三。
目标化合物谱图数据
N-(4-氯苯基)-4-甲基噻唑-5-甲酰胺(化合物13)
Figure PCTCN2018083596-appb-000027
1H NMR(400MHz,CDCl 3):δ8.81(s,1H),7.55(d,J＝8.8Hz,2H),7.52(s,1H),7.36(d,J＝8.8Hz,2H),2.83(s,3H). 13C NMR(100MHz,CDCl 3):δ159.93,156.74,152.86,135.85,130.16,129.20,121.73,17.33.HRMS(ESI)calcd for:C 11H 9ClN 2OS[M+H] +253.0202,found 253.0206。
N-(9-乙基-9H-咔唑-3-基)-4-甲基噻唑-5-甲酰胺(化合物14)
Figure PCTCN2018083596-appb-000028
1H NMR(400MHz,CDCl 3):δ8.70(s,1H),8.33(s,1H),8.05-7.99(m,2H),7.56–7.47(m,2H),7.40(d,J＝8.0Hz,1H),7.31(d,J＝8.4Hz,1H),7.22(t,J＝7.2Hz,1H),4.30(q,J＝7.2Hz,2H),2.81(s,3H),1.40(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ160.21,156.02,152.55,140.46,137.60,128.93,126.04,123.04,122.66,120.69,120.04,118.92,113.65,108.65,108.57,37.61,17.33,13.83.HRMS(ESI)calcd for:C 19H 17N 3OS[M+H] +336.1171,found 336.1176。
N-(蒽-2-基)-4-甲基噻唑-5-甲酰胺(化合物15)
Figure PCTCN2018083596-appb-000029
1H NMR(400MHz,DMSO-d 6):δ9.17(s,1H),8.53(d,J＝4.4Hz,2H),8.50(s,1H),8.09-8.05(m,3H),7.72(dd,J 1＝2.0Hz,J 2＝10.0Hz,1H),7.51-7.46(m,2H),2.68(s,3H). 13C  NMR(100MHz,DMSO-d 6):δ160.52,155.32,154.47,135.77,131.66,131.39,130.61,128.73128.66,128.05,127.74,126.29,125.86,125.65,125.28,125.10,121.63,115.62,79.23,16.95.HRMS(ESI)calcd for:C 19H 14N 2OS[M-H] +317.0749,found 317.0750。
4-甲基-N-(萘-2-基)噻唑-5-甲酰胺(化合物16)
Figure PCTCN2018083596-appb-000030
1H NMR(400MHz,CDCl 3):δ8.76(s,1H),8.25(s,1H),7.84–7.81(m,4H),7.56–7.44(m,3H),2.83(s,3H). 13C NMR(100MHz,CDCl 3):δ160.04,156.57,152.73,134.73,133.74,130.98,128.99,127.75,127.63,126.74,126.26,125.45,120.05,117.46,17.36.HRMS(ESI)calcd for:C 15H 12N 2OS[M-H] +267.0592,found 267.0590。
4-甲基-N-苯基噻唑-5-甲酰胺(化合物17)
Figure PCTCN2018083596-appb-000031
1H NMR(400MHz,CDCl 3):δ8.79(s,1H),7.59(d,J＝7.6Hz,2H),7.53(s,1H),7.40(t,J＝7.6Hz,2H),7.21(t,J＝7.6Hz,1H),2.83(s,3H). 13C NMR(100MHz,CDCl 3):δ159.99,156.31,152.76,137.28,129.17,126.34,125.12,120.52,17.27.HRMS(ESI)calcd for:C 11H 10N 2OS[M-H] +217.0436,found 217.0435。
N-(二苯并(b,d)噻吩-2-基)-2-甲基噻唑-5-甲酰胺(化合物18)
Figure PCTCN2018083596-appb-000032
HRMS(ESI)calcd for:C 17H 12N 2OS 2[M+H] +325.0469,found 325.0468。
实施例3：化合物19-55的合成通法：
硫脲的合成
Figure PCTCN2018083596-appb-000033
将芳胺(8mmol，1eq)溶解于24mL丙酮中，于搅拌条件下加入称好的三乙烯二胺(24mmol，3eq)，再滴加二硫化碳20mL，出现大量固体，继续室温搅拌24h，抽滤反应液，滤饼用石油醚洗，干燥后，将滤饼溶解于50mL氯仿中，称取BTC(2.7mmol，0.33eq)溶解于30mL氯仿中，1h内滴加至反应液中，室温下搅拌该溶液过夜。反应结束后，抽滤反应液，滤饼用二氯甲烷洗，得到的滤液直接加硅胶旋干后干法上样(PE洗脱)。
将NCS溶解于少量二氯甲烷中，加大大过量的氨水，0℃下搅拌3h，抽滤反应液，滤饼用水洗，干燥滤饼，即得硫脲，直接用于下一步反应。
目标化合物的合成
Figure PCTCN2018083596-appb-000034
将β-环糊精(590mg，0.52mmol)溶于10mL H 2O中，将该溶液升温至50℃至β-环糊精全部溶解形成一个无色透明的溶液，将相对应的乙酰乙酸乙酯用0.5mL丙酮稀释后滴加至β-环糊精水溶液中，搅拌均匀后称取NBS(138.9mg，0.780mmol)加入该混合溶液，搅拌1h后，再加芳香硫脲(0.52mmol)，TLC跟踪反应，待反应进行完全，用乙酸乙酯/饱和食盐水萃取反应液，收集得到的有机相用无水硫酸钠干燥后减压除溶剂，得到的粗品用硅胶柱层析进一步纯化(PE:EA＝10:1)。
目标化合物谱图数据
2-苯胺基-4-苯基-5-噻唑甲酸乙酯(化合物19)
Figure PCTCN2018083596-appb-000035
1H NMR(400MHz,CDCl 3):δ7.74-7.72(m,2H),7.38(d,J＝3.6Hz,3H),7.38(t,J＝8.0Hz,2H),7.14(d,J＝6.8Hz,3H),4.26-4.21(m,2H),1.26(t,J＝6.8Hz,3H). 13C NMR(100MHz,CDCl 3):δ178.42,168.09,161.76,158.65,139.35,134.13,129.79,129.49,129.14,127.69,124.47,120.04,109.92,60.89,29.58,14.24.HRMS(ESI)calcd for:C 18H 16N 2O 2S[M+H] +325.1011,found 325.1009。
2-(3,4-二甲基)苯胺基-4-苯基-5-噻唑甲酸乙酯(化合物20)
Figure PCTCN2018083596-appb-000036
1H NMR(400MHz,CDCl 3):δ7.74-7.72(m,2H),7.40-7.39(m,3H),7.12(d,J＝8.4Hz,1H),7.02(dd,J 1＝2.4Hz,J 2＝8.0Hz,1H),6.97(d,J＝2.0Hz,1H),4.25-4.20(m,2H),2.27(s,6H),1.26(t,J＝6.8Hz,3H). 13C NMR(100MHz,CDCl 3):δ161.67,158.13,138.06,136.90,133.83,133.63,130.54,129.73,129.12,127.67,122.08,122.02,117.95,117.90,60.85,19.93,19.26,14.24.HRMS(ESI)calcd for:C 20H 20N 2O 2S[M+H] +353.1324,found 353.1324。
2-(3-氯-4-甲基)-苯胺基-4-苯基-5-噻唑甲酸乙酯(化合物21)
Figure PCTCN2018083596-appb-000037
1H NMR(400MHz,CDCl 3):δ7.74-7.72(m,2H),7.40-7.39(m,3H),7.23(d,J＝2.4Hz,1H),7.19(d,J＝7.6Hz,1H),7.03(dd,J 1＝2.4Hz,J 2＝8.0Hz,1H),4.24(q,J＝7.2Hz,2H),2.37(s,3H),1.27(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ167.73,161.59,158.47,138.11,134.93,133.93,132.44,131.48,129.66,129.12,127.69,120.97,118.66,110.54,60.92,19.46,14.21.HRMS(ESI)calcd for:C 19H 17ClN 2O 2S[M+H] +373.0778,found 373.0778。
2-(4-甲氧基)-苯胺基-4-苯基-5-噻唑甲酸乙酯(化合物22)
Figure PCTCN2018083596-appb-000038
1H NMR(400MHz,CDCl 3):δ8.54(s,1H),7.69(dd,J 1＝3.2Hz,J 2＝4.4Hz,2H),7.37-7.35(m,3H),7.14(d,J＝9.2Hz,2H),6.88(d,J＝8.8Hz,2H),4.20(q,J＝7.2Hz,2H),3.85(s,3H),1.24(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ170.58,161.75,159.06,157.30,134.33,132.62,129.64,128.87,127.54,123.84,114.71,109.40,60.65,55.51,14.21.HRMS(ESI)calcd for:C 19H 18N 2O 3S[M+H] +355.1116,found 355.1115。
2-(3-三氟甲基-4-溴)-苯胺基-4-苯基-5-噻唑甲酸乙酯(化合物23)
Figure PCTCN2018083596-appb-000039
1H NMR(400MHz,CDCl 3):δ7.69-7.67(m,2H),7.53(d,J＝8.8Hz,1H),7.47(d,J＝2.8Hz,1H),7.33-7.29(m,3H),7.10(dd,J1＝2.8Hz,J 2＝8.6Hz,1H),4.28-4.23(m,2H),1.28(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ166.75,161.45,158.13,138.81,135.82,133.48,129.68,129.37,127.74,123.77,119.19,119.13,113.92,111.25,61.22,14.15.HRMS(ESI)calcd for:C 19H 14BrF 3N 2O 2S[M+H] +470.9990,found 470.9986。
2-(3,4-二氯)-苯胺基-4-苯基-5-噻唑甲酸乙酯(化合物24)
Figure PCTCN2018083596-appb-000040
1H NMR(400MHz,CDCl 3):δ7.70-7.67(m,2H),7.35(dd,J 1＝2.0Hz,J 2＝5.4Hz,3H),7.26(d,J＝8.8Hz,1H),7.14(d,J＝2.4Hz,1H),6.88(dd,J 1＝2.8Hz,J 2＝8.6Hz,1H),4.27-4.22(m,2H),1.27(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ167.54,161.52,158.29,138.82,133.68,133.09,130.82,129.65,129.34,127.83,127.76,121.83,119.38,110.73,61.14,14.22.HRMS(ESI)calcd for:C 18H 14C l2N 2O 2S[M+H] +393.0231,found 393.0234。
2-(4-氯)-苯胺基-4-苯基-5-噻唑甲酸乙酯(化合物25)
Figure PCTCN2018083596-appb-000041
1H NMR(400MHz,CDCl 3):δ10.59(s,1H),7.67(d,J＝6.4Hz,2H),7.36-7.28(m,3H),7.13(d,J＝8.4Hz,2H),6.85(d,J＝8.8Hz,2H),4.25-4.20(m,2H),1.25(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ168.23,161.60,158.519,137.94,134.03,129.76,129.59,129.41,129.23,127.74,121.57,110.14,60.98,14.22.HRMS(ESI)calcd for:C 18H 15ClN 2O 2S[M+H] +359.0621,found 359.0615。
2-(2-甲基-4-溴)-苯胺基-4-苯基-5-噻唑甲酸乙酯(化合物26)
Figure PCTCN2018083596-appb-000042
1H NMR(400MHz,CDCl 3):δ7.52-7.50(m,2H),7.36(dd,J1＝2.4Hz,J 2＝8.4Hz,1H),7.29(d,J＝2.0Hz,1H),7.27-7.23(m,2H),7.15(t,J＝3.6Hz,2H),4.19-4.14(m,2H),2.08(s, 3H),1.21(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ170.40,161.54,158.93,137.12,135.76,134.12,133.79,130.28,129.26,128.90,127.39,126.33,126.29,120.14,110.18,60.80,29.73,17.45,14.19.HRMS(ESI)calcd for:C 19H 17BrN 2O 2S[M+H] +417.0272,found 417.0271。
2-蒽氨基-4-苯基-5-噻唑甲酸乙酯(化合物27)
Figure PCTCN2018083596-appb-000043
1H NMR(400MHz,CDCl 3):8.43(s,2H),8.03(d,J＝8.8Hz,3H),7.99(d,J＝2.0Hz,1H),7.83-7.81(m,2H),7.54-7.46(m,5H),7.27(d,J＝2.0Hz,1H),4.32-4.27(m,2H),1.31(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ165.74,161.57,135.64,133.72,132.47,131.68,131.33,130.35,129.81,129.39,128.98,128.27,127.88,127.82,126.44,126.00,125.45,125.32,120.37,113.57,111.20,61.11,14.27,HRMS(ESI)calcd for:C 26H 20N 2O 2S[M+H] +425.1324,found 425.1324。
2-(3-三氟甲基-4-氯)-苯胺基-4-苯基-5-噻唑甲酸乙酯(化合物28)
Figure PCTCN2018083596-appb-000044
1H NMR(400MHz,CDCl 3):δ7.70-7.67(m,2H),7.50(d,J＝2.8Hz,1H),7.38-7.32(m,4H),7.22(dd,J 1＝2.8Hz,J 2＝8.8Hz,1H),4.28-4.23(m,2H),1.27(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ166.90,161.48,158.24,138.21,133.55,132.36,129.68,129.36,127.74,126.95,123.85,120.96,119.02,118.97,111.14,61.22,14.18.HRMS(ESI)calcd for:C 19H 14ClF 3N 2O 2S[M+H] +427.0495,found 427.0493。
2-(4-三氟甲基)-苯胺基-4-苯基-5-噻唑甲酸乙酯(化合物29)
Figure PCTCN2018083596-appb-000045
1H NMR(400MHz,CDCl 3):7.78-7.75(m,2H),7.59(d,J＝8.4Hz,2H),7.43-7.41(m,3H),7.34(d,J＝8.4Hz,2H),4.30-4.25(m,2H),1.29(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ166.39,161.50,158.21,142.18,133.82,129.81,129.43,127.79,126.62,126.59,118.66,111.10,61.17,14.21.HRMS(ESI)calcd for:C 19H 15F 3N 2O 2S[M+H] +393.0885,found 393.0884。
2-((3-氟-[1,1’-联苯]-4-基)氨基)-4-苯基-5-噻唑甲酸乙酯(化合物30)
Figure PCTCN2018083596-appb-000046
1H NMR(400MHz,CDCl 3):7.98(t,J＝8.4Hz,1H),7.81-7.79(m,2H),7.61-7.59(m,2H),7.50-7.40(m,8H),4.30-4.25(m,2H),1.30(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):165.85,161.61,158.62,154.64,152.19,139.25,138.19,138.11,134.05,129.75,129.13,129.01,127.80,127.60,126.78,126.72,126.60,123.25,123.22,120.69,114.31,114.11,111.75,61.04,29.73,14.24.HRMS(ESI)calcd for:C 24H 19FN 2O 2S[M+H] +419.1230,found 419.1232。
2-(苯并[d][1,3]二氧戊环-5-基-氨基)-4-苯基-5-噻唑甲酸乙酯(化合物31)
Figure PCTCN2018083596-appb-000047
1H NMR(400MHz,CDCl 3):δ7.68-7.66(m,2H),7.37-7.34(m,3H),6.75(d,J＝8.0Hz, 1H),6.65-6.68(m,2H),6.01(s,2H),4.23-4.18(m,2H),1.24(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ170.08,161.65,158.74,148.25,145.35,134.03,133.70,130.02,129.61,128.93,128.25,127.57,115.41,109.67,108.51,104.05,101.51,60.75,14.20.HRMS(ESI)calcd for:C 19H 16N 2O 4S[M+H] +369.0909,found 369.0902。
2-((9-乙基-9H-咔唑-3-基)氨基)-4-苯基-5-噻唑甲酸乙酯(化合物32)
Figure PCTCN2018083596-appb-000048
1H NMR(400MHz,CDCl 3):δ10.71(s,1H),8.36(d,J＝1.2Hz,1H),8.12(d,J＝7.6Hz,1H),7.79-7.76(m,2H),7.67-7.61(m,3H),7.49-7.44(m,4H),7.21(t,J＝7.2Hz,1H),4.48-4.43(m,2H),4.16-4.10(m,2H),1.33(t,J＝7.2Hz,3H),1.12(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ171.26,161.80,159.27,140.58,138.18,134.38,131.22,129.58,128.76,127.48,126.23,123.63 122.53,121.77,120.78,119.07,115.49,109.62,109.26,108.73,60.58,37.71,14.19,13.84.HRMS(ESI)calcd for:C 26H 23N 3O 2S[M+H] +442.1589,found 442.1582。
2-(3,5二氯)-苯胺基-4-苯基-5-噻唑甲酸乙酯(化合物33)
Figure PCTCN2018083596-appb-000049
1H NMR(400MHz,CDCl 3):δ7.74-7.72(m,2H),7.39-7.37(m,3H),7.06(d,J＝1.6Hz,1H),7.00(d,J＝1.6Hz,2H),4.30-4.24(m,2H),1.29(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ166.16,161.45,158.13,141.13,135.68,133.54,129.65,129.44,127.87,124.12,117.67,111.64,61.20,14.20.HRMS(ESI)calcd for:C 18H 14Cl 2N 2O 2S[M+H] +393.0231,found 393.0231。
2-((5,6,7,8-四氢萘-2-基)氨基)-4-苯基-5-噻唑甲酸乙酯(化合物34)
Figure PCTCN2018083596-appb-000050
1H NMR(400MHz,CDCl 3):δ7.76-7.73(m,2H),7.42-7.41(m,3H),7.72(d,J＝8.4Hz,1H),7.02(dd,J 1＝2.4Hz,J 2＝7.4Hz,1H),6.94(d,J＝2.0Hz,1H),4.27-4.21(m,2H),2.78(s,4H),1.85-1.81(m,4H),1.26(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ168.61,161.77,158.71,138.50,136.68,134.24,134.14,130.06,129.74,128.94,127.58,121.17,118.02,109.86,60.72,29.46,28.95,23.15,22.98,14.24.HRMS(ESI)calcd for:C 22H 22N 2O 2S[M+H] +379.1480,found 379.1481。
2-(4-叔丁基)-苯氨基-4-苯基-5-噻唑甲酸乙酯(化合物35)
Figure PCTCN2018083596-appb-000051
1H NMR(400MHz,CDCl 3):δ7.75-7.73(m,2H),7.40-7.38(m,5H),7.19(d,J＝8.4Hz,2H),4.26-4.21(m,2H),1.36(s,9H),1.27(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ168.40,161.72,158.73,147.77,136.66,134.20,129.73,129.01,127.56,126.35,120.19,109.85, 60.75,34.43,31.34,14.24.HRMS(ESI)calcd for:C 22H 24N 2O 2S[M+H] +381.1637,found 381.1635。
2-(3-氟-4-甲基)-苯胺基-4-苯基-5-噻唑甲酸乙酯(化合物36)
Figure PCTCN2018083596-appb-000052
1H NMR(400MHz,CDCl 3):δ7.72-7.70(m,2H),7.38-7.37(m,3H),7.08(t,J＝7.6Hz,1H),6.84-6.78(m,2H),4.26-4.21(m,2H),2.25(s,3H),1.26(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ168.12,162.43,161.64,159.99,158.54,138.48,138.38,133.99,131.85,131.79,129.72,129.12,127.70,121.08,120.91,115.66,115.63,110.09,107.59,107.33,60.92,29.73,14.23,14.12,14.09.HRMS(ESI)calcd for:C 19H 17FN 2O 2S[M+H] +357.1073,found 357.1068。
2-([1,1’-联苯]-4-基-氨基)-4-苯基-5-噻唑甲酸乙酯(化合物37)
Figure PCTCN2018083596-appb-000053
1H NMR(400MHz,CDCl 3):δ8.11-8.09(m,1H),7.75(dd,J1＝2.4Hz,J 2＝6.6Hz,2H),7.64-7.61(m,4H),7.48-7.44(m,5H),7.38(d,J＝8.0Hz,2H),4.29-4.23(m,2H),1.29(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ171.13,167.18,161.59,158.19,140.25,138.41,137.30,133.68,133.22,130.09,129.82,129.28,128.89,128.32,128.22,127.71,127.31,126.85,119.73,110.30,60.98,14.25.HRMS(ESI)calcd for:C 24H 20N 2O 2S[M+H] +401.1324,found 401.1318。
2-((3’-甲氧基-[1,1’-联苯]-4-基)氨基)-4-苯基-5-噻唑甲酸乙酯(化合物38)
Figure PCTCN2018083596-appb-000054
1H NMR(400MHz,CDCl 3):δ7.76-7.74(m,2H),7.51(d,J＝8.4Hz,2H),7.41-7.37(m,4H),7.17(d,J＝8.4Hz,3H),7.12(d,J＝2.0Hz,1H),6.93(dd,J1＝2.4Hz,J 2＝8.0Hz,1H),4.28-4.22(q,J＝7.2Hz,2H),3.91(s,3H),1.28(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ167.62,161.69,160.01,158.63,141.82,138.61,137.09,134.15,129.88,129.83,129.16,128.12,127.71,120.10,119.35,112.71,112.52,110.25,60.91,55.35,14.26.HRMS(ESI)calcd for:C 25H 22N 2O 3S[M+H] +431.1429,found 431.1432。
2-((3-氟-3’-甲氧基-[1,1’-联苯]-4-基)氨基)-4-苯基-5-噻唑甲酸乙酯(化合物39)
Figure PCTCN2018083596-appb-000055
1H NMR(400MHz,CDCl 3):δ8.00(t,J＝8.4Hz,1H),7.82-7.79(m,2H),7.48-7.38(m,6H),7.18(d,J＝7.6Hz,1H),7.12(s,1H),6.94(dd,J1＝2.4Hz,J 2＝8.4Hz,1H),4.30-4.25(m,2H),3.90(s,3H),1.30(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ165.55,161.57,160.12,158.54,154.44,152.00,140.75,137.92,137.85,134.05,130.01,129.77,129.13,127.60,126.84,126.73,123.29,123.26,120.42,119.25,114.32,114.12,113.09,112.6f4,111.92,61.03,55.36,14.21.HRMS(ESI)calcd for:C 25H 21FN 2O 3S[M+H] +449.1335,found 449.1331。
2-((3,5-二氟-3’-甲氧基-[1,1’-联苯]-4-基)氨基)-4-苯基-5-噻唑甲酸乙酯(化合物40)
Figure PCTCN2018083596-appb-000056
1H NMR(400MHz,CDCl 3):δ7.66(d,J＝7.6Hz,2H),7.43(t,J＝8.0Hz,1H),7.26(d,J＝7.0Hz,3H),7.19-7.16(m,3H),7.10(s,1H),7.01(d,J＝8.0Hz,1H),4.22-4.17(m,2H),3.92(s,3H),1.22(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ170.93,161.38,160.18,159.47,159.43,158.14,156.97,156.92,141.94,139.74,133.57,133.37,130.25,130.12,129.49,128.93,128.36,127.38,119.30,115.41,113.95,112.76,111.48,110.96,110.72,60.89,55.43,29.72,14.18.HRMS(ESI)calcd for:C 25H 20F 2N 2O 3S[M+H] +467.1241,found 467.1235。
2-((3-氯-4-苯氧基苯基)氨基)-4-苯基-5-噻唑甲酸乙酯(化合物41)
Figure PCTCN2018083596-appb-000057
1H NMR(400MHz,CDCl 3):δ7.72(s,2H),7.40-7.31(m,6H),7.15(t,J＝7.2Hz,1H),7.07-7.05(m,1H),6.99(d,J＝7.6Hz,2H),6.93(d,J＝8.8Hz,1H),4.27-4.22(m,2H),1.27(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ168.09,161.52,158.51,157.03,149.29,135.91,133.93,129.81,129.66,129.19,127.70,126.70,123.41,123.07,121.57,120.40,117.68,110.70,60.96,14.19.HRMS(ESI)calcd for:C 24H 19ClN 2O 3S[M+H] +451.0883,found 451.0882。
2-((4-(苄氧基)-3-氯苯基)氨基)-4-苯基-5-噻唑甲酸乙酯(化合物42)
Figure PCTCN2018083596-appb-000058
1H NMR(400MHz,CDCl 3):δ7.70(d,J＝3.2Hz,2H),7.50(d,J＝7.6Hz,2H),7.44(t,J＝8.8Hz,2H),7.39-7.36(m,4H),7.30(d,J＝2.4Hz,1H),7.09(dd,J 1＝2.4Hz,J 2＝8.8Hz,1H),6.93(d,J＝8.8Hz,1H),5.20(s,2H),4.25-4.20(m,2H),1.26(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ169.48,161.58,158.70,151.90,136.39,133.97,133.30,129.52,129.03,128.68,128.15,127.59,127.12,124.33,124.00,121.36,114.76,110.10,77.35,60.82,14.19.HRMS(ESI)calcd for:C 25H 21ClN 2O 3S[M+H] +465.1040,found 465.1032。
2-((3-氯-4-((2-氯-6-氟苯基)苯氧基)氨基)-4-苯基-5-噻唑甲酸乙酯(化合物43)
Figure PCTCN2018083596-appb-000059
1H NMR(400MHz,CDCl 3):δ7.63-7.61(m,2H),7.37-7.32(m,2H),7.30-7.26(m,3H),7.10(t,J＝8.0Hz,1H),7.01(d,J＝2.4Hz,1H),6.96(d,J＝8.8Hz,1H),6.90(dd,J 1＝2.4Hz,J 2＝8.8Hz,1H),5.25(s,2H),4.21(q,J＝7.2Hz,2H),1.24(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ169.36,163.32,161.62,160.81,158.77,151.79,136.72,136.68,133.91,133.82,131.07,130.97,129.53,129.10,127.63,125.70,125.67,124.61,124.14,121.98,121.81,121.20,115.65,114.51,114.28,109.99,62.96,62.92,60.86,14.22.HRMS(ESI)calcd for:C 25H19C l2FN 2O 3S[M+H] +517.0556,found 517.0562。
2-((2,3-二氢-1H-茚-5-基)氨基)-4-苯基-5-噻唑甲酸乙酯(化合物44)
Figure PCTCN2018083596-appb-000060
1H NMR(400MHz,CDCl 3):δ7.74-7.73(m,2H),7.39-7.38(m,3H),7.19(d,J＝8.0Hz,1H),7.07-6.99(m,2H),4.25-4.20(m,2H),2.91(t,J＝7.6Hz,4H),2.14-2.07(m,2H),1.26(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):161.78,158.78,145.92,141.21,137.52,134.27,129.73,128.96,127.62,125.07,118.72,117.07,117.03,60.75,33.01,32.38,25.63,14.25.HRMS(ESI)calcd for:C 21H 20N 2O 2S[M+H] +365.1324,found 365.1326。
2-萘氨基-4-苯基-5-噻唑甲酸乙酯(化合物45)
Figure PCTCN2018083596-appb-000061
1H NMR(400MHz,DMSO-d 6):δ10.90(s,1H),8.23(s,1H),7.92-7.63(m,6H),7.52-7.34(m,5H),4.27(q,J＝7.2Hz,2H),1.30(t,J＝7.2Hz,3H)。ESI[M+H] +found 375.3。
2-(3,4-二甲基)苯胺基-4-环丙基-5-噻唑甲酸乙酯(化合物46)
Figure PCTCN2018083596-appb-000062
1H NMR(400MHz,CDCl 3):δ7.52(s,1H),7.14(d,J＝8.8Hz,1H),7.07(d,J＝6.0Hz,2H),4.32(q,J＝7.2Hz,2H),3.06–2.99(m,1H),2.28(s,3H),2.26(s,3H),1.36(t,J＝7.2Hz,3H),1.10-1.09(m,2H),1.04-1.02(m,2H). 13C NMR(100MHz,CDCl 3):δ167.42,164.91,163.14,137.98,137.06,132.92,130.55,121.13,117.14,108.84,60.46,19.95,19.15,14.50,11.65,9.75.HRMS(ESI)calcd for:C 17H 20N 2O 2S[M+H] +317.1324,found 317.1175。
2-(3-氟-4-甲基)-苯胺基-4-环丙基-5-噻唑甲酸乙酯(化合物47)
Figure PCTCN2018083596-appb-000063
1H NMR(400MHz,CDCl 3):δ7.19-7.11(m,2H),6.96(dd,J 1＝2.0Hz,J 2＝8.0Hz,1H),4.33(q,J＝7.2Hz,2H),3.05-2.99(m,1H),2.27(s,3H),1.37(t,J＝7.2Hz,3H),1.11-1.09(m,2H),1.07-1.04(m,2H). 13C NMR(100MHz,CDCl 3):δ165.88,164.58,162.87,162.65,160.21,138.35,138.25,132.04,131.97,120.46,120.28,114.35,109.56,106.36,106.10,60.61,14.45,14.03,14.00,11.63,9.85.HRMS(ESI)calcd for:C 16H 17FN 2O 2S[M-H] +319.0917,found 319.0916。
2-(3-氯-4-甲基)-苯胺基-4-环丙基-5-噻唑甲酸乙酯(化合物48)
Figure PCTCN2018083596-appb-000064
1H NMR(400MHz,CDCl 3):δ7.40(d,J＝2.4Hz,1H),7.22(d,J＝8.4Hz,1H),7.13(dd,J 1＝2.4Hz,J 2＝8.0Hz,1H),4.33(q,J＝7.2Hz,2H),3.05–2.99(m,1H),2.37(s,3H),1.37(t,J＝7.2Hz,3H),1.13-1.09(m,2H),1.07-1.03(m,2H). 13C NMR(100MHz,CDCl 3):δ165.96,164.67,162.87,138.04,135.04,131.76,131.55,119.73,117.39,60.60,29.69,19.39,14.47,11.63,9.84.HRMS(ESI)calcd for:C 16H 17ClN 2O 2S[M+H] +337.0778,found 337.0770。
2-((5,6,7,8-四氢萘-2-基)氨基)-4-环丙基-5-噻唑甲酸乙酯(化合物49)
Figure PCTCN2018083596-appb-000065
1H NMR(400MHz,CDCl 3):δ7.56(s,1H),7.09-7.03(m,2H),7.01(s,1H),4.32(q,J＝7.2Hz,2H),3.06-3.00(m,1H),2.78-2.76(m,4H),1.81-1.80(m,4H),1.36(t,J＝7.2Hz,3H),1.11–1.08(m,2H),1.05-1.00(m,2H). 13C NMR(100MHz,CDCl 3):δ167.37,164.81,163.10,138.55,136.64,133.65,130.13,120.13,117.24,108.83,60.46,29.55,28.88,23.16,22.99,14.51,11.62,9.75.HRMS(ESI)calcd for:C 19H 22N 2O 2S[M+H] +343.1480,found 343.1477。
2-((2,3-二氢-1H-茚-5-基)氨基)-4-环丙基-5-噻唑甲酸乙酯(化合物50)
Figure PCTCN2018083596-appb-000066
1H NMR(400MHz,CDCl 3):δ7.73(s,1H),7.22(s,1H),7.20(d,J＝8.00Hz,1H),7.07(d,J＝8.0Hz,1H),4.32(q,J＝7.2Hz,2H),3.06-3.00(m,1H),2.95–2.88(m,4H),2.15-2.08(m,2H),1.36(t,J＝7.2Hz,3H),1.11-1.08(m,2H),1.04–1.00(m,2H). 13C NMR(100MHz,CDCl 3):167.67,164.97,163.15,145.93,140.71,137.57,125.11,118.12,116.16,108.80,60.46,33.05,32.35,25.62,14.51,11.66,9.75.HRMS(ESI)calcd for:C 18H 20N 2O 2S[M-H] +327.1167,found 327.1169。
2-(3,4-二甲基)苯胺基-4-叔丁基-5-噻唑甲酸乙酯(化合物51)
Figure PCTCN2018083596-appb-000067
1H NMR(400MHz,CDCl 3):δ7.16(d,J＝8.8Hz,1H),7.10(s,2H),4.28(q,J＝7.2Hz,2H),2.30(s,3H),2.27(s,3H),1.49(s,9H),1.35(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ170.04,165.38,161.71,138.05,137.17,132.74,130.59,120.84,116.74,109.63,60.70,36.39,29.27,20.02,19.92,19.20,14.41.HRMS(ESI)calcd for:C 18H 24N 2O 2S[M+H] +333.1637,found 333.1633。
2-(3-氟-4-甲基)-苯胺基-4-叔丁基-5-噻唑甲酸乙酯(化合物52)
Figure PCTCN2018083596-appb-000068
1H NMR(400MHz,CDCl 3):δ7.20-7.15(m,2H),6.99(dd,J 1＝2.0Hz,J 2＝8.0Hz,1H),4.29(q,J＝7.2Hz,2H),2.28(s,3H),1.50(s,9H),1.37(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ169.59,163.87,162.69,161.51,160.25,138.49,138.38,132.08,132.01,120.23,120.05,114.06,114.03,110.43,106.05,105.78,60.90,36.44,29.26,14.37.HRMS(ESI)calcd for:C 17H 21FN 2O 2S[M-H] +335.1230,found 335.1223。
2-(3-氯-4-甲基)-苯胺基-4-叔丁基-5-噻唑甲酸乙酯(化合物53)
Figure PCTCN2018083596-appb-000069
1H NMR(400MHz,CDCl 3):δ7.47(d,J＝2.0Hz,1H),7.23(d,J＝8.4Hz,1H),7.16(dd,J 1＝2.4Hz,J 2＝8.4Hz,1H),4.29(q,J＝7.2Hz,2H),2.37(s,3H),1.49(s,9H),1.36(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ169.80,163.94,161.58,138.29,135.03,131.53,131.40,119.43,117.06,110.58,60.87,36.48,29.29,19.39,14.36.HRMS(ESI)calcd for:C 17H 21ClN 2O 2S[M-H] +351.0934,found 351.0937。
2-((5,6,7,8-四氢萘-2-基)氨基)-4-叔丁基-5-噻唑甲酸乙酯(化合物54)
Figure PCTCN2018083596-appb-000070
1H NMR(400MHz,CDCl 3):δ7.11-7.07(m,2H),7.05(s,1H),4.28(q,J＝7.2Hz,2H),2.80-2.77(m,4H),1.83(s,4H),1.49(s,9H),1.35(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ169.81,165.27,161.64,138.62,136.68,133.51,130.20,119.82,116.88,109.62,60.71,36.35,29.25,26.64,23.16,22.99,14.40.HRMS(ESI)calcd for:C 20H 26N 2O 2S[M+H] +359.1793,found 359.1782。
2-((2,3-二氢-1H-茚-5-基)氨基)-4-叔丁基-5-噻唑甲酸乙酯(化合物55)
Figure PCTCN2018083596-appb-000071
1H NMR(400MHz,CDCl 3):δ7.45(s,1H),7.25-7.21(m,2H),7.09(dd,J 1＝2.0Hz,J 2＝8.0Hz,1H),4.27(q,J＝7.2Hz,2H),2.97-2.90(m,4H),2.17-2.09(m,2H),1.49(s,9H),1.35(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):169.96,165.58,161.68,146.03,140.59,137.61,125.17,117.73,115.82,109.57,60.69,36.36,33.07,32.36,29.26,25.63,14.41.HRMS(ESI)calcd for:C 19H 24N 2O 2S[M-H] +343.1480,found 343.1482。
实施例4：化合物56-75的合成
Figure PCTCN2018083596-appb-000072
芳基硫脲的合成采用实例3流程中硫脲合成的方法。
取1mmol的取代苯基硫脲和1mmol的2-氯乙酰丙酮(2-氯乙酰乙酸乙酯)溶于20mL甲醇，回流过夜，旋干甲醇，加入少量稀碳酸钾水溶液中和，饱和食盐水洗涤，乙酸乙酯萃取，有机层浓缩干燥柱层析得产品。
目标化合物谱图数据
2-(3,4-甲基苯胺基)-4-甲基-5-乙酰基噻唑(化合物56)
Figure PCTCN2018083596-appb-000073
1H NMR(400MHz,DMSO-d 6):δ10.58(s,1H),7.32(d,J＝8.0Hz,1H),7.28(s,1H),7.11(d,J＝8.4Hz,1H),2.53(s,3H),2.40(s,3H),2.21(s,3H),2.18(s,3H). 13C NMR(100MHz,DMSO-d 6):δ189.37,166.12,157.29,138.21,137.41,131.42,130.50,122.25,120.15,116.41, 56.50,30.12,20.16,19.22,18.94.HRMS(ESI)calcd for:C 14H 16N 2OS[M+H] +261.1062,found 261.1065。
2-(4-甲基-3-氯苯胺基)-4-甲基-5-乙酰基噻唑(化合物57)
Figure PCTCN2018083596-appb-000074
1H NMR(400MHz,DMSO-d 6):δ10.79(s,1H),7.80(d,J＝2.0Hz,1H),7.75(dd,J 1＝2.4Hz,J 2＝8.4Hz,1H),7.30(d,J＝8.0Hz,1H),2.55(s,3H),2.42(s,3H),2.27(s,3H). 13C NMR(100MHz,DMSO-d 6):δ189.70,165.12,156.91,139.58,133.81,131.93,129.60,123.15,118.37,117.12,56.51,30.17,19.33,19.00,18.94.HRMS(ESI)calcd for:C 13H 13ClN 2OS[M+H] +281.0515,found 281.0515。
2-(2-萘胺基)-4-甲基-5-乙酰基噻唑)(化合物58)
Figure PCTCN2018083596-appb-000075
1H NMR(400MHz,DMSO-d 6):δ 1H NMR(400MHz,DMSO-d 6):δ11.02(s,1H),8.25(d,J＝2.0Hz,1H),7.91(d,J＝8.8Hz,1H),7.85(d,J＝8.8Hz,2H),7.61(dd,J 1＝2.4Hz,J 2＝8.8Hz,1H),7.51–7.47(m,1H),7.43–7.39(m,1H),2.62(s,3H),2.46(s,3H). 13C NMR(100MHz,DMSO-d 6):189.71,165.44,157.06,138.10,134.08,129.86,129.37,128.02,127.62,127.15,124.97,123.03,119.93,113.72,30.23,19.01.HRMS(ESI)calcd for:C 16H 14N 2OS[M+H] +283.0905,found 283.0903。
2-(4-溴-3-三氟甲基苯胺基)-4-甲基-5-乙酰基噻唑(化合物59)
Figure PCTCN2018083596-appb-000076
1H NMR(400MHz,DMSO-d 6):δ11.12(s,1H),8.25(s,1H),7.82(s,2H),2.57(s,3H),2.45(s,3H). 13C NMR(100MHz,DMSO-d 6):189.95,164.44,156.51,140.27,136.01,129.32,129.01,124.60,124.00,122.80,121.88,117.20,117.14,110.48,56.51,30.16,18.88.HRMS(ESI)calcd for:C 13H 10BrF 3N 2OS[M+H] +378.9728,found 378.9724。
2-(4-溴苯胺基)-4-甲基-5-乙酰基噻唑(化合物60)
Figure PCTCN2018083596-appb-000077
1H NMR(400MHz,DMSO-d 6):δ10.87(s,1H),7.61(d,J＝8.8Hz,2H),7.53(d,J＝8.8Hz,2H),2.56(s,3H),2.44(s,3H). 13C NMR(100MHz,DMSO-d 6):189.26,164.55,156.38,139.30,131.78,122.76,119.81,113.93,56.01,29.68,18.41.HRMS(ESI)calcd for:C 12H 11BrN 2OS[M+H] +310.9854,found 310.9854。
2-(苯胺基)-4-甲基-5-乙酰基噻唑(化合物61)
Figure PCTCN2018083596-appb-000078
1H NMR(400MHz,DMSO-d 6):δ10.74(s,1H),7.60(d,J＝8.0Hz,2H),7.37(t,J＝8.0Hz,2H),7.05(t,J＝7.2Hz,1H),2.56(s,3H),2.43(s,3H). 13C NMR(100MHz,DMSO-d 6):189.67,165.69,157.17,140.41,129.62,123.28,122.71,118.62,56.54,30.12,18.90.HRMS(ESI)calcd for:C 12H 12N 2OS[M+H] +233.0749,found 233.0746。
2-(2-蒽胺基)-4-甲基-5-乙酰基噻唑(化合物62)
Figure PCTCN2018083596-appb-000079
1H NMR(400MHz,DMSO-d 6):δ11.06(s,1H),8.51–8.47(m,3H),8.10–8.04(m,3H),7.57–7.45(m,3H),2.65(s,3H),2.48(s,3H). 13C NMR(100MHz,DMSO-d 6):189.86,165.15,157.07,137.37,132.38,132.18,130.81,129.86,128.66,128.56,128.10,126.45,126.25,125.40,125.21,123.30,121.03,112.01,30.22,18.98.HRMS(ESI)calcd for:C 20H 16N 2OS[M+H] +333.1062,found 333.1057。
2-(9-乙基-9H-咔唑-3-氨基)-4-甲基-5-乙酰基噻唑(化合物63)
Figure PCTCN2018083596-appb-000080
1H NMR(400MHz,DMSO-d 6):δ10.68(s,1H),8.33(s,1H),8.13(d,J＝8.0Hz,1H),7.65-7.55(m,3H),7.47(t,J＝7.2Hz,1H),7.20(t,J＝7.2Hz,1H),4.47-4.42(m,2H)，2.57(s,3H),2.40(s,3H),1.32(t,J＝6.0Hz,3H).HRMS(ESI)calcd for C 20H 19N 3OS[M+H] +350.1327,found 350.1319。
2-(4-乙氧基苯胺基)-4-甲基-5-乙酰基噻唑(化合物64)
Figure PCTCN2018083596-appb-000081
1H NMR(400MHz,DMSO-d 6):δ7.40(d,J＝8.4Hz,2H),7.91(d,J＝8.8Hz,2H),4.02-3.97(m,2H),2.50(s,3H),2.36(s,3H),1.32(t,J＝6.8Hz,3H).HRMS(ESI)calcd for C 14H 16N 2O 2S[M+H] +277.1011,found 277.1009。
2-(4-叔丁基苯胺基)-4-甲基-5-乙酰基噻唑(化合物65)
Figure PCTCN2018083596-appb-000082
1H NMR(400MHz,DMSO-d 6):δ7.49(d,J＝8.4Hz,2H),7.38(d,J＝8.8Hz,2H),2.54(s,3H),2.42(s,3H),1.28(s,9H).HRMS(ESI)calcd for:C 16H 20N 2OS[M+H] +289.1375,found 289.1374。
2-(4-氯-3-三氟甲基苯胺基)-4-甲基-5-乙酰基噻唑(化合物66)
Figure PCTCN2018083596-appb-000083
1H NMR(400MHz,DMSO-d 6):δ11.13(s,1H),8.26(d,J＝2.4Hz,1H),7.91(dd,J 1＝2.4Hz,J 2＝8.8Hz,1H),7.69(d,J＝8.8Hz,1H),2.58(s,3H),2.46(s,3H). 13C NMR(100MHz,DMSO-d 6):189.92,164.46,156.50,139.80,132.61,127.51,127.20,124.49,123.95,123.03,122.66,121.77,116.80,116.74,56.51,30.11,18.85.HRMS(ESI)calcd for:C 13H 10ClF 3N 2OS[M+H] +335.0233,found 335.0231。
2-(4-乙氧基苯胺基)-4-甲基-5-甲酸乙酯噻唑(化合物67)
Figure PCTCN2018083596-appb-000084
1H NMR(400MHz,DMSO-d 6):δ7.45(d,J＝9.2Hz,2H),6.92(d,J＝8.8Hz,2H),4.21-4.16(m,2H),4.02-3.97(m,2H),2.46(s,3H),1.32(t,J＝6.8Hz,3H),1.25(t,J＝7.2Hz,3H)。HRMS(ESI)calcd for:C 15H 18N 2O 3S[M+H] +307.1116,found 307.1114。
2-(3,4-甲基苯胺基)-4-甲基-5-甲酸乙酯噻唑(化合物68)
Figure PCTCN2018083596-appb-000085
1H NMR(400MHz,CDCl 3):δ7.20-7.13(m,1H),7.07(d,J＝2.0Hz,2H),4.27(q,J＝7.2Hz,2H),2.55(s,3H),2.30(s,3H),2.26(s,3H),1.32(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ169.59,162.67,158.71,138.14,137.23,133.86,130.69,122.80,118.80,60.47,19.91,19.26,17.42,14.44.HRMS(ESI)calcd for:C 15H 18N 2O 2S[M+H] +291.1167,found 291.1164。
2-((9-乙基-9H-咔唑-3-氨基)-4-甲基-5-甲酸乙酯噻唑(化合物69)
Figure PCTCN2018083596-appb-000086
1H NMR(400MHz,DMSO-d 6):δ10.57(s,1H),8.32(d,J＝1.6Hz,1H),8.13(d,J＝7.6Hz,1H),7.65-7.55(m,3H),7.47(d,J＝7.6Hz,1H),7.20(d,J＝7.6Hz,1H),4.47-4.42(m,2H),4.22-4.16(m,2H),2.54(s,3H),1.33(t,J＝7.2Hz,3H),1.25(t,J＝7.2Hz,3H).HRMS(ESI)calcd for:C 21H 21N 3O 2S[M+H] +380.1433,found 380.1436。
2-(4-甲基3-氯苯胺基)-4-甲基-5-甲酸乙酯噻唑(化合物70)
Figure PCTCN2018083596-appb-000087
1H NMR(400MHz,DMSO-d 6):δ7.82(d,J＝2.0Hz,1H),7.40(dd,J 1＝2.0Hz,J 2＝8.4Hz,1H),7.31(d,J＝8.4Hz,1H),4.22(q,J＝7.2Hz,2H),2.53(s,3H),2.28(s,3H),1.27(t,J＝7.2Hz,3H). 13C NMR(100MHz,DMSO-d 6):164.97,162.26,158.85,139.71,133.77,131.93,129.41,118.29,117.05,109.86,60.79,19.33,17.83,14.74.HRMS(ESI)calcd for:C 14H 15ClN 2O 2S[M+H] +311.0621,found 311.0620。
2-(4-溴苯胺基)-4-甲基-5-甲酸乙酯噻唑(化合物71)
Figure PCTCN2018083596-appb-000088
1H NMR(400MHz,DMSO-d 6):δ7.62(d,J＝8.8Hz,2H),7.52(d,J＝8.8Hz,2H),4.22(q,J＝7.2Hz,2H),2.53(s,3H),1.27(t,J＝7.2Hz,3H). 13C NMR(100MHz,DMSO-d 6):164.89, 162.26,158.70,139.96,132.23,120.23,114.20,109.97,60.78,17.78,14.73.HRMS(ESI)calcd for:C 13H 13BrN 2O 2S[M+H] +340.9959,found 340.9951。
2-(2-蒽胺基)-4-甲基-5-甲酸乙酯噻唑(化合物72)
Figure PCTCN2018083596-appb-000089
1H NMR(400MHz,DMSO-d 6):δ8.51–8.46(m,3H),8.10–8.05(m,3H),7.56–7.46(m,3H),4.25(q,J＝7.2Hz,2H),2.62(s,3H),1.30(t,J＝7.2Hz,3H). 13C NMR(100MHz,DMSO-d 6):δ189.86,165.15,157.07,137.37,132.38,132.18,130.81,129.86,128.66,128.56,128.10,126.45,126.25,125.40,125.21,123.30,121.03,112.01,18.98.HRMS(ESI)calcd for:C 21H 18N 2O 2S[M+H] +363.1167,found 363.1172。
2-((2,3-二氢-1H-茚-5-基)氨基)-4-甲基-5-噻唑甲酸乙酯(化合物73)
Figure PCTCN2018083596-appb-000090
1H NMR(400MHz,CDCl 3):δ7.25(d,J＝8.0Hz,1H),7.21(s,1H),7.09(dd,J 1＝2.0Hz,J 2＝8.0Hz,1H),4.29(q,J＝7.2Hz,2H),2.97-2.91(m,4H),2.57(s,3H),2.17-2.10(m,2H),1.35(t,J＝6.8Hz,3H). 13C NMR(100MHz,CDCl 3):δ169.47,162.67,158.77,146.06,141.57,137.66,125.23,119.50,117.59,60.47,33.01,32.42,25.59,17.41,14.45.HRMS(ESI)calcd for:C 16H 18N 2O 2S[M+H] +303.1167,found 303.1163。
2-(3-氟-4-甲基)-苯胺基-4-甲基-5-噻唑甲酸乙酯(化合物74)
Figure PCTCN2018083596-appb-000091
1H NMR(400MHz,DMSO-d 6):δ10.73(s,1H),7.60(dd,J 1＝1.6Hz,J 2＝12.2Hz,1H),7.24(t,J＝8.4Hz,1H),7.19(dd,J 1＝2.0Hz,J 2＝8.4Hz,1H),4.21(q,J＝7.2Hz,2H),2.53(s,3H),2.18(q,J＝1.2Hz,3H),1.27(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ167.80,162.71,162.49,160.27,158.48,138.54,138.43,132.20,132.14,121.37,121.20,115.87,115.83,110.09,107.73,107.48,60.68,17.36,14.41,14.12,14.09.HRMS(ESI)calcd for:C 14H 15FN 2O 2S[M+H] +295.0917,found 295.0916。
2-((3,5-二氟-3’-甲氧基-[1,1’-联苯]-4-基)氨基)-4-甲基-5-噻唑甲酸乙酯(化合物75)
Figure PCTCN2018083596-appb-000092
1H NMR(400MHz,CDCl 3):δ7.42(t,J＝8.0Hz,1H),7.27(s,3H),7.17(d,J＝7.6Hz,1H),6.99(dd,J 1＝2.0Hz,J 2＝8.0Hz,1H),4.28(q,J＝7.2Hz,2H),3.91(s,3H),2.59(s,3H),1.33(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ170.60,162.34,160.17,159.45,157.94,156.95,141.95,139.59,130.20,119.32,115.70,114.10,112.66,111.08,111.02,110.84,60.64,55.41,16.85,14.383.HRMS(ESI)calcd for:C 20H 18F 2N 2O 3S[M+H] +405.1084,found 405.1083。
实施例5：化合物88-92的合成通法：
Figure PCTCN2018083596-appb-000093
芳基取代的异硫氰酸酯的合成采用实例3流程中NCS合成的方法。
将甲醇钠或者乙醇钠(41mmol)溶解在40mL甲醇或者乙醇中，冰浴条件下，将此溶液缓慢滴加至溶解有氰胺(41mmol)和取代异硫氰酸酯(41mmol)的乙醇(25mL)混合溶液中，搅拌过夜后，于反应液中滴加氯乙酸乙酯(41mmol)，继续搅拌过夜。待反应结束后，减压除去大量乙醇溶剂，粗品用乙酸乙酯和饱和食盐水萃取，收集到的有机相用无水硫酸钠干燥，旋蒸除去溶剂之后进一步用硅胶柱层析(PE/EA＝2/1，v/v)，得到白色纯品。
目标化合物谱图数据
2-(3-氯-4-三氟甲基)-苯胺基-4-氨基-5-噻唑甲酸甲酯(化合物88)
Figure PCTCN2018083596-appb-000094
1H NMR(400MHz,DMSO-d 6):δ11.00(s,1H),8.20(d,J＝2.4Hz,1H),7.91(dd,J 1＝2.4Hz,J  2＝8.8Hz,1H),7.67(d,J＝8.4Hz,1H),7.01(s,2H),3.32(s,3H). 13C NMR(100MHz,DMSO-d 6):δ164.75,164.17,139.79,132.67,127.59,127.29,124.52,123.25,123.07,121.80,117.25,117.20,117.14,51.17.HRMS(ESI)calcd for:C 12H 9ClF 3N 3O 2S[M+H] +352.0134,found 352.0130。
2-(3-三氟甲基-4-氯)-苯胺基-4-氨基-5-噻唑甲酸乙酯(化合物89)
Figure PCTCN2018083596-appb-000095
1H NMR(400MHz,DMSO-d 6):δ10.98(s,1H),8.17(d,J＝2.4Hz,1H),7.92(dd,J 1＝2.4Hz,J  2＝8.8Hz,1H),7.67(d,J＝8.8Hz,1H),6.98(s,2H),4.15(q,J＝7.2Hz,2H),1.23(t,J＝7.2Hz,3H). 13C NMR(100MHz,DMSO-d 6):δ164.71,163.86,139.80,132.68,127.60,127.29,124.52,123.22,123.05,121.80,117.27,117.22,117.16,117.10,59.60,15.09.HRMS(ESI)calcd for:C 13H 11ClF 3N 3O 2S[M+H] +366.0291,found 366.0292。
2-(3,4-二甲基)-苯胺基-4-氨基-5-噻唑甲酸乙酯(化合物90)
Figure PCTCN2018083596-appb-000096
1H NMR(400MHz,DMSO-d 6):δ10.40(s,1H),7.34(d,J＝9.6Hz,1H),7.31(s,1H),7.09(d,J＝8.4Hz,1H),6.89(s,2H),4.12(q,J＝7.2Hz,2H),2.21(s,3H),2.18(s,3H),1.21(t,J＝7.2Hz,3H). 13C NMR(100MHz,DMSO-d 6):δ166.06,163.90,138.14,137.29,131.40,130.37,120.46,116.76,59.30,20.14,19.22,15.14.HRMS(ESI)calcd for:C 14H 17N 3O 2S[M+H] +292.1120,found 292.1117。
2-(3,4-二氯)-苯胺基-4-氨基-5-噻唑甲酸乙酯(化合物91)
Figure PCTCN2018083596-appb-000097
1H NMR(400MHz,DMSO-d 6):δ10.87(s,1H),8.11(d,J＝2.4Hz,1H),7.73(d,J＝8.8Hz,1H),7.47(dd,J 1＝2.4Hz,J  2＝9.0Hz,1H),7.02(s,2H),4.14(q,J＝7.2Hz,2H),1.23(t,J＝7.2Hz,3H). 13C NMR(100MHz,DMSO-d 6):δ164.72,163.88,140.43,131.77,131.20,124.16,119.58,118.57,59.57,15.10.HRMS(ESI)calcd for:C 12H 11Cl 2N 3O 2S[M+H] +332.0027,found 332.0025。
2-(3-氟-4-甲基)-苯胺基-4-氨基-5-噻唑甲酸乙酯(化合物92)
Figure PCTCN2018083596-appb-000098
1H NMR(400MHz,DMSO-d 6):δ10.68(s,1H),7.68(d,J＝8.4Hz,1H),7.23(t,J＝8.4Hz,1H),7.16(dd,J＝1.6,8.0Hz,1H),6.97(s,2H),4.13(q,J＝7.2Hz,2H),2.18(s,3H),1.22(t,J＝7.2Hz,3H). 13C NMR(100MHz,DMSO-d 6):δ165.17,163.93,162.18,159.79,139.82,139.71,132.07,132.00,118.27,118.09,114.29,105.68,105.40,59.44,15.09,14.03.HRMS(ESI)calcd for:C 13H 14FN 3O 2S[M+H] +296.0869,found 296.0865。
实施例6：化合物88-92的合成通法：
Figure PCTCN2018083596-appb-000099
称取4-氨基-2-(取代苯胺基)噻唑-5-甲酸乙酯(304μmol)于25mL单口烧瓶中，加入5mL甲苯，滴加15滴三乙胺，待搅拌均匀后，于冰浴条件下缓慢滴加对应的酰氯(456μmol)，滴加完毕，冰浴搅拌10min后，升温至90℃，继续反应，TLC跟踪至原料完全转化。将反应液降至室温，减压除去过量溶剂，得到的粗品进一步用硅胶柱层析(PE/EA＝4/1，v/v)，得到的淡黄色固体再用PE/EA重结晶。
目标化合物谱图数据
4-环丙酰胺基-2-(3,4-二甲基)-苯胺基-5-噻唑甲酸乙酯(化合物93)
Figure PCTCN2018083596-appb-000100
1H NMR(400MHz,CDCl 3):δ7.31(d,J＝7.6Hz,1H),7.13(s,1H),7.10(d,J＝8.0Hz,1H),5.62(s,1H),4.27(q,J＝7.2Hz,2H),2.36(s,3H),2.35(s,3H),1.43-1.40(m,1H),1.33(t,J＝7.2Hz,3H),1.20–1.18(m,2H),0.84-0.81(m,2H). 13C NMR(100MHz,CDCl 3):δ173.98,165.07, 162.69,159.21,138.58,138.17,136.47,130.99,129.84,126.20,59.82,19.93,19.67,14.53,13.63,10.62.HRMS(ESI)calcd for:C 18H 21N 3O 3S[M+H] +360.1382,found 360.1388。
4-环丙酰胺基-2-(3,4-二氯)-苯胺基-5-噻唑甲酸乙酯(化合物94)
Figure PCTCN2018083596-appb-000101
1H NMR(400MHz,CDCl 3):δ7.66(d,J＝8.4Hz,1H),7.53(d,J＝2.4Hz,1H),7.26(dd,J 1＝2.4Hz,J  2＝8.8Hz,1H),4.28(q,J＝7.2Hz,2H),1.43-1.37(m,1H),1.34(t,J＝7.2Hz,3H),1.26-1.23(m,2H),0.95-0.90(m,2H). 13C NMR(100MHz,CDCl 3):δ173.00,165.07,161.88,158.80,138.10,133.92,133.87,131.55,131.33,128.70,60.04,14.50,13.87,10.92.HRMS(ESI)calcd for:C 16H 15Cl 2N 3O 3S[M+H] +400.0289,found 400.0289。
4-环丙酰胺基-2-(-三氟甲基-4-氯)-苯胺基-5-噻唑甲酸乙酯(化合物95)
Figure PCTCN2018083596-appb-000102
1H NMR(400MHz,CDCl 3):δ7.73-7.71(m,2H),7.53(dd,J 1＝2.0Hz,J  2＝8.4Hz,1H),4.28(q,J＝7.20Hz,2H),1.36-1.32(m,4H),1.28-1.26(m,2H),0.94-0.89(m,2H). 13C NMR(100MHz,CDCl 3):δ172.82,164.89,161.82,158.73,137.63,133.80,133.46,133.10,130.27,129.95,128.81,128.75,128.70,128.65,123.50,120.78,60.07,14.49,13.98,10.95.HRMS(ESI)calcd for:C 17H 15ClF 3N 3O 3S[M+H] +434.0553,found 434.0556。
4-苯甲酰胺基-2-(3-三氟甲基-4-氯)-苯胺基-5-噻唑甲酸乙酯(化合物96)
Figure PCTCN2018083596-appb-000103
1H NMR(400MHz,CDCl 3):δ7.55(d,J＝2.4Hz,1H),7.48(d,J＝8.8Hz,1H),7.40-7.27(m,6H),5.63(s,2H),4.32(q,J＝7.2Hz,2H),1.38(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ169.13,164.83,161.83,158.70,138.11,133.95,133.26,132.59,132.23,131.17,129.39,129.12,129.07,129.01,128.96,128.43,128.34,123.38,120.66,60.25,14.55.HRMS(ESI)calcd for:C 20H 15ClF 3N 3O 3S[M+H] +470.0553,found 470.0554。
4-苯甲酰胺基-2-苯胺基-5-噻唑甲酸乙酯(化合物97)
Figure PCTCN2018083596-appb-000104
1H NMR(400MHz,CDCl 3):δ7.40-7.30(m,6H),7.26-7.20(m,4H),5.64(s,2H),4.32(q,J＝7.2Hz,2H),1.38(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ169.64,165.02,162.63,159.07,139.38,134.03,130.60,129.68,129.17,128.78,128.59,127.89,60.06,14.60.HRMS(ESI)calcd for:C 19H 17N 3O 3S[M+H] +368.1069,found 368.1072。
4-苯甲酰胺基-2-(3,4-二甲基)-苯胺基-5-噻唑甲酸乙酯(化合物98)
Figure PCTCN2018083596-appb-000105
1H NMR(400MHz,CDCl 3):δ7.31(d,J＝8.0Hz,3H),7.21(t,J＝8.0Hz,2H),7.09(d,J＝8.0Hz,1H),6.99(s,1H),6.95(d,J＝8.0Hz,1H),5.67(s,2H),4.31(q,J＝7.2Hz,2H),2.25(s,3H),2.20(s,3H),1.37(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ169.77,165.03,162.97,159.19,137.68,137.43,136.88.HRMS(ESI)calcd for:C 21H 21N 3O 3S[M+H] +396.1382,found396.1381。
实施例7：化合物99-100的合成通法：
Figure PCTCN2018083596-appb-000106
称取4-苯基-2-(芳香胺基)噻唑-5-甲酸乙酯(617μmol)于25mL烧瓶中，加入3mL DMF，于氩气保护下加入NaH(1mmol)，待搅拌均匀后，将溶解于2mL DMF中的EtI(617μmol)滴加至反应液中，滴加完毕继续室温搅拌反应2h。待反应结束后，用饱和NH 4Cl水溶液淬灭反应，再用乙酸乙酯/饱和食盐水萃取反应液，得到的有机相用无水Na 2SO 4干燥，减压除去溶剂，得到的粗品进一步用硅胶柱层析(PE:EA＝15:1)，得到白色纯品。
目标化合物谱图数据
2-(乙基(苯胺基))-4-苯基-5-噻唑甲酸乙酯(化合物99)
Figure PCTCN2018083596-appb-000107
1H NMR(400MHz,CDCl 3):δ7.80(dd,J 1＝2.4Hz,J  2＝8.0Hz,2H),7.55–7.51(m,2H),7.45–7.39(m,6H),4.19–4.08(m,4H),1.30(t,J＝7.2Hz,3H),1.21(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ170.44,161.95,159.51,143.88,134.93,130.30,129.87,128.86,128.19,127.52,127.36,110.41,60.47,47.44,14.23,13.15.HRMS(ESI)calcd for:C 20H 20N 2O 2S[M+H] +353.1324,found 353.1328。
2-(甲基(5,6,7,8-四氢萘-2-基)氨基)-4-苯基-5-噻唑甲酸乙酯(化合物100)
Figure PCTCN2018083596-appb-000108
1H NMR(400MHz,CDCl 3):δ7.79(dd,J 1＝2.4Hz,J 2＝7.6Hz,2H),7.45-7.42(m,3H),7.18-7.13(m,3H),4.17(q,J＝7.2Hz,2H),3.58(s,3H),2.83(s,4H),1.86(s,4H),1.22(t,J＝7.2Hz,3H). 13C NMR(100MHz,CDCl 3):δ170.81,162.00,159.55,142.90,139.22,137.04,134.92,130.76,129.83,128.87,127.56,125.99,122.62,110.52,60.50,40.13,29.44,29.12,23.01,22.87,14.27.HRMS(ESI)calcd for:C 23H 24N 2O 2S[M+H] +393.1642,found 393.1637。
实施例8.目标化合物S1-S25的合成方法
1-(2-丙叉基)氨基硫脲1a
Figure PCTCN2018083596-appb-000109
称取氨基硫脲(3.81g，41.8mmol)于100mL两口瓶，加入乙醇60mL，搅拌下加入丙酮(3.1mL，41.8mmol)，醋酸0.5mL，加热回流，TLC跟踪反应至原料转化完全。反应液降至室温，析出白色晶体，抽滤得粗品，用水重结晶，得纯品4.5g，产率82％。
4-苯基-2-(2-丙叉基肼基)噻唑1c
Figure PCTCN2018083596-appb-000110
将得到的中间体1a(4.5g，34.3mmol)投入250mL圆底烧瓶，加入2-溴苯乙酮(7.5g，37.7mmol)，加75mL乙醇，磁力搅拌，加热回流，TLC跟踪反应，待原料转化完全，静置至室温，抽滤，得黄色粉末固体，干燥，得黄色粉末状固体，产率85％。
4-苯基-2-肼基噻唑1d
Figure PCTCN2018083596-appb-000111
称取原料1c(1.0g，4.3mmol)于50mL两口瓶，加乙醇30mL，加80％水合肼(0.6mL，12.3mmol)，氩气保护下加热回流，24h后停止反应，静置一夜，抽滤，得黄色晶体，所得粗品用乙醇重结晶，得浅黄色针状晶体300mg，产率36％。
1H NMR(400MHz,DMSO-d 6,ppm):δ8.52(s,1H),7.79(d,J＝7.6Hz,2H),7.35(t,J＝7.6Hz,2H),7.24(t,J＝7.2Hz,1H),7.09(s,1H),4.82(s,2H).
(E)-4-苯基-2-(2-羧基苄叉肼基)噻唑S1
Figure PCTCN2018083596-appb-000112
称取邻羧基苯甲醛(66mg，0.44mmol)于25mL茄形瓶，加入肼解产物1d(70mg，0.37mmol)，加入乙醇15mL，滴入两滴醋酸作催化剂，氩气保护下常温搅拌，TLC跟踪反应至原料转化完全，快速抽滤，滤饼用冰乙醇洗，得亮黄色粉末状固体100mg，产率85％。Mp 196.8-197.5℃.
1H NMR(400MHz,DMSO-d 6,ppm):δ13.45(br,1H),12.49(br,1H),8.81(s,1H),7.99(d,J＝7.6Hz,1H),7.87(m,3H),7.63(t,J＝7.4Hz,1H),7.47(t,J＝7.2Hz,1H),7.41(t,J＝7.6Hz,2H),7.33(s,1H),7.30(t,J＝7.4Hz,1H). 13C NMR(125MHz,DMSO-d 6,ppm):δ168.53,168.53,150.97,140.58,135.02,134.99,132.31,130.74,130.15,129.15,128.96,128.96,127.90,126.34,125.90,125.90,104.20.HRMS(ESI)calcd for C 18H 16N 3O 2S[M-H] -322.0650,found 322.0656.
(E)-4-苯基-2-(2-甲酰基苄叉肼基)噻唑S2
Figure PCTCN2018083596-appb-000113
称取邻苯二甲醛(105mg，0.78mmol)于50mL两口瓶中，加入15mL乙醇溶解，向溶液中加入1d(75mg，0.39mmol)，氩气保护下常温搅拌，约10min后出现亮黄色沉淀，TLC跟踪反应至原料转化完全，抽滤，滤饼用乙醇洗，干燥，得25mg产物，产率21％。
1H NMR(400MHz,DMSO-d 6,ppm):δ12.51(s,1H),10.26(s,1H),8.80(s,1H),7.97(d,J＝8Hz,1H),7.91(d,J＝7.6Hz,1H),7.87(d,J＝7.6Hz,1H),7.31(t,J＝7Hz,1H),7.61(t,J＝7.2Hz,1H),7.44-7.38(m,3H),7.31(t,J＝7.2Hz,1H). 13C NMR(125MHz,DMSO-d 6,ppm):δ193.96,168.45,151.18,139.07,135.35,135.04,134.08,133.74,132.82,129.60,129.10,129.10,128.07,127.43,126.01,126.01,104.63.2.5.HRMS(ESI)calcd for C 17H 14N 3O 2S[M+H] +308.0858,found 308.0853.
4-(2-氯苯基)-2-(2-丙叉基肼基)噻唑3c
Figure PCTCN2018083596-appb-000114
合成方法同1c，得到乳黄色粉末状固体，产率80％。
1H NMR(400MHz,CDCl 3,ppm):δ7.71(d,J＝7.4Hz,1H),7.52(d,J＝7.4Hz,1H),7.42(m,2H),7.00(s,1H),2.22(s,3H),2.13(s,3H).
4-(2-氯苯基)-2-肼基噻唑3d
Figure PCTCN2018083596-appb-000115
合成方法同1d，得乳黄色针状晶体1.3g，产率48％。
1H NMR(400MHz,DMSO-d 6,ppm):δ8.56(s,1H),7.84(dd,J 1＝7.6Hz,J 2＝2.0Hz,1H),7.48(dd,J 1＝7.6Hz,J 2＝1.6Hz,1H),7.36(td,J 1＝7.6Hz,J 2＝1.6Hz,1H),7.29(td,J 1＝7.6Hz,J 2＝2.0Hz,1H),7.14(s,1H),4.87(s,2H).
(E)-4-(2-氯苯基)-2-(2-羧基苄叉肼基)噻唑S3
Figure PCTCN2018083596-appb-000116
合成路线同S1，得亮黄色粉末状固体3.6g，产率81％。Mp 195.2-195.2℃.
1H NMR(400MHz,DMSO-d 6,ppm):δ13.2(br,1H),12.4(br,1H),8.82(s,1H),8.00(d,J＝7.6Hz,1H),7.88(t,J＝7.0Hz,2H),7.64(t,J＝7.4Hz,1H),7.6(d,J＝7.6Hz,1H),7.48(t,J＝7.6Hz,1H),7.42(t,J＝7.8Hz,1H),7.36(m,2H). 13C NMR(100MHz,DMSO-d 6,ppm):δ168.63,167.77,147.63,140.76,135.08,133.71,132.43,131.54,131.23,130.83,130.83,130.26,129.47,129.28,127.69,126.47,109.26.HRMS(ESI)calcd for C 17H 13N 3O 2SCl[M+H] +358.0417,found 358.0417.
5-甲基-4-苯基-2-肼基噻唑4d
Figure PCTCN2018083596-appb-000117
称取中间体1a(1.5g，11.4mmol)于50mL圆底烧瓶，加15mL乙醇作溶剂，搅拌下加入2-溴苯丙酮(1.74mL，11.4mmol)，加热至回流，TLC跟踪反应至原料转化完全，静置至室温，抽滤，干燥，得黄色粉末1.96g，未经纯化，直接用于下一步。称取上一步产物(1.0g，4.1mmol)于50mL两口瓶，加乙醇20mL，加入新的80％水合肼(0.6mL，12.3mmol)，氩气保护下加热回流24h后，停止反应，反应液静置一夜，抽滤，所得粗品乙醇重结晶，得黄色针状晶体200mg，产率26％。 1H NMR(400MHz,DMSO-d6,ppm)：δ8.25(s,1H),7.56(d,J＝7.2Hz,2H),7.38(t,J＝7.6Hz,2H),7.27(t,J＝7.2Hz,1H),4.74(s,2H),2.35(s,3H).
(E)-5-甲基-4-苯基-2-(2-羧基苄叉肼基)噻唑S4
Figure PCTCN2018083596-appb-000118
合成方法同S1，得土黄色粉末状固体100mg，产率76％。Mp 215.9-216.0℃.
1H NMR(400MHz,DMSO-d 6,ppm):δ12.7(br,2H),8.77(s,1H),7.99(d,J＝7.6Hz,1H),7.87(d,J＝8.0Hz,1H),7.63-7.59(m,3H),7.48-7.43(m,3H),7.33(t,J＝7.2Hz,1H),2.43(s,3H). 13C NMR(125MHz,DMSO-d 6,ppm):δ168.66,164.72,146.00,140.05,135.64,135.24,132.36,130.83,130.12,129.08,128.73,128.73,128.35,128.35,127.51,126.33,117.61,12.74.HRMS(ESI)calcd for C 18H 16N 3O 2S[M+H] +338.0963,found 338.0954.
2’-氯-2-溴苯丙酮5b
Figure PCTCN2018083596-appb-000119
称取2-氯苯丙酮(0.55g，3.3mmol)于50mL单口瓶，加入5mL乙醚作溶剂，滴入2滴醋酸，将液溴(0.18mL，3.4mmol)溶于适量乙醚，冰浴下滴加，滴完后撤去冰浴，室温搅拌过夜。反应完全后，反应液用饱和NaCO 3萃取三次，有机层加无水NaSO 4干燥，旋干溶剂，得淡黄色液体。硅胶柱层析(PE/DCM＝4/1，v/v)分离，得产物0.68g，产率84％。
1H NMR(400MHz,DMSO-d 6,ppm):δ7.81(d,J＝7.6Hz,1H),7.60-7.42(m,3H),5.61(q,J＝6.4Hz,1H),1.79(d,J＝6.8Hz,1H).GC-MS(EI)calcd for C 9H 8BrClO[M] +2547.5,found 248.0.
5-甲基-4-(2-氯苯基)-2-肼基噻唑5d
Figure PCTCN2018083596-appb-000120
合成方法同4d，粗品经薄层硅胶制备板分离得绿色针状固体65mg，产率46％。
1H NMR(400MHz,DMSO-d 6,ppm):δ8.22(s,1H),7.51-7.49(m,1H),7.37-7.34(m,3H),4.74(s,2H),2.05(s,3H).
(E)-5-甲基-4-(2-氯苯基)-2-(2-羧基苄叉肼基)噻唑S5
Figure PCTCN2018083596-appb-000121
合成方法同S1，得淡黄色粉末状固体60mg，产率80％。Mp 220.0-220.3℃.
1H NMR(400MHz,DMSO-d 6,ppm):δ12.7(br,2H),8.77(s,1H),7.99(d,J＝7.6Hz,1H),7.87(d,J＝7.2Hz,1H),7.62(t,J＝7.4Hz,1H),7.562-7.543(m,1H),7.481-7.397(m,4H),2.14(s,3H). 13C NMR(125MHz,DMSO-d 6,ppm):δ168.65,165.18,144.49,140.16,135.25,134.56,133.21,132.46,130.83,130.14,130.03,129.11,127.45,126.37,119.49,12.15.HRMS(ESI)calcd for C 18H 15N 3O 2SCl[M+H] +372.0574,found 372.0569.
2’-氯-2-溴苯丁酮6b
Figure PCTCN2018083596-appb-000122
称取2-氯苯丁酮(1.0g，5.5mmol)于50mL单口瓶中，加入5mL乙醚，搅拌下滴入2滴冰醋酸，冰浴下滴入液溴(0.88g，5.5mmol)的乙醚溶液，室温搅拌过夜，TLC跟踪反应至原料转化完全，反应液用饱和NaHCO 3萃取三次，饱和NaCl萃取三次，无水NaSO 4干燥，旋干溶剂，得1.04g黄色液体，产率89％。
1H NMR(400MHz,DMSO-d 6,ppm):δ7.80(d,J＝7.6Hz,1H),7.61-7.55(m,2H),7.48(t,J＝7.6Hz,1H),5.45(t,J＝6.8Hz,1H),2.19-2.12(m,1H),1.99-1.88(m,1H),1.04(t,J＝7.2Hz,3H).
5-乙基-4-(2-氯苯基)-2-(2-丙叉基肼基)噻唑6c
Figure PCTCN2018083596-appb-000123
合成方法同1c，得棕色粘稠液体0.6g，产率85％。
1H NMR(400MHz,DMSO-d 6,ppm):δ10.43(br,1H),7.54-7.52(m,1H),7.41-7.37(m,3H),2.44(q,J＝7.6Hz,2H),1.94(s,3H),1.89(s,3H),1.10(t,J＝7.4Hz,3H).
5-乙基-4-(2-氯苯基)-2-肼基噻唑6d
Figure PCTCN2018083596-appb-000124
称取6c(0.6g,2.0mmol)于25mL单口瓶中，加入12mL乙醇，搅拌下加入80％水合肼(0.3mL,6.0mmol)，氩气保护下回流，TLC跟踪反应至原料转化完全，旋干溶剂，粗品硅胶柱层析(PE:DCM:MeOH＝30:20:3,v/v/v)分离，得棕色固体190mg，产率37％。LC-MS(ESI)calcd for C 11H 13ClN 3S[M+H] +254.05,found 254.10.
(E)-5-乙基-4-(2-氯苯基)-2-(2-羧基苄叉肼基)噻唑S6
Figure PCTCN2018083596-appb-000125
合成方法同S1，得亮黄色粉末状固体70mg，产率68％。Mp 223.9-223.9℃.
1H NMR(500MHz,DMSO-d 6,ppm):δ12.57(br,2H),8.79(s,1H),8.01(d,J＝8.0Hz,1H),7.88(d,J＝8.0Hz,1H),7.62(t,J＝7.5Hz,1H),7.56–7.51(m,1H),7.46(t,J＝7.5Hz,1H),7.44-7.36(m,3H),2.49(q,J＝7.5Hz,1H),1.13(t,J＝7.5Hz,3H). 13C NMR(125MHz,DMSO-d 6,ppm):δ169.28,165.92,144.14,140.84,135.89,135.46,133.99,133.03,133.02,131.46,130.81,130.73,130.60,129.73,128.09,127.73,127.01,20.99,17.25.HRMS(ESI)calcd for C 19H 17N 3O 2SCl[M+H] +386.0730,found 386.0729.
(E)-4-(2-氯苯基)-2-[2-(2-羧基-4-氟苄叉基)肼基]噻唑S24
Figure PCTCN2018083596-appb-000126
合成方法同S1，得土黄色粉末状固体75mg，产率70％。Mp 211.6-212.8℃.
1H NMR(400MHz,DMSO-d 6,ppm):δ13.52(br,1H),12.38(br,1H),8.78(s,1H),8.04(dd,J 1＝J 2＝7.2Hz,1H),7.86(d,J＝7.6Hz,1H),7.64(dd,J 1＝9.2Hz,J 2＝2.4Hz,1H),7.55-7.50(m,2H),7.42(t,J＝7.2Hz,1H),7.37-7.34(m,2H).HRMS(ESI)calcd for C 17H 11N 3O 2SClFNa[M+Na] +398.0142,found 398.0133.
(E)-4-(2-氯苯基)-2-[2-(2-羧基-4-甲基苄叉基)肼基]噻唑S25
Figure PCTCN2018083596-appb-000127
合成方法同S1，得亮黄色粉末状固体75mg，产率70％。Mp 221.6-222.5℃.
1H NMR(400MHz,DMSO-d 6,ppm):δ13.37(br,1H),12.31(br,1H),8.78(s,1H),7.91-7.86(m,2H),7.70(s,1H),7.53(d,J＝7.6Hz,1H),7.45(d,J＝9.2Hz,1H),7.41(d,J＝7.6Hz,1H),7.37-7.34(m,2H),2.38(s,3H).HRMS(ESI)calcd for C 18H 15N 3O 2SCl[M+H] +372.0574,found 372.0568.
4-(2-氯苯基)-2-(1-乙基肼基)噻唑8d
Figure PCTCN2018083596-appb-000128
称取8c(0.5g，1.9mmol)于100mL圆底烧瓶中，加入碳酸铯(3.0g，5.6mmol)，20mL无水DMF，氩气保护下，滴入碘乙烷(0.185mL，2.2mmol)，升温至60℃，TLC跟踪反应，约10h后原料转化完全，将反应液降至室温，过滤，滤液加入200mL水，乙酸乙酯萃取三次，有机层饱和NaCl水溶液洗三次，无水NaSO 4干燥，旋干溶剂，得黄棕色油状物，产物未经纯化直接用于下一步。将得到的中间体溶于15mL THF，加入10mL水和10滴浓盐酸，氩气保护下于50℃反应约3h，待原料转化完全后用乙酸乙酯萃取三次，有机层先后用饱和NaHCO 3水溶液和饱和NaCl水溶液洗涤，无水NaSO 4干燥，旋干溶剂，粗品硅胶柱层析(DCM:MeOH＝100:1，v/v)分离，得棕黄色固体0.26g，产率55％。
1H NMR(400MHz,DMSO-d 6,ppm):δ7.87(d,J＝7.8Hz,1H),7.48(d,J＝7.6Hz,1H),7.38(t,J＝7.6Hz,1H),7.30(t,J＝7.8Hz,1H),7.14(s,1H),5.16(s,2H),3.66(q,J＝7.2Hz,2H),1.84(t,J＝7.2Hz,3H).
(E)-4-(2-氯苯基)-2-[1-乙基-2-(2-羧基苄叉基)肼基]噻唑S8
Figure PCTCN2018083596-appb-000129
称取中间体8d(60mg，0.63mmol)与邻羧基苯甲醛(104mg，0.69mmol)于50mL圆底烧瓶中，加入10mL乙醇，氩气保护下加入回流，TLC监测反应至原料转化完全，将反应降至室温，旋干溶剂，硅胶柱层析(DCM:MeOH＝50:1,v/v)分离，得黄色粉末状固体100mg，产率43％。Mp 203.3-204.1℃.
1H NMR(500MHz,DMSO-d 6,ppm):δ13.32(br,1H),8.64(s,1H),7.98–7.91(m,3H),7.66(t,J＝7.5Hz,1H),7.56–7.46(m,2H),7.45–7.39(m,2H),7.34(t,J＝6.8Hz,1H),4.32(q,J＝6.8Hz,2H),1.27(t,J＝7.0Hz,3H). 13C NMR(125MHz,DMSO-d 6,ppm):δ168.56,168.36,147.34,137.00,135.42,133.53,132.50,131.53,131.12,130.92,130.72,130.22,129.42,129.19,127.62,126.62,111.22,40.38,10.33.HRMS(ESI)calcd for C 19H 17N 3O 2SCl[M+H] +386.0730,found 386.0728.
4-(2-氯苯基)-2-(1-异丙基肼基)噻唑9d
Figure PCTCN2018083596-appb-000130
合成方法同8d，得棕色针状固体190mg，产率76％。
1H NMR(400MHz,DMSO-d 6,ppm):δ7.87(d,J＝7.6Hz,1H),7.48(d,J＝8.0Hz,1H),7.37(t,J＝7.4Hz,1H),7.29(t,J＝7.6Hz,1H),7.13(s,1H),4.91(s,2H),4.56(hept,J＝6.8Hz,1H),1.14(d,J＝6.8Hz,6H).LC-MS(ESI)cald for C 12H 15ClN 3S[M+H] +268.07,found 268.10.
(E)-4-(2-氯苯基)-2-[1-异丙基-2-(2-羧基苄叉基)肼基]噻唑S9
Figure PCTCN2018083596-appb-000131
合成方法同S8，得黄色粉末状固体130mg，产率93％。Mp185.6-187.0℃.
1H NMR(400MHz,DMSO-d 6,ppm):δ13.35(br,1H),8.91(s,1H),7.99(d,J＝8.0Hz,1H),7.95-7.92(m,2H),7.67(t,J＝7.6Hz,1H),7.54(d,J＝8.0Hz,1H),7.52(t,J＝7.6Hz,1H),7.46-7.42(m,2H),7.36(t,J＝7.6Hz,1H),5.22-5.11(m,1H),1.57(d,J＝6.8Hz,6H). 13C NMR(100MHz,DMSO-d 6,ppm):δ168.22,168.21,146.90,137.32,135.23,133.14,132.07,131.06,130.64,130.58,130.39,129.88,128.97,128.78,127.28,125.91,111.12,49.61,18.07,18.07.HRMS(ESI)calcd for C 20H 19N 3O 2SCl[M+H] +400.0887,found 400.0885.
4-(2-氯苯基)-2-(1-羟乙基肼基)噻唑10d
Figure PCTCN2018083596-appb-000132
合成方法同8d，得黄色粉末状固体120mg，产率50％。
1H NMR(400MHz,DMSO-d 6,ppm):δ7.86(d,J＝7.6Hz,1H),7.48(d,J＝7.6Hz,1H),7.37(t,J＝7.0Hz,1H),7.30(t,J＝7.6Hz,1H),7.14(s,1H),5.22(s,2H),4.81(br,1H),3.72(s,4H).LC-MS(ESI)calcd for C 11H 13ClN 3OS[M+H] +270.0,found 270.0.
(E)-4-(2-氯苯基)-2-[1-羟乙基-2-(2-羧基苄叉基)肼基]噻唑S10
Figure PCTCN2018083596-appb-000133
合成方法同S8，得土黄色粉末状固体93mg，产率46％。Mp 187.9-188.9℃.
1H NMR(400MHz,DMSO-d 6,ppm):δ13.24(br,1H),8.75(s,1H),7.98-7.01(m,3H),7.66(t,J＝7.6Hz,1H),7.54(d,J＝8.0Hz,1H),7.49(t,J＝7.6Hz,1H),7.45-7.41(m,2H),7.36(td,J 1＝7.6Hz,J 2＝1.6Hz,1H),4.35(t,J＝6.4Hz,2H),3.76(t,J＝6.4Hz,2H). 13C NMR(100MHz,DMSO-d 6,ppm):δ168.64,168.23,146.87,136.89,134.91,133.15,131.99,131.19,130.71,130.46,130.32,130.16,129.04,128.79,127.22,126.28,110.78,56.24,47.46.HRMS(ESI)calcd for C 19H 17N 3O 3SCl[M+H] +402.0679,found 402.0678.
4-(2-氯苯基)-2-(1-正丙基肼基)噻唑11d
Figure PCTCN2018083596-appb-000134
合成方法同8d，得棕色固体100mg，产率75％。
1H NMR(400MHz,DMSO-d 6,ppm):δ7.86(dd,J 1＝8.0Hz,J 2＝1.6Hz,1H),7.48(dd,J 1＝8.0Hz,J 2＝1.6Hz,1H),7.37(td,J 1＝7.6Hz,J 2＝1.2Hz,1H),7.30(td,J 1＝7.6Hz,J 2＝1.2Hz,1H),7.12(s,1H),5.16(br,2H),3.59(t,J＝7.2Hz,2H),1.73-1.63(m,2H),0.89(t,J＝7.2Hz,3H).LC-MS(ESI)calcd for C 12H 15ClN 3S[M+H] +268.1,found 268.1.
(E)-4-(2-氯苯基)-2-[1-正丙基-2-(2-羧基苄叉基)肼基]噻唑S11
Figure PCTCN2018083596-appb-000135
合成方法同S8，得黄色粉末状固体60mg，产率76％。Mp 203.3-204.1℃.
1H NMR(400MHz,DMSO-d 6,ppm):δ13.35(br,1H),8.65(s,1H),7.98(d,J＝8.0Hz,1H),7.95-7.92(m,2H),7.67(t,J＝7.2Hz,1H),7.54(d,J＝8.0Hz,1H),7.5(t,J＝7.6Hz,1H),7.45-7.42(m,2H),7.36(t,J＝7.6Hz,1H),4.25(t,J＝7.2Hz,2H),1.82-1.73(m,2H),0.97(t,J＝7.4Hz,1H). 13C NMR(100MHz,DMSO-d6,ppm):δ168.54,168.22 146.95,136.63,134.96,133.17,132.11,131.10,130.74,130.55,130.34,129.82,129.04,128.80,127.26,126.09,110.77,46.31,17.98,11.17.HRMS(ESI)calcd for C 20H 19N 3O 2SCl[M+H] +400.0887,found 400.0879.
4-(2-氯苯基)-2-[1-(2-丁基)肼基]噻唑12d
Figure PCTCN2018083596-appb-000136
合成方法同8d，得棕色粘稠固体100mg，产率62％。
1H NMR(400MHz,DMSO-d 6,ppm):δ7.86(dd,J 1＝8.0Hz,J 2＝1.6Hz,1H),7.48(dd,J 1＝8.0Hz,J 2＝1.2Hz,1H),7.37(td,J 1＝7.6Hz,J 2＝1.2Hz,1H),7.29(td,J 1＝7.6Hz,J 2＝1.2Hz,1H),7.10(s,1H),4.85(s,2H),4.40-4.32(m,1H),1.73-1.61(m,1H),1.52-1.42(m,1H),1.12(d,J＝6.8Hz,3H),0.85(t,J＝7.4Hz,3H).
(E)-4-(2-氯苯基)-2-[1-(2-丁基)-2-(2-羧基苄叉基)肼基]噻唑S12
Figure PCTCN2018083596-appb-000137
合成方法同S8，得黄色粉末状固体105mg，产率80％。Mp 170.5-170.6℃.
1H NMR(400MHz,DMSO-d 6,ppm):δ13.32(br,1H),8.91(s,1H),7.99(d,J＝8.0Hz,1H),7.95-7.90(m,2H),7.67(t,J＝7.6Hz,1H),7.55-7.48(m,2H),7.46-7.42(m,2H),7.36(t,J＝7.6Hz,1H),5.00-4.93(m,1H),2.35-2.24(m,1H),1.92-1.81(m,1H),1.54(d,J＝6.8Hz,3H),0.88(t,J＝7.2Hz,3H). 13C NMR(100MHz,DMSO-d 6,ppm):δ168.66,168.19,146.97,137.03,135.24,133.19,132.13,131.04,130.67,130.58,130.39,129.70,128.98,128.77,127.29,125.91,111.04,55.67,25.26,16.33,11.14.HRMS(ESI)calcd for C 21H 21N 3O 2SCl[M+H] +414.1043,found 414.1029.
4-(2-氯苯基)-2-[1-(2-戊基)肼基]噻唑13d
Figure PCTCN2018083596-appb-000138
合成方法同8d，得棕色粘稠固体120mg，产率65％。
1H NMR(400MHz,DMSO-d 6,ppm):δ7.86(dd,J 1＝7.6Hz,J 2＝1.6Hz,1H),7.47(d,J＝7.6Hz,1H),7.37(td,J 1＝7.6Hz,J 2＝1.2Hz,1H),7.29(td,J 1＝7.6Hz,J 2＝1.6Hz,1H),7.10(s,1H),4.85(br,2H),4.54-4.45(m,1H),1.73-1.64(m,1H),1.40-1.36(m,1H),1.32-1.26(m,2H), 1.11(d,J＝6.8Hz,3H),0.89(t,J＝6.8Hz,3H).LC-MS(ESI)calcd for C 14H 19ClN 3S[M+H] +296.1,found 296.1.
(E)-4-(2-氯苯基)-2-[1-(2-戊基)-2-(2-羧基苄叉基)肼基]噻唑S13
Figure PCTCN2018083596-appb-000139
合成方法同S8，得黄色固体70mg，产率68％。Mp 146.7-148.0℃.
1H NMR(400MHz,DMSO-d 6,ppm):δ13.35(br,1H),8.91(s,1H),7.98(d,J＝7.6Hz,1H),7.94(d,J＝8.0Hz,1H),7.91(dd,J 1＝7.6Hz,J 2＝1.6Hz,1H),7.67(t,J＝7.6Hz,1H),7.53(d,J＝8.0Hz,1H),7.49(t,J＝7.6Hz,1H),7.46-7.42(m,2H),7.36(td,J 1＝7.6Hz,J 2＝1.6Hz,1H),5.14-5.06(m,1H),2.34-2.25(m,1H),1.82-1.73(m,1H),1.53(d,J＝6.8Hz,3H),1.34-1.24(m,2H),0.89(t,J＝7.4Hz,1H). 13C NMR(100MHz,DMSO-d 6,ppm):δ168.68,168.20,146.98,137.04,135.30,133.20,132.14,131.00,130.68,130.59,130.40,129.68,128.99,127.30,125.90,111.09,53.81,34.20,19.46,16.46,13.60.HRMS(ESI)calcd for C 22H 23N 3O 2SCl[M+H] +428.1200,found 428.1193.
5-甲基-4-(2-氯苯基)-2-[1-(2-丁基)肼基]噻唑14d
Figure PCTCN2018083596-appb-000140
合成方法同8d，得棕色粘稠固体105mg，产率50％。
1H NMR(400MHz,DMSO-d 6,ppm):δ7.51-7.49(m,1H),7.40-7.36(m,3H),4.71(s,2H),4.36-4.26(m,1H),2.05(s,3H),1.71-1.57(m,1H),1.36-1.26(m,3H),1.06(d,J＝6.4Hz,3H),0.87(t,J＝7.2Hz,3H).LC-MS(ESI)calcd for C 15H 21ClN 3S[M+H] +310.11,found 310.10.
(E)-5-甲基-4-(2-氯苯基)-2-[1-(2-戊基)-2-(2-羧基苄叉基)肼基]噻唑S14
Figure PCTCN2018083596-appb-000141
合成方法同S8，得黄色固体130mg，产率65％。Mp 99.9-100.1℃.
1H NMR(400MHz,DMSO-d 6,ppm):δ13.29(br,1H),8.85(s,1H),7.98(d,J＝8.0Hz,1H),7.92(d,J＝7.6Hz,1H),7.65(t,J＝7.6Hz,1H),7.56-7.54(m,1H),7.51-7.41(m,4H),5.05-4.96(m,1H),2.29-2.22(m,1H),2.16(s,3H),1.75-1.67(m,1H),1.46(d,J＝7.2Hz,3H),1.28-1.23(m,2H),0.87(t,J＝7.6Hz,3H). 13C NMR(100MHz,DMSO-d 6,ppm):δ168.23,166.06,144.08,136.14,135.46,134.09,132.79,132.09,131.93,130.58,129.64,129.60,129.48,128.56,126.95,125.73,121.62,53.39,34.01,19.41,16.35,13.58,11.52.HRMS(ESI)calcd for C 23H 25N 3O 2SCl[M+H] +442.1356,found 442.1354.
2-甲基-1-(2-羧基苄叉基)氨基硫脲7h
Figure PCTCN2018083596-appb-000142
称取化合物7g(80mg，0.76mmol)于50mL单口瓶中，加入20mL乙醇，搅拌下加入邻羧基苯甲醛(114mg，0.76mmol)，加热至回流，TLC监测反应至原料转化完全，将反应液冷至室温，旋干溶剂，硅胶柱层析(DCM/MeOH＝120:1,v/v)，得白色粉末状固体100mg，产率56％。
1H NMR(400MHz,DMSO-d 6,ppm):δ13.36(br,1H),8.56(s,1H),8.51(s,1H),8.31(d,J＝7.6Hz,1H),8.25(s,1H),7.88(d,J＝8Hz,1H),7.59(t,J＝7.2Hz,1H),7.50(t,J＝7.2Hz,1H),3.77(s,3H).LC-MS(ESI)calcd for C 10H 12N 3O 2S[M] +238.1,found 238.1.
(E)-4-(2-氯苯基)-2-[1-甲基-2-(2-羧基苄叉基)肼基]噻唑S7
Figure PCTCN2018083596-appb-000143
称取7h(100mg，0.42mmol)于50mL单口瓶中，加入10mL乙醇，搅拌下加入2’-氯-2-溴苯乙酮(65μL，0.42mmol)，升温至回流，TLC跟踪反应至原料转化完全，将反应液冷至室温，旋干溶剂，硅胶柱层析(DCM/MeOH＝120:1,v/v)分离，得黄色粉末状固体106mg，产率68％。Mp 210.4-211.0℃.
1H NMR(400MHz,DMSO-d 6,ppm):δ13.30(s,1H),8.62(s,1H),8.02(d,J＝7.6Hz,1H),7.98–7.90(m,2H),7.66(t,J＝7.6Hz,1H),7.56–7.49(m,2H),7.47(s,1H),7.43(td,J 1＝7.4Hz,J 2＝1.2Hz,1H),7.36(td,J 1＝7.6Hz,J 2＝1.6Hz,1H),3.68(s,3H). 13C NMR(125MHz,DMSO-d 6,ppm):δ168.98,168.57,147.11,136.94,135.17,133.42,132.48,131.51,131.09,130.98,130.75,130.16,129.45,129.19,127.63,126.51,111.41,32.88.HRMS(ESI)calcd for C 18H 15N 3O 2SCl[M+H] +372.0574,found 372.0575.
(E)-4-苯基-2-[1-甲基-2-(2-羧基苄叉基)肼基]噻唑S15
Figure PCTCN2018083596-appb-000144
合成方法同S7，得黄色粉末状固体78mg，产率85％。Mp 200.6-201.8℃.
1H NMR(400MHz,DMSO-d 6,ppm):δ13.31(br,1H),8.62(s,1H),8.02(d,J＝7.6Hz,1H),7.94-7.91(m,3H),7.66(t,J＝7.2Hz,1H),7.49(t,J＝7.2Hz,1H),7.45-7.40(m,3H),7.31(t,J＝7.2Hz,1H),3.71(s,3H). 13C NMR(100MHz,DMSO-d 6,ppm):δ169.45,168.20,150.18,136.35,134.80,134.49,132.07,130.60,129.71,128.76,128.56,128.56,127.59,126.09,125.54,125.54,105.97,32.51.HRMS(ESI)calcd for C 18H 16N 3O 2S[M+H] +338.0963,found 338.0963.
(E)-4-(3-氯苯基)-2-[1-甲基-2-(2-羧基苄叉基)肼基]噻唑S16
Figure PCTCN2018083596-appb-000145
合成方法同S7，得黄色粉末状固体80mg，产率69％。Mp 244.7-245.4℃.
1H NMR(400MHz,DMSO-d 6,ppm):δ13.32(br,1H),8.63(s,1H),8.01(d,J＝7.6Hz,1H),7.97(s,1H),7.93(d,J＝7.6Hz,1H),7.88(d,J＝8.0Hz,1H),7.66(t,J＝7.6Hz,1H),7.61(s,1H),7.50(t,J＝7.6Hz,1H),7.45(t,J＝7.6Hz,1H),7.37(d,J＝8.0Hz,1H),3.71(s,3H). 13C NMR(100MHz,DMSO-d 6,ppm):δ169.57,168.18,148.56,136.64,136.50,134.72,133.48,132.06,130.59,130.44,129.76,128.81,127.28,126.12,125.16,124.05,107.56,32.52.HRMS(ESI)calcd for C 18H 15N 3O 2SCl[M+H] +372.0574,found 372.0574.
(E)-4-(2,5-二氯苯基)-2-[1-甲基-2-(2-羧基苄叉基)肼基]噻唑S17
Figure PCTCN2018083596-appb-000146
合成方法同S7，得黄色粉末状固体100mg，产率72％。Mp 268.4-269.5℃.
1H NMR(400MHz,DMSO-d 6,ppm):δ13.31(br,1H),8.63(s,1H),8.02-8.00(m,2H),7.93(d,J＝7.2Hz,1H),7.67(t,J＝7.6Hz,1H),7.63(s,1H),7.58(d,J＝7.6Hz,1H),7.50(t,J＝7.2Hz,1H),7.43(dd,J＝7.2Hz,1H),3.68(s,3H). 13C NMR(100MHz,DMSO-d 6,ppm):δ168.68,168.15,145.13,136.79,134.70,134.21,132.14,132.06,131.85,130.59,130.17,129.76,129.20,128.84,128.58,126.13,112.31,32.49.HRMS(ESI)calcd for C 18H 14N 3O 2SCl 2[M+H] +406.0184,found 406.0187.
(E)-4-(2-氯苯基)-2-[1-甲基-2-(2-羧基苄叉基)肼基]噻唑S18
Figure PCTCN2018083596-appb-000147
合成方法同S7，得黄色粉末状固体78mg，产率70％。Mp 208.8-209.8℃.
1H NMR(400MHz,DMSO-d 6,ppm):δ13.46(br,1H),8.60(s,1H),8.01(d,J＝8.0Hz,1H),7.92(d,J＝8.0Hz,1H),7.64(t,J＝7.4Hz,1H),7.56(d,J＝7.6Hz,1H),7.49-7.39(m,4H),3.56(s,3H),2.15(s,3H). 13C NMR(100MHz,DMSO-d 6,ppm):δ168.98,166.46,144.56,136.46,135.29,134.54,133.25,132.50,132.31,131.05,130.72,130.26,130.01,129.09,127.49,126.42,121.85,32.46,12.16.HRMS(ESI)calcd for C 19H 17N 3O 2SCl[M+H] +386.0730,found 386.0727.
(E)-5-甲基-4-苯基-2-[1-甲基-2-(2-羧基苄叉基)肼基]噻唑S19
Figure PCTCN2018083596-appb-000148
合成方法同S7，得黄色粉末状固体0.5g，产率60％。Mp 222.7-224.9℃.
1H NMR(400MHz,DMSO-d 6,ppm):δ13.32(br,1H),8.58(s,1H),8.01(d,J＝8.0Hz,1H),7.92(d,J＝7.6Hz,1H),7.68-7.63(m,3H),7.50-7.43(m,3H)，7.34(t,J＝7.4Hz,1H),3.62(s,3H),2.44(s,3H). 13C NMR(100MHz,DMSO-d 6,ppm):δ168.24,165.36,145.47,135.66,135.13,134.90,131.98,130.58,129.70,128.59,128.25,128.25,127.86,127.86,127.09,125.94,119.44,31.93,12.24.HRMS(ESI)calcd for C 19H 16N 3O 2S[M-H] -350.0963,found 350.0951.
2-甲酰基-5-三氟甲基苯甲酸20f
Figure PCTCN2018083596-appb-000149
将正丁基锂(3mL，7.4mmol，2.5mol/L in hexane)用注射器加入预先装有10mL无水THF的100mL低温反应瓶中，降温至-78℃，缓慢滴加2-溴-5-三氟甲基苯甲酸(1.0g，3.7mmol)的THF溶液，-78℃下搅拌1h，缓慢滴加1mL无水DMF，慢慢升至室温，室温下反应6h。在反应液中加入适量2N NaOH，用乙醚萃取，合并水层，用浓盐酸调pH至酸性，EA萃取三次，有机层用饱和NaCl洗，合并有机层，无水Na 2SO 4干燥，旋干溶剂后硅胶柱层析(PE/EA/AcOH＝6/1/0.1,v/v/v)分离，得70mg乳白色固体，产率18％。
1H NMR(400MHz,DMSO-d 6,ppm):δ8.17-8.13(m,2H),7.91(d,J＝8.0Hz,1H).GC-MS(EI)calcd for C 9H 5F 3O 3[M] +218.0,found 218.0.
2-甲基-1-(2-羧基-4-三氟甲基苄叉基)氨基硫脲20h
Figure PCTCN2018083596-appb-000150
称取2-甲酰基-5-三氟甲基苯甲酸(46mg，0.21mmol)于50mL圆底烧瓶中，称取2-甲基氨基硫脲(26mg，0.21mmol)，加入6mL乙醇，加热回流至原料转化完全，旋干溶剂，硅胶柱层析(DCM/MeOH＝100/1，v/v)，得亮黄色粉末状固体。
1H NMR(400MHz,DMSO-d 6,ppm):δ8.81(s,1H),8.58(s,1H),8.50(d,J＝8.4Hz,1H),8.40(s,1H),8.12(s,1H),7.75(d,J＝8.4Hz,1H),5.77(s,3H).LC-MS(ESI)calcd for C 11H 11F 3N 3O 2S[M+H] +306.05,found 306.05.
(E)-4-(2-氯苯基)-2-[1-甲基-2-(4-三氟甲基-2-羧基苄叉基)肼基]噻唑S20
Figure PCTCN2018083596-appb-000151
合成方法同S7，得土黄色粉末状固体50mg，产率56％。Mp 209.3-210.7℃.
1H NMR(400MHz,DMSO-d 6,ppm):δ14.02(br,1H),8.66(s,1H),8.21(d,J＝8.0Hz,1H),8.17(s,1H),8.02(d,J＝8.0Hz,1H),7.95(d,J＝7.6Hz,1H),7.56-7.53(m,2H),7.43(t,J＝7.6Hz,1H),7.37(t,J＝7.6Hz,1H),3.70(s,3H). 13C NMR(100MHz,DMSO-d 6,ppm):δ168.33,167.17,146.79,138.38,135.01,132.91,131.12,130.70,130.37,129.14,128.57,128.25,128.20,127.26,127.04,125.10,122.40,111.51,32.68.HRMS(ESI)calcd for C 19H 14N 3O 2SClF 3[M+H] +440.0447,found 440.0433.
2-甲酰基-5-甲基苯甲酸21f
Figure PCTCN2018083596-appb-000152
合成方法同20f，得白色粉末状固体0.4g，产率26％。
1H NMR(400MHz,DMSO-d 6,ppm):δ13.56(br,1H),10.42(br,1H),7.68-7.57(m,3H),2.44(s,3H).LC-MS(ESI)calcd for C 9H 7O 3[M-H] -163.04,163.05.
2-甲基-1-(2-羧基-4-甲基苄叉基)氨基硫脲21h
Figure PCTCN2018083596-appb-000153
合成方法同20h，得白色粉末状固体0.36g，产率60％。
1H NMR(400MHz,DMSO-d 6,ppm):δ13.28(br,1H),8.52(s,1H),8.47(br,1H),8.23-8.21(m,2H),7.69(s,1H),7.40(d,J＝8.0Hz,1H),3.75(s,3H),2.38(s,3H).
(E)-4-(2-氯苯基)-2-[1-甲基-2-(4-甲基-2-羧基苄叉基)肼基]噻唑S21
Figure PCTCN2018083596-appb-000154
合成方法同S7，得黄色粉末状固体120mg，产率76％。Mp 231.3-232.5℃.
1H NMR(400MHz,DMSO-d 6,ppm):δ13.30(br,1H),8.59(s,1H),7.96(d,J＝7.6Hz,1H),7.92(d,J＝8.0Hz,1H),7.75(s,1H),7.54(d,J＝7.6Hz,1H),7.49-7.46(m,2H),7.43(t,J＝7.6Hz,1H),7.36(t,J＝7.6Hz,1H),3.66(s,3H),2.38(s,3H). 13C NMR(100MHz,DMSO-d 6,ppm):δ168.60,168.35,146.68,138.54,136.64,133.03,132.70,132.07,131.11,130.86,130.67,130.34,129.83,129.00,127.21,126.04,110.84,32.39,20.69.HRMS(ESI)calcd for C 19H 17N 3O 2SCl[M+H] +386.0730,found 386.0738.
(E)-5-甲基-4-苯基-2-[1-甲基-2-(4-甲基-2-羧基苄叉基)肼基]噻唑S22
Figure PCTCN2018083596-appb-000155
合成方法同S7，得黄色粉末状固体0.46g，产率70％。Mp 243.2-245.2℃.
1H NMR(400MHz,DMSO-d 6,ppm):δ13.24(br,1H),8.54(s,1H),7.91(d,J＝8.0Hz,1H),7.73(s,1H),7.64-7.53(m,2H),7.46-7.42(m,3H),7.33(t,J＝7.4Hz,1H),3.60(s,3H),2.44(s,3H),2.38(s,3H). 13C NMR(100MHz,DMSO-d 6,ppm):δ168.35,165.40,145.43,138.33,135.76,135.16,132.68,132.22,130.86,129.62,128.24,128.24,127.85,127.85,127.06,125.89,119.27,31.85,20.68,12.24.HRMS(ESI)calcd for C 20H 20N 3O 2S[M+H] +366.1276,found 366.1273.
2-甲酰基-5-氟苯甲酸23f
Figure PCTCN2018083596-appb-000156
合成方法同20f，得淡黄色粉末状固体68mg，产率15％。
1H NMR(400MHz,DMSO-d 6,ppm):δ7.76-7.75(m,1H),7.69-7.62(m,2H).LC-MS(ESI)calcd for C 8H 4FO 3[M-H] -167.01,found 167.10.
1-(2-丙叉基)-2-甲基氨基硫脲23a
Figure PCTCN2018083596-appb-000157
称取7g(0.63g，6.0mmol)原料于50mL单口瓶中，加入25mL乙醇作溶剂，搅拌下加入丙酮(0.45mL，6.0mmol)，滴入5滴冰醋酸，加热至回流，TLC跟踪反应至原料转化完全， 硅胶柱层析(DCM/MeOH＝100/1,v/v)，得白色粉末状产物0.5g，产率58％。
1H NMR(400MHz,DMSO-d 6,ppm):δ8.56(s,1H),5.58(s,1H),3.10(s,3H),1.24(s,6H).4-(2-氯苯基)-2-(1-甲基肼基)噻唑23d
Figure PCTCN2018083596-appb-000158
合成方法同8d，棕色针状固体1.2g，产率61％。
1H NMR(400MHz,DMSO-d 6,ppm):δ7.88(dd,J 1＝7.6Hz,J 2＝1.6Hz,1H),7.49(dd,J 1＝8.0Hz,J 2＝1.6Hz,1H),7.38(td,J 1＝7.6Hz,J 2＝1.6Hz,1H),7.30(td,J 1＝8.0Hz,J 2＝1.6Hz,1H),7.17(s,1H),5.22(s,2H),3.25(s,3H).
(E)-4-(2-氯苯基)-2-[1-甲基-2-(2-羧基-4-氟苄叉基)肼基]噻唑S23
Figure PCTCN2018083596-appb-000159
合成方法同S8，得亮黄色粉末状固体35mg，产率57％。Mp 236.2-237.1℃.
1H NMR(400MHz,DMSO-d 6,ppm):δ8.61(s,1H),8.06-8.02(dd,J 1＝5.6Hz,J 2＝8.4Hz,1H),7.96(d,J＝7.2Hz,1H),7.67-7.64(dd,J 1＝9.6Hz,J 2＝2.4Hz,1H),7.55-7.51(m,2H),7.47(s,1H),7.43(t,J＝7.2Hz,1H),7.36(t,J＝7.2Hz,1H),3.68(s,3H). 13C NMR(100MHz,DMSO-d 6,ppm):δ168.55,168.01,159.74(d, 1J＝249Hz),146.67,133.68,133.10,131.50,131.12,130.72,130.32,130.10(d, 3J＝8.8Hz),129.06,127.23,125.53(d, 4J＝3.1Hz),121.75(d, 3J＝11.8Hz),118.76(d, 2J＝22Hz),111.13,32.28.HRMS(ESI)calcd for C 18H 14N 3O 2FSCl[M+H] +390.0479,found 390.0475.
实施例9.活性检测
本发明人检测了本发明的化合物以及阳性对照药物布喹那、蒽环类药物(柔红霉素、去甲氧柔红霉素或米托蒽醌)和阿糖胞苷等对急性髓细胞白血病细胞系的半数抑制浓度。
本实施例使用的实验材料如下：CCK8试剂购自Beyotime；THP-1、MV4-11、RS4-11、HL60细胞购自美国ATCC，MOLM13、MOLM14、SIG-M5、AML2、AML3、AML5、U937、MONOMAC6购自德国DSMZ公司；培养基购自美国Hylcone；胎牛血清购自美国Gibco公司；CO 2培养箱购自美国Thermo公司，型号为TM3111；生物安全柜购自Heal Force；超纯水仪购自Millipore Synergy UV；液氮罐购自乐山市东亚机电工贸有限公司；立式冷藏陈列柜购自浙江星星家电股份有限公司，型号为LSC-218C；台式低速离心机购自长沙湘仪离心机仪器有限公司，型号为L500；96孔板购美国Thermo公司；细胞计数仪购自美国Invitrogen公司；多功能酶标仪购自美国BioTek公司，型号为Synergy2；移液枪购自德国eppendorf公司；离心管、移液管、培养皿等耗材均购自美国Thermo公司；DMSO等试剂购自上海凌峰化学试剂有限公司。
实验方法：用含10％胎牛血清的培养基配成单个细胞悬液，以每孔8万/mL接种于96孔培养板中，每孔体积为100μL，然后将培养板移入CO 2培养箱中，在温度为37℃、5％CO 2 及饱和湿度条件下培养24h。取新鲜配制的化合物母液，并计算好所需的抑制剂浓度和稀释梯度(一般以10μM为起始浓度)，用培养基进行稀释获得化合物物梯度稀释液，加入到96孔板对应的孔中，拍打均匀，与细胞进行共同孵育，在细胞培养箱中培养孵育72h。孵育结束后每孔加入CCK8试剂10μL，再放入培养箱中孵育4-8小时，450nm下测定OD值。按以下公式计算药物对细胞生长的存活率：存活率(％)＝(OD 加药-OD 空白)/(OD 对照-OD 空白)×100％，拟合得IC 50及抑制曲线。
表1.化合物对急性髓细胞白血病细胞系的半数抑制浓度
IC 50(nM) THP-1 SIG-M5 AML2 AML5 HL60 MONOMAC6 AML3 U937 MOLM14 MOLM13
Brequinar 274 188 128 148 926 198 1033 344 410 235
S1 2261 1130 723 649 1557 1001 3780 1872 1603 630
S3 1096 610 272 391 6152 594 752 683 336 132
S4 1319 659 422 378 908 584 2091 1899 934 367
S5 1934 1153 669 802 741 476 1799 891 763 1349
S6 4497 1605 561 372 2695 1273 5904 1504 821 328
S7 122 61 39 35 84 54 204 101 145 345
S8 1410 725 302 418 1870 1000 2206 288 324 302
S9 2039 952 280 464 1042 1586 5459 894 745 914
S10 3917 2269 242 365 3674 603 4259 2577 1228 1629
S11 239 107 104 49 269 62 218 198 97 238
S12 700 417 241 289 2688 414 1428 631 466 573
S13 548 326 189 226 2105 324 1117 494 506 499
S14 440 262 152 182 1689 261 900 397 314 204
S15 709 422 244 293 2722 420 1447 639 556 418
S16 304 181 105 126 1167 180 620 274 193 277
S17 810 482 279 334 3108 479 1650 729 659 537
S18 1020 607 351 421 3916 603 2078 919 853 648
S19 252 150 87 104 969 149 513 204 199 626
S20 1815 801 173 345 5389 792 4207 645 716 583
S21 247 238 341 631 359 195 1834 364 472 312
S22 328 93 120 119 1041 413 579 290 315 240
S23 586 299 121 170 2599 297 1324 516 433 295
44 622 303 200 175 420 270 1008 505 751 1345
45 521 305 100 200 502 624 1204 774 720 1545
                     
从表1可以看，本发明的化合物对AML细胞的增殖均有抑制作用，普遍优于阳性对照药，其中化合物S7对AML细胞的增殖抑制效果甚至优于阳性对照药布喹那(Brequinar)。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (13)

  1. 式I所示化合物在制备治疗白血病的药物中的用途，
    Figure PCTCN2018083596-appb-100001
    式中，
    R a选自：氢、C 1-C 3烷基、
    Figure PCTCN2018083596-appb-100002
    R b选自：H、C 1-C 6烷基、卤素取代的C 1-C 6烷基、C 1-C 3烷基羰基、任选取代的苯甲酰基、羧基、氨基羰基、C 1-C 6烷氧基羰基、羟基、C 1-C 6烷氧基、任选取代的C 6-C 10芳基或杂芳基、氨基、NR 6R 7；
    R 6和R 7各自独立选自：H、或任选取代的羰基C 1-C 3烷基(优选C 1-C 3烷基或C 3-C 6环烷基取代的羰基；最优选环丙基取代的羰基)；
    R 2选自：H、C 1-C 10烷基或C 1-C 10卤代烷基、C 1-C 10烷氧基或C 1-C 10卤代烷氧基、或羟基C 1-C 6烷基或羟基C 1-C 6卤代烷基；
    R c选自：Ar或
    Figure PCTCN2018083596-appb-100003
    R 3选自：H、C 1-C 6烷基或C 1-C 6卤代烷基、C 1-C 6烷氧基羰基、任选取代的苯基、C 1-C 4烷基羰基、任选取代的苯甲酰基、C 1-C 3烷基羧基、酰胺基、任选取代的苯胺甲酰基；
    Ar选自：任选取代的C 6-C 14芳基、任选取代的C 6-C 14杂环基、任选取代的C 6-C 14芳基羰基、任选取代的C 6-C 14杂环基羰基、任选取代的C 6-C 14芳氧基烷基羰基；
    R 1选自：H、卤素、C 1-C 6烷基或C 1-C 6卤代烷基；
    R 5选自：H、卤素、OH、NR 8R 9、C 1-C 6烷氧基或C 1-C 6卤代烷氧基；
    R 8和R 9各自独立选自：H、或C 1-C 3烷基、或C 1-C 3卤代烷基；
    R选自：醛基CHO，羧基COOH，C 1-C 6烷氧基羰基；
    A选自：C 1-C 6烷基(优选C 1-C 3烷基)。
  2. 如权利要求1所述的用途，其特征在于，所述白血病包括但不限于：急性淋巴细胞白血病(ALL)、急性髓细胞白血病、慢性粒细胞白血病、慢性淋巴细胞白血病；优选急性髓细胞白血病。
  3. 如权利要求1或2所述的用途，其特征在于，式I所示化合物具有式Ia所示结构：
    Figure PCTCN2018083596-appb-100004
    式中，
    R 3选自：C 1-C 6烷基、C 1-C 6烷氧基羰基、任选取代的苯基、C 1-C 4烷基羰基、任选取代的苯甲酰基、C 1-C 3烷基羧基、酰胺基、任选取代的苯胺甲酰基；和
    Ar、R b如权利要求1所述。
  4. 如权利要求3所述的用途，其特征在于，Ar上具有0-5个取代基，所述取代基选自：C 1-C 10烷基、C 3-C 8环烷基、C 1-C 4烷氧基、任选取代的苯基、任选取代的苯氧基、苄氧基、CF 3、卤素。
  5. 如权利要求3所述的用途，其特征在于，R b选自：C 1-C 6烷基、CF 3、苯基、乙酰基、苯甲酰基、羧基、氨基甲酰基、C 1-C 6烷氧基羰基、氨基；更优选甲基、CF 3或苯基。
  6. 如权利要求3所述的用途，其特征在于，R 3选自：C 1-C 6烷基、苯基、C 1-C 3烷基羰基、任选取代的苯甲酰基、羧基、C 1-C 6烷氧基羰基、酰胺基、任选取代的苯胺甲酰基；优选C 1-C 3烷基羰基，C 1-C 3烷氧基羰基。
  7. 如权利要求3所述的用途，其特征在于，式I所示化合物选自化合物1-100。
  8. 如权利要求1或2所述的用途，其特征在于，式I所示化合物具有式Ib所示结构：
    Figure PCTCN2018083596-appb-100005
    式中，
    R 4选自：H、卤素、C 1-C 6烷基或C 1-C 6卤代烷基、或C 1-C 6烷氧基或C 1-C 6卤代烷氧基；
    m＝0～3的整数；
    R、R 1、R 2、R 3、R 5如权利要求1所述。
  9. 如权利要求8所述的用途，其特征在于，式I所示化合物具有式Ic所示结构：
    Figure PCTCN2018083596-appb-100006
    R 1选自H、F、Cl、Br、C 1-C 3烷基或C 1-C 3卤代烷基；
    R 2选自H、C 1-C 6烷基或C 1-C 6卤代烷基、C 1-C 6烷氧基或C 1-C 6卤代烷氧基、或羟基C 1-C 3烷基或羟基C 1-C 3卤代烷基；
    R 3自H、C 1-C 3烷基或C 1-3卤代烷基；
    R 4选自H、F、Cl、Br、C 1-C 3烷基或C 1-C 3卤代烷基、C 1-C 3烷氧基或C 1-C 3卤代烷氧基；
    R 5选自H、F、Cl、Br、OH、NH 2、OCH 3。
  10. 如权利要求8或9所述的用途，其特征在于，
    R 1选自H、C 1-C 3烷基；
    R 2选自C 1-C 3烷基；
    R 3选自H、C 1-C 3烷基；
    R 4选自H或Cl；
    R 5选自H。
  11. 如权利要求8所述的用途，其特征在于，式I所示化合物选自下组化合物：
    Figure PCTCN2018083596-appb-100007
    Figure PCTCN2018083596-appb-100008
  12. 如权利要求11所述的用途，其特征在于，式I所示化合物选自下组化合物：
    Figure PCTCN2018083596-appb-100009
  13. 一种非淋巴细胞性白血病的治疗方法，包括将治疗有效量的权利要求1-12中任一所述的化合物给予需要治疗白血病的患者。
PCT/CN2018/083596 2017-04-20 2018-04-18 噻唑衍生物在治疗非淋巴细胞性白血病中的应用 Ceased WO2018192535A1 (zh)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023011312A1 (zh) * 2021-08-02 2023-02-09 上海汇伦医药股份有限公司 多取代噻唑衍生物及其在疾病治疗中的应用
CN119431355A (zh) * 2024-11-06 2025-02-14 徐州医科大学 一类苯基噻唑类衍生物、组合物及其应用

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021083182A1 (zh) * 2019-10-28 2021-05-06 南京明德新药研发有限公司 一种尿酸促排剂及其合成方法和其在医药上的应用
CN112707874A (zh) * 2020-12-29 2021-04-27 广东中科药物研究有限公司 一种抗病毒化合物及其制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4319026A (en) * 1980-08-14 1982-03-09 Gulf Oil Corporation Heterocyclic-substituted hydrazides and hydrazones as plant growth regulators
CN1684959A (zh) * 2002-08-02 2005-10-19 Ab科学公司 2－(3－氨基芳基)氨基－4－芳基－噻唑及其作为c－kit抑制剂的应用
CN102151272A (zh) * 2011-02-25 2011-08-17 中国药科大学 Plk1抑制剂及其用途
CN103006653A (zh) * 2011-09-27 2013-04-03 华东理工大学 2,4-二取代噻唑类衍生物作为dhodh抑制剂的应用
CN103127095A (zh) * 2011-11-23 2013-06-05 华东理工大学 二氢噻吩酮衍生物作为pfDHODH抑制剂的合成及应用

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103058949A (zh) * 2011-10-18 2013-04-24 华东理工大学 做为dhodh抑制剂的噻唑衍生物及其应用
US9757378B2 (en) * 2013-05-17 2017-09-12 Universite De Montreal Methods to modulate acute myeloid leukemia stem/progenitor cell expansion and/or differentiation
CN106892878B (zh) * 2015-12-18 2020-01-10 华东理工大学 噻唑类衍生物及其在抑制二氢乳清酸脱氢酶中的应用
CN107382902B (zh) * 2016-05-17 2022-08-12 华东理工大学 噻唑类衍生物及其应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4319026A (en) * 1980-08-14 1982-03-09 Gulf Oil Corporation Heterocyclic-substituted hydrazides and hydrazones as plant growth regulators
CN1684959A (zh) * 2002-08-02 2005-10-19 Ab科学公司 2－(3－氨基芳基)氨基－4－芳基－噻唑及其作为c－kit抑制剂的应用
CN102151272A (zh) * 2011-02-25 2011-08-17 中国药科大学 Plk1抑制剂及其用途
CN103006653A (zh) * 2011-09-27 2013-04-03 华东理工大学 2,4-二取代噻唑类衍生物作为dhodh抑制剂的应用
CN103127095A (zh) * 2011-11-23 2013-06-05 华东理工大学 二氢噻吩酮衍生物作为pfDHODH抑制剂的合成及应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LI, S.L. ET AL.: "Rational Design of Benzylidenehydrazinyl-Substituted Thiazole Derivatives as Potent Inhibitors of Human Dihydroorotate Dehydrogenase with in Vivo Anti-arthritic Activity", SCIENTIFIC REPORTS, vol. 5, 7 October 2015 (2015-10-07), pages 1 - 19, XP055540082 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023011312A1 (zh) * 2021-08-02 2023-02-09 上海汇伦医药股份有限公司 多取代噻唑衍生物及其在疾病治疗中的应用
CN117769544A (zh) * 2021-08-02 2024-03-26 上海汇伦医药股份有限公司 多取代噻唑衍生物及其在疾病治疗中的应用
CN119431355A (zh) * 2024-11-06 2025-02-14 徐州医科大学 一类苯基噻唑类衍生物、组合物及其应用

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