[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2016127455A1 - Dérivé de pyrimidine, agent cytotoxique, composition pharmaceutique et utilisation de ceux-ci - Google Patents

Dérivé de pyrimidine, agent cytotoxique, composition pharmaceutique et utilisation de ceux-ci Download PDF

Info

Publication number
WO2016127455A1
WO2016127455A1 PCT/CN2015/073678 CN2015073678W WO2016127455A1 WO 2016127455 A1 WO2016127455 A1 WO 2016127455A1 CN 2015073678 W CN2015073678 W CN 2015073678W WO 2016127455 A1 WO2016127455 A1 WO 2016127455A1
Authority
WO
WIPO (PCT)
Prior art keywords
branched
group
optionally substituted
cyclic alkyl
linear
Prior art date
Application number
PCT/CN2015/073678
Other languages
English (en)
Chinese (zh)
Inventor
郭家林
裴亚中
郎恒元
Original Assignee
南京盖特医药技术有限公司
吉林大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 南京盖特医药技术有限公司, 吉林大学 filed Critical 南京盖特医药技术有限公司
Publication of WO2016127455A1 publication Critical patent/WO2016127455A1/fr

Links

Classifications

    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the PI3K/Akt/mTOR signaling pathway is a very important pathway in the cell signaling pathway, which regulates many important physiological functions of cells, such as cell growth, proliferation, differentiation, migration, survival, angiogenesis, glucose metabolism, and Fluctuations in cell membranes [1, 2] .
  • IA type PI3k is activated by receptor tyrosine kinases (RTK), including a regulatory subunit p85 and a catalytic subunit p110. According to different catalytic subunits, IA type PI3k is divided into p110 ⁇ , ⁇ and ⁇ . Subtype. Type IB PI3k has only one p110 ⁇ subtype, which includes an a p110 ⁇ catalytic subunit and a regulatory subunit of p101, which are activated by G protein-coupled receptors.
  • RTK receptor tyrosine kinases
  • Type I PI3K can catalyze the phosphorylation of the hydroxyl group at the 3 position of 4,5-phosphatidylinositol (4,5)-bisphosphate (PIP2) to form a signal molecule 3,4,5-phosphatidylinositol triphosphate Salt (phosphatidylinositol (3,4,5)-trisphosphate, PIP3), PIP3 activates downstream PDK1 and Akt kinases to signal transmission.
  • PIP3 Phosphatase and tensin homolog deleted on chromosome ten. The role of PTEN is to antagonize the activation of downstream pathway by PI3K.
  • Type II PI3K includes three subtypes of PI3K-C2 ⁇ , PI3K-C2 ⁇ and PI3K-C2 ⁇ , which are capable of phosphorylating phosphatidylinositol and 4-phosphatidylinositol phosphate but not phosphorylating 4,5-phosphatidylinositol diphosphate Salt (PIP2) [5] .
  • Type III PI3K has only one member, Vps34, which phosphorylates phosphatidylinositol to produce 3-phosphatidylinositol phosphate, a function associated with protein transport and autophagy [6] .
  • Type IV PI3K contains catalytic regions similar to other PI3K kinases, members of which include mTOR, ATR, ATM, DNA-PK [4,7] .
  • the dysregulation or abnormal activity of the PI3K signaling pathway is closely related to the occurrence of many diseases. Mutations in p110 ⁇ due to mutations have been found in a variety of tumors, and mutations in the PIK3CA gene encoding p110 ⁇ have been found in more than 30% of solid tumors [7] in 40% of ovarian cancers and 50% of cervical cancers. A mutation in PIK3CA was found [8] . P110 ⁇ and ⁇ are key enzymes in the leukocyte signaling system and can treat inflammation and autoimmune-related diseases by inhibiting their activity [9] .
  • PI3K inhibitors that have been reported are mainly classified into the following categories:
  • LY294002 and wortmannin are the first generation of non-selective type I PI3K inhibitors, both of which inhibit the p110 catalytic subunit.
  • LY294002 is a class of reversible ATP competitive inhibitors developed by Eli Lilly, which not only inhibits type I PI3K but also inhibits mTOR and DNA-PK.
  • Wortmannin is a natural product isolated from fungi that acts by covalent interaction with the Lys802 residue of p110 ⁇ and the Lys833 residue of p110 ⁇ . Due to their toxic side effects, poor pharmacological properties and lack of selectivity, there is no further clinical development [11,12] .
  • XL147 is able to inhibit PI3K signaling in tumor cells, which can cause tumor growth to slow down and contract in preclinical breast, lung, ovarian, and prostate cancer models.
  • XL147 has entered the clinical trial stage, and will be evaluated in the clinical stage for the safety and efficacy of single or combined drugs for solid tumors, lymphoma and metastatic breast cancer [1] .
  • GDC-0941 inhibits U87MG, PC3, SKOV-3, IGROV-1, Detroit 562, HCT116, SNUC2B and LoVo cell lines with lower IC50 values.
  • GDC-0941 also plays a very good role in the athymic mouse U87MG and IGROV-1 transplantation models. Currently, GDC-0941 is also in the clinical research stage [13] .
  • BKM120 is used in the treatment of acute lymphoblastic leukemia, acute myeloid leukemia, combined with INC424 for the treatment of myelofibrosis, and rituximab for the treatment of B-cell lymphoma in the first phase of clinical trials (http://www.clinicaltrials .gov/).
  • CAL-101 (Idelalisib) (structure shown in Figure 1) is a class of p110 ⁇ selective inhibitors developed by Gilead.
  • the selectivity of p110 ⁇ for other subtypes is between 40 and 300 times. It has a good clinical effect on many malignant blood diseases such as relapsed or refractory chronic myeloid leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma and multiple myeloma [1] .
  • Idelalisib (trade name: Zydelig) developed by Gilead, and Idelalisib became the first PI3K inhibitor to be marketed.
  • CLL chronic lymphocytic leukemia
  • FL non-Hodgkin's lymphoma
  • SLL recurrent small lymphocytic lymphoma
  • the anti-proliferation test showed activity below the micromolar level and was also effective in the HeLa human cervical cancer transplantation model test [15] .
  • This compound is effective in blocking the overactive PI3K signal by arresting the cell cycle in the G1 phase, and it is well tolerated.
  • NVP-BEZ235 also inhibits the abnormal activation of the PI3K/mTOR pathway by the oncogenic mutations of p110 ⁇ (E545K and H1047R). It has shown promising results in the evaluation of its effectiveness in combination with the traditional cytotoxic agent doxorubicin and vincristine. It is already in the clinical evaluation stage for the treatment of advanced solid tumors and breast cancer [1] ] .
  • a combination of XL-765 and an autophagy-inducing drug can increase its anti-tumor activity in pancreatic cancer.
  • the combination of XL-765 and chemotherapeutic drugs has been in clinical trials, and the data show that patients have a terminal half-life between 2-15 hours with patient-to-patient variability [13] .
  • GDC-0980 (structure shown in Figure 1) is a morphine derivative which acts as a dual inhibitor of PI3K/mTOR in phase II clinical research by replacing the indazole ring on GDC-0941 with 2-aminopyrimidine. Synthetic, this substitution increases the inhibitory activity of mTOR.
  • GDC-0980 has shown good activity in various cancer cell lines such as prostate cancer, breast cancer and lung cancer, but it has lower activity on melanoma and pancreatic cancer, which may be related to KRAS in these two tumors.
  • BRAF resistance markers It showed potent inhibition in both PC3 and MCF-7 neo/HER2 cell transplantation models [13] .
  • PKI-402 can induce apoptosis and show high anti-proliferative activity, and has anti-tumor effects in many tumor transplantation models [1] .
  • the mechanism of inhibition of PKI-402 production in MDA-MB-361 cell line was found to inhibit phosphorylation of Akt Ser473 and Thr308 in vivo and in vitro, and also inhibit phosphorylation of target molecules downstream of Akt; PKI-402MDA-MB -361 cell line apoptosis is dependent on the caspase-3 channel [13] .
  • the present invention is implemented as follows:
  • R 1 is hydrogen, optionally substituted aryl having C 1 -C 6 as a substituent, optionally substituted C 1 -C 6 linear, branched or cyclic alkyl, acylamino, halogen, in optionally substituted C 1 -C 6 linear, branched, cyclic alkyl group, a substituted aryl group, optionally substituted at C 1 -C 6 linear, branched, or cyclic alkyl group substituted a pyridyl group of the group, an optionally substituted C 1 -C 6 linear, branched, or cyclic alkyl group as a substituent of a sulfone group, optionally substituted C 1 -C 6 straight chain, branched or cyclic a sulfonyl group in which an alkyl group is a substituent, and an optionally substituted C 1 -C 6 linear, branched or cyclic alkyl group, pyridyl group, halogenated
  • R 2 is hydrogen, NHR 2 ' or NHCONHR 3 ;
  • R 10 is H or an optionally substituted C 1 -C 6 linear, branched or cyclic alkyl group; said R 2 'is H or a C 1 -C 6 linear, branched alkyl group An optionally substituted amide group having a C 3 -C 6 cycloalkyl group as a substituent, a trisubstituted amino group having an optionally substituted C 1 -C 6 linear, branched or cyclic alkyl group as a substituent An optionally substituted C 1 -C 6 linear, branched or cyclic alkyl group having one, two or three halogen atoms as a substituent, a C 1 -C 6 straight or branched alkoxy group, optionally substituted a C 1 -C 6 linear, branched or cyclic alcohol group, piperazinyl pyridyl, aminopyridyl, piperazinylaryl or halogen aryl; wherein piperazinyl and amine are
  • R 0 is hydrogen, hydroxy or an optionally substituted C1-C6 linear, branched or cyclic alcohol group.
  • R 1 an optionally substituted aryl group
  • R 2 H
  • R 0 -OH or R 0 'OH, wherein R 0 ' is an optionally substituted C 1 - C 6 straight chain, Chain or cyclic alkyl group
  • R 1 an optionally substituted aryl group
  • R 0 H, Or NHR 2 '
  • R 10 is H or an optionally substituted C 1 -C 6 straight chain, branched chain, or cyclic alkyl group
  • R 2 ' H or -CONHR 3
  • R 3 H, a C 1 -C 6 straight-chain, branched alkyl group, a C 3 -C 6 cycloalkyl group, a trisubstituted amino group having a C 1 -C 6 linear or branched alkyl group as a substituent, a halogenated C 1 - C 6 straight, branched or cyclic alkyl, dihalo C 1 -C 6 straight, branched or cyclic alkyl, trihalo C 1 -C 6 straight, branched or cyclic alkyl , -OR 8 , R 9 OH or
  • R 4 H, Or NHR 6 , wherein R 5 and R 6 are independently a C 1 -C 6 linear or branched alkyl group;
  • the R 8 is an optionally substituted C 1 -C 6 linear, branched or cyclic alkyl group
  • the R 9 is an optionally substituted C 1 -C 6 linear, branched or cyclic alkyl group
  • R 0 H
  • R 1 NHCONHR 3 '
  • R 2 CONHR 11
  • the R 3 ', R 11 are each independently H, an optionally substituted C 1 -C 6 straight chain, Chain or cyclic alkyl group
  • R 0 H
  • R 1 H or C 1 - C 6 linear, branched alkyl
  • R 2 NHCONHR 3
  • R 3 is an optionally substituted C 1 - C 6 straight chain, branch Chain or cyclic alkyl group
  • R 0 H
  • R 2 NHCONHR 3
  • R 3 is an optionally substituted C 1 -C 6 linear, branched or cyclic alkyl group, B OC , -R 24 -CY 3 , -R 25 -CY 3 , -R 27 -OH, -R 30 -OR 31 , -R 32 COOH,
  • R 11 , R 20 , R 21 are each independently H or an optionally substituted C 1 -C 6 linear, branched or cyclic alkyl group;
  • the R 14 is an optionally substituted C 1 -C 6 linear, branched or cyclic alkyl or trihalo C 1 -C 6 linear, branched, or cyclic alkyl group;
  • the R 15 is an optionally substituted C 1 -C 12 straight chain, branched chain, cyclic alkyl group or an optional substitution with a halogen or a C 1 -C 6 linear, branched or cyclic alkyl group as a substituent Aromatic hydrocarbon
  • the R 18 and R 19 are independently H, Boc or an optionally substituted C 1 -C 6 linear, branched or cyclic alkyl group;
  • the Y F, Cl, Br or I
  • the Z is F, Cl, Br, I or hydrogen
  • R 1 benzyl
  • R 2 H
  • R 0 is a hydroxyl group, methanol, ethanol, propanol, isopropanol or butanol
  • R 1 benzyl
  • R 0 H, NHR 2 ' or NHCONHR 3 ;
  • the R 10 is H, methyl, ethyl, propyl or butyl;
  • the R 2 ' H or CONHR 3 ;
  • R 3 H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, dimethylethylamine, fluoroethyl, difluoroethyl, trifluoroethyl , -OR 8 or R 9 OH;
  • R 4 H, Or NHR 6 , wherein R 5 and R 6 are independently methyl, ethyl, propyl or butyl;
  • the R8 is a methyl group, an ethyl group, a propyl group or a butyl group;
  • the R9 is a methyl group, an ethyl group, a propyl group or a butyl group;
  • R 0 H
  • R 1 NHCONHR 3 '
  • R 2 CONHR 11
  • each of R 3 ', R 11 is independently methyl, ethyl, propyl, isopropyl or butyl ;
  • R 0 H
  • R 1 H, methyl, ethyl, propyl, isopropyl or butyl
  • R 2 NHCONHR 3
  • R 3 methyl, ethyl, propyl, Isopropyl or butyl
  • R 0 H
  • R 2 NHCONHR 3
  • R 3 methyl, ethyl, propyl, isopropyl or butyl
  • B OC , -R 24 -CY 3 , -R 25 -CY 3 , -R 27 -OH, -R 30 -OR 31 , -R 32 COOH,
  • R 10 , R 11 , R 20 , R 21 are each independently H or methyl, ethyl, propyl, isopropyl or butyl;
  • R 12 , R 13 , R 16 , R 18a , R 23 , R 24 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 are each independently Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopentyl or cyclohexyl;
  • the R 14 is methyl, ethyl, propyl, isopropyl, butyl, monofluoro C 1 -C 4 straight or branched alkyl, difluoro C 1 -C 4 straight or branched Alkyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, trifluorobutyl or trifluoroisobutyl;
  • the R 15 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopentyl, cyclohexyl, monofluoro C 1 -C 4 linear, branched, cyclic alkyl , difluoro C 1 -C 4 straight chain, branched chain, cyclic alkyl group, trifluoro C 1 -C 4 straight chain, branched chain, cyclic alkyl group, with fluorine or C 1 -C 4 straight chain, a branched or cyclic alkyl group is a phenyl group in which a substituent is substituted, ortho, meta or unsubstituted;
  • R 18 , R 19 are independently H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or Boc;
  • the pyrimidine derivative of the present invention and various crystal forms thereof or a pharmaceutically acceptable salt thereof are one of the following compounds:
  • the preparation method of the pyrimidine derivative of the present invention and various crystal forms thereof or a pharmaceutically acceptable salt thereof is prepared from the compound 1, and the preparation method of the compound 1 is as follows:
  • the cytotoxic agent of the present invention comprises the pyrimidine derivative and various crystal forms thereof or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present invention comprises a therapeutically effective amount of said pyrimidine derivative, and various crystal forms thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • cytotoxic agent of the present invention for the preparation of a medicament for abnormal alteration of PI3K kinase and an antitumor drug.
  • composition of the present invention in the preparation of a medicament for the abnormal alteration of PI3K kinase and an antitumor drug.
  • GL-1 (94 mg, 0.2 mmol) was dissolved in 2 mL anhydrous DCM and triethylamine &lt The mixture was cooled in an ice-salt bath, and added to phosgene (30 mg, 0.1 mmol). After stirring for 15 min in an ice salt bath, 5 eq of amine in anhydrous DCM or amine hydrochloride and 6 eq of triethylamine were added to the above. The reaction was continued overnight in the reaction mixture. Water is added to the reaction and extracted with DCM. The organic phase is washed with water and saturated sodium chloride, and the solvent is evaporated to dryness under reduced pressure. Things.
  • the methods for preparing piperidine derivatives using GL-26 include the following two methods:
  • the GL-26 (100 mg, 0.15 mmol) was suspended in dichloromethane. EtOAc (EtOAc)EtOAc. The organic phase was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate.
  • GL-26 (100 mg, 0.15 mmol) was suspended in anhydrous dichloromethane. 3.6 eq of triethylamine was added and the mixture was cooled to 0 ° C. Then, a solution of 1.1 eq of an acid anhydride or an acid chloride in anhydrous dichloromethane was added dropwise to the reaction mixture, and the reaction was further stirred overnight or after the TLC monitoring reaction was completed, saturated sodium hydrogencarbonate and dichloromethane were added, and the organic phase was washed with water and saturated chlorine. The mixture was washed with sodium chloride, dried over anhydrous sodium sulfate and evaporated.
  • N-Boc-4-piperidinecarboxylic acid 230 mg, 1 mmol
  • CDI 292 mg, 1.8 mmol
  • nitromethane 183 mg, 3 mmol
  • DBU 685 mg, 4.5 mmol
  • step 1-2 The compound obtained in the above step 1-2 (8.912 g, 31 mmol) was dissolved in 80 mL of anhydrous diethyl ether. A solution of oxalyl chloride monoethyl ester (3.966 mL, 36 mmol) in anhydrous diethyl ether was added dropwise, and then the mixture was stirred at room temperature for 24 h. The reaction solution was cooled, and triethylamine (3.923 g, 38.8 mmol) was added dropwise at 0 °C. After the dropwise addition, the mixture was stirred at room temperature for 60 hr. Column chromatography under reduced pressure gave white product 1-3 (6.614 g, yield: 58%). Mp 59-61 ° C.
  • the compound 1-7 (60 mg, 0.2 mmol) obtained in the above step was dissolved in 2 mL of anhydrous THF, and then toluene (30 mg, 0.1 mmol). The reaction mixture was cooled to rt. Mp 142-144 ° C.
  • the ninth step is a first step.
  • GL-2 is a yellow solid (52 mg, yield 49%) which was synthesized by the synthesis of urea with the corresponding amine hydrochloride. Mp 147-149 ° C.
  • GL-4 is a yellow solid (46 mg, yield 50%) which was synthesized by the synthesis of urea from a methanol solution of ammonia. Mp204-206°C.
  • GL-6 is a yellow solid (41 mg, yield 37%) which was synthesized by the synthesis of the corresponding amine. Mp 205-206 ° C.
  • GL-14 is a yellow solid (76 mg, yield 68%) which was synthesized by the synthesis of the corresponding amine.
  • GL-15 is a white solid (61 mg, yield 52%) which was synthesized by the synthesis of the corresponding amine. mp201-202 °C.
  • GL-18 (45 mg, 0.058 mmol) was dissolved in 0.5 mL of DCM, then 2 mL of TFA was added, and the reaction was stirred at room temperature for 2 h. The solvent was evaporated to dryness. EtOAc was evaporated. The organic phase was concentrated under reduced pressure. Mp 156-158 ° C.
  • GL-21 is a white solid (81 mg, yield 54%) synthesized by the synthesis of urea with the corresponding amine hydrochloride. Mp 197-198 ° C.
  • GL-22 is a white solid (68 mg, yield 49%) which was synthesized by the synthesis of urea with the corresponding amine. Mp 185-186 ° C.
  • GL-1 (80 mg, 0.17 mmol) was dissolved in 2 mL of dry DCM and triethylamine (52 mg, 0.51 mmol) Then triphosgene (31 mg, 0.1 mmol) was added and the reaction was stirred under ice bath for 15 min. A solution of 1-methylethylamine (50 mg, 0.85 mmol) in anhydrous DCM was added to the mixture and stirred overnight. Water was added, the mixture was extracted with EtOAc EtOAc m. Mp 223-225 ° C.
  • GL-1 (141 mg, 0.3 mmol) was dissolved in 3 mL of anhydrous dioxane, and methyl isothiocyanate (24 mg, 0.33 mmol) was added and refluxed for 18 h. Additional methyl isothiocyanate (11 mg, 0.15 mmol) was added and the reaction was refluxed for 24 h. The reaction was concentrated to dryness and water and DCM. The organic phase was washed with EtOAc (EtOAc m.) Mp 175-177 ° C.
  • GL-1 (471 mg, 1 mmol) was dissolved in 4 mL DCM and triethylamine (126 mg, 1.25 mmol). A solution of methylcarbamoyl chloride (103 mg, 1.1 mmol) in DCM was slowly added to the mixture and refluxed for 3 d. The organic phase was washed with water and aq.
  • GL-2 (1.342 g, 2.54 mmol) was dissolved in 40 mL of DCE and then EtOAc-EtOAc (EtOAc. The reaction solution was concentrated to dryness. The methanol was evaporated to dryness under reduced pressure to give crude crystals (1. 50 mL of DCM and triethylamine (936 mg, 9.25 mmol) were added to the obtained crude product and cooled to 0 ° C under ice bath. A solution of (Boc) 2 O (618 mg, 2.83 mmol) in DCM was added dropwise to the mixture and the mixture was stirred for 3h. After adding water, the mixture was extracted with EtOAc EtOAc EtOAc. Mp 152-154 ° C.
  • GL-37 (330 mg, 0.61 mmol) was dissolved in 1 mL of DCM, 3 mL of TFA was added, and the reaction was stirred at room temperature for 2 h, evaporated to dryness under reduced pressure, and evaporated to dryness. 405 mg, yield 99%). Mp 211-213 ° C.
  • GL-26 (100 mg, 0.15 mmol) was suspended in acetonitrile, DIPEA (71 mg, 0.55 mmol) was added, and the mixture was cooled in an ice salt bath. Ethyl iodide (29 mg, 0.18 mmol) in acetonitrile was slowly added dropwise to the reaction mixture. The reaction was stirred for 1 h, and the reaction was stirred at room temperature for 5 h. The TLC monitoring was not completed, and the reaction was carried out at 65 ° C for 11 h, and then refluxed for 8 h.
  • GL-26 (100 mg, 0.15 mmol) was suspended in acetonitrile, DIPEA (117 mg, 0.91 mmol) was added, and the mixture was cooled in ice salt, and 3-bromomethylpyridine hydrochloride (46 mg, 0.18 mmol) was added to the reaction mixture. The reaction was stirred for 1 h and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. EtOAc m. Mp 146-148°C.
  • the GL-26 (100 mg, 0.15 mmol) was suspended in anhydrous THF, and triethylamine (76 mg, 0.75 mmol) was added, and the mixture was cooled in an ice bath, and a solution of methanesulfonyl chloride (29 mg, 0.18 mmol) in THF was slowly added dropwise to the reaction mixture. The reaction was further stirred for 1 h and allowed to react at room temperature for 15 h. TLC was not completely reacted and refluxed for 6 h. The solid which precipitated was filtered, and the filtrate was concentrated under reduced pressure, then water and DCM. Mp 261-263 ° C.
  • GL-31 is a khaki solid (70 mg, yield 97%) obtained by the procedure B from acetic acid. Mp 240-242 ° C.
  • GL-32 is a yellow solid (58 mg, yield 72%) which was obtained from the procedure Mp 158-160 ° C.
  • GL-34 is a yellow solid (77 mg, yield 95%) obtained from benzoyl chloride by the procedure B. Mp 175-177 ° C.
  • GL-36 is a white solid obtained by the procedure B from isopropyl chloroformate (74 mg, yield 94%). Mp 228-229°C.
  • GL-39 is a yellow-white solid (117 mg, yield 84%) that was synthesized from GL-26 (150 mg, 0.23 mmol) and 2-(tert-butoxycarbonylamino)isobutyric acid. Mp 180-182°C.
  • GL-26 (100 mg, 0.15 mmol) was suspended in ethanol, and DIPEA (71 mg, 0.55 mmol) and trifluoroethyl trifluoromethanesulfonate (51 mg, 0.22 mmol) were added, and the reaction was refluxed for 12 h. Further, DIPEA (23 mg, 0.18 mmol) and trifluoroethyl trifluoromethanesulfonate (21 mg, 0.09 mmol) were added and the mixture was refluxed for 5 h. The reaction mixture was concentrated under reduced pressure. EtOAc m. Mp 229-230 ° C.
  • GL-26 (100 mg, 0.15 mmol) was suspended in acetonitrile, and triethylamine was dissolved. The mixture was concentrated to dryness under reduced pressure. After stirring at room temperature overnight, the reaction was not completed by TLC, and the additional 1.2 eq of TFAA was immediately clarified. The reaction mixture was poured with water, EtOAc EtOAc m. Mp 203-205 ° C.
  • GL-26 (100 mg, 0.15 mmol) was suspended in acetonitrile, DIPEA (71 mg, 0.55 mmol) and 2-chloro-N,N-dimethylacetamide (25 mg, 0.21 mmol). (27 mg, 0.18 mmol) was stirred for 10 h. Concentration under reduced pressure, water and EtOAc (EtOAc)EtOAc. Mp 159-160 ° C.
  • GL-26 (100 mg, 0.15 mmol) was suspended in ethanol, and DIPEA (71 mg, 0.55 mmol), NaI (27 mg, 0.18 mmol) and 2-bromoethanol (25 mg, 0.20 mmol) were added and refluxed for 60 h. The organic layer was concentrated under reduced pressure. EtOAc (EtOAc). Mp 198-199 ° C.
  • GL-26 (100 mg, 0.15 mmol) was suspended in acetonitrile, and DIPEA (71 mg, 0.55 mmol) and ethyl bromoacetate (36 mg, 0.22 mmol). The reaction mixture was concentrated under reduced pressure. EtOAc m. Mp 221-223 ° C.
  • GL-26 (137 mg, 0.21 mmol) was suspended in anhydrous THF.
  • DIPEA 96 mg, 0.74 mmol was added, and the mixture was cooled with ice-cooling, and a solution of trifluoromethanesulfonyl chloride (51 mg, 0.30 mmol) in THF was added dropwise to the reaction mixture.
  • the reaction was further stirred for 1 h, stirred at room temperature overnight, and the reaction was not completely observed by TLC.
  • the mixture was warmed to 40 ° C for 5 h and then added trifluoromethanesulfonyl chloride (40 mg, 0.25 mmol).
  • the reaction mixture was concentrated, EtOAc (EtOAc)EtOAc. Mp 238-240°C.
  • GL-60 was a yellow-white solid (70 mg, yield 90%) from ⁇ /RTI> ⁇ /RTI> ⁇ /RTI> ⁇ /RTI> Mp 208-210°C.
  • GL-2 (528 mg, 1 mmol) was dissolved in 10 mL of anhydrous dioxane, and 0.52 mL of a self-made 2.3 mol/L hydrogen chloride anhydrous dioxane solution was added thereto, stirred at room temperature overnight, and evaporated to dryness under reduced pressure.
  • the hexacyclohexane was ultrasonically washed by adding 10 mL of anhydrous dichloromethane, and filtered to give a white solid (535 mg, yield 95%).
  • ESI-MS: m/z 528.38 [M+H] + .
  • the compound of the present invention having the structure of the formula (I) and a pharmaceutically acceptable salt thereof, in the antitumor side
  • the half-inhibitory concentration IC 50 value of the compound against the three tumor cell lines (U-87MG, PC-3 and BT-474) was measured by a CCK-8 test kit.
  • PC-3 human prostate cancer cell line (ordered at the Shanghai Cell Resource Center of the Chinese Academy of Sciences)
  • BT-474 human breast cancer cell line (ordered at the Shanghai Cell Resource Center of the Chinese Academy of Sciences)
  • Fetal bovine serum (Cat#10099-141, GIBCO)
  • the logarithmic growth phase cells were collected, counted, and the cells were resuspended in complete medium, and the cell concentration was adjusted to an appropriate concentration (determined according to the cell density optimization test results), and 96-well plates were seeded, and 100 ⁇ L of the cell suspension was added to each well.
  • the cells were incubated for 24 hours at 37 ° C in a 100% relative humidity, 5% CO 2 incubator.
  • the test compound was diluted with the medium to the corresponding concentration (5X) set, and added to the cells at 25 ⁇ L/well.
  • the final concentration of the compound was from 100 ⁇ M to 0 ⁇ M, a 4-fold gradient dilution, a total of 10 concentration points; or from 10 ⁇ M to 0 ⁇ M, a 4-fold gradient dilution, a total of 10 concentration points.
  • the cells were then incubated for 72 hours at 37 ° C in 100% relative humidity, 5% CO 2 incubator.
  • the medium was aspirated, and the complete medium containing 10% CCK-8 was added and incubated in a 37 ° C incubator for 2-4 hours.
  • the absorbance at a wavelength of 450 nm was measured on a SpectraMax M5 Microplate Reader with gentle shaking, and the absorbance at 650 nm was used as a reference to calculate the inhibition rate.
  • tumor cell growth inhibition rate % [(Ac-As) / (Ac-Ab)] ⁇ 100%
  • the IC 50 curve was fitted and the IC 50 value was calculated using the software Graphpad Prism 5 and using the calculation formula log(inhibitor) vs. normalized response-Variable slope.
  • PI3-Kinase human
  • HTRF TM Assay kit detection test compound inhibitory concentrations IC 50 of the inhibition of PI3K delta and half of the enzyme.
  • 4 ⁇ Reaction Buffer (Cat. 33-002, Millipore) was diluted to 1 ⁇ with ddH 2 O, and 1 M DTT was added to give a final concentration of 5 mM. Freshly prepared before each use. For example, 10 mL of 1 ⁇ Reaction Buffer is prepared, and 2.5 mL of 4 ⁇ Reaction Buffer, 50 ⁇ L of 1 M concentration of DTT and ddH 2 O 7.45 mL are added. Throughout the experiment, the ATP working solution, the substrate and the enzyme mixed working solution were prepared by using freshly prepared 1 ⁇ Reaction Buffer.
  • test compound was dissolved in DMSO to 50 ⁇ M as a stock solution, and 2 ⁇ L of each was added to 48 ⁇ L of ddH 2 O to obtain 2 ⁇ M of a compound solution containing 4% DMSO. After mixing, 2 ⁇ L of each was added to add 18 ⁇ L of 4% DMSO (in ddH 2 ). O) A 0.2 ⁇ M compound solution was obtained. 5 ⁇ L of each diluted solution was added to a 384-well plate such that the final concentration of the compound in the final 20 ⁇ L of the kinase reaction system was 500 nM and 50 nM, respectively, and contained 1% DMSO.
  • IC 50 The test compound was dissolved in DMSO to 10 mM as a stock solution, and 2 ⁇ L of each was added to 48 ⁇ L of 1 ⁇ Reaction Buffer to obtain 400,000 nM of a compound solution containing 4% DMSO. After mixing, 5 ⁇ L of each was added to the next 15 ⁇ L of 4% DMSO ( In the wells of 1 ⁇ Reaction Buffer), it was diluted sequentially to obtain 10 concentration gradients.
  • 2 ⁇ PIP2 working solution was prepared with 1 ⁇ reaction buffer to a final concentration of 20 ⁇ M, and the final concentration of PIP2 was 10 ⁇ M.
  • 1 mL of 1 ⁇ reaction buffer/PIP2 working solution was prepared, and 20 ⁇ L of PIP2 was added to 980 ⁇ L of 1 ⁇ reaction buffer.
  • This working fluid should be mixed with 0.1-0.2 mL to meet the control use and dead volume.
  • the kinase was diluted with 2 x PIP2 working solution at a concentration of 80 ng/well of kinase working solution. No kinase control (can be considered 100% inhibition) ie 2 x PIP2 working solution.
  • 10 mM ATP was diluted to 40 ⁇ M with 1 ⁇ reaction buffer.
  • concentration of ATP was 10 ⁇ M.
  • 2 mL of ATP working solution was prepared, and 8 ⁇ L of 10 mM ATP was added to a 1992 ⁇ L 1 ⁇ reaction buffer.
  • Stop A and Stop B are mixed in a ratio of 3:1 and allowed to stand at room temperature for at least 2 hours before use.
  • the stop solution can be stabilized at room temperature for 12 hours.
  • DM C, DM A and DM B were mixed in a ratio of 18:1:1 and allowed to stand at room temperature for at least 2 hours before use.
  • the test solution was stable at room temperature for 12 hours.
  • Emission Ratio (ER) 665nm Emission signal/620nm Emission signal
  • inhibition rate (ER sample - ER 0% ) / (ER 100% - ER 0% ) ⁇ 100%

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un dérivé de pyrimidine comme représenté par la formule (I) et une variété de formes cristallines ou un sel pharmaceutiquement acceptable de celui-ci, dans laquelle R1, R2 et R0 sont tels que décrits dans la description, et sont utilisés pour la préparation d'un agent cytotoxique et d'un médicament antitumoral.
PCT/CN2015/073678 2015-02-09 2015-03-05 Dérivé de pyrimidine, agent cytotoxique, composition pharmaceutique et utilisation de ceux-ci WO2016127455A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510066655.3A CN105985354B (zh) 2015-02-09 2015-02-09 嘧啶衍生物、细胞毒性剂、药物组合物及其应用
CN201510066655.3 2015-02-09

Publications (1)

Publication Number Publication Date
WO2016127455A1 true WO2016127455A1 (fr) 2016-08-18

Family

ID=56614065

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/073678 WO2016127455A1 (fr) 2015-02-09 2015-03-05 Dérivé de pyrimidine, agent cytotoxique, composition pharmaceutique et utilisation de ceux-ci

Country Status (2)

Country Link
CN (1) CN105985354B (fr)
WO (1) WO2016127455A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109824701B (zh) * 2019-03-26 2021-08-13 武汉工程大学 一种吡啶并噻唑类化合物及其制备方法和应用
CN111825698B (zh) * 2019-07-30 2021-10-15 杭州阿诺生物医药科技有限公司 腺苷受体拮抗剂

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008070740A1 (fr) * 2006-12-07 2008-06-12 F.Hoffmann-La Roche Ag Composés inhibant la phosphoinositide 3 kinase et procédés d'utilisation
WO2009045175A1 (fr) * 2007-10-05 2009-04-09 S*Bio Pte Ltd Dérivés de purine substitués par pyrimidine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008070740A1 (fr) * 2006-12-07 2008-06-12 F.Hoffmann-La Roche Ag Composés inhibant la phosphoinositide 3 kinase et procédés d'utilisation
WO2009045175A1 (fr) * 2007-10-05 2009-04-09 S*Bio Pte Ltd Dérivés de purine substitués par pyrimidine

Also Published As

Publication number Publication date
CN105985354B (zh) 2020-10-02
CN105985354A (zh) 2016-10-05

Similar Documents

Publication Publication Date Title
KR102236605B1 (ko) 피리도피리미딘온 cdk2/4/6 억제제
KR101686685B1 (ko) 피라졸로피리미딘 ｊａｋ 억제제 화합물 및 방법
CN101432284B (zh) 二氢吡唑并嘧啶酮衍生物
JP6162904B2 (ja) 新規複素環式化合物
JP6285918B2 (ja) テトラヒドロピラゾロピリミジン化合物
JP6181862B2 (ja) ピラゾロピロリジン誘導体および疾患の処置におけるその使用
TWI534145B (zh) 四氫吡啶并嘧啶衍生物
BRPI0622030A2 (pt) Derivados de purina 7-substituída, para imunossupressão
KR20190012167A (ko) 이소퀴놀린-3-일 카르복스아마이드 및 이의 제제와 용도
JP6564406B2 (ja) カゼインキナーゼ１デルタ／イプシロン阻害剤としてのイミダゾ−ピリダジン誘導体
AU2013312477A1 (en) Compounds and methods for kinase modulation, and indications therefor
CN105452257A (zh) 新型稠合嘧啶化合物或其盐
JP2021515767A (ja) Ｅｒｋ５阻害剤の同定及び使用
CA2973773C (fr) Derives de 2-phenyl-3h-imidazo[4,5-b]pyridine utiles comme inhibiteurs de l'activite de la tyrosine kinase mammifere ror11
KR20090024110A (ko) 키나제 억제제로서의 ３-치환된 Ｎ-(아릴- 또는 헤테로아릴)-피라졸로[１,５-ａ]피리미딘
CN114786673A (zh) Cdk抑制剂及其作为药物的用途
CN105481862A (zh) Flt3激酶的新型抑制剂及其用途
ES2689325T3 (es) Derivados de carbamoilo de carbonilamino-pirazoles bicíclicos como pro-fármacos
KR20170003667A (ko) 카르복스아미드 유도체
CN111032630B (zh) 一种化合物，其药物组合物及其用途及应用
EP3129378A1 (fr) Composés inhibiteurs de bromodomaine et composition pharmaceutique les comprenant pour prévenir ou traiter un cancer
JP2022532145A (ja) 置換ベンズイミダゾロン化合物
JP2016537384A (ja) ピロロピロロン誘導体およびｂｅｔ阻害剤としてのその使用
CN105985354B (zh) 嘧啶衍生物、细胞毒性剂、药物组合物及其应用
KR20090007391A (ko) 키나제 억제제로서의 ３-비치환된 Ｎ-(아릴- 또는 헤테로아릴)-피라졸로[１,５-ａ]피리미딘

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15881617

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15881617

Country of ref document: EP

Kind code of ref document: A1