WO2023109158A1 - Composé de 7-méthylthiazolo[5,4-d]pyrimidine, son procédé de préparation et son utilisation - Google Patents

Composé de 7-méthylthiazolo[5,4-d]pyrimidine, son procédé de préparation et son utilisation Download PDF

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WO2023109158A1
WO2023109158A1 PCT/CN2022/113008 CN2022113008W WO2023109158A1 WO 2023109158 A1 WO2023109158 A1 WO 2023109158A1 CN 2022113008 W CN2022113008 W CN 2022113008W WO 2023109158 A1 WO2023109158 A1 WO 2023109158A1
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compound
substituted
reaction
methylthiazolo
preparation
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谢军
姜春阳
李惠
李红昌
周小群
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上海博悦生物科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • the invention relates to the field of medicinal chemistry, in particular to 7-methylthiazolo[5,4-d]pyrimidine compounds, a preparation method and application thereof.
  • the phosphatidylinositol 3-kinase (PI3K) family is a class of kinases that specifically catalyze the phosphorylation of the 3-hydroxyl of phosphatidylinositol and produce inositol lipid substances with second messenger functions. .
  • the signaling pathway composed of PI3K and its downstream molecular signaling protein kinase B (Akt)/target of rapamycin (mTOR) is one of the most important intracellular signaling pathways in mammals, which is crucial to many important physiological functions. Includes cell cycle, cell survival, protein synthesis and growth, metabolism, motility, and angiogenesis.
  • PI3Ks as a family of lipid kinases, can be divided into three main classes (classes I, II, and III) based on their structure and substrate specificity. Class I PI3Ks are further divided into two main subclasses, class IA and class IB. Class IA PI3Ks include PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ , which are composed of their corresponding catalytic subunits p110 (p110 ⁇ , p110 ⁇ , p110 ⁇ ) and regulatory subunits p85 Class IB (PI3K ⁇ ) is composed of catalytic subunit p110 ⁇ and regulatory subunit p101 or p87.
  • Idelalisib On July 23, 2014, the U.S. FDA approved Idelalisib, which was developed and launched by Gilead Sciences. On September 18, 2014, the European EMA approved its listing. Idelranib is a PI3K ⁇ kinase inhibitor, which can induce apoptosis and inhibit cell proliferation. It is used in the treatment of relapsed chronic lymphocytic leukemia (CLL), relapsed follicular B-cell non-Hodgkin's lymphoma (FL) and relapsed small lymphocytic lymphoma (SLL).
  • CLL chronic lymphocytic leukemia
  • FL relapsed follicular B-cell non-Hodgkin's lymphoma
  • SLL small lymphocytic lymphoma
  • Copanlisib is a PI3K inhibitor that inhibits two kinase isoforms, PI3K- ⁇ and PI3K- ⁇ , for the treatment of adult patients with relapsed follicular lymphoma who have received at least two lines of systemic therapy.
  • Buparlisib (BKM120), developed by Novartis, is a pan-class I PI3K inhibitor that acts on p110 ⁇ / ⁇ / ⁇ / ⁇ .
  • the company is also developing treatments for follicular lymphoma, gastrointestinal stromal tumor, mantle cell lymphoma, prostate cancer, diffuse large B-cell lymphoma, non-small cell lung cancer, hepatocellular carcinoma, myelofibrosis, advanced intrauterine Phase II clinical studies in membranous cancer, melanoma, bladder cancer, pancreatic cancer and malignant glioma.
  • PI3K inhibitors approved by the FDA include duvelisib and alpelisib, and phosphatidylinositol-3-kinase inhibitors (PI3K) have broad application prospects. It is worth noting that the currently marketed PI3K inhibitors have been observed to have serious side effects in clinical applications, such as autoimmune dysfunction, opportunistic infections, skin toxicity, hypertension and hyperglycemia, etc. Both idelalisib and duvelisib have been approved by the FDA. Give a black box warning.
  • inhibition of PI3K signaling can mediate negative feedback loops and/or induce activation of other proliferative signaling pathways, thereby attenuating the antitumor efficacy of PI3K inhibitors.
  • the object of the present invention is to develop a 7-methylthiazolo[5,4-d]pyrimidine compound, a preparation method and its application.
  • This 7-methylthiazolo[5,4-d]pyrimidine PI3K inhibitor compound has a novel structure different from existing compounds, exhibits antiproliferative activity, and is therefore useful for preventing or treating diseases associated with hyperproliferation, especially Use in the preparation of medicines for inhibiting PI3 kinase.
  • One of the embodiments of the present invention provides a 7-methylthiazolo[5,4-d]pyrimidine compound, including a compound represented by formula (I) or a physiologically acceptable salt thereof:
  • R is hydrogen, substituted or unsubstituted alkyl, cycloalkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl;
  • R 2 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aromatic heterocyclic group.
  • R1 is selected from any one of hydrogen, acetyl, propionyl, cyclopropylformyl, deuterated acetyl, methyl, and cyclopropyl;
  • R2 is selected from 2,4-di Any one of fluorine-substituted phenylcyclyl, 4-fluoro-substituted phenylcyclyl, methyl, thien-2-yl, and cyclopropyl.
  • the present invention also provides a method for preparing 7-methylthiazolo[5,4-d]pyrimidine compounds, the method comprising the following steps:
  • Ra alkyl or cycloalkyl substituted amino target compounds
  • Ra is alkyl or cycloalkyl.
  • a preparation method of a 7-methylthiazolo[5,4-d]pyrimidine compound comprises the following steps:
  • R b is an alkyl acyl group
  • X is a halogen atom
  • the coupling reaction is carried out in the presence of potassium carbonate, dioxane and PdCl 2 .
  • the acylation reaction is carried out in the presence of pyridine using DCM as a solvent.
  • the amination reaction uses NMP as a solvent to react with ammonia water.
  • the compound It is prepared by the following steps:
  • the compound It is prepared by the following steps:
  • the compound It is prepared by the following steps:
  • the invention also provides the application of the 7-methylthiazolo[5,4-d]pyrimidine PI3K inhibitor compound in the preparation of medicines for treating PI3 kinase-related diseases. Especially the application in the preparation of medicines for treating tumor diseases.
  • the compounds of one or more embodiments of the present invention have shown excellent inhibitory effects in various tumor cell lines, especially the IC 50 value of compound Id in the lymphoma cell line DOHH2 is 0.063 ⁇ m, which is much better than the 0.53 ⁇ m of the control drug BKM120 ⁇ m.
  • Fig. 1 is the effect of compound Ic and Id on the body weight change of human gastric cancer HGC27 nude mice;
  • Fig. 2 is the experimental therapeutic effect of compounds Ic and Id on human gastric cancer HGC27 transplanted tumor in nude mice.
  • One embodiment of the invention includes compounds of formula (I):
  • R is hydrogen, substituted or unsubstituted alkyl, cycloalkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl;
  • R 2 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aromatic heterocyclic group.
  • the alkyl group is a C1-C8 alkyl group
  • the cycloalkyl group is a C3-C8 cycloalkyl group
  • the alkylcarbonyl group is a C2-C8 alkylcarbonyl group
  • the cycloalkylcarbonyl group is a C4-C8 cycloalkylcarbonyl group
  • the aryl group is phenyl and naphthyl
  • the aromatic heterocyclic group is thienyl, thiazolyl, pyrazolyl, pyridyl and furyl, and the substituents are halogen and alkyl.
  • the present invention includes compounds of formula (I), wherein R is selected from any one of hydrogen, acetyl, propionyl, cyclopropylformyl, deuteroacetyl, methyl, cyclopropyl .
  • the present invention includes compounds of formula (I), wherein R2 is selected from 2,4-difluorosubstituted phenylcyclyl, 4-fluorosubstituted phenylcyclyl, methyl, thiophen-2-yl, Any of the cyclopropyl groups.
  • the present invention includes any one of the compounds of the following formulae or a physiologically acceptable salt thereof.
  • compounds of one or more embodiments of the present invention exhibit unexpected phosphatidylinositol-3-kinase inhibitory activity as well as chemical and structural stability. This unexpected activity is believed to be based on the structure of the compounds, particularly the core of these compounds (7-methylthiazolo[5,4-d]pyrimidine compound).
  • appropriate selection of R1 and R2 provides the necessary activity against the appropriate isoform in view of activity in vivo.
  • One embodiment of the present invention also provides a preparation method of a 7-methylthiazolo[5,4-d]pyrimidine PI3K inhibitor compound.
  • Amino target compound 5-bromo-2-methoxypyridin-3-amine to prepare boronic acid ester intermediate 9, which is then coupled with intermediate 7 to obtain amino target compound. See Reaction Scheme 3 for details.
  • R2 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aromatic heterocyclic group, preferably 2,4-difluorosubstituted phenyl ring group, 4-fluoro-substituted phenylcyclyl, methyl, thien-2-yl, cyclopropyl;
  • the amino target compounds include compound Ic, compound Ia, compound Ie and compound If, etc.
  • R is alkyl, cycloalkyl, preferably methyl, cyclopropyl
  • R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, preferably 2,4-difluorosubstituted phenyl ring group, 4-fluoro-substituted phenylcyclyl, methyl, thien-2-yl, cyclopropyl;
  • alkyl-substituted amino compounds such as compounds In, Ip, Im and Io, etc.
  • the amino target compound is used as a substrate to perform an acylation reaction to obtain the acylated target compound, see Reaction Scheme 5 for details.
  • R b is an alkyl acyl group, preferably an acetyl group, a propionyl group, a cyclopropylformyl group, a deuterated acetyl group;
  • X is chlorine, bromine or fluorine
  • R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, preferably 2,4-difluorosubstituted phenyl ring group, 4-fluoro-substituted phenylcyclyl, methyl, thien-2-yl, cyclopropyl, etc.
  • the acylated target compound such as compound Ij, compound Il, compound Ir, compound Ib, compound Ii, compound Ik, compound Iq, compound Ig and compound Ih, etc.
  • Adopt sulfonic anhydride or sulfonyl chloride continue to use similar method to make following borate compound:
  • R 2 is 2,4-difluoro, methyl, cyclopropyl, thiophen-2-yl, and compound 9 corresponds to 9a, 9b, 9c and 9d, respectively, as shown in Table 2 below:
  • Step 1 Add 2-bromo-4-amino-5-methoxypyridine (10.15g, 0.05mol), DMAP (1.22g), and pyridine (7.12g, 0.09mol) into a three-necked flask and dissolve it in DCM (61ml), Cool down to -10-0°C, and replace with N 2 for 3 times.
  • a DCM solution (61 mL) of 2,4-difluorobenzenesulfonyl chloride (13.8 g, 0.065 mol) was added dropwise, and the reaction was monitored by TLC until the reaction was complete; the reaction solution was poured into 100 ml of water, stirred and separated.
  • Step 2 In a three-necked flask, add the previous step product S9a (18.9g), potassium acetate (14.7g), biboronic acid pinacol ester (15.6g), PdCl 2 (dppf) (1.24g), dioxygen Hexacyclic (330ml), stir. Nitrogen replacement 3 times. Raise the temperature to 90°C and react overnight.
  • Step 1 2-bromo-4-amino-5-methoxypyridine (10.15g, 0.05mol), DMAP (1.22g), and pyridine (7.12g, 0.09mol) were added to a three-necked flask and dissolved in DCM (61ml), Cool down to -10-0°C and replace with nitrogen 3 times. A DCM solution (61 mL) of methanesulfonic anhydride (11.37 g, 0.065 mol) was added dropwise, reacted at room temperature, followed by TLC until the reaction was complete.
  • Step 2 Add S9b (28.1g), potassium acetate (29.4g), pinacol borate (31.2g), PdCl 2 (dppf) (2.5g) into a three-necked flask and dissolve it in dioxane (660ml). Nitrogen replacement 3 times. Raise the temperature to 90°C and react overnight.
  • R 2 is 2,4-difluorophenyl, methyl, cyclopropyl and 2-thienyl
  • compound 9 corresponds to 9a, 9b, 9c and 9d, which are prepared by reacting with compound 7 to obtain compounds Ic, Ia, Ie, If.
  • reaction solution was poured into water, extracted three times with ethyl acetate; washed once with saturated brine; the organic phase was dried over an appropriate amount of anhydrous sodium sulfate, filtered and concentrated.
  • the crude product was purified by column to obtain product compound Ic with a yield of 50.7%, HPLC: 97.16%, MS[M+1]: 465.
  • R b is propionyl, cyclopropanoyl and deuterated acetyl, and compounds Ij, Il and Ir are prepared respectively.
  • Example 6 using Ic as a substrate and replacing acetyl chloride with cyclopropanoyl chloride, the preparation method was the same as that of compound Id to obtain compound Il with a yield of 54.4%.
  • HPLC 96.32%, 1 H NMR (400MHz, Acetone-d6) 8.54(s, 1H), 8.36(s, 1H), 7.95(m, 1H), 7.35(m, 1H), 7.21(m, 1H), 3.85(s,3H), 2.82(s,3H), 2.39(m,1H), 1.30(m,1H), 1.00(m,2H), 0.91(m,2H).
  • Example 6 using Ic as a substrate and replacing acetyl chloride with deuterated acetyl chloride, the preparation method was the same as that of compound Id to obtain compound Ir with a yield of 55.6%.
  • Example 6 using Ia as a substrate, reacted with acetyl chloride, propionyl chloride, cyclopropanoyl chloride, and deuterated acetyl chloride respectively, the preparation method was the same as that of compound Id, and compound Ib was obtained sequentially (yield 50.8%, HPLC: 95.33%, MS[M+1]: 409), compound Ii (yield 55.3%, HPLC: 96.26%, MS[M+1]: 423), compound Ik (yield 46.5%, HPLC: 96.11%, 1 HNMR (400MHz ,Acetone-d6) ⁇ 9.93(s,1H),8.59(s,1H),8.45(s,1H),4.05(s,3H),3.16(s,3H),2.81(s,3H),2.41 (m,1H), 1.30(m,1H), 1.00(m,2H), 0.90(m,2H). MS[M+1]: 435), compound Iq
  • Ra methyl, cyclopropyl, compounds In and Ip are prepared respectively.
  • Ra methyl, cyclopropyl, compound Im and Io are prepared respectively
  • Compounds were screened against kinases by ADP-Glo fluorescence detection with an ATP concentration of 25 ⁇ M. Compounds were screened against mTOR by Lance Ultra Assay assay with ATP concentration in Km and BKM120 and PI103 were used as control compounds.
  • Kinase detection 1) Equilibrate the ADP-Glo reagent to room temperature. 2) Add 5 ⁇ l of ADP-Glo reagent to each well to terminate the reaction 3) Mix briefly with a centrifuge, shake slowly on a shaker, and equilibrate for 120 minutes 4) Add 10ul of kinase detection reagent to each well, shake for 1 minute, equilibrate for 30 minutes, and then read the plate Luminescence is read on the instrument.
  • Inhibition percentage (max-sample RLU)/(max-min)*100.
  • Inhibition percentage (max-sample ratio)/(max-min)*100.
  • Embodiment 14 anti-tumor effect in vivo
  • the tumor volume was weighed and measured twice a week, 17 days after administration, the body weight was weighed on the 18th day, the tumor volume was measured, the nude mice were killed, the tumor mass was weighed, and the relative tumor volume (RTV) was calculated. ), relative tumor proliferation rate (T/C), and SPSS 19.0 was used for statistical analysis.
  • TV (tumor volume) 1/2 ⁇ a ⁇ b 2 , where a and b represent the length and width of the tumor, respectively;
  • RTV (relative tumor volume) V t /V 0 , wherein V0 is the tumor volume measured during group administration (ie d0), and Vt is the tumor volume at each measurement;
  • T/C (%) T RTV /C RTV * 100%, wherein T RTV is the RTV of treatment group, and C RTV is the RTV of solvent control group;
  • IR(%) (1-TWt/TWc) ⁇ 100%, wherein TWt is the tumor weight of the treatment group, and TWc is the tumor weight of the solvent control group.
  • the present invention has the following beneficial effects:
  • the 7-methylthiazolo[5,4-d]pyrimidine PI3K inhibitor compound of the present invention has a novel structure, has excellent inhibitory activity on PI3K kinases, and significantly improves the selectivity of PI3K ⁇ /mTOR.
  • the regulation of mTOR can reduce the safety risks caused by the strong inhibition of mTOR kinase, such as hyperglycemia, and the risks induced by some RTK enzymes, with better drug efficacy and lower toxicity.
  • the invention also provides a convenient preparation method of the 7-methylthiazolo[5,4-d]pyrimidine PI3K inhibitor compound.

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Abstract

La présente invention concerne un composé de 7-méthylthiazolo[5,4-d]pyrimidine, son procédé de préparation et son utilisation. Le composé comprend un composé représenté par la formule (I) ou un sel physiologiquement acceptable de celui-ci, R1 est hydrogène, alkyle substitué ou non substitué, cycloalkyle, alkylcarbonyle substitué ou non substitué, cycloalkyle carbonyle substitué ou non substitué ; et R2 est alkyle substitué ou non substitué, cycloalkyle substitué ou non substitué, aryle substitué ou non substitué et hétérocyclyle aromatique substitué ou non substitué.
PCT/CN2022/113008 2021-12-15 2022-08-17 Composé de 7-méthylthiazolo[5,4-d]pyrimidine, son procédé de préparation et son utilisation WO2023109158A1 (fr)

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