WO2022001916A1 - Idh突变体抑制剂及其用途 - Google Patents

Idh突变体抑制剂及其用途 Download PDF

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WO2022001916A1
WO2022001916A1 PCT/CN2021/102623 CN2021102623W WO2022001916A1 WO 2022001916 A1 WO2022001916 A1 WO 2022001916A1 CN 2021102623 W CN2021102623 W CN 2021102623W WO 2022001916 A1 WO2022001916 A1 WO 2022001916A1
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Prior art keywords
compound
pharmaceutically acceptable
compounds
mmol
present
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PCT/CN2021/102623
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English (en)
French (fr)
Inventor
谢雨礼
樊后兴
钱立晖
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微境生物医药科技(上海)有限公司
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Priority claimed from CN202010595326.9A external-priority patent/CN113845528A/zh
Application filed by 微境生物医药科技(上海)有限公司 filed Critical 微境生物医药科技(上海)有限公司
Priority to US17/922,345 priority Critical patent/US20230174550A1/en
Priority to CN202180044440.5A priority patent/CN115768775A/zh
Publication of WO2022001916A1 publication Critical patent/WO2022001916A1/zh

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    • 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
    • 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
    • A61K31/5365—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 ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention belongs to the field of medicinal chemistry, and more particularly, to a new class of IDH mutant inhibitors, a preparation method thereof, and a use method of the compound.
  • Isocitrate dehydrogenase is an important enzyme involved in the tricarboxylic acid cycle, catalyzing the conversion of isocitrate into ⁇ -ketoglutarate ( ⁇ -KG), which is a tricarboxylic acid The rate limiting step of the loop.
  • IDH1 is mainly located in the cytoplasm and peroxisomes
  • IDH2 and IDH3 are mainly located in the mitochondria.
  • IDH1 and IDH2 are the most frequently occurring metabolic genes in the identification of human cancer gene mutations. Cancer, myelodysplastic syndrome (myelodysplastic syndromes, MDS) and acute myeloid leukemia (acute myelocytic leukemia, AML) are present. IDH mutation sites in tumor cells are IDH1Arg132(R132), IDH2Arg172(R172) or IDH2Arg140(R140). These mutations result in the loss of wild-type function of the IDH protein, which in turn acquires the ability to convert ⁇ -KG to the oncogenic metabolite D-2-hydroxyglutarate (D-2HG).
  • D-2HG D-2-hydroxyglutarate
  • the oncogenic metabolite 2-HG inhibits DNA or histone demethylases, resulting in hypermethylation of DNA and histones, which in turn promotes cancer.
  • IDH inhibitors can inhibit the development of tumors by inhibiting the protein activity of IDH1/R132, IDH2/R172 or IDH2/R140 site mutations, reducing the oncogenic metabolite D-2HG in vivo, and inducing demethylation of histone H3K9me3. Therefore, targeting mutant IDH1 and IDH2 (mIDH1 and mIDH2) may be a promising avenue for cancer therapy.
  • IDH inhibitors such as Enasidenib and Ivosidenib developed by Agios, both of which are non-covalent inhibitors.
  • Eli Lilly and Company reported covalent inhibitors of IDH in patents WO2017019429, WO2017213910 and WO2018111707. Compared with wild-type IDH1 and IDH2, such covalent inhibitors have better selectivity for mutant IDH1 and IDH2.
  • no IDH covalent inhibitor has entered clinical research, so there is a need to research and discover covalent IDH inhibitors with better activity and better druggability.
  • the present invention aims to provide a compound represented by the general formula (1a) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • L a is the following group:
  • R 1 is Me, Et, -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 ,
  • R 2 and R 3 are independently H, Me or Et, or R 2 and R 3 share carbon atoms.
  • R 4 is Me, Et, -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 ,
  • the compound of general formula (1a) has one of the following structures:
  • the present invention aims to provide a compound represented by the general formula (1b) or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • L b is the following group:
  • R 1 is Me, Et, -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 ,
  • R 2 and R 3 are independently H, Me or Et, or R 2 and R 3 share carbon atoms.
  • R 4 is Me, Et, -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 ,
  • the compound of general formula (1b) has one of the following structures:
  • Another aspect of the present invention aims to provide a compound having the following structure, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:
  • Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of the present invention, or its isomers and crystal forms , a pharmaceutically acceptable salt, hydrate or solvate as the active ingredient.
  • Another object of the present invention provides the compound of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates or the above pharmaceutical compositions for preparing the treatment of IDH mutants Application of protein-related disease drugs.
  • Another object of the present invention also provides a method for treating, regulating and/or preventing a disease associated with an IDH mutant protein, comprising administering to a subject a therapeutically effective amount of the compound of the present invention, or each isomer, each Crystalline form, pharmaceutically acceptable salt, hydrate or solvate or the above-mentioned pharmaceutical composition.
  • the compounds of the invention described above can be synthesized using standard synthetic techniques or well-known techniques and methods incorporated herein.
  • the solvents, temperatures and other reaction conditions mentioned herein may vary.
  • Starting materials for the synthesis of compounds can be obtained synthetically or from commercial sources.
  • the compounds described herein are according to methods well known in the art.
  • the conditions of the method such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction and the like are not limited to the following explanations.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention belongs.
  • the present invention also provides a preparation method of the compound of the present invention, wherein the compound of the present invention can be prepared by the following general reaction scheme 1 and general reaction scheme 2:
  • the compounds of the present invention can be prepared according to general reaction scheme 2 (method B), wherein R 1 , R 2 , R 3 , R 4 and L b are as defined above, and PG represents a protecting group for an amine group.
  • Starting material B1 can be prepared by general reaction scheme 1. As shown in general reaction scheme 2, compound B1 undergoes elimination reaction under basic conditions to obtain compound B2, compound B2 is deprotected by PG (eg Boc) to obtain compound B3, and compound B3 reacts with acryloyl chloride to obtain target compound B4.
  • PG eg Boc
  • “Pharmaceutically acceptable” as used herein refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound and is relatively non-toxic, ie, administered to a subject, does not cause undesired biological effects or Interacts in a detrimental manner with any of the components it contains.
  • pharmaceutically acceptable salt refers to a compound in which it exists in a form that does not cause significant irritation to the administered organism and that does not abrogate the biological activity and properties of the compound.
  • pharmaceutically acceptable salts are obtained by reacting the compounds of the present invention with acids, such as inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid, formic acid, acetic acid, Propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • Organic acids and acidic amino acids such as aspartic acid and glutamic acid.
  • references to pharmaceutically acceptable salts include solvent addition forms or crystalline forms, especially solvates or polymorphs.
  • Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol.
  • Solvates of the compounds of this invention are conveniently prepared or formed according to the methods described herein.
  • the hydrate of the compound of the present invention is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent, and the organic solvent used includes, but is not limited to, tetrahydrofuran, acetone, ethanol or methanol.
  • the compounds mentioned herein can exist in unsolvated as well as solvated forms. In sum, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • the compounds described herein are prepared in various forms including, but not limited to, amorphous, comminuted and nano-particle forms.
  • the compounds of the present invention include crystalline forms and can also be used as polymorphic forms.
  • Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to dominate.
  • the compounds of the present invention may have chiral centers and/or axial chirality, and are thus available as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric compounds Enantiomeric forms, and cis-trans isomers occur.
  • Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • a deuterated compound can be formed by replacing a hydrogen atom with deuterium, and the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. It has the advantages of stability, enhanced efficacy, and prolonged half-life of drugs in vivo. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • acceptable refers to a formulation component or active ingredient that does not have undue deleterious effects on the health of the general target of treatment.
  • treatment include alleviating, inhibiting or ameliorating the symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing the underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the development of a disease or condition; alleviating a disease or symptom; reducing a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating symptoms caused by a disease or symptom.
  • a compound or pharmaceutical composition when administered, results in amelioration, especially improvement in severity, delay in onset, slow progression, or reduction in duration of a disease, symptom or condition. Whether fixed or temporary, continuous or intermittent, the conditions attributable to or associated with the administration.
  • Active ingredient refers to the compounds of the present invention, as well as pharmaceutically acceptable inorganic or organic salts of the compounds of the present invention.
  • the compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and are thus available as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric compounds in the form of enantiomers.
  • the number of asymmetric centers that can exist depends on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • composition a compound capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
  • administering refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound Wait.
  • the present invention provides methods of treating diseases, including, but not limited to, conditions involving IDH mutant proteins (eg, cancer) using the compounds or pharmaceutical compositions of the present invention.
  • methods for cancer treatment comprising administering to an individual in need thereof an effective amount of any of the foregoing pharmaceutical compositions comprising the compounds described herein.
  • the cancer is mediated by an IDH mutant protein.
  • the cancer is blood cancer and solid tumors, including but not limited to leukemia, lung cancer, pancreatic cancer, colon cancer, gallbladder cancer, or colorectal cancer.
  • the compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various formulations, which contain the compounds of the present invention or their pharmaceutically acceptable salts and pharmacologically acceptable excipients or carriers within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the safe and effective amount of the compound is determined according to the age, disease condition, course of treatment and other specific conditions of the object to be treated.
  • “Pharmaceutically acceptable excipient or carrier” means: one or more compatible solid or liquid filler or gelling substances, which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity .
  • “Compatibility” as used herein means that the components of the composition can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • pharmacologically acceptable excipients or carrier moieties are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose,
  • the compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
  • the administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • the present invention adopts the following abbreviations: AcOH (or HOAc) represents acetic acid; Ar represents argon; CDCl 3 represents deuterated chloroform; CDI represents carbonyldiimidazole; Cs 2 CO 3 represents cesium carbonate; CsF represents cesium fluoride; DBU stands for 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM stands for dichloromethane; DIPEA stands for diisopropylethylamine; DMF stands for dimethylformamide; DMSO stands for dimethylformamide sulfoxide; EA ethyl acetate Representative; EtOH ethanol Representative; for hour H; H 2 Representative hydrogen; representatives of NaOH sodium hydroxide; potassium hydroxide behalf of KOH; LC-MS liquid Representative - mass spectrometry; representative of lithium aluminum hydride LiAlH 4 ; inter-m-CPBA-chloroperbenzoic acid Representative; MeOH methanol Representative; min for minutes;
  • the target intermediates A-2 to A-6 were obtained by the synthesis method of intermediate A-1.
  • the target intermediates A-8 to A-13 were obtained by the synthesis method of intermediate A-7.
  • Ethyl 4-chloro-2-(methylmercapto)pyrimidine-5-carboxylate (50 g, 214.88 mmol) was dissolved in THF (500 mL), cooled to 0°C in an ice-salt bath, and TEA (43.49 g, 429.76 mmol, 59.82 mmol) was added. mL), after the addition was completed, the reaction was carried out at room temperature for 16 h. After the completion of the reaction was monitored by TLC, water (200 mL) was added, and EA (200 mL*2) was added for extraction. The combined organic phases were washed with saturated sodium chloride solution (100 mL), and anhydrous Na 2 SO 4 Dry, filter, and concentrate under reduced pressure to obtain the title compound (52.50 g, yield 96%).
  • N-isopropyl-5-((methylamino)methyl)-2-(methylmercapto)pyrimidin-4-amine (3.0 g, 13.25 mmol) was dissolved in dry THF (40 mL) and cooled in an ice-salt bath At 0°C, CDI (2.58g, 15.91mmol) and TEA (2.68g, 26.51mmol, 3.69mL) were added, the addition was completed, the temperature was raised to 80°C and the reaction was performed for 48h. After the completion of the reaction was monitored by TLC, the system was concentrated, and the residue was passed through the column layer. The target compound A-14 (2.18 g, yield 65%) was obtained by analysis.
  • N-isopropyl-2-(methylmercapto)-5-nitropyrimidin-4-amine (18.0 g, 78.85 mmol) was dissolved in MeOH (150 mL) and Pd/C (3.00 g, 78.85 mmol) was added slowly in portions mmol, 10% content), the H 2 three times substituted, rt H 2 through the reaction conditions of 2 hours, TLC monitoring completion of the reaction, the filter cake was washed with a small amount of MeOH, and the filtrate to give the title compound (11.0 g of, after the spin dry yield 70%).
  • N 4 - isopropyl-2- (methylmercapto) pyrimidine-4,5-diamine (11.00g, 55.47mmol) was dissolved in EtOH (200mL) was added ethyl glyoxylate (11.33g, 110.95mmol) , slowly add HOAc (11.55g, 192.33mmol, 11.00mL), after the addition, the temperature is raised to 100 ° C for 16 hours, after TLC monitoring is completed, the solvent is spin-dried under reduced pressure, and the residue is subjected to column chromatography to obtain the target compound A-15 (6.60 g, 50% yield).
  • the target intermediates B-2 to B-68 were obtained by the synthesis method of intermediate B-1.
  • Step 1 Synthesis of Compound 139-1
  • each optically pure isomer of the compound of the present invention can be prepared by using optically pure intermediates B1-B64 and different A1-A15 fragments as raw materials.
  • optically pure isomers of the compounds of the present invention can also be prepared using chiral HPLC or achiral HPLC.
  • Compound 1 of the present invention can be obtained by the above method to obtain two optically pure isomers 1-1 and 1-2 of compound 1:
  • U87 cells overexpressing IDH R132C mutation were seeded in 48-well plates at 50,000/well, and after overnight adherence, the supernatant was removed.
  • Cell culture media containing serially diluted compounds were added and incubated for 72 hours. After 72 hours, the culture medium was collected, diluted 10 times with water, and then acetonitrile was added to extract metabolites. The content of 2-HG in the culture medium was analyzed by LC-MS-MS, and the percentage of inhibition of 2-HG in the supernatant by the compound was calculated compared with the control group.
  • B means the inhibition rate is greater than 60%, but less than or equal to 90%
  • C indicates that the inhibition rate is greater than 30%, but less than or equal to 60%
  • D indicates that the inhibition rate is less than or equal to 30%.
  • mice were subcutaneously inoculated with 1*10 6 HT1080 cells, and when the tumor volume grew to 100-150 mm 3 , the mice were randomly divided into groups to receive the solvent control group, 20 mg/kg of compounds 1, 70, 79, 85, 96, 139, 157 or LY-3410738. Tumors were harvested after continuous administration for three days and seven days, and the tumor weight was weighed. After the lysate was lysed and homogenized, the level of 2-HG in tumor tissue was determined by LC-MS-MS. Compared with the control group, the percentage inhibition of 2-HG in tumor tissue by the compounds was calculated.
  • the compounds of the general formula (1b) of the present invention have a new parent structure. Compared with the IDH inhibitor Ivosidenib which has been on the market, these compounds have a stronger reduction in the activity of 2-HG, the catalytic product of IDH R132C mutant protein, in U87-IDH R132C cells. Compared with LY-3410738, these compounds also had similar or stronger activity in supernatant and tumor tissue levels.

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Abstract

本发明涉及一种通式(1a)或通式(1b)所示的化合物及其制备方法，及通式(1a)或通式(1b)化合物及其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为IDH突变体不可逆抑制剂在抗肿瘤等IDH突变体蛋白相关疾病的药物制备中的用途。

Description

IDH突变体抑制剂及其用途
本申请要求申请日为2020/6/28的中国专利申请CN202010595326.9和申请日为2021/3/22的中国专利申请CN202110302649.9的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属涉及药物化学领域，更具体而言，涉及一类新型IDH突变体抑制剂，及其制备方法和该类化合物的使用方法。
背景技术
异柠檬酸脱氢酶(isocitrate dehydrogenase,IDH)是参与三羧酸循环的重要酶，催化异柠檬酸转化为α-酮戊二酸(α-ketoglutarate,α-KG)，此反应是三羧酸循环的限速步骤。人类共有三种不同的异柠檬酸脱氢酶，分别是IDH1、IDH2和IDH3，IDH1主要定位于胞质和过氧化物酶体，IDH2和IDH3主要分布于线粒体中。
在人类癌症基因突变鉴定中，IDH1和IDH2是出现最频繁的代谢基因，IDH突变在低级胶质瘤、二级恶性胶质瘤、黑色素瘤、血管免疫母细胞性T细胞淋巴瘤、骨髓增生性肿瘤、骨髓增生异常综合征(myelodysplastic syndromes,MDS)以及急性骨髓性白血病(acute myelocytic leukemia,AML)中都存在。肿瘤细胞中IDH突变位点为IDH1Arg132(R132)，IDH2Arg172(R172)或IDH2Arg140(R140)。这些突变会导致IDH蛋白野生型功能缺失，转而获得将α-KG转化为致瘤代谢物D-2-羟戊二酸(D-2-hydroxyglutarate,D-2HG)的能力。致瘤代谢产物2-HG抑制DNA或组蛋白去甲基化酶，从而导致DNA和组蛋白的过度甲基化，进而促进癌症的发生。IDH抑制剂可以通过抑制IDH1/R132，IDH2/R172或IDH2/R140位点突变的蛋白活性，使体内致癌代谢物D-2HG减少，诱导组蛋白H3K9me3去甲基化，达到抑制肿瘤发展的效果。因此，将突变IDH1和IDH2(mIDH1和mIDH2)作为靶标可能是一种有希望的癌症治疗途径。
迄今为止，已经有IDH抑制剂小分子上市，如Agios公司研发的Enasidenib和Ivosidenib，两者为非共价抑制剂。礼来公司在专利WO2017019429、WO2017213910和WO2018111707中报道了IDH的共价抑制剂，相对于野生型IDH1和IDH2，该类共价抑制剂对于突变型的IDH1和IDH2具有更好的选择性。然而还没有IDH共价抑制剂进入临床研究，因此目前有研究和发现活性更好及成药性更佳的共价IDH抑制剂的需要。
发明内容
本发明旨在提供一种通式(1a)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2021102623-appb-000001
通式(1a)中：
L a为下列基团：
Figure PCTCN2021102623-appb-000002
Figure PCTCN2021102623-appb-000003
其中“*”表示和羰基相连的位点；
R 1为Me、Et、-CH 2CH 2CH 3、-CH(CH 3) 2、
Figure PCTCN2021102623-appb-000004
R 2和R 3独立为H、Me或Et，或者R 2和R 3共碳原子形成
Figure PCTCN2021102623-appb-000005
和
R 4为Me、Et、-CH 2CH 2CH 3、-CH(CH 3) 2、-CH 2CH(CH 3) 2、
Figure PCTCN2021102623-appb-000006
Figure PCTCN2021102623-appb-000007
在本发明的另一具体实施例中，通式(1a)化合物具有以下结构之一：
Figure PCTCN2021102623-appb-000008
Figure PCTCN2021102623-appb-000009
Figure PCTCN2021102623-appb-000010
Figure PCTCN2021102623-appb-000011
另一方面,本发明旨在提供一种通式(1b)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2021102623-appb-000012
通式(1b)中：
L b为下列基团：
Figure PCTCN2021102623-appb-000013
Figure PCTCN2021102623-appb-000014
其中“*”表示和羰基相连的位点；
Figure PCTCN2021102623-appb-000015
为下列基团：
Figure PCTCN2021102623-appb-000016
其中“**”表示位置为X端；
R 1为Me、Et、-CH 2CH 2CH 3、-CH(CH 3) 2、
Figure PCTCN2021102623-appb-000017
R 2和R 3独立为H、Me或Et，或者R 2和R 3共碳原子形成
Figure PCTCN2021102623-appb-000018
R 4为Me、Et、-CH 2CH 2CH 3、-CH(CH 3) 2、-CH 2CH(CH 3) 2、
Figure PCTCN2021102623-appb-000019
Figure PCTCN2021102623-appb-000020
在本发明的另一具体实施例中，通式(1b)化合物具有以下结构之一：
Figure PCTCN2021102623-appb-000021
Figure PCTCN2021102623-appb-000022
Figure PCTCN2021102623-appb-000023
Figure PCTCN2021102623-appb-000024
本发明的另一方面旨在提供具有以下结构的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2021102623-appb-000025
Figure PCTCN2021102623-appb-000026
本发明的另一个目的是提供了一种药物组合物，其含有药学上可接受的载体、稀释剂和/或赋形剂，以及本发明所述化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为活性成分。
本发明的再一个目的提供了本发明所述化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或上述药物组合物用于制备治疗IDH突变体蛋白相关疾病药物中的应用。
本发明的再一个目的还提供治疗、调节和/或预防与IDH突变体蛋白相关疾病的方法，包括对受试者给与治疗有效量的本发明所述化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或上述药物组合物。
应理解，本发明的前述一般性描述和以下详细描述都是示例性和说明性的，旨在提供对所要求保护的本发明的进一步说明。
化合物的合成
下面具体地描述本发明所述化合物的制备方法，但这些具体方法不对本发明构成任何限制。
以上说明的本发明所述化合物可使用标准的合成技术或公知的技术与文中结合的方法来合成。此外，在此提到的溶剂，温度和其他反应条件可以改变。用于化合物的合成的起始物料可以由合成或从商业来源上获得。本文所述的化合物和其他具有不同取代基的有关化合物可使用公知的技术和原料来合成，包括发现于March，ADVANCED ORGANIC CHEMISTRY 4 th Ed.，(Wiley 1992)；Carey和Sundberg，ADVANCED ORGANIC CHEMISTRY 4 th Ed.，Vols.A和B(Plenum 2000，2001)，Green和Wuts，PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed.，(Wiley 1999)中的方法。化合物制备的一般方法可通过使用适当的试剂和在此提供的分子式中引入不同基团的条件来改变。
一方面，本文所述的化合物根据工艺中公知的方法。然而方法的条件，例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。一方面，本发明还提供了一种本发明所述化合物的制备方法，其中本发明所述化合物可采用下列一般反应流程1和一般反应流程2制备：
一般反应流程1
Figure PCTCN2021102623-appb-000027
当“X 1＝Y 1”为下列基团：
Figure PCTCN2021102623-appb-000028
时，本发明所述化合物可根据一般反应流程1(方法A)制备，其中“**”表示位置为X 1端，L 0表示L a或L b，PG表示胺基的保护基，R 1、R 2、R 3、R 4、L a和L b如上文中所定义。如一般反应流程1所示,原料A1经氧化反应得到化合物A2,化合物A2和A3在碱性条件下反应得到化合物A4，化合物A4脱除保护基PG(例如Boc)得到化合物A5，化合物A5和丙烯酰氯反应生成目标化合物A6。
一般反应流程2
Figure PCTCN2021102623-appb-000029
当通式(1b)化合物中，
Figure PCTCN2021102623-appb-000030
为
Figure PCTCN2021102623-appb-000031
时，本发明所述化合物可根据一般反应流程2(方法B)制备，其中R 1、R 2、R 3、R 4和L b如上文中所定义，PG表示胺基的保护基。原料B1可经一般反应流程1制得。如一般反应流程2所示，化合物B1在碱性条件下进行消除反应得到化合物B2，化合物B2脱除保护基PG(例如Boc)得到化合物B3，化合物B3和丙烯酰氯反应生成目标化合物B4。
化合物的进一步形式
“药学上可接受”这里指一种物质，如载体或稀释液，不会使化合物的生物活性或性质消失，且相对无毒，如，给予个体某物质，不会引起不想要的生物影响或以有害的方式与任何其含有的组分相互作用。
术语“药学上可接受的盐”指一种化合物的存在形式，该形式不会引起对给药有机体的重要的刺激，且不会使化合物的生物活性和性质消失。在某些具体方面，药学上可接受的盐是通过本发明所述化合物与酸反应获得，如盐酸、氢溴酸、氢氟酸、硫酸、磷酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、三氟乙酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯磺酸、对甲苯磺酸等有机酸以及天冬氨酸、谷氨酸等酸性氨基酸。
应理解药学上可接受的盐的参考包括溶剂添加形式或结晶形式，尤其是溶剂化物或多晶型。溶剂化物含有化学计量或非化学计量的溶剂，且是在与药学上可接受溶剂如水，乙醇等，结晶化过程中选择性形成的。当溶剂是水时形成水合物，或当溶剂是乙醇时形成醇化物。本发明所述化合物的溶剂化物按照本文所述的方法，很方便的制得或形成。举例说明，本发明所述化合物的水合物从水/有机溶剂的混合溶剂中重结晶而方便的制得，使用的有机溶剂包括但不限于，四氢呋喃、丙酮、乙醇或甲醇。此外，在此提到的化合物能够以非溶剂化和溶剂化形式存在。总之，对于在此提供的化合物和方法为目的，溶剂化形式被认为相当于非溶剂化形式。
在其他具体实施例中，本发明所述化合物被制备成不同的形式，包括但不限于，无定形，粉碎形和毫微-粒度形式。此外，本发明所述化合物包括结晶型，也可以作为多晶型。多晶型包括化合物的相同元素组成的不同晶格排列。多晶型通常有不同的X-射线衍射图、红外光谱、熔点、密度、硬度、晶型、光和电的性质、稳定性和溶解性。不同的因素如重结晶溶剂，结晶速率和贮存温度可能引起单一晶型为主导。
在另一个方面，本发明所述化合物可能存在手性中心和/或轴手性，并因此以消旋体、 外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式、和顺反异构体的形式出现。每个手性中心或轴手性将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
本发明所述化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)、碘-125( 125I)和C-14( 14C)。又例如，可用重氢取代氢原子形成氘代化合物，氘与碳构成的键比普通氢和碳构成的键更坚固，相比于未氘代药物，通常氘代药物具有降低毒副作用、增加药物稳定性、增强疗效、延长药物体内半衰期等优势。本发明所述化合物的所有同位素组成的变换，无论放射性与否，都包含在本发明的范围之内。
术语
如果无另外说明，用于本发明申请，包括说明书和权利要求书中的术语，定义如下。
必须注意，在说明书和所附的权利要求书中，如果文中无另外清楚指示，单数形式“一个”包括复数意义。如果无另外说明，使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中，如果无另外说明，使用“或”或“和”指“和/或”。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
除非另有说明，用楔形实线键
Figure PCTCN2021102623-appb-000032
和楔形虚线键
Figure PCTCN2021102623-appb-000033
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2021102623-appb-000034
和直形虚线键
Figure PCTCN2021102623-appb-000035
表示立体中心的相对构型，用波浪线
Figure PCTCN2021102623-appb-000036
表示楔形实线键
Figure PCTCN2021102623-appb-000037
或楔形虚线键
Figure PCTCN2021102623-appb-000038
或用波浪线
Figure PCTCN2021102623-appb-000039
表示直形实线键
Figure PCTCN2021102623-appb-000040
或直形虚线键
Figure PCTCN2021102623-appb-000041
特定药学及医学术语
术语“可接受的”，如本文所用，指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。
术语“治疗”、“治疗过程”或“疗法”如本文所用，包括缓和、抑制或改善疾病的症状或状况；抑制并发症的产生；改善或预防潜在代谢综合症；抑制疾病或症状的产生，如控制疾病或情况的发展；减轻疾病或症状；使疾病或症状减退；减轻由疾病或症状引起的并发症，或预防或治疗由疾病或症状引起的征兆。如本文所用，某一化合物或药物组合物，给药后，可以使某一疾病、症状或情况得到改善，尤指其严重度得到改善，延迟发病，减 缓病情进展，或减少病情持续时间。无论固定给药或临时给药、持续给药或间歇给药，可以归因于或与给药有关的情况。
“活性成分”指本发明所述化合物，以及本发明所述化合物的药学上可接受的无机或有机盐。本发明的化合物可以含有一个或多个不对称中心(手性中心或轴手性)，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心，取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
“化合物(compound)”、“组合物(composition)”、“药剂(agent)”或“医药品(medicine or medicament)”等词在此可交替使用，且都是指当施用于个体(人类或动物)时，能够透过局部和/或全身性作用而诱发所亟求的药学和/或生理反应的一种化合物或组合物。
“施用(administered、administering或、administration)”一词在此是指直接施用所述的化合物或组合物，或施用活性化合物的前驱药(prodrug)、衍生物(derivative)、或类似物(analog)等。
虽然用以界定本发明较广范围的数值范围与参数皆是约略的数值，此处已尽可能精确地呈现具体实施例中的相关数值。然而，任何数值本质上不可避免地含有因个别测试方法所致的标准偏差。在此处，“约”通常是指实际数值在一特定数值或范围的正负10％、5％、1％或0.5％之内。或者是，“约”一词代表实际数值落在平均值的可接受标准误差之内，视本领域技术人员的考虑而定。除了实验例之外，或除非另有明确的说明，当可理解此处所用的所有范围、数量、数值与百分比(例如用以描述材料用量、时间长短、温度、操作条件、数量比例及其它相似者)均经过“约”的修饰。因此，除非另有相反的说明，本说明书与附随权利要求书所揭示的数值参数皆为约略的数值，且可视需求而更动。至少应将这些数值参数理解为所指出的有效位数与采用一般进位法所得到的数值。
除非本说明书另有定义，此处所用的科学与技术词汇的含义与本领域技术人员所理解的惯用的意义相同。此外，在不和上下文冲突的情形下，本说明书所用的单数名词涵盖该名词的复数型；而所用的复数名词时亦涵盖该名词的单数型。
治疗用途
本发明提供了使用本发明所述化合物或药物组合物治疗疾病的方法，包括但不限于涉及IDH突变体蛋白相关的病况(例如癌症)。
在一些实施例中，提供了用于癌症治疗的方法，该方法包括给予有需要的个体有效 量的任何前述的包括本发明所述化合物的药物组合物。在一些实施例中，癌症由IDH突变体蛋白介导。在其它实施例中，该癌症是血液癌和实体瘤，包括但不限于白血病、肺癌、胰腺癌、结肠癌、胆囊癌或结肠直肠癌。
给药途径
本发明的化合物及其药学上可接受的盐可制成各种制剂，其中包含安全、有效量范围内的本发明化合物或其药学上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全、有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。化合物的安全、有效量根据治疗对象的年龄、病情、疗程等具体情况来确定。
“药学上可以接受的赋形剂或载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能与本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药理上可以接受的赋形剂或载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2021102623-appb-000042
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
施用本发明化合物时，可以口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形 式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
具体实施方式
在下面的说明中将会详细阐述上述化合物、方法、药物组合物的各个具体方面、特性和优势，使本发明的内容变得十分明了。在此应理解，下述的详细说明及实例描述了具体的实施例，仅用于参考。在阅读了本发明的说明内容后，本领域的技术人员可对本 发明作各种改动或修改，这些等价形势同样落于本申请所限定的范围。
所有实施例中， 1H-NMR用Varian Mercury 400核磁共振仪记录，化学位移以δ(ppm)表示；分离用硅胶未说明均为200-300目，洗脱液的配比均为体积比。
本发明采用下述缩略词：AcOH(或HOAc)代表乙酸；Ar代表氩气；CDCl 3代表氘代氯仿；CDI代表羰基二咪唑；Cs 2CO 3代表碳酸铯；CsF代表氟化铯；DBU代表1,8-二氮杂双环[5.4.0]十一碳-7-烯；DCM代表二氯甲烷；DIPEA代表二异丙基乙基胺；DMF代表二甲基甲酰胺；DMSO代表二甲基亚砜；EA代表乙酸乙酯；EtOH代表乙醇；h代表小时；H 2代表氢气；NaOH代表氢氧化钠；KOH代表氢氧化钾；LC-MS代表液相-质谱；LiAlH 4代表氢化铝锂；m-CPBA代表间氯过氧苯甲酸；MeOH代表甲醇；min代表分钟；mL代表毫升；MnO 2代表二氧化锰；MS代表质谱；NaBH 3CN代表氰基硼氢化钠；NaBH 4代表硼氢化钠；n-BuLi代表正丁基锂；NaBH(OAc) 3代表三乙酰氧基硼氢化钠；Na 2SO 3代表亚硫酸钠；Na 2SO 4代表硫酸钠；NH 4Cl代表氯化铵；NMR代表核磁共振；Pd/C代表钯碳；PE代表石油醚；t-BuOK代表叔丁醇钾；TEA代表三乙胺；TFA(或CF 3COOH)代表三氟乙酸；THF代表四氢呋喃；Ti(O i-Pr) 4代表四异丙醇钛；Toluene代表甲苯。
制备例1 1-乙基-7-(甲硫基)-1,4-二氢-2H-嘧啶基[4,5-d][1,3]恶嗪-2-酮(A-1)的合成
Figure PCTCN2021102623-appb-000043
7-(甲硫基)-1,4-二氢-2H-嘧啶基[4,5-d][1,3]恶嗪-2-酮的合成
250mL单口瓶中将(4-氨基-2-(甲硫基)嘧啶-5-基)甲醇(4.5g,26.28mmol)溶于THF(50mL)中，加入DBU(8.0g,52.56mmol)和CDI(4.69g,28.91mmol),混合液氩气置换后室温搅拌反应2h。LC-MS检测反应完成后，混合液加H 2O(50mL)淬灭，用6N盐酸调pH至4～5，后再加入EA(15mL)/PE(15mL)，混合液室温搅拌30min后抽滤，滤饼用EA/PE＝1/1的混合液(10mL)淋洗，真空干燥,得浅棕色固体产物(3.57g,收率69％)，ESI-MS m/z:198[M+H] +。
1-乙基-7-(甲硫基)-1,4-二氢-2H-嘧啶基[4,5-d][1,3]恶嗪-2-酮的合成
250mL单口瓶中加入7-(甲硫基)-1,4-二氢-2H-嘧啶基[4,5-d][1,3]恶嗪-2-酮(3.69g,18.71mmol)溶于DMF(40mL)中，加入Cs 2CO 3(7.5g,23.01mmol)，氩气保护下冰浴降温至0～5℃，后滴加EtI(3.77g,24.14mmol)，滴毕，混合液室温搅拌反应20h。LC-MS检测反应完成后，混合液加H 2O(80mL)淬灭，EA(40mL*3)萃取，合并有机相用饱和氯化 钠溶液(40mL*2)洗涤两次，无水Na 2SO 4干燥，过滤，减压浓缩。残留物经柱层析纯化得到类白色固体产物A-1(3.9g,收率93％)，ESI-MS m/z:226[M+H] +。
制备例2-6 中间体A-2至A-6的合成
利用不同原料，采用中间体A-1的合成方法得到目标中间体A-2至A-6。
表1.中间体A-2至A-6结构式
Figure PCTCN2021102623-appb-000044
制备例7 1-异丙基-7-(甲巯基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(A-7)的合成
Figure PCTCN2021102623-appb-000045
4-(异丙氨基)-2-(甲巯基)嘧啶-5-甲腈的合成
4-氯-2(甲巯基)嘧啶-5-甲腈(3.71g,20mmol)溶于DMF(30mL)中，加入异丙基胺(1.2g，20mmol)和DIPEA(6.5g,50mmol)，加完，升温至60℃反应2小时，TLC检测反应完成后，加水(100mL)稀释，EA(50mL*3)萃取3次，合并有机相用饱和氯化钠溶液(50mL)洗涤，无水Na 2SO 4干燥，过滤，减压浓缩，得到粗产物(3.82g,收率92％)，ESI-MS  m/z:209[M+H] +。
5-(甲基氨基)-N-异丙基-2-(甲巯基)嘧啶-4-胺的合成
将上步所得4-(异丙氨基)-2-(甲巯基)嘧啶-5-甲腈(3.74g，18mmol)溶于干燥THF(15mL)中，氮气保护下冷却到0℃，LiAlH 4(1.37g,36mmol)溶于THF(40mL)的溶液缓慢加入到反应体系中，加完后，体系升至室温反应16小时，TLC监测反应完成后，在0℃缓慢加入Na 2SO 4·10H 2O(7g)至体系中,固体过滤，滤饼用少量THF洗，合并有机相，减压旋干溶剂得到中间体5-(甲基氨基)-N-异丙基-2-(甲巯基)嘧啶-4-胺(3.21g，收率84％)，ESI-MS m/z:213[M+H] +。
1-异丙基-7-(甲巯基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮的合成
将5-(甲基氨基)-N-异丙基-2-(甲巯基)嘧啶-4-胺(3.18g，15mmol)溶于干燥THF(50mL)中，冰盐浴冷却到0℃，加入CDI(2.92g，18mmol)和TEA(3.03g，30mmol)，继续反应0.5h，后升温至80℃反应16h，TLC监测反应完成后，浓缩，残留物经柱层析纯化得到1-异丙基-7-(甲巯基)-3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮(2.36g，产率66％)。
1H NMR(400MHz,DMSO-d 6)δ:8.18(s,1H),7.41(br s,1H),4.97(spt,J＝6.9Hz,1H),4.19(d,J＝0.9Hz,2H),2.49(s,3H),1.43(d,J＝6.9Hz,6H)；ESI-MS m/z:239[M+H] +.
制备例8-13 中间体A-8至A-13的合成
利用不同原料，采用中间体A-7的合成方法得到目标中间体A-8至A-13。
表2.中间体A-8至A-13结构式
Figure PCTCN2021102623-appb-000046
制备例14 1-异丙基-3-甲基-7-(甲巯基)-3,4-二氢嘧啶[4,5-d]嘧啶-2(1H)-酮(A-14)的合成
Figure PCTCN2021102623-appb-000047
4-(异丙氨基)-2-(甲巯基)嘧啶-5-甲酸乙酯的合成
将4-氯-2-(甲巯基)嘧啶-5-甲酸乙酯(50g,214.88mmol)溶于THF(500mL)中，冰盐浴冷却到0℃，加入TEA(43.49g,429.76mmol,59.82mL)，加完，室温反应16h，TLC监测反应完成后，加入水(200mL),EA(200mL*2)萃取，合并有机相用饱和氯化钠溶液(100mL)洗涤，无水Na 2SO 4干燥，过滤，减压浓缩，得到目标化合物(52.50g,收率96％)。
1H NMR(400MHz,DMSO-d 6)δ:8.54(s,1H),8.08(br d,J＝7.4Hz,1H),4.30-4.23(m,2H),2.48(s,3H),1.30(t,J＝7.1Hz,3H),1.23(d,J＝6.5Hz,6H)；ESI-MS m/z:256[M+H] +.
(4-(异丙氨基)-2-(甲巯基)嘧啶-5-基)甲醇的合成
将4-(异丙氨基)-2-(甲巯基)嘧啶-5-甲酸乙酯(30g,117.49mmol)溶于干燥THF(300mL)中，氮气保护下冷却到0℃，LiAlH 4(6.69g,176.24mmol)溶于THF(50mL)的溶液缓慢加入到反应体系中，加完后，继续反应3小时，TLC监测反应完成后，在0℃缓慢加入Na 2SO 4·10H 2O(10g)至体系中,固体过滤，滤饼用少量THF洗，合并有机相，减压旋干溶剂，残留物柱层析得到(4-(异丙氨基)-2-(甲巯基)嘧啶-5-基)甲醇(19.5g，收率78％)。
1H NMR(400MHz,DMSO-d 6)δ:7.82(s,1H),6.40(br d,J＝7.5Hz,1H),5.13(t,J＝5.5Hz,1H),4.31(d,J＝5.5Hz,2H),2.41(s,3H),1.18(d,J＝6.5Hz,5H),1.23-1.12(m,1H)；ESI-MS m/z:214[M+H] +.
4-(异丙氨基)-2-(甲巯基)嘧啶-5-甲醛的合成
将上步所得(4-(异丙氨基)-2-(甲巯基)嘧啶-5-基)甲醇(19.50g,91.42mmol)溶于DCM(150mL)中，加入MnO 2(119.22g,1.37mol)，室温反应16h，TLC监测反应完成后，过滤，滤饼用少量DCM洗，合并有机相，减压旋干溶剂，残留物柱层析得到4-(异丙氨基)-2-(甲巯基)嘧啶-5-甲醛(18.2g，收率94％)。
1H NMR(400MHz,DMSO-d 6)δ:9.84-9.68(m,1H),8.58-8.48(m,1H),4.48-4.25(m,1H), 2.51(s,3H),1.24(d,J＝6.5Hz,6H)；ESI-MS m/z:212[M+H] +.
N-异丙基-5-((甲胺基)甲基)-2-(甲巯基)嘧啶-4-胺的合成
4-(异丙氨基)-2-(甲巯基)嘧啶-5-甲醛(10g,47.33mmol)溶于MeOH(100mL)中，加入AcOH(2.84g,47.33mmol,2.71mL)、甲胺(14.70g,141.99mmol,30％水溶液)和NaBH 3CN(6.84g,108.86mmol)，加完，r.t.反应16h，TLC监测反应完成后，加入H 2O(30mL)，EA(100mL*2)萃取，合并有机相用饱和氯化钠溶液(50mL)洗涤，无水Na 2SO 4干燥，过滤，减压浓缩，残留物经柱层析得到目标化合物(5.70g,收率67％)。
1H NMR(400MHz,DMSO-d 6)δ:8.29(d,J＝1.3Hz,1H),8.16(s,1H),4.41-4.18(m,1H),4.03(q,J＝7.1Hz,1H),3.41(d,J＝1.3Hz,3H),2.46(s,3H),1.21(d,J＝6.6Hz,6H)；ESI-MS m/z:227[M+H] +.
1-异丙基-3-甲基-7-(甲巯基)-3,4-二氢嘧啶[4,5-d]嘧啶-2(1H)-酮(A-14)的合成
将N-异丙基-5-((甲胺基)甲基)-2-(甲巯基)嘧啶-4-胺(3.0g,13.25mmol)溶于干燥THF(40mL)中，冰盐浴冷却到0℃，加入CDI(2.58g,15.91mmol)和TEA(2.68g,26.51mmol,3.69mL)，加完，升温至80℃反应48h，TLC监测反应完成后，体系浓缩，残留物经柱层析得到目标化合物A-14(2.18g,收率65％)。
1H NMR(400MHz,DMSO-d 6)δ:8.20(s,1H),5.02(spt,J＝6.9Hz,1H),4.31(d,J＝0.8Hz,2H),2.90(s,3H),1.43(d,J＝6.9Hz,6H)；ESI-MS m/z:253[M+H] +.
制备例15 8-异丙基-2-(甲巯基)蝶啶-7(8H)-酮(A-15)的合成
Figure PCTCN2021102623-appb-000048
N-异丙基-2-(甲巯基)-5-硝基嘧啶-4-胺
将4-氯-2-甲巯基-5-硝基嘧啶(20.56g,100mmol)溶于DMF(150mL)中，加入异丙基胺(5.9g,100mmol)和DIPEA(32.5g,250mmol)，加完，升温至60℃反应2小时，TLC检测反应完成后，加水(400mL)稀释，EA(300mL*3)萃取3次，合并有机相用饱和氯化钠溶液(200mL)洗涤，无水Na 2SO 4干燥，过滤，减压浓缩，得到粗产物(18.55g,收率 81％)，ESI-MS m/z:229[M+H] +。
N 4-异丙基-2-(甲巯基)嘧啶-4,5-二胺
将N-异丙基-2-(甲巯基)-5-硝基嘧啶-4-胺(18.0g,78.85mmol)溶于MeOH(150mL)中，缓慢分批加入Pd/C(3.00g,78.85mmol,10％含量)，H 2置换三次，r.t.条件下通H 2反应2小时，TLC监测反应完成后，过滤，滤饼用少量MeOH洗涤，滤液旋干后得到目标化合物(11.0g,收率70％)。
1H NMR(400MHz,DMSO-d 6)δ:1.17(d,J＝6.48Hz,6H),2.30-2.39(m,3H),4.12-4.23(m,1H),4.54(br s,2H),6.26(br d,J＝7.09Hz,1H),7.38-7.44(m,1H)；ESI-MS m/z:199[M+H] +.
8-异丙基-2-(甲巯基)蝶啶-7(8H)-酮(A-15)的合成
将N 4-异丙基-2-(甲巯基)嘧啶-4,5-二胺(11.00g,55.47mmol)溶于EtOH(200mL)中，加入乙醛酸乙酯(11.33g,110.95mmol)，缓慢加入HOAc(11.55g,192.33mmol,11.00mL)，加完，升温至100℃反应16小时，TLC监测反应完成后，减压旋干溶剂，残留物经柱层析得到目标化合物A-15(6.60g,收率50％)。
1H NMR(400MHz,DMSO-d 6)δ:1.54(d,J＝6.97Hz,6H),2.62(s,3H),5.52(dt,J＝13.82,6.91Hz,1H),8.11-8.16(m,1H),8.94(s,1H)；ESI-MS m/z:237[M+H] +.
制备例16 4-(1-(4-((S)-1-氨基乙基)苯基)-2-环丙乙基)哌嗪-1-甲酸叔丁酯(B-1)的合成
Figure PCTCN2021102623-appb-000049
(S)-N-(1-(4-(2-环丙基乙酰基)苯基)乙基)-2,2,2-三氟乙酰胺的合成
将(S)-N-(1-(4-溴苯基)乙基)-2,2,2-三氟乙酰胺(10.7g,36.2mmol)溶于干燥THF(100mL)中,氩气保护下,-78℃下滴加n-BuLi(2.5M,30mL,72.3mmol)，滴毕，保温在-78℃至-60℃下反应约1h，后缓慢滴加2-环丙基-N-甲氧基-N-甲基乙酰胺(5.7g,39.8mmol)的 干燥THF(50mL)溶液，滴毕，继续保温反应0.5h。LC-MS检测反应完全后，加饱和NH 4Cl水溶液(100mL)淬灭反应，以EA(50mL*2)萃取两次，有机相浓缩，残留物柱层析纯化得白色固体产物(6.06g,收率56％),ESI-MS m/z:300[M+H] +。
叔丁基4-(2-环丙基-1-(4-((S)-1-(2,2,2-三氟乙酰氨基)乙基)苯基)乙基)哌嗪-1-羧酸酯的合成
将(S)-N-(1-(4-(2-环丙基乙酰基)苯基)乙基)-2,2,2-三氟乙酰胺(3.068g,10.25mmol)、哌嗪-1-羧酸叔丁酯(3.82g，20.5mmol)溶于干燥THF(50mL)，氩气保护下滴加Ti(i-PrO) 4(15mL,51.25mmol)，混合液60℃反应过夜。后冷却至室温，加入甲醇(20mL)，NaBH(OAc) 3(1.288g,20.5mmol),混合物室温反应10h，LC-MS检测剩余少量原料。加水(100mL)淬灭，EA(50mL*2)萃取，有机相浓缩，残留物柱层析纯化得白色固体产物(957mg,收率20％)，同时回收未反应原料(2.2g),ESI-MS m/z:470[M+H] +。
叔丁基4-(1-(4-((S)-1-氨基乙基)苯基)-2-环丙基乙基)哌嗪-1-羧酸酯(B-1)的合成
将叔丁基4-(2-环丙基-1-(4-((S)-1-(2,2,2-三氟乙酰氨基)乙基)苯基)乙基)哌嗪-1-羧酸酯(3.74g,7.97mmol)溶于EtOH/H 2O(100mL/20mL)中，冰浴冷却下，分批加KOH(2.24g,39.87mmol)，后氩气保护下升温至50℃反应3h。LC-MS检测反应完全，减压浓缩至剩余约30mL，加水(50mL)稀释，DCM(50mL*2)萃取，合并有机相，饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得目标化合物(3.854g,收率100％),ESI-MS m/z:374[M+H] +。
制备例17-83 中间体B-2至B-68的合成
利用不同原料，采用中间体B-1的合成方法得到目标中间体B-2至B-68。
表3.中间体B-2至B-68结构式
Figure PCTCN2021102623-appb-000050
Figure PCTCN2021102623-appb-000051
Figure PCTCN2021102623-appb-000052
Figure PCTCN2021102623-appb-000053
Figure PCTCN2021102623-appb-000054
实施例1 7-(((1S)-1-(4-(1-(4-丙烯酰哌嗪-1-基)-2-环丁基乙基)苯基)乙基)氨基)-1-乙基-1,4-二氢-2H-嘧啶并[4,5-d][1,3]噁嗪-2-酮(化合物139)的合成
Figure PCTCN2021102623-appb-000055
步骤1：化合物139-1的合成
将化合物A-1(2.85g,12.65mmol)溶于DCM(30mL)中，冰浴冷却下，加入m-CPBA(7,71g，37.95mmol)，r.t.搅拌反应1h。LC-MS监测反应完成后，混合液加入饱和Na 2S 2O 3(40mL)，碳酸氢钠溶液(20mL)淬灭，混合室温搅拌30min后分液，水相再用DCM(40mL*2)萃取，合并有机相用饱和氯化钠溶液(40mL)洗涤，无水Na 2SO 4干燥，过滤，减压浓缩得白色固体产物139-1(3.21g,收率99％)，ESI-MS m/z:258[M+H] +。
步骤2：化合物139-2的合成
将化合物139-1(40mg,0.16mmol)和化合物B-7(80mg,粗品，0.16mmol)溶于二甲亚砜(10mL)中，加CsF(71mg,0.47mmol)和DIPEA(30mg,0.23mmol)，60℃反应约1h，LC-MS检测反应完全后，混合液加入水(10mL)和EA(20mL)，搅拌，分液，水相再用EA(10mL)萃取，合并有机相，用饱和氯化钠溶液(10mL)洗涤，无水Na 2SO 4干燥，过滤，减压浓缩得黄色泡状固体粗品化合物139-2(100mg,收率100％)，ESI-MS m/z:565[M+H] +。
步骤3：化合物139-3的合成
将化合物139-2(100mg,粗品，0.16mmol)溶于EA(5mL)，加入4M的HCl/Diox(3mL,12mmol)，室温搅拌反应约1h，LC-MS检测反应完全后，混合液减压浓缩得棕色固体粗品(80mg,收率100％)，ESI-MS m/z:465[M+H] +。
步骤4：化合物139的合成
将化合物139-3(74mg,0.16mmol)溶于DCM(5mL)中，加入DIPEA(103mg,0.80mmol)，后滴加丙烯酰氯(14mg,0.16mmol)，室温反应约10min，LC-MS检测反应完全后，加水(10mL)，DCM(10mL*2)萃取，合并有机相旋干，pre-TLC纯化得淡黄色固体化合物139(12mg，收率14％)。
1H NMR(400MHz,CDCl 3)δ:7.88(s,1H),7.25(d,J＝7.1Hz,2H),7.08(d,J＝7.8Hz,2H),6.46(dd,J＝16.8,10.5Hz,1H),6.20(dd,J＝16.9,2.0Hz,1H),5.61(dd,J＝10.5,2.0Hz,1H),5.05(s,2H),3.92(td,J＝19.2,16.3,9.5Hz,2H),3.68-3.46(m,4H),3.46(s,1H),3.20(dd,J＝9.3,4.7Hz,1H),2.33(s,4H),2.04-1.64(m,9H),1.53(d,J＝6.9Hz,3H),1.07(s,3H)；ESI-MS m/z:519[M+H] +.
实施例2-105 化合物1-84,140-159的合成
类似于化合物139的合成，采用不同中间体为原料，可以得到表4中目标化合物1-84,140-159。
表4 化合物1-84,140-159
Figure PCTCN2021102623-appb-000056
Figure PCTCN2021102623-appb-000057
Figure PCTCN2021102623-appb-000058
Figure PCTCN2021102623-appb-000059
Figure PCTCN2021102623-appb-000060
Figure PCTCN2021102623-appb-000061
Figure PCTCN2021102623-appb-000062
实施例106 7-(((1S)-1-(4-(1-(4-丙烯酰基哌嗪-1-基)-2-环丙基乙基)苯基)乙基)氨基)-1-异丙基嘧啶[4,5-d]嘧啶-2(1H)-酮(化合物85)的合成
Figure PCTCN2021102623-appb-000063
步骤1：化合物85-1的合成：
将化合物85-0(100mg,0.182mmol，类似化合物119-2的合成)溶于THF(5mL)中，氩气保护下加入t-BuOK(100mg,0.88mmol)，混合液r.t.搅拌反应20h。LC-MS检测剩余部分原料，体系加入饱和氯化铵溶液(10mL)淬灭，后用EA(20mL*2)萃取,合并有机相用饱和氯化钠溶液(10mL)洗涤，无水Na 2SO 4干燥，过滤，浓缩得粗品化合物85-1(180mg，收率100％)，ESI-MS m/z:562[M+H] +。
步骤2：化合物85-2的合成：
将化合物85-1(180mg,0.182mmol)溶于DCM(10mL)中，加入TFA(3mL)，r.t.搅拌反应约1h。LC-MS检测反应完全后，混合液减压浓缩得棕色固体粗品化合物85-2(100mg,收率100％)，ESI-MS m/z:462[M+H] +。
步骤3：化合物85的合成：
将化合物85-2(100mg,0.182mmol)溶于DCM(10mL)中，加入DIPEA(103mg,0.80mmol)，后滴加丙烯酰氯(21mg,0.24mmol)，室温反应约10min，LC-MS检测反应完全。加水(10mL)，DCM(10mL*2)萃取，合并有机相，旋干，残留物经prep-HPLC纯化得淡黄色固体产物85(22mg，收率23％)。
1H NMR(400MHz,CDCl 3)δ:7.77(s,1H),7.28(d,J＝7.9Hz,2H),7.17(d,J＝7.8Hz,2H),6.46(dd,J＝16.8,10.5Hz,1H),6.21(dd,J＝16.9,1.9Hz,1H),5.62(dd,J＝10.5,1.9Hz,1H),5.01(s,1H),4.17(s,1H),3.63(s,2H),3.49(s,2H),3.40(s,1H),2.37(s,4H),1.86(d,J＝11.8Hz,2H),1.53(d,J＝6.9Hz,3H),1.36(t,J＝6.2Hz,3H),1.24(s,3H),0.43-0.32(m,1H),0.29(s,2H),-0.07(d,J＝15.0Hz,2H)；ESI-MS m/z:516[M+H] +.
实施例107-159 化合物86-138的合成
类似于化合物85的合成，采用不同中间体为原料，可以得到表5中目标化合物86- 138。
表5 化合物86-138
Figure PCTCN2021102623-appb-000064
Figure PCTCN2021102623-appb-000065
Figure PCTCN2021102623-appb-000066
Figure PCTCN2021102623-appb-000067
实施例160 本发明化合物的手性异构体制备
本发明化合物含有一个或多个手性中心，采用光学纯的中间体B1-B64和不同的A1-A15片段为原料，可以制得本发明化合物的各个光学纯异构体。或者采用手性HPLC或非手性HPLC也可以制备本发明化合物的各光学纯异构体。
本发明化合物1可以采用上述方法得到化合物1的两个光学纯异构体1-1和1-2：
Figure PCTCN2021102623-appb-000068
采用相同的合成或者制备方法，对化合物36、66、70、72、85、114、116、139、147和157进行手性拆分，各自分别得到其两个手性异构体36-1/36-2、66-1/66-2、70-1/70-2、72-1/72-2、85-1/85-2、114-1/114-2、116-1/116-2、139-1/139-2、147-1/147-2和157-1/157-2:
Figure PCTCN2021102623-appb-000069
本发明其它化合物也可以采用类似的合成或者制备方法得到其相应的手性异构体。
实施例161 U87-IDH R132C细胞上清中2-HG的检测
过表达IDH R132C突变的U87细胞按照50000/孔种于48孔板中，过夜贴壁后，去除上清。加入含有梯度稀释化合物的细胞培养液，孵育72小时。72小时后，收取培养液，以水稀释10倍后，加入乙腈提取代谢产物。用LC-MS-MS分析培养液中2-HG含量，与对照组相比，计算化合物抑制上清中2-HG的抑制百分比。
表6 化合物对U87-IDH R132C细胞上清中2-HG抑制率
Figure PCTCN2021102623-appb-000070
Figure PCTCN2021102623-appb-000071
A表示抑制率大于90％；
B表示抑制率大于60％，但小于或等于至90％；
C表示抑制率大于30％，但小于或等于至60％；
D表示抑制率小于或等于30％。
实施例162 肿瘤组织中2-HG的检测
裸鼠皮下接种1*10 6HT1080细胞,待肿瘤体积长至100-150mm 3后随机分组给药溶剂对照组，20mg/kg化合物1,70,79,85,96,139,157或LY-3410738。连续给药三天和七天后收取肿瘤，称重瘤重，裂解液裂解匀浆后，用LC-MS-MS测定肿瘤组织中2-HG的水平。与对照组相比，计算化合物抑制肿瘤组织中2-HG的百分比。
表7 化合物抑制HT1080肿瘤组织中2-HG的抑制率
Figure PCTCN2021102623-appb-000072
Figure PCTCN2021102623-appb-000073
从上表活性数据可知，本发明通式(1a)化合物具有新的La基团的结构，其活性和已经上市的IDH抑制剂Ivosidenib相比，这些化合物更强的抑制了U87-IDH R132C细胞上清中和肿瘤组织中2-HG的水平，提示其具有更强的抑制IDH R132C突变蛋白的能力。同时，和LY-3410738(专利WO2018111707中化合物2)相比，这些化合物也有类似或更强的活性。
本发明通式(1b)化合物具有新的母体结构，其活性和已经上市的IDH抑制剂Ivosidenib相比，这些化合物更强的降低了IDH R132C突变蛋白的催化产物2-HG在U87-IDH R132C细胞上清和肿瘤组织中的水平，与LY-3410738相比，这些化合物也有类似或更强的活性。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (8)

  1. 一种如通式(1a)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
    Figure PCTCN2021102623-appb-100001
    通式(1a)中：
    L a为下列基团：
    Figure PCTCN2021102623-appb-100002
    Figure PCTCN2021102623-appb-100003
    其中“*”表示和羰基相连的位点；
    R 1为Me、Et、-CH 2CH 2CH 3、-CH(CH 3) 2、
    Figure PCTCN2021102623-appb-100004
    R 2和R 3独立为H、Me或Et，或者R 2和R 3共碳原子形成
    Figure PCTCN2021102623-appb-100005
    和
    R 4为Me、Et、-CH 2CH 2CH 3、-CH(CH 3) 2、-CH 2CH(CH 3) 2、
    Figure PCTCN2021102623-appb-100006
    Figure PCTCN2021102623-appb-100007
  2. 如权利要求1所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物具有以下结构之一：
    Figure PCTCN2021102623-appb-100008
    Figure PCTCN2021102623-appb-100009
    Figure PCTCN2021102623-appb-100010
    Figure PCTCN2021102623-appb-100011
  3. 一种如通式(1b)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
    Figure PCTCN2021102623-appb-100012
    通式(1b)中：
    L b为下列基团：
    Figure PCTCN2021102623-appb-100013
    Figure PCTCN2021102623-appb-100014
    其中“*”表示和羰基相连的位点；
    Figure PCTCN2021102623-appb-100015
    为下列基团：
    Figure PCTCN2021102623-appb-100016
    其中“**”表示位置为X端；
    R 1为Me、Et、-CH 2CH 2CH 3、-CH(CH 3) 2、
    Figure PCTCN2021102623-appb-100017
    R 2和R 3独立为H、Me或Et，或者R 2和R 3共碳原子形成
    Figure PCTCN2021102623-appb-100018
    R 4为Me、Et、-CH 2CH 2CH 3、-CH(CH 3) 2、-CH 2CH(CH 3) 2、
    Figure PCTCN2021102623-appb-100019
    Figure PCTCN2021102623-appb-100020
  4. 如权利要求3所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物具有以下结构之一：
    Figure PCTCN2021102623-appb-100021
    Figure PCTCN2021102623-appb-100022
    Figure PCTCN2021102623-appb-100023
    Figure PCTCN2021102623-appb-100024
  5. 一种具有如下所示结构的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物具有以下结构之一：
    Figure PCTCN2021102623-appb-100025
    Figure PCTCN2021102623-appb-100026
  6. 一种用于治疗、调节和/或预防与IDH突变体蛋白相关的疾病的药物组合物，其特征在于，它含有药学上可接受的赋形剂或载体，以及如权利要求1-5中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为活性成分。
  7. 一种如权利要求1-5中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或如权利要求6所述的药物组合物的用途，其特征是用于治疗有需要的个体由IDH突变蛋白介导的疾患的方法。
  8. 如权利要求7所述的方法，其中所述的疾患是癌症，所述癌症是血液癌和实体瘤。
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WO2016171755A1 (en) * 2015-04-21 2016-10-27 Forma Therapeutics, Inc. Fused-bicyclic aryl quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
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