CN111662271A - Compound with IDH mutant inhibitory activity and preparation method and application thereof - Google Patents

Compound with IDH mutant inhibitory activity and preparation method and application thereof Download PDF

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CN111662271A
CN111662271A CN201910174468.5A CN201910174468A CN111662271A CN 111662271 A CN111662271 A CN 111662271A CN 201910174468 A CN201910174468 A CN 201910174468A CN 111662271 A CN111662271 A CN 111662271A
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idh2
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triazine compound
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赖宜生
刘海鹏
姚坤
刘鹏宇
曹鹏
杨杰
魏清筠
李月珍
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China Pharmaceutical University
Jiangsu Provincial Insititute of Traditional Chinese Medicine
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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Abstract

The invention belongs to the field of medicines, and particularly relates to an s-triazine compound with structural characteristics of a general formula I, or a pharmaceutically acceptable salt, a pharmaceutical composition, a preparation method and application thereof in preparation of an IDH2 mutant inhibitorCan be used for preparing medicaments for preventing and/or treating various related diseases caused by IDH2 mutation, wherein the diseases comprise cancers carrying IDH2 mutation.

Description

Compound with IDH mutant inhibitory activity and preparation method and application thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to an s-triazine compound with IDH mutant inhibitory activity or pharmaceutically acceptable salts thereof, a pharmaceutical composition, a preparation method thereof, and application thereof as an isocitrate dehydrogenase 2 mutant (mIDH2) inhibitor.
Background
The tricarboxylic acid cycle is a common metabolic pathway of three major nutrients of carbohydrates, lipids and amino acids in human bodies, not only is a main way for the bodies to obtain energy, but also provides important small molecule precursors for the biosynthesis of other substances. Thus, the tricarboxylic acid cycle has important physiological significance.
The tricarboxylic acid cycle consists of a series of enzymatic reactions. Among them, Isocitrate Dehydrogenase (IDH) is a key rate-limiting enzyme in the tricarboxylic acid cycle, and is responsible for catalyzing the conversion of isocitrate to α -ketoglutarate (α -KG). There are 3 kinds of IDH isozymes in human, of which IDH1 is localized to cytoplasm and peroxisome, while IDH2 and IDH3 are localized to mitochondria. Different IDH subtypes have their respective physiological functions, but in general they play important roles in processes such as energy metabolism, biosynthesis, and resistance to oxidative stress (Amino Acids,2017,49(1): 21-32).
The alpha-KG generated by IDH catalysis is not only involved in tricarboxylic acid cycle, but also is a cofactor of a plurality of dioxygenases in vivo, thus playing an important role in maintaining physiological functions of organisms. These dioxygenases include, among others, the JmjC domain-containing histone demethylases closely associated with tumor development and the TET family of 5-methylcytosine hydroxylases. They are able to regulate the demethylation process of histones and DNA, thus affecting DNA conformation, DNA stability and the way DNA interacts with proteins, ultimately altering gene expression (Cancer Lett,2015,356(2): 309-.
Rapid proliferation is the most prominent biological feature of tumor cells, while metabolic abnormalities are another fundamental property. During tumorigenesis, the cellular metabolic network needs to balance energy requirements and biosynthesis requirements through reprogramming so as to be beneficial to synthesizing biological macromolecules required by various cell structures, thereby meeting the requirement of rapid proliferation of cells. Metabolic reprogramming therefore plays an important role in the process of malignant transformation of cells as a result of genetic events (Neuropathology,2019,39(1): 3-13.). IDH1 and IDH2 gene mutations have been found to be closely related to human tumors.
In 2008, IDH gene mutation was first discovered in glioma patients by Parsons et al, university of John Hopkins (Science,2008,321(5897): 1807-1812). Subsequently, H84 and IDH 84 mutations were detected in a series of patients with colon Cancer (Oncogene,2010,29(49): 6409-. Numerous studies have shown that mutations in the IDH1 and IDH2 genes play an important role in human tumorigenesis and development, mainly in relation to the oncogenic metabolites they catalyze to produce.
Clinical studies have shown that IDH mutations in tumor patients occur predominantly at key amino acid residues in the active sites of IDH1 and IDH 2. Mutations in IDH1 occurred primarily at R132, with the highest frequency of mutations at R132H, followed by the R132C mutation. The mutation types of IDH2 include R140Q, R140L, R140W, R172K, R172M, R172S, R172G and R172W, wherein the most important mutation type is R140Q and the second is R172K mutation (Science,2008,321(5897):1807 and 1812). These IDH mutants (mIDH) lose the normal physiological functions of wild-type IDH, but gain a new catalytic function, which can convert alpha-KG to R (-) -2-hydroxyglutarate (2-HG) with the aid of NADPH, resulting in a large accumulation of intracellular 2-HG (Nature,2010,465(7300): 966; Cancer Cell,2010,17(3): 225-234). 2-HG is generally considered to be an oncogenic metabolite. This is probably due to the structural similarity of 2-HG and alpha-KG, which makes it occupy the same binding pocket of alpha-KG, thus competitively inhibiting alpha-KG dependent dioxygenase, including histone demethylase, DNA demethylase and proline hydroxylase, resulting in abnormal epigenetic regulation, causing histone and DNA hypermethylation, further inducing oncogene silencing, affecting normal differentiation of cells, promoting proliferation of cells, and finally promoting tumor generation and development (Cancer, Cell 2011,19(1): 17-30; Nature,2012,483(7390): 474-) -478). Meanwhile, excessive accumulation of 2-HG also causes the intracellular hypoxia inducible factor HIF-1 alpha to be increased, so as to reduce the content of endostatin, thereby promoting the generation and development of tumor vessels (Cancer Cell,2013,23(3): 274-276). Therefore, the IDH mutant becomes a new target for developing anti-cancer drugs.
In recent years, various academic institutions and pharmaceutical companies have successively reported IDH1 and IDH2 mutant inhibitors developed respectively, however, only a few candidate drugs are currently in clinical trials (J Med Chem,2018,61(20): 8981-. Among them, AG-221 and AG-120, developed by Agios corporation, were subsequently approved by the U.S. FDA for marketing, and were used to treat refractory and relapsed acute myeloid leukemia, respectively, carrying IDH2 and IDH1 mutations. IDH1 and IDH2 mutant inhibitors can reverse histone and DNA hypermethylation by reducing 2-HG level in tumor cells, thereby inducing tumor cell differentiation and playing the role of anti-tumor.
Disclosure of Invention
The purpose of the invention is as follows: in view of the prior art, the invention provides a heterocyclic compound or a pharmaceutically acceptable salt thereof, a preparation method, a pharmaceutical composition and an application thereof, and the compound has good mIDH2 inhibitory activity and can be used for preparing medicines for treating and/or preventing various related diseases caused by IDH2 mutation.
The technical scheme is as follows: the invention discloses an s-triazine compound shown in a general formula I or pharmaceutically acceptable salt thereof:
Figure BDA0001989105940000031
wherein:
T1and T2Independently selected from N or C; when T is1When is N, T2Is selected from C; when T is1When is C, T2Selected from C or N;
r is selected from hydrogen, halogen, hydroxyl, amido and C1-C4Alkyl or C1-C4Alkoxy, which alkyl may be optionally mono-or poly-substituted with halogen;
Y1、Y2and Y3Each independently selected from hydrogen and C1-C4Alkyl, hydroxy C1-C4Alkyl or carboxyl, which alkyl may optionally be mono-or polysubstituted by the following identical or different substituents: hydrogen, hydroxy, C1-C4Alkyl or hydroxy C1-C4An alkyl group.
Further, R is selected from halogen or C1-C4An alkyl group, which alkyl group may optionally be mono-or poly-substituted with halogen.
Still further, R is selected from chloro or trifluoromethyl.
Further, Y1、Y2And Y3Each independently selected from hydrogen, hydroxymethyl, 1, 2-dihydroxyethyl, 2, 3-dihydroxypropyl or carboxyl.
In particular, the compounds of the formula I are preferably selected from the following compounds I-1 to I-14:
Figure BDA0001989105940000041
the compound numbers referred to in the following pharmacological experiments are equivalent to the compounds corresponding to the numbers here.
The invention also discloses a preparation method of the compound shown in the general formula I, which comprises the following steps: 2-bromo-6-trifluoromethylpyridine and cuprous cyanide undergo nucleophilic substitution reaction to prepare cyanide 1,1 is hydrolyzed under the condition of concentrated hydrochloric acid to generate carboxylic acid 2, 2 and thionyl chloride are prepared into acyl chloride, and then the carboxylic acid and methanol react to prepare methyl ester 3; 3 and biuret ring to obtain an intermediate 4; 4 refluxing with phosphorus oxychloride to obtain chloride 5, and reacting with different substituted aminopyridine or aromatic amine to obtain an intermediate 6; 6 with fatty amines (Y)1Y2Y3CNH2) The compound with the general formula (I) is prepared by the following synthetic route:
Figure BDA0001989105940000051
wherein, R, T1、T2、Y1、Y2、Y3Have the meaning of the formula I.
The pharmaceutically acceptable salts of the compounds of formula I can be synthesized by conventional chemical methods. In general, salts can be prepared by reacting the free base or acid with a stoichiometric equivalent or excess of an acid (inorganic or organic) or base (inorganic or organic) in a suitable solvent or solvent composition.
The invention also provides a pharmaceutical composition, which consists of active components with effective treatment amount and pharmaceutically acceptable auxiliary materials; the active component comprises one or more of a compound in a general formula I and pharmaceutically acceptable salts thereof. In the pharmaceutical composition, the auxiliary materials comprise pharmaceutically acceptable carriers, diluents and/or excipients.
The pharmaceutical composition may be formulated into various types of administration unit dosage forms according to the therapeutic purpose, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (solutions and suspensions), and the like, preferably tablets, capsules, liquids, suspensions, and injections (solutions and suspensions). For shaping the pharmaceutical composition in the form of tablets, pills or suppositories, any excipient known and widely used in the art can be used.
For preparing the pharmaceutical composition in the form of injection, the solution or suspension may be sterilized (preferably by adding appropriate amount of sodium chloride, glucose or glycerol) and made into injection with blood isotonic pressure. In the preparation of injection, any carrier commonly used in the art may also be used. For example: water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyethoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan, and the like. In addition, usual dissolving agents, buffers and the like may be added.
The content of the composition in the pharmaceutical composition is not particularly limited, and can be selected within a wide range, and generally ranges from 5 to 95% by mass, and preferably ranges from 30 to 85% by mass.
The method of administration of the pharmaceutical composition of the present invention is not particularly limited. The formulation of various dosage forms can be selected for administration according to the age, sex and other conditions and symptoms of the patient.
The invention also discloses application of the compound in the general formula I, the pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparation of an isocitrate dehydrogenase 2(IDH2) mutant inhibitor. The IDH2 mutant inhibitor is used for preventing and treating diseases carrying IDH2 mutation, and the diseases related to IDH2 mutation are cancers.
The invention also discloses an application of the compound with the general formula I, the pharmaceutically acceptable salt thereof or the pharmaceutical composition in the aspect of tumor resistance, wherein the cancer is one or more of malignant melanoma, lung cancer, breast cancer, stomach cancer, colon cancer, bladder cancer, pancreatic cancer, lymph cancer, prostate cancer, testicular cancer, kidney cancer, brain cancer, head and neck cancer, ovarian cancer, cervical cancer, endometrial cancer, mesothelioma, thyroid cancer, liver cancer, esophageal cancer, leukemia, cholangiocarcinoma, chondrosarcoma or angioimmunoblastic T-cell lymphoma; the leukemia is acute myelogenous leukemia; the bile duct cancer is intrahepatic bile duct cancer; the brain tumor is primary glioma or secondary glioma.
The invention also discloses application of the compound with the general formula I, the pharmaceutically acceptable salt thereof or the pharmaceutical composition in combination with one or more chemotherapeutic agents, targeted antitumor drugs, immune checkpoint inhibitors, immune checkpoint agonists, antitumor vaccines, antiviral agents and antiviral vaccines in preparation of drugs for treating IDH2 mutation-carrying cancers. The chemotherapeutic agent is an alkylating agent, a tubulin inhibitor, a topoisomerase inhibitor, a platinum drug, an antimetabolite drug or a hormone antineoplastic drug; the targeted antitumor drug is a protein kinase inhibitor, a proteasome inhibitor, an isocitrate dehydrogenase inhibitor, an antitumor drug based on epigenetics or a cell cycle signal pathway inhibitor; the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor, a TIM-3 inhibitor, a VISTA inhibitor, a LAG3 inhibitor, a TIGIT inhibitor, an A2AR inhibitor or a VTCN1 inhibitor; the immune checkpoint agonist is a STING agonist, a 4-1BB agonist, an OX40 agonist, a ROR γ agonist, or an ICOS agonist.
Has the advantages that: the invention provides an s-triazine compound with a brand-new structure, a pharmaceutically acceptable salt thereof, a pharmaceutical composition, a preparation method thereof and application of the compounds in preparation of IDH2 mutant inhibitors. Pharmacological experiment results show that the compound has obvious inhibition effect on the activity of IDH2 mutant (mIDH2), can effectively inhibit the process that mIDH2 catalyzes alpha-ketoglutaric acid to generate 2-hydroxyglutaric acid, and can be used for preparing medicines for preventing and/or treating various related diseases caused by IDH2 mutation, wherein the diseases comprise cancers carrying IDH2 mutation.
Detailed Description
To further illustrate the present invention, a series of examples are given below, which are purely illustrative and are intended to be a detailed description of the invention only and should not be understood as limiting the invention.
Wherein, the positive control drug AG-221 used in the experiment is purchased from MCE company; all cell lines used were purchased from ATCC.
Example 1
Preparation of 6- (trifluoromethyl) pyridine-2-carbonitrile (1)
Figure BDA0001989105940000061
In a dry 500mL round bottom flask were added 2-bromo-6- (trifluoromethyl) pyridine (25.0g, 110.6mmol), N-dimethylformamide (80mL), cuprous cyanide (14.9g,165.9mmol) and potassium iodide (27.5g, 165.9mmol), respectively, and the mixture was heated to 130 ℃ for 12 h. After cooling, 600mL of ice water was poured in, 300mL of ethyl acetate was added, stirring was carried out for 15 minutes, the solid was filtered off, the filtrate was extracted with ethyl acetate (50 mL. times.12), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a pale yellow liquid which was directly put into the next reaction.
Preparation of 6- (trifluoromethyl) -pyridine-2-carboxylic acid (2)
Figure BDA0001989105940000071
Adding the intermediate 1 and concentrated hydrochloric acid (80mL) into a dry 250mL round-bottom flask respectively, heating to 80 ℃ to react for 6h, cooling, adding 500mL of water for dilution, adjusting the pH value of a saturated sodium bicarbonate solution to 8, extracting impurities by ethyl acetate (50mL × 6), adjusting the pH value of an aqueous phase to 5 by concentrated hydrochloric acid, precipitating a large amount of white solid, carrying out suction filtration, and drying to obtain 16.5g of white solid.1H NMR(DMSO-d6,300MHz)(ppm):13.10(s,1H),7.99-8.17(m,3H).
Preparation of methyl 6- (trifluoromethyl) -pyridine-2-carboxylate (3)
Figure BDA0001989105940000072
Intermediate 2(16.5g, 86.3mmol) and methanol (80mL) were added to a dry 250mL round bottom flask, and thionyl chloride (15.4g, 129.5mmol) was slowly added dropwise with stirring, and the mixture was allowed to rise to 80 ℃ for 12 h. Cooling, concentrating to dryness, adjusting pH to 8 with saturated sodium bicarbonate solution, filtering, and drying to obtain white solid 16.0g with yield of 90.4%.1H NMR(DMSO-d6,300MHz)(ppm):8.03-8.18(m,3H),3.80(s,3H).
Preparation of 6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4- (1H,3H) -dione (4)
Figure BDA0001989105940000073
Adding the intermediate 3(16.0g, 78.0mmol), biuret (9.6g, 93.2mmol) and absolute ethyl alcohol (80mL) into a dry 500mL round-bottom flask respectively, stirring at room temperature for 20min, adding ethyl titanate (53.4g, 234.2mmol), stirring for 1h under the protection of nitrogen, chopping sodium blocks (7.2g, 313.0mmol), adding into 80mL absolute ethyl alcohol, placing at room temperature under the protection of nitrogen to dissolve the sodium blocks, adding into the reaction solution, reacting at 80 ℃ under the protection of nitrogen for 72h, cooling, carrying out rotary evaporation concentration, adding 400mL water, stirring fully, adjusting the pH to 8 with concentrated hydrochloric acid, carrying out suction filtration, washing with water (200mL × 4), discarding filter cakes, combining filtrates, adjusting the pH to 5 with concentrated hydrochloric acid, extracting with ethyl acetate (50mL × 20), washing with saturated water, drying with anhydrous sodium sulfate to obtain a light yellow solid, adding 40mL methanol, stirring for 20min, drying to obtain a white solid, and obtaining a yield of 44.7%.1H NMR(DMSO-d6,300MHz)(ppm):12.32(s,1H),11.50(s,1H),8.48(d,J＝8.7Hz,1H),8.35(t,J＝7.5Hz,1H),8.19(d,J＝9.0Hz,1H).
Preparation of 2, 4-dichloro-6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine (5)
Figure BDA0001989105940000081
A100 mL dry round bottom flask was charged with intermediate 4(2g, 7.8mmol) and phosphorus oxychloride (20mL) separately and reacted at 110 ℃ for 48h under nitrogen. After cooling, 500mL of ice water was slowly added dropwise with stirring, and the mixture was extracted with dichloromethane (50 mL. times.12), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a red oil which was directly used in the next reaction.
Preparation of 4-chloro-6- (6- (trifluoromethyl) pyridin-2-yl) -N- (2- (trifluoromethyl) pyridin-4-yl) -1,3, 5-triazin-2-amine (6-1)
Figure BDA0001989105940000082
To 100mL dryThe intermediate 5 obtained in the previous step, 2-trifluoromethyl-4-aminopyridine (660mg, 4.1mmol), N-diisopropylethylamine (1.1g, 8.1mmol) and anhydrous tetrahydrofuran (40mL) were added to a dry round-bottom flask, reacted at 70 ℃ for 12 hours, cooled, diluted with 100mL of water, extracted with ethyl acetate (50mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified with silica gel column (petroleum ether: ethyl acetate: 25: 1) to obtain 0.9g of a pale yellow solid.1H NMR(DMSO-d6,300MHz)(ppm):11.66(s,1H),8.63-8.79(m,3H),8.37(t,J＝7.8Hz,1H),8.19(d,J＝6.3Hz,1H),7.93(s,1H).
Preparation of 2- ((4- (6- (trifluoromethyl) pyridin-2-yl) -6- ((2- (trifluoromethyl) pyridin-4-yl) amino) -1,3, 5-triazin-2-yl) amino-1, 3-propanediol (I-1)
Figure BDA0001989105940000083
Adding intermediate 6-1(100mg, 0.2mmol), serinol (50mg, 0.5mmol) and tetrahydrofuran (15mL) into a 50mL dry round-bottom flask respectively, reacting at 70 ℃ for 12H, cooling, adding 100mL water for dilution, extracting with ethyl acetate (50mL × 3), washing with saturated saline, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a pale yellow solid 110mg, yield 97.4%, mp199-201 ℃ and ES-MS:476.2[ M + H ], (M + H)]+；1H NMR(DMSO-d6,300MHz)(ppm):10.67(s,1H),8.54-8.68(m,3H),8.33(t,J＝7.5Hz,1H),8.11(d,J＝6.2Hz,1H),7.78-8.03(m,2H),4.76(dt,J＝21.2,5.9Hz,2H),4.05-4.31(m,1H),3.55-3.69(m,4H).
Example 2
Preparation of 3- ((4- (6- (trifluoromethyl) pyridin-2-yl) -6- ((2- (trifluoromethyl) pyridin-4-yl) amino) -1,3, 5-triazin-2-yl) amino-1, 2-propanediol (I-2)
Figure BDA0001989105940000091
Referring to the synthesis of I-1, the intermediate 6-1 was reacted with 3-amino-1, 2-propanediol to obtain a pale yellow solid with a yield of 88.5%, mp 131-. ES-MS 476.2[ M + H ]]+；1H NMR(DMSO-d6,300MHz)(ppm):10.59(s,1H),8.36-8.60(m,3H),8.23(t,J＝8.6Hz,1H),8.12(d,J＝20.7Hz,1H),7.98-8.03(m,2H),4.79(dd,J＝23.9,6.2Hz,1H),4.57(t,J＝4.5Hz,1H),3.64-3.69(m,1H),3.49(dd,J＝11.7,6.5Hz,2H),3.33(dd,J＝5.6,2.8Hz,2H).
Example 3
Preparation of (S) -3- ((4- (6- (trifluoromethyl) pyridin-2-yl) -6- ((2- (trifluoromethyl) pyridin-4-yl) amino) -1,3, 5-triazin-2-yl) amino-1, 2-propanediol (I-3)
Figure BDA0001989105940000092
Referring to the synthesis of I-1, a white solid was obtained from the reaction of intermediate 6-1 with (S) -3-amino-1, 2-propanediol in 88.5% yield, mp 213-. ES-MS 476.2[ M + H ]]+；1H NMR(DMSO-d6,300MHz)(ppm):10.59(s,1H),8.37-8.60(m,3H),8.23(t,J＝9.2Hz,1H),8.12(d,J＝21.1Hz,1H),7.98-8.04(m,2H),4.74-4.84(dd,J＝23.7,6.0Hz,1H),4.56(t,J＝6.1Hz,1H),3.64-3.69(m,1H),3.49(dd,J＝14.9,5.8Hz,2H),3.33(dd,J＝5.7,3.3Hz,2H).
Example 4
Preparation of (R) -3- ((4- (6- (trifluoromethyl) pyridin-2-yl) -6- ((2- (trifluoromethyl) pyridin-4-yl) amino) -1,3, 5-triazin-2-yl) amino-1, 2-propanediol (I-4)
Figure BDA0001989105940000101
Referring to the synthesis of I-1, a white solid was obtained from the reaction of intermediate 6-1 with (R) -3-amino-1, 2-propanediol in 88.5% yield, mp 211-. ES-MS 476.2[ M + H ]]+；1H NMR(DMSO-d6,300MHz)(ppm):10.59(s,1H),8.37-8.60(m,3H),8.23(t,J＝9.2Hz,1H),8.12(d,J＝21.3Hz,1H),7.98-8.03(m,2H),4.79(dd,J＝23.8,6.1Hz,1H),4.57(t,J＝6.3Hz,1H),3.62-3.72(m,1H),3.49(dd,J＝14.7,6.2Hz,2H),3.33(dd,J＝5.9,3.1Hz,2H).
Example 5
Preparation of (L) -N- ((4- (6- (trifluoromethyl) pyridin-2-yl) -6- ((2- (trifluoromethyl) pyridin-4-yl) amino) -1,3, 5-triazin-2-yl) serine (I-5)
Figure BDA0001989105940000102
Adding the intermediate 6-1(420mg, 1mmol), (L) -serine methyl ester hydrochloride (330mg, 2.1mmol), triethylamine (320mg, 3.1mmol) and tetrahydrofuran (20mL) into a 50mL dry round-bottom flask respectively, reacting for 12H at 70 ℃, adding 1mol/L sodium hydroxide solution (2.5mL), continuing to react for 12H at 70 ℃, cooling, adding 100mL water for dilution, adjusting the pH to 9 with 1mol/L sodium hydroxide solution, extracting impurities from ethyl acetate (50mL × 2), adjusting the pH of the aqueous phase to 5 with concentrated hydrochloric acid, extracting with ethyl acetate (50mL × 3), washing with saturated brine, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain 180mg of white solid with the yield of 36.8%, and obtaining an mp 207 ℃. (ES-MS): 490.2[ M + H ], (209 ℃)]+；1H NMR(DMSO-d6,300MHz)(ppm):12.79(s,1H),10.75(s,1H),8.53-8.62(m,2H),8.29-8.43(m,3H),8.12(dd,J＝6.1,3.1Hz,1H),8.02(d,J＝3.4Hz,1H),4.62(dd,J＝12.6,3.1Hz,1H),4.54(t,J＝3.2Hz,1H),3.88(d,J＝2.9Hz,2H).
Example 6
Preparation of sodium (L) -N- ((4- (6- (trifluoromethyl) pyridin-2-yl) -6- ((2- (trifluoromethyl) pyridin-4-yl) amino) -1,3, 5-triazin-2-yl) serine salt (I-6)
Figure BDA0001989105940000111
To a 50mL dry round-bottom flask were added compound I-5(150mg, 0.3mmol), solid sodium hydroxide (10mg, 0.25mmol) and methanol (10mL), respectively, and reacted at room temperature for 12 h. Concentrating under reduced pressure to precipitate a small amount of white solid, filtering, and drying to obtain 20mg of white solid with the yield of 12.8 percent and the temperature of mp 221-. ES-MS 512.2[ M + H ]]+；1H NMR(DMSO-d6,300MHz)(ppm):10.75(s,1H),8.53-8.62(m,2H),8.29-8.43(m,3H),8.12(dd,J＝5.8,2.9Hz,1H),8.02(d,J＝3.1Hz,1H),4.62(dd,J＝12.2,3.2Hz,1H),4.54(t,J＝3.3Hz,1H),3.88(d,J＝3.0Hz,2H).
Example 7
Preparation of 4-chloro-6- (6- (trifluoromethyl) pyridin-2-yl) -N- (3- (trifluoromethyl) phenyl) -1,3, 5-triazin-2-amine (6-2)
Figure BDA0001989105940000112
Referring to the synthesis of intermediate 6-1, a white solid was prepared from intermediate 5 by reaction with 3-trifluoromethylaniline.1HNMR(DMSO-d6,300MHz)(ppm):11.33(s,1H),8.62-8.69(m,2H),8.36(t,J＝8.8Hz,1H),8.19(d,J＝9.1Hz,1H),7.96(dd,J＝27.2,8.9Hz,1H),7.48-7.64(m,1H).
Preparation of 2- ((4- (6- (trifluoromethyl) pyridin-2-yl) -6- ((3- (trifluoromethyl) phenyl) amino) -1,3, 5-triazin-2-yl) amino-1, 3-propanediol (I-7)
Figure BDA0001989105940000113
Referring to the synthesis of I-1, a white solid was prepared from intermediate 6-2 by reaction with serinol in 97.4% yield, mp161-163 ℃. ES-MS 475.2[ M + H ]]+；1H NMR(DMSO-d6,300MHz)(ppm):10.21(s,1H),8.48-8.65(m,2H),8.30(t,J＝7.5Hz,1H),8.05(dd,J＝20.8,8.9Hz,2H),7.45-7.73(m,2H),7.34(d,J＝6.2Hz,1H),4.72(dt,J＝27.1,6.3Hz,2H),4.05-4.26(m,1H),3.61(t,J＝4.5Hz,4H).
Example 8
Preparation of 3- ((4- (6- (trifluoromethyl) pyridin-2-yl) -6- ((3- (trifluoromethyl) phenyl) amino) -1,3, 5-triazin-2-yl) amino-1, 2-propanediol (I-8)
Figure BDA0001989105940000121
Referring to the synthesis of I-1, a white solid was obtained in 88.5% yield from intermediate 6-2 by reaction with 3-amino-1, 2-propanediol, mp 193-. ES-MS 475.2[ M + H ]]+；1H NMR(DMSO-d6,300MHz)(ppm):10.24(s,1H),8.49-8.66(m,2H),8.30(t,J＝7.5Hz,1H),8.05-8.21(m,2H),7.51-7.93(m,2H),7.34(d,J＝9.4Hz,1H),4.85(dd,J＝29.6,6.1Hz,1H),4.64(dt,J＝21.2,6.3Hz,1H),3.70-3.78(m,1H),3.39-3.63(m,4H).
Example 9
Preparation of (S) -3- ((4- (6- (trifluoromethyl) pyridin-2-yl) -6- ((3- (trifluoromethyl) phenyl) amino) -1,3, 5-triazin-2-yl) amino-1, 2-propanediol (I-9)
Figure BDA0001989105940000122
Referring to the synthesis of I-1, a white solid was obtained from the reaction of intermediate 6-2 with (S) -3-amino-1, 2-propanediol in 88.5% yield, mp 211-. ES-MS 475.2[ M + H ]]+；1H NMR(DMSO-d6,300MHz)(ppm):10.24(s,1H),8.49-8.66(m,2H),8.30(t,J＝7.5Hz,1H),8.05-8.21(m,2H),7.51-7.94(m,2H),7.34(d,J＝6.4Hz,1H),4.86(dd,J＝30.1,6.2Hz,1H),4.64(dt,J＝21.2,6.1Hz,1H),3.71-3.78(m,1H),3.39-3.64(m,4H).
Example 10
Preparation of (R) -3- ((4- (6- (trifluoromethyl) pyridin-2-yl) -6- ((3- (trifluoromethyl) phenyl) amino) -1,3, 5-triazin-2-yl) amino-1, 2-propanediol (I-10)
Figure BDA0001989105940000131
Referring to the synthesis of I-1, a white solid was obtained in 88.5% yield from intermediate 6-2 reacted with (R) -3-amino-1, 2-propanediol at 209 ℃ under mp 207-. ES-MS 475.2[ M + H ]]+；1H NMR(DMSO-d6,300MHz)(ppm):10.24(s,1H),8.48-8.66(m,2H),8.30(t,J＝8.9Hz,1H),8.05-8.21(m,2H),7.51-7.94(m,2H),7.34(d,J＝6.2Hz,1H),4.85(dd,J＝30.1,6.2Hz,1H),4.64(dt,J＝20.9,5.9Hz,1H),3.70-3.77(m,1H),3.39-3.64(m,4H).
Example 11
Preparation of 4-chloro-6- (6- (trifluoromethyl) pyridin-2-yl) -N- (6-chloropyridin-2-yl) -1,3, 5-triazin-2-amine (6-3)
Figure BDA0001989105940000132
Referring to the synthesis of intermediate 6-1, a pale cyan solid was prepared from intermediate 5 by reaction with 2-amino-6-chloropyridine.1HNMR(DMSO-d6,300MHz)(ppm):11.05(s,1H),8.54(d,J＝9.2Hz,1H),8.41(t,J＝7.5Hz,1H),8.22(t,J＝6.1Hz,2H),7.94(t,J＝7.4Hz,1H),7.28(d,J＝9.2Hz,1H).
Preparation of 2- ((4- (6- (trifluoromethyl) pyridin-2-yl) -6- ((6-chloropyridin-2-yl) amino) -1,3, 5-triazin-2-yl) amino-1, 3-propanediol (I-11)
Figure BDA0001989105940000133
Referring to the synthesis of I-1, a white solid was prepared from intermediate 6-3 by reaction with serinol in 97.4% yield, mp221-223 ℃. ES-MS 440.1[ M-H ]]+；1H NMR(DMSO-d6,300MHz)(ppm):10.36(s,1H),8.57-8.62(m,1H),8.28-8.39(m,2H),8.10(d,J＝8.9Hz,1H),7.63-7.92(m,2H),7.12-7.16(m,1H),4.74(dt,J＝24.2,6.1Hz,2H),4.03-4.23(m,1H),3.51-3.64(m,4H).
Example 12
Preparation of 3- ((4- (6- (trifluoromethyl) pyridin-2-yl) -6- ((6-chloropyridin-2-yl) amino) -1,3, 5-triazin-2-yl) amino-1, 2-propanediol (I-12)
Figure BDA0001989105940000141
Referring to the synthesis of I-1, the intermediate 6-3 was reacted with 3-amino-1, 2-propanediol to obtain a pale yellow solid with a yield of 97.4% and mp 111-. ES-MS 440.1[ M-H ]]+；1H NMR(DMSO-d6,300MHz)(ppm):10.38(s,1H),8.41-8.61(m,2H),8.06-8.29(m,3H),7.77-7.91(m,1H),7.12(d,J＝9.3Hz,1H),4.63-4.93(m,2H),3.26-3.72(m,5H).
Example 13
Preparation of (S) -3- ((4- (6- (trifluoromethyl) pyridin-2-yl) -6- ((6-chloropyridin-2-yl) amino) -1,3, 5-triazin-2-yl) amino-1, 2-propanediol (I-13)
Figure BDA0001989105940000142
Referring to the synthesis of I-1, the intermediate 6-3 was reacted with (S) -3-amino-1, 2-propanediol to obtain a pale yellow solid with a yield of 97.4%, mp 181-. ES-MS 440.1[ M-H ]]+；1H NMR(DMSO-d6,300MHz)(ppm):10.38(s,1H),8.42-8.62(m,2H),8.06-8.31(m,3H),7.77-7.91(m,1H),7.13(d,J＝9.1Hz,1H),4.63-4.92(m,2H),3.23-3.73(m,5H).
Example 14
Preparation of (R) -3- ((4- (6- (trifluoromethyl) pyridin-2-yl) -6- ((6-chloropyridin-2-yl) amino) -1,3, 5-triazin-2-yl) amino-1, 2-propanediol (I-14)
Figure BDA0001989105940000143
Referring to the synthesis of I-1, the intermediate 6-3 was reacted with (R) -3-amino-1, 2-propanediol to obtain a pale yellow solid with a yield of 97.4% and mp 179. sup. 181 ℃. ES-MS 440.1[ M-H ]]+；1H NMR(DMSO-d6，300MHz)(ppm):10.39(s,1H),8.42-8.62(m,2H),8.06-8.31(m，3H),7.77-7.93(m,1H),7.12(dd,J＝9.1,3.1Hz,1H),4.89(dd,J＝33.1,6.2Hz,1H),4.69(dt,J＝18.1,6.0Hz,1H),3.22-3.78(m,5H).
Example 15
Pharmacological experiment 1: compound pair IDH2R140QMeasurement of inhibitory Activity
IDH2R140QThe mutant can catalyze the conversion of α -KG into 2-HG and simultaneously oxidize NADPH into NADP+Therefore, IDH2 can be evaluated by measuring the consumption value of NADPH by the compound of the present inventionR140QInhibitory activity of the mutant. The positive drug is AG-221.
The experimental method comprises the following steps: a96-well plate was added with a solution containing 25mM Tris (pH7.4), 150mM NaCl, 10mM MgCl20.03% BSA, followed by addition of a concentration gradient of the compound, and the substrate for the enzymatic reaction, 1mM α -KG and 100. mu. MNADPH, and finally addition of IDH2 at a concentration of 0.5. mu.g/mLR140QThe total volume was 200. mu.L. Continuous assay at 340nM wavelength at room temperature using Thermo enzyme readerThe absorbance change of NADPH was measured. Calculation of Compound Pair IDH2 at different time points of incubation based on NADPH consumptionR140QAnd IC was calculated by GraphPad Prism 5 software50The value is obtained. The test data are shown in Table 1.
Pharmacological experiment 2: compound pair IDH2WTMeasurement of inhibitory Activity
Wild type IDH2 in NADP+Under the assistance of the catalytic action, α -KG is generated by isocitrate, and NADPH is generated, so that the inhibitory activity of the compound on wild-type IDH2 can be detected by detecting the increase of NADPH.
The experimental method comprises the following steps: add 50mM Tris (pH7.4), 5mM MgCl to 96-well plates20.03% BSA, then 200. mu.M ICT and 200. mu.M NADP as substrate for the enzymatic reaction, and finally 0.3. mu.g/mL IDH2 in a total volume of 200. mu.L. The change in absorbance of NADPH was continuously measured at 340nM wavelength at room temperature using a Thermo microplate reader. Inhibition of IDH2 activity by compounds at various time points of incubation was calculated from the increase in NADPH and IC was calculated by GraphPad Prism 5 software50The value is obtained. The results are shown in Table 1.
Compounds IC in Table 150Range of values: a represents 1-300 nM, B represents 300-1000 nM, and C represents 1000nM or more.
TABLE 1 inhibitory Activity and Selectivity of the Compounds of the invention against IDH2
Figure BDA0001989105940000161
The experimental result shows that the compound of the invention can effectively inhibit IDH2 at very low concentrationR140QThe activity of the process. IC of which I-7, I-8, I-9 and I-1050Is obviously superior to a positive control drug AG-221, in particular to I-10 to IDH2R140QThe inhibiting activity of the compound is 58 times higher than that of AG-221. More rarely, the compound of the invention has weak inhibitory effect on the activity of wild type IDH2, shows extremely high selectivity and is remarkably superior to the positive drug AG-221.
Pharmacological experiment 3: compound (I)For IDH2R140QMutant TF-1 cell 2-HG inhibitory Activity assay
Use carrying IDH2R140QMutated TF-1 cells were evaluated for the inhibitory activity of compounds against 2-HG in tumor cells. TF-1_ IDH2R140QCells were purchased from ATCC. The intracellular 2-HG content was determined using LC-MS/MS. The positive control drug was AG-221.
The experimental method comprises the following steps: TF-1_ IDH2R140QThe cells are 5 × 104The cells were collected by seeding in 12-well plates at a density of/mL and incubating for 72 hours with a gradient of test compound concentration. The cell pellet was suspended in 100. mu.L of 80% aqueous methanol, centrifuged at 13000rpm for 10min to remove the pellet at 4 ℃ and stored in a freezer at-80 ℃. Before injection, the sample is centrifuged again at 13000rmp for 10min, and the supernatant (about 100. mu.L) is transferred to the liquid phase inner insert tube for injection. The standard substance is D-2-hydroxy glutaric acid disodium salt (Sigma-Aldrich)#H8378) The concentrations were set at 13.6ng/mL,68ng/mL,340ng/mL, 1.70. mu.g/mL, 8.48. mu.g/mL, and 42.4. mu.g/mL. The test instrument is Q activeTMPlus-OrbitrapTMMS, Thermo Scientific bench quadrupole-orbitrap high resolution mass spectrometer. The chromatographic column is WaterTMACQUITYTMUPLC HSS-T3-1.8 μm,21mm × 100mm, Part No186003539, mobile Phase aqueous formic acid (chromatographically pure), Phase B acetonitrile (chromatographically pure).
TABLE 2 LC-MS elution conditions
Time Flow[mL/min] ％B
0.000 Run
0.000 0.200 1％
1.500 0.200 1％
2.000 0.200 70％
3.500 0.200 70％
3.600 0.200 1％
5.000 0.200 1％
5.000 Stop Run
Figure BDA0001989105940000171
IC calculation by GraphPad Prism 5 software50The value is obtained. Partial compound pair TF-1_ IDH2 of the present inventionR140QThe inhibitory activity at intracellular 2-HG levels is shown in Table 3.
TABLE 3 Compound of the invention vs TF-1_ IDH2R140QCell 2-HGInhibiting activity of
Compound numbering IC50(nM)
AG-221 25.0
I-7 70.6
I-9 198.6
I-10 13.2
Experimental results show that the compound can effectively inhibit TF-1_ IDH2 at nM concentrationR140QThe activity of the compound I-10 is obviously better than that of a positive drug AG-221 at the level of 2-HG of cells.
Pharmacological experiment 4: compound in vitro liver microsome metabolic stability test
The in vitro metabolic stability of some of the compounds of the invention was evaluated using a liver microsome assay. Metabolic stability the in vitro elimination half-life (T) was calculated by analyzing the change in the residual substrate concentration level of the compound over time by the substrate elimination method1/2)。
Experimental materials:
name (R) Suppliers of goods Goods number Batch number
Human liver microsomes IVT X008070 IQF
Mouse liver microsome XENOTECH M1000 1610148
The test compound was incubated with human and murine liver microsomes in a total system volume of 100. mu.L. mu.L of the compound (final concentration 1. mu.M), 50. mu.L of liver microsomes (final concentration 0.5mg/mL), 40. mu.L of NADPH reaction system were added. Incubation is carried out in a constant temperature oscillating water bath (37 ℃) at medium temperature, 300 mu L of stop solution (acetonitrile solution with the final concentration of 100ng/mL tolbutamide) is added when the incubation time is 0, 5, 10, 20, 30 and 60min respectively, and the reaction is stopped. The tube was kept open throughout the experiment to ensure oxygen participation. After the reaction was terminated, the sample was centrifuged at 13000 Xg for 10min (4 ℃ C.), 5. mu.L of the supernatant was collected, and LC-MS/MS analysis was performed to analyze the remaining amount of the compound, and 3 times of experiments were performed in parallel to investigate the metabolic stability of the compound. Specific test data are shown in table 4.
TABLE 4 in vitro liver microsomal enzyme metabolic stability test data for compounds of the invention
Figure BDA0001989105940000181
The experimental result shows that the compound I-10 of the invention shows excellent in vitro metabolic stability which is obviously superior to 3 positive control drugs.
Pharmacological experiment 5: compound pair IDH2R140QEffect of mutated TF-1 cell proliferation and differentiation
Dependence of different TF-1 cell lines on GM-CSF: TF-1 cell lines depend on GM-CSF for proliferation. TF-1_ IDH2 is first putWT、TF-1_IDH2R140QThe cells were cultured in whole medium, GM-CSF was removed from the medium before measuring proliferation potency, cultured for 3 days, and TF-1_ IDH2 was examined by MTT methodWTAnd TF-1_ IDH2R140QThe proliferation potency of the transfected cell line was determined by the GM-CSF-dependent change in the transfected cell line.
Effect of compounds on cell proliferation: TF-1_ IDH2WTAnd TF-1_ IDH2R140QCells were incubated with a concentration of compound for 7 days, and the MTT method was used to determine the change in proliferative capacity of both cells in the presence and absence of the compound.
Effect of compounds on cell differentiation: TF-1_ IDH2WTAnd TF-1_ IDH2R140QThe cells are respectively incubated with a compound with a certain concentration for 7 days, GM-CSF in a culture medium is removed, Erythropoietin (EPO) is added to induce the cells to differentiate for 7 days, the cells are collected by centrifugation, PBS is used for washing, and the color change generated by cell heme is observed and photographed as an index of cell differentiation.
The test results show that the tested compound I-10 can obviously inhibit GM-CSF independent TF-1_ IDH2 at the concentration of 1 mu MR140QProliferation of cells and significant induction of TF-1_ IDH2R140QRe-differentiation of the cells.
Using the same procedure, the present invention also tested compound I-10 versus other IDH 2-carrying compoundsR140QThe proliferation inhibitory activity of the mutant tumor cell lines includes colon cancer HCT116 cells and glioblastoma U87 cells. The results showed that Compound I-10 was conjugated to HCT116_ IDH2R140QAnd U87_ IDH2R140QThe cell proliferation has inhibitory effect.
Pharmacological experiment 6: TF-1_ IDH2R140QEvaluation of drug efficacy of mutant cell subcutaneous transplantation tumor in vivo
Evaluation of in vivo 2-HG inhibitory Activity of Compound I-10 TF-1_ IDH 2-containingR140QNCG mice with mutant cell subcutaneous transplantation tumorThe process is carried out. NCG mice were purchased at the university of south kyo animal model research institute.
Amplification of TF-1_ IDH2R140QCells, logarithmic growth phase of tumor cells for in vivo tumor inoculation according to 5 × 106The cell amount/mouse is respectively inoculated to the lower part of the lower back of the right side of the body of the NCG mouse irradiated by sublethal dose, and the GM-CSF is intraperitoneally administered twice a day to a human until the tumor volume reaches 200mm3Groups were made at time and human GM-CSF was administered continuously. The control group without mutation was inoculated with TF-1 cell line, and the control group with the compound and a solvent (2% absolute ethanol: 10% Solutol: 88% physiological saline (v/v/v)) was inoculated with TF-1_ IDH2R140QAnd (4) inoculating. The compound solutions of the corresponding concentrations were administered to each group by gavage in a volume of 100. mu.L/10 g body weight, and the control group was administered the same volume of the blank vehicle. Mice were sacrificed 10 days after administration, tumors were detached, homogenized, and the 2-HG content in the tumors was examined. See example 17 Experimental methods section for LC-MS/MS analysis conditions. The 2-HG concentration of each animal tumor homogenate in each group was calculated as a percentage (2-HG%) by LC-MS/MS.
Figure BDA0001989105940000191
The relative percentage of 2-HG in the mouse tumor (mean) after administration of the test compound is shown in Table 5. The results showed that Compound I-10 was present against TF-1_ IDH2R140QThe inhibitory activity of 2-HG in the cell subcutaneous transplantation tumor is stronger than that of AG-221.
TABLE 5 intratumoral 2-HG% after 10 days of administration
Group of Dosage (mg/kg) 2-HG％
TF-1 control group - 0
TF-1_IDH2R140QControl group - 100
AG-221 7.5 50.3
AG-221 15 9.7
AG-221 30 -4.6
I-10 7.5 60.5
I-10 15 5.2
I-10 30 -8.6

Claims (10)

1. An s-triazine compound shown in a general formula I or a pharmaceutically acceptable salt thereof:
Figure FDA0001989105930000011
wherein:
T1and T2Independently selected from N or C; when T is1When is N, T2Is selected from C; when T is1When is C, T2Selected from C or N;
r is selected from hydrogen, halogen, hydroxyl, amido and C1-C4Alkyl or C1-C4Alkoxy, which alkyl may be optionally mono-or poly-substituted with halogen;
Y1、Y2and Y3Each independently selected from hydrogen and C1-C4Alkyl, hydroxy C1-C4Alkyl or carboxyl, which alkyl may optionally be mono-or polysubstituted by the following identical or different substituents: hydrogen, hydroxy, C1-C4Alkyl or hydroxy C1-C4An alkyl group.
2. The s-triazine compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein R is selected from halogen or C1-C4An alkyl group, which alkyl group may optionally be mono-or poly-substituted with halogen.
3. The s-triazine compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein R is selected from chlorine or trifluoromethyl.
4. The s-triazine compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein Y is1、Y2And Y3Each independently selected from hydrogen, hydroxymethyl, 1, 2-dihydroxyethyl, 2, 3-dihydroxypropyl or carboxyl.
5. The s-triazine compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the following compounds I-1 to I-14:
Figure FDA0001989105930000021
6. the process for preparing the s-triazine compound according to any one of claims 1 to 5, which comprises the steps of: 2-bromo-6-trifluoromethylpyridine and cuprous cyanide undergo nucleophilic substitution reaction to prepare cyanide 1,1 is hydrolyzed under the condition of concentrated hydrochloric acid to generate carboxylic acid 2, 2 and thionyl chloride are prepared into acyl chloride, and then the carboxylic acid and methanol react to prepare methyl ester 3; 3 and biuret ring to obtain an intermediate 4; 4 refluxing with phosphorus oxychloride to obtain chloride 5, and reacting with different substituted aminopyridine or aromatic amine to obtain an intermediate 6; 6 with fatty amines (Y)1Y2Y3CNH2) The compound with the general formula I is prepared by the following reaction route:
Figure FDA0001989105930000031
7. a pharmaceutical composition, which comprises the s-triazine compound and/or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, and pharmaceutically acceptable auxiliary materials.
8. Use of the s-triazine compound of any one of claims 1 to 5 and/or a pharmaceutically acceptable salt thereof for preparing an IDH2 mutant inhibitor.
9. Use of the s-triazine compound of any one of claims 1 to 5 and/or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a cancer carrying an IDH2 mutation.
10. Use of the s-triazine compound of any one of claims 1 to 5 and/or a pharmaceutically acceptable salt thereof in combination with one or more chemotherapeutic agents, targeted antineoplastic agents, immune checkpoint inhibitors, immune checkpoint agonists, antineoplastic vaccines, antiviral agents, antiviral vaccines for the manufacture of a medicament for the treatment of a cancer carrying the IDH2 mutation.
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