CN111662271B - 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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CN111662271B
CN111662271B CN201910174468.5A CN201910174468A CN111662271B CN 111662271 B CN111662271 B CN 111662271B CN 201910174468 A CN201910174468 A CN 201910174468A CN 111662271 B CN111662271 B CN 111662271B
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idh2
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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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    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D401/02—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 containing two hetero rings
    • C07D401/04—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 containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

The invention belongs to the field of medicines, and particularly relates to a s-triazine compound with a structural characteristic of a general formula I or pharmaceutically acceptable salt thereof, a pharmaceutical composition, a preparation method thereof and application thereof in preparing an IDH2 mutant inhibitor. The pharmacological experiment result shows that the compound has obvious inhibition effect on the activity of IDH2 mutant (mIDH 2), can effectively inhibit the process of catalyzing alpha-ketoglutarate to generate 2-hydroxyglutarate by mIDH2, and can 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 or pharmaceutically acceptable salt thereof with IDH mutant inhibitory activity, a pharmaceutical composition, a preparation method thereof and application of the s-triazine compound or pharmaceutically acceptable salt thereof as an isocitrate dehydrogenase 2 mutant (mIDH 2) inhibitor.
Background
The tricarboxylic acid cycle is a common metabolic pathway of three major nutrients of saccharides, lipids and amino acids in the human body, and is not only a main way for the body to obtain energy, but also provides important small molecule precursors for biosynthesis of other substances. Thus, the tricarboxylic acid cycle is of great 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 responsible for catalyzing the conversion of isocitrate to α -ketoglutarate (α -KG). There are 3 IDH isozymes in humans, where IDH1 is localized to the cytoplasm and peroxisomes, while IDH2 and IDH3 are localized to the mitochondria. The different IDH subtypes have individual physiological functions, but in general they play an important role in energy metabolism, biosynthesis and resistance to oxidative stress (Amino Acids,2017,49 (1): 21-32).
The alpha-KG generated by IDH catalysis plays an important role in maintaining the physiological functions of organisms because the alpha-KG participates in the tricarboxylic acid cycle and also plays a role in assisting the excessive dioxygenase in the body. Among these dioxygenases are the JmjC domain-containing histone demethylases and the 5-methylcytosine hydroxylase TET family, which are closely related to the occurrence of tumors. They are capable of regulating the process of demethylation of histones and DNA, thereby affecting DNA conformation, DNA stability and the way in which DNA interacts with proteins, ultimately altering gene expression (Cancer Lett,2015,356 (2): 309-314).
Rapid proliferation is the most prominent biological feature of tumor cells, while metabolic abnormalities are another essential feature. In tumorigenesis, the cellular metabolic network needs to balance energy requirements and biosynthesis requirements by reprogramming to facilitate synthesis of biomacromolecules required for various cellular structures to meet rapid proliferation of cells. Metabolic reprogramming thus plays an important role in the genetic event leading to malignant transformation of cells (Neuropathology, 2019,39 (1): 3-13.). It has now been found that IDH1 and IDH2 gene mutations are closely related to human tumors.
In 2008, parsons et al, john Hopkins university, U.S. first discovered an IDH gene mutation in glioma patients (Science, 2008,321 (5897):1807-1812). IDH1 and IDH2 mutations were then detected in a range of tumor patients such as colon Cancer (Oncogene, 2010,29 (49): 6409-6417), acute myelogenous leukemia (Blood, 2010,116 (12): 2122-2126), chondrosarcoma (J Pathol,2011,224 (3): 334-343), melanoma (Am J Pathol,2011,178 (3): 1395-1402), cholangiocarcinoma (oncology, 2012,17 (1): 72-79), breast Cancer (Expert Rev Mol Diagn,2018,18 (12): 1041-1051), angioimmunoblastic T cell lymphoma (Cancer discover, 2013,3 (7): 730-741), thyroid Cancer (Oncogene, 2012,31 (19): 2491-2498), and prostate Cancer (Oncogene 2012,31 (33): 3826). Numerous studies have shown that mutations in the IDH1 and IDH2 genes play an important role in human tumorigenesis and progression, primarily 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 occur predominantly at position R132, with the highest frequency of mutation at R132H followed by mutation at R132C. The mutation types of IDH2 include R140Q, R140 37140W and R172K, R172M, R172S, R172G, R W, wherein the most predominant mutation type is R140Q, followed by R172K mutation (Science, 2008,321 (5897):1807-1812). These IDH mutants (mIDH) lose the normal physiological function of wild-type IDH, but acquire a new catalytic function, and are capable of converting α -KG into 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 fact that 2-HG is structurally similar to α -KG, so that it can occupy the same binding pocket as α -KG, thereby competitively inhibiting α -KG-dependent dioxygenases, including histone demethylases, DNA demethylases and proline hydroxylases, resulting in abnormal epigenetic regulation, leading to high methylation of histones and DNA, thereby inducing Cancer suppressor gene silencing, affecting normal differentiation of cells, promoting proliferation of cells, and ultimately promoting the development and progression of tumors (Cancer Cell,2011,19 (1): 17-30; nature,2012,483 (7390): 474-478). Meanwhile, excessive accumulation of 2-HG also leads to the increase of the level of hypoxia-inducible factor HIF-1 alpha in cells, so as to reduce the content of endostatin, and further promote the generation and development of tumor blood vessels (Cancer Cell,2013,23 (3): 274-276). Therefore, IDH mutants have become new targets for the development of anticancer drugs.
In recent years, many academic institutions and pharmaceutical companies have reported on the development of IDH1 and IDH2 mutant inhibitors, respectively, however, only a few candidate drugs are currently entering clinical trials (J Med Chem,2018,61 (20): 8981-9003). Of these, AG-221 and AG-120 developed by Agios corporation have been approved by the United states FDA for the treatment of refractory and recurrent acute myelogenous leukemia carrying IDH2 and IDH1 mutations, respectively. IDH1 and IDH2 mutant inhibitors can induce tumor cell differentiation by reducing the level of 2-HG in tumor cells and reversing histone and DNA hypermethylation, thereby exerting an anti-tumor effect.
Disclosure of Invention
The invention aims to: aiming at the prior art, the invention provides a heterocyclic compound or pharmaceutically acceptable salt thereof, a preparation method, a pharmaceutical composition and application thereof, and the compound has good mIDH2 inhibition 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 a s-triazine compound shown in a general formula I or pharmaceutically acceptable salt thereof:
wherein:
T 1 and T 2 Independently selected from N or C; when T is 1 When N is N, T 2 Selected from C; when T is 1 When C is the same as T 2 Selected from C or N;
r is selected from hydrogen, halogen, hydroxy, amino, C 1 -C 4 Alkyl or C 1 -C 4 Alkoxy, said alkyl optionally being mono-or polysubstituted with halogen;
Y 1 、Y 2 and Y 3 Each independently selected from hydrogen, C 1 -C 4 Alkyl, hydroxy C 1 -C 4 An alkyl group or a carboxyl group, said alkyl group optionally being mono-or polysubstituted with identical or different substituents as follows: hydrogen, hydroxy, C 1 -C 4 Alkyl or hydroxy C 1 -C 4 An alkyl group.
Further, R is selected from halogen or C 1 -C 4 Alkyl optionally mono-or polysubstituted by halogen.
Still further, R is selected from chloro or trifluoromethyl.
Further, Y 1 、Y 2 And Y 3 Each independently selected from hydrogen, hydroxymethyl, 1, 2-dihydroxyethyl, 2, 3-dihydroxypropyl, or carboxyl.
Specifically, the compounds represented by the general formula I are preferably selected from the following compounds I-1 to I-14:
the numbers of the compounds referred to in the following pharmacological experiments are equivalent to the compounds corresponding to the numbers herein.
The invention also discloses a preparation method of the compound shown in the general formula I, which comprises the following steps: nucleophilic substitution reaction is carried out on 2-bromo-6-trifluoromethyl pyridine and cuprous cyanide to prepare cyanide 1,1 is hydrolyzed under the condition of concentrated hydrochloric acid to generate carboxylic acid 2,2 and thionyl chloride to prepare acyl chloride, and then the acyl chloride reacts with methanol to prepare methyl ester 3;3 with biuret to prepare intermediate 4;4 and phosphorus oxychloride are refluxed to prepare chloro 5,5 and react with aminopyridine or aromatic amine with different substitutions to prepare an intermediate 6;6 with fatty amine (Y) 1 Y 2 Y 3 CNH 2 ) The compound of the general formula (I) is prepared by reaction, and the synthetic route is as follows:
therein, R, T 1 、T 2、 Y 1 、Y 2 、Y 3 Has the meaning in the general formula I.
The pharmaceutically acceptable salts of the compounds of formula I may be synthesized by general chemical methods. In general, salts can be prepared by reacting the free base or acid with an equivalent stoichiometric 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 an active component with effective treatment dose and pharmaceutically acceptable auxiliary materials; the active component comprises one or more of a compound of 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 such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions) and the like, depending on the purpose of treatment, with tablets, capsules, liquids, suspensions, and injections (solutions and suspensions) being preferred. For shaping pharmaceutical compositions in the form of tablets, pills or suppositories, any excipient known and widely used in the art can be used.
For preparing pharmaceutical compositions in the form of injections, the solutions or suspensions may be sterilized (preferably by adding appropriate amounts of sodium chloride, glucose or glycerol) and prepared into injections isotonic with blood. In the preparation of the injection, any carrier commonly used in the art may be used. For example: water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyethoxylated isostearyl alcohol, fatty acid esters of polyethylene sorbitan, and the like. In addition, a general dissolving agent, a buffer, and the like may be added.
The content of the composition in the pharmaceutical composition of the present invention is not particularly limited, and may be selected in a wide range, and may be generally 5 to 95% by mass, preferably 30 to 85% by mass.
The method of administration of the pharmaceutical composition of the present invention is not particularly limited. The formulation of each dosage form may be selected for administration depending on the age, sex and other conditions and symptoms of the patient.
The invention further discloses application of the compound shown in the general formula I, pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparation of an isocitrate dehydrogenase 2 (IDH 2) 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 application of the compound with the general formula I, pharmaceutically acceptable salt thereof or the pharmaceutical composition in anti-tumor aspect, wherein the cancer is one or more of malignant melanoma, lung cancer, breast cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer, lymphoma, prostate cancer, testicular cancer, renal cancer, brain cancer, head and neck cancer, ovarian cancer, cervical cancer, endometrial cancer, mesothelioma, thyroid cancer, liver cancer, esophageal cancer, leukemia, bile duct cancer, 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, pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing medicines for treating cancers carrying IDH2 mutation by combining one or more chemotherapeutic agents, targeted antitumor drugs, immune checkpoint inhibitors, immune checkpoint agonists, antitumor vaccines, antiviral agents and antiviral vaccines. The chemotherapeutic agent is alkylating agent, tubulin inhibitor, topoisomerase inhibitor, platinum drug, antimetabolite or hormone antitumor drug; the targeted antitumor drug is a protein kinase inhibitor, a proteasome inhibitor, an isocitrate dehydrogenase inhibitor, an epigenetic antitumor drug or a cell cycle signal pathway inhibitor; the immune checkpoint inhibitor is CTLA-4 inhibitor, PD-1 inhibitor, PD-L2 inhibitor, TIM-3 inhibitor, VISTA inhibitor, LAG3 inhibitor, TIGIT inhibitor, A2AR inhibitor or VTCN1 inhibitor; the immune checkpoint agonist is STING agonist, 4-1BB agonist, OX40 agonist, rory agonist or ICOS agonist.
The beneficial effects are that: the invention provides a s-triazine compound with a brand new structure, pharmaceutically acceptable salts and pharmaceutical compositions thereof, a preparation method thereof and application thereof in preparing an IDH2 mutant inhibitor. The pharmacological experiment result shows that the compound has obvious inhibition effect on the activity of IDH2 mutant (mIDH 2), can effectively inhibit the process of catalyzing alpha-ketoglutarate to generate 2-hydroxyglutarate by mIDH2, and can 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.
Detailed Description
In order to further illustrate the invention, the following examples are set forth which are purely illustrative and are intended to be a detailed description of the invention and should not be taken as limiting the invention.
Wherein, the positive control agent AG-221 used for the experiment is purchased from MCE company; all cell lines were purchased from ATCC.
Example 1
Preparation of 6- (trifluoromethyl) pyridine-2-carbonitrile (1)
In a dry 500mL round bottom flask were added 2-bromo-6- (trifluoromethyl) pyridine (25.0 g,110.6 mmol), N-dimethylformamide (80 mL), cuprous cyanide (14.9 g,165.9 mmol) and potassium iodide (27.5 g,165.9 mmol), respectively, and the mixture was heated to 130℃and reacted for 12h. Cooled, poured into 600mL of ice water, 300mL of ethyl acetate was added, stirred for 15 minutes, the solid was filtered off, the filtrate was extracted with ethyl acetate (50 ml×12), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, 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)
In a dry 250mL round bottom flask, intermediate 1 and concentrated hydrochloric acid (80 mL) were added, respectively, and the mixture was heated to 80℃for reaction for 6h. Cooling, adding 500mL of water for dilution, regulating the pH to 8 by saturated sodium bicarbonate solution, extracting impurities by ethyl acetate (50 mL multiplied by 6), regulating the pH of the water 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. 1 H NMR(DMSO-d 6 ,300MHz)δ(ppm):13.10(s,1H),7.99-8.17(m,3H).
Preparation of 6- (trifluoromethyl) -pyridine-2-carboxylic acid methyl ester (3)
Intermediate 2 (16.5 g,86.3 mmol) and methanol (80 mL) were added separately to a dry 250mL round bottom flask, thionyl chloride (15.4 g,129.5 mmol) was slowly added dropwise with stirring and the mixture was allowed to react at 80℃for 12h. Cooling, concentrating to dryness, regulating pH to 8 with saturated sodium bicarbonate solution, suction filtering, and drying to obtain white solid 16.0g with a yield of 90.4%. 1 H NMR(DMSO-d 6 ,300MHz)δ(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)
To a dry 500mL round bottom flask were added intermediate 3 (16.0 g,78.0 mmol), biuret (9.6 g,93.2 mmol) and absolute ethanol (80 mL), and the mixture was stirred at room temperature for 20min, ethyl titanate (53.4 g,234.2 mmol) was added, stirring was continued under nitrogen protection for 1h, sodium block (7.2 g,313.0 mmol) was cut up and added to 80mL absolute ethanol, and the mixture was dissolved at room temperature under nitrogen protection and then added to the reaction solution, and reacted at 80℃for 72h under nitrogen protection. Cooling, concentrating by rotary evaporation, adding 400mL of water, stirring thoroughly, adjusting pH to 8 with concentrated hydrochloric acid, filtering, washing with water (200 mL×4), discarding filter cake, mixing filtrates, adjusting pH to 5 with concentrated hydrochloric acid, and adjusting pH to 5 with ethyl acetate (50 m)L×20), washing with saturated saline, drying with anhydrous sodium sulfate, concentrating to obtain a pale yellow solid, adding 40mL of methanol, stirring for 20min, suction filtering, and drying to obtain 9.0g of a white solid with a yield of 44.7%. 1 H NMR(DMSO-d 6 ,300MHz)δ(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)
To a 100mL dry round bottom flask was added intermediate 4 (2 g,7.8 mmol) and phosphorus oxychloride (20 mL), respectively, and reacted at 110℃for 48h under nitrogen. Cooled, 500mL of ice water was slowly dropped under stirring, extracted with methylene chloride (50 ml×12), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained red oil was directly put into 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)
To a 100mL dry round bottom flask were added the intermediate 5, 2-trifluoromethyl-4-aminopyridine obtained in the previous step (660 mg,4.1 mmol), N-diisopropylethylamine (1.1 g,8.1 mmol) and anhydrous tetrahydrofuran (40 mL), respectively, and reacted at 70℃for 12h. Cooled, diluted with 100mL of water, extracted with ethyl acetate (50 ml×3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column (petroleum ether: ethyl acetate=25:1) to give 0.9g of pale yellow solid. 1 H NMR(DMSO-d 6 ,300MHz)δ(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)
To a 50mL dry round bottom flask was added intermediate 6-1 (100 mg,0.2 mmol), serinol (50 mg,0.5 mmol) and tetrahydrofuran (15 mL), respectively, and reacted at 70℃for 12h. Cooled, diluted with 100mL of water, extracted with ethyl acetate (50 mL. Times.3), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 110mg of a pale yellow solid in 97.4% yield, mp 199-201 ℃. ES-MS 476.2[ M+H ]] + ； 1 H NMR(DMSO-d 6 ,300MHz)δ(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)
Referring to the synthesis of I-1, reaction of intermediate 6-1 with 3-amino-1, 2-propanediol produced a pale yellow solid in 88.5% yield, mp 131-133 ℃. ES-MS 476.2[ M+H ]] + ； 1 H NMR(DMSO-d 6 ,300MHz)δ(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)
Referring to the synthesis of I-1, reaction of intermediate 6-1 with (S) -3-amino-1, 2-propanediol produced a white solid in 88.5% yield, mp 213-215 ℃. ES-MS 476.2[ M+H ]] + ； 1 H NMR(DMSO-d 6 ,300MHz)δ(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)
Referring to the synthesis of I-1, reaction of intermediate 6-1 with (R) -3-amino-1, 2-propanediol produced a white solid in 88.5% yield, mp 211-213 ℃. ES-MS 476.2[ M+H ]] + ； 1 H NMR(DMSO-d 6 ,300MHz)δ(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)
To a 50mL dry round bottom flask was added intermediate 6-1 (420 mg,1 mmol), (L) -serine methyl ester hydrochloride (330 mg,2.1 mmol), triethylamine (320 mg,3.1 mmol) and tetrahydrofuran (20 mL), respectively, and the reaction was continued at 70℃for 12h, 1mol/L sodium hydroxide solution (2.5 mL) and 70℃for 12h. Cooling, diluting with 100mL of water, adjusting pH to 9 with 1mol/L sodium hydroxide solution, and adding ethyl acetate(50 mL. Times.2) the impurities were extracted, the aqueous phase was adjusted to pH 5 with concentrated hydrochloric acid, extracted with ethyl acetate (50 mL. Times.3), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 180mg of a white solid, yield 36.8%, mp 207-209 ℃. ES-MS 490.2[ M+H ]] + ； 1 H NMR(DMSO-d 6 ,300MHz)δ(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 salt of (L) -N- ((4- (6- (trifluoromethyl) pyridin-2-yl) -6- ((2- (trifluoromethyl) pyridin-4-yl) amino) -1,3, 5-triazin-2-yl) serine (I-6)
To a 50mL dry round bottom flask was added compound I-5 (150 mg,0.3 mmol), solid sodium hydroxide (10 mg,0.25 mmol) and methanol (10 mL), respectively, and reacted at room temperature for 12h. Concentrating under reduced pressure to precipitate a small amount of white solid, filtering, and drying to obtain white solid 20mg, yield 12.8%, mp221-223 ℃. ES-MS 512.2[ M+H ]] + ； 1 H NMR(DMSO-d 6 ,300MHz)δ(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)
Referring to the synthesis of intermediate 6-1, a white solid was prepared from intermediate 5 by reaction with 3-trifluoromethylaniline. 1 H NMR(DMSO-d 6 ,300MHz)δ(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)
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 ]] + ； 1 H NMR(DMSO-d 6 ,300MHz)δ(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)
Referring to the synthesis of I-1, reaction of intermediate 6-2 with 3-amino-1, 2-propanediol produced a white solid in 88.5% yield, mp 193-195 ℃. ES-MS 475.2[ M+H ]] + ； 1 H NMR(DMSO-d 6 ,300MHz)δ(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)
Referring to the synthesis of I-1, reaction of intermediate 6-2 with (S) -3-amino-1, 2-propanediol produced a white solid in 88.5% yield, mp 211-213 ℃. ES-MS 475.2[ M+H ]] + ； 1 H NMR(DMSO-d 6 ,300MHz)δ(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)
Referring to the synthesis of I-1, reaction of intermediate 6-2 with (R) -3-amino-1, 2-propanediol produced a white solid in 88.5% yield, mp 207-209 ℃. ES-MS 475.2[ M+H ]] + ； 1 H NMR(DMSO-d 6 ,300MHz)δ(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)
Referring to the synthesis of intermediate 6-1, pale blue solid was prepared by reacting intermediate 5 with 2-amino-6-chloropyridine. 1 H NMR(DMSO-d 6 ,300MHz)δ(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)
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 ]] + ； 1 H NMR(DMSO-d 6 ,300MHz)δ(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)
Referring to the synthesis of I-1, reaction of intermediate 6-3 with 3-amino-1, 2-propanediol produced a pale yellow solid in 97.4% yield, mp 111-113 ℃. ES-MS 440.1[ M-H ]] + ； 1 H NMR(DMSO-d 6 ,300MHz)δ(ppm):10.38(s,1H),8.41-8.61(m,2H),8.06-8.29(m,3H),7.77-7.91(m,1H),δ7.12(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)
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Referring to the synthesis of I-1, reaction of intermediate 6-3 with (S) -3-amino-1, 2-propanediol produced a pale yellow solid in 97.4% yield, mp 181-183 ℃. ES-MS 440.1[ M-H ]] + ； 1 H NMR(DMSO-d 6 ,300MHz)δ(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)
Referring to the synthesis of I-1, reaction of intermediate 6-3 with (R) -3-amino-1, 2-propanediol produced a pale yellow solid in 97.4% yield, mp 179-181 ℃. ES-MS 440.1[ M-H ]] + ； 1 H NMR(DMSO-d 6 ，300MHz)δ(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 IDH2 R140Q Inhibition activity assay of (2)
IDH2 R140Q The mutant can catalyze the conversion of alpha-KG to 2-HG while oxidizing NADPH to NADP + Thus, the compound of the present invention can be evaluated for IDH2 by detecting the consumption value of NADPH R140Q Inhibitory Activity of the mutants. The positive drug is AG-221.
The experimental method comprises the following steps: 25mM Tris (pH 7.4), 150mM NaCl,10mM MgCl, was added to a 96-well plate 2 Reaction buffer of 0.03% BSA, then compound of concentration gradient, substrate 1 mM. Alpha. -KG and 100. Mu.M NADPH for enzyme reaction, and finally IDH2 of concentration 0.5. Mu.g/mL were added R140Q The total volume was 200. Mu.L. The absorbance change of NADPH was continuously detected at 340nM wavelength at room temperature using a Thermo microplate reader. Calculation of compound pair IDH2 at different time points of incubation based on NADPH consumption R140Q Is calculated by GraphPad Prism 5 software 50 Values. The test data are shown in Table 1.
Pharmacological experiment 2: compound pair IDH2 WT Inhibition activity assay of (2)
Wild type IDH2 in NADP + With the help of this, the production of alpha-KG, accompanied by the production of NADPH, is catalyzed by isocitrate. Thus, the inhibitory activity of a compound against wild-type IDH2 can be detected by detecting the increased value of NADPH. The positive drug is AG-221.
The experimental method comprises the following steps: 50mM Tris (pH 7.4), 5mM MgCl was added to a 96-well plate 2 Reaction buffer of 0.03% BSA, followed by addition of compound in concentration gradient, and substrate 200. Mu.M ICT and 200. Mu.M NADP for enzyme reaction, and finally IDH2 in concentration of 0.3. Mu.g/mL in total volume of 200. Mu.L. The absorbance change of NADPH was continuously detected 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 based on the increase in NADPH and IC was calculated by GraphPad Prism 5 software 50 Values. The experimental results are shown in Table 1.
Compound IC in Table 1 50 Interval range of values: a represents 1-300 nM, B represents 300-1000 nM, and C represents more than 1000 nM.
TABLE 1 inhibitory Activity and Selectivity of the inventive Compounds for IDH2
Experimental results show that the compound can effectively inhibit IDH2 at very low concentration R140Q Activity of the process. IC in which I-7, I-8, I-9 and I-10 are 50 Is obviously superior to positive control medicine AG-221, especially I-10 pair IDH2 R140Q The inhibition activity of (C) was 58-fold higher than that of AG-221. More rarely, the compound has weak activity inhibition effect on wild IDH2, shows extremely high selectivity and is remarkably superior to a positive medicine AG-221.
Pharmacological experiment 3: compound pair IDH2 R140Q Determination of mutant TF-1 cell 2-HG inhibitory Activity
Use of carrying IDH2 R140Q Mutant TF-1 cells were evaluated for the inhibitory activity of the compounds against 2-HG in tumor cells. TF-1_IDH2 R140Q Cells were purchased from ATCC. The intracellular 2-HG content was detected using LC-MS/MS. Positive control medicineAG-221.
The experimental method comprises the following steps: TF-1_IDH2 R140Q Cells at 5X 10 4 The cells were collected by incubation with a concentration gradient of the test compound for 72 hours at a density of/mL seeded in a 12-well plate. The cell pellet was suspended in 100. Mu.L of 80% aqueous methanol, centrifuged at 13000rpm for 10min at 4℃to remove the pellet, and stored in a-80℃refrigerator. Before sample injection, 13000rmp was centrifuged again for 10min, and the supernatant (about 100. Mu.L) was transferred into the liquid phase inner cannula to be injected. The standard was D-2-hydroxyglutarate disodium salt (Sigma-Aldrich) # H8378 The concentration was set to 13.6ng/mL,68ng/mL,340ng/mL, 1.70. Mu.g/mL, 8.48. Mu.g/mL, 42.4. Mu.g/mL. The test instrument is Q exact TM Plus-Orbitrap TM MS, thermo Scientific bench-top quadrupole-orbitrap high-resolution mass spectrometer. The chromatographic column is Water TM ACQUITY TM UPLC HSS-T3-1.8 μm,21mm× 100mm,Part No 186003539, mobile phase formic acid aqueous solution (chromatographic purity); phase B: acetonitrile (chromatographic purity). The elution conditions are shown in Table 2:
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
Calculation of IC by GraphPad Prism 5 software 50 Values. Some of the compounds of the invention are useful against TF-1_IDH2 R140Q The inhibitory activity of intracellular 2-HG levels is shown in Table 3.
TABLE 3 Compound pair TF-1_IDH2 of the invention R140Q Inhibitory Activity of cell 2-HG
Numbering of compounds IC 50 (nM)
AG-221 25.0
I-7 70.6
I-9 198.6
I-10 13.2
Experimental results show that the compound of the invention can effectively inhibit TF-1_IDH2 at nM concentration R140Q At the level of 2-HG in the cells, the activity of the compound I-10 is obviously superior to that of the positive medicine AG-221.
Pharmacological experiment 4: compound in vitro liver microsome metabolic stability test
Liver microsome experiments were used to evaluate the in vitro metabolic stability of some of the compounds of the invention. Metabolic stability analysis of the residual substrate concentration levels of the compounds over time by substrate elimination method, calculation of in vitro elimination half-life (T 1/2 )。
Experimental materials:
name of the name Suppliers (suppliers) Goods number Lot number
Human liver microsome IVT X008070 IQF
Mouse liver microsome XENOTECH M1000 1610148
The test compounds were incubated with human and murine liver microsomes in a total volume of 100 μl. mu.L of the compound (final concentration 1. Mu.m), 50. Mu.L of liver microsomes (final concentration 0.5 mg/mL) and 40. Mu.L of NADPH reaction system were added. The reaction was terminated by adding 300. Mu.L of a stop solution (100 ng/mL of toluene sulfobutylurea in acetonitrile) at 0, 5, 10, 20, 30, 60min, respectively, in a constant temperature shaking water bath (37 ℃). The tube was kept open throughout the experiment to ensure oxygen participation. After the termination of the reaction, the sample was centrifuged at 13000 Xg for 10min (4 ℃ C.), 5. Mu.L of the supernatant was collected, and the remaining amount of the compound was analyzed by LC-MS/MS, and the metabolic stability of the compound was examined in parallel for 3 times. The specific test data are shown in Table 4.
TABLE 4 in vitro liver microsomal enzyme metabolic stability test data for the compounds of the invention
The experimental result shows that the compound I-10 of the invention has excellent in-vitro metabolic stability and is obviously superior to 3 positive control medicines.
Pharmacological experiment 5: compound pair IDH2 R140Q Effects of mutant TF-1 cell proliferation and differentiation
Different TF-1 cell strains against GMDependence of CSF: TF-1 cell lines rely on GM-CSF for proliferation. TF-1_IDH2 is first treated WT 、TF-1_IDH2 R140Q Cells were cultured in complete medium, GM-CSF was removed from the medium before proliferation potency was measured, cultured for 3 days, and TF-1_IDH2 was examined by MTT method WT And TF-1_IDH2 R140Q And (3) determining the change in the dependence of the transfected cell line on GM-CSF.
Effects of compounds on cell proliferation: TF-1_IDH2 was used to prepare the antibody WT And TF-1_IDH2 R140Q Cells were incubated with a concentration of the compound for 7 days, respectively, and the MTT assay was used to determine the change in proliferation potency of both cells in the presence and absence of the compound.
Effect of compounds on cell differentiation: TF-1_IDH2 was used to prepare the antibody WT And TF-1_IDH2 R140Q Cells were incubated with a concentration of compound for 7 days, GM-CSF was removed from the medium, erythropoietin (EPO) was added to induce cell differentiation for 7 days, cells were collected by centrifugation, washed with PBS, and the color change of heme production of cells was observed and photographed as an indicator of cell differentiation.
Test results show that the tested compound I-10 can obviously inhibit GM-CSF independent TF-1_IDH2 at the concentration of 1 mu M R140Q Proliferation of cells and can obviously induce TF-1_IDH2 R140Q Cell re-differentiation.
The present invention also detects the presence of compound I-10 in the same manner as other IDH 2-bearing compounds R140Q Proliferation-inhibiting activity of the mutant tumor cell lines, including colon carcinoma HCT116 cells and glioblastoma U87 cells. The results show that compound I-10 vs. HCT116_IDH2 R140Q And U87 IDH2 R140Q The cell proliferation has inhibiting effect.
Pharmacological experiment 6: TF-1_IDH2 R140Q Evaluation of efficacy in mutant cell subcutaneous tumor
In vivo 2-HG inhibitory Activity evaluation of Compound I-10 TF-1_IDH2-containing assay R140Q NCG mice with mutant cells subcutaneously transplanted with tumors. NCG mice were purchased from the university of south kyo animal model institute.
Amplification of TF-1_IDH2 R140Q Cells, using tumor cells in logarithmic growth phase for the bodyAnd (5) inoculating internal tumors. According to 5X 10 6 Cell amount/mouse is inoculated to the right side waist back of NCG mouse body after sublethal dose irradiation, and human GM-CSF is given to abdominal cavity twice daily until tumor volume reaches 200mm 3 Grouping is performed at this time and human GM-CSF is administered continuously. The non-mutant control group was inoculated with TF-1 cell line, and the compound and vehicle (2% absolute ethanol: 10% solutol:88% physiological saline (v/v/v)) control group was inoculated with TF-1_IDH2 R140Q And (5) inoculating. Each group was administered by gavage with a corresponding concentration of compound solution at a volume of 100. Mu.L/10 g body weight and the control group was given the same volume of blank vehicle. Mice were sacrificed 10 days after dosing, tumors were exfoliated, homogenized, and the 2-HG content within the tumors was measured. LC-MS/MS analysis conditions see example 17 experimental methods section. The percent (2-HG%) was calculated from the tumor homogenate 2-HG concentration of each animal in each group as measured by LC-MS/MS.
The relative percentages (mean) of 2-HG in the tumors of the mice after administration of the test compounds are shown in Table 5. The results show that the compound I-10 is used for preparing TF-1_IDH2 R140Q The inhibition activity of 2-HG in cell subcutaneous transplantation tumor is stronger than 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_IDH2 R140Q Control 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 (8)

1. S-triazine compounds shown in general formula I or pharmaceutically acceptable salts thereof:
wherein:
T 1 and T 2 Independently selected from N or C; when T is 1 When N is N, T 2 Selected from C; when T is 1 When C is the same as T 2 Selected from C or N;
r is halogen, C 1 -C 4 An alkyl group, which may be optionally mono-or polysubstituted with halogen;
Y 1 selected from hydrogen, Y 2 Selected from hydroxymethyl, Y 3 Selected from hydroxymethyl or carboxyl; or Y 1 、Y 2 Selected from hydrogen, Y 3 Selected from 1, 2-dihydroxyethyl groups.
2. The s-triazine compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R is selected from chloro or trifluoromethyl.
3. S-triazine compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the following compounds I-1 to I-14:
4. a process for the preparation of s-triazines according to any one of claims 1 to 3, comprising the steps of: nucleophilic substitution reaction is carried out on 2-bromo-6-trifluoromethyl pyridine and cuprous cyanide to prepare cyanide 1,1 is hydrolyzed under the condition of concentrated hydrochloric acid to generate carboxylic acid 2,2 and thionyl chloride to prepare acyl chloride, and then the acyl chloride reacts with methanol to prepare methyl ester 3;3 with biuret to prepare intermediate 4;4 and phosphorus oxychloride are refluxed to prepare chloro 5,5 and react with aminopyridine or aromatic amine with different substitutions to prepare an intermediate 6;6 with fatty amine (Y) 1 Y 2 Y 3 CNH 2 ) The compound of the general formula I is prepared by reaction, and the synthetic route is as follows:
T 1 、T 2 、R、Y 1 、Y 2 、Y 3 is defined as in claim 1.
5. A pharmaceutical composition comprising a s-triazine compound according to any one of claims 1 to 3 and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
6. Use of a s-triazine compound according to any one of claims 1 to 3 and/or a pharmaceutically acceptable salt thereof for the manufacture of an IDH2 mutant inhibitor medicament.
7. Use of a s-triazine compound according to any one of claims 1-3 and/or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer carrying IDH2 mutations.
8. Use of a s-triazine compound according to any one of claims 1-3 and/or a pharmaceutically acceptable salt thereof in combination with one or more chemotherapeutic agents, targeted anti-tumor agents, immune checkpoint inhibitors, immune checkpoint agonists, anti-tumor vaccines, antiviral agents, antiviral vaccines for the manufacture of a medicament for the treatment of cancer carrying IDH2 mutations.
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