CN111087408B - A macrocyclic IDH2 mutant inhibitor and its medicinal use - Google Patents
A macrocyclic IDH2 mutant inhibitor and its medicinal use Download PDFInfo
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- CN111087408B CN111087408B CN202010004386.9A CN202010004386A CN111087408B CN 111087408 B CN111087408 B CN 111087408B CN 202010004386 A CN202010004386 A CN 202010004386A CN 111087408 B CN111087408 B CN 111087408B
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- trifluoromethyl
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- pyridin
- oxa
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Classifications
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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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
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Abstract
本发明公开了一种大环化合物及其医药用途，为通式(I)所示的结构:或其药学上可接受的盐或溶剂化物，其中：L代表(CRaRb)n，其中1‑3个CRaRb基团可被O、NH、S或者CH＝CH替换；Z代表CRaRb，O，‑NH‑C(＝O)‑,‑O‑C(＝O)‑或‑NH‑；T为CH或者N；X代表H、卤素、C3‑C6的环烷基、C1‑C6的烷基或C1‑C6的卤代烷基；n为4‑10；Ra、Rb各自独立地选自H、卤素或C1‑C6的烷基。本发明提供的大环化合物在激酶水平上，对于IDH2的抑制作用优于现有药物；本发明能够增加分子的溶解性和整体的脂溶性，使其具有穿透血脑屏障的潜力，相对于现有技术更有利于解决脑部肿瘤的问题。The present invention discloses a macrocyclic compound and its medical use, which is the structure shown in general formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein: L represents (CR a R b ) n , wherein 1-3 CR a R b groups can be replaced by O, NH, S or CH=CH; Z represents CR a R b , O, -NH-C(=O)-, -O-C(=O) - or -NH-; T is CH or N; X represents H, halogen, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; n is 4- 10; R a and R b are each independently selected from H, halogen or C 1 -C 6 alkyl. The macrocyclic compound provided by the present invention has better inhibitory effect on IDH2 than existing drugs at the kinase level; the present invention can increase the solubility of the molecule and the overall lipid solubility, so that it has the potential to penetrate the blood-brain barrier. The existing technology is more conducive to solving the problem of brain tumors.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to an IDH2 mutant inhibitor with a macrocyclic structure and medical application thereof.
Background
Mitochondrial energy metabolism abnormalities are one of the important features of cancer, and the tricarboxylic acid cycle is an important pathway affecting energy metabolism. Isocitrate Dehydrogenase (IDH) is the rate-limiting enzyme in the tricarboxylic acid cycle involved in cellular energy metabolism, catalyzes the oxidative decarboxylation of Isocitrate to produce alpha-ketoglutarate (alpha-ketoglutarate, alpha-KG) and CO2. There are three IDH enzymes in humans, NADP-IDH1 in cytoplasm, NADP-IDH2 in mitochondria and NADP-IDH3 in mitochondria, respectively.
IDH mutations are one of the causes of some tissue canceration, and IDH1 and IDH2 mutations have been found in a variety of tumors, including acute myeloid leukemia, glioma, brain glioma, chondrosarcoma, and the like. IDH mutations in tumor cells result in loss of normal function and conversion of α -KG to the oncogenic metabolite 2-hydroxyglutarate (2HG), which accumulates in the mutated tumor cells, leading to DNA or histone hypermethylation. The IDH inhibitor acts on IDH mutation sites in tumor cells to reduce the in vivo carcinogenic metabolite 2HG, thereby inducing histone demethylation and achieving the effect of inhibiting tumor development. The IDH inhibitor is divided into three types, namely an IDH1 inhibitor, an IDH2 inhibitor and an IDH1/IDH2 inhibitor according to action targets. Acute Myeloid Leukemia (AML) is a malignant disease of the hematopoietic system, with rapid disease progression and poor prognosis. Among AML patients, about 13% of patients carry IDH2 mutations, including IDH2/R140Q, IDH2/R172K, etc., wherein IDH2/R140Q mutations account for about 75% -80% of cases of IDH2 mutation, and IDH2/R172K mutations account for about 20%; the IDH2/R140Q mutant patients have large population, and the IDH2 inhibitor has good treatment prognosis effect and can effectively improve the overall survival rate; the patients with IDH2/R172K mutation have small population, and the prognosis effect, the complete remission rate and the relapse rate are high after the treatment by the existing IDH2 inhibitor. (Mondest J, Willebens C, Touat M.et. al. IDH1 and IDH2 amounts as novel thermal targets: current polarities [ J ]. J Blood Med.2016,7: 171-. Therefore, the compound has better inhibition effect on one of IDH2/R140Q and IDH2/R172K, or has inhibition effect on double mutations of IDH2/R140Q and IDH2/R172K, and has outstanding advantages compared with the existing medicines. Clinical tests also prove that the IDH mutant has very good development prospect and clinical application value as a cancer treatment target spot of AML and the like. In 8 months of 2017 and 7 months of 2018, the IDH2 mutant inhibitor enasidenb (AG-221) and the IDH1 mutant inhibitor ivosidenb (AG-120) are sequentially approved by FDA to be marketed for the treatment of acute myelogenous leukemia, and the reliability of the IDH mutant as a tumor treatment target is proved. Therefore, the development of a novel IDH2 mutant inhibitor is expected to provide a clinical medicament with a brand-new action mechanism for treating tumors.
The macrocyclic compound is a cyclic compound containing 12 or more members, and has important value in the field of pharmaceutical chemistry. The conformational pre-assembly on the structure of the macrocyclic compound ensures that the macrocyclic compound does not have obvious entropy loss when being combined with a receptor, and a certain rotational freedom degree on the structure allows the macrocyclic compound to be fully acted with the surface of the receptor when being combined with the receptor, so that the macrocyclic compound has better druggability in the aspects of activity, selectivity, pharmacokinetics and the like compared with non-macrocyclic analogues of the macrocyclic compound. Particularly, by introducing a hydrophobic macrocyclic connecting chain, the molecular planarity can be effectively reduced, the lipid solubility of the compound is improved, and the compound has good capability of penetrating through a blood brain barrier, so that the problem of brain metastasis in the tumor treatment process is expected to be solved. Among the macrocyclic compounds, the ALK inhibitor lorentib, the integrin inhibitor cilangitide, the JAK2/FLT3 dual inhibitor pacritiniib, etc. all showed better potency than the corresponding non-macrocyclic compounds. Diseases caused by IDH2 mutation include glioma, brain glioma and the like, all belong to brain diseases, and the drug can enter the brain only by penetrating through a blood brain barrier, so the technical scheme of the macrocyclic compound has important significance for improving the lipophilicity of the compound and further improving the drug effect of the compound.
Disclosure of Invention
The purpose of the invention is: provides a compound with a macrocyclic structure or a pharmaceutically acceptable salt or solvate thereof as an IDH2 mutant inhibitor and application thereof in preparing medicaments for treating diseases caused by IDH2 mutation.
The invention adopts the following technical scheme:
the compound with the macrocyclic structure provided by the invention is a compound with a structure shown in a general formula (I), or pharmaceutically acceptable salt or solvate thereof:
wherein:
l represents (CR)aRb)nWherein 1-3 CRaRbA group may be replaced by O, NH, S or CH ═ CH;
z represents CRaRbO, -NH-C (═ O) -, -O-C (═ O) -or-NH-;
t is CH or N;
x represents H, halogen, C3-C6Cycloalkyl of, C1-C6Alkyl or C1-C6A haloalkyl group of (a);
n is 4 to 10;
Ra、Rbeach independently selected from H, halogen or C1-C6Alkyl group of (1).
Further, preferred compounds of the present invention are compounds having a structure represented by general formula (II) or pharmaceutically acceptable salts or solvates thereof:
wherein: q represents (CR)aRb)mWherein 1-2 CRaRbThe radicals being replaced by O, NH or CH ═ CHChanging; z represents CRaRbO, -NH-C (═ O) -or-O-C (═ O) -; x represents H, halogen, CF3Or C1-C3Alkyl groups of (a); m is 3 to 9; ra、RbEach independently selected from H or C1-C3Alkyl group of (1).
More preferably, Q represents (CR)aRb)mWherein 1-2 CRaRbA group may be replaced by O or CH ═ CH; z represents CH2O, -NH-C (═ O) -or-O-C (═ O) -; ra、RbEach independently selected from H or methyl;
further, preferred compounds of the present invention are compounds having a structure represented by the general formula (III):
wherein: a. the1Is (CH)2)yY is an integer of 0 to 2; a. the2Is O or CH2，A3Is- (CH)2)p-(CH＝CH)q-(CH2)t-; z represents CH2O, -NH-C ═ O-or-O-C ═ O-; x represents F, Cl, CF3Or CH3(ii) a p and q are selected from 0 or 1, t is selected from an integer of 0-2, and at least one of p, q and t is not 0; r1、R2Each independently selected from H or CH3；
Still further, preferred compounds of the present invention have the general structure (IV):
wherein: x, Y represents CH2Or an O atom;
represents a carbon-carbon single bond or a carbon-carbon double bond;
B1is CH2Or is absent and only if
When X is an O atom, B is a carbon-carbon double bond1Is CH2；
B2Is CH2Or is absent;
most preferably, the compound is a compound represented by any one of the following structures:
the invention also provides a preparation method of the macrocyclic compound, which comprises three methods:
the first preparation method comprises the following steps:
the target compound (I) is obtained by adding a segment with a terminal alkenyl group to the I position and the II position of the compound B through an olefin metathesis reaction (preferably using a second generation Glabra catalyst), and then cyclizing through the olefin metathesis reaction.
The second preparation method is that a connecting group is introduced into the I position of the compound B and directly forms a ring with the II position;
the third preparation method is that a connecting group is introduced into the II position of the compound B and directly forms a ring with the I position;
the salts of the macrocycles of the invention may be prepared by methods well known to those skilled in the art. The salt can be organic acid salt, inorganic acid salt and the like, and the organic acid salt comprises citrate, fumarate, oxalate, malate, lactate, camphorsulfonate, p-toluenesulfonate, methanesulfonate and the like; the inorganic acid salt comprises hydrohalic acid salt, sulfate, phosphate, nitrate and the like.
A second object of the present invention is to provide a pharmaceutical composition comprising at least one active ingredient, which may be any one or any plurality of the macrocyclic compounds of the present invention, pharmaceutically acceptable salts thereof, solvates thereof, together with one or more pharmaceutically acceptable carriers or excipients.
The carrier includes conventional diluent, excipient, filler, binder, wetting agent, disintegrating agent, absorption enhancer, surfactant, adsorption carrier, lubricant, etc., and flavoring agent, sweetener, etc. may be added if necessary. The medicine can be prepared into various forms such as tablets, powder, granules, capsules, oral liquid, injection and the like, and the medicines of the various forms can be prepared according to the conventional method in the pharmaceutical field.
The invention also provides an application of the compounds in the general formulas (I) to (III) or pharmaceutically acceptable salts or solvates thereof in preparing a medicament for treating diseases caused by IDH2 mutation, in particular an application in preparing a medicament for treating tumors caused by IDH2 mutation; the tumor comprises acute myelogenous leukemia, brain glioma, chondrosarcoma, intrahepatic cholangiocarcinoma, sarcoma, melanoma, non-small cell lung cancer, prostate cancer or angioimmunoblastic lymphoma.
The macrocyclic compound has the advantages that the macrocyclic compound provided by the invention has better inhibition effect on one of IDH2/R140Q and IDH2/R172K than the existing drug AG-221 on the level of kinase, wherein the inhibition effect of part of the macrocyclic compound on both IDH2/R140Q and IDH2/R172K is better than that of the existing drug AG-221, and all the compounds show good selectivity relative to wild type IDH2, and show that the macrocyclic compound is likely to obtain better treatment effect and less toxic and side effect in tumors caused by IDH2 mutation relative to the prior art;
the invention has another beneficial effect that the technical scheme of introducing the macrocyclic structure on the basis of the parent nucleus of the triazine compound is adopted, so that the solubility and the integral lipid solubility of molecules can be improved, the molecules have the potential of penetrating a blood brain barrier, and the brain tumor problem can be better solved compared with the prior art.
Detailed Description
The following examples are provided to illustrate the applicability of the present invention, and it will be understood by those skilled in the art that various modifications and substitutions can be made to the corresponding technical features according to the teachings of the prior art, and still fall within the scope of the present invention as claimed.
Example 1 Synthesis of intermediate 1
(1) Step 1 Synthesis of Compound 1-IM2
Sodium blocks (2.81g, 0.12mol) were added to a dry 500mL three-necked flask by shearing, 250mL of absolute ethanol was slowly added under ice-bath conditions after nitrogen substitution, stirred for 5-10 minutes and then heated to 50-55 ℃. Biuret (3.1g, 0.03mol) was added, stirred for 15 minutes after nitrogen substitution, then methyl 6-trifluoromethylpyridine-2-carboxylate (compound 1-IM1, 12.5g, 0.06mol) was added, nitrogen substitution was again carried out, and the temperature was raised to 75 to 80 ℃ for reaction for six hours. After the reaction is completed, performing rotary drying on ethanol under reduced pressure, supplementing 50mL of water, consuming the residual sodium ethoxide, performing reduced pressure distillation to remove the generated ethanol, supplementing a proper amount of water until the crude product is completely dissolved, measuring the pH value to be 11, slowly dropwise adding 6N hydrochloric acid, adjusting the pH value to 7-8, stirring under ice bath conditionsAnd (3) separating out a large amount of white solid after 1-2 hours, performing suction filtration, washing a filter cake by using a small amount of petroleum ether, and finally drying the filter cake to obtain a white solid compound 1-IM 2. The yield is 64.0%;1H NMR(500MHz,DMSO-d6)δ9.75(s,1H),8.40(d,J＝8.0Hz,1H),8.15(dd,J＝8.0,7.5Hz,1H),7.94(d,J＝7.5Hz,1H).ESI-MS:m/z＝259[M+H]+。
(2) step 2 Synthesis of Compound 1-IM3
Compound 1-IM2(4g, 15.49mmol) was placed in a 100mL two-necked flask, purged with nitrogen, 50mL of phosphorus oxychloride and N, N-dimethylaniline (3.75g, 30.98mmol) were added slowly in this order at 0 ℃ and heated to 105 ℃ and 110 ℃ for reaction for 3 hours. And (3) after the reaction is completed, removing phosphorus oxychloride by reduced pressure distillation, and separating and purifying the obtained crude product by using a silica gel chromatographic column to obtain a white solid compound 1-IM 3. The yield is 63.7%;1H NMR(500MHz,Chloroform-d)δ8.77(d,J＝8.0Hz,1H),8.18(dd,J＝8.0,8.0Hz,1H),7.98(d,J＝8.0Hz,1H).ESI-MS：m/z＝296[M+H]+。
(3) step 3 Synthesis of Compound 1-IM5
3-bromo-5- (trifluoromethyl) aniline (compound 1-IM4, 5g, 20.83mmol) was placed in a 100mL two-necked flask, and after nitrogen substitution, 40mL of anhydrous N, N-dimethylformamide, tributylallyltin (8.28g, 25.0mmol), and tetrakistriphenylphosphine palladium (2.40g, 2.08mmol) were added, and the mixture was heated to 85 ℃ for reaction overnight. After the reaction is completed, the reaction solution is cooled to room temperature, 50mL of water is added to dilute the reaction solution, ethyl acetate (50mL multiplied by 3) is used for extraction, organic layers are combined and washed by a saturated sodium chloride solution (50mL multiplied by 2), anhydrous sodium sulfate is dried, filtration is carried out, ethyl acetate is removed through reduced pressure distillation, and the obtained crude product is separated and purified by a silica gel chromatographic column to obtain a yellow oily liquid compound 1-IM 5. The yield is 87.8%;1H NMR(500MHz,DMSO-d6)δ6.69(s,1H),6.62(s,1H),6.60(s,1H),5.97–5.84(m,1H),5.54(s,2H),5.13–5.08(m,1H),5.08–5.04(m,1H),3.28(d,J＝7.0Hz,2H).ESI-MS:m/z＝202[M+H]+。
(4) step 4 Synthesis of intermediate 1
Compound 1-IM3(1.48g, 5mmol) was dissolved in 20mL tetrahydrofuran, and 3-allyl-5- (trifluoromethyl) aniline (1.11g, 5.5mmol) was stirred in an ice bath in 10mL of acetone: the water (1:1) mixed solution was slowly dropped while maintaining the internal temperature at about 0 ℃ and 5mL of saturated sodium bicarbonate was added at once to react at room temperature for 3 hours. After the reaction is finished, tetrahydrofuran and acetone are removed by reduced pressure distillation, ethyl acetate (5mL multiplied by 3) is used for extraction, organic layers are combined and washed by saturated sodium chloride solution (5mL multiplied by 2), anhydrous sodium sulfate is dried, filtration is carried out, ethyl acetate is removed by reduced pressure distillation, and the obtained crude product is separated and purified by a silica gel chromatographic column to obtain a yellow solid intermediate 1. The yield is 87.6 percent;1H NMR(500MHz,DMSO-d6)δ11.44–11.15(m,1H),8.69–8.58(m,1H),8.42–8.29(m,2H),8.22–8.16(m,1H),8.09–7.96(m,1H),7.37–7.29(m,1H),6.07–5.92(m,1H),5.22–5.08(m,2H),3.54–3.48(m,2H).ESI-MS:m/z＝460[M+H]+。
EXAMPLE 2 Synthesis of Compound 1 and Compound 4
(1) Step 1 Synthesis of Compound 1-IM7
Ethanolamine (compound 1-IM6, 343mg, 5.61mmol) was dissolved in 5mL of dichloromethane, di-tert-butyl dicarbonate (1.35g, 6.17mmol) was slowly added under ice-bath conditions, and then the reaction was carried out at room temperature for 5 hours. And (3) after the reaction is completed, carrying out rotary drying on the solvent under reduced pressure, and purifying the obtained crude product by silica gel column chromatography to obtain a yellow oily liquid compound 1-IM 7. The yield is 90.7%; ESI-MS: M/z 162[ M + H ]]+。
(2) Step 2 Synthesis of Compound 1-IM9
Di-tert-butyl dicarbonate (30g,137.46mmol) was placed in a dry single-necked flask, and allyl alcohol (compound 1-IM8, 30mL, 441.12mmol) and 4-dimethylaminopyridine (840mg, 6.87mmol) were added under ice-bath conditions, followed by reaction at room temperature for 1 hour after being placed in a condenser and a calcium chloride drying tube. And (3) when the reaction is complete, directly loading the crude product by a wet method, and purifying by silica gel column chromatography to obtain the colorless oily liquid compound 1-IM 9. The yield is 89.5%;1H NMR(500MHz,Chloroform-d)δ5.96(ddt,J＝17.0,10.5,6.0Hz,1H),5.36(ddt,J＝17.0,1.5,1.5Hz,1H),5.27(ddt,J＝10.5,1.5,1.5Hz,1H),4.58(ddd,J＝6.0,1.5,1.5Hz,2H),1.51(s,9H).ESI-MS：m/z＝159[M+H]+。
(3) step 3 Synthesis of Compound 1-IM10
Compound 1-IM7(1.6g, 7.94mmol), palladium tetrakistriphenylphosphine (0.92g, 0.79mmol) were charged into a 50mL two-necked flask, purged with nitrogen, 20mL deoxygenated toluene was added, compound 1-IM9(1.51g, 9.52mmol) was slowly added under 0 deg.C, and the mixture was heated to 70 deg.C for 5 hours. And (3) when the reaction is complete, removing the toluene by reduced pressure distillation, and separating and purifying the obtained crude product by a silica gel chromatographic column to obtain a yellow oily liquid compound 1-IM 10. The yield is 97.9%;1H NMR(500MHz,Chloroform-d)δ5.92(ddt,J＝17.0,10.5,5.5Hz,1H),5.29(ddt,J＝17.0,1.5,1.5Hz,1H),5.21(ddt,J＝10.5,1.5,1.5Hz,1H),4.92(s,1H),4.01(ddd,J＝5.5,1.5,1.5Hz,2H),3.52(t,J＝5.0Hz,2H),3.34(t,J＝5.0Hz,2H),1.47(s,9H).ESI-MS:m/z＝202[M+H]+。
(4) step 4 Synthesis of Compound 1-IM11
Compound 1-IM10(52mg, 0.26mmol) was dissolved in 520. mu.L of dichloromethane, and 260. mu.L of trifluoroacetic acid was added under ice-bath to react at room temperature for 3 hours. And (5) finishing the reaction. The dichloromethane and excess trifluoroacetic acid were removed by distillation under reduced pressure. The resulting product was dissolved in the appropriate amount of acetonitrile and slowly added to intermediate 1(100mg, 0.22mmol) in 2.04mL acetonitrile under ice: to the mixture of water (50: 1) was added N, N-diisopropylethylamine (144. mu.L, 0.87mmol), and the mixture was heated at 60 ℃ overnight. After the reaction is finished, removing acetonitrile by reduced pressure distillation, and separating and purifying the obtained crude product by a silica gel chromatographic column to obtain a yellow oily liquid compound 1-IM 11. The yield is 61.9%;1H NMR(500MHz,Chloroform-d)δ8.66–8.53(m,1H),8.20–7.92(m,2H),7.85–7.77(m,1H),7.65–7.45(m,1H),7.19–7.13(m,1H),6.18–6.05(m,1H),6.04–5.79(m,2H),5.34–5.26(m,1H),5.24–5.18(m,1H),5.18–5.14(m,1H),5.14–5.11(m,1H),4.08–3.99(m,2H),3.88–3.70(m,2H),3.70–3.62(m,2H),3.48–3.40(m,2H).ESI-MS:m/z＝525[M+H]+。
(5) step 5 Synthesis of Compound 1
Compound 1-IM11(87mg, 0.17mmol) was dissolved in 45mL of toluene solution, purged with nitrogen, and 10mL of toluene solution of Grubbs 2-substituted catalyst (14mg, 0.017mmol) was slowly added over 30 minutes, followed by heating at 130 ℃ for 2 hours. And after the reaction is finished, removing the toluene by reduced pressure distillation, and separating and purifying by a silica gel chromatographic column to obtain a white solid. The yield is 58.0%;1H NMR(500MHz,DMSO-d6)δ10.35–10.27(m,1H),8.84–8.73(m,1H),8.57–8.49(m,1H),8.33–8.20(m,2H),8.12–8.05(m,1H),7.56–7.47(m,1H),7.28–7.12(m,1H),5.99–5.57(m,2H),4.37–4.00(m,2H),3.65–3.48(m,6H).ESI-MS:m/z＝497[M+H]+。
(6) step 6 Synthesis of Compound 4
Compound 1(25mg, 0.05mmol) was added to a mixed solution of 1.32mL of methanol and ethyl acetate (10: 1), palladium on carbon (2.5mg, 10%) was added, hydrogen gas was substituted, and the mixture was heated at 40 ℃ for reaction for 6 hours. After the reaction, the palladium-carbon was filtered through celite, and the solvent was removed by distillation under reduced pressure to obtain a white solid compound 4. The yield is 80.6%; ESI-MS: M/z 499[ M + H ]]+。
EXAMPLE 3 Synthesis of Compound 2
Compound 2 was prepared according to the procedure of example 2, starting from intermediate 1 and isopropanolamine (instead of ethanolamine in example 2). The yield is 21.6%;1H NMR(500MHz,Chloroform-d)δ8.75–8.63(m,1H),8.58–8.50(m,1H),8.13–8.01(m,1H),7.88–7.81(m,1H),7.19–7.13(m,1H),7.13–7.06(m,1H),6.04–5.90(m,1H),5.81–5.67(m,1H),4.37–4.28(m,1H),4.27–4.19(m,1H),4.08–3.94(m,2H),3.64–3.35(m,2H),2.92–2.78(m,1H),1.27–1.23(m,3H).ESI-MS:m/z＝511[M+H]+。
EXAMPLE 4 Synthesis of Compound 3
Compound 3 was prepared in step 5 according to the procedure for example 2 starting from intermediate 1 and 1-amino-2-methyl-2-propanol (instead of ethanolamine in example 2). The yield is 21.6%;1H NMR(500MHz,Chloroform-d)δ9.09–8.91(m,1H),8.61–8.48(m,1H),8.14–7.99(m,1H),7.93–7.77(m,1H),7.21–7.02(m,2H),5.96–5.84(m,1H),5.84–5.71(m,1H),4.47–4.26(m,2H),3.84–3.75(m,2H),3.56–3.40(m,2H),1.37–1.27(m,6H).ESI-MS:m/z＝525[M+H]+。
EXAMPLE 5 Synthesis of Compound 5
Compound 5 was prepared according to the procedure of example 2, starting from intermediate 1 and isopropanolamine (instead of ethanolamine in example 2). The yield is 76.6%;1H NMR(500MHz,Methanol-d4)δ8.69–8.63(m,1H),8.63–8.58(m,1H),8.22–8.13(m,1H),8.00–7.92(m,1H),7.23–7.18(m,1H),7.16–7.11(m,1H),4.12–4.04(m,1H),3.96–3.86(m,1H),3.82–3.73(m,1H),3.67–3.56(m,1H),2.89–2.81(m,2H),2.77–2.69(m,1H),2.12–1.98(m,1H),1.79–1.66(m,2H),1.47–1.36(m,1H),1.35–1.20(m,2H),1.21–1.14(m,3H).ESI-MS:m/z＝513[M+H]+。
EXAMPLE 6 Synthesis of Compound 6
Compound 6 was prepared according to the procedure for example 2, starting from intermediate 1 and 1-amino-2-methyl-2-propanol (instead of ethanolamine in example 2). The yield is 74.8%;1H NMR(500MHz,Methanol-d4)δ9.12–9.02(m,1H),8.76–8.61(m,1H),8.26–8.12(m,1H),8.02–7.91(m,1H),7.26–7.09(m,2H),3.71–3.64(m,2H),3.64–3.56(m,2H),2.92–2.79(m,2H),1.85–1.74(m,2H),1.66–1.54(m,2H),1.29–1.25(m,6H).ESI-MS:m/z＝527[M+H]+。
EXAMPLE 7 Synthesis of Compound 7
Compound 7 was prepared according to the procedure for example 2, starting from intermediate 1 and 4-amino-2-methyl-2-butanol (instead of ethanolamine in example 2). The yield is 46.0%;1H NMR(500MHz,Chloroform-d)δ8.46(s,1H),7.71(dd,J＝6.0,3.5Hz,2H),7.53(dd,J＝6.0,3.5Hz,2H),7.16(s,1H),7.09–6.99(m,2H),3.78–3.63(m,2H),3.41(m,2H),2.73–2.61(m,2H),1.68(m,2H),1.64–1.50(m,4H),1.20(s,6H).ESI-MS:m/z＝541[M+H]+。
EXAMPLE 8 Synthesis of Compound 8
(1) Step 1 Synthesis of Compound 1-IM13
Tert-butyl (2- (allyloxy) -2-methylpropyl) carbamate (compound 1-IM12, 1.15g, 5mmol) was dissolved in tetrahydrofuran, purged with nitrogen, borane-tetrahydrofuran (3.5mL,3.5mmol) was added slowly via syringe and stirred at room temperature overnight. After the reaction was complete, it was cooled to 0 deg.C, 4mL of 3N sodium hydroxide was added slowly, and 30% hydrogen peroxide (204mg, 6mmol) was added dropwise and stirred at room temperature overnight. After the reaction was completed, sodium chloride solid was added to saturation, extraction was performed with ethyl acetate (20 mL. times.3), the organic layers were combined, washed with saturated NaCl solution (20 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain compound 1-IM13 as a pale yellow oily liquid. The yield is 90.6%; ESI-MS: M/z 248[ M + H ]]+。
(2) Step 2 Synthesis of Compound 1-IM14
Compound 1-IM13(124mg, 0.5mmol) and p-toluenesulfonyl chloride were dissolved in 2mL of dichloromethane, and 4-dimethylaminopyridine (190mg, 1mmol) was added thereto, followed by stirring at room temperature overnight. After the reaction, the dichloromethane is removed by reduced pressure distillation, ethyl acetate (15mL) is redissolved, water (5mL multiplied by 2) is washed, saturated sodium chloride solution (5mL multiplied by 2) is washed, anhydrous sodium sulfate is dried, the solvent is removed by reduced pressure distillation, and the crude product is purified by column chromatography to obtain the colorless transparent oily liquid compound 1-IM 14. The yield is 34.4%;1H NMR(500MHz,DMSO-d6)δ7.78(d,J＝8.5Hz,2H),7.48(d,J＝8.5Hz,2H),4.05(t,J＝6.0Hz,2H),3.25(t,J＝6.0Hz,2H),2.87(d,J＝6.0Hz,2H),2.42(s,3H),1.75–1.68(m,2H),1.37(s,9H),0.94(s,6H).ESI-MS：m/z＝402[M+H]+。
(3) step 3 Synthesis of Compound 1-IM15
3-Nitro-5- (trifluoromethyl) phenol (21mg, 0.1mmol) was dissolved in 10mL of anhydrous N, N-dimethylformamide, potassium carbonate (28mg, 0.2mmol) was added and stirred at room temperature for 30 minutes, then compound 1-IM14(40mg, 0.1mmol) was added and stirred at 95 ℃ overnight. After the reaction is finished, the mixture is cooled to room temperature, diluted by adding 30mL of water, extracted by ethyl acetate (10mL multiplied by 3), combined with organic layers, washed by water (10mL multiplied by 2), washed by saturated sodium chloride solution (10mL multiplied by 2), dried by anhydrous sodium sulfate, filtered, decompressed and distilled to remove the solvent, and the crude product is purified by column chromatography to obtain the colorless transparent oily liquid compound 1-IM 15. The yield is 70.5%; ESI-MS: M/z 437[ M + H ]]+。
(4) Step 4 Synthesis of Compound 1-IM16
Compound 1-IM16 was prepared according to the method of example 2, step 6 (compound 1-IM15 instead of compound 1) starting from compound 1-IM 15. The yield is 85.7%; ESI-MS: M/z 407[ M + H ]]+。
(5) Step 5 Synthesis of Compound 1-IM17
Compound 1-IM17 was prepared according to the procedure of step 4 of example 1 using compound 1-IM3 and compound 1-IM16 (instead of 3-allyl-5- (trifluoromethyl) aniline) as starting materials. The yield is 52.7%; ESI-MS: M/z 665[ M + H ]]+。
(6) Step 6 Synthesis of Compound 8
The compound1-IM17 was dissolved in 520. mu.L of dichloromethane, and 260. mu.L of trifluoroacetic acid was added thereto under ice-cooling to react at room temperature for 3 hours. And (5) finishing the reaction. The dichloromethane and excess trifluoroacetic acid were removed by distillation under reduced pressure. The resulting product was dissolved in the appropriate amount of acetonitrile and 2.04mL of acetonitrile was added slowly under ice bath: to the mixture of water (50: 1) was added N, N-diisopropylethylamine (144. mu.L, 0.87mmol), and the mixture was heated at 60 ℃ overnight. And after the reaction is finished, removing acetonitrile by reduced pressure distillation, and separating and purifying the obtained crude product by a silica gel chromatographic column to prepare the compound 8. The yield is 15.3%;1H NMR(500MHz,Chloroform-d)δ8.59–8.51(m,2H),8.04(t,J＝8.0,7.5Hz,1H),7.82(d,J＝7.5Hz,1H),7.60(s,1H),6.84(s,1H),6.69(s,1H),6.14(s,1H),4.46–4.37(m,2H),3.68–3.60(m,2H),3.56–3.46(m,2H),2.02–1.95(m,2H),1.26(s,6H).ESI-MS:m/z＝529[M+H]+。
EXAMPLE 9 Synthesis of Compound 9 and Compound 13
(1) Step 1 Synthesis of Compound 1-IM19
Compound 1-IM18 was dissolved in the appropriate amount of acetonitrile and slowly added to intermediate 1(100mg, 0.22mmol) in 2.04mL acetonitrile under ice: to the mixture of water (50: 1) was added N, N-diisopropylethylamine (144. mu.L, 0.87mmol), and the mixture was heated at 60 ℃ overnight. And after the reaction is finished, removing acetonitrile by reduced pressure distillation, and separating and purifying the obtained crude product by a silica gel chromatographic column to prepare the compound 1-IM 19. The yield is 95.0%;1H NMR(500MHz,Chloroform-d)δ8.67–8.50(m,1H),8.22–7.92(m,2H),7.86–7.78(m,1H),7.59–7.43(m,1H),7.21–7.12(m,1H),6.03–5.76(m,3H),5.22–5.09(m,3H),3.75–3.54(m,2H),3.49–3.40(m,2H),2.48–2.37(m,2H).ESI-MS:m/z＝495[M+H]+。
(2) step 2 Synthesis of Compound 9
Compound 9 was prepared according to the procedure of example 2, step 5, starting from compound 1-IM19 (instead of compound 1-IM11 in step 5 of example 2). The yield is 66.9%；1H NMR(500MHz,DMSO-d6)δ10.40–10.00(m,1H),8.81–8.47(m,2H),8.43–8.17(m,2H),8.16–7.97(m,1H),7.70–7.45(m,1H),7.30–7.05(m,1H),5.98–5.32(m,2H),3.64–3.39(m,4H),2.42–2.22(m,2H).ESI-MS：m/z＝467[M+H]+。
(3) Step 3 Synthesis of Compound 13
Compound 13 was prepared according to the procedure of step 6 of example 2 using compound 9 as a starting material (instead of compound 1 in step 6 of example 2). The yield is 88.6%;1H NMR(500MHz,DMSO-d6)δ10.35–10.07(m,1H),8.69–8.58(m,1H),8.58–8.49(m,1H),8.35–8.20(m,2H),8.14–8.04(m,1H),7.62–7.46(m,1H),7.24–7.08(m,1H),3.52–3.41(m,2H),2.78–2.61(m,2H),1.79–1.53(m,4H),1.52–1.34(m,2H),1.32–1.16(m,1H).ESI-MS:m/z＝469[M+H]+。
EXAMPLE 10 Synthesis of Compound 10 and Compound 14
(1) Step 1 Synthesis of Compound 1-IM21
5-bromo-1-pentene (1-IM20, 1g, 6.71mmol) was dissolved in 10mL of N, N-dimethylformamide, and sodium azide (654mg, 10.06mmol) was added portionwise at 0 ℃ to react at room temperature overnight. After the reaction is finished, adding 30mL of water for dilution, extracting with diethyl ether (10mL multiplied by 3), combining organic layers, washing with saturated sodium chloride solution (10mL multiplied by 2), distilling under reduced pressure to remove diethyl ether to obtain colorless oily liquid, and directly putting the obtained product 5-azido-1-pentene into the next step without purification.
The intermediate 5-azido-1-pentene (448mg, 4.03mmol) obtained in the previous step was dissolved in 2mL of tetrahydrofuran, triphenylphosphine (1.16g, 4.43mmol) was added in portions, followed by water (109. mu.L, 4.43mmol), and the mixture was stirred at room temperature overnight. After the reaction is finished, the obtained product 5-amino-1-pentene is directly put into the next step without purification.
Intermediate 1(1g, 2.17mmol) was dissolved in tetrahydrofuran and the intermediate 5-amino-1-pentene (221mg, 2.6mmol) from the previous step was added to tetrahydrofuran under iceThe reaction mixture was then added with N, N-diisopropylethylamine (1.43mL, 8.68mmol), and the mixture was heated to 60 ℃ for reaction overnight. After the reaction is finished, removing tetrahydrofuran by reduced pressure distillation, and separating and purifying the obtained crude product by a silica gel chromatographic column to obtain a yellow oily liquid compound 1-IM21 with the yield of 57.3%;1H NMR(500MHz,Chloroform-d)δ8.67–8.50(m,1H),8.24–7.94(m,2H),7.89–7.70(m,2H),7.45(s,1H),7.19–7.10(m,1H),6.01–5.74(m,3H),5.13–4.92(m,3H),3.66–3.30(m,4H),2.44(s,1H),2.23–2.06(m,2H),1.83–1.66(m,2H).ESI-MS:m/z＝509[M+H]+。
(2) step 2 Synthesis of Compound 10
Compound 10 was prepared according to the procedure of example 2, step 5, starting from compound 1-IM21 (instead of compound 1-IM11 in step 5 of example 2). The yield is 58.2%;1H NMR(500MHz,Methanol-d4)δ9.04–8.92(m,1H),8.70–8.40(m,1H),8.26–8.11(m,1H),7.98–7.88(m,1H),7.25–6.85(m,2H),6.00–5.58(m,2H),4.15–4.04(m,1H),3.77–3.52(m,2H),3.51–3.38(m,2H),2.16–2.03(m,2H),1.84–1.70(m,2H),1.26–1.20(m,1H).ESI-MS：m/z＝481[M+H]+。
(3) step 3 Synthesis of Compound 14
Compound 14 was prepared according to the procedure of step 6 of example 2 using compound 10 as a starting material (instead of compound 1 in step 6 of example 2). The yield is 83.4%;1H NMR(500MHz,Methanol-d4)δ8.71–8.55(m,1H),8.36–8.23(m,1H),8.22–8.09(m,1H),8.03–7.85(m,1H),7.28–7.04(m,2H),3.42–3.31(m,2H),2.95–2.71(m,2H),1.94–1.80(m,2H),1.79–1.63(m,2H),1.57–1.37(m,4H).ESI-MS:m/z＝483[M+H]+。
EXAMPLE 11 Synthesis of Compound 11
Compound 11 was prepared by the method of preparation of compound 10 in example 10 starting from 6-bromo-1-hexene (instead of 5-bromo-1-pentene in example 10) and intermediate 1. The yield is 64.6%;1H NMR(500MHz,DMSO-d6)δ10.29–10.16(m,1H),8.82–8.75(m,1H),8.58–8.51(m,1H),8.33–8.26(m,1H),8.25–8.18(m,1H),8.11–8.05(m,1H),7.54–7.44(m,1H),7.24–7.11(m,1H),5.71–5.37(m,2H),3.55–3.45(m,2H),3.38–3.28(m,2H),2.23–2.11(m,2H),1.78–1.50(m,4H).ESI-MS:m/z＝495[M+H]+。
EXAMPLE 12 Synthesis of Compound 12
Compound 12 was prepared by the method of example 10 using 7-bromo-1-heptene (instead of 5-bromo-1-pentene in example 10) and compound 1-IM6 as starting materials to prepare compound 10. The yield is 70.4%;1H NMR(500MHz,DMSO-d6)δ10.24–10.10(m,1H),8.59–8.53(m,1H),8.34–8.26(m,2H),8.19–8.03(m,2H),7.47–7.38(m,1H),7.30–7.16(m,1H),5.73–5.40(m,2H),3.52–3.43(m,3H),3.34–3.28(m,1H),2.22–2.07(m,2H),1.72–1.41(m,6H).ESI-MS:m/z＝509[M+H]+。
EXAMPLE 13 Synthesis of Compound 15
Compound 15 was prepared according to the procedure of step 6 of example 2 using compound 11 as a starting material (instead of compound 1 of step 6 of example 2). The yield is 80.8%;1H NMR(500MHz,DMSO-d6)δ10.26–10.15(m,1H),8.80–8.60(m,1H),8.59–8.51(m,1H),8.34–8.18(m,2H),8.13–8.03(m,1H),7.57–7.40(m,1H),7.33–7.09(m,1H),2.77–2.62(m,2H),1.72–1.54(m,4H),1.53–1.36(m,4H),1.34–1.15(m,2H).ESI-MS:m/z＝497[M+H]+。
EXAMPLE 14 Synthesis of Compound 16
Compound 16 was prepared according to the procedure of step 6 of example 2 using compound 12 as a starting material (instead of compound 1 of step 6 of example 2). The yield is 83.4%;1H NMR(500MHz,Chloroform-d)δ8.58–8.49(m,1H),8.34–8.22(m,1H),8.06–7.97(m,1H),7.85–7.77(m,1H),7.71–7.59(m,1H),7.20–7.13(m,1H),7.06–6.95(m,1H),6.12–5.80(m,1H),3.57–3.43(m,2H),2.77–2.63(m,2H),1.82–1.72(m,2H),1.70–1.59(m,2H),1.47–1.29(m,8H).ESI-MS:m/z＝511[M+H]+。
EXAMPLE 15 Synthesis of Compound 17
(1) Step 1 Synthesis of Compound 1-IM23
3-Nitro-5- (trifluoromethyl) phenol (1-IM22, 1g, 4.83mmol) was dissolved in 16mL of acetone, and cesium carbonate (3.15g, 9.66mmol) and 3-bromopropene (877mg, 7.25mmol) were slowly added under ice-bath and reacted at room temperature overnight. After the reaction is finished, filtering, distilling the filtrate under reduced pressure to remove acetone, redissolving ethyl acetate (30mL), washing with water (10mL multiplied by 2), washing with saturated sodium chloride solution (10mL multiplied by 2), drying with anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent, and obtaining the orange-red oily liquid compound 1-IM 23. The yield is 82.2%;1H NMR(500MHz,Chloroform-d)δ8.11–8.05(m,1H),7.92(d,J＝2.0Hz,1H),7.48(dq,J＝2.1,0.9Hz,1H),6.05(ddd,J＝17.0,10.5,5.5Hz,1H),5.47(dt,J＝17.0,1.5Hz,1H),5.39(dt,J＝10.5,1.5Hz,1H),4.69(dt,J＝5.5,1.5Hz,2H).
(2) step 2 Synthesis of Compound 1-IM24
Compound 1-IM23(1.19g, 4.81mmol) was dissolved in 5mL of ethanol and heated under reflux, and then a suspension of sodium sulfide (4.99g, 63.97mmol) in ethanol (10mL) was added in portions and heated under reflux for 3 hours. After the reaction was complete, a suspension of sodium hydroxide (231mg, 5.77mmol, 10%) in ethanol (2.6mL) was added and the reaction was continued under reflux for 1 hour. After the reaction is finished, removing the ethanol by reduced pressure distillation, dropwise adding 2N hydrochloric acid under ice bath till no bubbles emerge, then adding saturated sodium bicarbonate solution till the pH value is 7-8, extracting by ethyl acetate (10mL multiplied by 3),the organic layers were combined, washed with a saturated sodium chloride solution (10 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to give compound 1-IM24 as a red oily liquid. The yield is 84.3%;1H NMR(500MHz,Acetone-d6)δ6.47(s,1H),6.38(t,J＝2.0Hz,1H),6.34(s,1H),6.02(ddt,J＝17.5,10.5,5.0Hz,1H),5.39(ddt,J＝17.5,1.5Hz,1H),5.25(ddt,J＝10.5,1.5Hz,1H),4.52(dt,J＝5.0,1.5Hz,2H).ESI-MS:m/z＝218[M+H]+。
(3) step 3 Synthesis of Compound 1-IM25
Compound 1-IM25 was prepared according to the procedure of step 4 of example 1, starting from compound 1-IM3 and compound 1-IM24 (in place of 1-IM5 in step 4 of example 1). The yield is 47.7%;1H NMR(500MHz,Chloroform-d)δ8.77–8.65(m,1H),8.36–8.01(m,2H),7.94–7.86(m,1H),7.78–7.34(m,2H),7.01–6.93(m,1H),6.13–5.99(m,1H),5.55–5.25(m,2H),4.72–4.56(m,2H).ESI-MS:m/z＝476[M+H]+。
(4) step 4 Synthesis of Compound 1-IM26
Compounds 1-IM26 were prepared by the method of step 1 of example 9 starting from compounds 1-IM18 and 1-IM25 (replacing intermediate 1 of step 1 of example 9). The yield is 63.8%;1H NMR(500MHz,Chloroform-d)δ8.67–8.52(m,1H),8.21–8.11(m,1H),8.08–7.99(m,1H),7.87–7.79(m,1H),7.58–7.43(m,1H),7.20–7.13(m,1H),6.03–5.77(m,2H),5.21–5.08(m,4H),3.74–3.56(m,2H),3.50–3.38(m,2H),2.49–2.37(m,2H).ESI-MS:m/z＝511[M+H]+。
(5) step 5 Synthesis of Compound 17
Compound 17 was prepared according to the procedure of example 2, step 5, starting from compound 1-IM26 (instead of compound 1-IM11 in step 5 of example 2). The yield is 40.8%;1H NMR(500MHz,DMSO-d6)δ8.58–8.44(m,1H),8.39–8.26(m,1H),8.11–8.01(m,1H),7.93–7.82(m,1H),6.99–6.89(m,1H),6.85–6.74(m,1H),6.25–6.08(m,1H),5.64–5.47(m,1H),4.74–4.59(m,2H),4.13–3.98(m,2H),3.39–3.36(m,1H),2.27–2.18(m,2H).ESI-MS:m/z＝483[M+H]+。
(6) step 6 Synthesis of Compound 19
Compound 19 was prepared according to the procedure of step 6 of example 2 using compound 17 as a starting material (instead of compound 17 in step 6 of example 2). The yield is 77.6%;1H NMR(500MHz,DMSO-d6)δ10.42–10.30(m,1H),8.58–8.48(m,2H),8.46–8.37(m,1H),8.35–8.26(m,1H),8.13–8.04(m,1H),7.15–7.09(m,1H),6.80–6.70(m,1H),4.26–4.13(m,2H),3.33–3.19(m,2H),1.91–1.80(m,2H),1.79–1.66(m,2H),1.46–1.32(m,2H).ESI-MS:m/z＝485[M+H]+。
EXAMPLE 16 Synthesis of Compound 18
Compound a was prepared according to the procedure for step 1 of example 10 starting from compound 1-IM20 and compound 1-IM25 (instead of compound intermediate 1 in step 1 of example 10) to give compound a, and then compound 18 was prepared according to the procedure for example 15 starting from compound a instead of compound 17 in example 15. The yield is 55.6%;1H NMR(500MHz,Chloroform-d)δ8.27–8.21(m,1H),7.87–7.80(m,1H),7.62–7.56(m,1H),7.02–6.98(m,1H),6.91–6.84(m,2H),5.75–5.62(m,2H),4.89–4.85(m,1H),4.64–4.58(m,2H),3.33–3.27(m,2H),2.92–2.88(m,1H),1.98–1.90(m,2H),1.60–1.52(m,2H).ESI-MS:m/z＝497[M+H]+。
EXAMPLE 17 Synthesis of Compound 20
Compound 20 was prepared according to the procedure of step 6 of example 2 using compound 18 as a starting material (instead of compound 17 in step 6 of example 2). The yield is 80.8%;1H NMR(500MHz,DMSO-d6)δ10.30–10.23(m,1H),8.58–8.50(m,2H),8.43–8.36(m,1H),8.33–8.26(m,1H),8.13–8.05(m,1H),7.32–7.27(m,1H),6.86–6.81(m,1H),4.25–4.13(m,2H),1.84–1.67(m,4H),1.55–1.42(m,4H),1.29–1.18(m,2H).ESI-MS:m/z＝499[M+H]+。
EXAMPLE 18 Synthesis of Compound 21
(1) Step 1 Synthesis of Compound 1-IM27
Compound 1-IM27 was prepared by the method of step 4 of example 1 starting from compound 1-IM3 and 5-amino-1-pentanol (instead of compound 1-IM5 in step 4 of example 1). The yield is 83.6 percent; ESI-MS: M/z 362[ M + H ]]+。
(2) Step 2 Synthesis of Compound 21
Compound 1-IM27(275mg, 0.76mmol) was dissolved in 3mL acetonitrile, a solution of 3-amino-5- (trifluoromethyl) benzoic acid (187mg, 0.91mmol) in acetonitrile (2.4mL) was added at 0 deg.C, N-diisopropylethylamine (502. mu.L, 3.04mmol) was added dropwise at 0 deg.C, and the mixture was heated to 60 deg.C for reaction overnight. And after the reaction is finished, removing acetonitrile by reduced pressure distillation to obtain a yellow solid, and directly putting the obtained product into the next step without purification.
Dissolving the intermediate obtained in the last step in 250mL of tetrahydrofuran, sequentially adding 1-hydroxybenzotriazole (103mg, 0.76mmol), O-benzotriazole-tetramethylurea hexafluorophosphate (283mg, 0.76mmol) and N, N-diisopropylethylamine (369 mu L, 0.76mmol) under ice bath, heating to 40 ℃ for reaction, and standing overnight. After the reaction was completed, tetrahydrofuran was distilled off under reduced pressure, the mixture was redissolved with ethyl acetate (60mL), washed with a saturated sodium bicarbonate solution (20mL × 2), washed with a saturated sodium chloride solution (20mL × 2), dried over anhydrous sodium sulfate, filtered, and ethyl acetate was distilled off under reduced pressure to obtain a crude product, which was separated and purified by a silica gel column to obtain a yellow solid. The yield is 48.2%;1H NMR(500MHz,Acetone-d6)δ9.98–9.72(m,1H),8.79–8.57(m,1H),8.33–8.23(m,1H),8.08–7.92(m,3H),4.45–4.36(m,2H),3.79–3.48(m,2H),2.19–2.12(m,2H),1.97–1.89(m,2H),1.77–1.67(m,2H),0.98–0.82(m,2H).ESI-MS：m/z＝513[M+H]+.
EXAMPLE 19 Synthesis of Compound 22
Starting from compound 1-IM3, (4-aminobutyl) carbamic acid tert-butyl ester, the substitution reaction and isolation procedure was as in step 1 of example 18 to give the intermediate, which was used in the procedure of step 6 of example 8 and 3-amino-5- (trifluoromethyl) benzoic acid to give compound 22. The yield is 32.6%;1H NMR(500MHz,DMSO-d6)δ9.91–9.73(m,1H),8.67–8.37(m,2H),8.35–8.28(m,1H),8.16–8.07(m,1H),7.69–7.55(m,1H),7.51–7.43(m,1H),3.30–3.10(m,4H),1.95–1.75(m,2H),1.54–1.36(m,2H),1.33–1.17(m,2H).ESI-MS:m/z＝498[M+H]+。
EXAMPLE 20 Synthesis of Compound 23
Starting with compound 3-bromo-5-methylaniline, intermediate 3-amino-5-methylpropenylene was synthesized according to the method of step 3 in reference example 1, intermediate 3-amino-5-methylpropenylene and compound 1-IM3 intermediate N- (3-allyl-5-methylphenyl) -4-chloro-6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazin-2-amine was synthesized according to the method of step 4 in reference example 1, and this intermediate and compound 1-IM10 were prepared according to the method of step 5 in example 2 to give compound 23. The yield is 34.6%;1H NMR(500MHz,Chloroform-d)δ8.27–8.21(m,1H),7.88–7.80(m,1H),7.62–7.56(m,1H),7.33–7.28(m,1H),7.20–7.16(m,1H),6.98–6.93(m,1H),6.42–6.33(m,1H),5.73–5.63(m,1H),4.09–4.01(m,3H),3.63–3.57(m,2H),3.52–3.46(m,2H),3.25–3.19(m,2H),3.00–2.96(m,1H),2.30–2.26(m,3H).ESI-MS:m/z＝443[M+H]+。
EXAMPLE 21 Synthesis of Compound 24
Compound 24 was prepared according to the procedure for example 20 starting from compound 1-IM3, 3-bromo-5-fluoroaniline and compound 1-IM 10. The yield is 36.4%;1H NMR(500MHz,Chloroform-d)δ8.27–8.21(m,1H),7.87–7.80(m,1H),7.62–7.56(m,1H),7.20–7.15(m,1H),6.90–6.84(m,1H),6.85–6.79(m,1H),6.16–6.07(m,1H),5.80–5.71(m,1H),4.64–4.60(m,1H),4.07–4.01(m,2H),3.63–3.57(m,2H),3.52–3.46(m,2H),3.25–3.19(m,2H),2.97–2.93(m,1H).ESI-MS:m/z＝447[M+H]+。
EXAMPLE 22 Synthesis of Compound 25
Compound 25 was prepared according to the procedure for example 20 starting from compound 1-IM3, 3-bromo-5-chloroaniline and compound 1-IM 10. The yield is 42.1%;1H NMR(500MHz,Chloroform-d)δ8.27–8.21(m,1H),7.87–7.78(m,2H),7.62–7.56(m,1H),7.30–7.25(m,1H),7.12–7.07(m,1H),6.16–6.07(m,1H),5.79–5.71(m,1H),4.63–4.59(m,1H),4.07–4.01(m,2H),3.63–3.57(m,2H),3.52–3.46(m,2H),3.25–3.19(m,2H),2.97–2.93(m,1H).ESI-MS:m/z＝463[M+H]+。
EXAMPLE 23 Synthesis of Compound 26
Intermediate N was prepared from compound 1-IM3, 3-bromo-5-methylaniline and compound 1-IM10 by the method of example 202- (3-allyl-5-methylphenyl) -N4After- (2- (allyloxy) ethyl) -6- (6- (trifluoromethyl) pyridin-2-yl) -1,3, 5-triazine-2, 4-diamine, this intermediate was prepared according to the procedure of example 2, step 6 to provide compound 26. The yield is 58.3%;1H NMR(500MHz,Chloroform-d)δ8.29–8.23(m,1H),7.87–7.80(m,1H),7.62–7.56(m,1H),7.11–7.04(m,2H),6.73–6.68(m,1H),4.59–4.55(m,1H),3.63–3.57(m,2H),3.52–3.46(m,2H),3.38–3.32(m,2H),2.76–2.72(m,1H),2.56–2.50(m,2H),2.32–2.28(m,3H),1.65–1.55(m,2H),1.49–1.39(m,2H).ESI-MS:m/z＝445[M+H]+。
EXAMPLE 24 Synthesis of Compound 27
Compound 27 was prepared according to the procedure for example 23 starting from compound 1-IM3, 3-bromo-5-fluoroaniline and compound 1-IM 10. The yield is 60.6%;1H NMR(500MHz,Chloroform-d)δ8.29–8.23(m,1H),7.88–7.80(m,1H),7.62–7.56(m,1H),6.95–6.91(m,1H),6.80–6.74(m,2H),4.67–4.63(m,1H),3.63–3.57(m,2H),3.52–3.46(m,2H),3.38–3.32(m,2H),2.74–2.70(m,1H),2.56–2.50(m,2H),1.65–1.55(m,2H),1.49–1.39(m,2H).ESI-MS:m/z＝449[M+H]+。
EXAMPLE 25 Synthesis of Compound 28
Compound 28 was obtained by the method of example 23 using compound 1-IM3, 3-bromo-5-chloroaniline and compound 1-IM10 as starting materials. The yield is 63.6%;1H NMR(500MHz,Chloroform-d)δ8.29–8.23(m,1H),7.88–7.80(m,1H),7.72–7.68(m,1H),7.63–7.56(m,1H),7.07–6.98(m,2H),4.66–4.62(m,1H),3.63–3.57(m,2H),3.52–3.46(m,2H),3.38–3.32(m,2H),2.75–2.71(m,1H),2.56–2.50(m,2H),1.65–1.55(m,2H),1.49–1.39(m,2H).ESI-MS:m/z＝465[M+H]+。
example 26: determination of inhibitory Activity of Compounds on IDH2/R140Q
The IDH2/R140Q mutant can catalyze the conversion of alpha-KG to 2-HG and simultaneously oxidize NADPH to NADP+. Thus, the inhibitory activity of the compounds on IDH2/R140Q mutants can be determined by measuring the consumption value of NADPH.
The detailed method comprises the following steps: adding 50mM K into 96-well plate2HPO4(PH7.0)，150mM NaCl,10mM MgCl22mM DTT, 0.05% BSA, 100ng/ml IDH2/R140Q and various concentrations of compounds were added, incubated at 37 ℃ for 15 minutes, then 1mM α -KG and 12 μ M NADPH, 200 μ L in total, and the absorbance change of NADPH was continuously measured over 1 hour using an NADPH probe and envision (Pekinelmer) (Ex355/Em 460). The final concentration gradient of the compound was set to (10000,5000,1000,500,100,50,10,5,1,0.5,0.1,0.01) nM, and the inhibitory activity of the compound on IDH2/R140Q was calculated based on the consumption of NADPH.
Example 27: determination of inhibitory Activity of Compounds on IDH2/R172K
The IDH2/R172K mutant can catalyze the conversion of alpha-KG to 2-HG and simultaneously oxidize NADPH to NADP+. Thus, the inhibitory activity of the compounds on IDH2/R172K mutants can be determined by measuring the consumption value of NADPH.
The detailed measurement method was as in example 26.
Example 28: determination of inhibitory Activity of Compounds on wild-type IDH2
Wild type IDH2 in NADP+Under the auxiliary action, isocitric acid is catalyzed to alpha-KG, and NADPH is generated at the same time. Thus, the inhibitory activity of a compound against wild-type IDH2 can be determined by measuring the increase in NADPH.
The detailed method comprises the following steps: adding 50mM K into 96-well plate2HPO4(PH7.0),150mM NaCl,10mM MgCl22mM DTT, 0.05% BSA, 100ng/ml IDH2/R140Q and various concentrations of compounds were added, incubated at 37 ℃ for 15 minutes, then 75. mu.M sodium isocitrate (D) and 75. mu.M NADP, in total 200. mu.L, were added, and the change in the absorbance of NADPH was continuously measured over 30 minutes using an NADPH probe and envision (Pekinelmer) (Ex355/Em 460). The final concentration gradient of the compound was set to (10000,5000,1000,500,100,50,10,5,1,0.5,0.1,0.01) nM, and the inhibitory activity of the compound against IDH2/R140Q was calculated from the increase in NADPH.
Inhibitory Activity of the Compounds of Table 1 against IDH2/R140Q, IDH2/R172K and wild-type IDH2
As can be seen from the activity data in the table, all the tested compounds showed superior inhibitory activity to one of IDH2/R140Q and IDH2/R172K than the positive drug AG-221, some of the compounds showed superior inhibitory activity to both IDH2/R140Q and IDH2/R172K than AG-221, and all the compounds showed good selectivity to wild-type IDH 2. Therefore, the compound can be used as an IDH2 inhibitor with a novel structure.
In conclusion, the compound can be used as an IDH2 inhibitor and has a wide disease treatment application prospect.
Claims (9)
1. A macrocyclic compound having a structure according to formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
q represents (CR)aRb)mWherein 1-2 CRaRbThe group may be replaced by O, NH or CH ═ CH;
z represents CH2，O；
X represents CF3；
m is 3 to 9;
Ra、Rbeach independently selected from H or methyl.
2. The macrocyclic compound of claim 1, wherein:
q represents (CR)aRb)mWherein 1-2 CRaRbA group may be replaced by O or CH ═ CH.
3. The macrocyclic compound of any one of claims 1-2, wherein the macrocyclic compound has a structure according to formula (III):
or a pharmaceutically acceptable salt thereof, wherein:
A1is (CH)2)yY is an integer of 0 to 2;
A2is O or CH2，A3Is- (CH)2)p-(CH＝CH)q-(CH2)t-；
Z represents CH2，O；
X represents CF3；
p and q are each independently selected from 0 or 1, t is selected from an integer of 0 to 2, and at least one of p, q and t is not 0;
R1、R2each independently selected from H or CH3。
4. The macrocyclic compound of any one of claims 1-2, wherein the macrocyclic compound has a structure according to formula (IV):
or a pharmaceutically acceptable salt thereof, wherein:
x, Y represents CH2Or an O atom;
B1is CH2Or is absent and only if
When X is an O atom, B is a carbon-carbon double bond1Is CH2；
B2Is CH2Or missing.
5. The macrocyclic compound according to any one of claims 1 to 2, wherein the macrocyclic compound is selected from the group consisting of:
35- (trifluoromethyl) -16- (6- (trifluoromethyl) pyridin-2-yl) -8-oxa-2, 11-diaza-1 (2,4) -triazin-3 (1,3) -phencycloundecan-5-ene
9-methyl-35- (trifluoromethyl) -16- (6- (trifluoromethyl) pyridin-2-yl) -8-oxa-2, 11-diaza-1 (2,4) -triazin-3 (1,3) -phencycloundecan-5-ene
9, 9-dimethyl-35- (trifluoromethyl) -16- (6- (trifluoromethyl) pyridin-2-yl) -8-oxa-2, 11-diaza-1 (2,4) -triazin-3 (1,3) -phencycloundecan-5-ene
35- (trifluoromethyl) -16- (6- (trifluoromethyl) pyridin-2-yl) -8-oxa-2, 11-diaza-1 (2,4) -triazine-3 (1,3) -phencycloundecane
9-methyl-35- (trifluoromethyl) -16- (6- (trifluoromethyl) pyridin-2-yl) -8-oxa-2, 11-diaza-1 (2,4) -triazine-3 (1,3) -phencycloundecane
9, 9-dimethyl-35- (trifluoromethyl) -16- (6- (trifluoromethyl) pyridin-2-yl) -8-oxa-2, 11-diaza-1 (2,4) -triazine-3 (1,3) -phencycloundecane
9, 9-dimethyl-35- (trifluoromethyl) -16- (6- (trifluoromethyl) pyridin-2-yl) -8-oxa-2, 12-diaza-1 (2,4) -triazine-3 (1,3) -phenyldodecane
9, 9-dimethyl-35- (trifluoromethyl) -16- (6- (trifluoromethyl) pyridin-2-yl) -4, 8-dioxa-2, 11-diaza-1 (2,4) -triazine-3 (1,3) -phencycloundecane
35- (trifluoromethyl) -16- (6- (trifluoromethyl) pyridin-2-yl) -2, 10-diaza-1 (2,4) -triazin-3 (1,3) -phenycyclodecan-5-ene
35- (trifluoromethyl) -16- (6- (trifluoromethyl) pyridin-2-yl) -2, 11-diaza-1 (2,4) -triazin-3 (1,3) -phencycloundecan-5-ene
35- (trifluoromethyl) -16- (6- (trifluoromethyl) pyridin-2-yl) -2, 12-diaza-1 (2,4) -triazin-3 (1,3) -phencyclododecan-5-ene
35- (trifluoromethyl) -16- (6- (trifluoromethyl) pyridin-2-yl) -2, 10-diaza-1 (2,4) -triazine-3 (1,3) -phenycyclodecane
35- (trifluoromethyl) -16- (6- (trifluoromethyl) pyridin-2-yl) -2, 11-diaza-1 (2,4) -triazine-3 (1,3) -phencycloundecane
35- (trifluoromethyl) -16- (6- (trifluoromethyl) pyridin-2-yl) -2, 12-diaza-1 (2,4) -triazine-3 (1,3) -phenyldodecane
35- (trifluoromethyl) -16- (6- (trifluoromethyl) pyridin-2-yl) -4-oxa-2, 10-diaza-1 (2,4) -triazin-3 (1,3) -phen-cyclodecan-6-ene
35- (trifluoromethyl) -16- (6- (trifluoromethyl) pyridin-2-yl) -4-oxa-2, 11-diaza-1 (2,4) -triazin-3 (1,3) -phencycloundecan-6-ene
35- (trifluoromethyl) -16- (6- (trifluoromethyl) pyridin-2-yl) -4-oxa-2, 10-diaza-1 (2,4) -triazine-3 (1,3) -phencyclodecane
35- (trifluoromethyl) -16- (6- (trifluoromethyl) pyridin-2-yl) -4-oxa-2, 11-diaza-1 (2,4) -triazine-3 (1,3) -phencycloundecane
35-methyl-16- (6- (trifluoromethyl) pyridin-2-yl) -8-oxa-2, 11-diaza-1 (2,4) -triazin-3 (1,3) -phencycloundecan-5-ene
35-fluoro-16- (6- (trifluoromethyl) pyridin-2-yl) -8-oxa-2, 11-diaza-1 (2,4) -triazin-3 (1,3) -phencycloundecan-5-ene
35-chloro-16- (6- (trifluoromethyl) pyridin-2-yl) -8-oxa-2, 11-diaza-1 (2,4) -triazin-3 (1,3) -phencycloundecan-5-ene
35-methyl-16- (6- (trifluoromethyl) pyridin-2-yl) -8-oxa-2, 11-diaza-1 (2,4) -triazine-3 (1,3) -phencycloundecane
35-fluoro-16- (6- (trifluoromethyl) pyridine-2-yl) -8-oxa-2, 11-diaza-1 (2,4) -triazine-3 (1,3) -phencycloundecane
35-chloro-16- (6- (trifluoromethyl) pyridin-2-yl) -8-oxa-2, 11-diaza-1 (2,4) -triazine-3 (1,3) -phencycloundecane
Or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising at least one active ingredient selected from one or more of the compounds of any one of claims 1 to 5, together with one or more pharmaceutically acceptable carriers or excipients.
7. Use of a macrocyclic compound according to any of claims 1 to 5 for the manufacture of a medicament for the treatment of a disease caused by a mutation in IDH 2.
8. The use according to claim 7, wherein the disease is a tumor.
9. The use according to claim 8, wherein the type of tumor is selected from acute myeloid leukemia, glioma, intrahepatic cholangiocarcinoma, sarcoma, melanoma, non-small cell lung cancer, prostate cancer or angioimmunoblastic lymphoma.
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| CN105593215A (en) * | 2013-07-11 | 2016-05-18 | 安吉奥斯医药品有限公司 | 2,4- or 4,6-diaminopyrimidine compounds as IDH2 mutants inhibitors for the treatment of cancer |
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| CN105593215A (en) * | 2013-07-11 | 2016-05-18 | 安吉奥斯医药品有限公司 | 2,4- or 4,6-diaminopyrimidine compounds as IDH2 mutants inhibitors for the treatment of cancer |
| CN108366980A (en) * | 2015-10-15 | 2018-08-03 | 安吉奥斯医药品有限公司 | Combination treatment for treating malignant tumour |
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