CN113880772B - CDK kinase inhibitors and application thereof - Google Patents
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Abstract
The invention belongs to the field of medicinal chemistry, in particular to CDK7 kinase inhibitors shown in a general formula I or isomers and pharmaceutically acceptable salts thereof, a preparation method thereof, a pharmaceutical composition containing the compounds and application of the compounds or the compositions in treating CDK7 mediated diseases,the compound of the invention has strong inhibitory activity on CDK7 and IC on human breast cancer cells MDA-MB-231 and lung cancer A549 cells 50 Are all less than 0.025. Mu.M.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and in particular relates to CDK7 kinase inhibitors or isomers and pharmaceutically acceptable salts thereof, a preparation method of the CDK7 kinase inhibitors or isomers and pharmaceutically acceptable salts thereof, a pharmaceutical composition containing the compounds and application of the compounds or the compositions in treating CDK7 mediated diseases.
Background
Breast cancer (Breast cancer) is a common malignancy that severely jeopardizes human health. According to the global latest cancer data issued by the international cancer research Institute (IARC) of the world health organization, the global new breast cancer reaches 226 ten thousand in 2020, and the first cancer is the first global first cancer beyond lung cancer (221 ten thousand). China is a large country of breast cancer, about 42 tens of thousands of new breast cancers occur in 2020, and almost 12 tens of thousands of deaths occur.
Currently, the clinical treatment options for breast cancer are very limited, especially the total few effective therapeutic agents for breast cancer. Therefore, the development of a novel small molecule targeting drug effective for breast cancer is urgently needed in clinic, which is also a research hotspot in the current breast cancer treatment field and has important research significance.
With the continuous intensive research on the pathogenesis and genomics of breast cancer, it is found that the occurrence and development processes of breast cancer are highly dependent on the regulation and control of Cyclin-dependent kinase 7 (CDK 7) and have specificity, so that the phenomenon of over-expression, continuous activation or amplification of CDK7 occurs in breast cancer cells frequently, and if CDK7 in breast cancer cells is inhibited, gene silenced or knocked out, the death of the breast cancer cells can be induced. Thus, the study of selective inhibitors of CDK7 kinase may be a new option for the treatment of breast cancer.
Disclosure of Invention
It is an object of the present invention to provide a class of compounds having CDK7 inhibitory activity, or a pharmaceutically acceptable salt thereof, represented by the following general formula I.
It is a further object of the present invention to provide a process for the preparation of the compounds of formula I of the present invention or a pharmaceutically acceptable salt thereof.
It is a further object of the present invention to provide compositions comprising a compound of formula I of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, as well as compositions comprising a compound of formula I of the present invention or a pharmaceutically acceptable salt thereof and another drug or drugs.
It is a further object of the present invention to provide a method of treating and/or preventing a CDK 7-related disorder, using a compound of formula I or a pharmaceutically acceptable salt thereof according to the present invention, in the preparation of a medicament for treating and/or preventing a CDK 7-related disorder.
In order to achieve the above object, the present invention provides the following technical solutions:
in a first aspect, the present invention provides a compound of formula I or an isomer, pharmaceutically acceptable salt thereof,
wherein:
R 1 selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, and alkylsulfonyl;
x is halogen;
R 2 selected from the group consisting of hydrogen, alkyl, and alkoxy;
radicals (C)Is connected to the collar or para position of the benzene ring;
radicals (C)Attached in the ortho or para position of the benzene ring.
In some preferred embodiments, R 1 Selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methanesulfonyl, ethanesulfonyl, propanesulfonyl, and isopropylsulfonyl.
In some more preferred embodiments, R 1 Selected from hydrogen, bromo, methoxy, isopropyl sulfonyl.
In some preferred embodiments, X is chloro.
In some preferred embodiments, R 2 Selected from hydrogen, fluorine, chlorine, bromine, methyl, methoxy, isopropyl sulfonyl.
In some preferred embodiments of the present invention,attached meta to the benzene ring.
In some preferred embodiments of the present invention,is connected at para position of benzene ring.
The present invention provides the following specific compounds or pharmaceutically acceptable salts thereof:
specific compounds:
I-1
I-2
I-3
I-4
I-5
I-6
I-7
I-8
in a second aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention or an isomer, pharmaceutically acceptable salt thereof.
In some embodiments, the invention provides a compound of the invention, or an isomer, pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising a compound of the invention, or an isomer, pharmaceutically acceptable salt thereof, for use in the treatment of a CDK7 mediated disorder.
In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention or an isomer, a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The compounds of the present invention, or isomers, pharmaceutically acceptable salts thereof, may be admixed with pharmaceutically acceptable carriers, diluents or excipients to prepare pharmaceutical formulations suitable for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulation may be administered by any route, for example by infusion or bolus injection, by absorption through the epithelial or skin mucosa (e.g. oral mucosa or rectum, etc.). Administration may be systemic or local. Examples of formulations for oral administration include solid or liquid dosage forms, specifically including tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations may be prepared by methods known in the art and comprise carriers, diluents or excipients conventionally used in the art of pharmaceutical formulations.
In a third aspect, the invention provides a compound of formula I, or an isomer, pharmaceutically acceptable salt, or pharmaceutical composition comprising the same, of the invention for use in a method of treating a CDK7 mediated disorder and for use in the manufacture of a medicament for treating a CDK7 mediated disorder.
In some preferred embodiments, the invention provides methods for treating CDK7 mediated disorders, including but not limited to tumors, and the use of a compound of formula I of the invention, or an isomer, pharmaceutically acceptable salt, or pharmaceutical composition comprising the same, in the manufacture of a medicament for treating CDK7 mediated disorders. In some embodiments, the CDK7 mediated disorder described herein is breast cancer such as breast adenocarcinoma, breast papillary carcinoma, breast medullary carcinoma, triple negative breast carcinoma.
Definition of terms
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The "halogen" in the present invention means fluorine, chlorine, bromine, iodine. "halo" in the present invention means substituted with fluorine, chlorine, bromine or iodine.
"alkyl" in the present invention refers to a straight or branched saturated aliphatic hydrocarbon group, preferably a straight or branched group having 1 to 6 carbon atoms, further preferably a straight or branched group having 1 to 3 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be at any useful point of attachment.
"sulfonyl" in the context of the present invention means-S (O) 2 -。
The term "pharmaceutically acceptable salts" as used herein refers to salts of the compounds of the present invention which are safe and effective when used in a mammal, and which possess the desired biological activity.
The term "pharmaceutical composition" according to the instant invention shall mean a mixture comprising any one of the compounds of the instant invention, including the corresponding isomer, prodrug, solvate, pharmaceutically acceptable salt or chemically protected form thereof, and one or more pharmaceutically acceptable carriers and/or another drug or drugs. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism. The compositions are generally useful in the manufacture of medicaments for the treatment and/or prophylaxis of diseases mediated by one or more kinases.
By "pharmaceutically acceptable carrier" is meant a carrier that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the compound being administered, and that comprises all solvents, diluents or other excipients, dispersants, surfactant isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like. Unless any conventional carrier medium is incompatible with the compounds of the present invention. Some examples of pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, cellulose and cellulose acetate; malt, gelatin, and the like.
The "excipient" of the present invention refers to an inert substance added to a pharmaceutical composition to further facilitate administration of the compound. Excipients may include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols.
Detailed Description
The present invention will be described in further detail with reference to examples, but the present invention is not limited to these examples. The materials used in the examples below are commercially available unless otherwise specified.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1 preparation of (E) -N- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) phenyl) -4- (4- (dimethylamino) -2-butenamide) benzamide (I-1)
Step 1: preparation of 2, 5-dichloro-N- (2- ((1-methylethyl) sulfonyl) phenyl) -4-pyrimidinamine
2-Isopropanesulfonylaniline (1.0 g,10.75 mmol), 2,4, 5-trichloropyrimidine (1.79 g,9.78 mmol), DIEA (N, N-diisopropylethylamine) (1.5 g,11.6 mmol) were weighed into a 100ml eggplant-shaped bottle, 15ml of isopropanol was added for dissolution, the reaction was stopped after 3 hours of heating up, the reaction was concentrated under reduced pressure to remove the isopropanol in the reaction solution, the reaction solution was poured into a separating funnel, 25ml of cold water and 30ml of ethyl acetate were added for extraction three times, the organic phase was collected, the organic layer was dried under reduced pressure to obtain a solid target product, and the obtained yield was calculated to be 55%. Step 2: n (N) 2 - (4-aminophenyl) -5-chloro-N 4 Preparation of- (2-isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine
2, 5-dichloro-N- (2- ((1-methylethyl) sulfonyl) phenyl) -4-pyrimidinamine (2.0 g,5.8 mmol) and p-phenylenediamine (0.7 g,6.5 mmol) were weighed into a 100mL eggplant bottle, dissolved in 50mL methanol, added dropwise with 0.8mL concentrated hydrochloric acid, and reacted under reflux at 80℃for 6h. After the reaction was completed, the reaction solution was poured into a 250mL beaker, 100mL of water was added thereto, and a large amount of solids was precipitated at this time, and the filtrate was suction-filtered with saturated Na 2 CO 3 The pH of the aqueous solution is adjusted to 9-10, a large amount of white solid is precipitated, the white solid is obtained by suction filtration and filter cake drying, and the yield is 58%.
Step 3: preparation of 4-amino-N- (3- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) phenyl) benzamide
Boc-protected para-aminobenzoic acid (0.6 mmol) was weighed into a 100mL eggplant-type bottle, HOBT (1-hydroxybenzotriazole, 0.08g,0.6 mmol), EDCI (1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 0.11g,0.6 mmol) and DIEA (0.13 g,1.0 mmol) were dissolved in a 50mL eggplant-type bottle, and 5mL DMF was added thereto and stirred at room temperature for 30min. And then N is added 2 - (4-aminophenyl) -5-chloro-N 4 - (2-isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (0.6 mmol) was added to the reaction flask, and stirring was continued at room temperature for 6 hours. After completion of the reaction, the reaction mixture was diluted with 50mL of water, extracted twice with 50mL of ethyl acetate, the obtained organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, suction-filtered andconcentrated under reduced pressure, TFA (trifluoroacetic acid) in dichloromethane (3.0 mmol) was added, stirred for 30min, and purified by silica gel column chromatography after direct spin-drying. Obtained as white solid in 43% yield.
Step 4: (E) Preparation of-N- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) phenyl) -4- (4- (dimethylamino) -2-butenamide) benzamide (I-1)
4-amino-N- (3- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) phenyl) benzamide (3.6 g,24 mmol) was weighed into a 100mL eggplant-shaped bottle, 20mL acetonitrile and DIEA (48 mmol) were added and stirred at 0deg.C, N-dimethylcrotonyl chloride was slowly added dropwise to the eggplant-shaped bottle, and stirred for 2h at room temperature after the addition. After completion of the reaction, acetonitrile was removed from the reaction mixture by concentration under reduced pressure, the reaction mixture was poured into a 250mL beaker and 100mL of cold water was added thereto, and Na was used 2 CO 3 The pH was adjusted to 9-10, then the reaction solution was poured into a separating funnel, extracted twice with 150mL ethyl acetate, the organic phases were combined, filtered with suction and concentrated under reduced pressure to give a yellow solid in 48% yield. 1 H NMR(600MHz,DMSO-d 6 )(δ,ppm):10.30(s,1H),10.24(s,1H),9.83(s,1H),9.55(s,1H),8.65(s,1H),8.31(s,1H),8.26(s,1H),8.06(s,1H),7.82-7.75(m,2H),7.70-7.55(m,2H),7.41-7.20(m,5H),6.82-6.75(m,1H),6.25-6.20(m,1H),3.45-3.50(m,1H),3.12(d,2H),2.22(s,6H),1.18(d,J＝15.6Hz,6H). 13 C NMR(150MHz,DMSO-d 6 )(δ,ppm):165.2,164.0,158.2,155.7,155.2,142.6,142.6,140.5,139.7,138.4,135.2,131.3,129.8,129.1,128.8,126.1,124.4,123.8,118.8,116.0,115.3,113.1,105.3,60.1,55.4,45.6,15.3.
Example 2 preparation of (E) -N- (3- ((5-chloro-4- (phenylamino) pyrimidin-2-yl) amino) phenyl) -4- (4- (dimethylamino) -2-butenamide) benzamide (I-2)
Aniline and N, N-dimethylamino crotonic acid are used as raw materials, the operation is the same as that of I-1, and white solid is obtained through column chromatography separation, and the yield is 38%. 1 H NMR(600MHz,DMSO)δ10.34(s,1H),10.00(s,1H),9.36(s,1H),8.77(s,1H),8.15(s,1H),7.93(d,J＝8.7Hz,3H),7.79(d,J＝8.7Hz,2H),7.72(d,J＝7.9Hz,2H),7.40(d,J＝8.0Hz,1H),7.28(t,J＝7.8Hz,3H),7.14(t,J＝8.0Hz,1H),7.00(d,J＝7.4Hz,1H),6.78(d,J＝15.4Hz,2H),6.31(d,J＝15.4Hz,1H),3.10(s,2H),2.21(s,6H). 13 C NMR(150MHz,DMSO-d 6 )(δ,ppm):165.1,163.9,158.3,156.2,155.0,142.5,140.9,139.5,139.1,129.8,129.1,128.7,128.6,124.0,123.1,118.8,115.0,112.9,104.5,60.1,45.5。
Example 3 preparation of (E) -N- (3- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) phenyl) -4- (4- (dimethylamino) -2-butenamide) benzamide (I-3)
2-isopropylsulfonyl aniline, m-aminobenzoic acid and N, N-dimethylamino crotonic acid are used as raw materials, the operation is the same as that of I-1, and white solid is obtained through column chromatography separation, and the yield is 33.2%. H NMR (600 MHz, DMSO-d) 6 )(δ,ppm):10.40(s,1H),10.08(s,1H),9.63(s,1H),9.55(s,1H),8.70(s,1H),8.31(s,1H),8.06(s,1H),7.93(d,J＝8.6Hz,2H),7.82(dd,J＝25.2,8.6Hz,3H),7.66(m,1H),7.38(d,J＝7.8Hz,1H),7.31(t,J＝11.7Hz,1H),7.21-7.23(m,2H),6.65-6.79(m,1H),6.23-6.33(m,1H),3.45-3.50(m,1H),3.12(s,2H),2.22(s,6H),1.18(d,J＝15.3Hz,6H).
Example 4 preparation of (E) -N- (3- ((5-chloro-4- ((3- (methyl) phenyl) amino) pyrimidin-2-yl) amino) phenyl) -4- (4- (dimethylamino) -2-butenamide) benzamide (I-4)
The title compound is prepared from 3-methylaniline, p-aminobenzoic acid and N, N-dimethylaminocrotonyl chloride.
Example 5 preparation of (E) -N- (3- ((5-chloro-4- ((2- (methoxy) phenyl) amino) pyrimidin-2-yl) amino) phenyl) -4- (4- (dimethylamino) -2-butenamide) benzamide (I-5)
The title compound is prepared from 2-methoxyaniline, p-aminobenzoic acid and N, N-dimethylaminocrotonyl chloride.
Example 6 preparation of (E) -N- (3- ((5-chloro-4- ((3-bromophenyl) amino) pyrimidin-2-yl) amino) phenyl) -4- (4- (dimethylamino) -2-butenamide) benzamide (I-6)
The title compound is prepared from 2-methoxyaniline, p-aminobenzoic acid and N, N-dimethylaminocrotonyl chloride.
Example 7 preparation of (E) -N- (3- ((5-chloro-4- (phenylamino) pyrimidin-2-yl) amino) phenyl) -2-methyl-4- (4- (dimethylamino) -2-butenamide) benzamide (I-7)
The title compound is prepared from 2-methoxyaniline, 2-methyl-4-aminobenzoic acid and N, N-dimethylaminocrotonyl chloride.
Example 8 preparation of (E) -N- (3- ((5-chloro-4- (phenylamino) pyrimidin-2-yl) amino) phenyl)) -3-methoxy-4- (4- (dimethylamino) -2-butenamide) benzamide (I-8)
The title compound is prepared from 2-methoxyaniline, 3-methoxy-4-aminobenzoic acid and N, N-dimethylaminocrotonyl chloride.
Experimental example 1 CDK7 enzyme inhibition Activity test
In 384-well reaction plates, positive control wells and negative control wells were set, the remaining wells were each added with different concentrations of compound and CDK7 kinase/Cyclin H/MAT, centrifuged and incubated at room temperature for 15min, fluorogenic substrate and stop solution were added, fluorescent signals were continuously read using syngy and the linear reaction section was selected using syngy to obtain the slope (slope). And further calculating the percentage inhibition rate, wherein the calculation formula is as follows: enzyme inhibition = Mean (max) -sample signal/Mean (max) -blank multiplied by 100%, log of compound concentration as X-axis and corresponding percent inhibition as Y-axis, fitting the dose-response curve with analytical software GraphPad Prism 5 to give each compound inhibition. The experimental results are shown in Table 1
TABLE 1
The inhibitory activity of each of the compounds I-1 to I-8 on CDK7 kinase reached about 100% at a concentration of 200 nM.
The positive control THZ1 used in the present invention was (E) -N- (3- ((5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) -4- (4- (dimethylamino) -2-butenamide) benzamide, purchased from carbofuran.
The results show that the compounds of the invention have potent inhibitory activity on CDK 7. The inhibition activity of CDK7 kinase reaches more than 97% at 200nM concentration, which is equivalent to that of positive control THZ 1.
Experimental example 2 cell proliferation inhibitory Activity test
The experiment is provided with a solvent control group and a drug experiment group, wherein each group of the drug experiment group is provided with 5 concentrations, and each concentration is provided with 3 parallel holes. Each experiment was repeated three times. In 96-well plates, cells were added at a concentration of 1X 10 per well 5 mu.L of cell suspension per mL, i.e.3X 10 cells per well 3 In each case, the cells were homogeneously distributed in each well by taking care of seeding. To prevent evaporation of the liquid, a round of wells surrounding the 96-well plate were not seeded with cells and were moisturized by the addition of PBS. After cell attachment, 100. Mu.L of the target compound was added to each well of the drug test group at concentrations of 0, 4, 8, 12 and 16. Mu.g/mL to give final concentrations of 0, 2,4, 6 and 8. Mu.g/mL, respectively. The 96-well plate was placed at 37℃in 5% CO 2 Culturing in incubator for 72 hr, and stopping culturing. After 72h of drug treatment of the cells, 96-well plates were removed, 20. Mu.L of CCK-8 solution was added to each well, and after incubation in the cell incubator for 0.5-4 hours, absorbance values (A) were measured at 450nm on an automatic microplate reader. In the pre-experiment, the enzyme label instrument is used for detection after 0.5 hour, 1 hour, 2 hours and 4 hours respectively, and a time point (2 hours) with a proper absorbance range is selected for the subsequent experiment.
The growth inhibition of tumor cells by different drug concentrations was calculated as follows:
performing linear regression analysis on the drug concentration with inhibition rate, and calculating IC by using linear equation 50 Values. The detection result is expressed by mean ± standard deviation, the experimental result is statistically analyzed by SPSS15.0 software, and P is used<0.05 indicates a significant difference. The results show that the compounds I-1 to I-8 have IC on human breast cancer cells MDA-MB-231 and lung cancer cells A549 50 Are all less than 0.025 mu M, and THZ1 (IC 50 Less than 0.025. Mu.M) is equivalent to and superior to the positive control Seliclib (IC) 50 Greater than 1 μm) (purchased by mikrin corporation).
Claims (6)
1. A compound of formula I or a pharmaceutically acceptable salt thereof,
wherein:
R 1 selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methanesulfonyl, ethanesulfonyl, propanesulfonyl, and isopropylsulfonyl;
x is halogen;
R 2 selected from hydrogen, methyl, methoxy;
radicals (C)Attached meta to the benzene ring;
radicals (C)Is connected at para position of benzene ring.
2. The compound of claim 1, wherein R 1 Selected from hydrogen, bromo, methoxy, isopropyl sulfonyl.
3. The compound of claim 1, wherein X is chloro.
4. A compound or a pharmaceutically acceptable salt thereof, characterized in that said compound is selected from the group consisting of:
5. a pharmaceutical composition comprising a compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.
6. Use of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof or a composition according to claim 5 in the manufacture of a medicament for the treatment and/or prophylaxis of tumours.
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| CN112010828A (en) * | 2020-09-27 | 2020-12-01 | 中国医科大学 | CDK7 small-molecule inhibitor compound and application thereof |
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