CN111592522B - Arginine methylation transferase 5 small-molecule inhibitor and preparation method and application thereof - Google Patents
Arginine methylation transferase 5 small-molecule inhibitor and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of medicinal chemistry, and discloses an arginine methylation transferase 5 small-molecule inhibitor (PRMT5), a preparation method thereof and application thereof in preparing medicaments. Relates to a compound shown in a general formula I or pharmaceutically acceptable salt, solvate, hydrate, active metabolite, polymorph, ester, isotopic compound, stereoisomer or prodrug thereof, a pharmaceutical composition containing the compound with the structure of the formula I and application of the pharmaceutical composition as a PRMT5 inhibitor in preparation of medicines for diseases including but not limited to cancer, myelodysplastic syndrome, neurodegenerative diseases or diabetes and the like.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to an arginine methyltransferase 5 small molecule inhibitor (PRMT5), a preparation method thereof and application thereof in preparing medicaments.
Background
Arginine methylation mediated by PRMTs (protein arginine methylarasferases) family plays an important role in the processes of cell signal transduction, RNA treatment, gene transcription, cell transportation function and the like, has important cellular consequences on organisms, and has non-negligible influence on physiological processes, diseases and developmental disorders. PRMT5, protein arginine methyltransferase 5, is one of the important members of the PRMT family, belongs to the class II methyltransferase, and catalyzes the symmetric double methylation of arginine residues on protein substrates. The expression of target genes is regulated by this epigenetic means or key signal molecules are regulated by post-translational methylation modification pathways. The methylation of PRMT5 on protein relates to a plurality of cell functions related to signal transduction, transcription, DNA repair and mRNA splicing, and has important influence on different cell processes such as cell growth, differentiation, proliferation and development, and a plurality of researches prove that PRMT5 is an important post-translational modification methylation transferase, and the deletion or abnormal expression of the methylation transferase has important influence on the growth and development of organisms.
It was found that PRMT5 is overexpressed in many human tumors, including lung, ovarian, colorectal, breast, melanoma, leukemia or lymphoma, and glioblastomas, among others, while knockout PRMT5 decreases cell growth and survival of many cancer cell lines. Further experimental studies showed that overexpression of PRMT5 was sufficient to transform normal fibroblasts into cancer cells, indicating that PRMT5 is sufficient and necessary for cellular transformation. With intensive research on the relationship between PRMT and occurrence and development of tumors by researchers, PRMT5 is found to promote the proliferation and growth of cancer cells mainly by silencing cancer suppressor genes (p53, ST7, NM23 and MiR-29b), influencing the expression of key transcription factors (KLF4, FOXP1, SRSF1 and Ki-67) and activating the expression of oncogenes (cyclin D1, MYC and VHL). In addition, PRMT5 has certain relevance to human diseases such as neurodegenerative diseases and metabolic disorders. At present, PRMT5 has been proved to be an oncoprotein, the correlation between the oncogenesis development and the prognosis has been gradually proved, the inhibition of the activity can effectively inhibit the promotion effect of the oncogenesis development and the tumor development, and the anti-tumor therapy is a new target.
The research of the PRMT5 inhibitor is now a hot spot for the development of new drugs, and the research on the structure and crystal structure of the enzyme is also increasing. The first PRMT5 inhibitor enters clinical trials as an antitumor drug in 2018, and the PRMT5 inhibitor is expected to become an effective anticancer drug with a new action mechanism. To date, although many PRMT5 inhibitors have been developed, and there are few compounds with high activity and high selectivity, there is still a clinical lack of effective inhibitors against the PRMT5 target, and more arginine methylation drugs are required to be present in clinical evaluation, and the development potential thereof is still huge.
Disclosure of Invention
Aiming at PRMT5 target, the invention aims to provide a compound which has good activity and can be used as a PRMT5 inhibitor, and the compound is used for preventing or treating diseases related to excessive PRMT5 activity in human or mammals.
The PRMT5 inhibitor is a compound shown as a general formula I or a pharmaceutically acceptable salt, solvate, hydrate, active metabolite, polymorph, ester, isotopic compound, stereoisomer or prodrug thereof.
In the formula:
a ring is selected from substituted or unsubstituted C 4-7 An aromatic ring; substituted or unsubstituted C 4-7 Aromatic heterocycle, heteroatom is selected from N, O or S.
The B ring is selected from hydroxy-substituted C 4-7 Heterocycle, heteroatom selected from N, O or S.
R is selected from amino or substituted amino;
preferably, C is substituted in the A ring 4-7 Aromatic ring or C 4-7 The substituents in the aromatic heterocyclic ring are selected from halogen, hydroxy, cyano, amino, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 1-3 One or more of haloalkyl.
More preferably, the a ring is selected from, but not limited to, one of the following structures:
preferably, the B ring is a hydroxy-substituted C containing at least one N 5-7 A heterocycle; more preferably from but not limited to one of the following structures:
preferably, the substituents in the substituted amino group in the R group are selected from C 1-6 Saturated fatty chain, C 3-6 Saturated aliphatic rings, substituted aromatic rings or substituted aromatic heterocycles containing N, O or S; wherein the substituents in the substituted aromatic or heteroaromatic ring are selected from the group consisting of halogen, cyano, hydroxy, amino, carbonyl, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 1-3 Alkylamino radical, C 1-3 Haloalkyl, C 1-3 One or more of haloalkoxy groups. More preferably selected from, but not limited to, one of the following structures:
the PRMT5 inhibitor substituents are preferably as follows:
the A ring is selected from one of the following substituents:
the B ring is selected from one of the following substituents:
r is selected from one of the following substitutions:
use of a compound according to any one of the above in the manufacture of a medicament for the prevention or treatment of a PRMT5 mediated disease, including but not limited to cancer, myelodysplastic syndrome, neurodegenerative disease, or diabetes.
The cancer includes, but is not limited to, colon cancer, rectal cancer, breast cancer, lung cancer, pancreatic cancer, cervical cancer, kidney cancer, stomach cancer, esophageal cancer, oral cancer, bone cancer, larynx cancer, thyroid cancer, gallbladder cancer, fallopian tube cancer, head and neck cancer, testicular cancer, bladder cancer, liver cancer, ovarian cancer, multiple myeloma, lymphoma, glioma, leukemia or melanoma, and the like.
A route when ring B is 4-hydroxypiperidine comprising the steps of: (a) carrying out acylation reaction on the compound II and 4-piperidone to obtain a compound III; (b) carrying out a sulfur ylide reaction on the compound III to obtain a compound V; (c) reacting the compound V with 1,2,3, 4-tetrahydroisoquinoline to obtain a compound VI; (d) the compound VI is subjected to coupling reaction to generate a compound I;
the preparation method comprises the following steps:
a) in a solvent, carboxylic acid compounds (II) are used as initial raw materials and are subjected to acylation reaction with 4-piperidone under the alkaline condition of a condensing agent to generate corresponding amide compounds (III); wherein, the used solvents are: tetrahydrofuran, N-dimethylformamide, chloroform, dichloromethane or toluene, wherein the reaction can be carried out in the single solvent or the mixed solvent, and the volume ratio of the mixed solvent is 1: 0.1-1: 10; the condensing agent is T 3 P, EDC, EDCI, CDI or HATU; the alkali used in the reaction is sodium bicarbonate, potassium carbonate, triethylamine or pyridine; carboxylic acid compound (ii): condensing agent: the molar charge ratio of the alkali is 1.0: 1.0-5.0: 1.0 to 2.5; the reaction temperature is preferably 0-80 ℃; the reaction time is preferably 30 minutes to 12 hours.
b) Adding a sulfur ylide reagent into the amide compound (III) obtained in the step a) under the conditions of a solvent and alkalinity to react to obtain a compound (V) containing an epoxy group; wherein, the used solvents are: n, N-dimethylformamide, chloroform, tetrahydrofuran, dimethyl sulfoxide or toluene; the sulfur ylide reagent is trimethyl sulfur iodide or trimethyl sulfoxide iodide, and the alkali is potassium tert-butoxide, sodium tert-butoxide or sodium hydride; amide compound (iii): sulfur ylide reagent: the molar charge ratio of the strong base is 1.0: 1.0-5.0: 1.0 to 5.0; the reaction temperature is preferably-10-50 ℃; the reaction time is preferably 30 minutes to 5 hours.
c) Reacting the epoxy compound (V) obtained in the step b) with 1,2,3, 4-tetrahydroisoquinoline in a solvent under alkaline conditions to obtain a compound (VI); wherein the solvent is tetrahydrofuran, N-dimethylformamide, methanol or ethanol; the base used in the reaction is K 2 CO 3 、Na 2 CO 3 、Cs 2 CO 3 Or NaOH; the reaction temperature is preferably 50-100 ℃; the reaction time is preferably 30 minutes to 6 hours.
d) Reacting the compound (VI) obtained in the step c) with amino compounds containing different R groups in the presence of a palladium catalyst in a solvent and under alkaline conditions to obtain a compound (I); the solvent used in the reaction is dimethyl sulfoxide, tetrahydrofuran, N-dimethylformamide, chloroform, dichloromethane or toluene; the palladium catalyst is palladium tetratriphenylphosphine, palladium acetate, diphenylphosphine ferrocene palladium dichloride, palladium dichlorodiphenylphosphine or palladium-carbon; the base used in the reaction is Na 2 CO 3 、K 2 CO 3 Cs 2 CO 3 Potassium tert-butoxide or sodium tert-butoxide; compound VI: palladium catalyst: the molar ratio of the alkali is 1: 0.005-1.0: 1.0 to 5; the reaction temperature is preferably 30-120 ℃; the reaction time is preferably 5 to 48 hours.
Each of the products obtained in the reaction scheme may be obtained by conventional separation techniques including, but not limited to, filtration, distillation, crystallization, chromatographic separation and the like. The starting materials required for the synthesis can be synthesized by themselves or purchased from commercial establishments. The compounds described herein may be synthesized to give a single optical isomer or a mixture of optical isomers.
The invention has the advantages that: the synthetic route is simple, the synthesized compound shows good inhibitory activity to PRMT5 enzyme, and the biological activity evaluation shows that especially the compounds I-5, I-11, I-15 and I-22 have similar inhibitory activity to the positive control compound EPZ 015938. The derivative is used as an active ingredient and is used as a PRMT5 inhibitor for preparing medicaments for treating diseases such as, but not limited to, cancers, myelodysplastic syndromes, neurodegenerative diseases or diabetes.
Detailed Description
The invention will be better understood from the following examples. However, those skilled in the art will readily appreciate that the description of the embodiments is only for illustrating the present invention and should not be taken as limiting the invention as detailed in the claims.
EXAMPLE 1 Synthesis of Compound I-1
(1) Synthesis of 1- (3-bromobenzoyl) piperidin-4-one
1g (5mmol) of 3-bromobenzoic acid, 3.78g (10mmol) of CDI (N, N-carbonyldiimidazole) and potassium carbonate were charged in a reaction flask, 10mL of tetrahydrofuran was added, 1.34g (10mmol) of 4-piperidone hydrochloride was added, and the mixture was stirred at room temperature for 5 hours. 20mL of methylene chloride was added, and the mixture was washed with 10mL of water, then 10mL of saturated NaCl, then x 1, was washed with saturated NaCl, and then dried over anhydrous magnesium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether: ethyl acetate: 2:1) to obtain the desired compound as a yellow oily viscous liquid (7.2mg, yield 50.2%). 1 H NMR(400MHz,CDCl 3 )δ7.64-7.61(m,1H),7.61-7.57(m,1H),7.42-7.38(m,1H),7.36-7.30(m,1H),3.87(d,J＝90.5Hz,4H),2.53(s,4H).
(2) Synthesis of (3-bromophenyl) (1-oxa-6-azaspiro [2.5] oct-6-yl) methanone
Trimethyl sulphoxide iodide (1.45g,7.12mmol) and NaH (285mg,7.12mmol) were added to the flask under nitrogen. Adding 10mL DMSO solution into a reaction flask, stirring at room temperature for 2h, dissolving compound 2 with toluene, adding into the reaction flask, and adding 80%Reacting at the temperature of 6 hours. The reaction was quenched, 40mL of dichloromethane was added, and 10mL × 4 and 10mL × 1 of saturated NaCl solution were washed with water, dried over anhydrous magnesium sulfate, suction-filtered, the filtrate was concentrated, and column chromatography was performed (petroleum ether: ethyl acetate ═ 3:1) to obtain a compound as a yellow oily viscous liquid (500mg, yield 48%). 1 H NMR(400MHz,CDCl 3 )δ7.60-7.54(m,2H),7.35(dt,J＝7.6,1.3Hz,1H),7.32-7.28(m,1H),4.26(s,1H),3.54(s,3H),2.74(s,2H),1.93(d,J＝57.5Hz,2H),1.49(d,J＝47.3Hz,2H).
(3) Synthesis of (3-bromophenyl) (4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -4-hydroxypiperidin-1-yl) methanone
Weighing compound 3(1g,3.4mmol) in a reaction flask, adding Cs 2 CO 3 (3.3g,3mmol) DMF 5mL and 1.2.3.4-tetrahydroisoquinoline (847. mu.L, 7.1mmol) were reacted in an oil bath at 60 ℃ for 4 h. The solvent was removed by distillation under the reduced pressure, and the compound was isolated by column chromatography (dichloromethane: ethyl acetate 1:1) as a yellow viscous compound (700mg, yield 48.3%). 1 H NMR(400MHz,Acetone-d 6 )δ7.63-7.59(m,1H),7.57(d,J＝1.0Hz,1H),7.42-7.37(m,2H),7.12-7.05(m,3H),7.02-6.98(m,1H),4.33(s,1H),3.78(s,2H),3.62(s,1H),3.47(s,2H),3.22(s,1H),2.91-2.85(m,4H),2.55(s,2H),1.65(s,4H).
(4) (4- (((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -4-hydroxypiperidin-1-yl) (3- (oxetan-3-ylamino) phenyl) methanone
Weighing Compound 4(200mg,0.48mmol), K 2 CO 3 (129mg,0.97mmol) was added to the reaction flask, 4mL DMSO solvent was added to the reaction flask, 68. mu.L (0.97mmol) of 3-oxetanamine was added, 5.39mg,0.048mmol of tetrakis (triphenylphosphine) palladium was added, and the reaction was carried out at room temperature for 48 hours. Filtering with diatomaceous earth, concentrating, and separating with column chromatography (dichloromethane: methanol: 30:1)Compound I-1 was obtained as a white solid (25mg, yield 13%). 1 H NMR(400MHz,Acetone-d 6 )δ7.14(t,J＝7.8Hz,1H),7.12-7.05(m,3H),7.02-6.97(m,1H),6.64(d,J＝7.5Hz,1H),6.60-6.53(m,2H),4.88(t,J＝6.5Hz,2H),4.67-4.57(m,1H),4.46(t,J＝6.1Hz,2H),4.38-4.25(s,1H),3.80(s,2H),3.63-3.46(m,1H),3.45-3.32(s,1H),3.20(s,1H),2.93-2.84(m,4H),2.56(s,2H),2.09(s,1H),2.08-2.06(m,1H),1.60(s,4H). 13 C NMR(100MHz,Acetone-d 6 )δ170.56,148.15,138.99,136.18,135.19,129.97,129.41,127.31,126.88,126.36,116.32,114.13,111.72,78.96,70.41,68.70,58.91,54.17,48.97.
Example 2
(3- (Cyclobutylamino) phenyl) (4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -4-hydroxypiperidin-1-yl) methanone
A compound I-2: the procedure is as in example 1 except that the R group, 3-oxetane, is replaced by cyclobutylamine, a white solid in 17% yield. 1 H NMR(400MHz,Acetone-d 6 )δ7.15-7.04(m,4H),7.03-6.95(m,1H),6.63-6.52(m,3H),5.29(d,J＝6.6Hz,1H),4.29(s,1H),4.00-3.87(m,1H),3.78(s,2H),3.59(s,2H),3.26(dd,J＝55.3,14.5Hz,2H),2.94–2.86(m,4H),2.54(s,2H),2.43-2.33(m,2H),1.94-1.81(m,2H),1.85-1.71(m,J＝11.2H),1.60(s,4H). 13 C NMR(100MHz,Acetone-d 6 )δ170.74,148.78,138.87,136.46,135.30,129.71,129.38,127.27,126.79,126.29,115.36,114.08,111.55,70.54,68.81,59.02,54.23,49.44,31.51,15.78.
Example 3
(4- (((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -4-hydroxypiperidin-1-yl) (3- ((tetrahydro-2H-pyran-4-yl) amino) phenyl) methanone
A compound I-3: the procedure is as in example 1, except that the R group is 3-oxoThe heterocyclic butylamino was replaced with tetrahydro-2H-pyran-4-amine as a white solid in 11% yield. 1 H NMR(400MHz,Acetone-d 6 )δ7.15-7.05(m,4H),7.00(d,J＝5.3Hz,1H),6.726.63(m,3H),6.57(d,J＝7.3Hz,1H),5.01(d,J＝7.7Hz,1H),4.30(s,1H),3.89(dd,J＝8.3,3.2Hz,2H),3.77(s,2H),3.54(d,J＝5.8Hz,1H),3.50-3.43(m,2H),3.39(s,1H),3.20(s,1H),2.92-2.85(m,4H),2.53(s,2H),1.96(d,J＝11.4Hz,2H),1.59(s,4H),1.49-1.38(m,2H). 13 C NMR(101MHz,Acetone)δ169.79,147.72,138.06,135.55,134.38,128.85,128.48,126.36,125.88,125.39,114.36,113.56,110.91,69.61,67.92,66.28,58.11,53.32,48.54,33.23.
Example 4
(4- (((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -4-hydroxypiperidin-1-yl) (3-morpholinophenyl) methanone
Compound I-4: the synthesis was as in example 1 except that the R group 3-oxetanamine was replaced by morpholine and was a white solid in 12% yield. 1 H NMR(400MHz,Acetone-d 6 )δ7.30-7.24(m,1H),7.12-7.06(m,3H),6.99(dd,J＝7.8,2.1Hz,2H),6.94(s,1H),6.82(d,J＝7.4Hz,1H),4.32(s,1H),3.78(s,1H),3.77(s,4H),3.75(s,1H),3.52(s,1H),3.40(s,1H),3.24-3.07(m,5H),2.87(s,4H),2.53(s,2H),1.61(s,4H). 13 C NMR(101MHz,Acetone)δ170.45,152.41,138.91,136.46,135.30,129.79,129.40,127.28,126.80,126.31,118.37,116.76,114.51,70.52,68.79,67.35,59.02,54.22,49.67.
Example 5
(4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -4-hydroxypiperidin-1-yl) (3-thiomorpholinophenyl) methanone
Compound I-5: the synthesis was as in example 1 except that the R group 3-oxetanamine was replaced by thiomorpholine, a pale yellow solid, yield 15.9%. 1 H NMR(400MHz,Acetone-d 6 )δ7.29-7.22(m,1H),7.12-7.06(m,3H),7.02-6.95(m,2H),6.94-6.90(m,1H),6.81-6.76(m,1H),4.31(s,1H),3.78(s,2H),3.60-3.55(m,4H),3.56-3.13(br,4H),2.91-2.85(m,4H),2.72-2.66(m,4H),2.54(s,2H),δ1.69-1.50(brs,4H). 13 C NMR(101MHz,Acetone)δ170.41,151.95,139.09,136.43,135.28,129.94,129.40,127.28,126.81,126.31,118.04,117.95,115.69,70.50,68.77,59.01,54.22,52.41,26.92.
Example 6
(3- (cyclohexylamino) phenyl) (4- (((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -4-hydroxypiperidin-1-yl) methanone
Compound I-6: the synthesis was as in example 1 except that the R group 3-oxetanamine was replaced with cyclohexylamine as a pale yellow solid in 15.5% yield. LC-MS (ESI) M/z 448.29(M + H) +
Example 7
(3- (cyclopentylamino) phenyl) (4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -4-hydroxypiperidin-1-yl) methanone
Compounds I to 7: the synthesis was as in example 1 except that the R group, 3-oxetane, was replaced with cyclopentylamine as a white solid in 12.7% yield. LC-MS (ESI) M/z 434.28(M + H) +
Example 8
(4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -4-hydroxypiperidin-1-yl) (3- (pyrrolidin-1-yl) phenyl) methanone
Compounds I to 8: the synthesis is as in example 1, except that the R group 3-oxetane is replaced by pyrrolidineWhite solid, yield 14%. LC-MS (ESI) M/z 422.24(M + H) +
Example 9
(3- (Cyclobutylamino) phenyl) (3- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -3-hydroxypiperidin-1-yl) methanone
A compound I-9: the synthesis was as in example 2 except that 4-piperidone was replaced by 3-piperidone in the synthesis of intermediate 2 in a yield of 12%. LC-MS (ESI) M/z 420.26(M + H) +
Example 10
(3- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -3-hydroxypiperidin-1-yl) (3- (oxetan-3-ylamino) phenyl) methanone
Compounds I-10: the synthesis was as in example 9 except that the R group cyclobutylamine was replaced with 3-oxetane as a white solid in 10% yield. LC-MS (ESI) M/z 422.24(M + H) +
Example 11
(3- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -3-hydroxypiperidin-1-yl) (3- (phenylamino) phenyl) methanone
Compounds I to 11: the synthesis was as in example 9 except that the R group cyclobutylamine was replaced with aniline, a pale yellow solid in 11% yield. LC-MS (ESI) M/z 442.24(M + H) +
Example 12
(3- (benzylamino) phenyl) (3- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -3-hydroxypiperidin-1-yl) methanone
Compounds I to 12: the synthesis was as in example 9 except that the R group cyclobutylamine was replaced with benzylamine and was a white solid in 10% yield. LC-MS (ESI) M/z 456.26(M + H) +
Example 13
(3- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -3-hydroxypiperidin-1-yl) (3- (((2-fluorophenyl) amino) phenyl) methanone
Compounds I to 13: the synthesis was as in example 9 except that the R group cyclobutylamine was replaced with 2-fluoroaniline as an oily liquid in 12% yield. LC-MS (ESI) M/z 460.24(M + H) +
Example 14
(3- (Cyclobutylamino) -4-methylphenyl) (4- (((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -4-hydroxypiperidin-1-yl) methanone
Compounds I to 14: the synthesis was as in example 1 except that 3-bromobenzoic acid was replaced by 3-bromo-4-methylbenzoic acid in the synthesis of intermediate 1 as a brown solid in 12% yield. LC-MS (ESI) M/z 434.28(M + H) +
Example 15
(4- (((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -4-hydroxypiperidin-1-yl) (4-methyl-3- (oxetan-3-ylamino) phenyl) methanone
Compounds I-15: the synthesis was as in example 14 except that the R group cyclobutylamine was replaced with 3-oxetane as a white solid in 12% yield. LC-MS (ESI) M/z 436.25(M + H) +
Example 16
(4- (((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -4-hydroxypiperidin-1-yl) (4-methyl-3- (phenylamino) phenyl) methanone
Compounds I-16: the synthesis was as in example 14 except that the R group cyclobutylamine was replaced with aniline, a yellow solid in 12% yield. LC-MS (ESI) M/z 456.26(M + H) +
Example 17
(4- (((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -4-hydroxypiperidin-1-yl) (3- ((2-fluorophenyl) amino) -4-methylphenyl) methanone
Compounds I-17: the synthesis was as in example 14 except that the R group cyclobutylamine was replaced by 2-fluoroaniline for the white solid in 12% yield. LC-MS (ESI) M/z 474.25(M + H) +
Example 18
(3- (benzylamino) -4-methylphenyl ] [4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -4-hydroxypiperidin-1-yl) methanone
Compounds I-18: the synthesis was as in example 14 except that the R group cyclobutylamine was replaced with benzylamine and was a white solid in 12% yield. LC-MS (ESI) M/z 474.28(M + H) +
Example 19
(3- (Cyclobutylamino) -4-methylphenyl) (3- (((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -3-hydroxypiperidin-1-yl) methanone
Compounds I-19: synthesis procedure as in example 14, 4-piperidone was replaced by 3-piperidone as a pale yellow solid in 12% yield LC-MS (ESI) M/z 434.28(M + H) +
Example 20
(3- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -3-hydroxypiperidin-1-yl) (4-methyl-3- (oxetan-3-ylamino) phenyl) methanone
Compounds I-20: the synthesis was as in example 19 except that the R group cyclobutylamine was replaced with 3-oxetane as a white solid in 12% yield. LC-MS (ESI) M/z 436.26(M + H) +
Example 21
(3- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -3-hydroxypiperidin-1-yl) (4-methyl-3- (phenylamino) phenyl) methanone
Compounds I to 21: the synthesis was as in example 19 except that the R group cyclobutylamine was replaced with aniline, a white solid in 12% yield. LC-MS (ESI) M/z 456.26(M + H) +
Example 22
(3- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -3-hydroxypiperidin-1-yl) (3- ((2-fluorophenyl) amino) -4-methylphenyl) methanone
Compounds I-22: the synthesis was as in example 19 except that the R group cyclobutylamine was replaced with 2-fluoroaniline as a pale yellow solid in 12% yield. LC-MS (ESI) M/z 474.25(M + H) +
Example 23
3- (benzylamino) -4-methylphenyl ] [3- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -3-hydroxypiperidin-1-yl) methanone
Compounds I-23: the synthesis is as in example 19 except that the R group cyclobutylamine is replaced by benzylamine and a brown solid. LC-MS (ESI) M/z 470.28(M + H) +
Example 24
(2- (Cyclobutylamino) pyridin-4-yl) (4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -4-hydroxypiperidin-1-yl) methanone
Compounds I-24: the synthesis was as in example 1 except that 3-bromobenzoic acid was replaced with 2-bromoisonicotinic acid in the synthesis of intermediate 1 as a yellow solid in 12% yield. LC-MS (ESI) M/z 421.26(M + H) +
Example 25
(4- (((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -4-hydroxypiperidin-1-yl) (2- (oxetan-3-ylamino) pyridin-4-yl) methanone
Compounds I-25: the synthesis was as in example 24 except that the R group cyclobutylamine was replaced with 3-oxetane as a brown solid in 12% yield. LC-MS (ESI) M/z 423.23(M + H) +
Example 26
(4- ((3, 4-dihydroisoquinolin-2 (1H) -yl) methyl) -4-hydroxypiperidin-1-yl) (2- (phenylamino) pyridin-4-yl) methanone
Compounds I-26: the synthesis was as in example 24 except that the R group cyclobutylamine was replaced with aniline, a white solid in 12% yield. LC-MS (ESI) M/z 443.24(M + H) +
Application example 1 evaluation of biological Activity
The inhibitory effect of the compounds of the invention on PRMT5 was tested by the radiometmethylation method
The test method comprises the following steps: 1 × Assay buffer was prepared. Compound concentration preparation: test compound concentrations were 10 μ M starting, 3-fold diluted 8 concentrations; the EPZ015938 test concentration was 1 μ M starting, 3-fold diluted 10 concentrations. Compounds and positive controls were diluted 100 x of the assay concentration in DMSO, then test compounds were diluted 3-fold for 8 concentrations, while positive control compounds were diluted 3-fold for 10 concentrations, then diluted 1 x reaction solution for 20-fold (in this case DMSO concentration of 5% by mass), and finally added to 5 μ L to 384-well reaction plates to assay, each compound being set up for single well assay. Transfer 5. mu.L of 5% DMSO in Max and Min wells. A1 Xreaction solution was used to prepare a 2.5 Xprotein solution. A1 Xreaction solution was used to prepare a 2.5 Xsubstrate mixed solution. mu.L of 2.5 Xprotein solution was added to each well, centrifuged at 1000rpm for 1min, and incubated at room temperature for 15 min. mu.L of a 2.5 Xsubstrate mix solution was added to each well of the reaction plate, centrifuged at 1000rpm for 1min, and incubated at room temperature for 60 min. Add 5. mu.L stop buffer, centrifuge at 1000rpm for 60 seconds, transfer all solutions to FlashPlate for 60 minutes incubation at room temperature. Read with MicroBeta 2.
And (3) data analysis, namely calculating the inhibition rate by using a formula:
an inactivation (%) (Signal _ max-Signal _ sample)/Signal _ max-Signal _ min × 100 quantitative effect curve is fitted, wherein the quantitative effect curve is fitted by using the log value of the concentration as an X axis and the percent Inhibition rate as a Y axis and using the log (inhibitor) of GraphPad Prism 5, which is the analysis software, so as to obtain the IC of the compound for inhibiting the enzyme activity 50 The value is obtained.
Through the above experiments, the inhibitory rate IC of partial compounds of the invention on the activity of PRMT5 enzyme is tested 50 The value is obtained. Wherein, + ++: < 1. mu.M; +++: 1-5 mu M; ++: 5-10 mu M; +:>10 μ M. Experiment ofThe results are shown in Table 1.
The experimental results show that: the partial compounds of the invention show good inhibitory activity to PRMT5 enzyme, and the individual compounds and the positive control compound EPZ015938 have similar inhibitory activity.
TABLE 1
Claims (6)
1. An arginine methyltransferase 5 small-molecule inhibitor is characterized in that the inhibitor is a compound shown as a general formula I or a pharmaceutically acceptable salt thereof:
in the formula:
the A ring is selected from one of the following substituents:
ring B is selected from one of the following substituents:
r is selected from one of the following substituents:
2. an arginine methyltransferase 5 small molecule inhibitor, which is characterized by being selected from the following compounds:
3. the small molecule inhibitor of arginine methyltransferase 5 of claim 2 selected from the group consisting of:
I-5，I-11，I-15，I-22。
4. use of the small molecule inhibitor of arginine methyltransferase 5 according to any of claims 1 to 3 for the preparation of a medicament for the prevention or treatment of a PRMT 5-mediated disease, for the preparation of a medicament for the prevention or treatment of cancer, myelodysplastic syndrome, neurodegenerative disease, or diabetes.
5. Use of the small molecule inhibitor of arginine methyltransferase 5 in the manufacture of a medicament for preventing or treating a PRMT 5-mediated disease, wherein the cancer is selected from colon cancer, rectal cancer, breast cancer, lung cancer, pancreatic cancer, cervical cancer, kidney cancer, stomach cancer, esophageal cancer, oral cancer, bone cancer, laryngeal cancer, thyroid cancer, gallbladder cancer, fallopian tube cancer, head and neck cancer, testicular cancer, bladder cancer, liver cancer, ovarian cancer, multiple myeloma, lymphoma, glioma, leukemia or melanoma.
6. A method of preparing the small molecule inhibitor of arginine methyltransferase 5 of claim 1, wherein the route when the B-ring is 4-hydroxypiperidine is as follows:
wherein the A ring and the R group are as defined in claim 1;
a) in a solvent, carboxylic acid compounds (II) are used as initial raw materials, a condensing agent is added, and acylation reaction is carried out on the carboxylic acid compounds (II) and 4-piperidone under the alkaline condition to generate amide compounds (III); the solvents used were: tetrahydrofuran, N-dimethylformamide, chloroform, dichloromethane or toluene; the condensing agent is T 3 P, EDC, EDCI, CDI or HATU; the used alkali is sodium bicarbonate, potassium carbonate, triethylamine or pyridine;
b) adding a sulfur ylide reagent into the amide compound (III) obtained in the step a) under the conditions of a solvent and alkalinity to react to obtain a compound (V) containing an epoxy group; the solvents used were: n, N-dimethylformamide, chloroform, tetrahydrofuran, dimethyl sulfoxide or toluene; the sulfur ylide reagent is trimethyl sulfur iodide or trimethyl sulfoxide iodide, and the used alkali is potassium tert-butoxide, sodium tert-butoxide or sodium hydride;
c) reacting the epoxy compound (V) obtained in the step b) with 1,2,3, 4-tetrahydroisoquinoline in a solvent under alkaline conditions to obtain a compound (VI); the solvent is tetrahydrofuran, N-dimethylformamide, methanol or ethanol; the base used is K 2 CO 3 、Na 2 CO 3 、Cs 2 CO 3 Or NaOH;
d) reacting the compound (VI) obtained in the step c) with amino compounds containing different R groups in the presence of a palladium catalyst in a solvent and under alkaline conditions to obtain a compound (I); the used solvent is dimethyl sulfoxide, tetrahydrofuran, N-dimethylformamide, chloroform, dichloromethane or toluene; the palladium catalyst is tetrakis (triphenylphosphine) palladium, palladium acetate, diphenylphosphine ferrocene palladium dichloride, dichlorobis (triphenylphosphine) palladium or palladium-carbon; the alkali is Na 2 CO 3 、K 2 CO 3 、Cs 2 CO 3 Potassium tert-butoxide or sodium tert-butoxide;
the other B ring substituted compounds were prepared as described above.
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| WO2000021959A1 (en) * | 1998-10-09 | 2000-04-20 | Janssen Pharmaceutica N.V. | 4,5-dihydro-isoxazole derivatives and their pharmaceutical use |
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| WO2014100695A1 (en) * | 2012-12-21 | 2014-06-26 | Epizyme, Inc. | Prmt5 inhibitors and uses thereof |
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