CN118221696A - Pyrimidine heterocyclic compound containing N-methylpiperazine structure, and preparation method and application thereof - Google Patents
Pyrimidine heterocyclic compound containing N-methylpiperazine structure, and preparation method and application thereof Download PDFInfo
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- CN118221696A CN118221696A CN202311818470.4A CN202311818470A CN118221696A CN 118221696 A CN118221696 A CN 118221696A CN 202311818470 A CN202311818470 A CN 202311818470A CN 118221696 A CN118221696 A CN 118221696A
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- CN
- China
- Prior art keywords
- acid
- methylpiperazine
- pharmaceutically acceptable
- heterocyclic compound
- egfr
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- -1 Pyrimidine heterocyclic compound Chemical class 0.000 title claims abstract description 83
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical group CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- 150000003839 salts Chemical class 0.000 claims abstract description 18
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- 206010028980 Neoplasm Diseases 0.000 claims abstract description 9
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 8
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims abstract 5
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims abstract 5
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims abstract 4
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 17
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
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- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
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- OGUWOLDNYOTRBO-UHFFFAOYSA-N 4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1NCCC2=C1C=CS2 OGUWOLDNYOTRBO-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
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Abstract
The invention discloses a pyrimidine heterocyclic compound containing an N-methylpiperazine structure, a preparation method and application thereof, belongs to the technical field of medicines, and particularly discloses a pyrimidine heterocyclic compound containing an N-methylpiperazine structure shown in a general formula I or pharmaceutically acceptable salt thereof, wherein the compound has a function of remarkably inhibiting at least one EGFR kinase mutant, particularly has a strong inhibition effect on EGFR L858R/T790M/C797S mutation closely related to drug resistance generation, and has better selectivity on EGFR WT, and the compound has a novel chemical structure, has high inhibition activity and selectivity on EGFR triple mutant kinase in vitro research, and can be used for treating and preventing various diseases such as cancers.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a novel pyrimidine heterocyclic compound containing an N-methylpiperazine structure, a preparation method thereof and application of the compound or pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the compound in preparation of medicines for treating diseases related to epidermal growth factor receptor kinase mutation.
Background
The Epidermal Growth Factor Receptor (EGFR), a transmembrane receptor expressed in many different cell types, belongs to the ErbB receptor family. It generally consists of an extracellular ligand binding moiety and an intracellular tyrosine kinase domain. When the ligand binds to EGFR, receptor dimerization is caused, leading to the mutual phosphorylation of tyrosine kinase regions, triggering intracellular signaling pathways, ultimately leading to cell proliferation, migration and survival.
The ligand binding portion of EGFR comprises three domains: ig-like domain (domain 1), cysteine-rich region (domain 2), and transmembrane region. The Ig-like domain recognizes an epitope of the ligand and binds to the ligand. The cysteine-rich region is involved in receptor dimerization and signal transduction. The transmembrane region then immobilizes the entire receptor on the cell membrane.
The intracellular portion of EGFR contains a tyrosine kinase region and a carboxy terminal tail. The mutual phosphorylation of tyrosine kinase domains is a key step in EGFR signaling. When the ligand binds to EGFR, receptor dimerization occurs, resulting in the mutual phosphorylation of the two tyrosine kinase regions, triggering intracellular signaling pathways. In addition, the carboxy terminal tail is also involved in regulating EGFR distribution and stability, as well as the intensity and specificity of signal transduction. EGFR plays an important role in embryo development and tissue repair under normal physiological conditions. During development, the expression levels of EGFR are highly regulated, with different expression patterns in different tissues and organs. For example, in the development of the nervous system, expression of EGFR has an important role in the proliferation, migration and differentiation of neurons. In skin, EGFR expression plays an important role in proliferation, differentiation and repair of skin cells. However, in many diseases, particularly cancers, overexpression or mutation of EGFR occurs, resulting in uncontrolled cell proliferation and survival, thereby promoting tumor development and progression. In cancer, overexpression or mutation of EGFR is often associated with poor prognosis and chemotherapy resistance. In addition, amplification and mutation of some EGFR genes have been associated with specific cancer types, such as non-small cell lung cancer, breast cancer, colorectal cancer, head and neck cancer, and the like. Currently, targeted therapies against EGFR have been widely used in clinical practice. Some representative drugs include EGFR inhibitors (e.g., gefitinib, erlotinib, and panitumumab) and EGFR monoclonal antibodies (e.g., cetuximab and trastuzumab). These agents are able to effectively inhibit the growth and survival of tumor cells and improve the survival prognosis of patients by inhibiting the function of EGFR or blocking its interaction with ligands.
EGFR inhibitors are a class of drugs that inhibit EGFR tyrosine kinase activity. They inhibit signal transduction and cell proliferation by binding to the tyrosine kinase domain of EGFR, preventing its phosphorylation.
In summary, EGFR plays an important role in normal physiology and disease occurrence, and targeted therapies directed against it have been widely used in clinical practice, and new therapeutic strategies directed against EGFR still need to be further explored and studied in the future to improve therapeutic efficacy and patient survival.
Currently researchers have developed the third generation EGFR-TKIs, but EGFR C797S mutation (cysteine CYS797 to serine SER 797) is the primary cause of patient resistance to the third generation covalent EGFR-TKIs. Of these, the representative compound is octreotide (Osimertinib, AZD 9291). However, in clinical practice of treatment of patients with T790M mutant non-small cell lung cancer with octenib, resistance inevitably occurs after 10-16 months of administration, including those in which C797S is mutated to the predominant resistance mechanism (i.e., the cysteine residue in the kinase activation region is mutated to serine), accounting for about 20-40%, leading to failure of AZD 9291. Because EGFR C797S tertiary mutant appears, the formation of a covalent bond between tyrosine kinase and a third-generation inhibitor is prevented, and the clinical treatment effect of EGFR T790M mutant patients is severely restricted. Thus, there is an urgent need to develop novel inhibitors that overcome the triple mutant of EGFR L858R /T790M/C797S.
Disclosure of Invention
The primary aim of the invention is to provide a novel pyrimidine heterocyclic compound containing an N-methylpiperazine structure as shown in a general formula I and a preparation method thereof. In addition, the application of the compound or pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the compound in preparing medicines for treating diseases related to EGFR kinase mutation is also provided.
Wherein,
X is selected from NH, CH 2、O、S、S(O)、S(O)2;
R 1 is selected from H, halogen, nitro, trifluoromethyl, halo (C1-C6) alkyl, preferably H or Cl;
r 2 is selected from H, (C1-C6) alkyl, (C1-C6) alkoxy, halogen;
R 3 is selected from H, (C1-C6) alkyl, (C1-C6) alkoxy, halogen, cyano, nitro, hydroxy, amino, 5-8 membered heteroaromatic amide substituted with 0-4 identical or different R 3a, optionally containing 1-2 heteroatoms selected from N, O and S in the heteroaromatic amide;
R 3a is selected from H, halogen, cyano, nitro, hydroxy, carboxy, amino, (C1-C6) alkyl, (C1-C6) alkoxy, halogen or amino or cyano or carboxy-substituted (C1-C6) alkyl, (C1-C6) alkylamino, di (C1-C6) alkylamino, (C1-C6) alkylcarbonyl, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfonylamino, (C1-C6) alkylamido;
y is CH or N;
R 4 is selected from H, (C1-C6) alkyl, 3-14 membered heterocycle containing 1-3N, O and/or S heteroatoms and substituted with 1-3 identical or different R 5;
r 5 is selected from H, halogen, cyano, nitro, hydroxy, carboxy, amino, (C1-C6) alkyl, halogen or amino or cyano or carboxy substituted (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkylamino, di (C1-C6) alkylamino, (C1-C6) alkylcarbonyl, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfonylamino, (C1-C6) alkylamido, (C2-C6) alkenyl, halo (C2-C6) alkenyl, alkylamino substituted (C2-C6) alkenyl;
a is a six-membered heterocycloaromatic or aromatic-heterocyclic substituted amino or aromatic-ring heterocycloaromatic substituted amino containing 1-3N, O and/or S, and A is optionally substituted with 1-3 identical or different R 6;
r 6 is H, halogen, hydroxy, amino, cyano, trifluoromethyl, trifluoromethoxy, (C1-C6) alkyl, (C1-C6) alkoxy.
Further, in the general formula I,
X is selected from NH, CH 2 and O;
r 2 is selected from H, (C1-C6) alkoxy, halogen;
R 3 is selected from H, (C1-C3) alkoxy, halogen, 5-6 membered heteroaromatic amide substituted with 0-2 identical or different R 3a, wherein the heteroaromatic ring in the heteroaromatic amide optionally contains 1-2 heteroatoms selected from N, O and S;
R 3a is selected from H, halogen, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, halo (C1-C6) alkyl, hydroxy-substituted (C1-C6) alkyl;
R 4 is selected from H, (C1-C3) alkyl, 5-8 membered heterocycle containing 1-3N, O and/or S heteroatoms and substituted with 1-3 identical or different R 5;
R 5 is selected from H, halogen, (C1-C6) alkyl, halo (C1-C6) alkyl, hydroxy-substituted (C1-C6) alkyl, (C1-C6) alkylamino, di (C1-C6) alkylamino, (C1-C6) alkoxy;
A is an amino group substituted by a six-membered heterocyclo five-membered aromatic heterocycle or six-membered heterocyclo aromatic ring or aromatic heterocycle containing 1 to 3N, O and/or S or an amino group substituted by an aromatic ring five-membered ring, and A is optionally substituted by 1 to 3 identical or different R 6;
r 6 is H, trifluoromethyl, trifluoromethoxy, (C1-C6) alkyl, (C1-C6) alkoxy.
Still further, in the general formula I,
X is NH or O;
r 2 is selected from H, methoxy, cl;
R 3 is selected from H, methoxy, halogen, 5-6 membered heteroaromatic amide substituted with 1 independent R 3a, wherein the heteroaromatic ring in the heteroaromatic amide optionally contains 1-2N atoms;
R 3a is selected from H, halogen, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy;
R 4 is selected from H, methyl, 6-7 membered heterocyclic ring containing 1-3N atoms and substituted by 1-3 identical or different R 5;
R 5 is H or (C1-C6) alkyl;
A is an amino group substituted by a six-membered heterocyclo five-membered aromatic heterocycle or a six-membered heterocyclo benzene ring or pyrazole containing 1 to 3N, O or S or an amino group substituted by an aromatic five-membered ring, and A is optionally substituted by 1 to 3 identical or different R 6;
R 6 is H or methyl.
Still further, in the general formula I,
X is NH;
r 3 is selected from H, methoxy, cl, br and the following structure
R 4 is selected from H, methyl and the following structures:
A is selected from 4,5,6, 7-tetrahydrothieno [3,2-c ] pyridine, 1,2,3, 4-tetrahydroisoquinoline, 1-methyl-1H-pyrazol-4-amine, 2, 3-dihydro-1H-inden-5-amine;
Further, the pyrimidine heterocyclic compound containing the N-methylpiperazine structure or pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the compound, wherein the pyrimidine heterocyclic compound containing the N-methylpiperazine structure is any one of the following compounds I-1 to I-32:
The pharmaceutically acceptable salts comprise addition salts formed by inorganic acid and organic acid and the pyrimidine heterocyclic compound containing the N-methylpiperazine structure, wherein the inorganic acid and the organic acid comprise: hydrochloric acid, hydrogen olfactory acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, tea disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid.
"Halogen" in the present invention means fluorine, chlorine, bromine or iodine; "alkyl" refers to a straight or branched chain alkyl group; "heterocyclyl" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S.
The pyrimidine heterocyclic compound with the N-methylpiperazine structure shown in the general formula I or pharmaceutically acceptable salt thereof is taken as an active ingredient, is mixed with a pharmaceutically acceptable excipient to prepare a composition, and is prepared into a clinically acceptable dosage form, wherein the excipient refers to a diluent, an auxiliary agent or a carrier which can be used in the pharmaceutical field. The preparation comprises injection, tablet, capsule, aerosol, suppository, membrane, dripping pill, external liniment and ointment which are commonly used in clinic.
The pyrimidine heterocyclic compound containing the N-methylpiperazine structure has the function of obviously inhibiting at least one EGFR kinase mutant, particularly has a strong inhibition effect on EGFR L858R/T790M/C797S mutation closely related to drug resistance generation, and has better selectivity on EGFR WT, which is in clear contrast with the first-generation and second-generation inhibitors in the current research and development.
The pyrimidine heterocyclic compound containing the N-methylpiperazine structure or the pharmaceutical composition containing the same is particularly applied to preparation of medicines for inhibiting EGFR mutants, wherein the EGFR mutants are one or more of T790M, L858R, L R/T790M, L858R/T790M/C797S.
The invention relates to an application of pyrimidine heterocyclic compound containing an N-methylpiperazine structure or a pharmaceutical composition containing the same in preparation of a drug for treating cancer, wherein the cancer is preferably non-small cell lung cancer.
The following synthetic schemes (schemes 1, 2) describe the preparation of pyrimidine heterocycles containing N-methylpiperazine structures according to the invention as shown in formula I.
The synthetic route of the invention comprises the following steps:
synthetic route 1:
synthetic route 2:
Wherein Y, R 1、R2、R3、R4 and A are corresponding groups at corresponding positions of the compound.
The invention has the beneficial effects that:
The compound has a novel chemical structure, has high inhibition activity and selectivity on EGFR three-mutation kinase in vitro research, and can be used for treating and preventing various diseases such as cancers.
Detailed Description
In the examples which follow, methods for preparing a portion of the compounds of formula I are provided. It will be appreciated that the following methods, as well as other methods known to those of ordinary skill in the art, may be applicable to the preparation of all compounds described herein. The examples are intended to illustrate, but not limit the scope of the invention.
Example 1: 5-chloro-4- (6, 7-dihydrothieno [3,2-c ] pyridin-5 (4H) -yl) -N- (2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) pyrimidin-2-amine (I-1) prepared by the method of scheme 1.
Step 1:5- (2, 5-dichloropyrimidin-4-yl) -4,5,6, 7-tetrahydrothieno [3,2-c ] pyridine (intermediate B 1)
Potassium carbonate (23.3 g,169 mmol) and 4,5,6, 7-tetrahydrothiophene [3,2, c ] pyridine hydrochloride (14.2 g,81.0 mmol) were added to ethanol and water (100 mL) in a volume ratio of 3:1, followed by 2,4, 5-trichloropyrimidine (12.3 g,67.5 mmol). The reaction was carried out at room temperature for 6 hours. After the reaction was completed, the solvent was distilled off, and water was added to the residue to precipitate a solid, which was suction-filtered, and the cake was dried to give 16.1g of a yellow solid, yield 83.6%.
Step 2:1- (1- (3-methoxy-4-nitrophenyl) piperidin-4-yl) -4-methylpiperazine (intermediate D 1)
4-Fluoro-2-methoxy-1-nitrobenzene (6.85 g,40.0 mmol), 1-methyl-4- (piperidin-4-yl) piperazine (11.0 g,60.0 mmol) and potassium carbonate (6.62 g,48.0 mmol) were added to N, N-dimethylformamide (50 mL), and the reaction stirred at room temperature for 10 hours. After the reaction was completed, water was added thereto, extraction with methylene chloride was performed, and the solvent was distilled off to obtain 10.1g of a yellow solid, with a yield of 75.6%.
Step 3: 2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline (intermediate E 1)
Intermediate D 1 (16.7 g,50.0 mmol) and palladium on carbon (1.60 g) were added to a volume ratio of 1:1 dichloromethane to methanol (200 mL) and reacted in a hydrogen system at room temperature for 12 hours. After the reaction, the reaction mixture was filtered through celite, and the cake was washed with methanol, and the filtrate was evaporated to dryness to give 12.4g of a blackish brown solid with a yield of 81.3%.
Step 4: 5-chloro-4- (6, 7-dihydrothieno [3,2-c ] pyridin-5 (4H) -yl) -N- (2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) pyrimidin-2-amine (I-1)
Intermediate E 1 (12.2 g,40.0 mmol), 5- (2, 5-dichloropyrimidin-4-yl) -4,5,6, 7-tetrahydrothieno [3,2-c ] pyridine (intermediate B 1) (17.1 g,60.0 mmol), p-toluenesulfonic acid (3.44 g,20.0 mmol) were added to isopropanol (100 mL), and the reaction was warmed to 80℃and stirred for 10 hours. After the reaction is finished, filtering while the mixture is hot, washing a filter cake with cold ethanol, drying, filtering, and evaporating under reduced pressure to obtain a crude product. The crude product was purified by silica gel column using dichloromethane/methanol (20:1) as eluent to give 14.5g of yellow solid in 65.3% yield.
MS(ESI)m/z(%):554.2[M+H]+;1H NMR(400MHz,CDCl3)δ8.14(d,J=8.6Hz,1H),8.00
(s,1H),7.31(s,1H),7.29(s,1H),7.14(d,J=4.8Hz,1H),6.84(d,J=4.9Hz,1H),6.56(d,J=7.0Hz,2H),4.74(s,2H),3.98(t,J=5.0Hz,2H),3.87(s,3H),3.66(d,J=11.6Hz,2H),3.07(s,2H),2.70(t,J=11.3Hz,6H),2.47(dd,J=41.4,30.2Hz,5H),2.35(s,3H),2.02–1.93(m,2H),1.74(t,J=11.1Hz,2H).
According to the synthesis method of example 1, D 1 is prepared from 4-fluoronitrobenzene with different substitutions through substitution reaction, and then the compounds I-2 to I-6 of examples 2 to 6 are obtained through reduction and substitution reaction.
Example 2: 5-chloro-4- (6, 7-dihydrothieno [3,2-c ] pyridin-5 (4H) -yl) -N- (3-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) pyrimidin-2-amine (I-2)
ESI-MS m/z:554.2[M+H]+;1H NMR(400MHz,CDCl3)δ8.00(s,1H),7.26(s,1H),7.11(dd,J=22.1,5.5Hz,2H),6.96(d,J=8.4Hz,1H),6.89(d,J=8.4Hz,1H),6.79(d,J=4.8Hz,1H),4.73(s,2H),3.97(t,J=4.6Hz,2H),3.90(s,3H),3.50(d,J=10.9Hz,2H),3.05(s,2H),2.73(s,4H),2.63–2.44(m,7H),2.34(s,3H),1.86(dt,J=34.0,11.4Hz,4H).
Example 3: 5-chloro-N- (2-chloro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -4- (6, 7-dihydrothieno [3,2-c ] pyridin-5 (4H) -yl) pyrimidin-2-amine (I-3)
MS(ESI)m/z(%):558.2[M+H]+.
Example 4: 5-chloro-N- (3-chloro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -4- (6, 7-dihydrothieno [3,2-c ] pyridin-5 (4H) -yl) pyrimidin-2-amine (I-4)
MS(ESI)m/z(%):558.2[M+H]+;1H NMR(400MHz,CDCl3)δ7.99(s,1H),7.93(s,1H),7.25–7.08(m,3H),6.98(d,J=8.6Hz,1H),6.84(d,J=4.8Hz,1H),4.76(s,2H),4.00(t,J=4.7Hz,2H),3.40(d,J=10.9Hz,2H),3.07(s,2H),2.64(dd,J=20.7,8.6Hz,6H),2.42(dd,J=35.6,24.5Hz,5H),2.31(s,3H),1.93(d,J=11.6Hz,2H),1.78(q,J=11.3Hz,2H).
Example 5: 5-chloro-4- (6, 7-dihydrothieno [3,2-c ] pyridin-5 (4H) -yl) -N- (4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) pyrimidin-2-amine (I-5)
MS(ESI)m/z(%):524.2[M+H]+;1H NMR(400MHz,CDCl3)δ7.97(s,1H),7.39(d,J=8.1
Hz,2H),7.10(t,J=16.6Hz,2H),6.92(d,J=8.1Hz,2H),6.82(d,J=4.9Hz,1H),4.71(s,2H),3.96(t,J=4.7Hz,2H),3.67(d,J=11.6Hz,2H),3.03(s,2H),2.72–2.63(m,5H),2.55–2.29(m,9H),1.94(d,J=12.0Hz,2H),1.70(q,J=11.2Hz,2H).
Example 6: n- (5-bromo-2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -5-chloro-4- (6, 7-dihydrothieno [3,2-c ] pyridin-5 (4H) -yl) pyrimidin-2-amine (I-6)
MS(ESI)m/z(%):632.2[M+H]+.1H NMR(400MHz,CDCl3)δ8.63(d,J=82.7Hz,1H),
7.98(s,1H),7.38(s,1H),7.12(d,J=4.5Hz,1H),6.87(d,J=4.9Hz,1H),6.60(d,J=6.3Hz,1H),4.78(s,2H),4.01(s,2H),3.86(s,3H),3.46–3.33(m,2H),3.10(s,2H),2.81–2.46(m,11H),2.37(d,J=28.6Hz,3H),2.05–1.77(m,4H).
According to the synthetic method of example 1,2, 4, 5-trichloropyrimidine and 1,2,3,4 tetrahydroisoquinoline undergo substitution reaction to generate an intermediate B 1, 4-fluoronitrobenzene with different substitutions is subjected to substitution reaction to prepare an intermediate E 1, and the intermediate B 1 and E 1 undergo substitution reaction to obtain the compounds I-7 to I-12 of examples 7 to 12.
Example 7: 5-chloro-4- (3, 4-dihydroisoquinolin-2 (1H) -yl) -N- (2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) pyrimidin-2-amine (I-7)
MS(ESI)m/z(%):548.3[M+H]+;1H NMR(400MHz,CDCl3)δ8.17(d,J=8.5Hz,1H),7.98
(s,1H),7.29(s,1H),7.18(d,J=4.5Hz,4H),6.56(d,J=8.1Hz,2H),4.83(s,2H),3.96(t,J=5.3Hz,2H),3.87(s,3H),3.66(d,J=11.6Hz,2H),3.03(t,J=5.1Hz,2H),2.76–2.61(m,6H),2.52(s,2H),2.39(t,J=11.4Hz,1H),2.31(s,3H),2.27–2.09(m,2H),1.96(d,J=11.9Hz,2H),1.72(q,J=10.7Hz,2H).
Example 8: 5-chloro-4- (3, 4-dihydroisoquinolin-2 (1H) -yl) -N- (3-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) pyrimidin-2-amine (I-8)
MS(ESI)m/z(%):548.3[M+H]+;1H NMR(400MHz,CDCl3)δ7.99(s,1H),7.28(s,1H),7.19(d,J=5.1Hz,3H),7.12(d,J=2.7Hz,1H),6.96(t,J=9.0Hz,2H),6.90(d,J=8.4Hz,1H),4.83(s,2H),3.97–3.90(m,5H),3.51(d,J=11.0Hz,2H),3.03(t,J=5.3Hz,2H),2.69(s,4H),2.55(dd,J=21.3,9.7Hz,4H),2.31(s,3H),1.94–1.79(m,7H).
Example 9: 5-chloro-N- (2-chloro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -4- (3, 4-dihydroisoquinolin-2 (1H) -yl) pyrimidin-2-amine (I-9)
MS(ESI)m/z(%):552.2[M+H]+.
Example 10: 5-chloro-N- (3-chloro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -4- (3, 4-dihydroisoquinolin-2 (1H) -yl) pyrimidin-2-amine (I-10)
MS(ESI)m/z(%):552.2[M+H]+.1H NMR(400MHz,CDCl3)δ7.97(s,2H),7.53(s,1H),7.19(t,J=27.3Hz,5H),6.97(d,J=8.6Hz,1H),4.85(s,2H),3.97(d,J=5.2Hz,2H),3.41(s,2H),3.04(d,J=4.7Hz,2H),2.60(dd,J=38.3,26.6Hz,10H),2.42–2.28(m,4H),1.98–1.75(m,4H).
Example 11: 5-chloro-4- (3, 4-dihydroisoquinolin-2 (1H) -yl) -N- (4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) pyrimidin-2-amine (I-11)
MS(ESI)m/z(%):518.3[M+H]+;1H NMR(400MHz,CDCl3)δ7.97(s,1H),7.41(d,J=8.2
Hz,2H),7.21–7.13(m,4H),6.95(t,J=18.2Hz,3H),4.81(s,2H),3.95(t,J=5.4Hz,2H),3.67(d,J=11.8Hz,2H),3.02(t,J=5.2Hz,2H),2.74–2.61(m,6H),2.54–2.30(m,8H),1.95(d,J=12.0Hz,2H),1.71(q,J=10.8Hz,2H).
Example 12: n- (5-bromo-2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -5-chloro-4- (3, 4-dihydroisoquinolin-2 (1H) -yl) pyrimidin-2-amine (I-12)
MS(ESI)m/z(%):626.2[M+H]+.1H NMR(400MHz,CDCl3)δ8.17(d,J=8.5Hz,1H),7.98
(s,1H),7.30(s,1H),7.17(d,J=3.8Hz,3H),6.56(d,J=7.6Hz,1H),4.83(s,2H),4.04–3.85(m,5H),3.66(d,J=10.4Hz,2H),3.03(d,J=4.7Hz,2H),2.80–2.49(m,10H),2.40(dd,J=26.2,14.3Hz,4H),1.96(d,J=11.3Hz,2H),1.73(dd,J=21.4,10.3Hz,2H).
According to the synthetic method of example 1,2, 4, 5-trichloropyrimidine and 1-methyl-1H-pyrazol-4-amine undergo substitution reaction to generate an intermediate B 1, 4-fluoronitrobenzene with different substitutions is subjected to substitution reaction to prepare an intermediate E 1, and the intermediate B 1 and E 1 undergo substitution reaction to obtain the compounds I-13-I-18 of examples 13-18.
Example 13: 5-chloro-N 2 - (2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -N 4 - (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (I-13)
MS(ESI)m/z(%):512.3[M+H]+.1H NMR(400MHz,CDCl3)δ7.90(d,J=8.1Hz,2H),7.79
(s,1H),7.50(s,1H),7.13(s,1H),6.89(s,1H),6.57–6.49(m,2H),3.85(s,6H),3.66(d,J=11.4Hz,2H),2.73–2.61(m,6H),2.40(dd,J=37.1,27.0Hz,5H),2.30(s,3H),1.95(d,J=11.7Hz,2H),1.69(dd,J=23.0,11.4Hz,2H).
Example 14: 5-chloro-N 2 - (3-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -N 4 - (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (I-14)
MS(ESI)m/z(%):512.3[M+H]+;1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.79(s,1H),7.47(s,1H),7.34(s,1H),7.05(s,1H),6.97(d,J=8.4Hz,1H),6.89(d,J=9.1Hz,2H),3.81(s,3H),3.77(s,3H),3.50(d,J=10.9Hz,2H),2.66(s,3H),2.59–2.40(m,8H),2.30(s,3H),1.90(d,J=11.6Hz,2H),1.79(dd,J=22.7,11.2Hz,2H).
Example 15: 5-chloro-N 2 - (2-chloro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -N 4 - (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (I-15)
MS(ESI)m/z(%):516.2[M+H]+.
Example 16: 5-chloro-N 2 - (3-chloro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -N 4 - (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (I-16)
MS(ESI)m/z(%):516.2[M+H]+.1H NMR(400MHz,CDCl3)δ7.97(s,1H),7.80(s,1H),7.70(d,J=2.2Hz,1H),7.57(s,1H),7.47(s,1H),7.17(d,J=8.4Hz,1H),7.13–6.92(m,2H),3.86(s,3H),3.39(d,J=9.8Hz,2H),2.78–2.46(m,10H),2.44–2.29(m,4H),1.93(d,J=10.8Hz,2H),1.86–1.68(m,2H).
Example 17: 5-chloro-N 4 - (1-methyl-1H-pyrazol-4-yl) -N 2 - (4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) pyrimidine-2, 4-diamine (I-17)
MS(ESI)m/z(%):482.3[M+H]+;1H NMR(400MHz,CDCl3)δ7.96(s,1H),7.73(s,1H),7.46(s,1H),7.33(d,J=7.9Hz,2H),6.93(d,J=7.9Hz,3H),6.84(s,1H),3.81(s,3H),3.69(d,J=11.7Hz,2H),2.73–2.63(m,5H),2.40(dd,J=38.1,26.7Hz,5H),2.30(s,3H),1.96(d,J=11.5Hz,3H),1.68(q,J=11.1Hz,2H).
Example 18: n 2 - (5-bromo-2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -5-chloro-N 4 - (1-methyl-1H-pyrazol-4-yl) pyrimidine-2, 4-diamine (I-18)
MS(ESI)m/z(%):590.2[M+H]+.1H NMR(400MHz,CDCl3)δ8.03–7.90(m,2H),7.80(s,1H),7.52(s,1H),7.12(s,1H),6.83(s,1H),6.57–6.50(m,1H),3.86(d,J=7.6Hz,6H),3.66(d,J=11.1Hz,2H),2.87–2.61(m,11H),2.42(d,J=19.7Hz,3H),2.04–1.95(m,2H),1.79–1.69(m,2H).
According to the synthesis method of example 1, 2,4, 5-trichloropyrimidine and 2, 3-dihydro-1H indene-5-amine undergo substitution reaction to generate an intermediate B 1, 4-fluoronitrobenzene with different substitutions is subjected to substitution reaction to prepare an intermediate E 1, and the intermediate B 1 and E 1 undergo substitution reaction to obtain the compounds I-19-I-24 of examples 19-24.
Example 19: 5-chloro-N 4 - (2, 3-dihydro-1H-inden-5-yl) -N 2 - (2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) pyrimidine-2, 4-diamine (I-19)
MS(ESI)m/z(%):548.3[M+H]+;1H NMR(400MHz,CDCl3)δ8.06(d,J=8.7Hz,1H),8.01
(s,1H),7.52(s,1H),7.29(s,1H),7.20(d,J=8.0Hz,1H),6.98(s,1H),6.53(s,1H),6.43(d,J=8.7Hz,1H),3.84(s,3H),3.63(d,J=11.8Hz,2H),2.92(t,J=7.3Hz,4H),2.74–2.48(m,10H),2.44–2.37(m,1H),2.34(s,3H),2.14–2.10(m,2H),1.96(d,J=11.8Hz,2H),1.72(d,J=11.4Hz,2H).
Example 20: 5-chloro-N 4 - (2, 3-dihydro-1H-inden-5-yl) -N 2 - (3-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) pyrimidine-2, 4-diamine (I-20)
MS(ESI)m/z(%):548.3[M+H]+;1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.47(s,1H),7.26(s,1H),7.17(d,J=8.0Hz,1H),7.09(s,1H),6.98(d,J=8.3Hz,3H),6.84(d,J=8.4Hz,1H),3.67(s,3H),3.48(d,J=11.0Hz,2H),2.89(q,J=7.0Hz,4H),2.68(s,3H),2.57–2.39(m,6H),2.31(s,3H),2.18–2.05(m,4H),1.83(dt,J=34.9,11.7Hz,4H).
Example 21: 5-chloro-N 2 - (2-chloro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -N 4 - (2, 3-dihydro-1H-inden-5-yl) pyrimidine-2, 4-diamine (I-21)
MS(ESI)m/z(%):552.2[M+H]+.
Example 22: 5-chloro-N 2 - (3-chloro-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -N 4 - (2, 3-dihydro-1H-inden-5-yl) pyrimidine-2, 4-diamine (I-22)
MS(ESI)m/z(%):552.2[M+H]+;1H NMR(400MHz,CDCl3)δ8.01(s,1H),7.62(s,1H),7.40(s,1H),7.27(dd,J=10.1,6.8Hz,2H),7.23(s,1H),7.01(s,2H),6.92(d,J=8.6Hz,1H),3.37(d,J=10.9Hz,2H),2.91(t,J=7.3Hz,4H),2.71–2.47(m,9H),2.42–2.35(m,1H),2.31(s,3H),2.10(dt,J=14.6,7.3Hz,3H),1.92(d,J=11.7Hz,2H),1.77(q,J=11.3Hz,2H).
Example 23: 5-chloro-N 4 - (2, 3-dihydro-1H-inden-5-yl) -N 2 - (4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) pyrimidine-2, 4-diamine (I-23)
MS(ESI)m/z(%):518.3[M+H]+.1H NMR(400MHz,CDCl3)δ7.99(s,1H),7.51(s,1H),7.36(d,J=8.1Hz,2H),7.25(d,J=9.6Hz,1H),7.17(d,J=8.0Hz,1H),6.97(d,J=14.0Hz,2H),6.87(d,J=8.1Hz,2H),3.65(d,J=11.8Hz,2H),2.90(t,J=7.3Hz,4H),2.67(t,J=11.5Hz,6H),2.55–2.29(m,8H),2.14–2.05(m,2H),1.94(d,J=11.9Hz,2H),1.69(q,J=11.2Hz,2H).
Example 24: n 2 - (5-bromo-2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) -5-chloro-N 4 - (2, 3-dihydro-1H-inden-5-yl) pyrimidine-2, 4-diamine (I-24)
MS(ESI)m/z(%):626.2[M+H]+.1H NMR(400MHz,CDCl3)δ8.21–7.98(m,2H),7.51(s,1H),7.34–7.18(m,2H),6.99(s,1H),6.69–6.38(m,2H),3.84(s,3H),3.63(d,J=10.5Hz,2H),2.93(d,J=6.4Hz,5H),2.86–2.53(m,10H),2.41(d,J=25.7Hz,3H),2.18–1.92(m,4H),1.84–1.66(m,2H).
Example 25: 6-chloro-N- (5- ((5-chloro-4- (4, 7-dihydrothieno [2,3-c ] pyridin-6 (5H) -yl) pyrimidin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) nicotinamide prepared by the method of scheme 2.
Step 1:5- (2, 5-dichloropyrimidin-4-yl) -4,5,6, 7-tetrahydrothieno [3,2-c ] pyridine (intermediate B 2)
Potassium carbonate (23.3 g,169 mmol) and 4,5,6, 7-tetrahydrothiophene [3,2, c ] pyridine hydrochloride (14.2 g,81.0 mmol) were added to 3:1 ethanol and water (100 mL), followed by 2,4, 5-trichloropyrimidine (12.3 g,67.5 mmol). The reaction was carried out at room temperature for 6 hours. After the reaction was completed, the solvent was distilled off, and water was added to the residue to precipitate a solid, which was suction-filtered, and the cake was dried to give 16.1g of a yellow solid, yield 83.6%.
Step 2: 5-chloro-4- (4, 7-dihydrothieno [2,3-C ] pyridin-6 (5H) -yl) -N- (4-fluoro-2-methoxy-5-nitrophenyl) pyrimidin-2-amine (intermediate C 2)
5- (2, 5-Dichloropyrimidin-4-yl) -4,5,6, 7-tetrahydrothieno [3,2-c ] pyridine (1.00 g,3.50 mmol) and p-toluenesulfonic acid (1.00 g,5.26 mmol) were added to absolute ethanol (10 mL) followed by 4-fluoro-2-methoxy-5-nitroaniline (0.60 g,3.23 mmol). The reaction was carried out at 100℃for 6 hours. After the reaction, the mixture was filtered while hot, and the filter cake was dried to obtain 1.20g of a yellow solid with a yield of 79.0%.
Step 3: 5-chloro-4- (4, 7-dihydrothieno [2,3-c ] pyridin-6 (5H) -yl) -N- (2-methoxy-4- (4-methylpiperazin-1-yl) -5-nitrophenyl) pyrimidin-2-amine (intermediate D 2)
Intermediate C 2 (1.50 g,3.45 mmol), N-methylpiperazine (0.69 g,3.71 mmol), potassium carbonate (0.95 g,6.88 mmol) was added to N, N-dimethylformamide (10 mL) and reacted at 70℃for 5 hours. After the reaction was completed, water was added thereto, extraction with methylene chloride was performed, and after drying and solvent was distilled off, 1.60g of a yellow solid was obtained, and the yield was 90.0%.
Step 4: n 1 - (5-chloro-4- (4, 7-dihydrothieno [2,3-c ] pyridin-6 (5H) -yl) pyrimidin-2-yl) -6-methoxy-4- (4-methylpiperazin-1-yl) benzene-1, 3-diamine (intermediate E 2)
Intermediate D 2 (1.60 g,3.10 mmol), iron powder (1.04 g,18.6 mmol) and ammonium chloride (0.33 g,6.17 mmol) were added to methanol (10 mL) and reacted at 70℃for 12 hours. After the reaction was completed, the reaction solution was filtered through celite, and the cake was washed with methanol, and the filtrate was evaporated to dryness to give 1.25g of brown solid with a yield of 83.3%.
Step 5: 6-chloro-N- (5- ((5-chloro-4- (6, 7-dihydrothieno [3,2-c ] pyridin-5 (4H) -yl) pyrimidin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) nicotinamide (I-25)
6-Chloronicotinic acid (0.06 g,0.39 mmol), EDCI (0.09 g,0.47 mmol) and HOBT (0.11 g,0.81 mmol) were added to N, N-dimethylformamide (5 mL), and the reaction was stirred at room temperature for thirty minutes, followed by addition of intermediate E 2 (0.20 g,0.41 mmol) and reaction at room temperature for 6 hours. After the reaction is finished, water is added, dichloromethane extraction is carried out, drying is carried out, and the solvent is distilled off, thus obtaining crude product. The crude product was purified by silica gel column using methylene chloride/methanol (15:1) as eluent to give 0.058g of pale yellow solid in 22.9% yield.
ESI-MS m/z:647.2[M+Na]+;1H NMR(400MHz,CDCl3)δ9.62(s,1H),9.50(s,1H),8.61(d,J=4.9Hz,1H),8.04(s,1H),7.84(s,1H),7.70(d,J=4.7Hz,1H),7.59(s,1H),7.11(d,J=4.9Hz,1H),6.92(d,J=4.9Hz,1H),6.84(s,1H),4.91(s,2H),4.05(t,J=4.7Hz,2H),3.88(s,3H),3.08(s,2H),2.96(s,4H),2.66(s,4H),2.43(s,3H).
According to the synthesis of example 25, intermediate E 2 is acylated with various substituted carboxylic acids to give compounds I-26 to I-32 of examples 26 to 32.
Example 26: n- (5- ((5-chloro-4- (4, 7-dihydrothieno [2,3-c ] pyridin-6 (5H) -yl) pyrimidin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) pyrimidine-4-carboxamide
ESI-MS m/z:592.2[M+H]+;1H NMR(400MHz,CDCl3)δ11.06(s,1H),9.53(s,1H),9.36(s,1H),9.03(d,J=4.7Hz,1H),8.22(d,J=4.7Hz,1H),8.04(s,1H),7.56(s,1H),7.10(d,J=4.9Hz,1H),6.94(d,J=4.9Hz,1H),6.81(s,1H),4.92(s,2H),4.05(t,J=4.7Hz,2H),3.89(s,3H),3.15–3.04(m,3H),2.99(s,4H),2.72(d,J=15.7Hz,4H),2.45(s,3H).
Example 27: n- (5- ((5-chloro-4- (4, 7-dihydrothieno [2,3-c ] pyridin-6 (5H) -yl) pyrimidin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) pyrazine-2-carboxamide
ESI-MS m/z:592.2[M+H]+;1H NMR(400MHz,CDCl3)δ10.86(s,1H),9.53(d,J=7.5Hz,
2H),8.81(s,1H),8.65(s,1H),8.05(s,1H),7.56(s,1H),7.12(d,J=5.0Hz,1H),6.99(d,J=5.1Hz,1H),6.81(s,1H),4.95(s,2H),4.06(t,J=4.5Hz,2H),3.89(s,3H),3.09(s,2H),2.99(s,4H),2.73(s,4H),2.45(s,3H).
Example 28: n- (5- ((5-chloro-4- (4, 7-dihydrothieno [2,3-c ] pyridin-6 (5H) -yl) pyrimidin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) pyrimidine-2-carboxamide
ESI-MS m/z:592.2[M+H]+;1H NMR(400MHz,CDCl3)δ11.05(s,1H),9.59(s,1H),8.97(d,J=3.0Hz,2H),8.02(s,1H),7.51(d,J=25.1Hz,2H),7.17–7.04(m,2H),6.79(s,1H),4.92(s,2H),4.07(s,2H),3.87(s,3H),3.02(d,J=26.4Hz,6H),2.71(s,4H),2.42(s,3H).
Example 29: n- (5- ((5-chloro-4- (4, 7-dihydrothieno [2,3-c ] pyridin-6 (5H) -yl) pyrimidin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) isonicotinamide
ESI-MS m/z:591.2[M+H]+;1H NMR(400MHz,CDCl3)δ9.44(d,J=6.5Hz,2H),8.76(d,J
=3.4Hz,1H),7.95(s,1H),7.70(d,J=3.7Hz,1H),7.51(s,1H),7.04–6.74(m,2H),4.83(s,1H),3.88(d,J=66.5Hz,3H),2.93(d,J=39.3Hz,3H),2.46(d,J=92.8Hz,3H).
Example 30: n- (5- ((5-chloro-4- (4, 7-dihydrothieno [2,3-c ] pyridin-6 (5H) -yl) pyrimidin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) -5-hydroxynicotinamide
ESI-MS m/z:607.2[M+H]+;1H NMR(400MHz,CDCl3)δ9.48(s,1H),9.39(s,1H),8.04(s,1H),7.60–7.52(m,2H),7.10(d,J=4.9Hz,1H),7.02(s,1H),6.94(d,J=4.9Hz,1H),6.86–6.77(m,2H),4.90(s,2H),4.04(d,J=4.5Hz,2H),3.88(s,3H),3.07(s,2H),2.96(s,4H),2.67(s,4H),2.43(s,3H).
Example 31: n- (5- ((5-chloro-4- (4, 7-dihydrothieno [2,3-c ] pyridin-6 (5H) -yl) pyrimidin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) -3-methoxyisonicotinamide
ESI-MS m/z:643.2[M+Na]+;1H NMR(400MHz,CDCl3)δ10.30(s,1H),9.50(s,1H),8.56(s,1H),8.46(d,J=4.6Hz,1H),8.10(d,J=4.6Hz,1H),8.03(s,1H),7.53(s,1H),7.06(d,J=4.9Hz,1H),6.84–6.79(m,2H),4.90(s,2H),4.24(s,3H),4.05(t,J=4.8Hz,2H),3.88(s,3H),3.06(s,2H),2.96(s,3H),2.63(s,3H),2.40(s,3H),1.85(d,J=3.0Hz,2H).
Example 32: n- (5- ((5-chloro-4- (4, 7-dihydrothieno [2,3-c ] pyridin-6 (5H) -yl) pyrimidin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) -1-methyl-1H-imidazole-2-carboxamide
ESI-MS m/z:594.2[M+H]+;1H NMR(400MHz,CDCl3)δ10.26(s,1H),9.38(s,1H),8.03(s,1H),7.49(s,1H),7.11(s,1H),7.05(d,J=4.9Hz,1H),7.01(s,1H),6.78(s,2H),4.89(s,2H),4.06(s,5H),3.87(s,3H),3.06(s,2H),2.98(s,4H),2.76(s,4H),2.45(s,3H).
The invention provides biological activity research of the compounds I-1 to I-32
The invention provides an activity study of compounds I-1-I-32 for inhibiting EGFR mutant
The compounds I-1 to I-32 provided by the invention are screened for inhibiting EGFR L858R/T790M/C797S activity. The specific operation is as follows:
1. Compounds for preparing test kinase
1) The compound was diluted 100-fold with 100% dimethyl sulfoxide to the final desired highest reaction inhibitor concentration. 100 μl of the compound dilutions were transferred to one well of a 96-well plate. For example, if the highest inhibitor concentration required is 0.1. Mu.M, a 10. Mu.M solution of the compound in DMSO is prepared in this step.
2) 100 Μl of 100% DMSO solution was added to two wells of the same 96-well plate without compound control and without enzyme control. The plate is marked as a source plate.
3) 40 Μl of compound in the source plate was transferred to a new 384 well Echo plate as an intermediate plate.
4) 100NL of compound per well in 384-well Echo plates was transferred to 384-well assay plates by reflux.
2. Kinase reaction.
1) In addition to the control wells without enzyme (5. Mu.L 1 Xkinase buffer was added), 5. Mu.L kinase solution was added to each well of the assay plate.
2) Substrate and Adenosine Triphosphate (ATP) substrate solutions were formulated in 1x kinase reaction buffer, with the final concentration of each reagent being 2 times the concentration required in the assay.
3) Mu.L of substrate solution was added to each well of the assay plate.
4) 384 Well assay plates were incubated for 30 minutes or 60 minutes at room temperature.
5) A detection solution of kinase quenching buffer and antibody was prepared, and the final concentration of each reagent in the Lance detection buffer was 2 times the desired concentration.
6) 10. Mu.L of the detection solution was added thereto, and the mixture was left at room temperature for 60 minutes.
3. Curve fitting
1) The Lance signal ratio (665 nm/615 nm) in the Envision program was replicated.
2) The ratio values are converted to percent inhibition values.
A. percent inhibition = (max-sample rankine signal ratio)/(max-min) ×100.
"Minimum" means the ratio of the enzyme-free control and "maximum" means the ratio of the DMSO control.
3) The data are shown in MS Excel and fit to curve IC 50 using XLfit exceladd-in version 5.4.0.8 as: y=bottom+ (Top-Bottom)/(1+ (IC 50/X) ≡ HillSlope)
The results of the kinase inhibition rate test for compounds I-1 to I-32 inhibiting EGFR L858R/T790M/C797S are shown in the following table.
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From the test results, the compounds I-1 to I-32 to be protected have obvious inhibition activity on EGFR L858R/T790M/C797S mutant, which is obviously better than that on a control medicine AZD9291, and the compounds provided by the invention can be used for preparing EGFR mutant inhibitors.
The compounds of formula I of the present invention may be administered alone, but are typically administered in admixture with a pharmaceutically acceptable carrier selected according to the desired route of administration and standard pharmaceutical practice.
While the invention has been described in terms of specific embodiments, modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Claims (10)
1. Pyrimidine heterocyclic compounds containing an N-methylpiperazine structure shown in the general formula I or pharmaceutically acceptable salts thereof;
wherein X is NH or O;
y is CH or N;
r 1 is selected from H, halogen, nitro, trifluoromethyl, halo (C1-C6) alkyl;
r 2 is selected from H, methoxy, cl;
R 3 is selected from H, methoxy, halogen, 5-6 membered heteroaromatic amide substituted with 1 independent R 3a, wherein the heteroaromatic ring in the heteroaromatic amide optionally contains 1-2N atoms;
R 3a is selected from H, halogen, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy;
R 4 is selected from H, methyl, 6-7 membered heterocyclic ring containing 1-3N atoms and substituted by 1-3 identical or different R 5;
R 5 is H or (C1-C6) alkyl;
A is an amino group substituted by a six-membered heterocyclo five-membered aromatic heterocycle or a six-membered heterocyclo benzene ring or pyrazole containing 1 to 3N, O or S or an amino group substituted by an aromatic five-membered ring, and A is optionally substituted by 1 to 3 identical or different R 6;
R 6 is H or methyl.
2. The pyrimidine heterocyclic compound having an N-methylpiperazine structure or a pharmaceutically acceptable salt thereof according to claim 1, wherein in the general formula I,
X is NH;
R 3 is selected from H, methoxy, cl, br and the following structures:
R 4 is selected from H, methyl and the following structures:
A is selected from 4,5,6, 7-tetrahydrothieno [3,2-c ] pyridine, 1,2,3, 4-tetrahydroisoquinoline, 1-methyl-1H-pyrazol-4-amine, 2, 3-dihydro-1H-inden-5-amine.
3. The pyrimidine heterocyclic compound having an N-methylpiperazine structure according to claim 2, or a pharmaceutically acceptable salt thereof, which is any one of the following compounds I-1 to I-32 or pharmaceutically acceptable salts thereof:
4. a pyrimidine heterocyclic compound having an N-methylpiperazine structure or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein the pharmaceutically acceptable salt comprises an addition salt of an inorganic acid and an organic acid with the pyrimidine heterocyclic compound having an N-methylpiperazine structure, the inorganic acid and the organic acid comprising: hydrochloric acid, hydrogen olfactory acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, tea disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid.
5. The method for preparing a pyrimidine heterocyclic compound having an N-methylpiperazine structure or a pharmaceutically acceptable salt thereof as claimed in claim 3, comprising the steps of:
synthetic route 1:
synthetic route 2:
Wherein Y, R 1、R2、R3、R4 and A are corresponding groups at corresponding positions of the compound.
6. A pharmaceutical composition, characterized in that the pyrimidine heterocyclic compound containing an N-methylpiperazine structure or a pharmaceutically acceptable salt thereof as an active ingredient is mixed with a pharmaceutically acceptable excipient to prepare a composition, and is prepared into a clinically acceptable dosage form, wherein the excipient refers to a diluent, an auxiliary agent or a carrier which can be used in the pharmaceutical field; the preparation is in the form of injection, tablet, capsule, aerosol, suppository, pellicle, dripping pill, external liniment and unguent.
7. Use of a pyrimidine heterocyclic compound having an N-methylpiperazine structure according to any of claims 1-3 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 6 for the preparation of a medicament for inhibiting EGFR mutants.
8. The use of claim 7, wherein the EGFR mutant is one or more of T790M, L858R, L858R/T790M, L858R/T790M/C797S.
9. Use of a pyrimidine heterocyclic compound having an N-methylpiperazine structure according to any of claims 1-3 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 6 in the preparation of a medicament for the treatment of cancer.
10. The use of claim 9, wherein the cancer is non-small cell lung cancer.
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