CN106905245B - 2, 4-disubstituted pyrimidines - Google Patents

2, 4-disubstituted pyrimidines Download PDF

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CN106905245B
CN106905245B CN201510982545.1A CN201510982545A CN106905245B CN 106905245 B CN106905245 B CN 106905245B CN 201510982545 A CN201510982545 A CN 201510982545A CN 106905245 B CN106905245 B CN 106905245B
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cancer
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amino
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CN106905245A (en
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张寅生
高勇
任景
王庆璘
王昭
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention belongs to the field of medical chemistry, relates to a 2, 4-disubstituted pyrimidine compound, and particularly relates to a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, and an application thereof in treating EGFR (epidermal growth factor receptor) or/and ALK (anaplastic lymphoma kinase) mediated diseases.

Description

2, 4-disubstituted pyrimidines
Technical Field
The invention belongs to the field of medical chemistry, relates to a 2, 4-disubstituted pyrimidine compound, and particularly relates to a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, and an application thereof in treating EGFR (epidermal growth factor receptor) or/and ALK (anaplastic lymphoma kinase) mediated diseases.
Background
Epidermal Growth Factor Receptor (EGFR) is a Receptor for cell proliferation and signaling of the Epidermal Growth Factor (EGF), also known as HER1, ErbB 1. EGFR belongs to the ErbB receptor family, which includes EGFR (ErbB-1), HER2/c-neu (ErbB-2), HER3(ErbB-3) and HER4 (ErbB-4). EGFR is a glycoprotein belonging to tyrosine kinase type receptor, and has a penetrating cell membrane and a molecular weight of 170 KDa.
EGFR is localized on the surface of cell membranes and is activated by binding to ligands, including EGF and TGF α activation, after which EGFR is converted from monomers to dimers. The dimer includes both the binding of two cognate receptor molecules (homodimerization) and the binding of different members of the human EGF-related receptor (HER) tyrosine kinase family (heterodimerization). EGFR dimerization can activate its intracellular kinase pathways, including phosphorylation of key tyrosine residues in the intracellular domain, and results in stimulation of many intracellular signaling pathways involved in cell proliferation and survival.
There is high or abnormal expression of EGFR in many solid tumors. EGFR is involved in the inhibition of tumor cell proliferation, angiogenesis, tumor invasion, metastasis and apoptosis. It may be made with: high expression of EGFR leads to enhancement of downstream signaling; increased expression of mutant EGFR receptors or ligands results in sustained activation of EGFR; the effect of the autocrine loop is enhanced; disruption of receptor down-regulation mechanisms; activation of abnormal signaling pathways, etc. Overexpression of EGFR plays an important role in the progression of malignant tumors, and overexpression of EGFR has been found in all tissues such as glial cells, kidney cancer, lung cancer, prostate cancer, pancreatic cancer, and breast cancer.
Among them, abnormal expression of EGFR and Erb-B2 plays a critical role in tumor transformation and growth. In lung cancer as an example, EGFR is expressed in 50% of cases of non-small cell lung cancer (NSCLC), and its expression is poorly correlated with prognosis. These two factors make EGFR and its family members the main candidates for targeted therapy. Two small molecule inhibitors targeting EGFR, gefitinib and erlotinib, have received rapid FDA approval in the united states for the treatment of advanced NSCLC patients who have lost response to conventional chemotherapy.
Early clinical data indicated that 10% of NSCLC patients responded to gefitinib and erlotinib. Molecular biological analysis showed that in most cases, drug-responsive patients harbored specific mutations in the gene encoding EGFR: the deletion of 747-750 amino acids in exon 19 accounts for 45% of the mutation, and 10% of the mutations occur in exons 18 and 20. The most common EGFR activating mutations (L858R and del e746_ a750) result in increased affinity for small molecule Tyrosine Kinase Inhibitors (TKIs) and decreased affinity for Adenosine Triphosphate (ATP) relative to wild-type WT-EGFR. The T790M mutation is a point mutation in exon 20 of EGFR that results in acquired resistance to gefitinib or erlotinib treatment. Recent studies have shown that L858R combined with the T790M mutation has stronger affinity for ATP than L858R alone, and TKI is an ATP competitive kinase inhibitor, resulting in a decreased binding rate of TKI to the kinase domain.
The Anaplastic Lymphoma Kinase (ALK) is a superfamily member of receptor tyrosine Kinase protein kinases. ALK genetic alterations can cause a variety of hematologic or non-hematologic tumors. Abnormal expression of the full-length ALK receptor protein has been reported in neuroblastoma and glioblastoma; about 60% of anaplastic large cell lymphoma cases have NPM-ALK gene fusion phenomenon; about 5% of non-small cell lung cancers are due to the fusion phenomenon of the EML4-ALK gene. The ML4-ALK gene fusion can also cause other cancers, such as intestinal cancer, breast cancer or renal cancer, etc. Currently, marketed ALK inhibitors such as Crizotinib (Crizotinib) and Ceritinib (Ceritinib) have been successfully used for the treatment of non-small cell lung cancer.
Disclosure of Invention
The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
Figure BDA0000887872830000021
wherein the content of the first and second substances,
x or Y are each independently selected from N or CH;
R1selected from H, halogen, -CF3or-CN;
R2or R6Each independently selected from H or-OC1-6An alkyl group;
R3or R5Each independently selected from H or
Figure BDA0000887872830000022
R4Selected from 3-to 8-membered heterocycloalkyl or
Figure BDA0000887872830000023
R7Selected from H, -OC1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0000887872830000024
The 3-to 8-membered heterocycloalkyl contains 1,2 or 3 heteroatoms selected from N, O or S, and is optionally substituted by R8Substitution;
the R is8Is selected from-C1-4Alkyl, -C (O) -C1-4Alkyl, -NR9R10、-C(O)O-C1-4Alkyl, -C (O) NH-C1-4Alkyl, -SO2-C1-4Alkyl, -SO2NH2、-C(O)-C1-4alkylene-OH or
Figure BDA0000887872830000031
Z is selected from O, S or NR11；
The R is9、R10Or R11Each independently selected from H or-C1-4An alkyl group.
As a preferred embodiment of formula (I), R1Selected from H, -F, -Cl, -Br, -CF3or-CN.
As a preferred embodiment of formula (I), R2Or R6Each independently selected from H or-OC1-4An alkyl group.
As a more preferred embodiment of formula (I), R2Or R6Each independently selected from H, -OC1Alkyl, -OC2Alkyl, -OC3Alkyl or-OC4An alkyl group.
As a preferred embodiment of formula (I), R4Selected from 5-6 membered heterocycloalkyl or
Figure BDA0000887872830000032
As a preferred embodiment of formula (I), R7Selected from H, -OC1-4Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0000887872830000037
Figure BDA0000887872830000034
As a more preferred embodiment of formula (I), R7Selected from H, -OC1Alkyl, -OC2Alkyl, -OC3Alkyl, -OC4Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0000887872830000035
Figure BDA0000887872830000036
As a preferred embodiment of formula (I), the heterocycloalkyl contains 1 or 2 heteroatoms selected from N or O, and is optionally substituted by R8And (4) substitution.
As a more preferred embodiment of formula (i), said heterocycloalkyl is selected from morpholinyl, piperidinyl or piperazinyl.
As a preferred embodiment of formula (I), R8Is selected from-C1Alkyl, -C2Alkyl, -C3Alkyl, -C4Alkyl, -C (O) -C1Alkyl, -C (O) -C2Alkyl, -C (O) -C3Alkyl, -C (O) -C4Alkyl, -NR9R10、-C(O)O-C1Alkyl, -C (O) O-C2Alkyl, -C (O) O-C3Alkyl, -C (O) O-C4Alkyl, -C (O) NH-C1Alkyl, -C (O) NH-C2Alkyl, -C (O) NH-C3Alkyl, -C (O) NH-C4Alkyl, -SO2-C1Alkyl, -SO2-C2Alkyl, -SO2-C3Alkyl, -SO2-C4Alkyl, -SO2NH2、-C(O)-C1alkylene-OH, -C (O) -C2alkylene-OH, -C (O) -C3alkylene-OH, -C (O) -C4alkylene-OH or
Figure BDA0000887872830000041
As a preferred embodiment of formula (I)In one embodiment, Z is selected from O or NR11。
As a preferred embodiment of formula (I), R9、R10Or R11Each independently selected from H, -C1Alkyl, -C2Alkyl, -C3Alkyl or-C4An alkyl group.
As one embodiment of the present invention, there is provided a compound represented by formula (ii) or a pharmaceutically acceptable salt thereof:
Figure BDA0000887872830000042
wherein the content of the first and second substances,
x or Y are each independently selected from N or CH;
R1selected from H, -F, -Cl, -Br, -CF3or-CN;
R2、R6or R7Each independently selected from H, -OC1Alkyl, -OC2Alkyl, -OC3Alkyl or-OC4An alkyl group.
As an embodiment of the present invention, there is provided a compound represented by the formula (iii):
Figure BDA0000887872830000043
wherein the content of the first and second substances,
x or Y are each independently selected from N or CH;
R1selected from H, halogen, -CF3or-CN;
R2or R6Each independently selected from H or-OC1-6An alkyl group;
R7selected from H, -OC1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0000887872830000051
A is selected from O, NH, NR8Or CH-R8；
Z isSelected from O, S or NR11；
The R is8Is selected from-C1-4Alkyl, -C (O) -C1-4Alkyl, -NR9R10、-C(O)O-C1-4Alkyl, -C (O) NH-C1-4Alkyl, -SO2-C1-4Alkyl, -SO2NH2、-C(O)-C1-4alkylene-OH or
Figure BDA0000887872830000052
The R is9、R10Or R11Each independently selected from H or-C1-4An alkyl group.
As a preferred embodiment of formula (III), R1Selected from H, -F, -Cl, -Br, -CF3or-CN.
As a preferred embodiment of formula (III), R2Or R6Each independently selected from H or-OC1-4An alkyl group.
As a more preferred embodiment of formula (III), R2Or R6Each independently selected from H, -OC1Alkyl, -OC2Alkyl, -OC3Alkyl or-OC4An alkyl group.
As a preferred embodiment of formula (III), R7Selected from H, -OC1-4Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0000887872830000053
Figure BDA0000887872830000054
As a more preferred embodiment of formula (III), R7Selected from H, -OC1Alkyl, -OC2Alkyl, -OC3Alkyl, -OC4Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0000887872830000055
Figure BDA0000887872830000056
As a preferred embodiment of formula (III), R8Is selected from-C1Alkyl, -C2Alkyl, -C3Alkyl, -C4Alkyl, -C (O) -C1Alkyl, -C (O) -C2Alkyl, -C (O) -C3Alkyl, -C (O) -C4Alkyl, -NR9R10、-C(O)O-C1Alkyl, -C (O) O-C2Alkyl, -C (O) O-C3Alkyl, -C (O) O-C4Alkyl, -C (O) NH-C1Alkyl, -C (O) NH-C2Alkyl, -C (O) NH-C3Alkyl, -C (O) NH-C4Alkyl, -SO2-C1Alkyl, -SO2-C2Alkyl, -SO2-C3Alkyl, -SO2-C4Alkyl, -SO2NH2、-C(O)-C1alkylene-OH, -C (O) -C2alkylene-OH, -C (O) -C3alkylene-OH, -C (O) -C4alkylene-OH or
Figure BDA0000887872830000057
As a preferred embodiment of formula (III), Z is selected from O or NR11。
As a preferred embodiment of formula (III), R9、R10Or R11Each independently selected from H, -C1Alkyl, -C2Alkyl, -C3Alkyl or-C4An alkyl group.
As an embodiment of the present invention, there is provided a compound represented by the formula (iv):
Figure BDA0000887872830000061
wherein the content of the first and second substances,
x or Y are each independently selected from N or CH;
R1selected from H, halogen, -CF3or-CN;
R2or R6Each independently selected from H or-OC1-6An alkyl group;
R7selected from H, -OC1-6Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0000887872830000062
Z is selected from O, S or NR11；
The R is9、R10Or R11Each independently selected from H or-C1-4An alkyl group.
As a preferred embodiment of formula (IV), R1Selected from H, -F, -Cl, -Br, -CF3or-CN.
As a preferred embodiment of formula (IV), R2Or R6Each independently selected from H or-OC1-4An alkyl group.
As a more preferred embodiment of formula (IV), R2Or R6Each independently selected from H, -OC1Alkyl, -OC2Alkyl, -OC3Alkyl or-OC4An alkyl group.
As a preferred embodiment of formula (IV), R7Selected from H, -OC1-4Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0000887872830000063
Figure BDA0000887872830000064
As a more preferred embodiment of formula (IV), R7Selected from H, -OC1Alkyl, -OC2Alkyl, -OC3Alkyl, -OC4Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0000887872830000071
Figure BDA0000887872830000072
As a preferred embodiment of formula (IV), Z is selected from O or NR11。
As a preferred embodiment of formula (IV), R9、R10Or R11Each of which isIndependently selected from H, -C1Alkyl, -C2Alkyl, -C3Alkyl or-C4An alkyl group.
The following compounds or pharmaceutically acceptable salts thereof are preferred in the present invention:
Figure BDA0000887872830000073
Figure BDA0000887872830000081
Figure BDA0000887872830000091
Figure BDA0000887872830000101
Figure BDA0000887872830000111
Figure BDA0000887872830000121
Figure BDA0000887872830000131
Figure BDA0000887872830000141
another aspect of the present invention provides a method of treating EGFR or/and ALK mediated diseases, comprising administering a therapeutically effective amount of a compound of formula (i) or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides the use of a compound of formula (i), or a pharmaceutically acceptable salt thereof, in the treatment of EGFR-and/or ALK-mediated diseases.
In another aspect, the present invention provides the use of a compound of formula (i), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an EGFR or/and ALK mediated disease.
In some embodiments of the invention, the EGFR-mediated disease is selected from EGFR-L858R or/and EGFR-T790M mutation activation-mediated diseases.
In some embodiments of the invention, the ALK-mediated disease is selected from the group consisting of NPM-ALK or/and EML4-ALK gene fusion-mediated diseases.
In some embodiments of the invention, the EGFR-or/and ALK-mediated disease comprises cancer, inflammation, infection, immune disease, organ transplantation, viral disease, cardiovascular disease or metabolic disease.
In some embodiments of the invention, the cancer includes, but is not limited to: lung cancer, head and neck cancer, breast cancer, prostate cancer, esophageal cancer, rectal cancer, colon cancer, nasopharyngeal cancer, uterine cancer, pancreatic cancer, lymphoma, leukemia, osteosarcoma, melanoma, renal cancer, gastric cancer, liver cancer, bladder cancer, thyroid cancer or carcinoma of large intestine.
In some embodiments of the invention, the lung cancer is selected from non-small cell lung cancer.
In some preferred embodiments of the invention, the disease is selected from EGFR or/and ALK mediated diseases selected from non-small cell lung cancer.
In another aspect of the invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (i) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical compositions of the present invention may further comprise one or more additional therapeutic agents.
The pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention or a salt thereof with a suitable pharmaceutically acceptable carrier, and can be formulated, for example, into solid, semi-solid, liquid or gaseous preparations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.
Typical routes of administration of the compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The pharmaceutical compositions of the present invention may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing, and the like.
For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, slurries, suspensions and the like, for oral administration to a patient.
Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: the active compounds are mixed with solid excipients, the resulting mixture is optionally milled, if desired with further suitable auxiliaries, and the mixture is then processed to granules, to give tablets or dragee cores. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like. Such as microcrystalline cellulose, glucose solutions, gum arabic syrups, gelatin solutions, sucrose and starch pastes; talc, starch, magnesium stearate, calcium stearate or stearic acid; lactose, sucrose, starch, mannitol, sorbitol, or dicalcium phosphate; silicon dioxide; croscarmellose sodium, pregelatinized starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar, carboxymethylcellulose, crospovidone, and the like. The dragee cores may optionally be coated, in particular with enteric coatings, according to methods well known in normal pharmaceutical practice.
The pharmaceutical compositions may also be adapted for parenteral administration, as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
The compounds of formula (i) or pharmaceutically acceptable salts thereof as described herein may be administered by any suitable route and method, for example, orally or parenterally (e.g., intravenously). A therapeutically effective amount of a compound of formula (I) is from about 0.0001 to 20mg/Kg body weight/day, for example from 0.001 to 10mg/Kg body weight/day.
The frequency of dosage of the compounds of formula (I) is determined by the individual requirements of the patient, for example 1 or 2 times per day, or more times per day. Administration may be intermittent, for example, wherein a patient receives a daily dose of a compound of formula (i) over a period of several days, followed by a period of several days in which the patient does not receive a daily dose of a compound of formula (i).
Related definitions:
the following terms and phrases used herein have the following meanings, unless otherwise indicated. A particular term or phrase, unless specifically defined, should not be considered as indefinite or unclear, but rather construed according to ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.
C as used hereinm-nMeaning that the moiety has m-n carbon atoms. For example, "C1-6Alkyl "means that the alkyl group has 1 to 6 carbon atoms.
Numerical ranges herein refer to each integer in the given range. E.g. "C1-6By "is meant that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
The term "Cm"the word indicating the number of carbon atoms forms a group with a functional group including all isomeric forms thereof, for example: 1) "-C3Alkyl "includes all isomeric forms thereof, e.g. CH3CH2CH2-and (CH)3)2CH-；2)“-C4Alkyl "includes all isomeric forms thereof, e.g. CH3CH2CH2CH2-、CH3CH2(CH3)CH-、(CH3)2CHCH2-and (CH)3)3C-。
The term "halogen" refers to fluorine, chlorine, bromine and iodine.
The term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, which is attached to the rest of the molecule by a single bond. Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, and the like.
The term "alkylene" refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, which is attached to the rest of the molecule through two points of attachment. Non-limiting examples of this term include methylene (-CH)2-), 1-ethylidene (-CH (CH)3) -), 1, 2-ethylene (-CH)2CH2-), 1-propylene (-CH (CH)2CH3) -), 1, 2-propylene (-CH)2CH(CH3) -), 1, 3-propylene (-CH)2CH2CH2-) 1, 4-butylene (-CH2CH2CH2CH2-) and the like. The term "C4Alkylene "refers to an alkylene group having 4 carbon atoms.
The term "heterocycloalkyl" refers to a saturated monocyclic, fused polycyclic, bridged or spiro ring system radical in which some of the ring atoms are heteroatoms selected from N, O, S and the remaining ring atoms are C. Non-limiting examples of heterocyclyl groups include oxiranyl, thietanyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuryl, pyrrolidinyl, oxazolidinyl, tetrahydropyrazolyl, pyrrolinyl, dihydrofuranyl, dihydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyranyl, dihydrothiopyranyl, azepanyl, oxepanyl, thiepanyl, thiepinyl, oxaazabicyclo [2.2.1] heptyl, and azaspiro [3.3] heptyl groups and the like. The term "3-to 8-membered heterocycloalkyl" refers to heterocycloalkyl groups having 3 to 8 ring atoms.
When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2R, the group may optionally be substituted with up to two R, and there are separate options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
Examples of the pharmaceutically acceptable salt include a salt with an inorganic acid, a salt with an organic acid, and a salt with an acidic amino acid.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains an acid or base, by conventional chemical methods. In general, such salts are prepared by the following method: prepared by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid in water or an organic solvent or a mixture of the two.
Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous form.
Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present invention.
The illustrations of enantiomers, ambiscalemic and scalemic or enantiomerically pure compounds herein are from Maehr, J.chem.Ed.1985,62: 114-120. Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by wedge bonds and dashed bonds. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E, Z geometric isomer unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the invention.
The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
Optically active (R) -and (S) -isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one of the enantiomers of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers by fractional crystallization or chromatography, as is well known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).
The term "pharmaceutically acceptable carriers" refers to those carriers which do not significantly stimulate the organism and do not impair the biological activity and performance of the active compound. By "pharmaceutically acceptable carrier" is meant an inert substance which facilitates administration of the active ingredient in conjunction with administration of the active ingredient, including, but not limited to, any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonicity agent, solvent, or emulsifier acceptable for use in humans or animals (e.g., livestock) as permitted by the national food and drug administration. Non-limiting examples of such carriers include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, and the like. For additional information on The vector, reference may be made to Remington, The Science and Practice of Pharmacy,21st Ed., Lippincott, Williams & Wilkins (2005), The contents of which are incorporated herein by reference.
The term "excipient" generally refers to a carrier, diluent, and/or vehicle necessary to formulate an effective pharmaceutical composition.
The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For oral dosage forms of the invention, an "effective amount" of one active agent in a composition is the amount required to achieve the desired effect when combined with another active agent in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.
The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.
The phrase "therapeutically effective amount" as used herein refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that a researcher, veterinarian, medical doctor or other clinician is seeking in a tissue, system, animal, individual, or human, which includes one or more of the following:
(1) prevention of diseases: for example, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not experienced or developed disease pathology or symptomatology.
(2) Inhibiting the disease: for example, inhibiting the disease, disorder or condition (i.e., arresting the further development of the pathology and/or condition) in an individual who is experiencing or presenting the pathology or condition of the disease, disorder or condition.
(3) And (3) relieving the diseases: for example, relieving the disease, disorder or condition (i.e., reversing the pathology and/or symptomatology) in an individual who is experiencing or presenting with the pathology or symptomatology of the disease, disorder or condition.
The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, examples of the present invention.
Some of the compounds of formula (I) of the present invention may be prepared by those skilled in the art of organic synthesis via scheme 1 using standard procedures in the art, the substituents being as defined above:
Figure BDA0000887872830000191
as shown in scheme 1, a compound of formula 2 reacts with acryloyl chloride to obtain a compound of formula 3, the compound of formula 3 reduces nitro to obtain a compound of formula 4, the compound of formula 4 reacts with a compound of formula 5 under the catalysis of lewis acid to obtain a compound of formula 6, and the compound of formula 6 reacts with a compound of formula 7 under the basic condition or the catalysis of Pd metal to obtain a compound of formula (I).
Some of the compounds of formula (I) of the present invention may also be prepared by those skilled in the art of organic synthesis via scheme 2 using standard procedures in the art, the substituents being as defined above:
Figure BDA0000887872830000201
as shown in scheme 2, the compound of formula 5 reacts with the compound of formula 7 under alkaline conditions to obtain a compound of formula 8, and the compound of formula 8 can be condensed with the compound of formula 4 to obtain a compound of formula (I); the compound of formula 8 can also be reacted with the compound of formula 9 to obtain the compound of formula 10, the nitro group of the compound of formula 10 is reduced to obtain amino, and then the amino is reacted with acryloyl chloride to obtain the compound of formula (I).
The base used in the production process of the present invention includes inorganic bases and organic bases, and examples thereof include sodium hydride, tert-butyl magnesium chloride, lithium hydride, lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, NaHMDS, LiHMDS, methylimidazole (e.g., 1-methylimidazole, 2-methylimidazole, 4-methylimidazole), DBU, triethylamine, diisopropylamine or diisopropylethylamine.
The acid used in the production method of the present invention includes inorganic acids and organic acids, and examples thereof include hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid or naphthalenesulfonic acid.
In some embodiments of the present invention, one skilled in the art can prepare according to, rather than strictly following, the steps of scheme 1 or scheme 2, and depending on the structure of the final product, the order of the various steps can be increased, decreased, or altered for scheme 1 or scheme 2, and this is within the scope of the present invention.
The chemical reactions of the embodiments of the present invention are carried out in a suitable solvent that is compatible with the chemical changes of the present invention and the reagents and materials required therefor. In order to obtain the compounds of the present invention, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes based on the existing embodiments.
An important consideration in any synthetic route planning in the art is the selection of suitable protecting groups for reactive functional groups, such as amino groups in the present invention. Greene and Wuts (Protective Groups in Organic Synthesis, Wiley and Sons,1991) are the authorities of this area for trained practitioners. All references cited herein are incorporated herein in their entirety.
The reactions described herein can be monitored according to any suitable method known in the art. For example, it can be determined by a broad spectrum method such as nuclear magnetic resonance spectroscopy (e.g.1H or13C) Infrared spectroscopy, spectrophotometry (e.g. UV-visible light) or mass spectrometry, or monitoring product formation by chromatography, e.g. High Performance Liquid Chromatography (HPLC) or thin layer chromatography.
For clarity, the invention is further illustrated by examples. The embodiments are not limited to defining or specifying the scope of the invention.
In some embodiments of the invention, the starting materials or reagents for the reaction are commercially available (from Aldrich) or can be prepared by one of skill in the art using methods known in the chemical arts. All solvents used in the present invention are commercially available and can be used without further purification. All procedures involving experiments sensitive to water and/or oxygen were performed in a pre-dried glass apparatus under nitrogen atmosphere.
The compound is made by hand or
Figure BDA0000887872830000211
The software names, and the commercial compounds are under the supplier catalog name.
Detailed Description
The following specific examples are included to provide those skilled in the art with a clear understanding of the invention and are included to provide a further understanding of the invention. They should not be considered as limiting the scope of the invention but merely as being exemplary illustrations and representative of the invention.
Example 1N- (3- ((4-chloro-5-trifluoromethylpyridin-2-yl) amino) phenyl) acrylamide (6-1)
Figure BDA0000887872830000221
Step (1) N- (3-nitrophenyl) acrylamide (3-1)
To a reaction flask was added a compound of formula 2-1 (10.0g, 72.4mmol) dissolved in anhydrous waterTo tetrahydrofuran, Et was added3N (11.0g, 108.6mmol), dripping acryloyl chloride (10.29g, 113.7mmol) at 0 ℃, reacting at room temperature for 1.5-2 hrs after dripping, monitoring the reaction completion by TLC, evaporating the reaction solution by spinning, adding saturated Na2CO3Adjusting pH of the aqueous solution to 10, extracting with EA, drying, rotary evaporating to obtain crude product, passing through silica gel column, eluting with PE-EA, mixing, and concentrating to obtain compound of formula 3-1 (6.50 g).
1H-NMR(300M,CD3OD)：8.68(s,1H),7.96-7.92(t,2H),7.58-7.52(t,1H),6.44-6.42(t,2H),5.84-5.81(m,1H)。
HRMS(ESI,[M+H]+)m/z:193.0604。
Step (2) N- (3-aminophenyl) acrylamide (4-1)
To a reaction flask was added a compound of formula 3-1 (6.0g, 31.22mmol), ethanol and tetrahydrofuran as solvents, and SnCl was added2·2H2And (3) heating and refluxing O (35.2g, 156.1mmol) for 3-4 hrs, monitoring the reaction completion by TLC, evaporating the reaction solution to dryness, adding an aqueous NaOH solution to adjust the pH value to 12, extracting and drying EA, evaporating to obtain a crude product, passing through a silica gel column, eluting with PE-EA (4: 1-3: 2), and combining and concentrating to obtain the compound (3.20g) of the formula 4-1.
1H-NMR(300M,DMSO-d6):6.98(s,1H),6.89-6.94(t,1H),6.74-6.77(d,1H),6.37-6.46(m,1H),6.17-6.28(m,2H),5.67-5.70(d,1H)。
HRMS(ESI,[M+H]+)m/z：163.0867。
Step (3) N- (3- ((4-chloro-5-trifluoromethylpyrimidin-2-yl) amino) phenyl) acrylamide (6-1)
Compound 5-1(0.50g, 2.30mmol) was dissolved in 1, 2-dichloroethane and t-butanol (20mL each) under nitrogen. A1.0M solution of zinc chloride in diethyl ether (4.60mL, 4.60mmol) was added dropwise at 0 deg.C, and the reaction mixture was stirred at low temperature. Compound 4-1(0.374g, 2.30mmol) was added to the reaction, followed by dropwise addition of triethylamine (0.256g, 2.53mmol) in 1, 2-dichloroethane and tert-butanol. After several hours of reaction, the reaction was gradually returned to room temperature. After completion of the reaction monitored by TLC, the solvent was removed by rotary evaporation, and then water (30mL) was added to the reaction flask and sonicated for 30 min. And (4) carrying out suction filtration and washing to obtain a white solid, drying and purifying by recrystallization to finally obtain the compound of the formula 6-1 as the white solid.
1H-NMR(300MHz,DMSO-d6):10.69(s,1H),10.19(s,1H),8.79(s,1H),7.99(s,1H),7.42～7.47(t,1H),7.27～7.33(t,1H),6.43～6.52(m,2H),6.24～6.30(dd,1H),5.74～5.78(dd,1H)。
HRMS(ESI,[M+H]+)m/z:343.0555。
Example 2N- (3- ((4-chloro-5-trifluoromethylpyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (6-2)
Figure BDA0000887872830000231
Step (1) 4-methoxyaniline nitrate (12)
Taking 10g of the compound 11 into a 250mL three-necked bottle, adding 80mL of TBME and 20mL of THF into the reaction bottle, cooling the reaction liquid to 0-5 ℃, dropwise adding 7.8g of 65% nitric acid into the reaction liquid, keeping the temperature less than 20 ℃ in the dropwise adding process, controlling the reaction temperature to be about 0 ℃ after the dropwise adding is finished, reacting for about 1h, filtering the reaction liquid, washing a filter cake with TBME, and drying the filter cake overnight under vacuum at room temperature to obtain 14.68g of a product with the yield of 97.1%.
Step (2) 4-methoxy-3-nitroaniline (2-2)
63g of 95% concentrated sulfuric acid was weighed into a 500mL three-necked flask and cooled to 0 ℃. Suspending 12g of compound 12 in 120mL of dichloromethane to prepare a suspension, dropwise adding the suspension into cold concentrated sulfuric acid, controlling the temperature to be about 0 ℃ in the dropwise adding process, keeping the temperature for about 3 hours after the dropwise adding is finished, separating the reaction liquid, removing an acid layer, cooling 120mL of water to be about 0 ℃, slowly adding the acid layer into cold water, keeping the temperature to be not more than 20 ℃ in the process, dropwise adding ammonia water into the diluted reaction liquid until the pH value is 6-11, keeping the temperature to be not more than 20 ℃ in the dropwise adding process, extracting with 120mL of multiplied by 2DCM, washing an organic phase with saturated saline solution, and concentrating. 8.7g of a dark brown viscous oil are obtained in a yield of 80.3%.
1H-NMR(500M,DMSO):7.07(s,1H),7.05-7.06(m,2H),3.78(s,3H)。
HRMS(ESI，[M+H]+)：m/z 169.0613。
Step (3) N- (4-methoxy-3-nitrophenyl) acrylamide (3-2)
Adding 8.7g of compound 2-2 into a 250mL three-necked bottle under the protection of nitrogen, adding 40mL of dry THF into the bottle, adding 4.8mL of triethylamine into a reaction bottle, cooling the reaction solution to 0 ℃, dropwise adding 8.65mL of acryloyl chloride, keeping the temperature of the reaction solution at about 0 ℃ in the dropwise adding process, heating to room temperature to react for 3 hours after the dropwise adding is finished, concentrating the reaction solution, washing and extracting residues with 100mL of water and 100mL of ethyl acetate, washing the residues with saturated organic phase sodium chloride, drying, concentrating, stopping concentrating immediately when solid is separated out in the concentrating process, placing the solution in an ice water bath for 15 minutes, filtering, taking a filter cake, concentrating and filtering twice to obtain 8.6g of yellow solid with the yield of 75.1%.
1H-NMR(500M，DMSO):10.33(s,1H),8.32-8.33(m,1H),7.81-7.83(m,1H),7.35-7.37(m,1H),6.26-6.30(m,1H),5.77-5.80(m,1H),3.90(s,3H)。
HRMS(ESI，[M+H]+)m/z：223.0761。
Step (4) N- (3-amino-4-methoxyphenyl) acrylamide (4-2)
1.8g of the compound 3-2 was taken and added to a 250mL three-necked flask, 50mL of methanol and 55mL of a saturated aqueous ammonium chloride solution were sequentially added to the flask, stirred at room temperature, and 2.68g of zinc powder was weighed and added to the flask. Oil bath reaction at 60 ℃, TLC monitoring reaction completion, reaction liquid filtration, filtrate concentration to remove methanol, ethyl acetate 10mL × 2 extraction, liquid separation, organic phase drying, concentration, residue silica gel column purification to obtain 1.08g white solid, yield 69.4%.
1H-NMR(500M，DMSO):9.69(s,1H),7.02-7.03(m,1H),6.80-6.83(m,1H),6.70-6.71(m,1H),6.37-6.42(dd,J＝10Hz,J＝25Hz,1H),6.16-6.20(dd,J＝1.9Hz,J＝17Hz,1H),5.64-5.67(dd,J＝1.9Hz,J＝10.1Hz,1H),4.72(s,2H),3.72(s,3H)。
HRMS(ESI，[M+H]+)m/z:193.1003。
Step (5) N- (3- ((4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (6-2)
Compound 6-2 was prepared by the method of step (3) of reference example 1 using compounds 4-2 and 5-1 as starting materials.
1H NMR(300MHz,DMSO-d6)δ10.06(s,1H),9.78(s,1H),8.68(s,1H),7.81(d,J＝2.5Hz,1H),7.52(dd,J＝8.9,2.6Hz,1H),7.06(d,J＝8.9Hz,1H),6.41(dd,J＝16.9,10.0Hz,1H),6.22(dd,J＝16.9,2.2Hz,1H),5.72(dd,J＝9.9,2.2Hz,1H),3.75(s,3H)。
HRMS(ESI,[M+H]+)m/z：373.0685。
EXAMPLE 3N- (5- ((4-chloro-5-trifluoromethyl) pyrimidin-2-yl) amino) -2, 4-dimethoxy) acrylamide (6-3)
Figure BDA0000887872830000251
Step (1)1, 5-dimethoxy-2, 4-dinitrobenzene (14)
Dissolving sodium methoxide (11.40g, 211mmol) in methanol (200mL) to obtain a solution, adding compound 13(5.0g, 21.10mmol) into a reaction flask, adding sodium methoxide/methanol solution, heating and refluxing for 2 hours, monitoring by TLC that the raw material spot disappears, cooling the reaction solution, evaporating to dryness, adding EA to extract, drying and evaporating to obtain compound 14(4.51g, 19.73mmol)
1H-NMR(300MHz,DMSO-d6):8.67(s,1H),7.05(s,1H),4.11(s,6H)。
Step (2)2, 4-dimethoxy-5-nitroaniline (2-3)
Adding sodium hydrosulfide hydrate (5.37g, 67.07mmol), sulfur simple substance (0.82g, 25.65mmol) and sodium hydroxide (1.50g, 37.50mmol) into a reaction bottle, adding 150mL of water, heating to 80 ℃ until the sulfur simple substance is completely dissolved, cooling to room temperature, adding a water (50mL) suspension of compound 14(4.50g, 19.73mmol) into another reaction bottle, slowly dropwise adding the cooled mixed solution at 90 ℃, stopping heating and cooling the reaction solution after dropwise adding, stirring overnight, performing suction filtration and water washing the next day, and drying a filter cake to obtain a crude product. The crude product was dissolved and washed with silica gel to give 2-3(2.31g, 11.66mmol) of compound.
1H-NMR(300MHz,DMSO-d6):7.27(s,1H),6.75(s,1H),4.84(s,2H)，3.92(s,3H),3.87(s,3H)。
HRMS(ESI+,[M+H]+)m/z：199.0713。
Step (3) N- (2, 4-dimethoxy-5-nitrophenyl) acrylamide (3-3)
A reaction flask was charged with a solution of compound 2-3(2.20g, 11.10mmol) and triethylamine (1.68g, 16.60mmol) in freshly distilled THF (50mL), N2Under protection, dropping acryloyl chloride (2.01g, 22.20mmol) at 0 ℃, gradually heating to room temperature after dropping, reacting overnight, adding water the next day to terminate the reaction, evaporating the reaction solution to dryness, adding EA to extract and dry, and obtaining the compound 3-3(2.20g, 8.72 mmol).
1H-NMR(300MHz,DMSO-d6)：9.56(s，1H)，8.74(s，1H)，6.92(s，1H)，6.65-6.70(m，1H)，6.23-6.27(dd，1H)，5.73-5.75(dd，1H)，4.02(s，3H)，3.98(s，3H)，
HRMS(ESI+,[M+H]+)m/z：253.0820。
Step (4) N- (5-amino-2, 4-dimethoxyphenyl) acrylamide (4-3)
Adding the compound 3-3(2.10g, 8.33mmol), iron powder (0.93g, 16.66mmol), ammonium chloride (0.89g, 16.66mmol), ethanol-water mixed solvent into a reaction bottle, heating at 90 ℃ for reaction overnight, monitoring by TLC to confirm complete reaction, carrying out suction filtration on reaction liquid, carrying out rotary evaporation to dryness, carrying out extraction drying for sand preparation, passing through a silica gel column, and eluting by PE-EA (4: 1-2: 1) to obtain a compound IV-3(900 mg).
1H-NMR(300MHz,DMSO-d6)：9.03(s，1H)，7.32(s，1H)，6.62(s，1H)，6.58-6.61(m，1H)，6.15-6.19(dd，1H)，5.63-5.65(dd，1H)，4.31(s，1H)，3.77(s，1H)，3.74(s，1H)。
HRMS(ESI+,[M+H]+)m/z：223.1086。
Step (5) N- (5- ((4-chloro-5-trifluoromethylpyrimidin-2-yl) amino) -2, 4-dimethoxyphenyl) acrylamide (6-3)
Compound 6-3 was prepared by the method of step (3) of reference example 1 using compound 4-3 and 5-1 as starting materials.
MS(ESI+,[M+H]+)m/z：403.76。
With reference to the preparation methods shown in examples 1 to 3, the following intermediate compounds can be prepared from the existing starting materials:
Figure BDA0000887872830000261
Figure BDA0000887872830000271
example 41- (4- (4-amino-3-methoxyphenyl) piperazin-1-yl) ethanone (7-1)
Figure BDA0000887872830000281
Step (1)1- (4- (3-methoxy-4-nitrophenyl) piperazin-1-yl) ethanone (17)
A compound of formula 15 (9.0g, 52.6mmol), 30mL of N, N-dimethylacetamide, a compound of formula 16 (7.4g, 57.8mmol), N, N-diisopropylethylamine (8.1g, 63.1mmol), reaction at 90 ℃ for 5-6 h, TLC to monitor completion of the reaction, cooling to room temperature, pouring the reaction solution into 200mL of water, extracting with ethyl acetate (60 mL. times.3), combining the organic layers, washing with saturated brine, drying with anhydrous sodium sulfate, and rotary evaporation to give a compound of formula 17 (12.71g) as a yellow solid (yield 86.4%) was added to the reaction flask, respectively.
1H-NMR(300M,CDCl3):7.96(d,J＝9Hz,1H),6.41(d,J＝9Hz,1H),6.31(s,1H),3.95(s,3H),3.67-3.78(dd,J＝33Hz,4H),3.42-3.46(m,4H),2.15(s,3H)。
HRMS(ESI,[M+H]+)m/z：280.1289。
Step (2)1- (4- (4-amino-3-methoxyphenyl) piperazin-1-yl) ethanone (7-1)
A compound of formula 17 (10.0g, 35.8mmol), 150mL of anhydrous methanol was added to a reaction flask, the flask was purged with nitrogen twice, hydrogen was introduced, palladium on carbon (1.0g, 10%) was added under stirring, the reaction was carried out at room temperature for 24 hours, and the crude product was obtained by suction filtration and rotary evaporation of the mother liquor. With DCM: MeOH ═ 10: column chromatography of 1 afforded the compound of formula 7-1 (7.0g) as a purple solid (yield 78.5%).
1H-NMR(300M,CDCl3):6.64(d,J＝9Hz,1H),6.51(s,1H),6.40(d,J＝9Hz,1H),3.83(s,3H),3.60-3.76(dd,J＝48Hz,4H),3.00(s,4H),2.12(s,3H)。
HRMS(ESI,[M+H]+)m/z：250.1546。
Example 54- (4-Methylpiperazin-1-yl) aniline (7-2)
Figure BDA0000887872830000282
Step (1) 1-methyl-4- (4-nitrophenyl) piperazine (20)
Adding 80mL of DMF into a 250mL reaction bottle, respectively taking 10g of compound 18, 9.6mL of compound 19 and 11.8g of potassium carbonate, sequentially adding the materials into the reaction bottle, reacting at 80 ℃ for 1.5h, cooling the reaction liquid to room temperature, filtering to remove the potassium carbonate, slowly adding the filtrate into 200mL of water, precipitating a large amount of solid, filtering, and drying the obtained solid to obtain 13.23g of reddish brown solid 20 with the yield of 84.3%.
1H NMR(300Hz,CDCl3):8.06(d,J＝9.4Hz,2H),7.03(d,J＝9.4Hz,2H),3.44(t,J＝5.0Hz,4H),2.42(t,J＝5.0Hz,4H),2.21(s,3H)。
HRMS(ESI，[M+H]+)m/z:222.1240。
Step (2) intermediate 4- (4-methylpiperazin-1-yl) aniline (7-2)
To a 500mL reaction flask, 13.12g of compound 20 was added, 200mL of methanol was added, and 1.45g of 10% Pd/C was reacted overnight with hydrogen at room temperature, the reaction was terminated, palladium on carbon was removed by filtration, the filtrate was concentrated, and the residue was purified by column chromatography (MeOH: DCM ═ 10:1) to give 9.9g of gray solid 7-2. The yield was 89%.
1H-NMR(300M，CD3OD):6.83(d,J＝8.5Hz,2H),6.70(d,J＝8.5Hz,2H),3.02(m,4H),2.57-2.60(m,4H),2.32(s,3H)。
HRMS(ESI，[M+H]+)m/z:192.1498。
Example 62-methoxy-4- (4-methylpiperazin-1-yl) aniline (7-3)
Figure BDA0000887872830000291
Step 1)1- (3-methoxy-4-nitrophenyl) -4-methylpiperazine (21)
Adding 7.8mL of compound 19 into a 250mL reaction bottle, adding 100mL of DMF into the bottle, weighing 10g of compound 15 and 9.68g of potassium carbonate, sequentially adding the mixture into the reaction bottle, stirring the mixture in an oil bath at 80 ℃, monitoring the reaction by TLC, finishing the reaction of raw materials for 5h, cooling the reaction solution to room temperature, filtering to remove the potassium carbonate, diluting the filtrate by 100mL of water, extracting by 75mL of multiplied by 3 ethyl acetate, taking an organic phase, washing the organic phase by 50mL of multiplied by 3 water, drying the organic phase by anhydrous sodium sulfate, and concentrating to obtain 10.87g of yellow solid 7-3 with the yield of 74.7%.
1H-NMR(300M，CDCl3)：8.01(d,J＝9.3Hz,1H),6.43(d,J＝9.3Hz,1H),6.32(s,1H),3.95(s,3H),3.40-3.43(t,J＝5Hz,4H),2.54-2.57(t,J＝5Hz,4H),2.36(s,3H)。
HRMS(ESI，[M+H]+)m/z：252.1333。
Step (2) intermediate 2-methoxy-4- (4-methylpiperazin-1-yl) aniline (7-3)
Taking 10g of the compound 21, adding the compound into a 250mL reaction bottle, adding 100mL of methanol into the reaction bottle, weighing 1g of 10% Pd/C, adding the mixture into the reaction bottle, introducing hydrogen, reacting at room temperature for 4 hours, and filtering to remove palladium carbon after the reaction is finished. The filtrate was concentrated and the residue was purified on silica gel column (EA: DCM ═ 1:1) to give 8.1g of 7-3 as grey solid in 91.9% yield.
1H-NMR(300M,DMSO):6.48-6.53(m,2H),6.26(d,J＝8.3Hz,1H),3.73(s,3H),2.93-2.95(m,4H),2.41-2.49(m,4H),2.20(s,3H)。
HRMS(ESI，[M+H]+)m/z:222.1604。
Example 72-methoxy-4- (4-methanesulfonylpiperazin-1-yl) aniline (7-4)
Figure BDA0000887872830000301
Step (1)1- (3-methoxy-4-nitrophenyl) -4-methanesulfonylpiperazine (23)
10g of Compound 15 was weighed into a 250mL three-necked flask, 100mL of DMSO was added to the flask, 11.5g of Compound 22 and 24.2g of potassium carbonate were further added to the reaction flask, and the reaction flask was placed in an oil bath at 80 ℃ for reaction for 20 hours. After the reaction was completed, potassium carbonate was removed by filtration, the filtrate was added to 100mL of water, a large amount of yellow solid was precipitated, filtered, the filter cake was washed with water, and the filter cake was vacuum-dried at 70 ℃ for 6 hours to give 18g of yellow solid 23 with a yield of 98.7%.
HRMS(ESI，[M+H]+)：m/z 316.0974。
Step (2) 2-methoxy-4- (4-methanesulfonylpiperazin-1-yl) aniline (7-4)
Weighing 8g of compound 23, adding into a 250mL three-necked flask, adding 80mL of anhydrous methanol into the flask, and adding 0.8g of Pd/C10% and H into the flask2The reaction is carried out for 20h under normal pressure. After the reaction, 100mL of dichloromethane was added to the reaction solution and stirred for 10min (the product was completely dissolved), palladium on carbon was removed by filtration, the filtrate was concentrated, and the residue was slurried with ether to obtain 6.26g of ash as a white solid 7-4 with a yield of 86.5%.
HRMS(ESI,[M+H]+)m/z：286.1262。
Example 82-methoxy-4-morpholinylaniline (7-5)
Figure BDA0000887872830000302
Step (1)4- (3-methoxy-4-nitrophenyl) morpholine (25)
To a reaction flask were added compound 15(10.0g, 58.44mmol) and compound 24(6.11g, 70.12mmol), respectively, dissolved in DMF and K was added2CO3(11.31g, 81.81 mmol). The reaction is carried out at 70 ℃. And tracking by TLC. When the reaction is complete, the reaction system is poured into ice water, and yellow solid is separated out. The solid was filtered and dried to obtain 12.55g of compound 25, yield: 90.22 percent.
1H-NMR(300M，CDCl3)：8.01(d，J＝9.27Hz，1H)，6.45(d，J＝9.27Hz，1H)，6.37(s，1H)，3.96(s，3H)，3.87(t，J＝4.75Hz，4H)，3.35(t，J＝4.83Hz,4H)。
HRMS(ESI,[M+H]+)m/z：239.1027。
Step (2) 2-methoxy-4-morpholinylaniline (7-5)
To a reaction flask was added compound 25(14.58g, 61.23mmol) dissolved in THF and 1.5g Pd/C added. And (3) carrying out catalytic hydrogenation under the condition of normal temperature. And tracking by TLC. After the reaction was complete, the reaction was filtered through celite, and the solvent was removed by distillation under reduced pressure. Obtaining a crude solid product, pulping with diethyl ether to obtain pink powder, and drying to obtain 9.57g of compound 7-5 with the yield: 75.1 percent.
1H-NMR(300M，CDCl3)：6.65(d，J＝8.31Hz，1H)，6.50(d，J＝2..34Hz，1H)，6.40(d，J＝8..25Hz，1H)，3.86(s，3H)，3.84(d，J＝4.17Hz，4H)，3.04(d，J＝4.32Hz，4H)。
HRMS(ESI,[M+H]+)m/z：209.1286。
Example 91- (4-amino-3-methoxyphenyl) -N, N-dimethylpiperazin-4-amine (7-6)
Figure BDA0000887872830000311
Step (1)1- (3-methoxy-4-nitrophenyl) piperidin-4-ol (27)
Taking compound 15(30.00g,176mmol), dissolving in 190mL DMF, sequentially adding piperidinol 26(19.49g,193mmol) and potassium carbonate (29.00g,211mmol), reacting at 70 ℃ for 5h, and monitoring by TLC to complete the reaction; carrying out suction filtration, filtering insoluble solids, rinsing a filter cake with a small amount of DMF, pouring the filtrate into 800mL of water, and standing to separate out solids; suction filtration is carried out, and the filter cake is placed at 60 ℃ for vacuum drying for 24h to obtain 39.45g of yellow solid 27 with the yield of 88%.
MS(ESI,[M+H]+)m/z：253.21。
Step (2)1- (3-methoxy-4-nitrophenyl) piperidin-4-one (28)
Weighing the compound 27(30.00g,118mmol) in a reaction bottle, dissolving the compound in 300mL of dichloromethane, adding Dess-Martin oxidant (100g,236mmol) in batches, and stopping the reaction for about 3 hours after the addition is finished; adding sodium bisulfite solution (30g of sodium bisulfite dissolved in proper amount of water) to quench the reaction, and adjusting the pH of the reaction solution to neutrality with saturated sodium carbonate solution to separate a dichloromethane layer; extracting the water layer by using 200mL of dichloromethane for three times, combining dichloromethane layers, washing twice by using a sodium carbonate solution, washing once by using saturated salt solution, and drying by using anhydrous sodium sulfate; vacuum distilling to obtain crude product, pulping the crude product with 130mL of methanol, stirring for 1h, filtering, and vacuum drying the filter cake at 50 ℃ for 8h to obtain 21.10g of yellow-green solid 28 with the yield of 70.76%.
MS(ESI,[M+H]+)m/z：251.22。
Step (3)1- (3-methoxy-4-nitrophenyl) -N, N-dimethylpiperidin-4-amine (29)
After compound 28(5.10g,20.38mmol) was dissolved in 40mL of tetrahydrofuran in a reaction flask, 41mL of a tetrahydrofuran solution of dimethylamine (81.52mmol), trimethyl orthoformate (4.33g,40.76mmol), and 3mL of formic acid (81.52mmol) were sequentially added; reacting for 7 hours at 70 ℃, and stopping the reaction; distilling under reduced pressure, adding 100mL of water, precipitating a solid (TLC shows as a raw material), performing suction filtration, extracting the filtrate with ethyl acetate (50mLx3), combining ethyl acetate layers, washing with 50mL of water once, combining water layers, adjusting the pH of the water layer to 9 with 10% NaOH solution, extracting with dichloromethane (50mL x5), combining dichloromethane layers, washing with saturated salt water once, and drying with anhydrous sodium sulfate; distillation under reduced pressure gave 4.27g of solid 29 in 75.04% yield.
HRMS(ESI,[M+H]+)m/z：280.1665。
Step (4)1- (4-amino-3-methoxyphenyl) -N, N-dimethylpiperidin-4-amine (7-6)
Weighing 4.09g of the compound 29 into a reaction bottle, adding 40mL of methanol for dissolving, adding 0.4g of 10% Pd/C (the adding amount is 10% of the weight of II-2), and hydrogenating and reducing; TLC monitoring, about 6h, reaction completion, reaction stop; suction filtration, small amount of methanol rinse, reduced pressure distillation to obtain 3.38g brown solid 7-6, yield 92.60%.
1H-NMR(300M,CDCl3)：6.63(d,1H)，6.52(s,1H)，6.41-6.44(t,1H)，3.84(s,3H)，3.52(d,3H)，2.59-2.67(t,2H)，2.39(s,8H)，1.95-2.00(d,2H)，1.65-1.78(m,2H)。
HRMS(ESI,[M+H]+)m/z：250.1290。
Example 102-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline (7-7)
Figure BDA0000887872830000321
Step (1)1- (3-methoxy-4-nitrophenyl) piperidin-4-one (28)
Compound 15(40g,232mmol) was added to a reaction flask, and after 300mL of DMF was dissolved, compound 30(39.42g,290mmol), K were added2CO3(80.80g,586mmol), stirring, heating to 70 deg.C, reacting for 24h, and stopping reaction; TLC (petroleum ether: ethyl acetate 1:2) monitored that starting material remained. Filtering the reaction solution, and washing a filter cake with a small amount of DMF; pouring the filtrate into 900mL of water, and standing to separate out a solid; suction filtration was carried out and the filter cake was dried under vacuum at 60 ℃ for 24h to give 44.50g of yellow solid 28 with a yield of 76.72%.
1H NMR(300MHz,CDCl3):δ8.04(d,J＝9.2Hz,1H),6.46(dd,J＝9.2,2.3Hz,1H),6.38(d,J＝2.2Hz,1H),3.97(s,3H),3.79(t,J＝6.0Hz,4H),2.65(t,J＝6.0Hz,4H)。
MS(ESI,[M+H]+)m/z：251.22。
Step (2)1- (1- (3-methoxy-4-nitrophenyl) piperidin-4-yl) -4-methylpiperazine (32)
28(3.00g,12mmol) was weighed into a microwave reaction tube, and methylpiperazine 19(2.40g,24mmol), trimethyl orthoformate (2.55g,24mmol), 12mL of acetonitrile and 1.8mL of formic acid were added in this order; heating with microwave at 110 deg.C for 1 h; after distillation under reduced pressure, 30mL of water was added, the aqueous layer was extracted with ethyl acetate (30mLx3) until the aqueous layer was free of starting material, and the ethyl acetate layer was washed once with 20mL of water; the aqueous layers were combined, 10% NaOH solution was added dropwise until the aqueous layer became turbid by clarification, the aqueous layer was extracted with dichloromethane (30mLx3), the dichloromethane layers were combined, washed once with saturated brine, and dried over anhydrous sodium sulfate. Vacuum distilling to obtain solid, vacuum drying at 40 deg.C for 8 hr to obtain product 32(2.43g) with yield of 60.68%.
MS(ESI,[M+H]+)m/z：335.40。
Step (3) preparation of 2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) aniline (7-7)
Taking 3.67g of the compound 32 in a reaction bottle, dissolving in 40mL of methanol, adding 0.42g of 10% Pd/C, reducing by hydrogen, monitoring by TLC, and reacting completely within about 6 hours; suction filtration and reduced pressure distillation are carried out to obtain 3.02g of light purple solid 7-7, and the yield is 90.42%.
1H NMR(300MHz,CDCl3):δ6.63(d,J＝8.3Hz,1H),6.52(d,J＝2.3Hz,1H),6.41(dd,J＝8.3,2.4Hz,1H),3.83(s,3H),3.53-3.49(m,3H),2.66-2.40(m,10H),2.31(s,3H),1.94-1.64(m,4H)。
HRMS(ESI,[M+H]+)m/z:305.2338。
Example 111- (4-Aminophenyl) -N, N-dimethylpiperidin-4-amine (7-8)
Figure BDA0000887872830000331
Step (1)1- (4-Nitrophenyl) piperidin-4-ol (33)
Weighing compound 18(10.00g,70.87mmol) into a reaction bottle, adding piperidinol 26(7.87g,77.96mmol), potassium carbonate (11.74g,85.04mmol) and 85mL of DMF in sequence, heating and stirring at 70 ℃, stopping reaction for 5 h; suction filtration, filtration of insoluble solids, and washing with a small amount of DMF, pouring the filtrate into 650mL of water, standing to precipitate solids, suction filtration, filter cake placed at 60 ℃ and vacuum drying for 24h to obtain 13.56g of orange solids 33, yield 86.14%.
MS(ESI,[M+H]+)m/z:223.21。
Step (2) preparation of 1- (4-nitrophenyl) piperidin-4-one (34)
Dissolving the compound 33(13.52g,60.87mmol) in a reaction bottle with 200mL of dichloromethane, adding Dess-Martin oxidant (52g,121.7mmol) in batches, monitoring by TLC after the addition is finished, and stopping the reaction for about 3 h; adding sodium bisulfite solution (7g sodium bisulfite dissolved in water), quenching reaction, adding sodium carbonate solution, and adjusting pH to neutrality; the dichloromethane layer was separated, the aqueous layer was extracted three times with 200mL dichloromethane, the dichloromethane layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to give a yellow solid, which was dried under vacuum at 45 ℃ for 8h to give product 34(11.26g) in 84.02% yield.
1H-NMR(300M,CDCl3)：8.15-8.18(d,2H)，6.84-6.87(d,2H)，3.80-3.84(t,4H)，2.61-2.65(t,4H)。
MS(ESI,[M+H]+)m/z:221.21。
Step (3) N, N-dimethyl-1- (4-nitrophenyl) piperidin-4-amine (35)
Dissolving compound 35(5.18g,23.53mmol) in a reaction flask with 40mL of tetrahydrofuran, sequentially adding 24mL of tetrahydrofuran solution of dimethylamine (47.07mmol), trimethyl orthoformate (5.00g,47.04mmol) and 3.5mL of formic acid (94.12mmol), heating at 70 deg.C, stirring, and stopping reaction for 7 h; the reaction mixture was distilled under reduced pressure, 70mL of water was added to precipitate a solid (TLC showed starting material), the aqueous layer was extracted with ethyl acetate (40mLx2), the ethyl acetate layers were combined, 40mL of water was washed once, the aqueous layers were combined, the pH of the aqueous layer was adjusted to 9 with 10% NaOH solution, the aqueous layer was extracted with dichloromethane (40mLx5), the dichloromethane layers were combined, saturated brine was washed once, and dried over anhydrous sodium sulfate. Vacuum distilling to obtain yellow solid, vacuum drying at 45 deg.C for 8 hr to obtain product compound 35(1.18g), yield 20.14%.
1H-NMR(300M,CDCl3)：8.08-8.13(m,2H)，6.78-6.84(m,2H)，3.94-3.99(d,2H)，2.94-3.03(m,2H)，2.36-2.46(m,1H)，2.34(s,6H)，1.94-1.98(t,2H)，1.52-1.65(m,2H)。
HRMS(ESI,[M+H]+)m/z：250.1562。
Step (4)1- (4-aminophenyl) -N, N-dimethylpiperidin-4-amine (7-8)
Weighing 1.13g of compound 35 into a reaction bottle, adding 20mL of methanol for dissolving, adding 0.12g of 10% Pd/C, introducing hydrogen, monitoring by TLC, and stopping the reaction for about 6 hours; suction filtration, small amount of methanol rinse, filtrate vacuum distillation to obtain 0.83g light brown yellow solid, yield 83.50%.
1H-NMR(300M,CDCl3)：6.80-6.82(d,2H)，6.62-6.64(d,2H)，3.49-3.51(d,2H)，3.23(s,2H)，2.57-2.62(t,2H)，2.31(s,6H)，2.21-2.27(m,1H)，1.89-1.91(d,2H)，1.63-1.70(m,2H)。
HRMS(ESI,[M+H]+)m/z：220.1752。
Example 124- (4-amino-3-methoxyphenyl) piperazine-1-carboxylic acid tert-butyl ester (7-9)
Figure BDA0000887872830000351
Step (1) tert-butyl 4- (3-methoxy-4-nitrophenyl) piperazine-1-carboxylate (37)
To a reaction flask were added compound 15(12.0g, 70.12mmol) and compound 36(14.38g, 77.13mmol), respectively, dissolved in DMF, and K was added2CO3(14.58g, 105.18 mmol). The reaction was carried out at 80 ℃ and followed by TLC. When the reaction is complete, pouring the reaction system into ice water, separating out yellow solid, filtering the solid, pulping with diethyl ether, and drying to obtain 21.2g of a compound 37, wherein the yield is as follows: 89.68 percent.
1H-NMR(300M，CDCl3)：8.01(d，J＝9.33Hz，1H)，6.42(d，J＝9.45Hz，1H)，6.34(s，1H)，3.96(s，3H)，3.61(t，J＝4.35Hz，4H)，3.39(t，J＝5.10Hz,4H)，1.49(s，9H)。
HRMS(ESI,[M+H]+)m/z：338.1714。
Step (2) tert-butyl 4- (4-amino-3-methoxyphenyl) piperazine-1-carboxylate (7-9)
36(23.91g, 77.83mmol) was added to the reaction flask dissolved in ethanol and 2g Pd/C was added. Carrying out catalytic hydrogenation under the condition of normal temperature, tracking by TLC, filtering by using kieselguhr after complete reaction, distilling under reduced pressure to remove a solvent to obtain a solid crude product, pulping by using diethyl ether to obtain pink powder, and drying to obtain 21.4g of a compound 7-9, wherein the yield is as follows: 98.2 percent.
1H-NMR(300M，CDCl3)：6.64(d，J＝8.28Hz，1H)，6.52(s，1H)，6.42(d，J＝8..22Hz，1H)，3.84(s，3H)，3.58(t，J＝4.77Hz，4H)，2.98(s，4H)，1.48(s，9H)。
HRMS(ESI,[M+H]+)m/z：308.1969。
Example 134- (6-Aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (7-10)
Figure BDA0000887872830000352
Step (1) tert-butyl 4- (6-nitropyridin-3-yl) piperazine-1-carboxylate (39)
To a reaction flask were added compound 38(10.2g, 49.52mmol) and compound 36(10.40g, 54.47mmol) dissolved in DMF and DIPEA (7.78g, 59.42mmol) respectively. Reacting at 50 ℃, tracking by TLC, pouring a reaction system into ice water until the reaction is complete, separating out yellow solid, filtering the solid, pulping by EA, and drying to obtain 6.20g of a compound 39, wherein the yield is as follows: 40.63 percent.
1H-NMR(300M，CDCl3)：8.16(m，2H)，6.45(m，1H)，3.64(t，J＝4.89Hz，4H)，3.45(t，J＝5.67Hz,4H)，1.49(s，9H)。
HRMS(ESI,[M+H]+)m/z：309.1554。
Step (2) tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate (7-10)
Adding compound 39(5.65g, 18.34mmol) into a reaction bottle, dissolving in methanol, adding 0.5g Pd/C, carrying out catalytic hydrogenation at normal temperature, tracking by TLC, carrying out reaction completely, filtering by using kieselguhr, distilling under reduced pressure to remove the solvent to obtain a crude solid product, pulping by using petroleum ether-diethyl ether (30:1) to obtain pink powder, and drying to obtain 4.75g of compound 7-10, wherein the yield is as follows: 93.1 percent.
1H-NMR(300M，CDCl3)：7.76(d，J＝2.76Hz,1H)，7.18(dd，J＝2.88，8.82Hz，1H)，6.50(d，J＝8.79Hz，1H)，6.40(d，J＝8..25Hz，1H)，3.57(t，J＝4.92Hz，4H)，2.95(t，J＝5.1Hz,4H)，1.48(s，9H)。
HRMS(ESI,[M+H]+)m/z：279.1808。
Example 144- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (7-11)
Figure BDA0000887872830000361
Step (1)4- (4-nitrophenyl) piperazine-1-carboxylic acid tert-butyl ester (40)
Separately adding the compound to the reaction flask18(10.0g, 70.87mmol), Compound 36(15.84g, 85.05mmol) are dissolved in DMF and K is added2CO3(15.67g, 113.39mmol), reacting at 80 ℃, tracking by TLC, pouring the reaction system into ice water until the reaction is complete, separating out yellow solid, filtering the solid, pulping with diethyl ether, and drying to obtain 18.58g of compound 40, wherein the yield is as follows: 85.3 percent.
1H-NMR(300M，CDCl3)：8.13(d，J＝9.27Hz，2H)，6.82(d，J＝9.33Hz，2H)，3.61(t，J＝4.71Hz，4H)，3.42(t，J＝5.46Hz,4H)，1.49(s，9H)。
HRMS(ESI,[M+H]+)m/z：308.1077。
Step (2) intermediate 4- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (7-11)
Adding compound 40(17.57g, 63.39mmol) into a reaction bottle, dissolving in methanol, adding 1.7g Pd/C, carrying out catalytic hydrogenation at normal temperature, tracking by TLC until the reaction is complete, filtering by using kieselguhr, distilling under reduced pressure to remove the solvent to obtain a crude solid product, pulping by using diethyl ether to obtain pink powder, and drying to obtain 12.31g of compound 7-11, wherein the yield is as follows: 73.8 percent.
1H-NMR(300M，CDCl3)：6.82(d，J＝8.64Hz，2H)，6.65(d，J＝8.61Hz，2H)，3.57(t，J＝4.8Hz，4H)，2.97(t，J＝4.83Hz，4H)，1.48(s，9H)。
HRMS(ESI,[M+H]+m/z：278.1862。
Example 151- (4- (6-aminopyridin-3-yl) piperazin-1-yl) ethanone (7-12)
Figure BDA0000887872830000371
Step (1)1- (4- (6-nitropyridin-3-yl) piperazin-1-yl) ethanone (41)
A compound of formula 38 (10.0g, 49.2mmol), 100mL of N, N-dimethylacetamide, 1-acetylpiperazine 16(8.2g, 64.0mmol), N, N-diisopropylethylamine (19.1g, 147.8mmol), reaction at 90 ℃ for 7-8 h, TLC to monitor completion of the reaction, cooling to room temperature, pouring the reaction solution into 300mL of water, extracting with ethyl acetate (80 mL. times.3), combining the organic layers, washing with saturated brine, drying over anhydrous sodium sulfate, and rotary evaporation to give a compound of formula 41 (9.9g) as a beige solid (yield 80.6%) was added to the reaction flask, respectively.
1H-NMR(300M，CDCl3)：8.14-8.20(m，2H)，7.70-7.24(m，1H)，3.78(d，J＝39Hz，4H)，3.47-3.52(m，4H)，2.16(s，3H)。
HRMS(ESI,[M+H]+)m/z：251.1144。
Step (2)1- (4- (6-aminopyridin-3-yl) piperazin-1-yl) ethanone (7-12)
Adding the compound of formula X-16 (8.0g, 32.0mmol) and 90ml of anhydrous methanol into a reaction bottle, replacing nitrogen twice, adding palladium-carbon (0.8g, 10%) under stirring, reacting at room temperature for 24h, filtering, leaching the palladium-carbon with anhydrous methanol, and rotary-distilling the mother liquor to obtain a brown crude product. Mixing the raw materials in DCM: MeOH ═ 10: column chromatography of 1 afforded the compound of formula XI-12 (5.3g) as a dark purple solid (74.7% yield).
1H-NMR(300M，CDCl3)：7.76(d，J＝3Hz，1H)，7.15-7.18(m，1H)，6.49(d，J＝3Hz，1H)，3.60-3.75(dd，J＝45Hz，4H)，2.95-3.02(m，4H),2.12(s，3H)。
HRMS(ESI,[M+H]+)m/z：221.1399。
Example 165- (4-Methylpiperazin-1-yl) piperidin-2-amine (7-13)
Figure BDA0000887872830000381
Step (1) 1-methyl-4- (6-nitropyridin-3-yl) piperazine (42)
10g of the compound 38 is weighed and added into a 250mL reaction flask, 80mL of DMF, 9mL of DIPEA and 8.47g of the compound 19 are added into the flask, the reaction is placed in an oil bath at 90 ℃ for reaction for 20 hours, 100mL of multiplied by 3 ethyl acetate is used for extraction after the reaction is finished, liquid separation is carried out, an organic phase is washed by saturated saline, anhydrous sodium sulfate is dried and concentrated, and the residue is pulped by methyl tert-butyl ether, so that 6g of yellow solid compound 42 is obtained, and the yield is 54.6%.
1H-NMR(300M，CDCl3)：8.12-8.17(m,2H),7.18-7.27(m,1H),3.46-3.49(t,J＝5.0Hz,4H),2.57-2.60(t,J＝5.0Hz,4H),2.34(s,3H)。
HRMS(ESI，[M+H]+)m/z:223.1178。
Step (2)5- (4-methylpiperazin-1-yl) piperidin-2-amine (7-13)
Taking 5g of the compound 42, adding the compound into a 250mL reaction bottle, adding 80mL of methanol into the bottle, adding 0.5g of 10% palladium carbon, introducing hydrogen, reacting at room temperature for 16h, filtering to remove the palladium carbon, concentrating the filtrate, and pulping the obtained residue with methyl tert-butyl ether to obtain 4.05g of light purple solid compound 7-13 with the yield of 93.6%.
1H-NMR(300M，DMSO)：7.60(d,J＝1.7Hz,1H),7.13-7.15(dd,J＝1.7Hz,J＝5.3Hz,1H),6.6.40(d,J＝5.0Hz,1H),2.90-2.92(t,J＝2.8Hz,4H),2.41-2.43(t,J＝2.8Hz,4H),2.19(s,3H)。
HRMS(ESI，[M+H]+)m/z：193.1476。
Example 171- (4- (4-aminophenyl) piperazin-1-yl) ethanone (7-14)
Figure BDA0000887872830000382
Step (1)1- (4- (4-nitrophenyl) piperazin-1-yl) ethanone (43)
A compound of formula 18 (6.0g, 42.5mmol), 24mL of N, N-dimethylacetamide, 1-acetylpiperazine 16(6.5g, 51.0mmol), N, N-diisopropylethylamine (7.1g, 55.3mmol), reaction at 90 ℃ for 4-5 h, TLC to monitor completion of the reaction, cooling to room temperature, pouring the reaction solution into 180mL of water, extracting with ethyl acetate (50 mL. times.3), combining the organic layers, washing with saturated brine, drying with anhydrous sodium sulfate, and rotary evaporation to give a compound of formula 43 (8.8g) as a pale yellow solid (yield 83.7%) was added to the reaction flask, respectively.
1H-NMR(300M,CDCl3):8.11-8.16(m,2H),6.80-6.86(m,2H),3.67-3.80(dd,4H),3.46(s,4H),2.15(s,3H)。
HRMS(ESI,[M+H]+)m/z：250.1188。
Step (2)1- (4- (4-aminophenyl) piperazin-1-yl) ethanone (7-14)
A compound of formula 43 (5.0g, 20.0mmol), 80mL of anhydrous methanol was added to a reaction flask, the flask was purged with nitrogen twice, palladium on carbon (0.5g, 10%) was added with stirring, hydrogen was added, the reaction was carried out at room temperature for 24h, and the crude product was obtained by suction filtration and rotary evaporation of the mother liquor. With DCM: MeOH ═ 10: column chromatography of 1 afforded 3.6g of the compound of formula 7-14 as a pale purple solid (yield 82.3%).
1H-NMR(300M,CDCl3):6.81(d,J＝9Hz,2H),6.64(d,J＝9Hz,2H),3.59-3.75(dd,4H),2.99(s,4H),2.12(s,3H)。
HRMS(ESI,[M+H]+)m/z：220.1289。
With reference to the preparation methods shown in examples 4 to 17, the following intermediate compounds can be prepared from the existing starting materials:
Figure BDA0000887872830000391
Figure BDA0000887872830000401
example 18N- (3- ((4- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -5-trifluoromethylpyrimidin-2-yl) amino) phenyl) acrylamide (I-16)
Figure BDA0000887872830000402
Under nitrogen, compound 6-1(0.2g, 0.58mmol), compound 7-2(0.358g, 1.87mmol), and ethanol (8mL) were added to a microwave reaction flask, respectively. Microwave heating to 120 deg.C (150PSI,150POWER) and after two hours of reaction, TLC monitored the reaction for substantial completion. And (3) dropwise adding a saturated sodium carbonate aqueous solution into the reaction mixture, separating out white solid, and carrying out suction filtration to obtain a solid product. The solid product obtained was dried by passing through a reduced pressure oven at 50 ℃. The objective compound (0.29g) was finally obtained as a white solid.
1H-NMR(300MHz,DMSO-d6):9.99(s,1H),9.59(s,1H),8.46(s,1H),8.30(s,1H),7.66(s,1H),7.28～7.37(m,4H),6.98～7.04(t,J＝8.13Hz,1H),6.89～6.91(d,J＝8.91Hz,2H),6.42～6.51(m,1H),6.21～6.28(dd,1H),5.71～5.76(dd,1H),3.10～3.13(t,J＝4.59Hz，4H)，2.45～2.48(t,4H),2.24(s,3H)。
HRMS(ESI,[M+H]+)m/z:498.2211。
Example 19N- (3- ((4- ((4- (4-acetylpiperazin-1-yl) -2-methoxyphenyl) amino) -5-trifluoromethylpyrimidin-2-yl) amino) phenyl) acrylamide (I-1)
Figure BDA0000887872830000411
The objective compound was prepared by the method of example 18 using compounds 6-1 and 7-1 as starting materials.
1H-NMR(300MHz,DMSO-d6):10.00(s,1H),9.61(s,1H),8.47(s,1H),8.30(s,1H),7.67(s,1H),7.28～7.37(m,4H),7.00～7.05(t,1H),6.91～6.94(d,J＝8.76Hz,2H),6.41～6.50(dd,1H),6.22～6.27(d,1H),5.71～5.76(d,1H),3.58(s,4H),3.13(t,2H),3.07(t,2H),2.05(s,3H)。
HRMS(ESI,[M+H]+)m/z:556.2248。
Example 20N- (3- ((4- ((2-methoxy-4-morpholinylphenyl) amino) -5-trifluoromethylpyrimidin-2-yl) amino) phenyl) acrylamide (I-6)
Figure BDA0000887872830000412
Compound 6-1(0.4g, 1.17mmol) was added to a solution of compound 7-5(0.292g, 1.404mmol) in 1, 4-dioxane (12mL) under nitrogen, followed by the base DIPEA (0.227g,1.75 mmol). The reaction was heated to 102 ℃ and allowed to react overnight. After TLC monitoring reaction is completed, rotary evaporation is carried out to remove the solvent, and the obtained crude product is separated and purified by column chromatography. The obtained solid product was dried by passing through a reduced-pressure oven at 50 ℃ to finally obtain the objective compound (0.439g) as a white solid.
1H-NMR(300MHz,DMSO-d6):10.02(s,1H),9.67(s,1H),8.31(s,1H),7.91(s,1H),7.63～7.68(br,2H),7.30～7.36(t,J＝9.81Hz,1H),7.03～7.08(t,J＝8.10Hz,1H),6.68(s,1H),6.41～6.50(m,2H),6.21～6.27(d,1H)5.71～5.75(m,1H),3.78(s,3H),3.75～3.76(t,4H),3.11～3.14(t,4H)。
HRMS(ESI,[M+H]+)m/z:515.1975。
Example 21A tert-butyl 4- (4- ((2- ((3-acrylamidophenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -3-methoxyphenyl) piperazine-1-carboxylic acid tert-butyl ester (I-7)
Figure BDA0000887872830000421
A solution of the compound of formula 6-1 (2.436g,7.11mmol) in 1, 4-dioxane (50mL) containing the compound of formula 7-9 (2.003g 6.498mmol) was added to a reaction flask under nitrogen and heated to 106 ℃ for reaction overnight. TLC monitored the reaction complete. The crude product was isolated by column chromatography to give 2.469g of the title compound.
1H-NMR(300M,CDCl3):8.26(s,1H),8.06-8.09(d,1H),7.82(s,1H),7.56(m,2H),7.36-7.44(m,2H),7.16-7.27(m,2H),6.41-6.54(m,3H),6.19-6.28(m,1H),5.72-5.76(d,1H),3.88(s,3H),3.57-3.60(t,4H),3.09-3.12(t,4H),1.49(s,9H)。
HRMS(ESI,[M+H]+)m/z:614.2706。
Example 21B N- (3((4- ((2-methoxy-4- (piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) acrylamide (I-8)
Figure BDA0000887872830000422
Adding TFA (15.134g,133mmol) and DCM solution of the compound (2.715g,4.424mmol) obtained in example 21A into a sealed tube under nitrogen protection, heating to 65 deg.C, reacting for 3hr, detecting by TLC to find reaction is complete, removing EA solution after vacuum drying, adjusting pH to alkalinity with 2M NaOH aqueous solution, extracting with EA, washing organic phase with Brine and MgSO4Drying, suction filtering organic phase, spin drying, and column chromatographyCrude product 2.160g was obtained and 500mg of the column-passed product was slurried with EA to give pure target compound (309 mg).
1H-NMR(300M,DMSO-d6):10.06(s,1H),9.70(s,1H),8.87(br,1H),8.31(s,1H),7.96(s,1H),7.62(m,2H),7.33-7.37(t,2H),7.01-7.06(t,1H),6.73(s,1H),6.41-6.50(m,2H),6.20-6.26(d,1H),5.71-5.75(d,1H),3.79(s,3H),3.35-3.36(d,4H),3.26-3.27(d,4H)。
HRMS(ESI,[M+H]+)m/z:514.2164。
Example 22N- (3- ((4- ((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) acrylamide (I-13)
Figure BDA0000887872830000431
A compound of formula 6-1 (400mg,1.17mmol), ethanol (15mL) as solvent, intermediate 7-7(426mg,1.4mmol) were added to a microwave tube, the reaction was microwaved for 2 hours and monitored by TLC for substantial completion. After the reaction mixture was returned to room temperature, stirring was continued for 30 minutes, and a large amount of white solid was precipitated. The reaction mixture was filtered, and the filter cake was washed with ethanol (5 mL. times.3), saturated aqueous sodium carbonate (10 mL. times.3), ethanol (5 mL. times.2) and ether (10 mL. times.3), respectively, and dried under reduced pressure to give the objective compound (603mg) as an off-white solid with a yield of 85%.
1H NMR(300MHz,DMSO-d6)δ10.14(s,1H),9.68(s,1H),8.30(s,1H),7.90(s,1H),7.72–7.53(m,2H),7.35(d,J＝8.1Hz,2H),7.05(t,J＝8.1Hz,1H),6.66(d,J＝2.5Hz,1H),6.56–6.40(m,2H),6.24(dd,J＝17.0,2.5Hz,1H),5.73(dd,J＝10.1,2.2Hz,1H),3.76(s,3H),3.59-3.14(m,4H),2.96-2.62(m,9H),2.50(s,3H),1.91(m,2H),1.56(m,2H)。
HRMS(ESI,[M+H]+)m/z：611.3035。
Example 23N- (3- ((4- ((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) acrylamide (I-17)
Figure BDA0000887872830000432
The objective compound was prepared by the method of example 22 using compounds 6-1 and 7-3 as starting materials.
1H NMR(300MHz,DMSO-d6)δ10.19(s,1H),9.69(s,1H),8.32(s,1H),7.97(s,1H),7.75-7.57(m,2H),7.34(t,J＝6.2Hz,2H),7.05(t,J＝8.1Hz,1H),6.75(d,J＝2.5Hz,1H),6.58–6.42(m,2H),6.24(dd,J＝17.0,2.1Hz,1H),5.74(dd,J＝10.0,2.1Hz,1H),3.80(s,3H),3.40-3.19(m,8H),2.82(s,3H)。
HRMS(ESI,[M+H]+)m/z：528.2330。
Example 24N- (3- ((4- ((2-methoxy-4- (4- (methylsulfonyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) acrylamide (I-31)
Figure BDA0000887872830000441
The objective compound was obtained as in example 22, starting from compounds 6-1 and 7-4.
1H NMR(300MHz,DMSO-d6)δ10.03(s,1H),9.69(s,1H),8.32(s,1H),7.92(s,1H),7.74-7.58(m,2H),7.33(dd,J＝13.0,8.2Hz,2H),7.07(t,J＝8.1Hz,1H),6.73(d,J＝2.5Hz,1H),6.46(dd,J＝17.0,9.9Hz,2H),6.24(dd,J＝17.0,2.2Hz,1H),5.74(dd,J＝10.0,2.2Hz,1H),3.80(s,3H),3.29-3.20(m,8H),2.95(s,3H)。
HRMS(ESI,[M+H]+)m/z：592.1946。
Example 25N- (3- ((4- ((4- (4-acetylpiperazin-1-yl) -2-methoxyphenyl) amino) -5-bromopyrimidin-2-yl) amino) phenyl) acrylamide (I-5)
Figure BDA0000887872830000442
Step (1)1- (4- (4- ((5-bromo-2-chloropyrimidin-4-yl) amino) -3-methoxyphenyl) piperazin-1-yl) ethanone (8-1)
Compound 5-2(1.0g,4.39mmol) and DIPEA (0.85g,6.59mmol) were added to a solution of compound 7-1(1.09g,4.39mmol) in n-BuOH under nitrogen. The reaction was heated to 110 ℃ and after 3 hours, TLC monitored the completion of the reaction and the reaction was allowed to cool to room temperature. Ice water (25mL) was added thereto, and after stirring for half an hour, the mixture was filtered with suction and washed with water. The obtained solid was dried by passing through a reduced-pressure oven at 50 ℃ to finally obtain the compound of formula 8-1 (1.81g) as a white solid (yield 93.63%).
1H-NMR(300MHz,CDCl3):8.29～8.32(d,J＝9.3Hz,1H),8.23(s,1H),7.93(s,1H),6.57～6.60(m,2H),3.94(s,3H),3.78～3.81(t,J＝4.53Hz,2H),3.63～3.66(t,J＝4.62Hz,2H),3.14～3.20(m,4H),2.15(s,3H)。
HRMS(ESI,[M+H]+)m/z:440.0483。
Step (2) N- (3- ((4- ((4- (4-acetylpiperazin-1-yl) -2-methoxyphenyl) amino) -5-bromopyrimidin-2-yl) amino) phenyl) acrylamide
Under nitrogen, compound 8-1(0.50g, 1.13mmol), compound 4-1(0.184g, 1.13mmol), 2-BuOH (15mL) were added to the flask, respectively, followed by TFA (0.194g, 1.70 mmol). The reaction was heated to 100 ℃ and after 6 hours, TLC monitored the reaction was complete, the reaction was allowed to cool to room temperature and saturated aqueous sodium carbonate was added to adjust the pH to alkaline. Extraction with DCM, combining the organic phases, washing once with saturated brine, separating the organic phase, drying with anhydrous magnesium sulphate. And removing the drying agent by suction filtration, removing the solvent by rotary evaporation, and separating the obtained crude product by column chromatography. The obtained solid product was dried by passing through a reduced-pressure oven at 50 ℃ to finally obtain the objective compound (0.24g) as a white solid.
1H-NMR(300MHz,DMSO-d6):10.02(s,1H),9.34(s,1H),8.17(s,1H),7.91～7.94(d,J＝8.7,1H),7.85(s,1H),7.76(s,1H),7.35～7.37(d,J＝8.10Hz,1H),7.28～7.31(d,J＝8.04Hz,1H),7.08～7.14(t,2H),6.41～6.50(m,1H),6.21～6.27(dd,1H),5.71～5.75(dd,1H),3.79(s,3H),3.59(s,4H),3.15(t,2H),3.09(t,2H),2.06(s,3H)。
HRMS(ESI,[M+H]+)m/z:568.1494。
Example 26N- (3- ((4- ((4- (4-acetylpiperazin-1-yl) -2-methoxyphenyl) amino) -5-fluoropyrimidin-2-yl) amino) phenyl) acrylamide (I-3)
Figure BDA0000887872830000451
Step (1)1- (4- (4- ((2-chloro-5-fluoropyrimidin-4-yl) amino) -3-methoxyphenyl) piperazin-1-yl) ethanone (8-2)
Starting from compounds 5-3 and 7-1, compound 8-2 was prepared by the method of step (1) of reference example 25.
1H-NMR(300MHz,CDCl3):8.30～8.33(d,J＝8.67Hz,1H),7.99～8.00(d,J＝2.67Hz，1H),7.51(s,1H),6.55～6.59(m,2H),3.92(s,3H),3.78～3.81(t,J＝4.92Hz,2H),3.63～3.66(t,J＝4.68Hz,2H),3.13～3.19(m,4H),2.15(s,3H)。
HRMS(ESI,[M+H]+)m/z:380.1275。
Step (2) N- (3- ((4- ((4- (4-acetylpiperazin-1-yl) -2-methoxyphenyl) amino) -5-fluoropyrimidin-2-yl) amino) phenyl) acrylamide
The objective compound was prepared by the method of step (2) of reference example 25 using compounds 4-1 and 8-2 as starting materials.
1H-NMR(300MHz,DMSO-d6):9.98(s,1H),9.09(s,1H),8.21(s,1H),7.99～8.01(d,J＝3.6Hz，1H),7.74(s,1H),7.59～7.62(d,J＝8.67Hz,1H),7.35～7.38(d,J＝8.22Hz,1H),7.24～7.27(d,J＝8.16Hz,1H),7.02～7.08(t,J＝8.1Hz,1H),6.69～6.70(d,J＝2.04Hz,1H),6.42～6.50(m,2H),6.20～6.26(dd,J＝1.89Hz,1H),5.70～5.74(dd,J＝1.83,1H),3.80(s,3H),3.59(br,4H),3.17(t,2H),3.10(t,2H),2.06(s,3H)。
HRMS(ESI,[M+H]+)m/z:506.2284。
Example 27N- (3- ((4- ((4- (4-acetylpiperazin-1-yl) -2-methoxyphenyl) amino) -5-chloropyrimidin-2-yl) amino) phenyl) acrylamide (I-4)
Figure BDA0000887872830000461
Step (1)1- (4- (4- ((2, 5-chloropyrimidin-4-yl) amino) -3-methoxyphenyl) piperazin-1-yl) ethanone (8-3)
Starting from compounds 5-4 and 7-1, compound 8-3 was prepared by the method of step (1) of reference example 25.
1H-NMR(300MHz,CDCl3):8.29～8.32(d,J＝8.58Hz,1H),8.12(s,1H),7.88(s,1H),6.56～6.59(m,2H),3.93(s,3H),3.78～3.79(t,2H),3.63～3.64(t,2H),3.14～3.16(m,4H),2.15(s,3H)；
HRMS(ESI,[M+H]+)m/z:396.0982。
Step (2) N- (3- ((4- ((4- (4-acetylpiperazin-1-yl) -2-methoxyphenyl) amino) -5-chloropyrimidin-2-yl) amino) phenyl) acrylamide
The objective compound was prepared by the method of step (2) of reference example 25 using compounds 4-1 and 8-3 as starting materials.
1H-NMR(300MHz,DMSO-d6):10.02(s,1H),9.31(s,1H),8.08(s,1H),7.99(s,1H),7.79～7.82(d,J＝8.731H),7.73(s,1H),7.35～7.38(d,J＝8.13Hz,1H),7.27～7.29(d,J＝7.65Hz,1H),7.06～7.11(t,J＝8.1Hz,1H),6.71～6.72(d,J＝2.01Hz,1H),6.41～6.50(m,2H),6.20～6.27(dd,J＝1.80Hz,1H),5.71～5.76(dd,J＝1.80,1H),3.83(s,3H),3.59(br,4H),3.16(t,2H),3.10(t,2H),2.06(s,3H)。
HRMS(ESI,M+H+)m/z:522.1998。
Example 28N- (3- ((4- ((4- (4-acetylpiperazin-1-yl) -2-methoxyphenyl) amino) pyrimidin-2-yl) amino) phenyl) acrylamide (I-2)
Figure BDA0000887872830000471
Step (1)1- (4- (4- ((2-chloropyrimidin-4-yl) amino) -3-methoxyphenyl) piperazin-1-yl) ethanone (8-4)
Starting from compounds 5-5 and 7-1, compound 8-4 was prepared by the method of step (1) of reference example 25.
1H-NMR(300MHz,CDCl3):8.04～8.06(d,J＝5.88Hz,1H),7.55～7.62(br,1H),7.12(s,1H),6.52～6.54(d,J＝6.51Hz,2H),6.44～6.46(d,J＝5.91Hz,1H),3.85(s,3H),3.78～3.81(t,J＝4.652H),3.63～3.66(t,J＝4.35Hz,2H),3.14～3.21(m,4H),2.15(s,3H)。
HRMS(ESI,[M+H]+)m/z:362.1374。
Step (2) N- (3- ((4- ((4- (4-acetylpiperazin-1-yl) -2-methoxyphenyl) amino) pyrimidin-2-yl) amino) phenyl) acrylamide
The objective compound was prepared by the method of step (2) of reference example 25 using compounds 4-1 and 8-4 as starting materials.
1H-NMR(300MHz,DMSO-d6):9.97(s,1H),8.99(s,1H),8.26(s,1H),7.86～7.92(dd,1H),7.66～7.69(d,J＝8.31Hz,1H),7.44～7.47(d,J＝7.89Hz,1H),7.30～7.32(d,J＝7.86Hz,1H),7.09～7.14(t,J＝8.07Hz,1H),6.67(s,1H),6.43～6.52(m,2H),6.27(s,1H),6.15～6.22(m,1H),5.71～5.74(d,J＝9.99Hz,1H),3.81(s,3H),3.58～3.59(m,4H),3.14(t,2H),3.09(t,2H),2.05(S,3H)。
HRMS(ESI,[M+H]+)m/z:488.2366。
Example 29N- (6- ((4- ((4- (4-acetylpiperazin-1-yl) -2-methoxyphenyl) amino) -5-chloropyrimidin-2-yl) amino) pyridin-2-yl) acrylamide (I-12)
Figure BDA0000887872830000472
Step (1)1- (4- (4- ((2- ((6-aminopyrimidin-2-yl) amino) -5-chloropyrimidin-4-yl) amino) -3-methoxyphenyl) piperazin-1-yl) ethanone
Weighing the compounds 8-3(500mg,1.26mmol), 2, 6-diaminopyridine 44(138mg,1.26mmol), solvent 1, 4-dioxane 20mL, adding cesium carbonate (822mg,2.52mmol), adding catalyst tris (dibenzylideneacetone) dipalladium (116mg,126umol) and ligand 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (73mg,126umol, also known as Xantphos), performing microwave reaction at 120 ℃, for 2hr, monitoring by TLC for disappearance of raw material points, performing suction filtration on reaction liquid, passing the filtrate through a silica gel column to obtain a crude product, and performing reverse phase separation by using a high pressure preparation column to obtain the target compound (220 mg).
1H-NMR(300MHz,DMSO-d6):8.59(s，1H)，8.10-8.14(d，2H)，7.70-7.73(d，1H)，7.03-7.15(m，3H)，6.66-6.72(m，1H)，6.52-6.55(dd，1H)，6.02-6.05(d，1H)，5.63(s，1H)，3.80(s，3H)，3.60(s，4H)，3.14-3.18(m，4H)，2.06(s，3H)。
HRMS(ESI+,[M+H]+)m/z：469.1947。
Step (2) N- (6- ((4- ((4- (4-acetylpiperazin-1-yl) -2-methoxyphenyl) amino) -5-chloropyrimidin-2-yl) amino) pyridin-2-yl) acrylamide
Taking the compound (200mg,426umol) obtained in the step 1, adding 10mL of DMF for dissolving, adding 30mL of THF and 65mg (640umol) of triethylamine, dropwise adding acryloyl chloride at-5 ℃, reacting for 3hr, reacting overnight at rt, performing rotary evaporation to obtain a reaction solution, adding saturated Na2CO3Diluting the solution, extracting and drying by EA, carrying out rotary evaporation on the filtrate, preparing sand from the residue, passing through a silica gel column, and eluting to obtain the target compound (90 mg).
1H-NMR(300MHz,DMSO-d6)：10.28(s，1H)，8.83(s，1H)，8.27(s，1H)，8.12(s，1H)，7.69-7.72(m，1H)，7.58-7.61(d，1H)，7.47-7.49(m，2H)，6.73-6.74(d，1H)，6.59-6.68(m，1H)，6.50-6.54(dd，1H)，6.25-6.31(dd，1H)，5.73-5.76(t，1H)，3.79(s，3H)，3.61(s，4H)，3.15-3.20(m，4H)，2.06(s，3H)。
HRMS(ESI+,[M+H]+)m/z：523.2028。
Example 30N- (5- ((4- ((4- (4-acetylpiperazin-1-yl) -2-methoxyphenyl) amino) -5-chloropyrimidin-2-yl) amino) -2-methoxyphenyl) acrylamide (I-9)
Figure BDA0000887872830000491
Step (1) N- (2-methoxy-5-nitrophenyl) acrylamide (3-4)
DIPEA (0.85g, 6.55mmol) was added to a solution of compound 2-4(1.0g, 5.95mmol) in DCM (50mL) under nitrogen. After stirring at 0 ℃ for half an hour, acryloyl chloride (0.57g, 6.25mmol) was added dropwise to the reaction. The reaction was gradually warmed to room temperature and TLC monitored for completion of the reaction. Adding saturated sodium carbonate aqueous solution to quench the reaction, separating liquid, adding anhydrous magnesium sulfate into the organic phase and drying. Removing the drying agent by suction filtration, removing the solvent by rotary evaporation to obtain a solid crude product, and adding PE (polyethylene), EA (4:1 beating. The resulting solid product was finally dried by passing through a reduced-pressure oven at 50 ℃ to finally obtain the compound of formula 3-4 (1.67g) as a yellow solid.
1H-NMR(300MHz,CDCl3):9.37～9.38(d,J＝2.67Hz,1H),7.98～8.02(dd,1H),7.93(s,1H),6.94～6.97(d,J＝9.03Hz,1H),6.44～6.50(m,1H),6.27～6.36(m,1H),5.81～5.85(d,J＝9.96Hz,1H).4.03(s,3H)。
HRMS(ESI,[M+H]+)m/z:223.0712。
Step (2) N- (5-amino-2-methoxyphenyl) acrylamide (4-4)
Compound 3-4(1.2g, 5.4mmol) was dissolved in ethanol (8mL) and tetrahydrofuran (8mL) under nitrogen, tin dichloride dihydrate (4.87g, 21.6mmol) was added to the reaction in portions, and after the addition was complete, the reaction was heated to 70 ℃. After 2.5 hours of reaction, TLC monitored the reaction for completion. The solvent was removed by rotary evaporation and deionized water (20mL) was added. Solid sodium hydroxide was added at 0 ℃ to a strongly basic pH. Extraction was then carried out with DCM, the combined organic phases were washed once with saturated brine and the organic phase was dried over anhydrous magnesium sulfate. The drying agent was removed by suction filtration and the solvent was removed by rotary evaporation. The resulting solid product was finally dried by passing through a reduced-pressure oven at 50 ℃ to finally obtain a compound of formula 4-4 (0.73 g).
1H-NMR(300MHz,CDCl3):7.96(s,1H),7.87(br,1H),6.68～6.71(d,8.58Hz,1H),6.36～6.42(m,2H),6.21～6.30(dd,1H),5.71～5.75(dd,1H),3.81(s,3H)。
HRMS(ESI,[M+H]+)m/z:193.0967。
Step (3) N- (5- ((4- ((4- (4-acetylpiperazin-1-yl) -2-methoxyphenyl) amino) -5-chloropyrimidin-2-yl) amino) -2-methoxyphenyl) acrylamide
The objective compound was prepared by the method of step (2) of reference example 25 using compounds 4-4 and 8-3 as starting materials.
1H-NMR(300MHz,DMSO-d6):9.28(s,1H),9.08(s,1H),8.09(s,1H),8.04(s,1H),7.84～7.88(m,1H),7.33～7.35(d,J＝5.01Hz,1H),6.83～6.84(d,J＝5.34Hz,1H),6.64～6.70(m,1H),6.45～6.47(d,J＝5.04Hz,1H),6.18～6.21(d,1H),5.68～5.74(m,1H),3.83(s,3H),3.79(s,3H),3.59(s,4H),3.17(t,2H),3.11(t,2H),2.05(s,3H)。
HRMS(ESI,[M+H]+)m/z:552.2110。
Example 31N- (3- ((4- ((4- (4-acetylpiperazin-1-yl) -2-methoxyphenyl) amino) -5-chloropyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (I-10)
Figure BDA0000887872830000501
Step (1)1- (4- (4- ((5-chloro-2- ((2-methoxy-5-nitrophenyl) amino) pyrimidin-4-yl) amino) -3-methoxyphenyl) piperazin-1-yl) ethanone (10-1)
Compound 10-1 was prepared by the method of step (2) of reference example 25 using compounds 2-4 and 8-3 as starting materials.
1H-NMR(300MHz,CDCl3):9.16～9.17(d,J＝2.28Hz,1H),8.11～8.13(d,J＝8.64Hz,1H),8.07(s,1H),7.86～7.91(dd,1H),7.71(br,1H),7.65(s,1H),6.89～6.92(d,J＝8.97Hz),6.52～6.57(m,2H),4.00(s,3H),3.92(s,3H),3.80(t,2H),3.65(t,3H),3.16～3.21(m,4H),2.15(s,3H)。
HRMS(ESI,[M+H]+)m/z:528.1745。
Step (2)1- (4- (4- ((2- ((5-amino-2-methoxyphenyl) amino) -5-chloropyrimidin-4-yl) amino) -3-methoxyphenyl) piperazin-1-yl) ethanone
Under nitrogen, compound 10-1(0.86g, 1.63mmol), iron powder (0.46g, 8.15mmol), ammonium chloride (0.44g, 8.15mmol), ethanol (15mL), and water (5mL) were added to the reaction flask, respectively. The reaction was heated to 85 deg.C for reaction. Two hours, TLC monitored the reaction completion. The reaction was quenched by adding saturated aqueous sodium carbonate solution, extracted with DCM, the organic phases combined and dried over anhydrous magnesium sulphate. The drying agent was removed by suction filtration and the solvent was removed by rotary evaporation. The resulting solid product was finally dried by passing through a reduced-pressure oven at 50 ℃ to finally obtain the objective compound (0.76g) in a yield of 93.83%.
1H-NMR(300MHz,DMSO-d6):8.12(s,1H),8.03(s,1H),7.53～7.57(m,2H),7.21～7.22(d,J＝2.19Hz,1H),6.67～6.72(m,2H),6.54～6.57(d,8.7Hz,1H),6.13～6.17(dd,1H),3.79(s,3H),3.69(s,3H),3.59(br,4H),3.14～3.18(m,4H),2.06(s,3H)。
HRMS(ESI,[M+H]+)m/z:498.2033。
Step (3) N- (3- ((4- ((4- (4-acetylpiperazin-1-yl) -2-methoxyphenyl) amino) -5-chloropyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (I-10)
The title compound was prepared by reacting the compound obtained in step 2 with acrylic acid chloride in the same manner as in step (2) of reference example 29.
1H-NMR(300MHz,DMSO-d6):9.92(s,1H),8.08(s,1H),7.84～8.02(m,3H),7.46～7.48(dd,1H),6.97～6.99(d,J＝5.31Hz,1H),6.67～6.68(d,J＝1.41Hz,1H),6.41～6.46(dd,1H),6.35～6.37(dd,1H),6.21～6.24(dd,1H),5.70～5.72(dd,1H),3.85(s,3H),3.78(s,3H),3.56～3.57(m,4H)，3.11(t,2H),3.05(t,3H),2.05(s,3H)。
HRMS(ESI,[M+H]+)m/z:552.2130。
Example 32N- (3- ((5-chloro-4- ((4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (I-28)
Figure BDA0000887872830000521
Step (1)2, 5-dichloro-N- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) pyrimidin-4-amine (8-5)
Starting from compounds 7-6 and 5-4, compound 8-5 was prepared by the method of step (1) of reference example 25.
1H-NMR(300MHz,DMSO-d6):8.81(s,1H),8.26(s,1H),7.24～7.27(d,J＝8.67Hz,1H),6.64～6.65(d,J＝2.25Hz,1H),6.51～6.54(dd,1H),3.77(s,3H),3.71～3.77(t,2H),2.67～2.74(t,2H),2.19(s,6H),1.81～1.85(m,2H),1.40～1.53(m,2H)。
HRMS(ESI,[M+H]+)m/z:396.1351。
Step (2) N- (3- ((5-chloro-4- ((4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (I-28)
The objective compound (I-28) was obtained by the method of step (2) of reference example 25, starting from compounds 8-5 and 4-2.
1H-NMR(300MHz,DMSO-d6):9.98(s,1H),8.09(s,1H),8.01～8.02(d,J＝2.04Hz,1H),7.92(s,1H),7.84～7.87(m,2H),7.47～7.51(dd,1H),6.97～7.00(d,J＝8.88Hz,1H),6.65～6.66(d,J＝1.98Hz,1H),6.35～6.49(m,2H),6.20～6.26(dd,1H),5.70～5.74(dd,1H),3.84(s,3H),3.78(s,3H),3.75(m,2H),3.06(m,2H),2.68(s,6H),1.99～2.03(m,2H),1.59～1.70(m,2H)。
HRMS(ESI,[M+H]+)m/z:552.2531。
Example 33N, N' - ((((5- (trifluoromethyl) pyrimidin-2, 4-diyl) bisamino) bis (3, 1-phenylene)) bisacrylamide (I-43)
Figure BDA0000887872830000531
Step (1) N- (3- ((2-chloro-5- (trifluoromethyl) pyrimidin-4-yl-amino) phenyl) acrylamide (8-6)
Adding a compound of formula 45 (3.2g, 19.73mmol) into a reaction bottle under nitrogen, dissolving the compound in n-butanol, dropwise adding 2, 4-dichloro-5-trifluoromethylpyrimidine 5-1(4.28g, 19.73mmol) and DIPEA (3.06g, 23.68mmol) at 0 ℃, reacting for 2-3 hrs at room temperature, detecting by TLC that a raw material point disappears, evaporating the reaction liquid to be nearly dry, adding saturated Na2CO3Adjusting pH of the aqueous solution to 10, extracting with EA, drying, passing through silica gel column, eluting with PE-EA (5:1 to 2:1), mixing, concentrating to obtain target product 6.35g, and preparing target product 8-6 by HPLC.
1H-NMR(300M，DMSO-d6):10.22(s，1H)，9.57(s，1H)，8.58(s，1H)，7.79(s，1H)，7.49-7.52(d，1H)，7.33-7.38(t，1H)，7.13-7.16(d，1H)，6.40-6.49(m，1H)，6.23-6.29(d，1H)，5.75-5.78(d，1H)。
HRMS(ESI,[M+H]+)m/z:343.0566。
Step (2) N, N' - ((((5- (trifluoromethyl) pyrimidin-2, 4-diyl) bisamino) bis (3, 1-phenylene)) bisacrylamide (I-43)
The objective compound (I-43) was prepared by the method of step (2) of reference example 25, starting from compounds 8-6 and 45.
1H-NMR(300MHz,DMSO-d6):10.13(s,1H),9.96(s,1H),9.67(s,1H),8.73(s,1H),8.37(s,1H),7.76(s,1H),7.64(s,1H),7.52～7.55(d,J＝7.83Hz,1H),7.42～7.45(d,J＝8.10Hz,1H),7.21～7.33(m,1H),6.94～7.00(t,J＝7.77Hz,1H),6.40～6.49(m,2H),6.21～6.29(m,2H),5.71～5.77(m,2H)。
HRMS(ESI,[M+H]+)m/z:469.1588。
Example 34N, N' - (((5-bromopyrimidin-2, 4-diyl) bisamino) bis (3, 1-phenylene)) bisacrylamide (I-44)
Figure BDA0000887872830000532
Step (1) N- (3- ((5-bromo-2-chloropyrimidin-4-yl) amino) phenyl) acrylamide (8-7)
Starting from compounds 5-2 and 45, compounds 8-7 were prepared by the method of step (1) of reference example 33.
HRMS(ESI,[M+H]+)m/z:352.9794。
Step (2) N, N' - ((((5-bromopyrimidine-2, 4-diyl) bisamino) bis (3, 1-phenylene)) bisacrylamide (I-44)
The objective compound (I-44) was obtained by the method of step (2) of reference example 25, starting from compounds 8-7 and 45.
1H-NMR(300MHz,DMSO-d6):10.11(s,1H),9.98(s,1H),9.30(s,1H),8.62(s,1H),8.22(s,1H),7.84(s,1H),7.69(s,1H),7.45～7.47(d,2H),7.36～7.39(d,J＝8.55Hz,1H),7.22～7.30(m,2H),7.00～7.05(t,1H),6.40～6.49(m,2H),6.20～6.29(m,2H),5.70～5.77(m,2H)。
HRMS(ESI,[M+H]+)m/z:479.0818。
Example 35N- (3- ((4- ((4- (4-acetylpiperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) acrylamide (I-39)
Figure BDA0000887872830000541
The objective compound (I-39) was prepared by the method of reference example 22 starting from compounds 6-1 and 7-14.
1H-NMR(300MHz,DMSO-d6):10.00(s,1H),9.61(s,1H),8.47(s,1H),8.30(s,1H),7.67(s,1H),7.28～7.37(m,4H),7.00～7.05(t,1H),6.91～6.94(d,J＝8.76Hz,2H),6.41～6.50(dd,1H),6.22～6.27(d,1H),5.71～5.76(d,1H),3.58(s,4H),3.13(t,2H),3.07(t,2H),2.05(s,3H)。
HRMS(ESI,[M+H]+)m/z:526.2182。
Example 36N- (4-methoxy-3- ((4- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) acrylamide (I-47)
Figure BDA0000887872830000542
The objective compound (I-47) was prepared by the method of reference example 22 starting from compounds 6-2 and 7-2.
1H NMR(500MHz,DMSO-d6)δ10.09(s,1H),8.40(brs,1H),8.30(d,J＝14.9Hz,2H),7.88(brs,1H),7.51(dd,J＝8.9,2.6Hz,1H),7.37-7.31(m,2H),6.99(d,J＝8.9Hz,1H),6.78(d,J＝8.6Hz,2H),6.49(dd,J＝17.0,10.1Hz,1H),6.25(dd,J＝17.0,2.1Hz,1H),5.78-5.71(m,1H),3.75(s,3H),3.28-3.06(m,4H),2.75-2.59(m,4H),2.39(s,3H)。
HRMS(ESI,[M+H]+)m/z：528.2358。
Example 37N- (4-methoxy-3- ((4- ((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) acrylamide (I-48)
Figure BDA0000887872830000551
The objective compound (I-48) was prepared by the method of reference example 22 starting from compounds 6-2 and 7-3.
1H-NMR(300MHz,DMSO-d6):10.02(s,1H),8.64(br,1H),8.30(s,1H),7.86(s,1H),7.79～7.81(d,1H),7.66(s,1H),7.55～7.57(m,1H),7.02～7.04(D,1H),6.62(s,1H),6.40～6.45(m,1H),6.22～6.25(dd,2H),5.72～5.74(d,1H),3.82(s,3H),3.76(s,3H),3.09(s,4H),2.47～2.51(d,4H),2.25(s,3H)。
HRMS(ESI,[M+H]+)m/z:558.2838。
EXAMPLE 38N- (2, 4-dimethoxy-5- ((4- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) acryloylamide (I-52)
Figure BDA0000887872830000552
The objective compound (I-52) was prepared by the method of reference example 22 starting from compounds 6-3 and 7-2.
1H-NMR(500MHz,DMSO-d6)δ9.31(s,1H),8.46(brs,1H),8.22(s,1H),8.15(s,1H),8.08(s,1H),7.31(d,J＝8.4Hz,2H),6.83–6.63(m,4H),6.19(dd,J＝17.0,2.0Hz,1H),5.68(dd,J＝10.1,2.1Hz,1H),3.89(s,3H),3.78(s,3H),3.11-3.03(m,4H),2.49-2.45(m,4H),2.25(s,3H)。
HRMS(ESI,[M+H]+)m/z：558.2521。
Example 39N- (3- ((4- ((4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) acrylamide (I-58)
Figure BDA0000887872830000561
The objective compound (I-58) was prepared by the method of reference example 22 starting from compounds 6-1 and 7-6.
1H-NMR(300MHz,DMSO-d6):10.06(s,1H),9.70(s,1H),8.31(s,1H),7.93(s,1H),7.67(br,1H),7.60(br,1H),7.32～7.37(m,2H),7.04～7.07(t,1H),6.66～6.67(d,1H),6.44～6.49(m,2H),6.23～6.27(dd,1H),5.73～5.77(dd,1H),3.78(s,3H),3.72～3.75(d,2H),2.66～2.71(t,2H),2.26(s,6H),1.86`1.88(d,2H),1.48～1.54(m,2H)。
HRMS(ESI,[M+H]+)m/z:556.3066。
Example 40N- (3- ((4- ((4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) acrylamide (I-59)
Figure BDA0000887872830000562
The objective compound (I-59) was prepared by the method of reference example 22 starting from compounds 6-3 and 7-6.
1H-NMR(300MHz,DMSO-d6):9.341(s,1H),8.66(s,1H),8.24(s,1H),8.08(s,1H),7.81(br,1H),7.55(s,1H),6.82(s,1H),6.64～6.70(dd,1H),6.60(s,1H),6.26(br,1H),6.15～6.19(dd,1H),5.66～5.68(d,1H),3.91(s,3H),3.82(s,3H),3.78(s,3H),3.66～3.68(d,2H),2.60～2.65(t,2H),2.29(s,6H),1.86～1.88(d,2H),1.47`1.54(m,2H)。
HRMS(ESI,[M+H]+)m/z:616.2865。
Example 41N- (3- ((4- ((4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (I-60)
Figure BDA0000887872830000571
The objective compound (I-60) was prepared by the method of reference example 22 starting from compounds 6-2 and 7-6.
1H NMR(500MHz,DMSO-d6)δ10.03(s,1H),8.65(brs,1H),8.30(s,1H),7.85(brs,1H),7.79(d,J＝8.9Hz,1H),7.65(s,1H),7.58(dd,J＝8.9,2.6Hz,1H),7.03(d,J＝8.9Hz,1H),6.61(d,J＝2.5Hz,1H),6.44(dd,J＝17.0,10.1Hz,1H),6.29–6.19(m,2H),5.73(dd,J＝10.1,2.1Hz,1H),3.82(s,3H),3.76(s,3H),3.68-3.59(m,2H),2.66-2.55(m,2H),2.32-2.22(m,1H),2.26(s,6H),1.88–1.78(m,2H),1.53-1.41(m,2H)。
HRMS(ESI,[M+H]+)m/z：586.2778。
Example 42N- (4-methoxy-3- ((4- ((2-methoxy-4- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) acryloylamide (I-63)
Figure BDA0000887872830000572
The objective compound (I-63) was prepared by the method of reference example 22 starting from compounds 6-2 and 7-7.
1H NMR(500MHz,DMSO-d6)δ10.02(s,1H),8.64(brs,1H),8.30(s,1H),7.86(brs,1H),7.79(d,J＝8.8Hz,1H),7.65(s,1H),7.57(dd,J＝8.9,2.6Hz,1H),7.03(d,J＝8.9Hz,1H),6.60(d,J＝2.5Hz,1H),6.43(dd,J＝16.9,10.1Hz,1H),6.28-6.20(m,2H),5.73(dd,J＝10.1,2.1Hz,1H),3.81(s,3H),3.76(s,3H),3.67-3.59(m,2H),3.42-3.29(m,4H),2.64-2.52(m,3H),2.42-2.24(m,4H),2.17(s,3H),1.86-1.77(m,2H),1.54-1.42(m,2H)。
HRMS(ESI,[M+H]+)m/z：641.3208。
Example 43N- (3- ((4- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) acrylamide (I-79)
Figure BDA0000887872830000581
Step (1) N1- (3-methoxy-4-nitrophenyl) -N1, N2, N2-trimethylethane-1, 2-diamine (46)
Compound 46 was produced by the method of step (1) of reference example 6, starting from compound 15 and N1, N1, N2-trimethylethane-1, 2-diamine.
1H-NMR(300MHz,DMSO-d6):7.88～7.91(d,1H),6.35～6.39(dd,1H),6.24～6.25(d,J＝2.28Hz,1H),3.90(s,3H),3.54～3.58(t,J＝6.84Hz,2H),3.07(s,3H),2.41～2.45(t,J＝6.84Hz,2H),2.20(s,6H)。
HRMS(ESI,[M+H]+)m/z:254.1505。
Step (2) N1- (2- (dimethylamino) ethyl) -3-methoxy-N1-methylbenzene-1, 4-diamine (7-24)
Starting from compound 46, compounds 7 to 24 were prepared by the method of example 6, step (2).
1H-NMR(300MHz,DMSO-d6):6.45～6.49(dd,1H),6.31～6.32(d,J＝2.43Hz,1H),6.11～6.14(dd,1H),3.73(s,3H),3.20～3.25(t,J＝7.02Hz,2H),2.75(s,3H),2.30～2.35(t,J＝7.32Hz,2H),2.15(s,6H)。
HRMS(ESI,[M+H]+)m/z:224.1745。
Step (3) N- (3- ((4- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) acrylamide (I-79)
The objective compound (I-79) was prepared by the method of reference example 22 starting from compounds 6-1 and 7-24.
1H-NMR(300MHz,DMSO-d6):10.04(s,1H),9.66(s,1H),8.29(s,1H),7.91(s,1H),7.65(br,1H),7.47(br,1H),7.40～7.42(d,J＝4.8Hz,1H),7.29～7.30(d,J＝4.5Hz,1H),7.00(br,1H),6.43～6.48(m,1H),6.39(s,1H),6.23～6.26(m,2H),5.72～5.74(d,J＝6.0Hz,1H),3.76(s,3H),3.44～3.47(t,J＝3.9Hz,2H),2.95(s,3H),2.42～2.45(t,J＝3.9Hz,2H),2.22(s,6H)。
HRMS(ESI,[M+H]+)m/z:530.3002。
Example 44N- (3- ((4- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide (I-80)
Figure BDA0000887872830000591
The objective compound (I-80) was prepared by the method of reference example 22 starting from compounds 6-2 and 7-24.
1H-NMR(300MHz,DMSO-d6):9.99(s,1H),8.53(br,1H),8.27(s,1H),7.90(s,1H),7.69～7.71(d,1H),7.62(br,1H),7.53～7.56(dd,1H),7.00～7.02(d,1H),6.40～6.45(dd,1H),6.34(s,1H),6.21～6.25(m,1H),6.05～6.06(d,1H),5.71～5.73(d,1H),3.81(s,3H),3.76(s,3H),3.38～3.41(t,2H),2.87(s,3H),2.38～2.40(t,2H),2.22(s,6H)。
HRMS(ESI,[M+H]+)m/z:560.3014。
Experimental example 1 evaluation of inhibitory activity of epidermal growth factor receptor EGFR and oncogenic driver ALK.
The purpose of this experiment was to evaluate and compare the effect of some of the compounds synthesized in this patent on the proliferation of tumor cells H1975(EGFR L858R/T790M), NCI-H3122(ALK), NCI-H292(EGFR), or A431(EGFR) cultured in vitro.
The preparation method comprises the following steps: preparing 10mM stock solutions of all samples to be tested by using DMSO; when in use, the culture solution is prepared to the required concentration.
Cell line A431 cells were purchased from cell bank of Shanghai Life sciences of Chinese academy of sciences and cultured in RPMI 1640/DMEM medium containing 10% Fetal Bovine Serum (FBS). Lung cancer NCI-H292(EGFR WT) was purchased from the Shanghai Living sciences cell bank of Chinese academy of sciences, H1975 cells were purchased from the Shanghai Living sciences cell bank of Chinese academy of sciences, and NCI-H3122 was purchased from the National Cancer Institute (NCI), and they were cultured in RPMI 1640 medium containing 10% Fetal Bovine Serum (FBS).
Reagents and instruments: RPMI-1640 was purchased from Gibco BRL; FBS was purchased from Hyclone; multifunctional microplate reader Synergy H4 was purchased from BioTek corporation; sulfonylrhodamine B (SRB) was purchased from Sigma.
Test methods SRB method: the SRB protein staining method is used for detecting the inhibition effect of the medicine on the proliferation and growth of tumor cells. The method mainly comprises the following steps: cells in logarithmic growth phase are inoculated in a 96-well culture plate, drugs with different concentrations (1-10000nM) are added, 3 multiple wells are arranged for each concentration, and a solvent control with corresponding concentration is arranged at the same time. Tumor cells were incubated at 37 ℃ with 5% CO2Cultured under the conditions for 72 hours. The cells were stained with SRB at room temperature, and finally dissolved in Tris solution, OD was measured at 510nm using a microplate reader (BioTek), and the cell growth inhibition rate was calculated according to the following formula:
inhibition rate (OD value)Control wellOD valueMedicine feeding hole) OD valueControl well×100％。
Calculating half inhibitory concentration IC according to non-linear regression method based on each concentration inhibition rate50。
The tests were carried out in three batches and the results are shown in tables 1,2 and 3 below:
TABLE 1 IC inhibition of proliferation of in vitro cultured tumor cells by compounds50(first batch)
Figure BDA0000887872830000601
TABLE 2 IC inhibition of proliferation of in vitro cultured tumor cells by compounds50(second batch)
Figure BDA0000887872830000602
Figure BDA0000887872830000611
TABLE 2 IC inhibition of proliferation of in vitro cultured tumor cells by compounds50(third batch)
Figure BDA0000887872830000612

Claims (12)

1. A compound according to (I) or a pharmaceutically acceptable salt thereof:
Figure FDA0002920771460000011
wherein the content of the first and second substances,
x or Y are each independently selected from CH;
R1is selected from-CF3；
R2Is selected from-OC1-6An alkyl group;
R6is selected from H;
R3or R5Each independently selected from H;
R4is selected from
Figure FDA0002920771460000012
R7Is selected from H;
z is selected from NR11；
The R is9、R10Or R11Each independently selected from H or-C1-4An alkyl group.
2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is2Is selected from-OC1-4An alkyl group.
3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is2Is selected from-OC1Alkyl or-OC2An alkyl group.
4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is9、R10Or R11Each independently selected from H, -C1Alkyl or-C2An alkyl group.
5. A compound as shown below, or a pharmaceutically acceptable salt thereof:
Figure FDA0002920771460000021
6. use of a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an EGFR and ALK mediated disease.
7. The use according to claim 6, wherein the EGFR-mediated disease is selected from EGFR-L858R or EGFR-T790M mutation activation-mediated diseases.
8. The use according to claim 6, wherein the ALK-mediated disease is selected from the group consisting of NPM-ALK or EML4-ALK gene fusion-mediated diseases.
9. The use according to claim 6, wherein the EGFR and ALK mediated disease is cancer.
10. Use according to claim 9, wherein the cancer is selected from lung cancer, head and neck cancer, breast cancer, prostate cancer, esophageal cancer, rectal cancer, colon cancer, nasopharyngeal cancer, uterine cancer, pancreatic cancer, lymphoma, leukemia, osteosarcoma, melanoma, renal cancer, gastric cancer, liver cancer, bladder cancer, thyroid cancer or colorectal cancer.
11. Use according to claim 10, wherein the lung cancer is selected from non-small cell lung cancer.
12. A pharmaceutical composition comprising a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
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CN107674022A (en) * 2017-10-12 2018-02-09 黑龙江鑫创生物科技开发有限公司 A kind of pa wins the synthetic method of XiLin intermediate
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102482277A (en) * 2009-05-05 2012-05-30 达纳-法伯癌症研究所有限公司 Egfr inhibitors and methods of treating disorders
CN105384694A (en) * 2014-08-22 2016-03-09 四川海思科制药有限公司 Substituted aminopyrimidine derivative, preparation method therefor and pharmaceutical application thereof
CN105384695A (en) * 2014-08-22 2016-03-09 四川海思科制药有限公司 Pyrimidine derivative, preparation method therefor and application thereof in medicine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102482277A (en) * 2009-05-05 2012-05-30 达纳-法伯癌症研究所有限公司 Egfr inhibitors and methods of treating disorders
CN105384694A (en) * 2014-08-22 2016-03-09 四川海思科制药有限公司 Substituted aminopyrimidine derivative, preparation method therefor and pharmaceutical application thereof
CN105384695A (en) * 2014-08-22 2016-03-09 四川海思科制药有限公司 Pyrimidine derivative, preparation method therefor and application thereof in medicine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer;Darren A.E. Cross，et al.;《Cancer Discovery》;20141231;第4卷;第1046-1061页 *

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