CN108191861B - N- [5- (pyrimidin-2-amino) -2, 4-disubstituted-phenyl ] -trans-2, 4-pentadiene-amide - Google Patents

N- [5- (pyrimidin-2-amino) -2, 4-disubstituted-phenyl ] -trans-2, 4-pentadiene-amide Download PDF

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CN108191861B
CN108191861B CN201810171625.2A CN201810171625A CN108191861B CN 108191861 B CN108191861 B CN 108191861B CN 201810171625 A CN201810171625 A CN 201810171625A CN 108191861 B CN108191861 B CN 108191861B
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马军安
曾俊良
张发光
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Tianjin University
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • 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
    • C07D401/14—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 three or more hetero rings
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

The invention provides an N- [5- (pyrimidine-2-amino) -2, 4-disubstituted phenyl]-trans-2, 4-pentadiene amide, a compound of formula (I), a pharmaceutically acceptable salt thereof or a prodrug thereof. Compared with the prior art, the compound provided by the invention can inhibit the activities of mutants EGFRL858R, EGFRT790M and exon-19 deletion activation mutants, so that the compound shown in the formula (I), pharmaceutically acceptable salts thereof or prodrugs thereof can be used as EGFR modulators for treating or preventing cancers, and the compounds have long fat chain lengthHigh liposolubility, thus improving bioavailability, increasing blood concentration, enlarging administration time interval, finally reducing medical dosage and reducing toxic and side effects.

Description

N- [5- (pyrimidin-2-amino) -2, 4-disubstituted-phenyl ] -trans-2, 4-pentadiene-amide
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to N- [5- (pyrimidine-2-amino) -2, 4-disubstituted phenyl ] -trans-2, 4-pentadiene amide and application thereof.
Background
EGFR is an important member of HER/erbB family, widely distributed on cell membranes of various tissues of human body, and has a structure divided into extracellular region, transmembrane region and intracellular region. After the EGFR receptor is acted by a corresponding ligand, the EGFR receptor can be induced to form a homodimer or a heterodimer to cause the conformational change of an extracellular structure, so that intracellular tyrosine kinase is activated, residues of the tyrosine kinase are phosphorylated, downstream signal paths such as a MARK path and a PI3K path are further activated, and finally a series of biological behaviors of tumors such as the generation and development, proliferation, invasion and metastasis of the tumors are caused.
Many cancers in humans (e.g., gastric, lung, breast, bladder, head and neck squamous cell carcinomas, etc.) have increased EGFR expression. erbB therefore possesses a reasonable target for binding to anticancer drugs, and many inhibitors targeting EGFR or erbB2 are now in clinical use, such as gefitinib, erlotinib, lapatinib, afatinib, canertinib, dacomitinib, etc., as discussed in detail in biochemical Research Communications (2004,319,1-11) and New England journal medicine (2008,358, 1160-. The EGFR Tyrosine Kinase Inhibitor (TKI) is a small molecule EGFR inhibitor, and competitively binds to EGFR through an endogenous ligand to inhibit the activation of tyrosine kinase, so as to block an EGFR signal channel, and finally generate a series of biological effects of inhibiting the proliferation and the metastasis of tumor cells, promoting the apoptosis of the tumor cells and the like.
With the widespread use of these anti-cancer drugs, acquired resistance has emerged during cancer therapy, for example due to mutation of the gatekeeper residue T790M, which is reported to be detected in 50-60% of clinically resistant patients, and development of novel EGFR mutant inhibitors is highly urgent and desirable.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide an N- [5- (pyrimidine-2-amino) -2, 4-disubstituted phenyl ] -trans-2, 4-pentadiene amide and its use, wherein the fatty chain of the compound is increased, thereby improving the bioavailability thereof.
The invention provides N- [5- (pyrimidine-2-amino) -2, 4-disubstituted phenyl ] -trans-2, 4-pentadiene amide, which is a compound shown as a formula (I), a pharmaceutically acceptable salt thereof or a prodrug thereof:
Figure BDA0001586008370000011
wherein A is selected from substituted or unsubstituted pyrazolopyridyl, substituted or unsubstituted hydropyrazolopyridyl, substituted or unsubstituted indolyl; the substituent of the substituted pyrazolopyridyl group, the substituted hydropyrazolopyridyl group and the substituted indolyl group is respectively and independently selected from C1-C5 alkyl;
R1selected from hydrogen, halogen, C1-C5 alkyl or cyano;
R2is selected from alkoxy of C1-C5 or fluoro alkoxy of C1-C5;
R3selected from a substituted or unsubstituted azaheterocyclyl group, or a substituent represented by formula (II):
Figure BDA0001586008370000012
wherein R is4Alkyl selected from C1-C3; r5And R6Each independently selected from hydrogen or C1-C3 alkyl which is not simultaneously hydrogen, or R5And R6Connecting to form a ring; n is an integer of 2-5;
the substituent in the substituted nitrogen heterocyclic group is selected from alkyl of C1-C5 or alkylamino of C1-C5.
Preferably, a is selected from 4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl or pyrazolo [1,5-a ] pyridin-3-yl.
Preferably, said R is1Selected from hydrogen, chloro, methyl or cyano;
the R is2Selected from methoxy, difluoromethoxy or trifluoromethoxy.
Preferably, said R is3Selected from (3R) -3- (dimethylamino) pyrrolidin-1-yl, (3S) -3- (dimethylamino) pyrrolidin-1-yl, 3- (dimethylamino) azetidin-1-yl, [2- (dimethylamino) ethyl](methyl) amino, [2- (methylamino) ethyl](methyl) amino, 5-methyl-2, 5-diazaspiro [3,4]]Oct-2-yl, (3aR,6aR) -5-methylhexahydropyrrolo [3,4-b ]]Pyrrol-1 (2H) -yl, 1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl, 4-methylpiperazin-1-yl, 4- [2- (dimethylamino) -1-oxoethyl]Piperazin-1-yl, methyl [2- (4-methylpiperazin-1-yl) ethyl]Amino, methyl [2- (morpholin-4-yl) ethyl]Amino, 4- [ (2S) -2-aminopropionyl group]Piperazin-1-yl.
Preferably, one or more compounds represented by the formulas (I-1) to (I-89):
Figure BDA0001586008370000021
Figure BDA0001586008370000031
Figure BDA0001586008370000041
the invention also provides application of the N- [5- (pyrimidine-2-amino) -2, 4-disubstituted phenyl ] -trans-2, 4-pentadiene amide as an epidermal growth factor receptor inhibitor.
The invention also provides application of the N- [5- (pyrimidine-2-amino) -2, 4-disubstituted phenyl ] -trans-2, 4-pentadiene amide in preparation of a medicine for treating and/or preventing cancers.
Preferably, the cancer is selected from lung cancer, brain cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin lymphoma, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, mesothelioma, and complications thereof.
Preferably, the cancer is a non-small cell cancer.
The invention also provides a pharmaceutical composition which comprises the N- [5- (pyrimidine-2-amino) -2, 4-disubstituted phenyl ] -trans-2, 4-pentadiene amide.
The invention provides an N- [5- (pyrimidine-2-amino) -2, 4-disubstituted phenyl]-trans-2, 4-pentadiene amide, a compound of formula (I), a pharmaceutically acceptable salt or prodrug thereof, wherein a is selected from the group consisting of substituted or unsubstituted pyrazolopyridyl, substituted or unsubstituted hydropyrazolopyridyl, substituted or unsubstituted indolyl; the substituent of the substituted pyrazolopyridyl group, the substituted hydropyrazolopyridyl group and the substituted indolyl group is respectively and independently selected from C1-C5 alkyl; r1Selected from hydrogen, halogen, C1-C5 alkyl or cyano; r2Is selected from alkoxy of C1-C5 or fluoro alkoxy of C1-C5; r3Selected from a substituted or unsubstituted azaheterocyclyl group, or a substituent represented by formula (II): wherein R is4Alkyl selected from C1-C3; r5And R6Each independently selected from hydrogen or C1-C3 alkyl and not simultaneously hydrogen; n is an integer of 2-5; the substituent in the substituted nitrogen heterocyclic group is selected from alkyl of C1-C5 or alkylamino of C1-C5. Compared with the prior art, the compound provided by the invention can inhibit the activities of mutants EGFRL858R, EGFRT790M and exon-19 deletion activation mutants, so that the compound shown in the formula (I), pharmaceutically acceptable salts thereof or prodrugs thereof can be used as an EGFR modulator for treating or preventing cancers.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention provides N- [5- (pyrimidine-2-amino) -2, 4-disubstituted phenyl ] -trans-2, 4-pentadiene amide, which is a compound shown as a formula (I), a pharmaceutically acceptable salt thereof or a prodrug thereof:
Figure BDA0001586008370000051
wherein A is a substituted or unsubstituted pyrazolopyridyl group, a substituted or unsubstituted hydropyrazolopyridyl group, a substituted or unsubstituted indolyl group; the substituents in the substituted pyrazolopyridinyl, substituted hydropyrazolopyridinyl and substituted indolyl are independently C1-C5 alkyl, preferably C1-C3 alkyl, more preferably C1-C2 alkyl, and even more preferably methyl; in the present invention, said A is preferably 4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl or pyrazolo [1,5-a ] pyridin-3-yl.
R1Is hydrogen, halogen, C1-C5 alkyl or cyano; preferably hydrogen, chlorine, C1-C3 alkyl or cyano; more preferably hydrogen, chlorine, C1-C2 alkyl or cyano; more preferably hydrogen, chlorine, methyl or cyano.
R2Is alkoxy of C1-C5 or fluoro alkoxy of C1-C5; preferably C1-C3 alkoxy or C1-C3 fluoroalkoxy; more preferably C1-C2 alkoxy or C1-C2 fluoroalkoxy; more preferably methoxy or fluoromethoxy; most preferably methoxy, difluoromethoxy or trifluoromethoxy;
R3is a substituted or unsubstituted azaheterocyclyl group, or a substituent represented by formula (II):
Figure BDA0001586008370000052
wherein R is4Is C1-C3 alkyl, preferably C1-C2 alkyl, and more preferably methyl; r5And R6Each independently selected from hydrogen or C1-C3 alkyl and not simultaneously hydrogen, preferably hydrogen or C1-C2 alkyl, more preferably hydrogen or methyl; or R5And R6Linked to form a ring, preferably a ring of C4-C6; preferably containing heteroatoms in the ring, more preferably containing O; n is an integer of 2 to 5, preferably an integer of 2 to 4, and more preferably an integer of 2 to 3.
The substituent in the substituted nitrogen heterocyclic group is C1-C5 alkyl or C1-C5 alkylamino, preferably C1-C3 alkyl or C1-C3 alkylamino, more preferably C1-C2 alkyl or C1-C2 alkylamino, and most preferably methyl, methylamino or dimethylamino.
The nitrogen heterocyclic group may be any nitrogen heterocyclic group known to those skilled in the art, and may be saturated or unsaturated, and is not particularly limited, and in the present invention, it is preferably a pyridyl group, a hydropyridyl group, a piperazinyl group, a pyrrolyl group, a pyrrolidinyl group, an azacycloalkyl group having from C2 to C6, an azaspiro group, or any two of the above groups forming a condensed ring.
In the present invention, said R3Most preferred are (3R) -3- (dimethylamino) pyrrolidin-1-yl, (3S) -3- (dimethylamino) pyrrolidin-1-yl, 3- (dimethylamino) azetidin-1-yl, [2- (dimethylamino) ethyl](methyl) amino, [2- (methylamino) ethyl](methyl) amino, 5-methyl-2, 5-diazaspiro [3,4]]Oct-2-yl, (3aR,6aR) -5-methylhexahydropyrrolo [3,4-b ]]Pyrrol-1 (2H) -yl, 1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl, 4-methylpiperazin-1-yl, 4- [2- (dimethylamino) -1-oxoethyl]Piperazin-1-yl, methyl [2- (4-methylpiperazin-1-yl) ethyl]Amino, methyl [2- (morpholin-4-yl) ethyl]Amino or 4- [ (2S) -2-aminopropionyl group]Piperazin-1-yl.
According to the present invention, the pharmaceutically acceptable salt of the compound represented by formula (I) is a pharmaceutically acceptable salt well known to those skilled in the art, and may be a salt of the compound represented by formula (I) with an inorganic acid or a salt of the compound represented by formula (I) with an organic acid, without any particular limitation, and in the present invention, an acid addition salt formed by one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, maleic acid, oxalic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and trifluoroacetic acid with the compound represented by formula (I) is preferred.
The N- [5- (pyrimidine-2-amino) -2, 4-disubstituted phenyl ] -trans-2, 4-pentadiene amide provided by the invention is most preferably one or more compounds shown in the formulas (I-1) to (I-89):
Figure BDA0001586008370000053
Figure BDA0001586008370000061
Figure BDA0001586008370000071
Figure BDA0001586008370000081
the prodrug of the compound of formula (I) is not particularly limited as long as it is known to those skilled in the art, and the prodrug can be decomposed in the human body or animal body to produce the compound of formula (I), and in the present invention, an in vivo hydrolysable ester of the compound of formula (I) is preferred. An internally hydrolysable ester may be formed by esterifying a hydroxyl group in a compound of formula (I).
The compound provided by the invention can inhibit the activities of mutants EGFRL858R, EGFRT790M and exon-19 deletion activation mutants, so that the compound shown in the formula (I), pharmaceutically acceptable salts thereof or prodrugs thereof can be used as an EGFR modulator for treating or preventing cancers.
The invention also provides an application of the N- [5- (pyrimidine-2-amino) -2, 4-disubstituted phenyl ] -trans-2, 4-pentadiene amide as an epidermal growth factor receptor inhibitor, and the N- [5- (pyrimidine-2-amino) -2, 4-disubstituted phenyl ] -trans-2, 4-pentadiene amide can treat and/or prevent an epidermal growth factor receptor EGFR (epidermal growth factor receptor) regulatory disease at an effective treatment dose; these compounds or their salts have certain selectivity for certain mutant forms of epidermal growth factor receptors (e.g., L858R-activating mutants, exon-19 deletion-activating mutants, and T790M-resistant mutants), and can block the transmission of proliferation signals for the treatment or prevention of diseases or conditions. These compounds or their salts are useful in the treatment or prevention of several different cancers.
The invention also provides an application of the N- [5- (pyrimidine-2-amino) -2, 4-disubstituted phenyl ] -trans-2, 4-pentadiene amide in preparing a medicament for treating and/or preventing cancers; the cancer is an epidermal growth factor receptor EGFR-mediated disease well known to those skilled in the art, preferably lung cancer, brain cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin lymphoma, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, cholangiocarcinoma, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, mesothelioma, and complications thereof, more preferably non-small cell cancer. When the compound is used for preparing a medicament for treating and/or preventing cancer, the compound can be independently administered or can be administered together with other medicaments.
The invention also provides a pharmaceutical composition which comprises the N- [5- (pyrimidine-2-amino) -2, 4-disubstituted phenyl ] -trans-2, 4-pentadiene amide.
The dosage form of the pharmaceutical composition is well known to those skilled in the art, and is not particularly limited, but in the present invention, preferred are tablets, capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups, creams, ointments, gels, aqueous solutions, oily solutions, fine powders, liquid aerosol veins, sterile aqueous or sterile oily solutions; the administration can be oral (e.g., tablets, capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups); topical application (e.g., creams, ointments, gels, or aqueous or oily solutions); administration by inhalation (e.g., fine powder or liquid aerosol); by insufflation (e.g. fine powders) or parenterally (e.g. sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular or intramuscular administration).
The pharmaceutical composition further comprises a pharmaceutically acceptable diluent or carrier; the compounds of formula (I), pharmaceutically acceptable salts thereof and prodrugs thereof, as active ingredients, may be intimately admixed with pharmaceutical carriers according to conventional pharmaceutical compounding techniques, which carriers may be formulated for administration by any of a wide variety of means, including oral or intravenous injection. Pharmaceutically acceptable carriers are well known in the art and, for example, a description of some of these pharmaceutically acceptable carriers can be found in the handbook of pharmaceutical excipients, which is published by the American society for pharmacy and British pharmaceutical society in combination. In the present invention, the carrier preferably includes an inert diluent, a filler, water, and various organic solvents. If pre-designed, the pharmaceutical formulation may include additional ingredients such as flavorings, antidiarrheal agents, excipients, and the like. Thus, for oral administration, tablets containing various excipients, such as citric acid, may be combined with various disintegrants, such as starch, alginic acid, certain silicate complexes and some antidiarrheal agents, such as sucrose, gelatin and acacia; additionally, lubricants such as magnesium stearate, sodium lauryl sulfate, talc, and the like are also useful for making tablets; solid compounds of a similar type may also be used for either soft or hard gel capsule filling; therefore, preferred materials include lactose or milk sugar and high molecular weight polyethylene ethers. When the aqueous suspension or the liqueur is used as a necessary product for oral administration, the active ingredients may be combined with different sweeteners or other flavorings, coloring agents and coloring agents, and optionally an emulsifier or suspending agent, and a diluent such as water, alcohol, propylene glycol, glycerin or a mixture thereof.
Administration of the active ingredient may be effected by any means which is capable of delivering the ingredient to the site of action (e.g.tumour cells). Such means may include oral routes, rectal routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical administration, and the like. The dosage of the active ingredient to be administered will depend on the subject being treated, the severity of the pain, the mode of administration and the judgment of the prescribing physician. However, an effective dose is preferably between about 0.001 mg and 400 mg (usually between about 0.01 mg and 100mg, more preferably between about 0.1 mg and 40 mg), and a specific dosage can be from about 0.001 mg per kg of body weight per day to about 400 mg per kg of body weight per day (more usually 0.01 mg per kg of body weight per day to 100mg per kg of body weight per day, more preferably 0.1 mg per kg of body weight per day to 40mg per kg of body weight per day).
The term "subject" as used herein refers to an animal, particularly a mammal, most often a human, who is often treated as a prophylactic, therapeutic, observation or test subject. The term "therapeutically effective amount" refers to an amount of active compound or pharmaceutical ingredient that will elicit the biological or medical response of a tissue, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. The term "ingredient" refers to a product resulting, directly or indirectly, from the specified amount of the specified ingredient or ingredients, and any mixtures of the specified ingredients in the specified amount. Therefore, pharmaceutical compositions containing the compounds of the present invention or pharmaceutically acceptable salts thereof as an active ingredient, and processes for preparing these compounds or pharmaceutically acceptable salts thereof are all aspects of the present invention. Moreover, certain compounds and salts thereof may be prepared in crystalline forms, which may exist as polymorphs and as such are included in the present invention. In addition, some compounds and salts thereof may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included in the scope of the present invention. The term "combination" refers to administration in parallel, simultaneously, sequentially, or separately with a compound of the invention or a salt thereof.
The invention also provides a preparation method of the compound shown in the formula (I), which comprises the following steps: mixing the intermediate 4, trans-2, 4-pentadienoyl chloride and alkali in an organic solvent for reaction to obtain a compound shown in a formula (I); the reaction formula is as follows:
Figure BDA0001586008370000091
the preparation of said intermediate 4 can be carried out according to published procedures such as d.j.abraham, Burger's Medicinal Chemistry and Drug Discovery (Wiley,2003) and r.a.ward et al, j.med.chem. (2013,56, 7025-; the base is a base well known to those skilled in the art, and is not particularly limited, and in the present invention, an organic base is preferable, an amine organic base is more preferable, and Diisopropylethylamine (DIPEA) is further preferable; the organic solvent is not particularly limited as long as it is well known to those skilled in the art, and in the present invention, a weakly polar organic solvent is preferable, and dichloromethane and/or tetrahydrofuran is more preferable; the temperature of the mixing reaction is preferably 0-30 ℃; the mixing reaction time is preferably 30 min-5 h; the mixing reaction is preferably carried out in a protective atmosphere; the protective atmosphere is not particularly limited as long as it is known to those skilled in the art, and nitrogen is preferred in the present invention; after mixing and reacting, sodium bicarbonate solution can be directly added to quench and react with a small amount of methanol; or dissolving in organic solvent after concentrating, adding sodium bicarbonate solution and a small amount of methanol for quenching reaction; after quenching, the reaction is preferably washed with water, dried, freed from the organic solvent and purified by chromatography to give the compound of the formula (I).
According to the invention, the preparation process is preferably as follows: and (3) mixing the intermediate 4, alkali and an organic solvent, then dropwise adding a trans-2, 4-pentadienoyl chloride solution, and reacting to obtain the compound shown in the formula (I).
To further illustrate the present invention, the following examples are provided to describe in detail N- [5- (pyrimidin-2-amino) -2, 4-disubstituted-phenyl ] -trans-2, 4-pentadiene amide and its uses.
The reagents used in the following examples are all commercially available; unless otherwise specified, all parts and percentages are parts by mass and percentages by mass, and the temperatures indicated are in degrees centigrade; abbreviations in the examples are as follows: TFA, trifluoroacetic acid; ATP, adenosine triphosphate; DMF, N-dimethylformamide; DMSO, dimethyl sulfoxide; EtOAc, ethyl acetate; THF, tetrahydrofuran; DIPEA, diisopropylethylamine; GSR, glutathione-S-transferase; CrK, CT10, chicken tumor retrovirus 10; SDS, sodium dodecyl sulfate; SDS-PAGE, sodium dodecyl sulfate-polyamide electrophoresis gel; rt, room temperature; TLC, thin layer chromatography.
All chemicals were purchased from commercial suppliers and used directly without further purification treatment unless otherwise specified. The Qingdao ocean chemical industry standard silica gel with 200-300 meshes is used for rapid column chromatography; a Qingdao ocean chemical industry 0.20mm standard plate for thin-layer chromatography; nuclear magnetic resonance spectroscopy data (NMR) were obtained using Bruker (Bruker)400 or 600 million nuclear magnetic resonance spectroscopy measurements with tetramethylsilane as an internal standard and deuterated chloroform or deuterated dimethyl sulfoxide or deuterated methanol as a solvent (s represents a single peak, d represents a doublet, t represents a triplet, q represents a quadruplet, m represents a multiplet, br represents a broad peak); mass spectral data were obtained using a MicroTOF-QII or Waters Micromass GCT Premier instrument.
Example 1: n- { 4-methoxy-2- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) -5- { [ 5-methyl-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } phenyl } -trans-2, 4-pentadiene-mide
Figure BDA0001586008370000101
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.5mL CH) was dissolved under protection2Cl2Middle) was added dropwise to 6-methoxy-4- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) -N'- { 5-methyl-4-pyrazolo [1,5-a ]]Pyridin-3-yl) pyrimidin-2-yl } benzene-1, 3-diamine (88mg,0.2mmol) and DIPEA (39mg,0.3mmol) in CH2Cl2(6mL) and the resulting mixture was stirred at 0 ℃ for 1h, then saturated NaHCO was added3(4mL) and 3-5 drops of methanol, washing the organic phase with 4mL of water, and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH2Cl2The resulting solution was concentrated to give the desired product (52mg, 50%) with MeOH (5-25%) as eluent.1H NMR:2.26(3H,s),2.35(2H,m),2.40(3H,s),2.50-2.55(2H,m),2.95(2H,m),3.85(3H,d),5.20(1H,dd),5.26(1H,d),5.40(1H,d),6.36(1H,m),6.60(1H,m),6.85(1H,s),7.05(1H,t),7.38-7.41(2H,m),7.95(1H,s),8.14(1H,s),8.30(1H,s),8.46(1H,d),8.56(1H,s),8.78(1H,d),9.27(1H,S)；ES(m/z):M+H+522.2。
Example 2: n- {5- { [ 5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl ] amino } -4-methoxy-2- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) phenyl } -trans-2, 4-pentadiene-mide
Figure BDA0001586008370000102
At-10 ℃ and N2Trans-2, 4-pentadienoyl chloride (58mg,0.5mmol, dissolved in 0.5mL THF) was added dropwise to N' - [ 5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl ] under protection]-4-methoxy-6- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) benzene-1, 3-diamine (230mg,0.5mmol) and DIPEA (78mg,0.6mmol) in THF (6 mL); stirring the obtained mixture at 0 ℃ for reacting for 2h, and then concentrating in vacuum; the residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and 3-5 drops of methanol, washing the organic phase with 4mL of water, and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation; the crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (103mg, 38%) with MeOH (5-25%) as eluent.1H NMR:2.27(3H,s),2.36(2H,m),2.54(2H,m),2.95(2H,d),3.84(3H,s),5.21(1H,dd),5.27(1H,d),5.41(1H,d),6.30(1H,m),6.61(1H,m),6.85(1H,s),7.09(1H,t),7.19(1H,t),7.37(1H,dd),7.46(1H,d),7.95(1H,s),8.32(1H,s),8.34(1H,d),8.40(1H,s),8.47(1H,s),9.26(1H,s),11.83(1H,S)；ES(m/z):M+H+541.2。
Example 3: n- {5- { [4- (1H-indol-3-yl) -5-methylpyrimidin-2-yl ] amino } -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl } -trans-2, 4-pentadiene-amide
Figure BDA0001586008370000103
At-5 ℃ and N2Trans-2, 4-pentadienoyl chloride (58mg,0.5mmol, dissolved in 0.5mL THF) was added dropwise to N' - [4- (1H-indol-3-yl) -5-methylpyrimidin-2-yl ] with protection]-4-methoxy-6- (4-methylpiperidin-1-yl) benzene-1, 3-diamine (222mg,0.5mmol) and DIPEA (78mg,0.6mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 1h, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH2Cl2The resulting solution was concentrated with MeOH (5-25%) as eluent to afford the desired product (81mg, 31%).1H NMR:2.26(3H,s),2.37(3H,s),2.45-2.55(4H,m),2.80-2.89(4H,m),3.83(3H,s),5.19(1H,dd),5.25(1H,d),5.40(1H,d),6.55(1H,m),6.85(1H,s),7.04(1H,dd),7.12(1H,t),7.40-7.42(2H,m),7.82(1H,s),7.95(1H,d),8.20(1H,s),8.33(1H,d),8.45(1H,s),8.94(1H,s),11.65(1H,s)；ES(m/z):M+H+524.2。
Example 4: n- {5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -2- [ (3R) -3-dimethylaminopyrrolidin-1-yl ] -4-methoxyphenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000104
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (47mg,0.4mmol, dissolved in 0.5mL CH) with protection2Cl2Middle) was added dropwise to N- { 5-chloro-4-pyrazolo [1, 5-a)]Pyridin-3-ylpyrimidin-2-yl } -4- [ (3R) -3-dimethylaminopyrrolidin-1-yl) -6-methoxybenzene-1, 3-diamine (192mg,0.4mmol) and DIPEA (65mg,0.5mmol) in CH2Cl2(8mL) in solution. The resulting mixture was warmed to room temperature and stirred for 2 h. Then saturated NaHCO was added3The reaction was quenched (4mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4mL) and MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (72mg, 32%) with MeOH (5-25%) as eluent.1H NMR:1.52-1.79(1H,m),2.02-2.13(1H,m),2.16(6H,s),2.60-2.74(1H,m),3.14-3.25(3H,m),3.34-3.44(1H,m),3.75(3H,s),5.19(1H,dd),5.25(1H,d),5.40(1H,d),6.52(1H,s),6.57(1H,m),7.10(1H,t),7.35(1H,t),7.41-7.44(2H,m),8.25-8.43(2H,m),8.53(1H,s),8.80(1H,d),8.91(1H,s),9.32(1H,s)；ES(m/z):M+H+559.2。
Example 5: n- {5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -2- [ 3-dimethylaminoazetidin-1-yl ] -4-methoxyphenyl } -trans-2, 4-pentadiene-amide
Figure BDA0001586008370000111
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (47mg,0.4mmol, dissolved in 0.5mL CH) with protection2Cl2Middle) was added dropwise to N- { 5-chloro-4-pyrazolo [1, 5-a)]Pyridin-3-ylpyrimidin-2-yl } -4- [ 3-dimethylaminoazetidi-1-yl) -6-methoxybenzene-1, 3-diamine (176mg,0.4mmol) and DIPEA (65mg,0.5mmol) in CH2Cl2(8mL) in solution. The resulting mixture was warmed to room temperature and stirred for 2 hours. Then saturated NaHCO was added3The reaction was quenched (4mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4mL) and MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The obtained crude productThe extract was purified by silica gel column chromatography using CH2Cl2The resulting solution was concentrated to give the desired product (89mg, 41%) with MeOH (5-25%) as eluent.1H NMR:2.07(6H,s),3.05(1H,p),3.52-3.58(2H,m),3.72(3H,s),3.95(2H,t),5.18(1H,dd),5.24(1H,d),5.38(1H,d),6.52(1H,m),7.08(1H,dd),7.32(1H,s),7.38-7.42(2H,m),8.22-8.35(1H,m),8.32(1H,s),8.43(1H,s),8.79(1H,d),8.90(1H,s),9.21(1H,s)；19FNMR:-117.92(1F,dd)；ES(m/z):M+H+545.2。
Example 6: n- {5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -2- [ 2-dimethylaminoethyl-methylamino ] -4-methoxyphenyl } -trans-2, 4-pentadiene-amide
Figure BDA0001586008370000112
At-5 ℃ and N2Trans-2, 4-pentadienoyl chloride (58mg,0.5mmol, dissolved in 0.5mL THF) was added dropwise to N under protection4- { 5-chloro-4-pyrazolo [1,5-a ]]Pyridin-3-ylpyrimidin-2-yl } -N1- (2-dimethylaminoethyl) -N1-methyl-5-methoxybenzene-1, 2, 4-triamine (233.5mg,0.5mmol) and DIPEA (78mg,0.6mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 2h, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3The reaction was quenched (4mL) with a small amount of methanol (3-5 drops), and the organic phase was washed with water (4mL) and MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH2Cl2The resulting solution was concentrated to give the desired product (115mg, 42%) with MeOH (5-25%) as eluent.1HNMR:2.27(6H,s),2.34(2H,t),2.71(3H,s),3.82-2.90(2H,m),3.84(3H,s),5.22(1H,dd),5.26(1H,d),5.41(1H,d),6.49(1H,m),6.83(1H,s),7.00(1H,td),7.22-7.33(1H,m),7.40-7.44(2H,m),8.42(1H,s),8.50(1H,d),8.55(1H,d),8.91(1H,s),9.36(1H,s),10.02(1H,s)；ES(m/z):M+H+547.2。
Example 7: n- {2- { (3aR,6aR) -5-Methylhexahydropyrrolo [3,4-b ] pyrrol-1 (2H) -yl } -5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -4-methoxyphenyl } -trans-2, 4-pentadiene-namide
Figure BDA0001586008370000113
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.3mL THF) was added dropwise to 4- { (3aR,6aR) -5-methylhexahydropyrrolo [3,4-b ] with protection]Pyrrol-1 (2H) -yl } -N- {5- { [ 5-chloro-4-pyrazolo [1, 5-a)]Pyridin-3-ylpyrimidin-2-yl } -6-methoxybenzene-1, 3-diamine (98mg,0.2mmol) and DIPEA (39mg,0.3mmol) in THF (3 mL). The mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 2h, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (55mg, 48%) with MeOH (5-25%) as eluent.1H NMR:1.72-1.78(1H,m),1.92-2.13(5H,m),2.20-2.32(1H,m),2.34-2.43(1H,m),2.82-2.88(1H,m),3.15-3.20(1H,m),3.34-3.42(1H,m),3.75(3H,s),4.30-4.35(1H,m),5.21(1H,dd),5.25(1H,d),5.39(1H,d),6.51(1H,m),6.63(1H,s),7.07(1H,dt),7.30-7.37(1H,m),7.44(1H,dd),7.62(1H,s),8.29-8.38(2H,m),8.53(1H,s),8.79(1H,d),8.90(1H,s),9.37(1H,s)；ES(m/z):M+H+571.2。
Example 8: n- {5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -4-methoxy-2- (5-methyl-2, 5-diazaspiro [3,4] oct-2-yl) phenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000121
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (12mg,0.1mmol, dissolved in 0.2mL THF) was added dropwise to N- {5- { [ 5-chloro-N-chlorohexy-l under protection-4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl]-4-methoxy-6- (5-methyl-2, 5-diazaspiro [3,4]]Oct-2-yl) benzene-1, 3-diamine (49mg,0.1mmol) and DIPEA (26mg,0.2mmol) in THF (3 mL). The mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 3h, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH2Cl2The resulting solution was concentrated to give the desired product (23mg, 40%) with MeOH (5-25%) as eluent.1H NMR：1.67(2H,dd),1.95-2.09(2H,m),2.35(3H,s),2.60(2H,t),3.63(2H,d),3.74(3H,s),3.92(2H,d),5.18(1H,dd),5.23(1H,d),5.37(1H,d),6.42(1H,s),6.57(1H,m),7.08(1H,t),7.27(1H,s),7.32-7.41(2H,m),8.32(2H,s),8.40(1H,s),8.78(1H,d),8.90(1H,s),9.18(1H,s)；ES(m/z):M+H+571.2。
Example 9: n- {5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -4-methoxy-2- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) phenyl } -trans-2, 4-pentadiene-mide
Figure BDA0001586008370000122
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (58mg,0.5mmol, dissolved in 0.5mL THF) was added dropwise to N- {5- { [ 5-chloro-4-pyrazolo [1,5-a ] with protection]Pyridin-3-ylpyrimidin-2-yl]-4-methoxy-6- (1-methyl-3, 6-dihydro-2H-pyridin-4-yl) benzene-1, 3-diamine (231mg,0.5mmol) and DIPEA (78mg,0.6mmol) in THF (6 mL). The resulting mixture was stirred at 0 ℃ for 4h and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH2Cl2/MeOH(5-25%) as an eluent, and the resulting solution was concentrated to obtain the objective product (81mg, 30%).1H NMR：2.25(3H,s),2.36(2H,s),2.53(2H,t),2.95(2H,d),3.80(3H,s),5.20(1H,dd),5.24(1H,d),5.38(1H,d),6.15(1H,dd),6.53(1H,m),6.84(1H,s),7.10(1H,dt),7.35-7.44(2H,m),7.80(1H,s),8.38-8.45(2H,m),8.60(1H,s),8.82(1H,d),8.93(1H,s),9.32(1H,s)；ES(m/z):M+H+542.2。
Example 10: n- {5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -2- [4- (2-dimethylamino-1-oxyethyl) piperazin-1-yl ] -4-methoxyphenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000123
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (12mg,0.1mmol, dissolved in 0.2mL THF) was added dropwise to N- {5- { [ 5-chloro-4-pyrazolo [1,5-a ] with protection]Pyridin-3-ylpyrimidin-2-yl]-4-methoxy-2- [4- (2-dimethylamino-1-oxyethyl) piperazin-1-yl]Benzene-1, 3-diamine (54mg,0.1mmol) and DIPEA (26mg,0.2mmol) in THF (4 mL). The resulting mixture was stirred at 0 ℃ for 4h and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH2Cl2The resulting solution was concentrated to give the desired product (27mg, 44%) with MeOH (5-25%) as eluent.1H NMR：2.74(4H,s),2.88-2.94(4H,m),2.95(3H,s),3.10(3H,s),3.27(2H,s),3.84(3H,s),5.21(1H,dd),5.25(1H,d),5.42(1H,d),6.56(1H,m),6.77(1H,s),6.87(1H,t),7.25(1H,d),7.39-7.42(2H,m),8.40(1H,s),8.43-8.53(3H,m),8.91(1H,s),9.31(1H,s)；ES(m/z):M+H+616.4。
Example 11: (S) -N- {2- [4- (2-aminopropionyl) piperazin-1-yl ] -5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -4-methoxyphenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000131
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.5mL CH) with protection2Cl2Middle) was added dropwise to (S) -tert-butyl N- [1- (4- { 2-amino-4- [ (5-chloro-4-pyrazolo [1, 5-a)]Pyridin-3-ylpyrimidin-2-yl) amino groups]-5-methoxyphenyl } piperazin-1-yl) -1-oxoprop-2-yl]Carbamate (121mg,0.2mmol) and DIPEA (39mg,0.3mmol) in CH2Cl2(8mL) in solution. The resulting mixture was warmed to room temperature and stirred for 2 h. Then 2M Na was added2CO3The reaction was quenched with a small amount of water (5mL) and the organic phase was washed with water (4mL) and MgSO was added4Drying, and removing the organic solvent by thin film rotary evaporation. Dissolving the residue in CH2Cl2After the solution (5mL) was treated with TFA (0.2mL), the solution was allowed to stand for 30 minutes, and then treated with TFA (0.2mL) again, followed by standing for another 30 minutes. Removing organic solvent by thin film rotary evaporation, purifying the obtained crude product by silica gel column chromatography, and purifying with CH2Cl2/MeOH-Et3The resulting solution was concentrated using N (5-25%) as eluent to obtain the desired product (42mg, 35%).1H NMR：1.26(3H,d),2.82-3.00(4H,m),3.65-3.85(7H,m),4.20-4.32(1H,m),5.20(1H,dd),5.26(1H,d),5.41(1H,d),6.49(1H,m),6.74(1H,s),7.10-7.15(1H,m),7.35-7.42(2H,m),8.22-8.30(2H,m),8.38-8.45(2H,m),8.72(1H,s),8.85-8.90(1H,m),8.97(1H,s),9.15-9.20(1H,m)；ES(m/z):M+H+602.2。
Example 12: n- {5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -2- [ (3S) -3-dimethylaminopyrrolidin-1-yl ] -4-methoxyphenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000132
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (47mg,0.4mmol, dissolved in 0.5mL CH) with protection2Cl2Middle) was added dropwise to N- { 5-chloro-4-pyrazolo [1, 5-a)]Pyridin-3-ylpyrimidin-2-yl } -4- [ (ii)3S) -3-Dimethylaminopyrrolidin-1-yl) -6-methoxybenzene-1, 3-diamine (192mg,0.4mmol) and DIPEA (65mg,0.5mmol) in CH2Cl2(8mL) in solution. The resulting mixture was warmed to room temperature and stirred for reaction for 3 h. Then saturated NaHCO was added3The solution (4mL) and a small amount of methanol (3-5 drops) are quenched for reaction, and the organic phase is washed with water (4mL) and added with MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (100mg, 45%) with MeOH (5-25%) as eluent.1H NMR：1.67-1.80(1H,m),2.01-2.15(1H,m),2.15(6H,s),2.62-2.75(1H,m),3.15-3.26(3H,m),3.33-3.45(1H,m),3.75(3H,s),5.21(1H,dd),5.25(1H,d),5.42(1H,d),6.54-6.58(2H,m),7.10(1H,t),7.34(1H,t),7.40-7.45(2H,m),8.30-8.45(2H,m),8.51(1H,s),8.80(1H,d),8.91(1H,s),9.34(1H,s)；ES(m/z):M+H+559.2。
Example 13: n- {5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000133
At 10 ℃ and N2Trans-2, 4-pentadienoyl chloride (58mg,0.5mmol, dissolved in 0.5mL CH) with protection2Cl2In (b)) was added dropwise to N' -5- { 5-chloro-4-pyrazolo [1, 5-a)]Pyridin-3-ylpyrimidin-2-yl } -4-methoxy-6- (4-methylpiperazin-1-yl) benzene-1, 3-diamine (233mg,0.5mmol) and DIPEA (78mg,0.6mmol) in CH2Cl2(8mL) in solution. The resulting mixture was warmed to room temperature and stirred for 2 h. Then saturated NaHCO was added3The solution (4mL) and a small amount of methanol (3-5 drops) are quenched for reaction, and the organic phase is washed with water (4mL) and added with MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (109mg, 40%) with MeOH (5-25%) as eluent.1H NMR：2.25(3H,s),2.50-2.59(4H,m),2.81-2.95(4H,m),3.74(3H,s),5.22(1H,dd),5.26(1H,d),5.43(1H,d),6.51(1H,m),6.86(1H,s),7.07(1H,t),7.29-7.38(1H,m),7.42(1H,dd),8.06(1H,s),8.25-8.44(2H,m),8.71(1H,s),8.80(1H,d),8.91(1H,s),9.05(1H,s)；ES(m/z):M+H+545.2。
Example 14: n- {5- { [ 5-cyano-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000141
At 10 ℃ and N2Trans-2, 4-pentadienoyl chloride (58mg,0.5mmol, dissolved in 0.5mL CH) with protection2Cl2In (b) was added dropwise to N' -5- { 5-cyano-4-pyrazolo [1,5-a ]]Pyridin-3-ylpyrimidin-2-yl } -4-methoxy-6- (4-methylpiperazin-1-yl) benzene-1, 3-diamine (228mg,0.5mmol) and DIPEA (78mg,0.6mmol) in CH2Cl2(8mL) solution, the resulting mixture was warmed to room temperature and stirred for 3h, then saturated NaHCO was added3The solution (4mL) and a small amount of methanol (3-5 drops) are quenched for reaction, and the organic phase is washed with water (4mL) and added with MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (128mg, 48%) with MeOH (5-25%) as eluent.1H NMR：2.28(3H,s),2.54-2.60(4H,m),2.90-2.97(4H,m),3.77(3H,s),5.20(1H,dd),5.25(1H,d),5.44(1H,d),6.50(1H,m),6.90(1H,s),7.10(1H,t),7.38-7.42(2H,m),8.21(1H,s),8.30(1H,d),8.60(1H,s),8.69(1H,br),8.77(1H,d),8.90(1H,s),9.00(1H,s)；ES(m/z):M+H+536.4。
Example 15: n- {5- { [4- (1H-indol-3-yl) pyrimidin-2-yl ] amino } -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000142
At 5 ℃ and N2Under protection, trans-2, 4-pentadienoyl chloride (58mg,0.5mmol, v/v) was dissolvedIn 0.5ml of THF) was added dropwise to N' - [4- (1H-indol-3-yl) pyrimidin-2-yl]-4-methoxy-6- (4-methylpiperidin-1-yl) benzene-1, 3-diamine (215mg,0.5mmol) and DIPEA (78mg,0.6mmol) in THF (6mL), the resulting mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 3h, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3The solution (4mL) and a small amount of methanol (3-5 drops) are quenched for reaction, and the organic phase is washed with water (4mL) and added with MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (82mg, 32%) with MeOH (5-25%) as eluent.1H NMR:2.25(3H,s),2.52-2.59(4H,m),2.80-2.92(4H,m),3.82(3H,d),5.21(1H,dd),5.27(1H,d),5.42(1H,d),6.52(1H,m),6.86(1H,s),7.07-7.22(2H,m),7.24(1H,d),7.41-7.44(2H,m),7.88(1H,s),8.30(1H,d),8.33(1H,d),8.41(1H,s),8.72(1H,s),9.08(1H,s)；ES(m/z):M+H+510.2。
Example 16: n- { 4-methoxy-2- (4-methylpiperazin-1-yl) -5- { [ 4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } phenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000143
At 20 ℃ and N2Trans-2, 4-pentadienoyl chloride (58mg,0.5mmol, dissolved in 0.5mL CH) with protection2Cl2In (b) was added dropwise to 4-methoxy-6- (4-methylpiperazin-1-yl) -N' - { 4-pyrazolo [1,5-a ]]Pyridin-3-ylpyrimidin-2-yl } benzene-1, 3-diamine (215mg,0.5mmol) and DIPEA (78mg,0.6mmol) in CH2Cl2(8mL) solution, the resulting mixture was warmed to room temperature and stirred for 2 hours, then saturated NaHCO was added3The solution (4mL) and a small amount of methanol (3-5 drops) are quenched for reaction, and the organic phase is washed with water (4mL) and added with MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2using/MeOH (5-25%) as eluent, concentrating the obtained solution to obtain the targetProduct (107mg, 42%).1H NMR：2.30-2.41(3H,m),2.61-2.79(4H,m),2.92(4H,s),3.85(3H,s),5.22(1H,dd),5.26(1H,d),5.43(1H,d),6.54(1H,m),6.86(1H,s),7.05-7.10(1H,m),7.25(1H,d),7.34-7.42(2H,m),8.16(1H,s),8.32(1H,d),8.42(1H,d),8.50(1H,s),8.78(1H,d),8.83(1H,s),9.08(1H,s)；ES(m/z):M+H+511.2。
Example 17: n- {5- { [ 5-chloro-4- (1H-indol-3-yl) -pyrimidin-2-yl ] amino } -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000151
At 5 ℃ and N2Trans-2, 4-pentadienoyl chloride (58mg,0.5mmol, dissolved in 0.5mL THF) was added dropwise to N' - [ 5-chloro-4- (1H-indol-3-yl) -pyrimidin-2-yl ] under protection]-4-methoxy-6- (4-methylpiperidin-1-yl) benzene-1, 3-diamine (232mg,0.5mmol) and DIPEA (78mg,0.6mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 2h, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3The solution (4mL) and a small amount of methanol (3-5 drops) are quenched for reaction, and the organic phase is washed with water (4mL) and added with MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (120mg, 44%) with MeOH (5-25%) as eluent.1H NMR:2.26(3H,s),2.50-2.58(4H,m),2.85-2.95(4H,m),3.74(3H,s),5.21(1H,dd),5.25(1H,d),5.46(1H,d),6.57(1H,m),6.88(1H,s),7.02(1H,t),7.16(1H,t),7.41-7.45(2H,m),8.16(1H,s),8.30(1H,d),8.35(1H,s),8.44(1H,s),8.50(1H,d),8.95(1H,s),11.72(1H,s)；ES(m/z):M+H+544.2。
Example 18: n- { 4-methoxy-5- { [ 5-methyl-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } -2- (4-methylpiperazin-1-yl) phenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000152
At 15 ℃ and N2Trans-2, 4-pentadienoyl chloride (58mg,0.5mmol, dissolved in 0.5mL THF) was added dropwise to 4-methoxy-N' - [ 5-methyl-4- (1-methylindol-3-yl) pyrimidin-2-yl with protection](4-methylpiperidin-1-yl) benzene-1, 3-diamine (229mg,0.5mmol) and DIPEA (78mg,0.6mmol) in THF (6mL), the resulting mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 2h, concentrated in vacuo, and the residue was dissolved in CH2Cl2(8mL) and saturated NaHCO was added3The solution (4mL) and a small amount of methanol (3-5 drops) are quenched for reaction, and the organic phase is washed with water (4mL) and added with MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (102mg, 38%) with MeOH (5-25%) as eluent.1H NMR:2.26(3H,s),2.36(3H,s),2.47-2.52(4H,m),2.80-2.91(4H,m),3.81(3H,s),3.88(3H,s),5.18(1H,dd),5.25(1H,d),5.45(1H,d),6.55(1H,m),6.87(1H,s),7.07(1H,t),7.22(1H,t),7.42-7.47(2H,m),7.85(1H,s),8.02(1H,s),8.22(1H,s),8.37(1H,d),8.45(1H,s),9.02(1H,s)；ES(m/z):M+H+538.4。
Example 19: n- {2- (2-dimethylaminoethyl-methylamino) -4-methoxy-5- { [ 5-methyl-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -trans-2, 4-pentadiene-namide
Figure BDA0001586008370000153
At-5 ℃ and N2Trans-2, 4-pentadienoyl chloride (58mg,0.5mmol, dissolved in 0.5mL THF) was added dropwise to N under protection1- (2-dimethylaminoethyl) -5-methoxy-N1-methyl-N4- { 5-methyl-4- (1-methylindol-3-yl) pyrimidin-2-yl } benzene-1, 2, 4-triamine (230mg,0.5mmol) and DIPEA (78mg,0.6mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 3h, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and added toAnd NaHCO3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (109mg, 44%) with MeOH (5-25%) as eluent.1H NMR：2.25(6H,s),2.27-2.32(2H,m),2.36(3H,s),2.71(3H,s),2.90(2H,t),3.80(3H,s),3.88(3H,s),5.21(1H,dd),5.26(1H,d),5.43(1H,d),6.54(1H,m),6.91(1H,s),7.07(1H,d),7.15-7.20(1H,m),7.40-7.44(2H,m),7.90(1H,s),8.05(1H,s),8.22(1H,s),8.37(1H,d),8.72(1H,s),8.77(1H,s),10.09(1H,s)；ES(m/z):M+H+540.4。
Example 20: n- {2- [ (3R) -3-dimethylaminopyrrolidin-1-yl ] -4-methoxy-5- { [ 5-methyl-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -trans-2, 4-pentadiene-namide
Figure BDA0001586008370000161
At-5 ℃ and N2Trans-2, 4-pentadienoyl chloride (35mg,0.3mmol, dissolved in 0.4mL THF) was added dropwise to 4- [ (3R) -3-dimethylaminopyrrolidin-1-yl ester with protection]-6-methoxy-N- { 5-methyl-4- (1-methylindol-3-yl) pyrimidin-2-yl } benzene-1, 3-diamine (142mg,0.3mmol) and DIPEA (59mg,0.45mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30 minutes, allowed to warm to room temperature for 2 hours, concentrated in vacuo, and the residue was dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (79mg, 48%) with MeOH (5-25%) as eluent.1H NMR：1.66-1.80(1H,m),2.07(1H,s),2.19(6H,s),2.34(3H,s),2.72(1H,s),3.18(3H,t),3.29-3.38(1H,m),3.83(3H,s),3.90(3H,s),5.20(1H,dd),5.25(1H,d),5.42(1H,d),6.55(1H,m),6.62(1H,s),7.10(1H,t),7.22(1H,t),7.41-7.46(2H,m),7.78(1H,s),7.95(1H,s),8.05(1H,s),8.20(1H,s),8.42(1H,d),9.30(1H,s)；ES(m/z):M+H+552.2。
Example 21: n- {5- { [ 5-chloro-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } -2- [ (3R) -3-dimethylaminopyrrolidin-1-yl ] -4-methoxyphenyl } -trans-2, 4-pentadiene-amide
Figure BDA0001586008370000162
At 10 ℃ and N2Trans-2, 4-pentadienoyl chloride (12mg,0.1mmol, dissolved in 0.2mL THF) was added dropwise to N- { 5-chloro-4- (1-methylindol-3-yl) pyrimidin-2-yl } -4- [ (3R) -3-dimethylaminopyrrolidin-1-yl) with protection]-6-methoxybenzene-1, 3-diamine (49mg,0.1mmol) and DIPEA (26mg,0.2mmol) in THF (4mL), the resulting mixture was stirred at 0 ℃ for 30 minutes, allowed to warm to room temperature for 3 hours, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3The solution (4mL) and a small amount of methanol (3-5 drops) are quenched for reaction, and the organic phase is washed with water (4mL) and added with MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (29mg, 50%) with MeOH (5-25%) as eluent.1HNMR：1.66-1.79(1H,m),2.02-2.10(1H,m),2.16(6H,s),2.62-2.72(1H,m),3.21(3H,dd),3.30-3.40(1H,m),3.80(3H,s),3.91(3H,s),5.18(1H,dd),5.25(1H,d),5.45(1H,d),6.55-6.60(2H,m),7.07(1H,t),7.22(1H,t),7.42-7.46(2H,m),7.53(1H,s),8.29-8.38(3H,m),8.54(1H,s),9.33(1H,s)；ES(m/z):M+H+572.2。
Example 22: n- {5- { [ 5-cyano-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } -2- [ (3R) -3-dimethylaminopyrrolidin-1-yl ] -4-methoxyphenyl } -trans-2, 4-pentadiene-namide
Figure BDA0001586008370000163
At 0 ℃ and N2Under protection, will be trans-2, 4-Pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.3mL THF) was added dropwise to N- { 5-cyano-4- (1-methylindol-3-yl) pyrimidin-2-yl } -4- [ (3R) -3-dimethylaminopyrrolidin-1-yl]-6-methoxybenzene-1, 3-diamine (97mg,0.2mmol) and DIPEA (39mg,0.3mmol) in THF (4mL), the resulting mixture was stirred at 0 deg.C for 30min, allowed to warm to room temperature for 3h, and concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3The solution (4mL) and a small amount of methanol (3-5 drops) are quenched for reaction, and the organic phase is washed with water (4mL) and added with MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (46mg, 41%) with MeOH (5-25%) as eluent.1H NMR:1.80(1H,dq),2.00-2.10(1H,m),2.24(6H,d),2.83(1H,dd),3.22-3.38(4H,m),3.77(3H,s),3.89(3H,s),5.22(1H,dd),5.27(1H,d),5.48(1H,d),6.55-6.60(2H,m),7.09(1H,t),7.22(1H,t),7.43-7.47(2H,m),7.66(1H,s),8.30(1H,d),8.41(1H,s),8.57(1H,s),8.74(1H,s),8.99(1H,s)；ES(m/z):M+H+563.2。
Example 23: n- {5- { [ 5-cyano-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000171
At 15 ℃ and N2Trans-2, 4-pentadienoyl chloride (47mg,0.4mmol, dissolved in 0.5mL THF) was added dropwise to 4-methoxy-N' - [ 5-cyano-4- (1-methylindol-3-yl) pyrimidin-2-yl ester with protection]-6- (4-methylpiperidin-1-yl) benzene-1, 3-diamine (187mg,0.4mmol) and DIPEA (78mg,0.6mmol) in THF (6 mL). The resulting mixture was stirred at 0 ℃ for 30 minutes, warmed to room temperature for 2 hours, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. Will be provided withThe crude product was purified by silica gel column chromatography using CH2Cl2The resulting solution was concentrated to give the desired product (103mg, 47%) with MeOH (5-25%) as eluent.1H NMR：2.25(3H,s),2.52-2.60(4H,m),2.88-2.93(4H,m),3.76(3H,s),3.90(3H,s),5.18(1H,dd),5.25(1H,d),5.45(1H,d),6.55(1H,m),6.89(1H,s),7.03(1H,br),7.22(1H,s),7.43(1H,m),7.54(1H,d),7.86(1H,br),8.03(1H,s),8.47(1H,s),8.50(1H,s),8.70(1H,s),9.08(1H,s),9.45(1H,s)；ES(m/z):M+H+549.2。
Example 24: n- {5- { [ 5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl ] amino } -2- [ (3R) -3-dimethylaminopyrrolidin-1-yl ] -4-methoxyphenyl } -trans-2, 4-pentadiene-amide
Figure BDA0001586008370000172
At 10 ℃ and N2Trans-2, 4-pentadienoyl chloride (12mg,0.1mmol, dissolved in 0.2mL THF) was added dropwise to N- { 5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl } -4- [ (3R) -3-dimethylaminopyrrolidin-1-yl) with protection]-6-methoxybenzene-1, 3-diamine (49mg,0.1mmol) and DIPEA (26mg,0.2mmol) in THF (4 mL). Stirring the obtained mixture at 0 deg.C for 30min, heating to room temperature for 2 hr, vacuum concentrating, and dissolving the residue in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (26mg, 46%) with MeOH (5-25%) as eluent.1H NMR:1.64-1.79(1H,m),2.02-2.14(1H,m),2.16(6H,s),2.62-2.76(1H,m),3.10-3.26(3H,m),3.33-3.40(1H,m),3.76(3H,s),5.18(1H,dd),5.25(1H,d),5.45(1H,d),6.55-6.60(2H,m),7.07(1H,t),7.15(1H,t),7.43-7.47(2H,m),7.52(1H,s),8.22-8.39(3H,m),8.47(1H,d),9.30(1H,s),11.82(1H,s)；ES(m/z):M+H+558.2。
Example 25: n- {5- { [ 5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl ] amino } -2- (2-dimethylaminoethyl-methylamino) -4-methoxyphenyl } -trans-2, 4-pentadiene-amide
Figure BDA0001586008370000173
At-5 ℃ and N2Trans-2, 4-pentadienoyl chloride (35mg,0.3mmol, dissolved in 0.4mL THF) was added dropwise to N under protection4- [ 5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl]-N1- (2-dimethylaminoethyl) -5-methoxy-N1-methylbenzene-1, 2, 4-triamine (140mg,0.3mmol) and DIPEA (59mg,0.45mmol) in THF (6 mL). The resulting mixture was stirred at 0 ℃ for 30 minutes, allowed to warm to room temperature for 3 hours, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (85mg, 52%) with MeOH (5-25%) as eluent.1H NMR:2.23(6H,s),2.36(2H,br),2.72(3H,s),2.85-2.93(2H,m),3.77(3H,s),5.18(1H,dd),5.25(1H,d),5.45(1H,d),6.55(1H,m),6.96(1H,t),7.04(1H,s),7.13(1H,t),7.43-7.47(2H,m),8.26(1H,d),8.36(1H,s),8.47(1H,s),8.52(1H,d),8.57(1H,s),10.10(1H,s),11.80(1H,s)；ES(m/z):M+H+546.2。
Example 26: n- {5- { [ 5-chloro-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } -2- (2-dimethylaminoethyl-methylamino) -4-methoxyphenyl } -trans-2, 4-pentadiene-namide
Figure BDA0001586008370000181
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (47mg,0.4mmol, dissolved in 0.5mL THF) was added dropwise to N under protection4- [ 5-chloro-4- (1-methylindol-3-yl) pyrimidin-2-yl]-N1- (2-dimethylaminoethyl) -5-methoxy-N1-methylbenzene-1, 2, 4-triamine (192mg,0.4mmol) and DIPEA (78mg,0.6mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 3h, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated with MeOH (5-25%) as eluent to afford the desired product (121mg, 54%).1H NMR:2.25(6H,s),2.21-2.30(2H,m),2.72(3H,s),2.85-2.88(2H,m),3.85(3H,s),3.92(3H,s),5.21(1H,dd),5.25(1H,d),5.46(1H,d),6.57(1H,m),6.80(1H,s),7.19-7.36(3H,m),7.42(1H,m),7.55(1H,s),8.36-8.44(3H,m),9.55(1H,s),10.10(1H,s)；ES(m/z):M+H+560.2。
Example 27: n- {5- { [ 5-cyano-4- (1H-indol-3-yl) pyrimidin-2-yl ] amino } -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000182
At 10 ℃ and N2Trans-2, 4-pentadienoyl chloride (47mg,0.4mmol, dissolved in 0.5mL THF) was added dropwise to 4-methoxy-N' - [ 5-cyano-4- (1H-indol-3-yl) pyrimidin-2-yl with protection]-6- (4-methylpiperidin-1-yl) benzene-1, 3-diamine (182mg,0.4mmol) and DIPEA (78mg,0.6mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 3h, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (96mg, 45%) with MeOH (5-25%) as eluent.1H NMR:2.26(3H,s),2.56-2.64(4H,m),2.92(4H,s),3.76(3H,s),5.20(1H,dd),5.24(1H,d),5.46(1H,d),6.55(1H,m),6.90(1H,s),7.00(1H,t),7.17(1H,s),7.45-7.48(2H,m),8.01(1H,s),8.52(1H,s),8.66(1H,s),9.07(1H,s),9.42(1H,s),11.98(1H,s)；ES(m/z):M+H+535.2。
Example 28: n- {2- (2-dimethylaminoethyl-methylamino) -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -trans-24-pentadiene-namide
Figure BDA0001586008370000183
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (1.16g,10mmol, dissolved in 4mL THF) was added dropwise to N with protection1- (2-dimethylaminoethyl) -5-methoxy-N1-methyl-N4- [4- (1-methylindol-3-yl) pyrimidin-2-yl]Benzene-1, 2, 4-triamine (4.46g,10mmol) and DIPEA (1.55g,12mmol) in THF (20 mL). The mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 3h, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(30mL) and saturated NaHCO was added3The reaction was quenched (5mL) with a small amount of methanol (5 drops), and the organic phase was washed with water (6mL) and MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH2Cl2The resulting solution was concentrated to give the desired product (3.05g, 58%) with MeOH (5-25%) as eluent.1H NMR:2.21(6H,s),2.25(2H,t),2.68(3H,s),2.97(2H,t),3.89(3H,s),3.96(3H,s),5.18(1H,dd),5.24(1H,d),5.44(1H,d),6.55(1H,m),6.81(1H,s),7.20(1H,d),7.25-7.28(2H,m),7.38-7.40(2H,m),7.74(1H,s),8.05-8.08(1H,m),8.38(1H,d),8.92(1H,s),9.71(1H,s),10.48(1H,s)；ES(m/z):M+H+526.2。
Example 29: n- {5- { [ 5-cyano-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } -2- (2-dimethylaminoethyl-methylamino) -4-methoxyphenyl } -trans-2, 4-pentadiene-namide
Figure BDA0001586008370000184
At 10 ℃ and N2Trans-2, 4-pentadienoyl chloride (35mg,0.3mmol in 0.4mL THF) was added dropwise to N with protection4- [ 5-cyano-4- (1H-indol-3-yl) pyrimidin-2-yl]-N1- (2-dimethylaminoethyl) -5-methoxy-N1-methylbenzene-1, 2, 4-triamine (141mg,0.3mmol) and DIPEA (59mg,0.45mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 3h, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3The solution (4mL) and a small amount of methanol (3-5 drops) are quenched for reaction, and the organic phase is washed with water (4mL) and added with MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (73mg, 44%) with MeOH (5-25%) as eluent.1H NMR:2.20(6H,s),2.38(2H,t),2.78(3H,s),2.95(2H,t),3.75(3H,s),3.88(3H,s),5.21(1H,dd),5.26(1H,d),5.47(1H,d),6.58(1H,m),6.86(1H,s),7.10-7.24(2H,m),7.43-7.47(2H,m),8.20(1H,d),8.44(1H,s),8.46(1H,s),8.62(1H,s),8.85(1H,s),9.54(1H,s)；ES(m/z):M+H+551.2。
Example 30: n- {2- [ (3R) -3-dimethylaminopyrrolidin-1-yl ] -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -trans-2, 4-pentadiene-amide
Figure BDA0001586008370000191
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (11mg,0.1mmol, dissolved in 0.2mL THF) was added dropwise to 4- [ (3R) -3-dimethylaminopyrrolidin-1-yl group with protection]-6-methoxy-N- {4- (1-methylindol-3-yl) pyrimidin-2-yl } benzene-1, 3-diamine (45mg,0.1mmol) and DIPEA (26mg,0.2mmol) in THF (4 mL). The mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 2h, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4DryingAnd (3) removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (25mg, 47%) with MeOH (5-25%) as eluent.1H NMR:1.85-1.95(1H,m),2.10-2.19(1H,m),2.27(6H,s),2.86-2.96(1H,m),3.02-3.19(4H,m),3.86(3H,s),3.98(3H,s),5.17(1H,dd),5.22(1H,d),5.44(1H,d),6.53(1H,m),6.76(1H,s),7.17(1H,d),7.20-7.32(2H,m),7.36-7.40(2H,m),7.66(1H,s),8.02(1H,d),8.37(1H,d),8.47(1H,s),9.01(1H,s),9.78(1H,s)；ES(m/z):M+H+538.2。
Example 31: n- {5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -4-methoxy-2- [ methyl- (2-morpholin-4-ylethyl) amino ] phenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000192
At 15 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.2mL CH) with protection2Cl2In) dropwise addition to N4- { 5-chloro-4-pyrazolo [1,5-a ]]Pyridin-3-ylpyrimidin-2-yl } -5-methoxy-N1-methyl-N1- (2-Morpholin-4-ylethyl) benzene-1, 2, 4-triamine (102mg,0.2mmol) and DIPEA (39mg,0.3mmol) in CH2Cl2(4mL) in solution. The resulting mixture was warmed to room temperature and stirred for 2 h. Then saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (61mg, 52%) with MeOH (5-25%) as eluent.1H NMR:2.27-2.38(4H,m),2.43(2H,t),2.72(3H,s),3.04(2H,t),3.50-3.60(4H,m),3.76(3H,s),5.20(1H,dd),5.25(1H,d),5.49(1H,d),6.58(1H,m),7.00(1H,s),7.11(1H,t),7.28-7.38(1H,m),7.48(1H,m),8.26(1H,s),8.38-8.42(2H,m),8.65(1H,s),8.84(1H,d),8.97(1H,s),9.30(1H,s)；ES(m/z):M+H+589.2。
Example 32: n- {5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -4-methoxy-2- [ methyl- [2- (4-methylpiperazin-1-ylethyl) amino ] phenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000193
At 20 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.2mL CH) with protection2Cl2In) dropwise addition to N4- { 5-chloro-4-pyrazolo [1,5-a ]]Pyridin-3-ylpyrimidin-2-yl } -5-methoxy-N1-methyl-N1- [2- (4-methylpiperazin-1-ylethyl) benzene-1, 2, 4-triamine (105mg,0.2mmol) and DIPEA (39mg,0.3mmol) in CH2Cl2(4mL) in solution. The resulting mixture was warmed to room temperature and stirred for 4 hours. Then saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (64mg, 53%) with MeOH (5-25%) as eluent.1H NMR:2.29(3H,s),2.36-2.61(10H,m),2.66(3H,s),3.01(2H,t),3.86(3H,s),5.20(1H,dd),5.26(1H,d),5.45(1H,d),6.57(1H,m),6.76(1H,s),6.92(1H,t),7.28(1H,t),7.44-7.47(2H,m),8.46(1H,s),8.55(2H,t),8.95(1H,s),9.12(1H,s),9.38(1H,s)；ES(m/z):M+H+602.2。
Example 33: n- { 4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } -2- (4-methylpiperazin-1-yl) phenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000201
At 10 ℃ and N2Trans-2, 4-pentadienoyl chloride (47mg,0.4mmol, dissolved in 0.5mL THF) was added dropwise to 4-methoxy-N' - [4- (1-methylindol-3-yl) pyrimidin-2-yl with protection]-6- (4-methylpiperidin-1-yl) benzene-1, 3-diamine (177mg,0.4mmol) and DIPEA (78mg,0.6mmol) in THF (6 mL). Will be describedThe mixture is stirred and reacted for 30min at the temperature of 0 ℃, then is heated to room temperature for reaction for 3h, and is concentrated in vacuum. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH2Cl2The resulting solution was concentrated to give the desired product (105mg, 50%) with MeOH (5-25%) as eluent.1H NMR:2.26(3H,s),2.52-2.60(4H,m),2.82-2.92(4H,m),3.86(3H,s),3.93(3H,s),5.20(1H,dd),5.25(1H,d),5.49(1H,d),6.58(1H,m),6.88(1H,s),7.11-7.26(3H,m),7.42(1H,m),7.52(1H,d),7.88(1H,s),8.26(1H,d),8.32(1H,d),8.57(1H,s),8.81(1H,s),9.09(1H,s)；ES(m/z):M+H+524.2。
Example 34: n- {5- { [ 5-chloro-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } -2- [ 3-dimethylaminoazetidin-1-yl ] -4-methoxyphenyl } -trans-2, 4-pentadiene-amide
Figure BDA0001586008370000202
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (47mg,0.4mmol, dissolved in 0.5mL CH) with protection2Cl2In (b) is added dropwise to N- [ 5-chloro-4- (1-methylindol-3-yl) pyrimidin-2-yl]-4- [ 3-Dimethylaminoazetidin-1-yl) -6-methoxybenzene-1, 3-diamine (191mg,0.4mmol) and DIPEA (78mg,0.6mmol) in CH2Cl2(8mL) in solution. The resulting mixture was warmed to room temperature and stirred for 2 hours, then saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (105mg, 47%) with MeOH (5-25%) as eluent.1H NMR:2.11(6H,s),3.02-3.12(1H,m),3.55-3.62(2H,m),3.75(3H,s),3.92(3H,s),3.98(2H,t),5.20(1H,dd),5.25(1H,d),5.49(1H,d),6.55-6.60(2H,m),,7.09(1H,t),7.22(1H,t),7.45-7.53(3H,m),8.16-8.34(3H,m),8.52(1H,s),9.20(1H,s)；ES(m/z):M+H+558.2。
Example 35: n- {2- [ 3-dimethylaminoazetidin-1-yl ] -4-methoxy-5- { [ 5-methyl-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -trans-2, 4-pentadiene-mide
Figure BDA0001586008370000203
At 20 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.3mL CH) with protection2Cl2In (b)) dropwise addition to 4- [ 3-dimethylaminoazetidin-1-yl) -6-methoxy-N- [ 5-methyl-4- (1-methylindol-3-yl) pyrimidin-2-yl]Benzene-1, 3-diamine (92mg,0.2mmol) and DIPEA (39mg,0.3mmol) in CH2Cl2(5mL) in solution. The resulting mixture was warmed to room temperature and stirred for reaction for 3 hours. Then saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH2Cl2The resulting solution was concentrated with MeOH (5-25%) as eluent to afford the desired product (51mg, 47%).1H NMR:2.06(6H,s),2.36(3H,s),3.02-3.12(1H,m),3.56(2H,t),3.85(3H,s),3.89(3H,s),3.95(2H,t),5.20(1H,dd),5.26(1H,d),5.45(1H,d),6.36(1H,s),6.57(1H,m),7.11(1H,t),7.22(1H,t),7.44-7.47(2H,m),7.67(1H,s),7.82(1H,s),7.98(1H,s),8.17(1H,s),8.40(1H,d),9.18(1H,s)；ES(m/z):M+H+538.2。
Example 36: n- {2- [ 3-dimethylaminoazetidin-1-yl ] -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -trans-2, 4-pentadiene-namide
Figure BDA0001586008370000211
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (47mg,0.4mmol, dissolved in 0.5mL CH) with protection2Cl2In (b)) dropwise addition to 4- [ 3-dimethylaminoazetidin-1-yl) -6-methoxy-N- [4- (1-methylindol-3-yl) pyrimidin-2-yl]Benzene-1, 3-diamine (177mg,0.4mmol) and DIPEA (78mg,0.6mmol) in CH2Cl2(8mL) in solution. The resulting mixture was warmed to room temperature and stirred for reaction for 3 hours. Then saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (109mg, 52%) with MeOH (5-25%) as eluent.1H NMR:2.12(6H,s),3.06(1H,t),3.55(2H,t),3.86(3H,s),3.90(3H,s),3.95(2H,t),5.20(1H,dd),5.26(1H,d),5.45(1H,d),6.55-6.58(2H,m),7.12(1H,d),7.18-7.28(2H,m),7.41(1H,m),7.52(1H,d),7.76(1H,s),7.99(1H,s),8.25(1H,d),8.35(2H,d),9.28(1H,s)；ES(m/z):M+H+524.2。
Example 37: n- {5- { [ 5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl ] amino } -2- [ 3-dimethylaminoazetidin-1-yl ] -4-methoxyphenyl } -trans-2, 4-pentadiene-amide
Figure BDA0001586008370000212
At 20 ℃ and N2Trans-2, 4-pentadienoyl chloride (47mg,0.4mmol, dissolved in 0.5mL CH) with protection2Cl2In (b) is added dropwise to N- [ 5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl]-4- [ 3-Dimethylaminoazetidin-1-yl) -6-methoxybenzene-1, 3-diamine (198mg,0.4mmol) and DIPEA (78mg,0.6mmol) in CH2Cl2(8mL) in solution. The resulting mixture was warmed to room temperature and stirred for 2 hours. Then saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (104mg, 48%) with MeOH (5-25%) as eluent.1H NMR:2.10(6H,s),3.02-2.12(1H,m),3.57(2H,t),3.77(3H,s),3.97(3H,s),5.20(1H,dd),5.26(1H,d),5.45(1H,d),6.46(1H,s),6.57(1H,m),7.07(1H,t),7.15(1H,t),7.44-7.48(2H,m),7.50(1H,s),8.22(1H,s),8.27-8.30(1H,m),8.33(1H,s),8.45(1H,d),9.23(1H,s),11.77(1H,s)；ES(m/z):M+H+544.2。
Example 38: n- {5- { [ 5-cyano-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -2- [ (3R) -3-dimethylaminopyrrolidin-1-yl ] -4-methoxyphenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000213
At 10 ℃ and N2Under protection, trans-2, 4-pentadienoyl chloride (47mg,0.4mmol, in 0.5mL CH)2Cl2In (b) was added dropwise to N- { 5-cyano-4-pyrazolo [1,5-a ]]Pyridin-3-ylpyrimidin-2-yl } -4- [ (3R) -3-dimethylaminopyrrolidin-1-yl) -6-methoxybenzene-1, 3-diamine (188mg,0.4mmol) and DIPEA (79mg,0.6mmol) in CH2Cl2(8mL) in solution. The resulting mixture was warmed to room temperature and stirred for reaction for 3 hours. Then saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (101mg, 46%) with MeOH (5-25%) as eluent.1H NMR:1.80(1H,dq),2.04-2.09(1H,m),2.23(6H,s),2.80-2.90(1H,m),3.20-3.44(4H,m),3.77(3H,s),5.20(1H,dd),5.26(1H,d),5.45(1H,d),6.57(1H,m),6.67(1H,s),7.10(1H,t),7.35-7.46(2H,m),7.56(1H,s),8.32(1H,d),8.65(1H,s),8.77(1H,d),8.91(2H,s),9.01(1H,s)；ES(m/z):M+H+550.2。
Example 39: n- {5- { [ 5-cyano-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -2- [ 2-dimethylaminoethyl-methylamino ] -4-methoxyphenyl } -trans-2, 4-pentadiene-amide
Figure BDA0001586008370000221
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (55mg,0.5mmol, dissolved in 0.5mL THF) was added dropwise to N under protection4- { 5-cyano-4-pyrazolo [1,5-a ]]Pyridin-3-ylpyrimidin-2-yl } -N1- (2-dimethylaminoethyl) -N1-methyl-5-methoxybenzene-1, 2, 4-triamine (229mg,0.5mmol) and DIPEA (78mg,0.6mmol) in THF (6 mL). The resulting mixture was stirred at 0 ℃ for 30 minutes, allowed to warm to room temperature for 4 hours, concentrated in vacuo, and the residue was dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (178mg, 67%) with MeOH (5-25%) as eluent.1HNMR:2.24(6H,s),2.28(2H,dd),2.66(3H,d),3.78-2.87(2H,m),3.80(3H,s),5.22(1H,dd),5.25(1H,d),5.44(1H,d),6.55(1H,m),6.76(1H,s),6.90(1H,d),7.22(1H,s),7.45(1H,m),7.66(1H,s),8.51(2H,dd),8.60(1H,s),9.02(1H,s),9.29(1H,s),10.05(1H,s)；ES(m/z):M+H+538.2。
Example 40: n- {5- { [ 5-cyano-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -2- [ 3-dimethylaminoazetidin-1-yl ] -4-methoxyphenyl } -trans-2, 4-pentadiene-amide
Figure BDA0001586008370000222
At 25 ℃ and N2Trans-2, 4-pentadienoyl chloride (47mg,0.4mmol, dissolved in 0.5mL CH) with protection2Cl2In (b) was added dropwise to N- { 5-cyano-4-pyrazolo [1,5-a ]]Pyridin-3-ylpyrimidin-2-yl } -4- [ 3-dimethylaminoazetidi-1-yl) -6-methoxybenzene-1, 3-diamine (182mg,0.4mmol) and DIPEA (78mg,0.6mmol) in CH2Cl2(8mL) in solution. The resulting mixture was warmed to room temperature and stirred for 2 hours. Then saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), and the organic phase is quenched with waterAfter washing (4mL), MgSO was added4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated with MeOH (5-25%) as eluent to afford the desired product (109mg, 51%).1H NMR:2.11(6H,s),3.06-3.14(1H,m),3.64(2H,t),3.76(3H,s),4.00(2H,s),5.20(1H,dd),5.26(1H,d),5.45(1H,d),6.34(1H,s),6.46(1H,s),7.12(1H,br),7.25(1H,s),7.42-7.46(2H,m),7.96(1H,br),8.66(1H,s),8.87(1H,br),8.92(1H,s),9.27(1H,s),9.33(1H,s)；ES(m/z):M+H+536.2。
Example 41: n- {2- (3aR,6aR) -5-Methylhexahydropyrrolo [3,4-b ] pyrrol-1-yl } -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -trans-2, 4-pentadiene-namide
Figure BDA0001586008370000223
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.3mL THF) was added dropwise to 4- { (3aR,6aR) -5-methylhexahydropyrrolo [3,4-b ] with protection]Pyrrol-1 (2H) -yl } -6-methoxy-N- [4- (1-methylindol-3-yl) pyrimidin-2-yl]Benzene-1, 3-diamine (94mg,0.2mmol) and DIPEA (39mg,0.3mmol) in THF (3 mL). The mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 3h, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3The solution (4mL) and a small amount of methanol (3-5 drops) are quenched for reaction, and the organic phase is washed with water (4mL) and added with MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (53mg, 48%) with MeOH (5-25%) as eluent.1H NMR:1.75-1.94(2H,m),2.13-2.23(1H,m),2.28(3H,s),2.29-2.38(1H,m),2.74(1H,d),2.81(1H,d),2.83-2.90(1H,m),2.94(1H,td),3.20(1H,t),3.58-3.69(1H,m),3.87(3H,s),4.01(3H,s),5.20(1H,dd),5.26(1H,d),5.45(1H,d),6.57(1H,m),6.81(1H,s),7.20(1H,d),7.22-7.30(2H,m),7.35-7.42(2H,m),7.70(1H,s),8.02-8.10(1H,m),8.37(1H,d),9.08(1H,s),9.45(1H,s),9.88(1H,s)；ES(m/z):M+H+550.2。
Example 42: n- {2- [ 2-dimethylaminoethyl-methylamino ] -4-methoxy-5- { [4- (4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl ] amino } phenyl } -trans-2, 4-pentadiene-mide
Figure BDA0001586008370000231
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.3mL THF) was added dropwise to N under protection1- (2-dimethylaminoethyl) -5-methoxy-N1-methyl-N4- {4- (4,5,6, 7-Tetrahydropyrazolo [1,5-a ]]Pyridin-3-yl) pyrimidin-2-yl } benzene-1, 2, 4-triamine (87mg,0.2mmol) and DIPEA (39mg,0.3mmol) in THF (5 mL). The resulting mixture was stirred at 0 ℃ for 30 minutes, allowed to warm to room temperature for 2 hours, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (54mg, 52%) with MeOH (5-25%) as eluent.1H NMR:1.67-1.75(2H,m),1.87-1.96(2H,m),2.23(6H,s),2.26(2H,t),2.72(3H,s),2.87(2H,t),3.05(2H,t),3.85(3H,s),4.08(2H,t),5.18(1H,dd),5.25(1H,d),5.44(1H,d),6.55(1H,m),6.84(1H,s),6.95-7.01(1H,m),7.49(1H,m),7.85(1H,s),8.12(1H,s),8.32(1H,d),8.87(1H,s),10.07(1H,s)；ES(m/z):M+H+517.4。
Example 43: n- {2- (3aR,6aR) -5-Methylhexahydropyrrolo [3,4-b ] pyrrol-1-yl } -4-methoxy-5- { [4- (4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl ] amino } phenyl } -trans-24-pentadiene-namide
Figure BDA0001586008370000232
At 0DEG C and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.3mL THF) was added dropwise to 4- { (3aR,6aR) -5-methylhexahydropyrrolo [3,4-b ] with protection]Pyrrol-1 (2H) -yl } -6-methoxy-N- [4- (4,5,6, 7-tetrahydropyrazolo [1, 5-a)]Pyridin-3-yl) pyrimidin-2-yl]Benzene-1, 3-diamine (92mg,0.2mmol) and DIPEA (39mg,0.3mmol) in THF (3 mL). The resulting mixture was stirred at 0 ℃ for 30 minutes, warmed to room temperature for 4 hours, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated with MeOH (5-25%) as eluent to afford the desired product (55mg, 51%).1H NMR:1.80-1.95(4H,m),2,00-2.06(2H,m),2.12-2.22(1H,s),2.25-2.36(1H,m),2.29(3H,s),2.67-2.96(4H,m),3.17-3.28(3H,m),3.65(1H,br),3.86(3H,s),4.18(2H,t),5.21(1H,dd),5.27(1H,d),5.47(1H,d),6.55(1H,m),6.80(1H,s),6.87(1H,d),7.42-7.47(2H,m),7.99(1H,s),8.36(1H,d),9.25(1H,s),9.46(1H,s)；ES(m/z):M+H+541.4。
Example 44: n- {2- [ (3R) -3-dimethylaminopyrrolidin-1-yl ] -4-methoxy-5- { [4- (4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl ] amino } phenyl } -trans-2, 4-pentadiene-mide
Figure BDA0001586008370000233
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (22mg,0.2mmol, dissolved in 0.3mL THF) was added dropwise to 4- { (3R) -3-dimethylaminopyrrolidin-1-yl } -6-methoxy-N- [4- (4,5,6, 7-tetrahydropyrazolo [1,5-a ] with protection]Pyridin-3-yl) pyrimidin-2-yl]Benzene-1, 3-diamine (90mg,0.2mmol) and DIPEA (39mg,0.3mmol) in THF (3 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 4h, and concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (56mg, 54%) with MeOH (5-25%) as eluent.1H NMR:1.67-1.80(3H,m),1.88-1.97(2H,m),2.01-2.10(1H,m),2.18(6H,s),2.66-2.75(1H,m),3.00-3.05(2H,m),3.12-3.20(3H,m),3.30-3.39(1H,m),3.85(3H,s),4.08(2H,t),5.18(1H,dd),5.25(1H,d),5.44(1H,d),6.55(1H,m),6.66(1H,s),6.97(1H,d),7.45(1H,m),7.72(1H,s),8.04(2H,d),8.30(1H,d),9.33(1H,s)；ES(m/z):M+H+529.4。
Example 45: n- { 4-methoxy-2- [ 1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl ] -5- { [4- (4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl ] amino } phenyl } -trans-2, 4-pentadiene-mide
Figure BDA0001586008370000241
At 10 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.3mL THF) was added dropwise to 4-methoxy-6- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) -N' - {4- (4,5,6, 7-tetrahydropyrazolo [1,5-a ] with protection]Pyridin-3-yl) pyrimidin-2-yl } benzene-1, 3-diamine (86mg,0.2mmol) and DIPEA (39mg,0.3mmol) in THF (3 mL). Stirring the obtained mixture at 0 deg.C for 30min, heating to room temperature for 4 hr, vacuum concentrating, and dissolving the residue in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (56mg, 55%) with MeOH (5-25%) as eluent.1H NMR:1.77-1.85(2H,m),1.90-1.98(2H,m),2.26(3H,s),2.32-2.39(2H,m),2.48-2.57(2H,m),2.95-2.99(2H,m),3.09(2H,t),3.90(3H,s),4.10(2H,t),5.18(1H,dd),5.25(1H,d),5.44(1H,d),5.70(1H,m),6.55(1H,m),6.86(1H,s),7.07(1H,d),7.48(1H,m),7.84(1H,s),8.12(1H,s),8.32-8.38(2H,m),9.34(1H,s)；ES(m/z):M+H+512.2。
Example 46: n- {2- (3-dimethylamino-azetidin-1-yl) -4-methoxy-5- { [4- (4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl ] amino } phenyl } -trans-2, 4-pentadiene-mide
Figure BDA0001586008370000242
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.3mL THF) was added dropwise to 4- (3-dimethylaminoazetidin-1-yl) -6-methoxy-N- {4- (4,5,6, 7-tetrahydropyrazolo [1,5-a ] with protection]Pyridin-3-yl) pyrimidin-2-yl } benzene-1, 3-diamine (87mg,0.2mmol) and DIPEA (39mg,0.3mmol) in THF (3 mL). The resulting mixture was stirred at 0 ℃ for 30 minutes, allowed to warm to room temperature for 3 hours, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (50mg, 49%) with MeOH (5-25%) as eluent.1H NMR:1.74-1.80(2H,m),1.90-1.98(2H,m),2.08(6H,s),2.99-3.09(3H,m),3.56(2H,t),3.86(3H,s),3.94(2H,t),4.10(2H,t),5.20(1H,dd),5.26(1H,d),5.47(1H,d),6.55-6.58(2H,m),6.98(1H,d),7.43(1H,m),7.72(1H,s),7.89(1H,s),8.04(1H,s),8.26(1H,d),9.26(1H,s)；ES(m/z):M+H+515.4。
Example 47: n- { 4-methoxy-2- (5-methyl-2, 5-diazaspiro [3,4] oct-2-yl) -5- { [4- (4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl ] amino } phenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000243
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.3mL THF) was added dropwise to 4-methoxy-6- (5-methyl-2, 5-diazaspiro [3,4] ring with protection]Oct-2-yl) -N' - {4- (4,5,6, 7-tetrahydropyrazolo [1,5-a ]]Pyridin-3-yl) pyrimidin-2-yl } benzene-1, 3-diamine (92mg,0.2mmol) and DIPEA (39mg,0.3mmol) in THF (3 mL). The mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 3h, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated with MeOH (5-25%) as eluent to afford the desired product (55mg, 51%).1H NMR:1.60-1.74(2H,m),1.72-1.84(2H,m),1.86-1.98(2H,m),2.04(2H,t),2.36(3H,s),2.63(2H,t),3.02(2H,t),3.60(2H,d),3.86(3H,s),3.90(2H,d),4.08(2H,t),5.21(1H,dd),5.27(1H,d),5.48(1H,d),6.55-6.59(2H,m),6.96(1H,d),7.46(1H,m),7.72(1H,s),7.82(1H,s),8.06(1H,s),8.27(1H,d),9.28(1H,s)；ES(m/z):M+H+541.4。
Example 48: n- { 4-methoxy-2- [ 1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl ] -5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -trans-2, 4-pentadiene-amide
Figure BDA0001586008370000251
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.3mL THF) was added dropwise, with protection, to a solution of 4-methoxy-6- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) -N' - {4- (1-methylindol-3-yl) pyrimidin-2-yl } benzene-1, 3-diamine (88mg,0.2mmol) and DIPEA (39mg,0.3mmol) in THF (3 mL). Stirring the obtained mixture at 0 deg.C for 30min, heating to room temperature, reacting for 3 hr, vacuum concentrating, and dissolving the residue in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), quenching the reaction, and reusing the organic phaseAfter washing with water (4mL), MgSO was added4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated with MeOH (5-25%) as eluent to afford the desired product (53mg, 51%).1H NMR:2.27(3H,s),2.36-2.42(2H,m),2.52-2.58(2H,m),2.97-3.01(2H,m),3.91(3H,s),3.93(3H,s),5.18(1H,dd),5.25(1H,d),5.44(1H,d),5.72(1H,m),6.55(1H,m),6.86(1H,s),7.19-7.28(3H,m),7.42(1H,m),7.54-7.56(1H,m),7.89(1H,s),8.32-8.36(2H,m),8.42(1H,s),8.46(1H,s),9.35(1H,s)；ES(m/z):M+H+521.2。
Example 49: n- { 4-methoxy-2- { 5-methyl-2, 5-diazaspiro [3,4] oct-2-yl } -5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -trans-2, 4-pentadiene-namide
Figure BDA0001586008370000252
At 5 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.3mL THF) was added dropwise to 4-methoxy-6- (5-methyl-2, 5-diazaspiro [3,4] ring with protection]Oct-2-yl) -N' - {4- (1-methylindol-3-yl) pyrimidin-2-yl } benzene-1, 3-diamine (94mg,0.2mmol) and DIPEA (39mg,0.3mmol) in THF (3 mL). The resulting mixture was stirred at 0 ℃ for 30 minutes, allowed to warm to room temperature for 3 hours, concentrated in vacuo, and the residue was dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH2Cl2The resulting solution was concentrated to give the desired product (53mg, 48%) with MeOH (5-25%) as eluent.1HNMR:1.62-1.75(2H,m),2.00-2.09(2H,m),2.36(3H,s),2.65(2H,t),3.65(2H,d),3.86(3H,s),3.90(3H,s),5.21(1H,dd),5.27(1H,d),5.48(1H,d),6.55-6.59(2H,m),7.12(1H,d),7.15-7.28(2H,m),7.42(1H,m),7.52(1H,d),7.72(1H,s),7.92(1H,s),8.27(1H,d),8.30-8.39(2H,m),9.25(1H,s)；ES(m/z):M+H+550.2。
Example 50: n- {2- [ (3S) -3-dimethylaminopyrrolidin-1-yl ] -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -trans-2, 4-pentadiene-amide
Figure BDA0001586008370000253
At 15 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.3mL THF) was added dropwise to 4- [ (3S) -3-dimethylaminopyrrolidin-1-yl group with protection]-6-methoxy-N' - {4- (1-methylindol-3-yl) pyrimidin-2-yl } benzene-1, 3-diamine (92mg,0.2mmol) and DIPEA (39mg,0.3mmol) in THF (3 mL). The mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 3h, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH2Cl2The resulting solution was concentrated to give the desired product (50mg, 47%) with MeOH (5-25%) as eluent.1H NMR:1.75-1.78(1H,m),2.07(1H,s),2.17(6H,s),2.70-2.74(1H,m),3.16(1H,s),3.22(2H,d),3.31-3.45(1H,m),3.86(3H,s),3.90(3H,s),5.18(1H,dd),5.25(1H,d),5.44(1H,d),6.55(1H,m),6.66(1H,s),7.17-7.22(3H,m),7.40(1H,m),7.52(1H,d),7.76(1H,s),8.16(1H,s),8.26(1H,d),8.33(1H,d),8.37(1H,s),9.35(1H,s)；ES(m/z):M+H+538.4。
Example 51: n- { 4-methoxy-2- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) -5- { [ 4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } phenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000261
At-5 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.5mL CH) with protection2Cl2In (1) dropwise addition to 4-methoxy-6- (1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl) -N' - { 4-pyrazolo [1, 5-a)]Pyridin-3-yl) pyrimidin-2-yl } benzene-1, 3-diamine (86mg,0.2mmol) and DIPEA (39mg,0.3mmol) in CH2Cl2(6mL) and the resulting mixture was stirred at 0 ℃ for 1 h. Then saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated with MeOH (5-25%) as eluent to afford the desired product (51mg, 50%).1H NMR:2.32(3H,s),2.41(2H,s),2.58(2H,d),3.05(2H,d),3.86(3H,s),5.19(1H,dd),5.24(1H,d),5.46(1H,d),5.73(1H,m),6.55(1H,m),6.87(1H,s),7.07(1H,t),7.32(1H,d),7.44-7.49(2H,m),8.13(1H,s),8.22(1H,s),8.38(1H,d),8.52(1H,d),8.79-8.85(2H,m),9.37(1H,s)；ES(m/z):M+H+508.2。
Example 52: n- {2- [ (3R) -3-dimethylaminopyrrolidin-1-yl ] -4-methoxy-5- { [ 4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } phenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000262
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.4mL CH) with protection2Cl2Middle) was added dropwise to 4- [ (3R) -3-dimethylaminopyrrolidin-1-yl) -6-methoxy-N- { 4-pyrazolo [1, 5-a)]Pyridin-3-ylpyrimidin-2-yl } benzene-1, 3-diamine (89mg,0.2mmol) and DIPEA (39mg,0.3mmol) in CH2Cl2(8mL) in solution. The resulting mixture was warmed to room temperature and stirred for 2 hours, then saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (59mg, 56%) with MeOH (5-25%) as eluent.1H NMR:1.70-1.80(1H,m),2.04-2.12(1H,m),2.18(6H,s),2.67-2.77(1H,m),3.18-3.26(3H,m),3.35-3.42(1H,m),3.86(3H,s),5.20(1H,dd),5.25(1H,d),5.46(1H,d),6.54(1H,m),6.66(1H,s),7.07(1H,dd),7.22(1H,d),7.40-7.46(2H,m),7.86(1H,s),8.02(1H,s),8.31(1H,d),8.47(1H,d),8.77(1H,s),8.79(1H,d),9.37(1H,s)；ES(m/z):M+H+525.2。
Example 53: n- {2- [ 3-dimethylaminoazetidin-1-yl ] -4-methoxy-5- { [ 4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -phenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000263
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (35mg,0.3mmol, dissolved in 0.4mL CH) with protection2Cl2In (b) was added dropwise to 4- (3-dimethylaminoazetidin-1-yl) -6-methoxy-N- { 4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } benzene-1, 3-diamine (129mg,0.3mmol) and DIPEA (59mg,0.45mmol) in CH2Cl2(8mL) in solution. The resulting mixture was warmed to room temperature and stirred for reaction for 3 hours. Then saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (89mg, 58%) with MeOH (5-25%) as eluent.1H NMR:2.10(6H,s),3.05-3.12(1H,m),3.54-3.62(2H,m),3.85(3H,s),3.96(2H,t),5.18(1H,dd),5.25(1H,d),5.44(1H,d),6.54-6.57(2H,m),7.07(1H,td),7.22(1H,d),7.42-7.47(2H,m),7.73(1H,s),8.02(1H,s),8.27(1H,d),8.45(1H,br),8.76(1H,s),8.78(1H,d),9.30(1H,s)；ES(m/z):M+H+511.2。
Example 54: n- {2- [ 2-dimethylaminoethyl-methylamino ] -4-methoxy-5- { [ 4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } phenyl } -trans-2, 4-pentadiene-amide
Figure BDA0001586008370000264
At-5 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.4mL THF) was added dropwise to N under protection1- (2-dimethylaminoethyl) -5-methoxy-N1-methyl-N4- { 4-pyrazolo [1,5-a ]]Pyridin-3-ylpyrimidin-2-yl } benzene-1, 2, 4-triamine (86mg,0.2mmol) and DIPEA (78mg,0.6mmol) in THF (6 mL). The resulting mixture was stirred at 0 ℃ for 30 minutes, warmed to room temperature for 2 hours, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (62mg, 60%) with MeOH (5-25%) as eluent.1H NMR:2.24(6H,s),2.34(2H,t),2.73(3H,s),2.95(2H,t),3.84(3H,s),5.20(1H,dd),5.25(1H,d),5.46(1H,d),6.54(1H,m),6.96(1H,s),7.05(1H,d),7.26(1H,d),7.29-7.35(1H,m),7.44(1H,m),8.16(1H,s),8.35(1H,d),8.45(1H,d),8.77-8.81(2H,m),8.82(1H,s),10.08(1H,br)；ES(m/z):M+H+513.2。
Example 55: n- {2- { (3aR,6aR) -5-Methylhexahydropyrrolo [3,4-b ] pyrrol-1 (2H) -yl } -5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -4-methoxyphenyl } -trans-2, 4-pentadiene-namide
Figure BDA0001586008370000271
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.3mL THF) was added dropwise to 4- { (3aR,6aR) -5-methylhexahydropyrrolo [3,4-b ] with protection]Pyrrol-1 (2H) -yl } -6-methoxy-N- { 4-pyrazolo [1, 5-a)]Pyridin-3-ylpyrimidin-2-yl } benzene-1, 3-diamine (91mg,0.2mmol) and DIPEA (39mg,0.3mmol) in THF (3 mL). The resulting mixture was stirred at 0 ℃ for 30 minutes, allowed to warm to room temperature for 4 hours, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) in combination withSaturated NaHCO is added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated with MeOH (5-25%) as eluent to afford the desired product (59mg, 55%).1H NMR:1.75-1.79(1H,m),1.95-2.15(1H,m),2.12(3H,s),2.29(1H,d),2.39-2.48(1H,m),2.86(1H,s),3.10-3.20(1H,m),3.33-3.42(2H,m),3.82(3H,s),4.25-4.33(1H,m),5.21(1H,dd),5.26(1H,d),5.45(1H,d),6.55(1H,m),6.76(1H,s),7.05(1H,td),7.22(1H,d),7.37-7.44(2H,m),8.04(1H,s),8.09(1H,d),8.31(1H,d),8.42(1H,d),8.74-8.80(2H,m),9.45(1H,s)；ES(m/z):M+H+537.2。
Example 56: n- { 4-methoxy-2- (5-methyl-2, 5-diazaspiro [3,4] oct-2-yl) -5- { [ 4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } phenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000272
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.3mL THF) was added dropwise to 4-methoxy-6- (5-methyl-2, 5-diazaspiro [3,4] ring with protection]Oct-2-yl) -N' - { 4-pyrazolo [1,5-a]Pyridin-3-ylpyrimidin-2-yl } benzene-1, 3-diamine (91mg,0.2mmol) and DIPEA (39mg,0.3mmol) in THF (3 mL). Stirring the obtained mixture at 0 deg.C for 30min, heating to room temperature, reacting for 3 hr, vacuum concentrating, and dissolving the residue in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (58mg, 54%) with MeOH (5-25%) as eluent.1HNMR:1.65-1.70(2H,m),2.03-2.09(2H,m),2.36(3H,s),2.64(2H,t),3.66(2H,d),3.84(3H,s),3.95(2H,d),5.21(1H,dd),5.26(1H,d),5.45(1H,d),6.50-6.55(2H,m),7.07(1H,td),7.20(1H,d),7.44-7.47(2H,m),7.66(1H,s),7.99(1H,s),8.27(1H,d),8.47(1H,d),8.75(1H,s),8.79(1H,d),9.28(1H,s)；ES(m/z):M+H+537.2。
Example 57: n- {2- [ (3R) -3-dimethylaminopyrrolidin-1-yl ] -5- { [4- (1H-indol-3-yl) pyrimidin-2-yl ] amino } -4-methoxyphenyl } -trans-2, 4-pentadiene-namide
Figure BDA0001586008370000273
At-5 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.3mL THF) was added dropwise to 4- [ (3R) -3-dimethylaminopyrrolidin-1-yl group with protection]-N- {4- (1-methylindol-3-yl) pyrimidin-2-yl } -6-methoxybenzene-1, 3-diamine (89mg,0.2mmol) and DIPEA (39mg,0.3mmol) in THF (3 mL). The mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 3h, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2Concentration of the resulting solution with MeOH (5-25%) as eluent gave the desired product (50mg, 48%).1H NMR:1.95-2.00(1H,m),2.19(1H,d),2.94(1H,s),3.10(4H,d),3.89(3H,s),5.20(1H,dd),5.25(1H,d),5.43(1H,d),6.55(1H,m),6.77(1H,s),7.17(1H,d),7.22-7.26(1H,m),7.40-7.46(2H,m),7.66(1H,s),8.17(1H,s),8.40(1H,d),8.46(1H,s),8.77(1H,s),8.90(1H,s),9.58(1H,s)；ES(m/z):M+H+524.2。
Example 58: n- {2- [ 3-dimethylamino-azetidin-1-yl ] -5- { [4- (1H-indol-3-yl) pyrimidin-2-yl ] amino } -4-methoxyphenyl } -trans-2, 4-pentadiene-amide
Figure BDA0001586008370000281
At 0 ℃ and N2Under protection, the trans-2, 4-pentanDianylchloride (23mg,0.2mmol, dissolved in 0.4mL CH)2Cl2In (b)) dropwise addition to 4- [ 3-dimethylaminoazetidin-1-yl) -N- [4- (1H-indol-3-yl) pyrimidin-2-yl]-6-methoxy-benzene-1, 3-diamine (86mg,0.2mmol) and DIPEA (39mg,0.3mmol) in CH2Cl2(8mL) in solution. The resulting mixture was warmed to room temperature and stirred for reaction for 3 hours. Then saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (55mg, 54%) with MeOH (5-25%) as eluent.1H NMR:2.06(6H,d),3.08(1H,s),3.56(2H,t),3.86(3H,s),3.97(2H,t),5.21(1H,dd),5.26(1H,d),5.45(1H,d),6.36(1H,s),6.55(1H,m),7.10(2H,dt),7.16(1H,t),7.40-7.45(2H,m),7.81(1H,s),7.91(1H,s),8.22(1H,d),8.32(1H,d),8.39(1H,d),9.35(1H,s),11.78(1H,s)；ES(m/z):M+H+510.2。
Example 59: n- {2- (2-dimethylaminoethyl-methylamino) -5- { [4- (1H-indol-3-yl) pyrimidin-2-yl ] amino } -4-methoxyphenyl } -trans-2, 4-pentadiene-amide
Figure BDA0001586008370000282
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 3mL THF) was added dropwise to N with protection1- (2-dimethylaminoethyl) -N4- [4- (1H-indol-3-yl) pyrimidin-2-yl]-5-methoxy-N1-methylbenzene-1, 2, 4-triamine (86mg,0.2mmol) and DIPEA (39mg,0.3mmol) in THF (5 mL). The mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 3h, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH2Cl2/MeOH (5-25%) as eluent, and the resulting solution was concentrated to obtain the desired product (49mg, 48%).1H NMR:2.21(6H,s),2.26-2.34(2H,m),2.69(3H,s),2.84-2.94(2H,m),3.86(3H,s),5.20(1H,dd),5.25(1H,d),5.43(1H,d),6.55(1H,m),6.79(1H,s),7.00(1H,d),7.07-7.18(1H,m),7.34(1H,dd),7.43(1H,m),7.66(1H,s),8.12(1H,d),8.25(1H,d),8.58(1H,s),9.76(1H,s),9.98(1H,s),10.25(1H,s)；ES(m/z):M+H+512.2。
Example 60: n- { 4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } -2- [ methyl- (2-methylaminoethyl) amino ] phenyl } -trans-2, 4-pentadiene-namide
Figure BDA0001586008370000283
At 0 ℃ and N2Under protection, N- [2- [ [ 5-methoxy-4- [ [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino acid]Amino-2- (trans-2, 4-pentadienylamino) phenyl]-methylamino radical]Ethyl-N-methylcarbamic acid tert-butyl ester (122mg,0.2mmol) and TFA (1mL) was added to 6mLCH2Cl2Then, the mixture was stirred at room temperature for 1 hour and concentrated in vacuo. To the residue was then added 10% MeOH/CH2Cl2And with saturated NaHCO3Washed (4mL), the organic phase washed again with water (3mL), and MgSO 4 was added4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH2Cl2The resulting solution was concentrated to give the desired product (82mg, 80%) with MeOH (5-25%) as eluent.1H NMR:2.34(3H,s),2.56-2.60(2H,m),2.72(3H,s),2.84-2.89(2H,m),3.86(3H,s),3.93(3H,s),5.20(1H,dd),5.25(1H,d),5.43(1H,d),6.55(1H,m),6.99(1H,s),7.15(1H,t),7.22-7.27(2H,m),7.41(1H,m),7.54(1H,d),7.88(1H,s),8.24(1H,d),8.32(1H,d),8.67(1H,s),9.18(1H,s),10.34(1H,s)；ES(m/z):M+H+512.2。
Example 61: n- {2- (2-dimethylaminoethyl-methylamino) -5- [ 4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino-4-trifluoromethoxyphenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000291
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (47mg,0.4mmol, dissolved in 0.5mL THF) was added dropwise to N under protection1- (2-dimethylaminoethyl) -N1-methyl-N4- { 4-pyrazolo [1,5-a ]]Pyridin-3-ylpyrimidin-2-yl } -5-trifluoromethoxybenzene-1, 2, 4-triamine (195mg,0.4mmol) and DIPEA (78mg,0.6mmol) in THF (5 mL). The mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 3h, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (101mg, 45%) with MeOH (5-25%) as eluent.1H NMR:2.25(6H,s),2.36(2H,t),2.74(3H,s),2.96(2H,t),5.18(1H,dd),5.24(1H,d),5.45(1H,d),6.56(1H,m),6.94(1H,s),7.02(1H,d),7.23(1H,d),7.28-7.33(1H,m),7.46(1H,m),8.17(1H,s),8.34(1H,d),8.44(1H,d),8.77-8.82(2H,m),8.85(1H,s),10.08(1H,br)；19FNMR:-57.7(3F,s)；ES(m/z):M+H+567.2。
Example 62: n- {5- [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino-2- (2-dimethylaminoethyl-methylamino) -4-trifluoromethoxyphenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000292
At 15 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.3mL THF) was added dropwise to N under protection4- { 5-chloro-4-pyrazolo [1,5-a ]]Pyridin-3-ylpyrimidin-2-yl } -N1- (2-dimethylaminoethyl) -N1-methyl-5-trifluoromethoxybenzene-1, 2, 4-triamine (104mg,0.2mmol) and DIPEA (39mg,0.3mmol) in THF (5 mL). The resulting mixture was reacted at room temperature for 4h and then concentrated in vacuo. Then dissolving the residueIs solved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (72mg, 60%) with MeOH (5-25%) as eluent.1H NMR:2.26(6H,s),2.33(2H,t),2.70(3H,s),3.82-2.92(2H,m),5.19(1H,dd),5.25(1H,d),5.47(1H,d),6.55(1H,m),6.82(1H,s),7.02(1H,td),7.22-7.34(1H,m),7.43-7.46(2H,m),8.40(1H,s),8.49(1H,d),8.53(1H,d),8.90(1H,s),9.35(1H,s),10.04(1H,s)；19F NMR:-57.4(3F,s)；ES(m/z):M+H+601.2。
Example 63: n- {2- [ 2-dimethylaminoethyl-methylamino ] -5- [ 5-methyl-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino-4-trifluoromethoxyphenyl } -trans-2, 4-pentadiene-amide
Figure BDA0001586008370000293
At 20 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.4mL THF) was added dropwise to N under protection1- (2-dimethylaminoethyl) -N1-methyl-N4- { 5-methyl-4-pyrazolo [1,5-a ]]Pyridin-3-ylpyrimidin-2-yl } -5-trifluoromethoxybenzene-1, 2, 4-triamine (100mg,0.5mmol) and DIPEA (39mg,0.3mmol) in THF (5 mL). The resulting mixture was reacted at room temperature for 3 hours and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH2Cl2The resulting solution was concentrated to give the desired product (55mg, 47%) with MeOH (5-25%) as eluent.1H NMR:2.27(6H,s),2.31(2H,t),2.38(3H,s),2.74(3H,s),3.82-2.90(2H,m),5.20(1H,dd),5.25(1H,d),5.43(1H,d),6.55(1H,m),6.80(1H,s),7.00(1H,td),7.22-7.31(1H,m),7.42-7.45(2H,m),8.43(1H,s),8.46(1H,d),8.51(1H,d),8.91(1H,s),9.33(1H,s),10.00(1H,s)；19F NMR:-58.0(3F,s)；ES(m/z):M+H+581.2。
Example 64: n- {5- { [ 5-cyano-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -2- [ 2-dimethylaminoethyl-methylamino ] -4-trifluoromethoxyphenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000301
At-5 ℃ and N2Trans-2, 4-pentadienoyl chloride (35mg,0.3mmol, dissolved in 0.4mL THF) was added dropwise to N under protection4- { 5-cyano-4-pyrazolo [1,5-a ]]Pyridin-3-ylpyrimidin-2-yl } -N1- (2-dimethylaminoethyl) -N1-methyl-5-trifluoromethoxybenzene-1, 2, 4-triamine (154mg,0.3mmol) and DIPEA (59mg,0.45mmol) in THF (6 mL). The mixture was stirred at-5 ℃ for 30min, allowed to warm to room temperature for 4h, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated with MeOH (5-25%) as eluent to afford the desired product (101mg, 57%).1H NMR:2.23(6H,s),2.29(2H,dd),2.65(3H,d),3.76-2.85(2H,m),5.18(1H,dd),5.24(1H,d),5.45(1H,d),6.56(1H,m),6.72(1H,s),6.98(1H,d),7.20(1H,s),7.45(1H,m),7.64(1H,s),8.55(2H,dd),8.62(1H,s),9.00(1H,s),9.28(1H,s),10.20(1H,s)；19F NMR:-58.1(3F,s)；ES(m/z):M+H+592.2。
Example 65: n- { 4-Difluoromethoxy-2- [ 2-dimethylaminoethyl-methylamino ] -5- { [ 4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } phenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000302
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (47mg,0.4mmol, dissolved in 0.5mL CH) with protection2Cl2In (1) dropwise addition to 5-difluoromethoxy-N1- (2-dimethylaminoethyl) -N1-methyl-N4- { 4-pyrazolo [1,5-a ]]Pyridin-3-ylpyrimidin-2-yl } -benzene-1, 2, 4-triamine (188mg,0.4mmol) and DIPEA (78mg,0.6mmol) in CH2Cl2(6mL) in solution. The mixture was stirred at 0 ℃ for 30 minutes, warmed to room temperature and reacted for 3 hours, and then saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (127mg, 58%) with MeOH (5-25%) as eluent.1H NMR:2.27(6H,s),2.37(2H,t),2.73(3H,s),2.97(2H,t),5.19(1H,dd),5.25(1H,d),5.47(1H,d),6.55(1H,m),6.93(1H,s),7.01(1H,d),7.22(1H,d),7.29-7.34(1H,m),7.45(1H,m),8.19(1H,s),8.35(1H,d),8.46(1H,d),8.77-8.83(2H,m),8.84(1H,s),10.11(1H,br)；19F NMR:-80.7(2F,d)；ES(m/z):M+H+549.2。
Example 66: n- {5- { [ 5-chloro-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -4-difluoromethoxy-2- [ 2-dimethylaminoethyl-methylamino ] phenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000303
At-10 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol in 0.3mL THF) was added dropwise to N with protection4- { 5-chloro-4-pyrazolo [1,5-a ]]Pyridin-3-ylpyrimidin-2-yl } -5-difluoromethoxy-N1- (2-dimethylaminoethyl) -N1-methylbenzene-1, 2, 4-triamine (101mg,0.2mmol) and DIPEA (39mg,0.3mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 4h, and concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) in combination withSaturated NaHCO is added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH2Cl2The resulting solution was concentrated to give the desired product (64mg, 55%) with MeOH (5-25%) as eluent.1HNMR:2.26(6H,s),2.34(2H,t),2.71(3H,s),3.84-2.93(2H,m),5.20(1H,dd),5.26(1H,d),5.48(1H,d),6.57(1H,m),6.80(1H,s),7.01(1H,td),7.24-7.34(1H,m),7.43-7.47(2H,m),8.43(1H,s),8.51(1H,d),8.55(1H,d),8.92(1H,s),9.37(1H,s),10.22(1H,s)；19F NMR:-80.5(2F,d)；ES(m/z):M+H+583.2。
Example 67: n- { 4-Difluoromethoxy-2- [ 2-dimethylaminoethyl-methylamino ] -5- { [ 5-methyl-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } phenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000311
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (38mg,0.33mmol, dissolved in 0.4mL CH) was dissolved under protection2Cl2In) dropwise addition to N4- { 5-chloro-4-pyrazolo [1,5-a ]]Pyridin-3-ylpyrimidin-2-yl } -5-difluoromethoxy-N1- (2-dimethylaminoethyl) -N1-methylbenzene-1, 2, 4-triamine (159mg,0.33mmol) and DIPEA (65mg,0.5mmol) in CH2Cl2(6mL) in solution. Stirring the obtained mixture at 0 ℃ for reaction for 30min, raising the temperature to room temperature for reaction for 2h, and adding saturated NaHCO3The solution (4mL) and a small amount of methanol (3-5 drops) are quenched for reaction, and the organic phase is washed with water (4mL) and added with MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH2Cl2The resulting solution was concentrated to give the desired product (83mg, 45%) with MeOH (5-25%) as eluent.1H NMR:2.25(6H,s),2.30(2H,t),2.36(3H,s),2.78(3H,s),3.80-2.91(2H,m),5.17(1H,dd),5.22(1H,d),5.45(1H,d),6.53(1H,m),6.81(1H,s),7.03(1H,td),7.23-7.32(1H,m),7.43-7.46(2H,m),8.49(1H,s),8.47(1H,d),8.52(1H,d),8.93(1H,s),9.35(1H,s),10.08(1H,s)；19F NMR:-80.7(2F,d)；ES(m/z):M+H+563.2。
Example 68: n- {5- { [ 5-cyano-4-pyrazolo [1,5-a ] pyridin-3-ylpyrimidin-2-yl ] amino } -4-difluoromethoxy-2- [ 2-dimethylaminoethyl-methylamino ] phenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000312
At 20 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.4mL THF) was added dropwise to N under protection4- { 5-cyano-4-pyrazolo [1,5-a ]]Pyridin-3-ylpyrimidin-2-yl } -5-difluoromethoxy-N1- (2-dimethylaminoethyl) -N1-methylbenzene-1, 2, 4-triamine (99mg,0.2mmol) and DIPEA (39mg,0.3mmol) in THF (6 mL). The resulting mixture was reacted at room temperature for 4h and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH2Cl2The resulting solution was concentrated with MeOH (5-25%) as eluent to afford the desired product (57mg, 50%).1H NMR:2.25(6H,s),2.26(2H,dd),2.63(3H,d),3.74-2.83(2H,m),5.19(1H,dd),5.25(1H,d),5.47(1H,d),6.55(1H,m),6.71(1H,s),6.94(1H,d),7.19(1H,s),7.42(1H,m),7.63(1H,s),8.52(2H,dd),8.60(1H,s),9.01(1H,s),9.26(1H,s),10.18(1H,s)；19F NMR:-80.6(2F,d)；ES(m/z):M+H+574.2。
Example 69: n- {2- (2-dimethylaminoethyl-methylamino) -5- [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino-4-trifluoromethoxyphenyl } -trans-2, 4-pentadiene-mide
Figure BDA0001586008370000313
At 0 ℃ and N2Under protection, the trans-2, 4-pentanDiacryloyl chloride (55mg,0.5mmol, dissolved in 0.6mL THF) was added dropwise to N1- (2-dimethylaminoethyl) -N1-methyl-N4- [4- (1-methylindol-3-yl) pyrimidin-2-yl]-5-trifluoromethoxybenzene-1, 2, 4-triamine (250mg,0.5mmol) and DIPEA (78mg,0.6mmol) in THF (80 mL). The mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 3h, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(10mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH2Cl2The resulting solution was concentrated to give the desired product (220mg, 77%) with MeOH (5-25%) as eluent.1H NMR:2.22(6H,s),2.26(2H,t),2.69(3H,s),2.95(2H,t),3.85(3H,s),5.20(1H,dd),5.26(1H,d),5.46(1H,d),6.56(1H,m),6.81(1H,s),7.20(1H,d),7.25-7.29(2H,m),7.39(1H,m),7.46(1H,m),7.72(1H,s),8.05(1H,m),8.40(1H,d),8.90(1H,s),9.70(1H,s),10.51(1H,s)；19FNMR:-57.7(3F,s)；ES(m/z):M+H+580.2。
Example 70: n- {5- [ 5-chloro-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino-2- (2-dimethylaminoethyl-methylamino) -4-trifluoromethoxyphenyl } -trans-2, 4-pentadiene-namide
Figure BDA0001586008370000321
At 10 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.4mL CH) with protection2Cl2In) dropwise addition to N1- (2-dimethylaminoethyl) -N1-methyl-N4- [4- (1-methylindol-3-yl) pyrimidin-2-yl]-5-trifluoromethoxybenzene-1, 2, 4-triamine (107mg,0.2mmol) and DIPEA (39mg,0.3mmol) in CH2Cl2(6mL) in solution. Stirring the obtained mixture at 10 deg.C for reaction for 30min, heating to room temperature for reaction for 3h, adding saturated NaHCO3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (85mg, 52%) with MeOH (5-25%) as eluent.1H NMR:2.24(6H,s),2.40(2H,t),2.79(3H,s),2.96(2H,t),3.75(3H,s),5.21(1H,dd),5.27(1H,d),5.46(1H,d),6.58(1H,m),7.12-7.20(2H,m),7.42-7.46(2H,m),8.20(1H,d),8.42(1H,s),8.45(1H,s),8.65(1H,s),8.85(1H,s),9.51(1H,s)；19FNMR:-57.9(3F,s)；ES(m/z):M+H+614.2。
Example 71: n- {2- (2-dimethylaminoethyl-methylamino) -5- [ 5-methyl-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino-4-trifluoromethoxyphenyl } -trans-2, 4-pentadiene-namide
Figure BDA0001586008370000322
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (47mg,0.4mmol, dissolved in 0.5mL THF) was added dropwise to N under protection1- (2-dimethylaminoethyl) -N1-methyl-N4- [4- (1-methylindol-3-yl) pyrimidin-2-yl]-5-trifluoromethoxybenzene-1, 2, 4-triamine (205mg,0.4mmol) and DIPEA (79mg,0.6mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 4h, and concentrated in vacuo. The residue was then dissolved in CH2Cl2(10mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (112mg, 47%) with MeOH (5-25%) as eluent.1H NMR:2.22(6H,s),2.38(2H,t),2.42(3H,s),2.78(3H,s),2.94(2H,t),3.73(3H,s),5.17(1H,dd),5.22(1H,d),5.45(1H,d),6.53(1H,m),6.80(1H,s),7.11-7.20(2H,m),7.38(1H,d),7.46(1H,m),8.17(1H,d),8.40(1H,s),8.41(1H,s),8.62(1H,s),8.80(1H,s),9.50(1H,s)；19FNMR:-57.7(3F,s)；ES(m/z):M+H+594.2。
Example 72: n- {5- [ 5-cyano-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino-2- (2-dimethylaminoethyl-methylamino) -4-trifluoromethoxyphenyl } -trans-2, 4-pentadiene-namide
Figure BDA0001586008370000323
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.4mL THF) was added dropwise to N under protection4- [ 5-cyano-4- (1-methylindol-3-yl) pyrimidin-2-yl]-N1- (2-dimethylaminoethyl) -N1-methyl-5-trifluoromethoxybenzene-1, 2, 4-triamine (105mg,0.2mmol) and DIPEA (39mg,0.3mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 3h, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH2Cl2The resulting solution was concentrated to give the desired product (54mg, 45%) with MeOH (5-25%) as eluent.1H NMR:2.21(6H,s),2.39(2H,t),2.76(3H,s),2.94(2H,t),3.74(3H,s),5.19(1H,dd),5.26(1H,d),5.47(1H,d),6.55(1H,m),6.88(1H,s),7.10-7.22(2H,m),7.44-7.47(2H,m),8.22(1H,d),8.45(1H,s),8.47(1H,s),8.66(1H,s),8.87(1H,s),9.56(1H,s)；19F NMR:-57.9(3F,s)；ES(m/z):M+H+605.2。
Example 73: n- { 4-Difluoromethoxy-2- (2-dimethylaminoethyl-methylamino) -5- [4- (1-methylindol-3-yl) pyrimidin-2-yl ] aminophenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000331
At-10 ℃ and N2Trans-2, 4-pentadienoyl chloride (58mg,0.5mmol, dissolved in 0.6mL THF) was added dropwise to 5-difluoromethoxy-N with protection1- (2-dimethylaminoethyl)Radical) -N1-methyl-N4- [4- (1-methylindol-3-yl) pyrimidin-2-yl]Benzene-1, 2, 4-triamine (241mg,0.5mmol) and DIPEA (79mg,0.6mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 3h, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(10mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated with MeOH (5-25%) as eluent to afford the desired product (154mg, 55%).1H NMR:2.23(6H,s),2.27(2H,t),2.75(3H,s),2.95(2H,t),3.80(3H,s),5.21(1H,dd),5.27(1H,d),5.46(1H,d),6.56(1H,m),6.80(1H,s),7.23(1H,d),7.25-7.30(2H,m),7.37(1H,m),7.46(1H,m),7.73(1H,s),8.07(1H,m),8.42(1H,d),8.92(1H,s),9.73(1H,s),10.55(1H,s)；19F NMR:-80.1(2F,d)；ES(m/z):M+H+562.2。
Example 74: n- {5- [ 5-chloro-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino-4-difluoromethoxy-2- (2-dimethylaminoethyl-methylamino) phenyl } -trans-2, 4-pentadiene-namide
Figure BDA0001586008370000332
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (35mg,0.3mmol, dissolved in 0.4mL CH) with protection2Cl2In (1) dropwise addition to 5-difluoromethoxy-N1- (2-dimethylaminoethyl) -N1-methyl-N4- [4- (1-methylindol-3-yl) pyrimidin-2-yl]Benzene-1, 2, 4-triamine (155mg,0.3mmol) and DIPEA (59mg,0.45mmol) in CH2Cl2(8mL) in solution. Stirring the obtained mixture at 0 deg.C for reaction for 30min, heating to room temperature for reaction for 3h, and adding saturated NaHCO3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (84mg, 47%) with MeOH (5-25%) as eluent.1H NMR:2.26(6H,s),2.41(2H,t),2.82(3H,s),2.97(2H,t),3.78(3H,s),5.19(1H,dd),5.26(1H,d),5.47(1H,d),6.57(1H,m),6.86(1H,s),7.14-7.22(2H,m),7.44-7.47(2H,m),8.25(1H,d),8.42(1H,s),8.46(1H,s),8.67(1H,s),8.88(1H,s),9.59(1H,s)；19F NMR:-80.7(2F,d)；ES(m/z):M+H+596.2。
Example 75: n- { 4-Difluoromethoxy-2- (2-dimethylaminoethyl-methylamino) -5- [ 5-methyl-4- (1-methylindol-3-yl) pyrimidin-2-yl ] aminophenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000333
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (12mg,0.1mmol, dissolved in 0.3mL THF) was added dropwise to 5-difluoromethoxy-N with protection1- (2-dimethylaminoethyl) -N1-methyl-N4- [4- (1-methylindol-3-yl) pyrimidin-2-yl]Benzene-1, 2, 4-triamine (50mg,0.1mmol) and DIPEA (20mg,0.15mmol) in THF (10 mL). The mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 3h, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (35mg, 60%) with MeOH (5-25%) as eluent.1H NMR:2.25(6H,s),2.32(2H,t),2.37(3H,s),2.76(3H,s),2.91(2H,t),3.73(3H,s),5.19(1H,dd),5.26(1H,d),5.45(1H,d),6.57(1H,m),6.85(1H,s),7.10-7.20(2H,m),7.42-7.46(2H,m),8.17(1H,d),8.41(1H,s),8.46(1H,s),8.66(1H,s),8.82(1H,s),9.57(1H,s)；19F NMR:-80.4(2F,d)；ES(m/z):M+H+576.2。
Example 76: n- {5- [ 5-cyano-4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino-4-difluoromethoxy-2- (2-dimethylaminoethyl-methylamino) phenyl } -trans-2, 4-pentadiene-namide
Figure BDA0001586008370000341
At 20 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.3mL THF) was added dropwise to N under protection4- [ 5-cyano-4- (1-methylindol-3-yl) pyrimidin-2-yl]-5-difluoromethoxy-N1- (2-dimethylaminoethyl) -N1-methylbenzene-1, 2, 4-triamine (101mg,0.2mmol) and DIPEA (39mg,0.3mmol) in THF (6 mL). The resulting mixture was reacted at room temperature for 3h and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (60mg, 51%) with MeOH (5-25%) as eluent.1H NMR:2.24(6H,s),2.35(2H,t),2.77(3H,s),2.95(2H,t),3.77(3H,s),5.20(1H,dd),5.25(1H,d),5.45(1H,d),6.55(1H,m),6.89(1H,s),7.09-7.20(2H,m),7.43-7.46(2H,m),8.19(1H,d),8.38(1H,s),8.42(1H,s),8.60(1H,s),8.82(1H,s),9.53(1H,s)；19F NMR:-80.8(2F,d)；ES(m/z):M+H+587.2。
Example 77: n- {2- (2-dimethylaminoethyl-methylamino) -5- [4- (1H-indol-3-yl) pyrimidin-2-yl ] amino-4-trifluoromethoxyphenyl } -trans-2, 4-pentadiene-amide
Figure BDA0001586008370000342
At-20 ℃ and N2Trans-2, 4-pentadienoyl chloride (53mg,0.45mmol, dissolved in 0.6mL THF) was added dropwise to N under protection1- (2-dimethylaminoethyl) -N4- [4- (1H-indol-3-yl) pyrimidin-2-yl]-N1A solution of (methyl) -5-trifluoromethoxybenzene-1, 2, 4-triamine (219mg,0.45mmol) and DIPEA (79mg,0.6mmol) in THF (7mL)In (1). The resulting mixture was stirred at 0 ℃ for 30 minutes, warmed to room temperature for 3 hours, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(10mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated with MeOH (5-25%) as eluent to afford the desired product (145mg, 57%).1HNMR:2.25(6H,s),2.33(2H,t),2.70(3H,s),2.93(2H,t),5.20(1H,dd),5.27(1H,d),5.48(1H,d),6.59(1H,m),6.98(1H,s),7.07(1H,d),7.25(1H,d),7.29-7.34(1H,m),7.45(1H,m),8.17(1H,s),8.36(1H,d),8.47(1H,d),8.77-8.83(2H,m),8.84(1H,s),10.09(1H,br)；19F NMR:-58.1(3F,s)；ES(m/z):M+H+566.2。
Example 78: n- {5- [ 5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl ] amino-2- (2-dimethylaminoethyl-methylamino) -4-trifluoromethoxyphenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000343
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.3mL THF) was added dropwise to N under protection1- (2-dimethylaminoethyl) -N4- [4- (1H-indol-3-yl) pyrimidin-2-yl]-N1-methyl-5-trifluoromethoxybenzene-1, 2, 4-triamine (104mg,0.2mmol) and DIPEA (39mg,0.3mmol) in THF (5 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 4h, and concentrated in vacuo. The residue was then dissolved in CH2Cl2(15mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated with MeOH (5-25%) as eluent to afford the desired product (59mg, 49%).1H NMR:2.25(6H,s),2.37(2H,br),2.71(3H,s),2.85-2.92(2H,m),5.19(1H,dd),5.26(1H,d),5.45(1H,d),6.56(1H,m),6.90(1H,s),7.03(1H,s),7.12(1H,t),7.44-7.47(2H,m),8.27(1H,d),8.38(1H,s),8.45(1H,s),8.54(1H,d),8.59(1H,s),10.11(1H,s),11.89(1H,s)；19F NMR:-58.2(3F,s)；ES(m/z):M+H+600.2。
Example 79: n- {2- (2-dimethylaminoethyl-methylamino) -5- [ 5-methyl-4- (1H-indol-3-yl) pyrimidin-2-yl ] amino-4-trifluoromethoxyphenyl } -trans-2, 4-pentadiene-mide
Figure BDA0001586008370000351
At 10 ℃ and N2Trans-2, 4-pentadienoyl chloride (35mg,0.3mmol, dissolved in 0.5mL CH) with protection2Cl2In) dropwise addition to N1- (2-dimethylaminoethyl) -N4- [4- (1H-indol-3-yl) pyrimidin-2-yl]-N1-methyl-5-trifluoromethoxybenzene-1, 2, 4-triamine (150mg,0.3mmol) and DIPEA (59mg,0.45mmol) in CH2Cl2(8mL) in solution. The resulting mixture was reacted at room temperature for 5h and then saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH2Cl2The resulting solution was concentrated to give the desired product (80mg, 46%) with MeOH (5-25%) as eluent.1HNMR:2.21(6H,s),2.34(2H,t),2.36(3H,s),2.74(3H,s),2.90(2H,t),5.20(1H,dd),5.25(1H,d),5.45(1H,d),6.55(1H,m),6.81(1H,s),7.10-7.20(2H,m),7.40-7.45(2H,m),8.18(1H,d),8.42(1H,s),8.43(1H,s),8.60(1H,s),8.81(1H,s),9.52(1H,s)；19F NMR:-58.1(3F,s)；ES(m/z):M+H+580.2。
Example 80: n- {5- [ 5-cyano-4- (1H-indol-3-yl) pyrimidin-2-yl ] amino-2- (2-dimethylaminoethyl-methylamino) -4-trifluoromethoxyphenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000352
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (35mg,0.3mmol, dissolved in 0.4mL THF) was added dropwise to N under protection4- [ 5-cyano-4- (1H-indol-3-yl) pyrimidin-2-yl]-N1- (2-dimethylaminoethyl) -N1-methyl-5-trifluoromethoxybenzene-1, 2, 4-triamine (153mg,0.3mmol) and DIPEA (59mg,0.45mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 3h, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated with MeOH (5-25%) as eluent to afford the desired product (83mg, 47%).1H NMR:2.23(6H,s),2.40(2H,t),2.72(3H,s),2.90(2H,t),5.20(1H,dd),5.27(1H,d),5.48(1H,d),6.57(1H,m),6.89(1H,s),7.10-7.20(2H,m),7.43-7.47(2H,m),8.24(1H,d),8.46(1H,s),8.48(1H,s),8.68(1H,s),8.89(1H,s),9.57(1H,s)；19F NMR:-58.0(3F,s)；ES(m/z):M+H+591.2。
Example 81: n- { 4-Difluoromethoxy-5- [4- (1H-indol-3-yl) pyrimidin-2-yl ] amino-2- (2-dimethylaminoethyl-methylamino) phenyl } -trans-2, 4-pentadiene-namide
Figure BDA0001586008370000353
At-20 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.4mL THF) was added dropwise to 5-difluoromethoxy-N with protection1- (2-dimethylaminoethyl) -N4- [4- (1H-indol-3-yl) pyrimidin-2-yl]-N1-methylbenzene-1, 2, 4-triamine (94mg,0.2mmol) and DIPEA (39mg,0.3mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30min, warmed to room temperature for 4h, and concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated Na was addedHCO3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated with MeOH (5-25%) as eluent to afford the desired product (62mg, 57%).1H NMR:2.26(6H,s),2.34(2H,t),2.69(3H,s),2.91(2H,t),5.20(1H,dd),5.27(1H,d),5.48(1H,d),6.58(1H,m),6.96(1H,s),7.05(1H,d),7.21(1H,d),7.29-7.33(1H,m),7.44(1H,m),8.16(1H,s),8.34(1H,d),8.46(1H,d),8.77-8.84(2H,m),8.87(1H,s),10.10(1H,br)；19F NMR:-80.0(2F,d)；ES(m/z):M+H+548.2。
Example 82: n- {5- [ 5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl ] amino-4-difluoromethoxy-2- (2-dimethylaminoethyl-methylamino) phenyl } -trans-2, 4-pentadiene-namide
Figure BDA0001586008370000354
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (35mg,0.3mmol, dissolved in 0.4mL CH) with protection2Cl2In) dropwise addition to N4- [ 5-chloro-4- (1H-indol-3-yl) pyrimidin-2-yl]-5-difluoromethoxy-N1- (2-dimethylaminoethyl) -N1-methylbenzene-1, 2, 4-triamine (151mg,0.3mmol) and DIPEA (59mg,0.45mmol) in CH2Cl2(7mL) in solution. Stirring the obtained mixture at 0 deg.C for reaction for 30min, heating to room temperature for reaction for 3h, and adding saturated NaHCO3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (89mg, 51%) with MeOH (5-25%) as eluent.1H NMR:2.27(6H,s),2.36(2H,br),2.70(3H,s),2.85-2.94(2H,m),5.20(1H,dd),5.27(1H,d),5.48(1H,d),6.57(1H,m),6.94(1H,s),7.07(1H,s),7.15(1H,t),7.42-7.46(2H,m),8.22(1H,d),8.36(1H,s),8.47(1H,s),8.50(1H,d),8.58(1H,s),10.10(1H,s),11.87(1H,s)；19F NMR:-80.0(2F,d)；ES(m/z):M+H+582.2。
Example 83: n- { 4-Difluoromethoxy-2- (2-dimethylaminoethyl-methylamino) -5- [ 5-methyl-4- (1H-indol-3-yl) pyrimidin-2-yl ] aminophenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000361
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.3mL THF) was added dropwise to 5-difluoromethoxy-N with protection1- (2-dimethylaminoethyl) -N4- [4- (1H-indol-3-yl) pyrimidin-2-yl]-N1-methylbenzene-1, 2, 4-triamine (96mg,0.2mmol) and DIPEA (39mg,0.3mmol) in THF (6 mL). The mixture was stirred at 0 ℃ for 30min, allowed to warm to room temperature for 3h, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (55mg, 49%) with MeOH (5-25%) as eluent.1H NMR:2.23(6H,s),2.35(2H,t),2.37(3H,s),2.70(3H,s),2.91(2H,t),5.20(1H,dd),5.27(1H,d),5.48(1H,d),6.57(1H,m),6.80(1H,s),7.10-7.22(2H,m),7.38(1H,d),7.45(1H,m),8.16(1H,d),8.40(1H,s),8.45(1H,s),8.67(1H,s),8.82(1H,s),9.58(1H,s)；19F NMR:-80.0(2F,d)；ES(m/z):M+H+562.2。
Example 84: n- {5- [ 5-cyano-4- (1H-indol-3-yl) pyrimidin-2-yl ] amino-4-difluoromethoxy-2- (2-dimethylaminoethyl-methylamino) phenyl } -trans-2, 4-pentadiene-namide
Figure BDA0001586008370000362
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol,dissolved in 0.4mL CH2Cl2In) dropwise addition to N4- [ 5-cyano-4- (1H-indol-3-yl) pyrimidin-2-yl]-N1- (2-dimethylaminoethyl) -5-methoxy-N1-methylbenzene-1, 2, 4-triamine (99mg,0.2mmol) and DIPEA (39mg,0.3mmol) in CH2Cl2(6mL) in solution. The mixture is stirred and reacted for 30 minutes at the temperature of 0 ℃, and then is heated to room temperature for reaction for 3 hours, and then saturated NaHCO is added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography over CH2Cl2The resulting solution was concentrated to give the desired product (60mg, 52%) with MeOH (5-25%) as eluent.1H NMR:2.25(6H,s),2.41(2H,t),2.70(3H,s),2.92(2H,t),5.20(1H,dd),5.27(1H,d),5.48(1H,d),6.58(1H,m),6.88(1H,s),7.12-7.23(2H,m),7.44-7.47(2H,m),8.21(1H,d),8.42(1H,s),8.49(1H,s),8.70(1H,s),8.91(1H,s),9.59(1H,s)；19F NMR:-80.1(2F,d)；ES(m/z):M+H+573.2。
Example 85: n- {2- [ 2-dimethylaminoethyl-methylamino ] -5- [4- (4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl ] amino-4-trifluoromethoxyphenyl } -trans-2, 4-pentadiene-amide
Figure BDA0001586008370000363
At 0 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.3mL THF) was added dropwise to N under protection1- (2-dimethylaminoethyl) -N1-methyl-N4- {4- (4,5,6, 7-Tetrahydropyrazolo [1,5-a ]]Pyridin-3-yl) pyrimidin-2-yl } -5-trifluoromethoxybenzene-1, 2, 4-triamine (98mg,0.2mmol) and DIPEA (39mg,0.3mmol) in THF (5 mL). The resulting mixture was stirred at 0 ℃ for 30 minutes, allowed to warm to room temperature for 4 hours, and then concentrated in vacuo. The residue was then dissolved in CH2Cl2(8mL) and saturated NaHCO was added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4The mixture is dried and then is dried,and (5) removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH2Cl2The resulting solution was concentrated with MeOH (5-25%) as eluent to afford the desired product (63mg, 55%).1H NMR:1.68-1.77(2H,m),1.90-1.97(2H,m),2.24(6H,s),2.28(2H,t),2.73(3H,s),2.85(2H,t),3.03(2H,t),4.09(2H,t),5.20(1H,dd),5.27(1H,d),5.48(1H,d),6.57(1H,m),6.87(1H,s),6.96-7.07(1H,m),7.44(1H,m),7.87(1H,s),8.15(1H,s),8.35(1H,d),8.89(1H,s),10.10(1H,s)；19F NMR:-58.0(3F,s)；ES(m/z):M+H+571.2。
Example 86: n- { 4-Difluoromethoxy-2- [ 2-dimethylaminoethyl-methylamino ] -5- [4- (4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl) pyrimidin-2-yl ] aminophenyl } -trans-2, 4-pentadiene amide
Figure BDA0001586008370000371
At-10 ℃ and N2Trans-2, 4-pentadienoyl chloride (23mg,0.2mmol, dissolved in 0.3mL CH) with protection2Cl2In (1) dropwise addition to 5-difluoromethoxy-N1- (2-dimethylaminoethyl) -N1-methyl-N4- {4- (4,5,6, 7-Tetrahydropyrazolo [1,5-a ]]Pyridin-3-yl) pyrimidin-2-yl } benzene-1, 2, 4-triamine (95mg,0.2mmol) and DIPEA (39mg,0.3mmol) in CH2Cl2(6mL) in solution. The mixture is stirred and reacted for 30 minutes at the temperature of 0 ℃, then the temperature is raised to room temperature for reaction for 3 hours, and saturated NaHCO is added3(4mL) and a small amount of methanol (3-5 drops), washing the organic phase with water (4mL), and adding MgSO4Drying, and removing the organic solvent by thin film rotary evaporation. The crude product was purified by silica gel column chromatography using CH2Cl2The resulting solution was concentrated with MeOH (5-25%) as eluent to afford the desired product (57mg, 52%).1H NMR:1.65-1.74(2H,m),1.87-1.95(2H,m),2.26(6H,s),2.27(2H,t),2.71(3H,s),2.89(2H,t),3.02(2H,t),4.07(2H,t),5.20(1H,dd),5.25(1H,d),5.44(1H,d),6.55(1H,m),6.89(1H,s),6.97-7.10(1H,m),7.45(1H,m),7.88(1H,s),8.18(1H,s),8.37(1H,d),8.92(1H,s),10.11(1H,s)；19F NMR:-80.1(2F,d)；ES(m/z):M+H+553.2。
Example 87: n- {2- (2-dimethylaminoethyl-methylamino) -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -trans-2, 4-pentadiene-namide methanesulfonate
Figure BDA0001586008370000372
The method comprises the following steps: mixing N- {2- (2-dimethylaminoethyl-methylamino) -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl]Amino } phenyl } -trans-2, 4-pentadiene amide (example 28,105mg,0.2mmol) was dissolved in ethanol (6mL) and ethyl acetate (2mL), stirred and warmed to 75 deg.C, to which was slowly dropped a solution of methanesulfonic acid (19mg,0.2mmol) in ethyl acetate (1 mL). The resulting mixture was stirred for 2 hours, filtered to give a solid compound, and dried under vacuum at 80 ℃ overnight to give the polymorphic target product (117mg, 94%).1HNMR:2.75(3H,s),2.95(3H,s),3.03(6H,s),3.60(3H,t),3.89-4.02(7H,m),5.18(1H,dd),5.24(1H,d),5.41(1H,d),6.54(1H,m),7.11(1H,t),7.22(1H,t),7.28(1H,s),7.39-7.44(3H,m),8.08-8.18(3H,m),8.58(1H,s),9.32(1H,s),9.62(1H,s),9.70(1H,s)。
The method 2 comprises the following steps: n- {2- (2-dimethylaminoethyl-methylamino) -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -trans-2, 4-pentadiene-namide (example 28,105mg,0.2mmol) was dissolved in acetone (4mL) and water (0.5mL), stirred to warm to 50 ℃ and a solution of methanesulfonic acid (19mg,0.2mmol) in acetone (0.5mL) was slowly dropped thereinto. The resulting mixture was stirred for 2 hours, filtered to give a solid compound, and dried under vacuum at 80 ℃ overnight to give the polymorphic target product (115mg, 93%).
The method 3 comprises the following steps: n- {2- (2-dimethylaminoethyl-methylamino) -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl } -trans-2, 4-pentadiene-namide (example 28,105mg,0.2mmol) was dissolved in acetonitrile (4mL), stirred to warm to 70 ℃ and a solution of methanesulfonic acid (19mg,0.2mmol) in acetonitrile (1mL) was slowly added dropwise thereto. The resulting mixture was stirred for 2 hours, filtered to give a solid compound, and dried under vacuum at 80 ℃ overnight to give the polymorphic target product (113mg, 91%).
Example 88: n- {2- (2-dimethylaminoethyl-methylamino) -5- [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino-4-trifluoromethoxyphenyl } -trans-2, 4-pentadiene-namide methanesulfonate
Figure BDA0001586008370000373
The method comprises the following steps: mixing N- {2- (2-dimethylaminoethyl-methylamino) -5- [4- (1-methylindol-3-yl) pyrimidin-2-yl]Amino-4-trifluoromethoxyphenyl } -trans-2, 4-pentadiene amide (example 69,116mg,0.2mmol) was dissolved in ethanol (6mL) and ethyl acetate (2mL), stirred at elevated temperature to 75 ℃ and a solution of methanesulfonic acid (19mg,0.2mmol) in ethyl acetate (1mL) was slowly added dropwise thereto. The resulting mixture was stirred for 2h, filtered to give a solid compound, which was dried under vacuum at 80 ℃ overnight to give the polymorphic target product (124mg, 92%).1H NMR:2.74(3H,s),2.92(3H,s),3.01(6H,s),3.62(3H,t),3.88-4.01(4H,m),5.20(1H,dd),5.25(1H,d),5.45(1H,d),6.57(1H,m),7.12(1H,t),7.23(1H,t),7.29(1H,s),7.40-7.44(3H,m),8.07-8.18(3H,m),8.59(1H,s),9.34(1H,s),9.64(1H,s),9.72(1H,s)；19F NMR:-58.0(3F,s)。
The method 2 comprises the following steps: n- {2- (2-dimethylaminoethyl-methylamino) -5- [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino-4-trifluoromethoxyphenyl } -trans-2, 4-pentadiene-mide (example 69,116mg,0.2mmol) was dissolved in 4mL of acetone and 0.5mL of water, stirred to raise the temperature to 50 ℃ and a solution of methanesulfonic acid (19mg,0.2mmol) in acetone (0.5mL) was slowly dropped thereinto. The resulting mixture was stirred for 2h, filtered to give a solid compound, and dried under vacuum at 80 ℃ overnight to give the polymorphic target product (125mg, 94%).
The method 3 comprises the following steps: n- {2- (2-dimethylaminoethyl-methylamino) -5- [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino-4-trifluoromethoxyphenyl } -trans-2, 4-pentadiene-mide (example 69,116mg,0.2mmol) was dissolved in acetonitrile (4mL), stirred to warm to 70 ℃ and a solution of methanesulfonic acid (19mg,0.2mmol) in acetonitrile (1mL) was slowly added dropwise thereto. The resulting mixture was stirred for 2 hours, filtered to give a solid compound, and dried under vacuum at 80 ℃ overnight to give the polymorphic target product (124mg, 92%).
Example 89: n- { 4-Difluoromethoxy-2- (2-dimethylaminoethyl-methylamino) -5- [4- (1-methylindol-3-yl) pyrimidin-2-yl ] aminophenyl } -trans-2, 4-pentadiene amide methanesulfonate
Figure BDA0001586008370000381
Mixing N- { 4-difluoromethoxy-2- (2-dimethylaminoethyl-methylamino) -5- [4- (1-methylindol-3-yl) pyrimidin-2-yl]Aminophenyl } -trans-2, 4-pentadiene-amide (example 73,112mg,0.2mmol) was dissolved in acetone (4mL), and the temperature was raised to 35 ℃ with stirring, to which was slowly dropped a solution of methanesulfonic acid (19mg,0.2mmol) in acetone (1 mL). The resulting mixture was stirred for 2 hours, filtered to give a solid compound, and dried under vacuum at 80 ℃ overnight to give the polymorphic target product (120mg, 92%).1H NMR:2.72(3H,s),2.90(3H,s),3.00(6H,s),3.61(3H,t),3.85-4.00(4H,m),5.21(1H,dd),5.27(1H,d),5.46(1H,d),6.56(1H,m),,7.11(1H,t),7.25(1H,t),7.28(1H,s),7.42-7.44(3H,m),8.08-8.19(3H,m),8.60(1H,s),9.33(1H,s),9.65(1H,s),9.75(1H,s)；19F NMR:-80.7(2F,d)。
Example 90: formulation of hard gel capsules
As a definite embodiment of an oral preparation, 80mg of the compound of example 87 was weighed out, and mixed with sufficiently fine lactose to give a total amount of about 580mg, which was filled into O-shaped hard gel capsules.
Biological Properties
Test 1-L858R/T790M EGFR (double mutant) cell phosphorylation test: mu.L of cells of the human lung cell line NCI-H197540 were seeded in the growth medium in Corning's black clear-bottomed 384-well plates at 37 ℃ with 5% CO2The culture was carried out overnight. Serial dilutions of compounds in 100% DMSO were added to cells using sonication. The plates were incubated for an additional 2 hours and after gentle mixing of the media, 40. mu.L of lysis buffer was added to each well. Greiner black high binding 384 well plates were covered with capture antibody and then blocked with 3% BSA. The blocking solution was then removed and 15. mu.L of lysate was transferred to Greiner black high binding 384 well platesAnd cultured for 2 hours. After gentle mixing and washing of the plates with PBS, 20 μ L of detection antibody was added and incubated for 2 hours. After gentle mixing and washing of the plates with PBS, 20 μ L of fluorescent peroxidase substrate was added and incubated for 1 hour. mu.L of stop solution was added to the plate and fluorescence was read in an Envision microplate detector using an excitation wavelength of 352nm and an emission wavelength of 460 nm. The appropriate fitted curve was obtained based on the data using Origin et al software and the IC determined by calculating the concentration of compound required to obtain a 50% effect50The results are shown in Table 1.
Test 2-Exon 19 deletion EGFR (activating single mutant) cell phosphorylation test: human lung cell line PC9(Exon19 deleted EGFR) as R&The assay for measuring cellular phosphorylation of endogenous p-EGFR in cell lysates was performed as specified by D Systems DuoSet IC Human Phospho-EGF R ELISA. mu.L of cells were seeded in Corning black clear bottom 384-well plates in growth medium at 37 ℃ in 5% CO2The culture was carried out overnight. Serial dilutions of compounds in 100% DMSO were added to cells using sonication. The plates were incubated for an additional 2 hours and after gentle mixing of the media, 40. mu.L of lysis buffer was added to each well. Greiner black high binding 384 well plates were covered with capture antibody and then blocked with 3% BSA. The blocking solution was then removed and 15 μ L of the lysate was transferred to Greiner black high binding 384 well plates and incubated for 2 hours. After gentle mixing and washing of the plates with PBS, 20 μ L of detection antibody was added and incubated for 2 hours. After gentle mixing and washing of the plates with PBS, 20 μ L of fluorescent peroxidase substrate was added and incubated for 1 hour. mu.L of stop solution was added to the plate and fluorescence was read in an Envision microplate detector using an excitation wavelength of 352nm and an emission wavelength of 460 nm. The appropriate fitted curve was obtained based on the data using Origin et al software and the IC determined by calculating the concentration of compound required to obtain a 50% effect50The results are shown in Table 1.
Test 3-wild type EGFR cell phosphorylation test: human colon cell line LoVo according to R&D SystemsDuoSet IC human Phospho-EGF R ELISA to perform the measurements of the contents of the cell lysateExamination of cellular phosphorylation of the derived p-EGFR. mu.L of cells were seeded in Corning black clear bottom 384-well plates in growth medium at 37 ℃ 5% CO2The culture was carried out overnight. Serial dilutions of compounds in 100% DMSO were added to cells using sonication. The plates were incubated for 2 hours and after gentle mixing of the media, 40. mu.L of lysis buffer was added to each well. Greiner black high binding 384 well plates were covered with capture antibody and then blocked with 3% BSA. The blocking solution was then removed and 15 μ L of the lysate was transferred to Greiner black high binding 384 well plates and incubated for 2 hours. After gentle mixing and washing of the plates with PBS, 20 μ L of detection antibody was added and incubated for 2 hours. After gentle mixing and washing of the plates with PBS, 20 μ L of fluorescent peroxidase substrate was added and incubated for 1 hour. mu.L of stop solution was added to the plate and fluorescence was read in an Envision microplate detector using an excitation wavelength of 352nm and an emission wavelength of 460 nm. The appropriate fitted curve was obtained based on the data using Origin et al software and the IC determined by calculating the concentration of compound required to obtain a 50% effect50The results are shown in Table 1.
The test data (. mu.M) in the examples of the present patent application are shown in the following table. Although the detection data is expressed by a certain number of significant figures, it should not be considered as a number indicating that the data has been determined to be exactly a significant figure.
TABLE 1 biological Property test results
Examples Test 1(μ M) Test 2(μ M) Test 3(μ M) Examples Test 1(μ M) Test 2(μ M) Test 3(μ M)
1 0.005831 0.008533 0.7805 46 0.018721 0.013824 0.8873
2 0.004436 0.004983 0.2274 47 0.018855 0.199821 0.9983
3 0.009987 0.020871 0.5783 48 0.020267 0.031123 1.4921
4 0.002234 0.014512 0.5871 49 0.007834 0.065221 0.4492
5 0.004575 0.010845 0.8021 50 0.103845 0.129663 3.1122
6 0.001022 0.003186 0.2132 51 0.006332 0.009983 0.2267
7 0.002137 0.002367 0.4982 52 0.060003 0.031189 0.4561
8 0.006581 0.032355 0.8301 53 0.012922 0.012932 0.9745
9 0.001711 0.021491 0.7764 54 0.001743 0.002112 0.2221
10 0.039432 0.055344 5.4778 55 0.002561 0.005667 0.3981
11 0.015627 0.017553 0.7893 56 0.023342 0.040009 2.2119
12 0.003988 0.031124 2.1122 57 0.007823 0.007782 0.0445
13 0.015232 0.126242 6.5513 58 0.006442 0.005044 0.8972
14 0.016672 0.033422 7.4351 59 0.004055 0.003329 0.1100
15 0.037756 0.011267 1.1109 60 0.043478 0.021183 0.9110
16 0.504300 0.112872 8.2213 61 0.000321 0.002101 0.1115
17 0.004519 0.011354 0.5561 62 0.000542 0.001192 0.1149
18 0.020244 0.034322 1.1932 63 0.000449 0.002214 0.2000
19 0.001221 0.001993 0.0224 64 0.002001 0.008722 0.5429
20 0.004133 0.007252 0.1475 65 0.000994 0.003002 0.1900
21 0.001887 0.002112 0.0998 66 0.000774 0.002338 0.2000
22 0.002121 0.001997 0.0554 67 0.002706 0.001998 0.2013
23 0.021192 0.023393 1.3024 68 0.000528 0.001990 0.1821
24 0.001022 0.001486 0.0123 69 0.000525 0.002021 0.4247
25 0.000822 0.008732 0.0492 70 0.006724 0.003211 0.2967
26 0.003875 0.001244 0.0824 71 0.005543 0.002331 0.4201
27 0.021331 0.004941 0.0345 72 0.001444 0.020011 0.4458
28 0.001044 0.001115 0.2243 73 0.020001 0.011174 0.4392
29 0.001191 0.001321 0.0321 74 0.007733 0.008728 0.5568
30 0.045324 0.024325 0.0822 75 0.005745 0.060113 0.2112
31 0.002444 0.026441 1.8999 76 0.002033 0.004591 0.6673
32 0.018737 0.118462 11.1092 77 0.000310 0.005509 0.0221
33 0.015589 0.566348 1.4458 78 0.000321 0.005009 0.0432
34 0.002344 0.021432 0.1331 79 0.001100 0.004492 0.0300
35 0.005238 0.007005 0.1422 80 0.000388 0.005001 0.0220
36 0.020333 0.021221 0.7056 81 0.000299 0.007821 0.0300
37 0.002438 0.002334 0.0412 82 0.000399 0.001011 0.0119
38 0.002494 0.004588 0.5333 83 0.000633 0.002001 0.0446
39 0.000744 0.003255 0.5126 84 0.000722 0.000998 0.0492
40 0.003289 0.020466 6.3078 85 0.000896 0.001109 0.0545
41 0.009993 0.032324 0.9987 86 0.000678 0.002334 0.0829
42 0.008893 0.005611 0.4472 87 0.011528 0.020021 0.9953
43 0.009321 0.020012 0.7893 88 0.008233 0.002011 0.9429
44 0.029221 0.033221 2.3004 89 0.009921 0.005213 0.9538
45 0.003244 0.098892 0.7783 AZD-9291 0.013468 0.014112 0.5003
Test results show that all the examples have effects on activating mutation, double mutation and wild type mutation, and have good selectivity and better application prospects.
Stability tests show that the half-life of the compounds is mostly more than 48h, so that the dosage of the medicines can be well reduced, the time interval of the use of the medicines is enlarged, and the medicines have lower toxicity.
The compounds disclosed in the present invention can be used alone or in combination with other agents for the treatment of various cancers, and are not limited to non-small cell lung cancer, prostate cancer, leukemia, lymphoma, non-hodgkin's lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, and the like.

Claims (8)

1. An N- [5- (pyrimidin-2-amino) -2, 4-disubstituted phenyl ] -trans-2, 4-pentadiene amide, a compound of formula (I), a pharmaceutically acceptable salt thereof, or a prodrug thereof:
Figure FDA0002562406220000011
wherein A is selected from 4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyridin-3-yl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl or pyrazolo [1,5-a ] pyridin-3-yl;
R1selected from hydrogen, halogen, C1-C5 alkyl or cyano;
R2is selected from alkoxy of C1-C5 or fluoro alkoxy of C1-C5;
R3selected from (3R) -3- (dimethylamino) pyrrolidin-1-yl, (3S) -3- (dimethylamino) pyrrolidin-1-yl, 3- (dimethylamino) azetidin-1-yl, [2- (dimethylamino) ethyl](methyl) amino, [2- (methylamino) ethyl](methyl) amino, 5-methyl-2, 5-diazaspiro [3,4]]Oct-2-yl, (3aR,6aR) -5-methylhexahydropyrrolo [3,4-b ]]Pyrrol-1 (2H) -yl, 1-methyl-1, 2,3, 6-tetrahydropyridin-4-yl, 4-methylpiperazin-1-yl, 4- [2- (dimethylamino) -1-oxoethyl]Piperazin-1-yl, methyl [2- (4-methylpiperazin-1-yl) ethyl]Amino, methyl [2- (morpholin-4-yl) ethyl]Amino, 4- [ (2S) -2-aminopropionyl group]Piperazin-1-yl.
2. N- [5- (pyrimidin-2-amino) -2, 4-disubstituted-phenyl according to claim 1]-trans-2, 4-glutaramide, characterized in that said R is1Selected from hydrogen, chloro, methyl or cyano;
the R is2Selected from methoxy, difluoromethoxy or trifluoromethoxy.
3. N- [5- (pyrimidin-2-amino) -2, 4-disubstituted-phenyl ] -trans-2, 4-pentadiene amide according to claim 1, characterized by one or more compounds of formula (I-1) to formula (I-89):
Figure FDA0002562406220000021
Figure FDA0002562406220000031
Figure FDA0002562406220000041
Figure FDA0002562406220000051
Figure FDA0002562406220000061
4. use of N- [5- (pyrimidin-2-amino) -2, 4-disubstituted-phenyl ] -trans-2, 4-pentadiene amide according to any one of claims 1 to 3 for the preparation of an epidermal growth factor receptor inhibitor medicament.
5. Use of N- [5- (pyrimidin-2-amino) -2, 4-disubstituted-phenyl ] -trans-2, 4-pentadienamide according to any one of claims 1 to 3 for the preparation of a medicament for the treatment and/or prevention of cancer.
6. The use of claim 5, wherein the cancer is selected from the group consisting of lung cancer, brain cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, mesothelioma, and complications thereof.
7. The use of claim 5, wherein the cancer is a non-small cell cancer.
8. A pharmaceutical composition comprising N- [5- (pyrimidin-2-amino) -2, 4-disubstituted phenyl ] -trans-2, 4-pentadienamide according to any one of claims 1 to 3.
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