CN110256429B - Aminopyrimidine compound with spiro structure and preparation method and application thereof - Google Patents

Aminopyrimidine compound with spiro structure and preparation method and application thereof Download PDF

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CN110256429B
CN110256429B CN201910521671.5A CN201910521671A CN110256429B CN 110256429 B CN110256429 B CN 110256429B CN 201910521671 A CN201910521671 A CN 201910521671A CN 110256429 B CN110256429 B CN 110256429B
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叶连宝
石培琪
朱大潜
赵涛
陈伟强
高伟
罗艳
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Guangdong Pharmaceutical University
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Abstract

The invention discloses an aminopyrimidine compound with a spiro structure and a preparation method and application thereof. The structure of the compound is shown as a formula I or a formula II. The aminopyrimidine compound containing the spiro structure has good inhibition effect on multiple EGFR mutations, especially compounds A1, A2, A3 and A4, especially compounds A1 and A2, and inhibition IC (integrated circuit) of EGFR T790M50The value reaches 89nM, and the inhibition IC for EGF-R d747-749/A750P, EGF-R L858R, EGF-R L861Q and EGF-R T790M/L858R50Values reached 53nM, 86nM, 76nM and 90nM, respectively; the compound is expected to make a great contribution in the aspect of tumor drug resistance.

Description

Aminopyrimidine compound with spiro structure and preparation method and application thereof
Technical Field
The invention relates to the technical field of antitumor drug chemistry, and in particular relates to an aminopyrimidine compound with a spiro structure, and a preparation method and application thereof.
Background
The human Epidermal Growth Factor Receptor (EGFR) family is composed of 4 different Receptor Tyrosine Kinases (RTKs), EGFR, human epidermal growth factor receptor 2 (HER 2), human epidermal growth factor receptor 3 (HER 3), and human epidermal growth factor receptor 4 (HER 4), respectively. They are involved in activating a series of complex cell signaling pathways, and are closely related to the occurrence, development and prognosis of various malignant tumors. The EGFR family RTKs, particularly EGFR and HER2, have become new targets for anti-tumor therapy. Clinical studies have shown that EGFR and HER2 are closely related to the proliferation and differentiation processes of many normal tissue cells. In many malignancies, there is overexpression or aberrant activation of EGFR and HER 2. Compared with a single-target kinase inhibitor, the double-target kinase inhibitor can simultaneously act on EGFR and HER2 targets, inhibit or block multiple cell signal conduction paths, better play an anti-tumor effect and reduce adverse reactions. Currently, EGFR/HER2 dual-target kinase inhibitors have become one of the hot spots for the research of antitumor drugs.
Neratinib (nerlinx) is an oral, potent irreversible tyrosine kinase inhibitor, like lapatinib and atorvastatin, used for the prolonged adjuvant treatment of adult patients with early HER2 overexpression/amplification of breast cancer, with the aim of anticancer by preventing transduction through the Epidermal Growth Factor Receptor (EGFR), HER1, HER2 and HER4 signaling pathways. After the FDA approves the medicine, a new choice is provided for the reinforcement treatment of breast cancer patients with early stage, HER2 positive, standard trastuzumab adjuvant therapy and high risk. Recent research shows that neratinib has better inhibiting effect on various EGFR mutations such as EGFR T790, MEGF-R L858R, EGF-R L861Q and EGF-R T790M/L858R.
Since compounds having inhibitors against multiple EGFR receptors simultaneously have better antitumor effects, there is a need for further research and development of multi-target kinase inhibitors.
Disclosure of Invention
The invention aims to provide an aminopyrimidine compound with a spiro structure. The novel Met inhibitor spiro [ indoline-3, 4' -piperidine ] discovered by Neratinib and the subject group]-2-ketone compound Met-2 is a lead compound, and ammonia containing a spiro structure is designed and synthesizedThe compounds have good inhibitory effect on various EGFR mutations, especially compounds A1, A2, A3 and A4, especially compounds A1 and A2, and inhibit IC of EGFR T790M50The value reaches 89nM, and the inhibition IC for EGF-R d747-749/A750P, EGF-R L858R, EGF-R L861Q and EGF-R T790M/L858R50Values reached 53nM, 86nM, 76nM and 90nM, respectively; the compound is expected to make a great contribution in the aspect of tumor drug resistance.
The invention also aims to provide a preparation method of the aminopyrimidine compound with a spiro structure.
The invention further aims to provide application of the aminopyrimidine compound with a spiro structure.
The above object of the present invention is achieved by the following scheme:
an aminopyrimidine compound with a spiro structure, wherein the structure of the compound is shown as a formula I or a formula II:
Figure BDA0002096900170000021
wherein R is1Is hydrogen, C2-4Trifluoroacetyl, sulfonyl, sulfonylalkyl, vinylsulfone, 1- (dimethylamino) -2-en-butyryl chloride, -COR5、C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkenyl radical, C5-6Aryl or heteroaryl, C3-6Hetero alicyclic group or C6Aromatic ring C3-6A heterocyclic group; the number of heteroatoms of the aromatic hetero group is 1-4, and the heteroatoms are O, S or N; the R is5Is C1-4Alkyl radical, C1-4Alkenyl radical, C1-4Alkylamino or C1-4An alkylamino group;
R2is hydrogen, halogen, nitro, amino, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino or C2-6An alkenyl group;
R3is hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Cycloalkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, C3-6Cyclic amino group, C5-6Heteroaryl amino or C3-6A heteroalicyclic amino group; the number of heteroatoms of the aromatic hetero group is 1-4, and the heteroatoms are O, S or N;
R4is a five-membered or six-membered aryl group, a five-membered or six-membered substituted aryl group, a five-membered or six-membered heteroaryl group, a five-membered or six-membered substituted heteroaryl group, the number of heteroatoms of the aromatic hetero group is 1 to 4, and the heteroatoms are O, S or N; the substituent in the substituted aryl is halogen, nitryl, amino, benzene ring, benzyloxy, pyridyl or pyridine substituted methoxyl.
Preferably, said R is1Is hydrogen, C2-4Trifluoroacetyl, -COR5、C1-4Alkyl radical, C1-4Alkoxy or C1-4An alkenyl group; the R is5Is C1-4Alkyl radical, C1-4Alkenyl radical, C1-4Alkylamino or C1-4An alkylamino group;
R2is hydrogen, halogen, nitro, amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino or C2-4An alkenyl group;
R3is hydrogen, halogen, cyano, C1-4Alkyl radical, C1-4Cycloalkyl radical, C1-4Alkoxy radical, C1-4Alkylamino or C3-6A cyclic amino group;
R4is composed of
Figure BDA0002096900170000031
Wherein said R6And R7Each independently hydrogen, halogen, benzene ring, benzyloxy, pyridyl or pyridine substituted methoxy.
Preferably, said R is1Is hydrogen, -COR5、C1-4Alkyl radical, C1-4Alkoxy or C1-4An alkenyl group; the R is5Is methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, methoxy, ethoxy or N, N-dimethylpropenyl;
R2is hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, ethenyl or propenyl;
R3is hydrogen, cyano, methyl, ethyl, methoxy or ethoxy;
R4is composed of
Figure BDA0002096900170000032
One kind of (1).
Preferably, the compound is selected from one of the following structures:
Figure BDA0002096900170000033
the chemical names of the compounds are respectively as follows according to the sequence:
2- { [ 5-methoxy-1 '-methyl-1- (prop-2-enoyl) -1, 2-dihydrospiro [ indole-3, 4' -piperidin ] -6-yl ] amino } -4- { [4- (pyridin-2-methoxy) phenyl ] amino } pyrimidine-5-carbonitrile;
4- { [ 3-chloro-4- (pyridin-2-methoxy) phenyl ] amino } -2- { [ 5-methoxy-1 '-methyl-1- (prop-2-enoyl) -1, 2-dihydrospiro [ indole-3, 4' -piperidin ] -6-yl ] amino } pyrimidine-5-carbonitrile;
4- { [4- (benzyloxy) -3-chlorophenyl ] amino } -2- { [ 5-methoxy-1 '-methyl-1- (prop-2-enoyl) -1, 2-dihydrospiro [ indole-3, 4' -piperidin ] -6-yl ] amino } pyrimidine-5-carbonitrile;
2- { [ 5-methoxy-1 '-methyl-1- (prop-2-enoyl) -1, 2-dihydrospiro [ indole-3, 4' -piperidin ] -6-yl ] amino } -4- { [1- (pyridin-2-methyl) -1H-pyrazol-4-yl ] amino } pyrimidine-5-carbonitrile;
(2E) -4- {6'- [ (5-cyano-4- { [4- (pyridin-2-methoxy) phenyl ] amino } pyrimidin-2-yl) amino ] -5' -methoxyspiro [ cyclopropane-1, 3 '-indol ] -1' -yl } -1- (dimethylamino) -4-oxobut-2-en-2-yl;
(2E) -4- {6'- [ (4- { [ 3-chloro-4- (pyridin-2-methoxy) phenyl ] amino } -5-cyanopyrimidin-2-yl) amino ] -5' -methoxyspiro [ cyclopropane-1, 3 '-indol ] -1' -yl } -1- (dimethylamino) -4-oxobut-2-en-2-yl;
4- { [4- (benzyloxy) -3-chlorophenyl ] amino } -2- ({1'- [ (2E) -4- (dimethylamino) but-2-enoyl ] -5' -methoxy-1 ',2' -dihydrospiro [ cyclopropane-1, 3 '-indol ] -6' -yl } amino) pyrimidine-5-carbonitrile;
3- {6'- [ (5-cyano-4- { [4- (pyridin-2-methoxy) phenyl ] amino } pyrimidin-2-yl) amino ] -5' -methoxyspiro [ cyclopropane-1, 3 '-indol ] -1' -yl } -3-oxoprop-1-en-2-yl;
3- {6'- [ (4- { [ 3-chloro-4- (pyridin-2-methoxy) phenyl ] amino } -5-cyanopyrimidin-2-yl) amino ] -5' -methoxyspiro [ cyclopropane-1, 3 '-indol ] -1' -yl } -3-oxoprop-1-en-2-yl;
(2E) -4- {6'- [ (5-cyano-4- { [1- (pyridin-2-methyl) pyrazol-4-yl ] amino } pyrimidin-2-yl) amino ] -5' -methoxyspiro [ cyclopropane-1, 3 '-indol ] -1' -yl } -1- (dimethylamino) -4-oxobut-2-en-2-yl;
3- {6'- [ (5-cyano-4- { [1- (pyridin-2-methyl) pyrazol-4-yl ] amino } pyrimidin-2-yl) amino ] -5' -methoxyspiro [ cyclopropane-1, 3 '-indol ] -1' -yl } -3-oxoprop-1-en-2-yl.
More preferably, the compound is selected from one of the following structures:
Figure BDA0002096900170000041
the pharmaceutically acceptable salt of the aminopyrimidine compound with the spiro structure obtained by the reaction of the compound with the structure shown in the formula I or the formula II and acid is also within the protection scope of the invention.
Preferably, the acid is hydrochloric acid, nitric acid, sulfuric acid or trifluoroacetic acid, phosphoric acid, acetic acid, carbonic acid.
The invention also provides a preparation method of the aminopyrimidine compound with the spiro structure, which comprises the following steps:
Figure BDA0002096900170000051
performing cyclization on a phenylhydrazine hydrochloride compound 1 and 4-formylpiperidine-1-benzyl formate to generate a compound 2; then carrying out dry acylation reaction with trifluoroacetic acid under the inert gas atmosphere to obtain an acylation product compound 3; compound 3 is further reacted with copper nitrateCarrying out nitration reaction with acetic anhydride to obtain a compound 4; then reducing the nitro group in the compound 4 into amino group to obtain a compound 5; performing alkylation reaction on the compound 5 and methyl iodide to obtain a spiro-segmented compound 6; reacting with 2, 4-dichloropyrimidine derivative at 75 deg.C to obtain intermediate compound 7, reacting under weak alkaline condition to obtain hydrolysis product compound 8, reacting with compound 8 containing R1Reacting the compound of the substituent group to obtain the compound shown in the formula I;
the preparation of the compound of formula II is shown below:
Figure BDA0002096900170000052
2, 3-dihydro-1H-indol-2-one compound 2-1 reacts with diisopropylamine and n-butyllithium to obtain 1',2' -dihydrospiro [ cyclopropane-1, 3-indole]-2' -keto compound 2-2; then carrying out nitration reaction with nitric acid to obtain a nitration product compound 2-3; then nitro is reduced to obtain an amino product compound 2-4; then reducing to generate a spiro fragment compound 2-5; stirring the compound 2-5 and halogenated pyrimidine derivatives at 100 ℃ to react to obtain an intermediate compound 2-6; then reacting with zinc dinitrile to obtain product and finally reacting with the product containing R1And (3) reacting the substituent compound to obtain the compound shown in the formula II.
Preferably, in the preparation process of the compound shown in the formula I, the equivalent ratio of the reaction between the phenylhydrazine hydrochloride compound 1 and the 4-formylpiperidine-1-benzyl formate is 1: 2.52; the reaction temperature is 40 ℃;
the inert gas atmosphere is nitrogen atmosphere;
carrying out nitration reaction on the compound 3 at room temperature, and carrying out alkylation reaction on the compound 5 at room temperature;
the equivalent ratio of the compound 5 to the methyl iodide is 1: 1.3;
carrying out catalytic reduction on the compound 4 by 10% palladium-carbon to generate a compound 5;
the reaction temperature of the compound 6 and the 2, 4-dichloropyrimidine derivative is 75 ℃;
said group containing R1The compound of the substituent is acyl chloride compound or sulfone compound.
More preferably, the compound containing R1The compound of the substituent is propane-2-acryloyl chloride, 1- (dimethylamino) -2-alkene-butyryl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride or vinyl sulfone.
The equivalent ratio of the compound 2-2 to the nitric acid for nitration is 1: 1.8; the reaction temperature is room temperature;
preferably, in the preparation process of the compound shown in the formula II, the compound 2-3 is reduced into the compound 2-4 at 70 ℃ by taking iron powder as a reducing agent;
reducing the compound 2-4 into a compound 2-5 at 70 ℃ by taking lithium aluminum hydride as a reducing agent;
the compound 2-5 reacts at the temperature of 100 ℃ to generate a compound 2-6
Said group containing R1The compound of the substituent is acyl chloride compound or sulfone compound.
More preferably, the compound containing R1The compound of the substituent is propane-2-acryloyl chloride, 1- (dimethylamino) -2-alkene-butyryl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride or vinyl sulfone.
The application of the aminopyrimidine compound with a spiro structure or pharmaceutically acceptable salts thereof in preparing tyrosine kinase and/or mutant inhibitors thereof is also within the protection scope of the invention.
Preferably, the mutant is one or more of EGF-R d747-749/A750P, EGF-RL858R, EGF-R L861Q or EGF-R T790M/L858R.
The invention also protects the application of the aminopyrimidine compound with a spiro structure or pharmaceutically acceptable salt thereof in preparing anticancer drugs.
Preferably, the anticancer drug is one or more of melanoma, liver cancer, kidney cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, carcinoma of fallopian tubes, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, cancer of the bladder, cancer of the kidney or fallopian tubes, spinal axis tumor, pituitary adenoma, gastrointestinal stromal tumor, colorectal cancer, non-small cell cancer, small cell lung cancer, mastocytosis, glioma, sarcoma or lymphoma caused by abnormal expression of tyrosine kinase and/or a mutant thereof.
The invention also discloses a pharmaceutical composition which comprises one or more of aminopyrimidine compounds with spiro structures shown in formula I or formula II, pharmaceutically acceptable salts, hydrates, solvates, polymorphs, tautomers, stereoisomers or prodrugs thereof.
Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant and/or carrier.
Preferably, the auxiliary material comprises at least one of the following substances: solvents, propellants, solubilizers, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-chelating agents, integration agents, penetration enhancers, pH regulators, buffers, plasticizers, solubilizing agents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, surfactants, foaming agents, antifoaming agents, thickeners, encapsulation agents, humectants, absorbents, release agents, flocculants and deflocculants, filter aids, release retardants.
The pharmaceutical composition of the invention can be prepared into various dosage forms: the following preparations can be prepared according to the dispersion system of the dosage form: solution type, colloidal solution type, emulsion type, suspension type, gas dispersion type, fine particle dispersion type, solid dispersion type; according to the morphological classification, the preparation can be prepared into the following dosage forms: liquid dosage forms (such as aromatic water agent, solution, injection, mixture, lotion, liniment, etc.), solid dosage forms (such as powder, pill, tablet, pellicle, etc.), and semisolid dosage forms (such as ointment, suppository, paste, etc.).
Compared with the prior art, the invention has the following beneficial effects:
the aminopyrimidine compound containing the spiro structure has good inhibition effect on multiple EGFR mutations, especially compounds A1, A2, A3 and A4, especially compounds A1 and A2, and inhibition IC (integrated circuit) of EGFR T790M50The value reaches 89nM, and the inhibition IC for EGF-R d747-749/A750P, EGF-R L858R, EGF-R L861Q and EGF-R T790M/L858R50Values reached 53nM, 86nM, 76nM and 90nM, respectively; the compound is expected to make a great contribution in the aspect of tumor drug resistance.
Detailed Description
The present invention is further described in detail below with reference to specific examples, which are provided for illustration only and are not intended to limit the scope of the present invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.
Example 1: synthesis of 2- { [ 5-methoxy-1 '-methyl-1- (prop-2-enoyl) -1, 2-dihydrospiro [ indole-3, 4' -piperidin ] -6-yl ] amino } -4- { [4- (pyridin-2-methoxy) phenyl ] amino } pyrimidine-5-carbonitrile (A1)
1. Synthesis of benzyl 5-methoxy-1, 2-dihydrospiro [ indole-3, 4 '-piperidine ] -1' -carboxylate (2)
Figure BDA0002096900170000071
Dissolving p-methoxybenzyl hydrazine hydrochloride and 4-formylpiperidine-1-benzyl formate in the mixed solution of toluene and acetonitrile, adding trifluoroacetic acid, stirring for 12 hr, cooling, adding methanol, adding sodium borohydride, and dissolving in the solution of 0-5%℃Stirring for 3 hours, adding a proper amount of water, extracting with ethyl acetate, separating an organic layer, drying with anhydrous sodium sulfate, filtering, concentrating in vacuum, and recrystallizing with petroleum ether to obtain 2, 4.5g of a compound with a yield of 45%.1H NMR(300MHz,DMSO-d6)δ7.39-7.35(m,5H),6.67(d,J＝2.5Hz,1H),6.57-6.49(m,1H),6.42(d,J＝8.4Hz,1H),5.11(m,3H),4.13-3.86(m,2H),3.67(s,3H),3.34(s,2H),3.01-2.95(m,2H),1.71-1.51(m,4H)ppm；ESI-MS m/z:353[M+1]+。
2. Synthesis of benzyl 5-methoxy-1- (trifluoroacetyl) -1, 2-dihydrospiro [ indole-3, 4 '-piperidine ] -1' -carboxylate (3)
Figure BDA0002096900170000081
Under the stirring of 0 ℃, trifluoroacetic anhydride is slowly added into a dichloromethane solution of the compound 2 and triethylamine, the mixture is stirred for 12 hours under the protection of nitrogen, water is added for dilution, dichloromethane extraction is carried out, anhydrous sodium sulfate is dried, suction filtration and vacuum concentration are carried out, and the mixture is passed through a gradient flash chromatographic column (10-35% of ethyl acetate/petroleum ether) to obtain yellow solid compound 3, 3.8g, and the yield is 66%.1H NMR(300MHz,DMSO-d6)δ7.96(d,J＝8.9Hz,1H),7.44-7.27(m,5H),7.05(d,J＝2.6Hz,1H),6.86(dd,J＝8.9,2.6Hz,1H),5.11(s,2H),4.20(s,2H),4.06-3.99(m,2H),3.76(s,3H),3.01(s,2H),1.85(td,J＝13.2,4.7Hz,2H),1.65(d,J＝13.0Hz,2H)ppm；ESI-MS m/z:449[M+1]+。
3. Synthesis of benzyl-5-methoxy-6-nitro-1- (trifluoroacetyl) -1, 2-dihydrospiro [ indole-3, 4 '-piperidine ] -1' -carboxylate (4)
Figure BDA0002096900170000082
Under the stirring of 0 ℃, copper nitrate trihydrate is added into an acetic anhydride solution of the compound 3, the mixture is stirred for 3 hours at room temperature, water is added for quenching reaction, dichloromethane is used for extraction, anhydrous sodium sulfate is used for drying, suction filtration and vacuum concentration are carried out, and a gradient flash chromatographic column (0-80% of ethyl acetate/petroleum ether) is used for obtaining yellow solid compound 4, 3.9g, and the yield is 86%.1H NMR(300MHz,DMSO-d6)δ8.47(s,1H),7.57(s,1H),7.52-7.23(m,5H),5.12(s,2H),4.29(s,2H),4.16-4.03(m,2H),4.00(s,3H),3.05-2.96(m,2H),1.99-1.91(m,2H),1.73(d,J＝13.2Hz,2H)ppm；ESI-MS m/z:494[M+1]+。
4. Synthesis of 1- { 6-amino-5-methoxy-1, 2-dihydrospiro [ indole-3, 4' -piperidin ] -1-yl } -2,2, 2-trifluoroacetyl-1-one (5)
Figure BDA0002096900170000091
To the methanol solution of compound 4 was added palladium on carbon and the mixture was stirred under hydrogen atmosphere for 5 h. Suction filtration is carried out, and the filtrate is concentrated in vacuum to obtain the compound 5. 2.4g, 92% yield.1H NMR(300MHz,DMSO-d6)δ7.47(s,1H),6.79(s,1H),4.88(s,2H),4.04(s,2H),3.79(s,3H),2.99-2.85(m,2H),2.63-2.43(m,3H),1.75(td,J＝12.8,4.3Hz,2H),1.52-1.42(m,2H)ppm；ESI-MS m/z:330[M+1]+。
5. Synthesis of 1- { 6-amino-5-methoxy-1 '-methyl-1, 2-dihydrospiro [ indole-3, 4' -piperidine ] -1-yl } -2,2, 2-trifluoroacetyl-1-one (6)
Figure BDA0002096900170000092
To a solution of compound 5(2.4g, 7.29mmol) and triethylamine (2.2g, 21.74mmol) in tetrahydrofuran was added methyl iodide (1.35g, 9.5 mmol). After stirring for 6 hours, the mixture was concentrated in vacuo and passed through a gradient flash column (dichloromethane/methanol 0-10%) to give compound 6 as a pale yellow solid, 1.4g, 58% yield.1H NMR(300MHz,DMSO-d6)δ7.46(s,1H),6.81(s,1H),4.89(s,2H),4.01(s,2H),2.77(d,J＝8.0Hz,2H),2.21(s,3H),1.96-1.79(m,4H),1.53(d,J＝10.5Hz,2H)ppm；ESI-MS m/z:344[M+1]+。
6. Synthesis of 2- { [ 5-methoxy-1 '-methyl-1- (trifluoroacetyl) -1, 2-dihydrospiro [ indole-3, 4' -piperidin ] -6-yl ] amino } -4- { [4- (pyridine) -2-methoxy) phenyl ] amino } pyrimidine-5-carbonitrile (7a)
Figure BDA0002096900170000101
To 2-chloro-4- [ [4- (pyridin-2-ylmethoxy) phenyl]Amino group]To a solution of pyrimidine-5-carbonitrile (300mg, 0.89mmol) and compound 6(200mg, 0.58mmol) in 2-propanol was added p-toluenesulfonic acid (153mg, 0.89 mmol). The reaction mixture was stirred at 75 deg.CAfter completion, the reaction mixture was diluted with saturated aqueous sodium bicarbonate (50mL) and extracted with ethyl acetate (3X 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered with suction and concentrated in vacuo to afford compound 7a as a yellow crude solid, 370mg, 71% yield. ESI-MS M/z 645[ M +1 ]]+。
7. Synthesis of 2- ({ 5-methoxy-1 '-methyl-1, 2-dihydrospiro [ indole-3, 4' -piperidin ] -6-yl } amino) -4- { [4- (pyridine-2-methoxy) phenyl ] amino } pyrimidine-5-carbonitrile (8a)
Figure BDA0002096900170000102
To a solution of 7a (370mg, 0.40 mmol) in methanol was added potassium carbonate (280mg, 2.03 mmol). After stirring for 2 hours, the mixture was diluted with water and extracted with ethyl acetate (30mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative liquid phase [ column: XBridge Shield RP18OBD column, 5um, 19 × 150 mm; mobile phase A: water containing 10mmol/L ammonium bicarbonate, mobile phase B: acetonitrile; flow rate: 30 mL/min; gradient: 10% B to 60% B in 13 minutes; yellow solid 8a, 64mg, yield 26% was obtained.1H NMR(300MHz,DMSO-d6)δ9.25(s,1H),8.58(ddd,J＝4.9,1.8,1.0Hz,1H),8.45(s,1H),8.39(s,1H),7.84(td,J＝7.7,1.8Hz,1H),7.50-7.37(m,3H),7.35(ddd,J＝7.6,4.8,1.3Hz,1H),7.00-6.91(m,2H),6.83(s,1H),6.79(s,1H),5.15(s,2H),4.91(s,1H),3.68(s,3H),3.24(s,2H),2.78-2.60(m,2H),2.20(s,3H),1.98(t,J＝11.7Hz,2H),1.90-1.73(m,2H),1.61-1.44(m,2H)ppm；ESI-MS m/z:549[M+1]+。
8. Synthesis of 2- { [ 5-methoxy-1 '-methyl-1- (prop-2-enoyl) -1, 2-dihydrospiro [ indole-3, 4' -piperidin ] -6-yl ] amino } -4- { [4- (pyridin-2-methoxy) phenyl ] amino } pyrimidine-5-carbonitrile (A1)
Figure BDA0002096900170000111
8a (42mg, 0.08mmol) and triethylamine (80mg, 0.79mmol) were dissolved in bisMethyl chloride, and a solution of prop-2-enoyl chloride (5.6mg, 0.06mmol) in methylene chloride was added under nitrogen. After stirring the reaction for 1 hour, the mixture was concentrated in vacuo. The reaction was carried out by preparative high performance liquid [ column: XBridge Shield RP18OBD column, 5um, 19 × 150 mm; : using 10mmol/L ammonium bicarbonate water solution, mobile phase B: acetonitrile) the crude product was purified. Gradient: 25.0% B, up to 48.0% B, 10 minutes; a detector: UV220 nm]Compound a1 was obtained as a white solid, 14.4mg, 31% yield.1H NMR(300MHz,DMSO-d6)δ10.17(s,1H),9.19(s,1H),9.00(s,1H),8.60(d,J＝4.2Hz,1H),8.40(s,1H),8.24(s,1H),7.84(td,J＝7.8,1.8Hz,1H),7.50-7.34(m,4H),6.81-6.71(m,3H),6.30(d,J＝18.0Hz,1H),5.84(d,J＝11.1Hz,1H),5.09(s,2H),4.23(s,2H),3.74(s,3H),3.47-3.43(s,2H),3.20-3.13(m,2H),2.80(s,3H),2.24(t,J＝12.0Hz,2H),1.89-1.85(m,2H)ppm；ESI-MS m/z:603[M+1]+。
EXAMPLE synthesis of 24- { [ 3-chloro-4- (pyridin-2-methoxy) phenyl ] amino } -2- { [ 5-methoxy-1 '-methyl-1- (prop-2-enoyl) -1, 2-dihydrospiro [ indole-3, 4' -piperidin ] -6-yl ] amino } pyrimidine-5-carbonitrile (A2)
1. Synthesis of 4- { [ 3-chloro-4- (pyridin-2-methoxy) phenyl ] amino } -2- { [ 5-methoxy-1 '-methyl-1- (trifluoroacetyl) -1, 2-dihydrospiro [ indole-3, 4' -piperidin ] -6-yl ] amino } pyrimidine-5-carbonitrile (7b)
Figure BDA0002096900170000112
Using compound 6 prepared in example 1 as a starting material, compound 7b was prepared in 290mg with a yield of 63% according to the method for compound 7 a. ESI-MS M/z 679[ M +1 ]]+。
2. Synthesis of 4- { [ 3-chloro-4- (pyridin-2-methoxy) phenyl ] amino } -2- ({ 5-methoxy-1 '-methyl-1, 2-dihydrospiro [ indole-3, 4' -piperidin ] -6-yl } amino) pyrimidine-5-carbonitrile (8b)
Figure BDA0002096900170000121
Reference example 1 SynthesisCompound 7b after compound 8b was synthesized according to the method for synthesizing compound 8a, 46mg, 29% yield.1H NMR(300MHz,DMSO-d6)δ9.31(s,1H),8.69-8.54(m,2H),8.41(s,1H),7.87(td,J＝7.7,1.8Hz,1H),7.64(s,1H),7.58-7.54(m,2H),7.42-7.30(m,1H),7.14(d,J＝9.0Hz,1H),6.81(s,1H),6.74(s,1H),5.25(s,2H),4.94(s,1H),3.68(s,3H),3.24(s,2H),2.67(d,J＝10.5Hz,2H),2.17(s,3H),2.00-1.71(m,4H),1.52(d,J＝11.8Hz,2H)ppm；ESI-MSm/z:583[M+1]+。
3. Synthesis of 4- { [ 3-chloro-4- (pyridin-2-methoxy) phenyl ] amino } -2- { [ 5-methoxy-1 '-methyl-1- (prop-2-enoyl) -1, 2-dihydrospiro [ indole-3, 4' -piperidin ] -6-yl ] amino } pyrimidine-5-carbonitrile (A2)
Figure BDA0002096900170000122
Referring to example 1, synthesis of compound a2 after synthesis of compound 8b, compound a2 was synthesized according to the method for synthesizing compound a1, 4.2mg, 12% yield.1H NMR(300MHz,Methanol-d4)δ8.64(s,1H),8.57(dt,J＝4.8,1.4Hz,1H),8.35(s,1H),7.91(dd,J＝8.5,6.7Hz,1H),7.73-7.64(m,2H),7.46-7.29(m,2H),6.97-6.94(m,2H),6.77(dd,J＝16.7,10.3Hz,1H),6.30(d,J＝16.8Hz,1H),5.77(d,J＝10.6Hz,1H),5.16(s,2H),4.12(s,2H),3.90(s,3H),2.93(d,J＝12.0Hz,2H),2.39(s,3H),2.23(t,J＝12.3Hz,2H),2.04(dt,J＝14.3,7.2Hz,2H),1.72(d,J＝13.4Hz,2H)ppm；ESI-MS m/z:637[M+1]+。
Example Synthesis of 34- { [4- (benzyloxy) -3-chlorophenyl ] amino } -2- { [ 5-methoxy-1 '-methyl-1- (prop-2-enoyl) -1, 2-dihydrospiro [ indole-3, 4' -piperidin ] -6-yl ] amino } pyrimidine-5-carbonitrile (A3)
1. Synthesis of 4- { [4- (benzyloxy) -3-chlorophenyl ] amino } -2- { [ 5-methoxy-1 '-methyl-1- (trifluoroacetyl) -1, 2-dihydrospiro [ indole-3, 4' -piperidine ] ] -6-yl ] amino } pyrimidine-5-carbonitrile (7c)
Figure BDA0002096900170000131
Referring to example 1, synthesis of compound 6, compound 7c reference the synthesis of compound 7a, 210mg, 53% yield. ESI-MS M/z 678[ M +1 ]]+。
2. Synthesis of 4- { [4- (benzyloxy) -3-chlorophenyl ] amino } -2- ({ 5-methoxy-1 '-methyl-1, 2-dihydrospiro [ indole-3, 4' -piperidin ] -6-yl } amino) pyrimidine-5-carbonitrile (8c)
Figure BDA0002096900170000132
Referring to example 1, synthesis of compound 7c, synthesis of compound 8c referring to the synthesis of compound 8a, 70mg, 60% yield.1H NMR(300MHz,DMSO-d6)δ9.30(s,1H),8.60(s,1H),8.41(s,1H),7.63(s,1H),7.59-7.51(m,1H),7.50-7.30(m,5H),7.15(d,J＝9.0Hz,1H),6.81(s,1H),6.75(s,1H),5.17(s,2H),4.94(s,1H),3.68(s,3H),3.28-3.19(m,2H),2.68(d,J＝10.7Hz,2H),2.17(s,3H),2.02-1.75(m,4H),1.53(d,J＝12.0Hz,2H)ppm；ESI-MS m/z:582[M+1]+。
3. Synthesis of 4- { [4- (benzyloxy) -3-chlorophenyl ] amino } -2- { [ 5-methoxy-1 '-methyl-1- (prop-2-enoyl) -1, 2-dihydrospiro [ indole-3, 4' -piperidin ] -6-yl ] amino } pyrimidine-5-carbonitrile (A3)
Figure BDA0002096900170000133
Reference example 1 synthesis of compound 8c, compound A3 synthesis reference compound a1 synthesis, 23.1mg, 38% yield.1H NMR(300MHz,DMSO-d6)δ8.41(s,1H),8.25(s,1H),7.70(d,J＝2.6Hz,1H),7.54-7.24(m,6H),6.98(d,J＝9.3Hz,1H),6.92(s,1H),6.72(dd,J＝16.6,10.3Hz,1H),6.25(d,J＝16.6Hz,1H),5.81(d,J＝10.4Hz,1H),5.13(s,2H),4.17(s,2H),3.76(s,3H),3.43(d,J＝12.7Hz,2H),3.22-3.03(m,2H),2.81(s,3H),2.19-1.97(m,2H),1.85(d,J＝13.9Hz,2H)ppm；ESI-MS m/z:636[M+1]+。
EXAMPLE 42 Synthesis of- { [ 5-methoxy-1 '-methyl-1- (prop-2-enoyl) -1, 2-dihydrospiro [ indole-3, 4' -piperidin ] -6-yl ] amino } -4- { [1- (pyridin-2-yl) -1H-pyrazol-4-yl ] amino } pyrimidine-5-carbonitrile Compound (A4)
1. Synthesis of 2- { [ 5-methoxy-1 '-methyl-1- (trifluoroacetyl) -1, 2-dihydrospiro [ indole-3, 4' -piperidin ] -6-yl ] amino } -4- { [1- (pyridin) -2-ylmethyl) -1H-pyrazol-4-yl ] amino } pyrimidine-5-carbonitrile (7d)
Figure BDA0002096900170000141
Referring to example 1, synthesis of compound 6, compound 7d referring to the synthesis of compound 7a, 360mg, 93% yield. ESI-MSm/z 619[ M +1 ]]+。
2. Synthesis of 2- ({ 5-methoxy-1 '-methyl-1, 2-dihydrospiro [ indole-3, 4' -piperidinyl ] -6-yl } -amino) -4- { [1- (pyridin-2-methyl) - ] -1H-pyrazol-4-yl ] amino } pyrimidine-5-carbonitrile (8d)
Figure BDA0002096900170000142
Reference example 1 synthesis of compound 7d, synthesis of compound 8d reference the synthesis of compound 8a, 67mg, 34% yield.1H NMR(300MHz,DMSO-d6)δ9.64(s,1H),8.81(s,1H),8.51(dd,J＝5.0,1.6Hz,1H),8.36(s,1H),7.80-7.55(m,2H),7.34-7.22(m,1H),6.86(s,1H),6.79(s,1H),6.74(s,1H),5.31(s,2H),5.15(s,1H),3.65(s,3H),3.20(s,2H),2.63(d,J＝10.9Hz,2H),2.17(s,3H),1.90(t,J＝11.6Hz,2H),1.75(t,J＝12.5Hz,2H),1.43(d,J＝12.4Hz,2H)ppm；ESI-MS m/z:523[M+1]+。
3. Synthesis of 2- { [ 5-methoxy-1 '-methyl-1- (prop-2-enoyl) -1, 2-dihydrospiro [ indole-3, 4' -piperidin ] -6-yl ] amino } -4- { [1- (pyridin-2-methyl) -1H-pyrazol-4-yl ] amino } pyrimidine-5-carbonitrile Compound (A4)
Figure BDA0002096900170000151
After synthesis of compound 8d with reference to example 1,synthesis of compound a4 reference was made to the synthesis of compound a1,14 mg, 32% yield.1H NMR(300MHz,DMSO-d6)δ9.65(s,1H),9.12(s,1H),8.56-8.44(m,1H),8.36(s,1H),8.22(s,1H),7.71-7.67(m,2H),7.27(dd,J＝7.4,4.9Hz,1H),7.04(s,1H),6.77(dd,J＝16.5,10.2Hz,1H),6.22(dd,J＝16.5,2.3Hz,1H),5.75(dd,J＝10.2,2.3Hz,1H),5.16(s,2H),3.98(s,2H),3.73(s,3H),2.81-2.57(m,2H),2.20(s,3H),2.07-1.76(m,4H),1.48(d,J＝11.7Hz,2H)ppm；ESI-MS m/z:577[M+1]+。
EXAMPLE Synthesis of 5(2E) -4- {6'- (5-cyano-4- { [4- (pyridin-2-methoxy) phenyl ] amino } pyrimidin-2-yl) amino ] -5' -methoxyspiro [ cyclopropane-1, 3 '-indol ] -1' -yl } -1- (dimethylamino) -4-oxobut-2-en-2-yl (B1)
1. Synthesis of 5' -methoxy-1 ',2' -dihydrospiro [ cyclopropane-1, 3' -indol ] -2' -one (10)
Figure BDA0002096900170000152
To a solution of 5-methoxy-2, 3-dihydro-1H-indol-2-one (5g, 30.64mmol) and diisopropylamine (6.14g, 60.79mmol) in dry tetrahydrofuran (50mL) was slowly added n-butyllithium (49mL, 122.68mmol, 2.5M in hexane). The mixture was stirred for 1 hour and 1, 2-dibromoethane (6.89g, 36.68mmol) was added slowly. The mixed solution was transferred to room temperature for reaction. The reaction was then quenched by the addition of 100mL water and extracted with ethyl acetate (3X 300 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered with suction, and concentrated in vacuo. Gradient flash chromatographic column (ethyl acetate/petroleum ether)
Figure BDA0002096900170000153
) Compound 10 was obtained as an off-white solid, 2.5g, 43% yield.1H NMR(300MHz,CDCl3)δ8.89(s,1H),6.89(d,J＝9.6Hz,1H),6.86(dd,J1＝8.7Hz,J2＝2.7Hz,1H),6.47(d,J＝2.4Hz,1H),3.77(s,3H),1.78-1.74(m,2H),1.53-1.49(m,2H)ppm；ESI-MS m/z:190[M+1]+。
2. Synthesis of 5 '-methoxy-6' -nitro-1 ',2' -dihydrospiro [ cyclopropane-1, 3 '-indolin ] -2' -one (11)
Figure BDA0002096900170000161
To a mixed solution of 10(2.5g, 13.21mmol) of ethyl acetate (2.0g, 19.59mmol) and dichloromethane was added nitric acid (1.5g, 23.80 mmol). After the mixed solution was stirred at room temperature for 2 hours, a saturated sodium bicarbonate solution was added to quench the reaction, followed by suction filtration and drying under reduced pressure to obtain yellow solid compound 11, 1.7g, in 55% yield.1H NMR(300MHz,DMSO-d6)δ10.68(s,1H),7.37(s,1H),7.13(s,1H),3.87(s,3H),1.79-1.71(m,2H),1.61-1.58(m,2H)ppm；ESI-MS m/z:235[M+1]+。
3. Synthesis of 6 '-amino-5' -methoxy-1 ',2' -dihydrospiro [ cyclopropane-1, 3 '-indolin ] -2' -one (12)
Figure BDA0002096900170000162
5mmol) was dissolved in methanol and water (10mL) to degas, and the solution was stirred for reaction for 6 hours. The reaction mixture was diluted with water (20mL) and extracted with ethyl acetate (3X 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum with suction filtration to give compound 12 as a yellow solid, 1.1g, 74% yield. H1NMR(400MHz,DMSO-d6)δ10.07(s,1H),6.50(s,1H),6.34(s,1H),4.68(s,2H),3.69(s,3H),1.38-1.35(m,2H),1.32-1.30(m,2H)ppm；ESI-MS m/z:205[M+1]+。
4. Synthesis of 5' -methoxy-1 ',2' -dihydrospiro [ cyclopropane-1, 3' -indoline ] -6' -amine (13)
Figure BDA0002096900170000163
To a solution of compound 12(500mg, 2.45mmol) in anhydrous tetrahydrofuran (10mL) was added lithium aluminum hydride (375mg, 9.87mmol) at room temperature. The resulting solution was stirred at 70 ℃ for 4 hours. The reaction was then quenched by addition of water (20mL) and thenExtraction with ethyl acetate (3X 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered with suction, and concentrated in vacuo. Gradient flash chromatographic column (ethyl acetate/petroleum ether)
Figure BDA0002096900170000164
) Compound 13 was obtained as a brown solid, 260mg, 56% yield.1H NMR(300MHz,DMSO-d6)δ6.14(s,1H),5.94(s,1H),4.92(s,1H),4.04(s,2H),3.61(s,3H),3.31(s,2H),0.80-0.72(m,4H)ppm；ESI-MSm/z:191[M+1]+。
5. Synthesis of 5-bromo-2-N- {5' -methoxy-1 ',2' -dihydrospiro [ cyclopropane-1, 3' -indol ] -6' -yl } -4-N- [4- (pyridin-2-methoxy) phenyl ] pyrimidine-2, 4-diamine (14a)
Figure BDA0002096900170000171
To compound 13(450mg, 2.37mmol) and 5-bromo-2-chloro-N- [4- (pyridin-2-methoxy) phenyl]To a solution of pyrimidine-2, 4-diamine (647mg, 1.65mmol) in dioxane (to 10mL) was added 4-methylbenzene-1-sulfonic acid monohydrate (408mg, 2.37 mmol). The mixed solution was stirred at 100 ℃ to complete the reaction. The reaction mixture was then diluted with water (20mL) and extracted with ethyl acetate (3X 30 mL). The combined organic layers were dried over sodium sulfate, filtered off with suction and concentrated in vacuo. Over gradient flash chromatography column method (ethyl acetate/petroleum ether)
Figure BDA0002096900170000173
) This gave 14a as an off-white solid, 260mg, 20% yield.1H NMR(300MHz,DMSO-d6)δ8.59(d,J＝4.5Hz,1H),8.51(s,1H),8.17(s,1H),7.87(dd,J1＝7.5Hz,1.8Hz,1H),7.56-7.47(m,3H),7.37-7.33(m,2H),7.07(d,J＝8.7Hz,1H),6.26(s,1H),5.18(s,2H),4.18-4.01(br,1H),3.93(s,2H),3.67(s,3H),0.94(d,J＝3.0Hz,4H)ppm；ESI-MSm/z:545[M+1]+。
6. Synthesis of 2- ({5' -methoxy-1 ',2' -dihydrospiro [ cyclopropane-1, 3' -indol ] -6' -yl } amino) -4- { [4 (pyridine-2-methoxy) phenyl ] amino } pyrimidine-5-carbonitrile (15a)
Figure BDA0002096900170000172
Compound 14a (200mg, 0.37mmol), zinc dinitrile (214mg, 1.82mmol), tris (dibenzylideneacetone) dipalladium (39mg, 0.04mmol) and 1,1' -bis (di-phenylphosphino) ferrocene (41mg, 0.07mmol)) were dissolved in N, N-dimethylformamide and water to be degassed, and the reaction was stirred in a microwave reactor for 3 hours. The reaction mixture was diluted with water (25mL) and extracted with ethyl acetate (3X 15 mL). The combined organic layers were dried over sodium sulfate, filtered off with suction and concentrated in vacuo. Gradient flash column chromatography (ethyl acetate/petroleum ether)
Figure BDA0002096900170000174
) Compound 15a was obtained as a brown solid, 110mg, 50% yield.1H NMR(300MHz,DMSO-d6)δ9.35(br,1H),8.59(d,J＝4.5Hz,1H),8.46(s,1H),7.87(dd,J1＝7.8,1.5Hz,1H),7.55(br,2H),7.37-7.33(m,2H),7.16-7.01(m,3H),6.29(s,1H),5.18(s,2H),4.65(s,1H),4.04-3.97(m,2H),3.75(br,1H),3.69(s,3H),1.00-0.95(m,4H)ppm；ESI-MS m/z:492[M+1]+。
7. Synthesis of (2E) -4- {6'- (5-cyano-4- { [4- (pyridin-2-methoxy) phenyl ] amino } pyrimidin-2-yl) amino ] -5' -methoxyspiro [ cyclopropane-1, 3 '-indol ] -1' -yl } -1- (dimethylamino) -4-oxobut-2-en-2-yl (B1)
Figure BDA0002096900170000181
To a solution of compound 15a (40mg, 0.08mmol) and N, N-diisopropylethylamine (31.53mg, 0.24mmol) in dry tetrahydrofuran was added a solution of (2E) -4-bromobut-2-enoyl chloride in dry tetrahydrofuran (0.5 mL). c reaction was stirred for 1 hour and then dimethylamine in tetrahydrofuran (2mL, 2M) was added. The reaction was stirred at room temperature for 18 hours, and the reaction mixture was diluted with saturated sodium bicarbonate solution (30mL) and extracted with ethyl acetate (50 mL. times.3). The combined organic phases were washed with saturated sodium chloride solution (50 mL. times.3) and dried over anhydrous magnesium sulfateDrying, suction filtering, and vacuum concentrating the filtrate. Preparative liquid phase purification [ column: xbridge RP18,5 μm, 19X 150 mm; mobile phase: water (0.05% ammonium bicarbonate) and acetonitrile (35% acetonitrile, up to 65% in 12 minutes); detector, UV220 and 254nm]Compound B1 was obtained as an off-white solid, 1.3mg, 3% yield.1H NMR(300MHz,DMSO-d6)δ8.97(s,1H),8.81(s,1H),8.56(d,J＝4.2Hz,1H),8.48-8.44(m,2H),7.81(dd,J1＝7.8Hz,J2＝1.8Hz),7.53-7.42(m,3H),7.33-7.31(m,1H),6.98(d,J＝8.7Hz,2H),6.70-6.65(m,1H),6.51(s,1H),6.32(dd,J1＝17.1Hz,J＝2.1Hz,1H),5.14(s,2H),4.09(s,2H),3.75(s,3H),2.16(s,6H),1.09(s,4H)ppm；ESI-MS m/z:603[M+1]+。
EXAMPLE 6 Synthesis of (2E) -4- {6'- [ (4- { [ 3-chloro-4- (pyridin-2-methoxy) phenyl ] amino } -5-cyanopyrimidin-2-yl) amino ] -5' -methoxyspiro [ cyclopropane-1, 3 '-indol ] -1' -yl } -1- (dimethylamino) -4-oxobut-2-en-2-yl (B2)
1. Synthesis of 5-bromo-4-N- [ 3-chloro-4- (pyridine-2-methoxy) phenyl ] -2-N- {5' -methoxy-1 ',2' -dihydrospiro [ cyclopropane-1, 3' -indol ] -6' -yl } pyrimidine-2, 4-diamine (14b)
Figure BDA0002096900170000191
Reference example 5 synthesis of compound 13, compound 14b synthesis of compound 14a synthesis of compound 11.5mg, 8% yield.1H NMR(400MHz,DMSO-d6)δ8.65-8.60(m,2H),8.23(s,1H),7.91-7.87(m,2H),7.61-7.54(m,2H),7.39-7.36(m,1H),7.26-7.24(m,1H),6.30(s,1H),5.28(s,2H),4.20(br,1H),3.99(s,2H),3.69(s,3H),0.95(d,J＝3.0Hz,4H)ppm；ESI-MSm/z:579[M+1]+。
2. Synthesis of 4- [ [ 3-chloro-4- (pyridin-2-methoxy) phenyl ] amino ] -2- ([5' -methoxy-1 ',2' -dihydrospiro [ cyclopropane-1, 3' -indol ] -6' -yl ] amino) pyrimidine-5-carbonitrile (15b)
Figure BDA0002096900170000192
Referring to example 5, synthesis of compound 14b, compound 15b was performed according to the method for synthesizing compound 15a, 5.3mg, 12% yield.1H NMR(300MHz,DMSO-d6)δ8.60-8.50(m,2H),7.96-7.36(m,6H),7.24-7.10(m,1H),6.33(s,1H),5.27(s,2H),4.17-4.07(m,2H),3.71(br,3H),3.69(s,3H),1.04-0.98(m,4H)ppm；ESI-MS m/z:526[M+1]+。
3. Synthesis of (2E) -4- {6'- [ (4- { [ 3-chloro-4- (pyridin-2-methoxy) phenyl ] amino } -5-cyanopyrimidin-2-yl) amino ] -5' -methoxyspiro [ cyclopropane-1, 3 '-indol ] -1' -yl } -1- (dimethylamino) -4-oxobut-2-en-2-yl (B2)
Figure BDA0002096900170000193
Referring to example 5, synthesis of compound 15B, compound B2 was performed according to the method for synthesizing compound B1, 1.2mg, 2% yield.1H NMR(300MHz,DMSO-d6)δ8.81(s,1H),8.58-8.56(m,2H),8.51(s,1H),7.87-7.52(m,5H),7.35-7.31(m,1H),7.16-7.13(m,1H),6.73-6.62(m,1H),6.51(s,1H),6.41-6.31(m,1H),5.22(s,2H),4.12(s,2H),3.76(s,3H),2.16(s,6H),1.08(s,4H)ppm；ESI-MS m/z:637[M+1]+。
EXAMPLE Synthesis of 74- { [4- (benzyloxy) -3-chlorophenyl ] amino } -2- ({1'- [ (2E) -4- (dimethylamino) but-2-enoyl ] -5' -methoxy-1 ',2' -dihydrospiro [ cyclopropane-1, 3 '-indol ] -6' -yl } amino) pyrimidine-5-carbonitrile (B3)
1. Synthesis of 4-N- [4- (benzyloxy) -3-chlorophenyl ] -5-bromo-2-N- {5' -methoxy-1 ',2' -dihydrospiro [ cyclopropane-1, 3' -indol ] -6' -yl } pyrimidine-2, 4-diamine (14c)
Figure BDA0002096900170000201
Referring to example 5, synthesis of compound 13, compound 14c was performed according to the method for synthesizing compound 14a, 14.6mg, yield 10%.1H NMR(400MHz,DMSO-d6)δ8.63(s,1H),8.22(s,1H),7.85(s,1H),7.54(d,J＝8.3Hz,1H),7.49(d,J＝7.5Hz,2H),7.42(t,J＝7.5Hz,2H),7.35(t,J＝7.2Hz,1H),7.25(d,J＝8.9Hz,1H),6.29(s,1H),5.20(s,2H),4.32(s,3H),3.97(s,2H),3.68(s,3H),0.95(d,J＝9.8Hz,4H)ppm；ESI-MS m/z:578，580[M+1]+。
2. Synthesis of 4- { [4- (benzyloxy) -3-chlorophenyl ] amino } -2- ({5' -methoxy-1 ',2' -dihydrospiro [ cyclopropane-1, 3' -indol ] -6' -yl } amino) pyrimidine-5-carbonitrile (15c)
Figure BDA0002096900170000202
Reference example 5 synthesis of compound 14c, compound 15c reference the synthesis of compound 15a, 4.2mg, 9% yield.1H NMR(300MHz,DMSO-d6)δ9.15(s,1H),8.46(s,1H),7.75(s,1H),7.49-7.22(s,8H),6.30(s,1H),5.20(s,2H),4.17-4.07(m,2H),4.04(s,2H),3.71(s,3H),0.97(s,4H)ppm；ESI-MS m/z:525[M+1]+。
3. Synthesis of 4- { [4- (benzyloxy) -3-chlorophenyl ] amino } -2- ({1'- [ (2E) -4- (dimethylamino) but-2-enoyl ] -5' -methoxy-1 ',2' -dihydrospiro [ cyclopropane-1, 3 '-indol ] -6' -yl } amino) pyrimidine-5-carbonitrile (B3)
Figure BDA0002096900170000211
Referring to example 5, synthesis of compound 15c, compound B3 was synthesized according to the method for synthesizing compound B1, 3.8mg, 6% yield.1H NMR(300MHz,DMSO-d6)δ8.80(s,1H),8.60(s,1H),8.51(s,1H),7.80(s,1H),7.53-7.37(m,7H),7.14-7.12(m,1H),6.71-6.61(m,1H),6.52(s,1H),6.35-6.27(m,1H),5.16(s,2H),4.11(s,2H),3.76(s,3H),2.15(s,6H),1.12-1.08(m,4H)ppm；ESI-MSm/z:636[M+1]+。
EXAMPLE Synthesis of 83- {6'- [ (5-cyano-4- { [4- (pyridin-2-ylmethoxy) phenyl ] amino } pyrimidin-2-yl) amino ] -5' -methoxyspiro [ cyclopropane-1, 3 '-indol ] -1' -yl } -3-oxoprop-1-en-2-yl (B4)
1. Synthesis of 5-bromo-2-N- {5' -methoxy-1 ',2' -dihydrospiro [ cyclopropane-1, 3' -indol ] -6' -yl } -4-N- [1- (pyridin-2-methyl) -1H-pyrazol-4-yl ] pyrimidine-2, 4-diamine (14d)
Figure BDA0002096900170000212
Reference example 5 synthesis of compound 13, compound 14c synthesis of compound 14a synthesis of compound 260mg, 32% yield.1H NMR(300MHz,DMSO-d6)δ8.80(s,1H),8.54(d,J＝4.8Hz,1H),8.14(s,1H),8.09(s,1H),7.79-7.73(m,2H),7.62(s,1H),7.34-7.29(m,1H),7.07(d,J＝7.8Hz,1H),6.28(s,1H),5.41(s,2H),4.46(br,2H),4.00(s,2H),3.68(s,3H),0.94-0.93(m,4H)ppm；ESI-MS m/z:519[M+1]+。
2. Synthesis of 2- ({5' -methoxy-1 ',2' -dihydrospiro [ cyclopropane-1, 3' -indol ] -6' -yl } amino) -4- { [1- (pyridin-2-methyl) -1H-pyrazol-4-yl ] amino } pyrimidine-5-carbonitrile (15d)
Figure BDA0002096900170000221
Reference example 5 synthesis of compound 14d, compound 15d reference the synthesis of compound 15a, 110mg, 68% yield.1H NMR(300MHz,DMSO-d6)δ9.67(s,1H),8.54(d,J＝3.6Hz,1H),8.46(s,1H),8.09(s,1H),7.79-7.74(m,3H),7.34-7.30(m,1H),7.07-7.05(m,1H),6.32(s,1H),5.42(s,2H),4.66(br,2H),4.08(s,2H),3.71(s,3H),0.97(s,4H)ppm；ESI-MS m/z:466[M+1]+。
3. Synthesis of 3- {6'- [ (5-cyano-4- { [4- (pyridin-2-methoxy) phenyl ] amino } pyrimidin-2-yl) amino ] -5' -methoxyspiro [ cyclopropane-1, 3 '-indol ] -1' -yl } -3-oxoprop-1-en-2-yl (B4)
Figure BDA0002096900170000222
Reference example 5 Synthesis of Compound 15a, Synthesis of Compound B4 reference example B1 Synthesis, 21.9mg, yield 35%.1H NMR(300MHz,DMSO-d6)δ8.84(s,1H),8.78(s,1H),8.56(d,J＝4.2Hz,1H),8.48-8.44(m,2H),7.83(dd,J1＝7.8Hz,J2＝1.8Hz),7.77-7.46(m,3H),7.32-7.28(m,1H),6.98(d,J＝8.7Hz,1H),6.54-6.45(m,2H),6.19(dd,J1＝17.1Hz,J＝2.1Hz,1H),5.62(dd,J1＝10.5Hz,J＝2.1Hz,1H),5.14(s,2H),4.10(s,2H),3.75(s,3H),1.09(s,4H)ppm；ESI-MS m/z:546[M+1]+。
EXAMPLE Synthesis of 93- {6'- [ (4- { [ 3-chloro-4- (pyridin-2-methoxy) phenyl ] amino } -5-cyanopyrimidin-2-yl) amino ] -5' -methoxyspiro [ cyclopropane-1, 3 '-indol ] -1' -yl } -3-oxoprop-1-en-2-yl (B5)
Figure BDA0002096900170000231
Referring to example 5, synthesis of compound 15e, compound B5 reference the synthesis of compound B1, 1.6mg, 1% yield.1H NMR(300MHz,DMSO-d6)δ8.91(s,1H),8.56(d,J＝4.2Hz,2H),8.51(s,1H),7.85-7.82(m,2H),7.56-7.51(m,2H),7.34-7.28(m,1H),7.16-7.12(m,1H),6.56-6.51(m,2H),6.19(d,J＝10.5Hz,1H),5.62(d,J＝10.5Hz,1H),5.22(s,2H),4.12(s,2H),3.77(s,3H),1.10(d,J＝6.0Hz,4H)ppm；ESI-MS m/z:580[M+1]+。
EXAMPLE 10 Synthesis of (2E) -4- {6'- [ (5-cyano-4- { [1- (pyridin-2-ylmethyl) pyrazol-4-yl ] amino } pyrimidin-2-yl) amino ] -5' -methoxyspiro [ cyclopropane-1, 3 '-indol ] -1' -yl } -1- (dimethylamino) -4-oxobut-2-en-2-yl trifluoroacetate (B6)
Figure BDA0002096900170000232
Referring to example 5, synthesis of compound 15f, compound B6 was synthesized according to the method for synthesizing compound B1, 3.8mg, 6% yield.
Compound B6 was salified with trifluoroacetic acid, the structure after salification is shown below:
Figure BDA0002096900170000233
1H NMR(300MHz,DMSO-d6)δ9.35(s,1H),9.14(s,1H),8.70(s,1H),8.52(d,J＝8.4Hz,1H),8.44(s,1H),8.03(s,1H),7.78-7.72(m,2H),7.32-7.28(m,1H),7.12-7.09(m,1H),6.76-6.55(m,3H),5.37(s,2H),4.16(s,2H),3.90(d,J＝2.8Hz,2H),3.78(s,3H),2.82(s,6H),1.13(t,J＝6.7Hz,4H)ppm；ESI-MS m/z:577[M+1]+。
EXAMPLE Synthesis of 113- {6'- [ (5-cyano-4- { [1- (pyridin-2-ylmethyl) pyrazol-4-yl ] amino } pyrimidin-2-yl) amino ] -5' -methoxyspiro [ cyclopropane-1, 3 '-indol ] -1' -yl } -3-oxoprop-1-en-2-yl (B7)
Figure BDA0002096900170000241
Referring to example 5, synthesis of compound B7 after synthesis of 15g, compound B1 synthesis, 12mg, 27% yield.1H NMR(300MHz,DMSO-d6)δ9.74(s,1H),9.32(s,1H),8.80(s,1H),8.55(d,J＝8.4Hz,2H),8.11(s,1H),7.80-7.77(m,2H),7.34-7.30(m,1H),7.06(d,J＝8.4Hz,1H),6.63-6.58(m,2H),6.24(d,J＝17.7Hz,1H),5.72(d,J＝8.4Hz,1H),5.42(s,2H),4.17(s,2H),3.78(s,3H),1.13(t,J＝8.7Hz,4H)；ESI-MSm/z:520[M+1]+。
Example 12: determination of EGFR-wt and HER2 kinase Activity by Compounds
1) Preparing 0.5 mu M solution of a compound to be detected;
2) the assay was performed by adding 20. mu.L of assay buffer, 5. mu.L of ATP solution, 5. mu.L of test compound (containing 10% DMSO), and 20. mu.L of enzyme/substrate mixture sequentially to 96-well FlashPlates, both protein kinase reaction mixtures containing 70mM HEPES-NaOH pH 7.5, 3mM MnCl23 μ M sodium orthovanadate, 1.2mM DTT, ATP. ERBB2 assay additionally contained 50. mu.g/mL PEG 20000;
3) incubate at room temperature for 60 minutes, then 50. mu.L of 2% (v/v) H3PO4The reaction was stopped and 200. mu.L of 0.9% (w/v) Na was addedWashing the plate twice with Cl;
4) the content of 33Pi ("cpm" count) was determined with a microplate scintillation counter. (the median cpm with complete reaction mixture without protein kinase was defined as the low control; the median cpm with complete reaction mixture and kinase without inhibitor was defined as the high control; the difference between the high and low controls was defined as 100% activity of the enzyme; the high control value minus the low control value for each kinase minus the corresponding "compound value" minus the low control value was used as the data evaluation part.)
Residual activity (%) < 100 × [ (cpm of compound-low control)/(high control-low control) ]
The results of the assay using Neratinib as a positive control drug are shown in table 1.
TABLE 10.5 residual Activity of Compounds on EGFR-wt and HER2 at drug concentrations of μ M
Figure BDA0002096900170000251
As can be seen from Table 1, the compounds provided in the examples exhibit a certain degree of inhibition of both EGFR-wt and HER2, with the inhibition of compounds A1 through A4 being more pronounced.
EXAMPLE 13 determination of the Activity of the Compounds on 7 mutant protein kinases
1) Preparation of 1X 10-5-3×10-10A solution of a test compound;
2) the assay was performed as 10. mu.L of nonradioactive ATP solution, 25. mu.L of assay buffer/[ gamma-33P ]]ATP mix, 5. mu.L of test compound (10% DMSO in), 10. mu.L of enzyme/substrate mix were added sequentially to 96-well FlashPlates. TM. and both protein kinase reaction mixtures contained 70mM HEPES-NaOH pH 7.5, 3mM MnCl23 μ M sodium orthovanadate, 1.2mM DTT, [ γ -33P ]]-ATP, protein kinase and substrate;
3) incubate at room temperature for 60 minutes, then 50. mu.L of 2% (v/v) H3PO4The reaction was stopped and the plate was washed twice with 200. mu.L of 0.9% (w/v) NaCl;
4) the content of 33Pi ("cpm" count) was determined with a microplate scintillation counter. (the median cpm with complete reaction mixture without protein kinase was defined as the low control; the median cpm with complete reaction mixture and kinase without inhibitor was defined as the high control; the difference between the high and low controls was defined as 100% activity of the enzyme; the high control value minus the low control value for each kinase, the corresponding "compound value" value minus the low control value was used as the data evaluation part.)
Residual activity (%) < 100 × [ (cpm of compound-low control)/(high control-low control) ]
The results of the tests, represented by compounds A1 and A2, are shown in Table 2.
TABLE 2 Biochemical IC of Compounds on EGFR wt, HER2 and 7 EGFR mutant protein kinases50Value of
Figure BDA0002096900170000252
Figure BDA0002096900170000261
Kinase assay tests show that most of the compounds designed and synthesized by the invention have stronger inhibitory effect on EGFR-wt and ERBB2 than Neratinib, especially the compounds A1 and A2 have better inhibitory effect on EGFR wt, HER2 and 7 EGFR mutant protein kinases than Neratinib, and can be used for preventing and treating clinical diseases related to EGFR wt, HER2 and 7 EGFR mutant protein kinases, such as melanoma, liver cancer, kidney cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine tumor, ovarian cancer, rectal cancer, anal region cancer, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophagus cancer, small intestine cancer, cancer of endocrine system, thyroid cancer, parathyroid cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, cervical cancer, Bladder cancer, renal or fallopian tube cancer, spinal axis tumor, pituitary adenoma, gastrointestinal stromal tumor, colorectal cancer, non-small cell carcinoma, small cell lung cancer, and the like.
It should be finally noted that the above examples are only intended to illustrate the technical solutions of the present invention, and not to limit the scope of the present invention, and that other variations and modifications based on the above description and thought may be made by those skilled in the art, and that all embodiments need not be exhaustive. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.

Claims (9)

1. An aminopyrimidine compound with a spiro structure is characterized in that the structure of the compound is shown as a formula I or a formula II:
Figure FDA0003014003480000011
wherein R is1is-COR5(ii) a The R is5Is C1-4Alkenyl or C2-4An alkenylalkylamino group;
R2is C1-6An alkoxy group;
R3is cyano;
R4is composed of
Figure FDA0003014003480000012
One kind of (1).
2. A pharmaceutically acceptable salt of an aminopyrimidine compound with a spiro structure, which is a salt obtained by reacting a compound with a structure shown in formula i or formula ii according to claim 1 with an acid.
3. A process for preparing aminopyrimidines having a spiro structure according to claim 1, wherein the compound of formula i is prepared as follows:
Figure FDA0003014003480000013
performing cyclization on a phenylhydrazine hydrochloride compound 1 and 4-formylpiperidine-1-benzyl formate to generate a compound 2; then carrying out acylation reaction with trifluoroacetic anhydride under the atmosphere of inert gas to obtain an acylation product compound 3; carrying out nitration reaction on the compound 3, copper nitrate and acetic anhydride to obtain a compound 4; then reducing the nitro group in the compound 4 into amino group to obtain a compound 5; performing alkylation reaction on the compound 5 and methyl iodide to obtain a spiro-segmented compound 6; reacting with 2, 4-dichloropyrimidine derivative at 75 deg.C to obtain intermediate compound 7, reacting under weak alkaline condition to obtain hydrolysis product compound 8, reacting with compound 8 containing R1Reacting the compound of the substituent group to obtain the compound shown in the formula I;
the preparation of the compound of formula II is shown below:
Figure FDA0003014003480000021
2, 3-dihydro-1H-indol-2-one compound 2-1 reacts with diisopropylamine and n-butyllithium to obtain 1',2' -dihydrospiro [ cyclopropane-1, 3-indole]-2' -keto compound 2-2; then carrying out nitration reaction with nitric acid to obtain a nitration product compound 2-3; then nitro is reduced to obtain an amino product compound 2-4; then reducing to generate a spiro fragment compound 2-5; stirring the compound 2-5 and halogenated pyrimidine derivatives at 100 ℃ to react to obtain an intermediate compound 2-6; then reacting with zinc dinitrile to obtain product and finally reacting with the product containing R1And (3) reacting the substituent compound to obtain the compound shown in the formula II.
4. Use of an aminopyrimidine compound having a spiro structure or a pharmaceutically acceptable salt thereof according to claim 1 or 2 for the preparation of inhibitors of tyrosine kinases and/or mutants thereof, wherein the tyrosine kinase is EGFR kinase.
5. The use of claim 4, wherein the mutant is one or more of EGF-R d747-749/A750P, EGF-RL858R, EGF-R L861Q or EGF-R T790M/L858R.
6. Use of an aminopyrimidine compound having a spiro structure or a pharmaceutically acceptable salt thereof according to claim 1 or 2 for the manufacture of an anticancer drug.
7. The use of claim 6, wherein the anticancer agent is one or more of melanoma, liver cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, carcinoma of fallopian tubes, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, parathyroid cancer, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, cancer of the bladder, cancer of the kidney or fallopian tubes, spinal axis tumor, pituitary adenoma, gastrointestinal stromal tumor, non-small cell carcinoma, small cell lung cancer, mastocytosis, glioma, sarcoma or lymphoma caused by abnormal expression of tyrosine kinase and/or its mutant.
8. The use according to claim 7, wherein the anti-cancer drug is melanoma caused by abnormal expression of tyrosine kinase and/or its mutant and is melanoma on skin or eyes.
9. A pharmaceutical composition comprising one or both of the aminopyrimidine compounds having a spiro structure according to claim 1 and pharmaceutically acceptable salts thereof.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101687822A (en) * 2007-07-06 2010-03-31 安斯泰来制药株式会社 Di(arylamino)aryl compound
CN104974140A (en) * 2014-04-14 2015-10-14 上海海雁医药科技有限公司 2,3,4,6-tetrasubstituted benzene-1,5-diamine derivatives, preparation method thereof and medicinal application thereof
CN106536503A (en) * 2014-04-18 2017-03-22 山东轩竹医药科技有限公司 Tyrosine kinase inhibitor and uses thereof
CN107074870A (en) * 2014-09-12 2017-08-18 勃林格殷格翰国际有限公司 The spiro-compound inhibitor of cathepsin C
CN107438593A (en) * 2015-01-30 2017-12-05 基因泰克公司 Therapeutic compounds and application thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101687822A (en) * 2007-07-06 2010-03-31 安斯泰来制药株式会社 Di(arylamino)aryl compound
CN104974140A (en) * 2014-04-14 2015-10-14 上海海雁医药科技有限公司 2,3,4,6-tetrasubstituted benzene-1,5-diamine derivatives, preparation method thereof and medicinal application thereof
CN106536503A (en) * 2014-04-18 2017-03-22 山东轩竹医药科技有限公司 Tyrosine kinase inhibitor and uses thereof
CN107074870A (en) * 2014-09-12 2017-08-18 勃林格殷格翰国际有限公司 The spiro-compound inhibitor of cathepsin C
CN107438593A (en) * 2015-01-30 2017-12-05 基因泰克公司 Therapeutic compounds and application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Discovery of aminopyridine-containing spiro";Lianbao Ye et al.;《Journal of Enzyme Inhibition and Medicinal Chemistry》;20190709;第34卷;第1233-1246页 *

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