CN107216319B - 2, 4-diaminopyrimidine derivative, preparation method and application thereof - Google Patents

2, 4-diaminopyrimidine derivative, preparation method and application thereof Download PDF

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CN107216319B
CN107216319B CN201610160658.8A CN201610160658A CN107216319B CN 107216319 B CN107216319 B CN 107216319B CN 201610160658 A CN201610160658 A CN 201610160658A CN 107216319 B CN107216319 B CN 107216319B
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张翱
耿美玉
宋子兰
艾青
刘志清
陈奕
彭霞
丁健
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Shanghai Institute of Materia Medica of CAS
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention discloses a 2, 4-diaminopyrimidine derivative, and a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. Also discloses a preparation method and application thereof. The 2, 4-diaminopyrimidine derivative, and pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof can be used as a tyrosine kinase inhibitor.

Description

2, 4-diaminopyrimidine derivative, preparation method and application thereof
Technical Field
The invention relates to a compound with selective inhibition activity of tyrosine kinase ALK, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compounds in preparing medicaments for preventing or treating diseases related to abnormal cell proliferation, morphological change, hyperkinesia and the like in organisms and related to gradual change lymphoma enzyme, and diseases related to angiogenesis or cancer metastasis, in particular to medicaments for treating or preventing tumor growth and metastasis.
Background
Progressive lymphoma enzyme (ALK) is a receptor tyrosine kinase, belonging to the insulin receptor superfamily. ALK was first found in progressively larger cell lymphoma (ALCL) in about 60% -85% of ALCL, whereas normal ALK was exclusively expressed in the nervous system, especially in the neonatal brain. The ALK gene expression level in a human body is reduced along with the developmental maturity of the brain, the amount in the mature brain tissue is very low, and the expression has certain regionality; ALK expression is not found in other systems, particularly the hematopoietic system. The ALK gene is poorly expressed in most nonhematopoietic tumors and normal tissues, indicating that the distribution range of the ALK protein is extremely narrow.
The ALK gene is located at the 2p23 site of chromosome, and can be transcribed to generate mRNA with the size of 6222bp, which is composed of 29 exons and encodes 1620 type I transmembrane protein ALKs with the amino acid sequence of 200 KDa. The ALK gene is usually dormant, and the cell is deteriorated and develops into a malignant tumor due to fusion with other genes. However, there are many genes capable of fusing with the protein, and the gene is mainly fused with EML4 gene (echinoderm microtubule-associated protein-like 4) in non-small cell lung cancer (NSCLC), and the incidence rate of the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene in NSCLC is 3% -7%.
With the ongoing and intensive molecular biology research on non-small cell lung cancer (NSCLC), individualized therapies based on molecular markers have gone from the laboratory to the clinic and have made significant clinical progress in the treatment of advanced NSCLC patients. Also importantly, in addition to the traditional histopathological classification, NSCLC can also perform molecular phenotype classification according to the different expressions of various molecular markers, and research and develop new drugs by taking driving genes related to tumorigenesis and development as targets, perform targeted individualized molecular targeted therapy and improve the prognosis of patients. Ideally, all NSCLC patients should be tested for relevant molecular markers before treatment, and targeted treatment should be performed under the condition that the expression characteristics of tumor molecules of the patients are fully understood, so that the treatment effect is improved. In this context, tyrosine kinases have become popular molecular targets for recent years, and selective inhibitors thereof, or multi-targeted small molecule inhibitors surrounding ALK, have become hot spots for research of antitumor drugs.
Currently, the small molecule inhibitor Crizotinib (Crizotinib) developed by Pfizer corporation has been approved by the FDA in the united states for marketing on 8/26 of 2011. However, clinical studies have shown that resistance to Crizotinib occurs, and the factors causing Crizotinib resistance mainly include secondary mutation, activation of bypass signals and some unknown factors. Two second-generation inhibitors, namely, aletinib (aletinib) and Ceritinib (Ceritinib), aiming at ALK secondary mutation are marketed in 2014, the ALK secondary mutation is nearly 20, the ALK secondary mutation is different from EGFR secondary mutation mainly in T790M, and the nearly 20 mutations are slightly common except for the gate control site L1196M and have other similar basic probabilities. But Alectinib and Ceritinib, especially Ceritinib, are only active against a few mutations [ Curr Opin oncol.2015; 27(2):118-24]. Therefore, the development of the ALK inhibitor faces a new challenge, and a new derivative with better ALK inhibitory activity and metabolic property is obtained by modifying two strategies of directly introducing a flexible fragment into a piperidine N atom of Ceritinib and removing a piperidine ring and directly introducing a flexible water-soluble fragment into a polysubstituted benzene ring aiming at a solvent region of Ceritinib.
Figure BDA0000946094520000021
Disclosure of Invention
The invention aims to provide a compound taking 2, 4-diaminopyrimidine as a parent nucleus structure, and a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. The compound is a tyrosine kinase inhibitor, and ALK has a good inhibition effect.
The invention provides a 2, 4-diaminopyrimidine derivative, which has a structure shown in the following general formula (I):
Figure BDA0000946094520000031
wherein:
R1selected from hydrogen, C1-C3 alkyl, halogen;
t is selected from oxygen and piperidine ring;
R2，R3together form a 4-to 10-membered heterocycloalkyl group or a 3-to 6-membered cycloalkyl group; the heteroatom in the 4-10 membered heterocycloalkyl is selected from oxygen, nitrogen and sulfur atoms, the 4-10 membered heterocycloalkyl can be saturated or partially unsaturated heterocyclic group, and can also be monocyclic, bicyclic, bridged or spiro heterocyclic cycloalkyl;
R4selected from a hydroxyl group, a hydroxyC 1-C3 alkyl group, a C1-C3 alkyl group, a 4-to 10-membered heterocycloalkyl C1-C3 alkyl group containing one or more heteroatoms selected from oxygen, nitrogen and sulfur atoms, a 4-to 10-membered heterocycloalkyl C1-C3 alkyl group substituted with a halogen atom containing one or more heteroatoms selected from oxygen, nitrogen and sulfur atoms, an amino group, a 4-to 10-membered heterocycloalkyl substituted amino group containing one or more heteroatoms selected from oxygen, nitrogen and sulfur atoms, a 4-to 10-membered heterocycloalkyl substituted C1-C3 alkylamino group containing one or more heteroatoms selected from oxygen, nitrogen and sulfur atoms substituted with a hydroxyl group, a 4-to 10-membered heterocycloalkyl substituted C1-C3 alkylamino group containing one or more heteroatoms selected from oxygen, nitrogen and sulfur atoms substituted with a hydroxyl group and 1 to 3C 1-C3 alkyl groups, an amide group, amino-substituted C1-C3 alkylamido, hydroxy-substituted C1-C3 alkylamidoAnd a 4-to 10-membered heterocycloalkyl-substituted amide group containing one or more hetero atoms selected from oxygen, nitrogen and sulfur atoms.
Preferably, the first and second liquid crystal materials are,
R1selected from hydrogen, C1-C3 alkyl;
t is selected from oxygen and piperidine ring;
R2，R3together form a 4-6 membered heterocycloalkyl or 3-6 membered cycloalkyl, wherein the heteroatoms in the 4-6 membered heterocycloalkyl are selected from oxygen and nitrogen atoms, and the 4-6 membered heterocycloalkyl is a saturated heterocycloalkyl.
R4Selected from a hydroxyl group, a hydroxyC 1-C3 alkyl group, a C1-C3 alkyl group, a 4-to 6-membered heterocycloalkyl C1-C3 alkyl group containing one or more heteroatoms selected from oxygen, nitrogen and sulfur atoms, a 4-to 6-membered heterocycloalkyl C1-C3 alkyl group containing one or more heteroatoms selected from oxygen, nitrogen and sulfur atoms substituted with a halogen, an amino group, a 4-to 6-membered heterocycloalkyl substituted amino group containing one or more heteroatoms selected from oxygen, nitrogen and sulfur atoms substituted with a hydroxyl group, a 4-to 6-membered heterocycloalkyl substituted C1-C3 alkylamino group containing one or more heteroatoms selected from oxygen, nitrogen and sulfur atoms substituted with a hydroxyl group, a 4-to 6-membered heterocycloalkyl substituted C1-C3 alkylamino group containing one or more heteroatoms selected from oxygen, nitrogen and sulfur atoms substituted with a hydroxyl group and 1 to 3C 1-C3 alkyl groups, an amide group, an amino-substituted C1-C3 alkylamide group, a hydroxyl-substituted C1-C3 alkylamide group, a 4-to 6-membered heterocycloalkyl-substituted amide group containing one or more hetero atoms selected from oxygen, nitrogen and sulfur atoms.
It is further preferred that the first and second liquid crystal compositions,
R1selected from hydrogen, methyl;
t is selected from oxygen and piperidine ring;
R2，R3may together form a 4-azacyclohexyl, 3-azetidinyl, cyclopropyl, 3-oxetanyl or 4-oxacyclohexyl group.
R4Selected from hydroxyl, hydroxymethyl, methyl, 4-to 6-membered heterocycloalkyl C1-C3 alkyl containing one or more heteroatoms selected from oxygen and nitrogen atoms, halogen-substituted alkyl containing one or more heteroatoms selected from oxygen and nitrogen atoms4-6 membered heterocycloalkyl C1-C3 alkyl group containing one or more hetero atoms, amino group, 4-6 membered heterocycloalkyl substituted amino group containing one or more hetero atoms selected from oxygen and nitrogen atoms, 4-6 membered heterocycloalkyl substituted C1-C3 alkylamino group containing one or more hetero atoms selected from oxygen and nitrogen atoms substituted with hydroxyl group, 4-6 membered heterocycloalkyl substituted C1-C3 alkylamino group containing one or more hetero atoms selected from oxygen and nitrogen atoms substituted with hydroxyl group and 1 to 3 methyl groups, amide group, amino substituted C1-C3 alkylamide group, hydroxyl substituted C1-C3 alkylamide group, 4-6 membered heterocycloalkyl substituted amide group containing one or more hetero atoms selected from oxygen, nitrogen and sulfur atoms.
The pharmaceutically acceptable salts of the compounds represented by the general formula (I) include, but are not limited to, inorganic acid salts, organic acid salts, alkylsulfonic acid salts and arylsulfonic acid salts; the inorganic acid salt comprises hydrochloride, hydrobromide, nitrate, sulfate, phosphate and the like; the organic acid salt comprises formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate and the like; the alkyl sulfonate includes methyl sulfonate, ethyl sulfonate and the like; the aryl sulfonate includes benzene sulfonate, p-toluene sulfonate and the like.
The pharmaceutically acceptable solvates of the compounds represented by the general formula (I) include, but are not limited to, solvates of the compounds represented by the general formula (I) with water, ethanol, isopropanol, diethyl ether, acetone or the like.
The compound represented by the general formula (I) of the present invention is more preferably a specific compound as follows:
Figure BDA0000946094520000051
Figure BDA0000946094520000061
the invention also provides a method for preparing the compound represented by the general formula (I), wherein the following three preparation methods are adopted:
the preparation method comprises the following steps:
Figure BDA0000946094520000062
according to a preparation reference method of the compound i (J.Med.chem.2013,56,5675-5690), methane sulfonate iia and the compound i are subjected to substitution reaction under the action of organic base Diisopropylethylamine (DIPEA) to obtain a compound iii; or the compound i and the spiro compound iib are subjected to ring-opening reaction under the action of organic base Diisopropylethylamine (DIPEA) to obtain a compound iii; wherein R is2，R3Together form a 4-to 10-membered heterocycloalkyl group or a 3-to 6-membered cycloalkyl group; the hetero atom in the 4-to 10-membered heterocycloalkyl group is selected from oxygen, nitrogen and sulfur atoms, and the 4-to 10-membered heterocycloalkyl group may be a saturated or partially unsaturated heterocyclic group; r4The definitions are the same as previously described.
The second preparation method comprises the following steps:
Figure BDA0000946094520000071
(1) carrying out substitution reaction on the compound iv and the compound v under the action of potassium tert-butoxide to obtain a compound vi;
(2) carrying out palladium-carbon catalytic hydrogenation on the compound vi at room temperature to obtain a compound vii;
(3) preparation of compound ix reference method (J.Med.chem.2013,56,5675-5690), compound vii and compound viii are subjected to substitution reaction under the action of organic acid camphorsulfonic acid to obtain compound ix;
(4) different R can be obtained by the reduction ammoniation reaction, substitution reaction or acylation reaction of the compound ix4A substituted compound x.
The preparation method comprises the following steps:
Figure BDA0000946094520000072
(1) carrying out substitution reaction on the compound iv-b and the compound v-b under the action of inorganic base to obtain a compound vi-b;
(2) carrying out substitution reaction on the compound vi-b and the compound v under the action of inorganic base to obtain vii-b;
(3) carrying out palladium-carbon catalytic hydrogenation on the compound vii-b, and reacting at room temperature to obtain a compound viii-b;
(4) and heating the compound viii-b and the compound viii under the action of organic acid or performing Pd catalyzed coupling reaction to obtain a compound ix-b.
The inorganic base in the step (1) is preferably potassium carbonate;
the inorganic base of step (2) is preferably cesium carbonate;
the organic acid in the step (4) is preferably camphorsulfonic acid;
the reaction temperature of the heating reaction in the step (4) is preferably 135 ℃, and the reaction temperature of the coupling reaction is preferably 100 ℃.
The compounds prepared by the invention are used for preventing or treating diseases related to abnormal cell proliferation, morphological change, hyperkinesia and the like in organisms and related to the gradual change of lymphoma enzyme, and diseases related to angiogenesis or cancer metastasis, and are particularly used for treating or preventing tumor growth and metastasis.
The invention provides the use of said compounds as tyrosine kinase inhibitors.
The invention also provides application of the compound in preparing a medicament for preventing and/or treating diseases related to abnormal cell proliferation, morphological change, hyperkinesia and the like related to in vivo and gradual change lymphoma enzyme and diseases related to angiogenesis or cancer metastasis.
Detailed Description
The invention will be further illustrated with reference to specific examples. These examples are for illustrative purposes only and do not limit the scope and spirit of the present invention.
1H-NMR is measured by a Varian MercuryAMX300 type instrument, all solvents are redistilled before use, and the used anhydrous solvents are obtained by drying according to a standard method; all reactions were carried out under nitrogen atmosphere, unless otherwise indicatedPerforming TLC tracking, and washing with saturated sodium chloride aqueous solution and drying with anhydrous sodium sulfate during post-treatment; purification of the product except for the indication silica gel (200 and 300 mesh) column chromatography was used; wherein the silica gel (200-300 mesh) is produced by Qingdao ocean factory, and the GF-254 thin layer silica gel plate is produced by Yangttai Jiangyou silica gel development company Limited.
Preparation example 1 preparation of compound S1
Figure BDA0000946094520000081
Reference method for the preparation of compound 1-1 (J.Med.chem.2013,56, 5675-5690).
Synthesis of compound S1:
compound 1-1 and (3- (bromomethyl) oxetanon-3-yl) methanol (2eq) were dissolved in acetonitrile, and Diisopropylethylamine (DIPEA) (3eq) was added and heated to 90 ℃ under reflux overnight. Cooling the reaction solution after the reaction is completed, slowly pouring the reaction solution into ice water, extracting the reaction solution for three times by using ethyl acetate, washing an organic phase by using saturated salt water, drying the organic phase by using anhydrous sodium sulfate, mixing the sample, loading the mixture on a column, and performing reaction on the mixture by using CH2Cl2MeOH (volume ratio) 20:1, compound S1 was obtained.1H NMR(300MHz,DMSO)δ9.41(s,1H),8.42(d,J＝8.3Hz,1H),8.20(s,1H),8.04(s,1H),7.81(dd,J＝8.0,1.6Hz,1H),7.64–7.55(m,1H),7.52(s,1H),7.42–7.27(m,1H),6.83(s,1H),4.64–4.48(m,1H),4.39–4.14(m,4H),3.48(d,J＝8.1Hz,2H),3.46–3.30(m,1H),2.72(m,1H),2.52–2.43(m,4H),2.31(s,3H),2.28(s,2H),1.85–1.60(m,4H),1.22(d,J＝6.0Hz,6H),1.16(d,J＝6.8Hz,6H).
Preparation example 2 preparation of compound S2
Figure BDA0000946094520000091
Synthesis of compound S2:
compound 1-1 and 3- (bromomethyl) -3-methyloxetanone (2eq) were dissolved in acetonitrile, DIPEA (3eq) was added, and the mixture was heated to 90 ℃ and refluxed overnight. After the reaction is completed, the reaction solution is cooled, slowly poured into ice water, and usedExtracting with ethyl acetate for three times, washing the organic phase with saturated salt water, drying with anhydrous sodium sulfate, mixing with sample, loading onto column, and purifying with CH2Cl2MeOH: 30:1 gave compound S2.1H NMR(300MHz,DMSO)δ9.44(s,1H),8.44(d,J＝8.3Hz,1H),8.22(s,1H),8.06(s,1H),7.82(dd,J＝8.0,1.6Hz,1H),7.65–7.56(m,1H),7.51(s,1H),7.40–7.26(m,1H),6.82(s,1H),4.66–4.49(m,1H),4.39–4.14(m,4H),3.48–3.32(m,1H),2.68(m,1H),2.51-2.42(m,4H),2.31(s,3H),2.26(s,3H),1.88–1.60(m,4H),1.22(d,J＝6.0Hz,6H),1.16(d,J＝6.8Hz,6H).
Preparation example 3 preparation of compound S3
Figure BDA0000946094520000101
Reference is made to the literature procedures for the preparation of compound 3-1 (WO 2013024130).
Synthesis of compound S3:
compound 1-1 and intermediate 3-1 were dissolved in ethanol, DIPEA (3eq) was added, and the mixture was heated to 90 ℃ and refluxed overnight. Cooling the reaction solution after the reaction is completed, slowly pouring the reaction solution into ice water, extracting the reaction solution for three times by using ethyl acetate, washing an organic phase by using saturated salt water, drying the organic phase by using anhydrous sodium sulfate, mixing the sample, loading the mixture on a column, and performing reaction on the mixture by using CH2Cl2MeOH (volume ratio) 30:1, compound S3 was obtained.1H NMR(300MHz,DMSO)δ9.45(s,1H),8.46(d,J＝8.3Hz,1H),8.24(s,1H),8.04(s,1H),7.83(dd,J＝8.0,1.6Hz,1H),7.65–7.56(m,1H),7.52(s,1H),7.41–7.28(m,1H),6.83(s,1H),4.65–4.49(m,1H),4.13(s,1H),3.73–3.53(m,4H),3.51–3.37(m,1H),3.03(d,J＝11.0Hz,2H),2.56(s,1H),2.37–2.20(m,4H),2.11(s,3H),1.78–1.52(m,6H),1.37(d,J＝13.0Hz,2H),1.22(d,J＝6.0Hz,6H),1.16(d,J＝6.8Hz,6H).
Preparation example 4 preparation of compound S4
Figure BDA0000946094520000102
Synthesis of Compounds 4-3:
(1-Hydroxymethylcyclopropyl) -tert-butoxycarbonylamino was dissolved in tetrahydrofuran [ THF ] solution, potassium tert-butoxide (1.5eq) was added at low temperature, stirred for 30min, added with 4-fluoro-2-isopropoxy-1-nitrobenzene (1.3eq) and heated to 50 ℃ overnight. After the reaction is completed, the reaction solution is cooled, poured into water, extracted with ethyl acetate for three times, the organic phase is washed with saturated common salt, dried by anhydrous sodium sulfate and then loaded on a column, and the volume ratio of PE [ petroleum ether ]: EA [ ethyl acetate ] (volume ratio) is 5:1, so that the compound 4-3 is obtained.
Synthesis of Compounds 4-4:
dissolving the compound 4-3 in methanol, adding 20% palladium carbon, and catalytically hydrogenating for 6 h. After the reaction is completed, the palladium-carbon is removed by suction filtration, the filtrate is dried on a column by spinning, and a compound 4-4 is obtained by taking PE and EA (volume ratio) as 5:1 as developing agents. Reference is made to the literature methods for the preparation of compounds 4-5 (J.Med.chem.2013,56, 5675-5690).
Synthesis of compound S4:
dissolving compound 4-4 and compound 4-5(2eq) in n-butanol, adding 2eq camphorsulfonic acid [ D-CSA ]]And heating to 135 ℃ for reaction for 6 h. After the reaction is completed, cooling the reaction liquid to room temperature, decompressing and spinning out n-butyl alcohol, adding water for dilution, and using NaHCO for reaction3Adjusting pH to 7-8. Extracting with ethyl acetate for three times, washing the organic phase with saturated salt water, drying with anhydrous sodium sulfate, mixing with the sample, loading onto column, and purifying with CH2Cl220:1 to obtain the compound S4.1H NMR(300MHz,CDCl3)δ9.52(s,1H),8.57(d,J＝8.3Hz,1H),8.12(s,1H),8.05(d,J＝8.8Hz,1H),7.89(dd,J＝7.9,1.7Hz,1H),7.64–7.56(m,1H),7.34(s,1H),7.23(d,J＝8.4Hz,1H),6.55(d,J＝2.5Hz,1H),6.36(dd,J＝8.8,2.7Hz,1H),4.56(p,J＝6.0Hz,1H),3.80(s,2H),3.21(q,J＝6.9Hz,1H),1.36(d,J＝6.1Hz,6H),1.30(d,J＝6.8Hz,6H),0.78–0.71(m,2H),0.64(d,J＝4.7Hz,2H).
Preparation example 5 preparation of Compound S5
Figure BDA0000946094520000111
Synthesis of Compound 5-1:
5-fluoro-4-methyl-2-nitrophenol and cesium carbonate (1.5eq) are dissolved in N, N-dimethylformamide, 2-bromopropane (1.5eq) is added dropwise, the temperature is raised to 65 ℃, and the reaction is completed after 5 hours. The reaction solution is cooled to room temperature and poured into water, ethyl acetate is used for extraction for three times, the organic phase is washed by saturated common salt, dried by anhydrous sodium sulfate and then mixed with a sample to be loaded on a column, and PE: EA (volume ratio) is 10:1, so that the compound 5-1 is obtained.
Synthesis of Compound 5-2:
the compound 4-1 was dissolved in THF solution, potassium tert-butoxide (1.5eq) was added at low temperature, followed by stirring for 30min and then the compound 5-1 (1.3eq) was added and heated to 50 ℃ overnight. After the reaction is completed, the reaction solution is cooled, poured into water, extracted with ethyl acetate for three times, an organic phase is washed with saturated common salt, dried by anhydrous sodium sulfate and then loaded on a column, and the PE: EA (volume ratio) is 5:1, so that the compound 5-2 is obtained.
Synthesis of Compounds 5-3:
dissolving the compound 5-2 in methanol, adding 20% palladium carbon, and catalytically hydrogenating for 6 h. After the reaction is completed, the palladium-carbon is removed by suction filtration, the filtrate is dried on a column by spinning, and a compound 5-3 is obtained by taking PE and EA (volume ratio) as 5:1 as developing agents.
Synthesis of compound S5:
dissolving compound 5-3 and compound 4-5(2eq) in n-butanol, adding (2eq) camphorsulfonic acid [ D-CSA]And heating to 135 ℃ for reaction for 6 h. After the reaction is completed, cooling the reaction liquid to room temperature, decompressing and spinning out n-butyl alcohol, adding water for dilution, and using NaHCO for reaction3Adjusting pH to 7-8. Extracting with ethyl acetate for three times, washing the organic phase with saturated salt water, drying with anhydrous sodium sulfate, mixing with the sample, loading onto column, and purifying with CH2Cl2MeOH (volume ratio) 30:1, compound S5 was obtained.1H NMR(300MHz,CDCl3)δ9.51(s,1H),8.58(d,J＝8.4Hz,1H),8.13(s,1H),7.92(d,J＝6.8Hz,2H),7.65–7.56(m,1H),7.34(s,1H),7.24(d,J＝7.3Hz,1H),6.46(s,1H),4.50(p,J＝6.1Hz,1H),3.80(s,2H),3.26(p,J＝6.9Hz,1H),2.13(s,3H),1.91(s,2H),1.36(d,J＝6.1Hz,6H),1.32(d,J＝6.8Hz,6H),0.74(s,2H),0.66(s,2H).
Preparation example 6 preparation of Compound S6
Figure BDA0000946094520000121
Synthesis of compound S6:
compound S4 and 3-oxetanone (5eq) were dissolved in dry dichloromethane, stirred for 30min, then sodium cyanoborohydride (4eq) was added, and heated to 40 ℃ overnight. Pouring the reaction solution into water after the reaction is completed, extracting the reaction solution for 3 times by using dichloromethane, washing an organic phase by using saturated salt water, drying the organic phase by using anhydrous sodium sulfate, mixing the dried organic phase with a sample, loading the sample on a column, and performing reaction on the mixture by using CH2Cl2MeOH: 30:1 gave compound S6.1H NMR(300MHz,CDCl3)δ9.54(s,1H),8.59(d,J＝8.4Hz,1H),8.13(s,1H),8.07(d,J＝8.8Hz,1H),7.92(d,J＝7.9Hz,1H),7.65–7.58(m,1H),7.38(s,1H),7.26(d,J＝8.2Hz,1H),6.52(d,J＝2.6Hz,1H),6.33(dd,J＝8.9,2.6Hz,1H),4.82(t,J＝6.9Hz,2H),4.62–4.54(m,1H),4.44(t,J＝6.6Hz,2H),4.17(q,J＝7.0Hz,1H),3.66(s,2H),3.24(q,J＝6.8Hz,1H),1.39(d,J＝6.1Hz,6H),1.32(d,J＝6.8Hz,6H),0.77(q,J＝4.6,4.1Hz,2H),0.64(q,J＝4.4Hz,2H).
Preparation example 7 preparation of compound S7
Figure BDA0000946094520000131
Synthesis of Compound 7-2:
compound S5 and 1-Boc-3-azetidinone (5eq) were dissolved in dry dichloromethane, stirred for 30min, added sodium cyanoborohydride (4eq) and heated to 40 ℃ overnight. Pouring the reaction solution into water after the reaction is completed, extracting the reaction solution for 3 times by using dichloromethane, washing an organic phase by using saturated salt water, drying the organic phase by using anhydrous sodium sulfate, mixing the dried organic phase with a sample, loading the sample on a column, and performing reaction on the mixture by using CH2Cl2MeOH (volume ratio) 30:1, compound 7-2 was obtained.
Synthesis of compound S7:
compound 7-2 was dissolved in methylene chloride, and trifluoroacetic acid (10eq) was added thereto and the mixture was stirred at room temperature overnight. Pouring the reaction solution into water after the reaction is completed, extracting the reaction solution for three times by using dichloromethane, washing an organic phase by using saturated salt water, drying the organic phase by using anhydrous sodium sulfate, mixing the dried organic phase with a sample, loading the mixture on a column, and performing reaction on the mixture by using CH2Cl220:1 to obtain the compound S7.1H NMR(300MHz,CDCl3)δ9.51(s,1H),8.56(d,J＝8.4Hz,1H),8.12(s,1H),7.92(d,J＝7.8Hz,2H),7.66–7.61(m,1H),7.34(s,1H),7.30(d,J＝7.9Hz,1H),6.35(s,1H),4.52–4.44(m,1H),4.14(t,J＝10.2Hz,3H),3.80(d,J＝9.6Hz,2H),3.67(s,2H),3.30–3.22(m,1H),2.12(s,3H),1.37–1.30(m,12H),0.74(d,J＝5.8Hz,2H),0.64(d,J＝4.0Hz,2H).
Preparation example 8 preparation of Compound S8
Figure BDA0000946094520000132
Synthesis of compound S8:
compounds S5 and 6-1 were dissolved in dry dichloromethane, stirred for 30min, added sodium cyanoborohydride (4eq) and heated to 40 ℃ overnight. Pouring the reaction solution into water after the reaction is completed, extracting the reaction solution for 3 times by using dichloromethane, washing an organic phase by using saturated salt water, drying the organic phase by using anhydrous sodium sulfate, mixing the dried organic phase with a sample, loading the sample on a column, and performing reaction on the mixture by using CH2Cl2MeOH: 30:1 gave compound S8.1H NMR(300MHz,CDCl3)δ9.44(s,1H),8.50(d,J＝8.3Hz,1H),8.06(s,1H),7.86(d,J＝9.7Hz,2H),7.54(t,J＝7.8Hz,1H),7.28(s,1H),7.17(s,1H),6.30(s,1H),4.75(t,J＝6.9Hz,2H),4.39(dt,J＝13.3,6.4Hz,3H),4.17–4.09(m,1H),3.58(s,2H),3.23–3.15(m,1H),2.08(s,3H),1.27(dd,J＝10.2,6.5Hz,12H),0.74–0.65(m,2H),0.58(d,J＝4.2Hz,2H).
Preparation example 9 preparation of compound S9
Figure BDA0000946094520000141
Synthesis of compound S9:
compound S4 and 3-1(3eq) were dissolved in ethanol, DIPEA (5eq) was added dropwise, and the mixture was heated to 80 ℃ for reaction overnight. After the reaction is completed, the ethanol is spun out under reduced pressure, the sample is mixed and loaded on a column, and CH2Cl2MeOH (volume ratio) 30:1, compound S9 was obtained.1H NMR(300MHz,CDCl3)δ9.55(s,1H),8.60(dd,J＝8.6,1.2Hz,1H),8.14(s,1H),8.08(d,J＝8.9Hz,1H),7.92(dd,J＝8.0,1.6Hz,1H),7.62(ddd,J＝8.7,7.3,1.7Hz,1H),7.38(s,1H),7.27–7.23(m,1H),6.55(d,J＝2.7Hz,1H),6.40(dd,J＝8.9,2.7Hz,1H),4.58(p,J＝6.0Hz,1H),3.85(s,2H),3.77(dt,J＝8.4,2.7Hz,4H),3.29–3.20(m,1H),2.68(s,2H),1.60–1.51(m,2H),1.45(d,J＝2.3Hz,2H),1.39(d,J＝6.1Hz,6H),1.32(d,J＝6.9Hz,6H),0.80–0.73(m,2H),0.70–0.63(m,2H).
Preparation example 10 preparation of compound S10
Figure BDA0000946094520000151
Reference is made to the literature methods for the preparation of compound 10-1 (WO 2013024130).
Synthesis of Compound 10-2:
compound S5 and intermediate 10-1(3eq) were dissolved in ethanol, DIPEA (5eq) was added dropwise, and the mixture was heated to 80 ℃ for reaction overnight. After the reaction is completed, the ethanol is spun out under reduced pressure, the sample is mixed and loaded on a column, and CH2Cl2MeOH (volume ratio) 30:1, compound 10-2 was obtained.
Synthesis of compound S10:
compound 10-2 was dissolved in methylene chloride, and trifluoroacetic acid (10eq) was added thereto and the mixture was stirred at room temperature overnight. Pouring the reaction solution into water after the reaction is completed, extracting the reaction solution for three times by using dichloromethane, neutralizing an organic phase by using a saturated sodium bicarbonate solution, washing the organic phase by using saturated salt water, drying the organic phase by using anhydrous sodium sulfate, mixing the sample, loading the sample on a column, and performing reaction on the mixture by using CH2Cl220:1 to obtain the compound S10.1H NMR(300MHz,CDCl3)δ9.50(s,1H),9.36(s,1H),8.56(d,J＝8.3Hz,1H),8.13(s,1H),7.92(d,J＝10.0Hz,2H),7.62(t,J＝7.9Hz,1H),7.36(s,1H),7.28(s,1H),6.44(s,1H),4.51(p,J＝6.1Hz,1H),3.83(s,2H),3.39–3.21(m,5H),2.82(s,2H),2.08(s,3H),1.91(q,J＝10.2,5.8Hz,2H),1.68(d,J＝13.5Hz,2H),1.36(d,J＝6.1Hz,6H),1.31(d,J＝6.9Hz,6H),0.80(s,2H),0.69(s,2H).
Preparation of Compound S11 of preparation example 11
Figure BDA0000946094520000152
Reference is made to the literature methods for the preparation of compound 11-1 (WO 2013024130).
Synthesis of compound S11:
compound S5 and intermediate 11-1(3eq) were dissolved in ethanol, DIPEA (5eq) was added dropwise, and the mixture was heated to 80 ℃ for reaction overnight. After the reaction is completed, the ethanol is spun out under reduced pressure, the sample is mixed and loaded on a column, and CH2Cl2MeOH: 30:1, compound S11 was obtained.1H NMR(300MHz,CDCl3δ9.53(s,1H),8.59(d,J＝8.4Hz,1H),8.13(s,1H),7.93(d,J＝9.1Hz,2H),7.63–7.57(m,1H),7.36(s,1H),7.27–7.23(m,1H),6.45(s,1H),4.55–4.47(m,1H),3.92–3.81(m,4H),3.25(q,J＝6.9Hz,1H),2.66(s,2H),2.12(s,3H),1.46(d,J＝13.1Hz,2H),1.37(d,J＝6.0Hz,6H),1.32(d,J＝6.9Hz,6H),1.18(s,3H),1.16(s,3H),1.09(t,J＝12.2Hz,2H),0.75(d,J＝4.5Hz,2H),0.67(d,J＝4.6Hz,2H).
Preparation example 12 preparation of compound S12
Figure BDA0000946094520000161
Synthesis of compound S12:
compound S5 and intermediate 3-1(3eq) were dissolved in ethanol, DIPEA (5eq) was added dropwise, and the mixture was heated to 80 ℃ for reaction overnight. After the reaction is completed, the ethanol is spun out under reduced pressure, the sample is mixed and loaded on a column, and CH2Cl2MeOH (volume ratio) 30:1, compound S12 was obtained.1H NMR(300MHz,CDCl3)δ9.52(s,1H),8.58(d,J＝8.5Hz,1H),8.13(s,1H),7.99–7.86(m,2H),7.65–7.56(m,1H),7.35(s,1H),7.24(d,J＝8.3Hz,1H),6.46(s,1H),4.51(p,J＝6.2Hz,1H),3.84(s,2H),3.77(d,J＝8.1Hz,4H),3.31–3.23(m,1H),2.71(s,2H),2.11(s,3H),1.60–1.51(m,2H),1.44(d,J＝12.8Hz,2H),1.37(d,J＝6.1Hz,6H),1.32(d,J＝6.9Hz,6H),0.76(d,J＝3.8Hz,2H),0.66(d,J＝6.4Hz,2H).
Preparation example 13 preparation of compound S13
Figure BDA0000946094520000162
Synthesis of Compound 13-2:
compound S4, 1-N-Boc-3-azetidinecarboxylic acid (1.3eq) and O-benzotriazol-N, N, N ', N' -tetramethyluronium tetrafluoroborate [ TBTU ]](1.5eq) was dissolved in DMF and DIPEA (2eq) was added and stirred at room temperature overnight. After the reaction is completed, pouring the reaction solution into water after the reaction is completed, extracting with dichloromethane for three times, washing an organic phase with saturated salt water, drying with anhydrous sodium sulfate, mixing the sample, loading the sample on a column, and performing reaction on the mixture by using CH2Cl2MeOH (volume ratio) 20:1, compound 13-2 was obtained.
Synthesis of compound S13:
compound 13-2 was dissolved in methylene chloride, and trifluoroacetic acid (10eq) was added thereto and the mixture was stirred at room temperature overnight. Pouring the reaction solution into water after the reaction is completed, extracting the reaction solution for three times by using dichloromethane, washing an organic phase by using saturated salt water, drying the organic phase by using anhydrous sodium sulfate, mixing the dried organic phase with a sample, loading the mixture on a column, and performing reaction on the mixture by using CH2Cl2MeOH (volume ratio) 20:1, compound S13 was obtained.1H NMR(300MHz,CDCl3)δ9.45(s,1H),8.48(d,J＝8.4Hz,1H),8.02(s,1H),7.81(d,J＝8.0Hz,2H),7.74(s,1H),7.50(t,J＝8.3Hz,1H),7.15(d,J＝7.3Hz,1H),6.39(s,1H),4.43–4.37(m,1H),4.17(d,J＝17.0Hz,4H),3.91(s,2H),3.76(s,1H),3.64(d,J＝7.0Hz,1H),3.21–3.12(m,1H),1.97(s,3H),1.23(d,J＝1.9Hz,6H),1.21(d,J＝2.7Hz,6H),0.87(s,4H).
Preparation example 14 preparation of compound S14
Figure BDA0000946094520000171
Synthesis of Compound 14-1:
the compound S4, 13-1(1.3eq) and TBTU (1.5eq) were dissolved in DMF, DIPEA (2eq) was added, and the mixture was stirred at room temperature overnight. After the reaction is completed, pouring the reaction solution into water after the reaction is completed, extracting with dichloromethane for three times, washing an organic phase with saturated salt water, drying with anhydrous sodium sulfate, mixing the sample, loading the sample on a column, and performing reaction on the mixture by using CH2Cl2MeOH (volume ratio) 20:1, compound 14-1 was obtained.
Synthesis of compound S14:
compound 14-1 was dissolved in methylene chloride, and trifluoroacetic acid (10eq) was added thereto and the mixture was stirred at room temperature overnight. After the reaction is completed, the reaction is carried outPouring the solution into water, extracting with dichloromethane for three times, washing the organic phase with saturated salt water, drying with anhydrous sodium sulfate, mixing with sample, loading onto column, and collecting the filtrate with CH2Cl2MeOH (volume ratio) 20:1, compound S14 was obtained.1H NMR(300MHz,CDCl3)δ9.53(s,1H),8.56(d,J＝8.3Hz,1H),8.13(s,1H),8.05(d,J＝8.9Hz,1H),7.92(dd,J＝7.9,1.6Hz,1H),7.63(ddd,J＝8.7,7.4,1.7Hz,1H),7.36(s,1H),7.30(s,1H),6.53(dd,J＝12.5,2.6Hz,2H),6.37(dd,J＝8.9,2.7Hz,1H),4.55(td,J＝6.1,2.8Hz,1H),4.02(s,2H),3.76(dt,J＝26.7,7.7Hz,4H),3.33–3.20(m,2H),2.41(s,1H),1.37(d,J＝6.1Hz,6H),1.31(d,J＝6.9Hz,6H),1.00–0.91(m,4H).
Preparation example 15 preparation of compound S15
Figure BDA0000946094520000181
Synthesis of Compound 15-2:
compound S5, BOC-L-proline (1.3eq) and TBTU (1.5eq) were dissolved in DMF, DIPEA (2eq) was added, and stirring was carried out overnight at room temperature. After the reaction is completed, pouring the reaction solution into water after the reaction is completed, extracting with dichloromethane for three times, washing an organic phase with saturated salt water, drying with anhydrous sodium sulfate, mixing the sample, loading the sample on a column, and performing reaction on the mixture by using CH2Cl2MeOH (volume ratio) 20:1, compound 15-2.
Synthesis of compound S15:
compound 15-2 was dissolved in methylene chloride, and trifluoroacetic acid (10eq) was added thereto and the mixture was stirred at room temperature overnight. Pouring the reaction solution into water after the reaction is completed, extracting the reaction solution for three times by using dichloromethane, washing an organic phase by using saturated salt water, drying the organic phase by using anhydrous sodium sulfate, mixing the dried organic phase with a sample, loading the mixture on a column, and performing reaction on the mixture by using CH2Cl2MeOH (volume ratio) 20:1, compound S15 was obtained.1H NMR(300MHz,CDCl3)δ9.50(s,1H),8.58(d,J＝8.4Hz,1H),8.13(s,1H),8.05(s,1H),7.91(d,J＝9.7Hz,2H),7.61(d,J＝7.9Hz,1H),7.32(s,1H),7.23(d,J＝7.4Hz,1H),6.45(s,1H),4.50(dt,J＝12.2,6.2Hz,1H),4.06–3.93(m,2H),3.67(dd,J＝9.1,5.4Hz,1H),3.26(p,J＝6.8Hz,1H),2.99(dt,J＝10.2,6.7Hz,1H),2.86(dt,J＝10.1,6.3Hz,1H),2.10(s,4H),1.83(dt,J＝12.4,6.0Hz,1H),1.71–1.61(m,2H),1.39–1.28(m,12H),0.95(d,J＝4.1Hz,2H),0.91(d,J＝3.7Hz,2H).
Preparation of Compound S16 of preparation example 16
Figure BDA0000946094520000191
Synthesis of Compound 16-2:
compound S5, BOC-glycine (1.3eq) and TBTU (1.5eq) were dissolved in DMF, DIPEA (2eq) was added, and stirring was carried out overnight at room temperature. After the reaction is completed, pouring the reaction solution into water after the reaction is completed, extracting with dichloromethane for three times, washing an organic phase with saturated salt water, drying with anhydrous sodium sulfate, mixing the sample, loading the sample on a column, and performing reaction on the mixture by using CH2Cl2MeOH (volume ratio) 20:1, compound 16-2 was obtained.
Synthesis of compound S16:
compound 16-2 was dissolved in methylene chloride, and trifluoroacetic acid (10eq) was added thereto and the mixture was stirred at room temperature overnight. Pouring the reaction solution into water after the reaction is completed, extracting the reaction solution for three times by using dichloromethane, washing an organic phase by using saturated salt water, drying the organic phase by using anhydrous sodium sulfate, mixing the dried organic phase with a sample, loading the mixture on a column, and performing reaction on the mixture by using CH2Cl2MeOH (volume ratio) 30:1, compound S16 was obtained.1H NMR(300MHz,CDCl3)δ9.50(s,1H),8.58(d,J＝8.4Hz,1H),8.13(s,1H),7.92(d,J＝6.4Hz,2H),7.70(s,1H),7.61(t,J＝8.4Hz,1H),7.33(s,1H),7.23(d,J＝7.5Hz,1H),6.47(s,1H),4.50(p,J＝6.0,5.5Hz,1H),4.01(s,2H),3.29(d,J＝5.6Hz,2H),3.25(d,J＝6.9Hz,1H),2.10(s,3H),1.58(s,2H),1.33(dd,J＝8.6,6.5Hz,12H),0.99(d,J＝3.4Hz,2H),0.97–0.91(m,2H).
Preparation of Compound S17 of preparation example 17
Figure BDA0000946094520000192
Synthesis of compound S17:
compound S5, glycolic acid (1.3eq) and TBTU (1.5eq) were dissolved in DMF, DIPEA (2eq) was added, and stirring was carried out overnight at room temperature. After the reaction is completed, the reaction is carried out after the reaction is completedPouring the solution into water, extracting with dichloromethane for three times, washing the organic phase with saturated salt water, drying with anhydrous sodium sulfate, mixing with sample, loading onto column, and collecting the filtrate with CH2Cl2MeOH (volume ratio) 20:1, compound S17 was obtained.1H NMR(300MHz,CDCl3)δ9.53(s,1H),8.58(d,J＝8.3Hz,1H),8.07(s,1H),7.91(d,J＝7.8Hz,1H),7.76(s,1H),7.61(t,J＝7.5Hz,1H),7.24–7.19(m,1H),7.00(s,1H),6.49(s,1H),4.48(dt,J＝12.2,5.5Hz,1H),4.04(s,2H),3.95(s,2H),3.30–3.21(m,1H),2.11(s,3H),1.32(t,J＝6.0Hz,12H),1.02–0.91(m,4H).
Preparation example 18 preparation of compound S18
Figure BDA0000946094520000201
Synthesis of Compound 18-1:
the compound 3-bromomethyl-3-hydroxymethyl-1-oxetane, 1-tert-butoxycarbonylpiperazine (1.5eq), potassium carbonate (2eq) and potassium iodide (0.2eq) were dissolved in acetonitrile and heated to 75 ℃ for 4 h. Filtering potassium carbonate after the reaction is completed, and carrying out spin-drying, sample mixing and column loading on filtrate, wherein the product is CH2Cl2MeOH (volume ratio) 50:1, compound 18-1 was obtained.
Synthesis of Compound 18-2:
dissolving the compound 18-1, the compound 5-1(1.2eq) and cesium carbonate (2eq) in DMF, heating to 65 ℃ for reaction for 5h, and after the reaction is completed, cooling to room temperature. Pouring the reaction solution into water, extracting with ethyl acetate for 3 times, washing the organic phase with saturated salt water, drying with anhydrous sodium sulfate, separating with column, and collecting the filtrate with the residue2Cl2MeOH (volume ratio) is 100:1, and then the compound 18-2 is obtained.
Synthesis of Compound 18-3:
dissolving the compound 20-3 in methanol, adding 20% palladium carbon, and catalytically hydrogenating for 6 h. After the reaction is completed, the palladium-carbon is removed by suction filtration, the filtrate is dried on a column by spinning, and a compound 18-3 is obtained by taking PE as a developing agent and EA as 6: 1.
Synthesis of compound S18:
mixing compound 18-3, compound 4-5(1.1eq), 2-dicyclohexyl phosphorus-2 ',4',6' -triisopropyl biphenyl [ x-phos](0.05eq)、Tris (dibenzylideneacetone) dipalladium [ Pd ]2(dba)3](0.075eq) and potassium carbonate (2eq) were dissolved in 1, 4-dioxane and heated to 100 ℃ under reflux. The reaction was complete after 6 h. Pouring the reaction solution into water, extracting with ethyl acetate for 3 times, washing the organic phase with saturated salt water, drying with anhydrous sodium sulfate, mixing with sample, loading onto column, and collecting CH2Cl250:1 MeOH (volume ratio) to obtain compound S18.1H NMR(300MHz,CDCl3)δ9.52(s,1H),8.58(d,J＝8.4Hz,1H),8.14(s,1H),7.99–7.89(m,2H),7.60(t,J＝7.8Hz,1H),7.37(s,1H),7.23(s,1H),6.54(s,1H),4.63–4.47(m,5H),4.17(s,2H),3.26(dt,J＝13.6,6.9Hz,1H),3.14(s,4H),2.91(s,2H),2.72(s,4H),2.05(s,3H),1.39(d,J＝6.1Hz,6H),1.32(d,J＝6.8Hz,6H).
Preparation of Compound S19 of preparation example 19
Figure BDA0000946094520000211
Synthesis of Compound 19-2:
the compound 1-2, 3-fluidectin hydrochloride (1.5eq), potassium carbonate (2eq) and potassium iodide (0.2eq) were dissolved in acetonitrile and heated to 75 ℃ for 4 h. Filtering potassium carbonate after the reaction is completed, and carrying out spin-drying on the filtrate, mixing the sample with the filtrate, and loading the mixture on a column, wherein a developing agent is CH2Cl2MeOH (volume ratio) 50:1, compound 19-2 was obtained.
Synthesis of Compound 19-3:
dissolving the compound 19-2, the compound 5-1(1.2eq) and cesium carbonate (2eq) in DMF, heating to 65 ℃ for reaction for 5h, and after the reaction is completed, cooling to room temperature. Pouring the reaction solution into water, extracting with ethyl acetate for 3 times, washing the organic phase with saturated salt water, drying with anhydrous sodium sulfate, mixing with sample, loading onto column, and collecting CH2Cl2MeOH (volume ratio) is 100:1, and then the compound 19-3 is obtained.
Synthesis of Compound 19-4:
dissolving the compound 19-3 in methanol, adding 20% palladium carbon, and catalytically hydrogenating for 6 h. After the reaction is completed, the palladium-carbon is removed by suction filtration, the filtrate is dried on a column by spinning, and a compound 19-4 is obtained by taking PE: EA (volume ratio) as 6:1 as a developing agent.
Synthesis of compound S19:
mixing the compound 19-4, the compound 4-5(1.1eq), x-phos (0.05eq), Pd2(dba)3(0.075eq) and potassium carbonate (2eq) were dissolved in 1, 4-dioxane and heated to 100 ℃ under reflux. The reaction was complete after 6 h. Pouring the reaction solution into water, extracting with ethyl acetate for 3 times, washing the organic phase with saturated salt water, drying with anhydrous sodium sulfate, mixing with sample, loading onto column, and collecting CH2Cl250:1 in MeOH to obtain compound S19.1H NMR(300MHz,CDCl3)δ9.52(s,1H),8.58(d,J＝8.4Hz,1H),8.13(s,1H),7.95–7.86(m,2H),7.60(ddd,J＝8.8,7.4,1.6Hz,1H),7.37(s,1H),7.26–7.20(m,1H),6.53(s,1H),5.21–5.14(m,1H),4.97(q,J＝5.1Hz,1H),4.59–4.50(m,5H),4.10(s,2H),3.74–3.64(m,2H),3.36–3.22(m,3H),3.01(s,2H),2.07(s,3H),1.38(d,J＝6.0Hz,6H),1.32(d,J＝6.8Hz,6H).
Preparation example 20 preparation of compound S20
Figure BDA0000946094520000221
Synthesis of Compound 20-2:
the compound 1-2, 3-difluoroacridine hydrochloride (1.5eq), potassium carbonate (2eq) and potassium iodide (0.2eq) were dissolved in acetonitrile and heated to 75 ℃ for 4 h. Filtering potassium carbonate after the reaction is completed, and carrying out spin-drying on the filtrate, mixing the sample with the filtrate, and loading the mixture on a column, wherein a developing agent is CH2Cl2MeOH (volume ratio) 50:1, compound 20-2.
Synthesis of Compound 20-3:
dissolving the compound 20-2, the compound 5-1(1.2eq) and cesium carbonate (2eq) in DMF, heating to 65 ℃ for reaction for 5h, and after the reaction is completed, cooling to room temperature. Pouring the reaction solution into water, extracting with ethyl acetate for 3 times, washing the organic phase with saturated salt water, drying with anhydrous sodium sulfate, mixing with sample, loading onto column, and collecting CH2Cl2MeOH (volume ratio) is 100:1, and then the compound 20-3 is obtained.
Synthesis of Compounds 20-4:
dissolving the compound 20-3 in methanol, adding 20% palladium carbon, and catalytically hydrogenating for 6 h. After the reaction is completed, the palladium-carbon is removed by suction filtration, the filtrate is dried on a column by spinning, and a compound 20-4 is obtained by taking PE: EA (volume ratio) as 6:1 as a developing agent. Synthesis of compound S20:
20-4 of the compound, 4-5 of the compound (1.1eq), x-phos (0.05eq) and Pd2(dba)3(0.075eq) and potassium carbonate (2eq) were dissolved in 1, 4-dioxane and heated to 100 ℃ under reflux. The reaction was complete after 6 h. Pouring the reaction solution into water, extracting with ethyl acetate for 3 times, washing the organic phase with saturated salt water, drying with anhydrous sodium sulfate, mixing with sample, loading onto column, and collecting CH2Cl250:1 MeOH (volume ratio) to obtain compound S20.1H NMR(300MHz,CDCl3)δ9.49(s,1H),8.56(d,J＝8.6Hz,1H),8.12(s,1H),7.94–7.86(m,2H),7.62–7.54(m,1H),7.33(s,1H),7.21(d,J＝8.3Hz,1H),6.51(s,1H),4.58–4.46(m,5H),4.08(s,2H),3.68(dd,J＝14.4,7.5Hz,2H),3.33(d,J＝6.9Hz,1H),3.23(q,J＝6.8Hz,2H),2.99(s,2H),2.24–2.17(m,1H),2.05(s,3H),1.36(d,J＝6.1Hz,6H),1.30(d,J＝6.9Hz,6H).
Experimental examples: evaluation of molecular level Activity of molecular receptor tyrosine kinase ALK
1. Preliminary evaluation experiment for enzyme activity inhibition of receptor-alanine kinase ALK molecular level
(1) The enzyme reaction substrate Poly (Glu, Tyr) (molar ratio 4:1) was diluted to 20. mu.g/mL with PBS (10mM sodium phosphate buffer, 150mM NaCl, pH7.2-7.4) without potassium ions, coated with 125. mu.L/well of an ELISA plate, and reacted at 37 ℃ for 12-16 hours. The liquid in the wells was discarded. The plate was washed three times with 5 minutes each time using 200. mu.L/well of T-PBS (potassium ion-free PBS containing 0.1% Tween-20). The microplate was dried in an oven at 37 ℃ for 1-2 hours.
(2) Reaction buffer (50mM HEPES pH 7.4, 50mM MgCl) was added to each well2，0.5mM MnCl2，0.2mM Na3VO41mM DTT) was added to each well, 1. mu.L of the compound was added, the test compound was added, and 50. mu.L of each kinase domain recombinant protein diluted in the reaction buffer was added to start the reaction, and two wells of each experiment were not equipped with ATP control wells. The reaction was carried out on a shaker (100rpm) at 37 ℃ for 1 hour. The wells were discarded and the plate washed three times with T-PBS.
(3) The antibody PY 99100. mu.L/well (antibody diluted with T-PBS 1:500 containing BSA 5 mg/mL) was added thereto, and the mixture was subjected to shake reaction at 37 ℃ for 0.5 hour. The wells were discarded and the plate washed three times with T-PBS.
(4) Horseradish peroxidase-labeled goat anti-mouse secondary antibody was added at 100. mu.L/well (the antibody was diluted with T-PBS 1:2000 containing BSA 5 mg/ml), and shaking-reacted at 37 ℃ for 0.5 hour. The wells were discarded and the plate washed three times with T-PBS.
(5) Adding OPD developing solution 2mg/ml 100 μ L/well (containing 0.03% H)2O2Diluted with 0.1M citric acid-sodium citrate buffer (pH 5.4), and reacted at 25 ℃ for 1 to 10 minutes in the absence of light.
(6) 2M H was added2SO4The reaction was stopped at 50. mu.L/well and read using a variable wavelength microplate reader VERSAmax at a wavelength of 490 nm.
(7) Analysis of results
Figure BDA0000946094520000241
2. Inhibitory IC of receptor tyrosine kinase ALK enzyme activity50Evaluation experiment
The inhibition level of the compound on the enzyme activity of receptor tyrosine kinase ALK is shown in the following table:
compound (I) Inhibition ratio (%) IC50(μM) Compound (I) Inhibition ratio (%) IC50(μM)
S1 [email protected]μM <0.01 S2 [email protected]μM <0.01
S3 [email protected]μM <0.01 S4 [email protected] <0.1
S5 [email protected]μM <0.1 S6 [email protected]μM <0.1
S7 [email protected]μM <0.01 S8 [email protected]μM <0.01
S9 [email protected]μM <0.1 S10 [email protected]μM <0.01
S11 [email protected]μM <0.1 S12 [email protected]μM <0.01
S13 [email protected]μM <0.01 S14 [email protected]μM <0.1
S15 [email protected]μM <0.01 S16 [email protected]μM <0.1
S17 [email protected]μM <0.1 S18 [email protected]μM <0.1
S19 [email protected]μM <0.1 S20 [email protected]μM <0.1
Experimental examples: evaluation of cell level Activity of partial Compound receptor tyrosine kinase ALK
Inhibition of proliferation of SU-DHL-1 cells by the compounds was examined using the CCK-8 cell counting kit (Dojindo). The method comprises the following specific steps: SU-DHL-1 cells in logarithmic growth phase are inoculated at a suitable density into 96-well culture plates at 90. mu.L per well, incubated overnight, then added with compounds at different concentrations for 72hr, and a solvent control group (negative control) is set. After the compound acts on cells for 72 hours, the influence of the compound on cell proliferation is detected by a CCK-8 cell counting kit (Dojindo), 10 mu L of CCK-8 reagent is added into each hole, the hole is placed in an incubator at 37 ℃ for 2 to 4 hours, a SpectraMax 190 reading is carried out by a full-wavelength microplate reader, and the determination wavelength is determined to be 450 nm.
The inhibition (%) of the tumor cell growth by the compound was calculated using the following formula:
inhibition (%) - (OD control well-OD administration well)/OD control well X100%
The proliferation inhibition rate of the compound on SU-DHL-1 cells is shown in the following table:
Figure BDA0000946094520000242
Figure BDA0000946094520000251
the cell level activity test result shows that the inhibitory activity of the compounds S1, S2 and S3 is stronger than that of Ceritinib.
Experimental examples: rat pharmacokinetics study of some Compounds
1. Dosing regimens
21 SD rats, male, weighing 200-220g, randomly divided into 6 groups of 4 or 3 per group, administered the compounds S1, S2, S3 intragastrically or intravenously, with the specific schedule as shown in the following table:
Figure BDA0000946094520000252
fasted for 12h before the test, water was freely available. The diets were uniformly fed 2h after dosing.
2. Blood sampling time points and sample treatment:
intragastric administration: 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h after administration;
intravenous administration: 5min, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h after administration;
taking 0.3ml of venous blood from the retrobulbar venous plexus of the rat at the set time point, placing the venous blood into a heparinized test tube, centrifuging at 11000rpm for 5min, separating plasma, and freezing in a refrigerator at the temperature of 20 ℃ below zero.
3. Sample testing and data analysis
The concentrations of S1, S2 and S3 in rat plasma were determined by LC/MS/MS method.
Pharmacokinetic parameters after administration were calculated using a non-compartmental model of WinNonlin 6.3 software (Pharsight, usa).
Peak concentration of CmaxAnd time to peak TmaxIs an actual measurement value;
area under the time curve AUC0-tThe value: calculating by adopting a trapezoidal method; AUC0-∞＝AUC0-t+Ct/ke，CtBlood concentration for the last measurable time point;
keto eliminate the rate constant;
elimination of half-life t1/2＝0.693/ke；
Clearance rate CL ═ D/AUC0-∞；
Volume V of steady state distributionss＝CL×MRT；
Absolute bioavailability F ═ AUC (AUC)Gavage stomach×DVein)/(AUCVein×DGavage stomach)×100％。
4. Test results
Figure BDA0000946094520000261
Three compounds showed better pharmacokinetic properties.
Experimental examples: in vivo efficacy test of Compound mice
1. Growth inhibition effect on human lymphoma Karpas-299SCID mouse subcutaneous transplantation tumor
(1) Dose setting
Both compounds S1, S3 were set up in two dose groups, 50mg/kg and 10mg/kg respectively. The dose of the positive control drug Crizotinib was 50 mg/kg.
(2) Animal(s) production
SCID mice, female, 4-5 weeks old, weight 14 + -2 g, purchased from Beijing Huafukang Biotech GmbH, quality Certification number: no. 11401300013295. Producing license numbers: SCXK (Jing) 2014-. License number for drug use: SYXK (Shanghai) 2013-0049. Number of animals per group: the negative control group comprises 10 animals, and the administration group comprises 5 animals.
(3) Cell line
The human lymphoma Karpas-299 cell strain is preserved in our house. The cells were inoculated subcutaneously into the right axilla of SCID mice at 5X 106After the formation of the transplantable tumor, the mice were used for 2 passages in SCID mice.
(4) Experimental methods
Cutting tumor tissue in vigorous growth stage into 1.5mm3Left and right, under sterile conditions, were inoculated subcutaneously into the right axilla of SCID mice. SCID mice subcutaneous graft tumor diameter was measured with vernier caliper until the average tumor volume grew to about 130mm3Animals were randomized into groups after left and right. S1, S350 mg/kg and 10mg/kg, administered orally once daily for 14 consecutive days. The positive control drug PF 234106650 mg/kg group was orally administered once a day for 14 days. Solvent control group was given equal amount of solvent. Throughout the experiment, the diameter of the transplanted tumor was measured 2 times per week, while the body weight of the mice was weighed. The formula for Tumor Volume (TV) is: TV 1/2 × a × b2Wherein a and b represent length and width, respectively. Calculating Relative Tumor Volume (RTV) according to the measurement result, wherein the calculation formula is as follows: RTV ═ Vt/V0. Wherein V0When administered separately from the cage (i.e. d)0) Measurement of the resulting tumor volume, VtFor the tumor at each measurementVolume. The evaluation indexes of the antitumor activity are as follows: (1) the relative tumor proliferation rate T/C (%) was calculated as follows: T/C (%) ═ TRTV/CRTV)×100％，TRTV: treatment group RTV; cRTV: negative control group RTV; (2) the tumor volume growth inhibition ratio GI (%) is calculated as follows: GI (%) - (1- (TVt-TV)0)/(CVt-CV0)]X 100%, TVt is the tumor volume measured for each treatment group; TV (television)0Tumor volume obtained when cage-administered as a therapeutic component; CVt is the tumor volume measured in each time in the control group; CV of0Tumor volume obtained when cage-administered as control component; (3) the tumor weight inhibition rate is calculated according to the following formula: tumor weight inhibition ratio [ (% Wc-W) ]T) Wc × 100%, Wc: tumor weight of control group, WT: the treated group had heavy tumor.
(5) Results
The compound S150 mg/kg group was orally administered once a day for 14 days, which showed a very significant inhibitory effect on the growth of subcutaneous transplantable tumors in human lymphoma Karpas-299SCID mice, with the T/C percentage obtained on day 14 being 6.03%, whereas the 10mg/kg dose group was orally administered once a day for 14 days, which showed no significant inhibitory effect on the growth of subcutaneous transplantable tumors in human lymphoma Karpas-299SCID mice, with the T/C percentage obtained on day 14 being 84.37%.
The compound S350 mg/kg group was orally administered once a day for 14 days, which had a very significant inhibitory effect on the growth of subcutaneous transplantable tumors of human lymphoma Karpas-299SCID mice, with a T/C percentage of 0.00% obtained on day 14, and by the end of the experiment, all 5 tumors of the test mice were completely regressed. The composition is orally taken once a day for 14 days in a 10mg/kg dose group, and has a remarkable inhibition effect on the growth of subcutaneous transplantation tumor of a human lymphoma Karpas-299SCID mouse, and the T/C percentage obtained on the 14 th day is 23.66%.
The dosing regimen and test results are given in the following table:
Figure BDA0000946094520000281
2. growth inhibition effect of compound on NIH/3T3-ALK-L1196M nude mouse subcutaneous transplantation tumor
(1) Dose setting
S3 two dose groups were set, 50mg/kg and 10mg/kg groups, respectively. The dose of the positive control drug Crizotinib is 100 mg/kg; both Ceritinib and Alectoib were set to one dose group at 50 mg/kg.
(2) Animal(s) production
BALB/cA nude mouse, female, 4-5 weeks old, body weight 17 + -2 g, produced by Shanghai pharmaceutical research institute of Chinese academy of sciences, production license number: SCXK (Shanghai) 2013-0017. Shanghai drug use license number: SYXK (Shanghai) 2013-0049. Number of animals per group: negative control group 12, administration group 6.
(3) Cell line
The NIH/3T3-ALK-L1196M cell strain was inoculated subcutaneously into the right axilla of a nude mouse, the inoculation amount of the cells was 5X 106/mouse, and the cells were used after 1 generation in vivo transfer of the nude mouse after forming a transplantation tumor.
(4) Experimental methods
Cutting tumor tissue in vigorous growth stage into 1.5mm3And left and right, under aseptic conditions, inoculated subcutaneously in the right axilla of nude mice. Measuring the diameter of the transplanted tumor by using a vernier caliper in the nude mouse subcutaneous transplanted tumor until the average tumor volume grows to about 150mm3Animals were randomized into groups after left and right. S3 two dose groups, 50mg/kg and 10mg/kg groups, were set for once daily oral administration for 14 consecutive days. The positive control drug Crizotinib 100mg/kg group is orally taken once a day for 14 days continuously; LDK378 and CH 542480250 mg/kg, administered orally once daily for 14 days. Solvent control group was given equal amount of solvent. Throughout the experiment, the diameter of the transplanted tumor was measured 2 times per week, while the body weight of the mice was weighed. The formula for Tumor Volume (TV) is: TV 1/2 × a × b2Wherein a and b represent length and width, respectively. Calculating Relative Tumor Volume (RTV) according to the measurement result, wherein the calculation formula is as follows: RTV ═ Vt/V0. Wherein V0When administered separately from the cage (i.e. d)0) Measurement of the resulting tumor volume, VtFor the tumor volume at each measurement. The evaluation index of antitumor activity was 1) relative tumor proliferation rate T/C (%), calculatedThe calculation formula is as follows: T/C (%) ═ TRTV/CRTV)×100％，TRTV: treatment group RTV; cRTV: negative control group RTV; 2) the tumor volume growth inhibition ratio GI (%) is calculated as follows: GI (%) - (1- (TVt-TV)0)/(CVt-CV0)]X 100%, TVt is the tumor volume measured for each treatment group; TV (television)0Tumor volume obtained when cage-administered as a therapeutic component; CVt is the tumor volume measured in each time in the control group; CV of0Tumor volume obtained when cage-administered as control component; 3) the tumor weight inhibition rate is calculated according to the following formula: tumor weight inhibition ratio (%) - (Wc-W)T) Wc × 100%, Wc: tumor weight of control group, WT: the treated group had heavy tumor.
(5) Results
The compound S350 mg/kg group is orally taken once a day, has extremely obvious inhibition effect on the growth of subcutaneous transplanted tumors of NIH/3T3-ALK-L1196M nude mice, is continuously taken for 14 days, and the T/C percentage obtained on the 14 th day is 1.42%; the group of 10mg/kg is orally taken once a day for 14 days continuously, has obvious inhibition effect on the growth of subcutaneous transplanted tumors of NIH/3T3-ALK-L1196M nude mice, and the T/C percentage obtained on the 14 th day is 37.05%. The test results are given in the following table:
Figure BDA0000946094520000291
the piperidine N atom of the new compound introduces flexible water-soluble groups and removes the piperidine ring to directly introduce flexible water-soluble fragments on a polysubstituted benzene ring, thereby greatly reducing the cLogP value of Ceritinib (the Ceritinib cLogP value is as high as 5.62), reducing the rigidity of the compound and improving the pharmacokinetic property of the compound. The test results of representative compounds show that the novel compounds are prepared by ALK molecular level, cell level, in vivo metabolism research and in vivo drug effect even including ALKL1196MThe mutation models all show comparable or even better results than Ceritinib and are therefore very potential ALK inhibitors.

Claims (8)

1. A2, 4-diaminopyrimidine derivative and a pharmaceutically acceptable salt thereof, wherein the 2, 4-diaminopyrimidine derivative has a structure shown in the following general formula (I):
Figure FDA0003200344790000011
wherein:
R1selected from C1-C3 alkyl;
t is a piperidine ring;
R2，R3together form a 4-6 membered heterocycloalkyl group; the hetero atom in the 4-6 membered heterocycloalkyl group is selected from oxygen atom and sulfur atom, and the 4-6 membered heterocycloalkyl group is saturated heterocycloalkyl group;
R4selected from hydroxyl, hydroxyl C1-C3 alkyl, C1-C3 alkyl.
2. The 2, 4-diaminopyrimidine derivative according to claim 1, wherein,
R1is selected from methyl;
R2，R3together form a 3-oxetanyl or 4-oxetanyl group;
R4selected from hydroxyl, hydroxymethyl and methyl.
3. The 2, 4-diaminopyrimidine derivative according to claim 1, wherein the 2, 4-diaminopyrimidine derivative is selected from the group consisting of:
Figure FDA0003200344790000012
4. the 2, 4-diaminopyrimidine derivative according to any one of claims 1 to 3, wherein:
the pharmaceutically acceptable salt is selected from hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, methanesulfonate, ethylsulfonate, benzenesulfonate, p-toluenesulfonate.
5. A process for the preparation of 2, 4-diaminopyrimidine derivatives according to any one of claims 1 to 3, which comprises the following reaction scheme:
Figure FDA0003200344790000021
the compound iia and the compound i have substitution reaction under the action of organic base diisopropylethylamine to obtain a compound iii; wherein R is2，R3And R4The definitions are the same as in the corresponding claims 1 to 3.
6. A process for the preparation of 2, 4-diaminopyrimidine derivatives according to any one of claims 1 to 3, which comprises the following reaction scheme:
Figure FDA0003200344790000022
carrying out a ring-opening reaction on the compound i and the spiro compound iib under the action of organic base diisopropylethylamine to obtain a compound iii; wherein R is2，R3As defined in corresponding claims 1 to 3, R4Is a hydroxyl group.
7. Use of the 2, 4-diaminopyrimidine derivatives of any one of claims 1 to 4 and pharmaceutically acceptable salts thereof in the manufacture of a medicament for use as a tyrosine kinase inhibitor.
8. Use of the 2, 4-diaminopyrimidine derivative according to any one of claims 1 to 4 and a pharmaceutically acceptable salt thereof for producing a medicament for preventing and/or treating diseases associated with abnormal cell proliferation, morphological changes and hyperkinesia associated with in vivo and progressive lymphoma enzyme, and diseases associated with angiogenesis or cancer metastasis.
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