CN103483345B - PI3K inhibitors of kinases, the pharmaceutical composition comprising it and application thereof - Google Patents

PI3K inhibitors of kinases, the pharmaceutical composition comprising it and application thereof Download PDF

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CN103483345B
CN103483345B CN201310442704.XA CN201310442704A CN103483345B CN 103483345 B CN103483345 B CN 103483345B CN 201310442704 A CN201310442704 A CN 201310442704A CN 103483345 B CN103483345 B CN 103483345B
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morpholine
amine
trifluoromethyl
pyrimidine
pyridine
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CN103483345A (en
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鲁桂
张吉泉
陈晖旋
罗羽
罗永杰
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National Sun Yat Sen University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems

Abstract

The invention discloses a kind of PI3K inhibitors of kinases, the pharmaceutical composition comprising it and application thereof.Wherein PI3K inhibitors of kinases, including the pyrimidine compound with formula I, its stereoisomer, hydrate or pharmaceutically acceptable salt, described formula I structure is as follows:

Description

PI3K inhibitors of kinases, the pharmaceutical composition comprising it and application thereof
Technical field
The present invention relates to pharmaceutical technology field, more specifically refer to a kind of PI3K inhibitors of kinases, the pharmaceutical composition comprising it and application thereof.
Background technology
Malignant tumor is the class disease that serious threat human life is healthy, and its M & M is in the trend risen year by year, and the mankind are at the second place because mortality rate that cancer causes is only second to cardiovascular and cerebrovascular disease.At present, the medicine for treatment of tumor is divided into conventional cell poison class medicine and novel molecular targeted drug clinically.The former is owing to mainly acting on the life-and-death common constituent of DNA, RNA and tubulin etc. and cell, non-specifically block cell division thus causing cell death, while killing tumor cell, also destroy human normal cell, cause that its selectivity is low, toxicity is big；The latter is then generally of relatively unambiguous target spot, mainly act on the regulating cell growth that difference is huge in normal cell and tumor cell, the key molecule bred and signal transduction pathway thereof, growth of tumour cell can be suppressed to reduce Normocellular effect, thus adding the selectivity to tumor, reducing the toxicity of normal tissue, drastically increase treatment level.
The development of anti-tumor drugs targeting is accelerated by each drugmaker, and it is sought-after to the antitumor drug of this classification to add market, and molecular targeted agents has become as fastest-rising part on antitumor drug market, the whole world.Phosphatidylinositol-3-kinase (phosphoinositide3-kinase, PI3K) is signaling molecule crucial in many vital movements.The signal path (PI3K/Akt/m-TOR) of PI3K mediation controls numerous vital cell biological processes in tumor development, including cell proliferation, apoptosis, transcribe, translate, metabolism, angiogenesis and cell cycle regulation and control etc..In human tumor cells, this signal path compared with other signal path, producer change as gene mutation, gene amplification, gene rearrangement probability higher, thus developing with tumor, shifting and drug resistance is closely related.Therefore, PI3K inhibitor has the advantage of uniqueness in suppressing tumor cell proliferation, inducing apoptosis of tumour cell and reversing tumor cellular drug resistance etc., it is possible to individually medication or with other targeted drug drug combination.One of antitumor drug research focus becoming neoplasm targeted therapy that key molecule is target spot in PI3K signal path.
PI3Ks is the phosphatidyl inositol kinase in class born of the same parents with serine/threonine (Ser/Thr) kinase whose activity, can phosphorylation phosphatidylinositols (PtdIns), phosphatidylinositol-4phosphate (PtdIns4P), phosphatidylinositols-4,3 hydroxyls of 5-diphosphonic acid (PtdIns (4,5) P2).According to its architectural feature and substrate specificity specificity, PI3Ks family can be divided into four classes: I type, II type, type III and IV type.Up to the present, most study is I type PI3K, is divided into according to the difference of catalytic subunit: PI3K tetra-hypotypes (Nat.Rev.DrugDiscov.2009,8,627-644) of α, PI3K β, PI3K γ and PI3K δ.Although the four of I type PI3K kinds of hypotypes have higher homology on structure forms, its physiological function has certain overlap, but due to the difference of its active pocket peripheral structure, causes that they play a different role in function and cancer develop.
Existing nearly 20 compounds enter clinical experimental stage at present, wherein have tens compounds to be in II phase clinical stage, have 4 compounds to enter III clinical trial phase.The Perifosine (KRX-0401) with structural formula 4 of the Rigosertib (ON-01910) with structural formula 2, the Idelalisib (CAL-101, GS-1101) with structural formula 3 of ICOS company exploitation and the exploitation of ASTAMedica company that the Buparlisib (NVP-BKM120) with structural formula 1 of compound respectively Novartis company exploitation of entrance III clinical trial phase, OnconovaTherapeutics company develop.Structure above 1-4 is as follows:
But, there is no the listing of PI3K inhibitor so far, research staff also needs to research and develop more PI3K kinase inhibition agent molecule, in order to effectiveness of selection and the better compound of selectivity are used for the treatment of cancer.
Summary of the invention
It is desirable to provide a kind of PI3K inhibitors of kinases, the pharmaceutical composition comprising it and application thereof, in order to effectiveness of selection and the better compound of selectivity are used for the treatment of cancer.
To achieve these goals, according to an aspect of the invention, it is provided a kind of PI3K inhibitors of kinases, including the pyrimidine compound with formula I, its stereoisomer, hydrate or pharmaceutically acceptable salt, described formula I structure is as follows:
In described formula I: X, Y, Z, W are independently selected from N or-CH-；R1, R2Independently selected from H, C1-C4Alkyl, C containing one or more substituent groups1-C4Alkyl, C1-C4Alkoxyl, C containing one or more substituent groups1-C4Alkoxyl, C3-C6Heterocyclic radical, C containing one or more substituent groups3-C6Heterocyclic radical, C4-C8Condense assorted bicyclic group or the C containing one or more substituent groups4-C8Condensing assorted bicyclic group, described substituent group is selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, C1-C4Alkyl, halo C1-C4Alkyl, hydroxyl C1-C4Alkyl, C1-C4Alkoxyl, halo C1-C4Alkoxyl, hydroxyl C1-C4Alkoxyl or C1-C4Alkoxy C1-C4Alkyl；R3Selected from H ,-CN ,-CH3,-CF3Or-SO2NH2；R4Selected from H or halogen.
Further, above-mentioned R3For-CF3；
Further, above-mentioned PI3K inhibitors of kinases includes the pyrimidine compound with formula II and/or general formula III, its stereoisomer, hydrate or pharmaceutically acceptable salt；Formula II and general formula III structure are as follows:
In described formula II and general formula III: R1, R2Independently selected from H, C1-C4Alkyl, C containing one or more substituent groups1-C4Alkyl, C1-C4Alkoxyl, C containing one or more substituent groups1-C4Alkoxyl, C3-C6Heterocyclic radical, C containing one or more substituent groups3-C6Heterocyclic radical, C4-C8Condense assorted bicyclic group or the C containing one or more substituent groups4-C8Condensing assorted bicyclic group, described substituent group is selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, C1-C4Alkyl, halo C1-C4Alkyl, hydroxyl C1-C4Alkyl, C1-C4Alkoxyl, halo C1-C4Alkoxyl, hydroxyl C1-C4Alkoxyl or C1-C4Alkoxy C1-C4Alkyl.
Further, R in above-mentioned formula I or in formula II and III1, R2Independently selected from following structure:
Wherein, A, B, C, D, E, F is independently selected from-CH2-,-O-,-S-or-NR11-；R5, R6, R7, R8, R9, R10, R11Independently selected from H, halogen, hydroxyl, amino, C1-C4Alkyl, halo C1-C4Alkyl, hydroxyl C1-C4Alkyl, C1-C4Alkoxyl, halo C1-C4Alkoxyl, hydroxyl C1-C4Alkoxyl, or C1-C4Alkyl sulphonyl；
Further, in above-mentioned formula I, R in formula II or general formula III1, R2Independently selected from following structure:
Further, R in above-mentioned formula I, formula II or general formula III1It is selected from structure:
Further, R in above-mentioned formula I, formula II or general formula III2It is selected from structure:
Further, above-mentioned pyrimidine compound is:
Rac-5-(6-morpholine-2-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two) [2,3-c] pyrroles-6 (3H)-Ji) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine；
5-(2-((1R, 4R)-2-oxygen-5-azabicyclo [2.2.1] heptane-5-base)-6-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine；
5-(2-((2R, 6S)-2,6-thebaine)-6-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine；
5-(2-((4RS, 7SR)-dihydro-2H-[1,4] two [2,3-c] pyrroles-6 (3H, 7H, 7aH)-Ji)-6-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine；
5-(6-((2R, 6S)-2,6-thebaine)-2-((4SR, 7RS)-tetrahydrochysene-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-Ji) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine；
5-(6-((2R, 6S)-2,6-thebaine)-2-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine；
5-(2-morpholine-6-((4SR, 7RS)-tetrahydrochysene-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-Ji) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine；
Rac-5-(2-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-Ji) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine；
Rac-6-morpholine-2-((4RS, 7RS)-tetrahydrochysene)-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-Ji)-[4,5 '-Sulfadiazine Compound]-2 '-amine
4-(6-amino-4-(trifluoromethyl) pyridin-3-yl)-6-morpholine-N-(2-morpholine ethyl) pyrimidine-2-amine；
4-(6-amino-4-(trifluoromethyl) pyridin-3-yl)-6-morpholine-N-(4-morpholinyl phenyl) pyrimidine-2-amine；
(-)-5-(6-morpholine-2-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two) [2,3-c] pyrroles-6 (3H)-Ji) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine；
(+)-5-(6-morpholine-2-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two) [2,3-c] pyrroles-6 (3H)-Ji) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine；
5-(4-((1R, 4R)-2-oxygen-5-azabicyclo [2.2.1] heptane-5-base)-6-morpholine-1,3,5-three nitrogen piperazine-2-base)-4-(trifluoromethyl) pyridine-2-amine；
5-(2-(4-(mesyl) piperazine-1-base)-6-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine；
5-(4-((1R, 4R)-2-oxygen-5-azabicyclo [2.2.1] heptane-5-base)-6-((2R, 6S)-2,6-thebaine)-1,3,5-tri-nitrogen piperazine-2-base)-4-(trifluoromethyl) pyridine-2-amine；
Rac-5-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-Ji)-1,3,5-three nitrogen piperazine-2-base)-4-(trifluoromethyl) pyridine-2-amine；
(-)-5-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-Ji)-1,3,5-tri-nitrogen piperazine-2-base)-4-(trifluoromethyl) pyridine-2-amine；Or
(+)-5-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-Ji)-1,3,5-tri-nitrogen piperazine-2-base)-4-(trifluoromethyl) pyridine-2-amine.
According to a further aspect in the invention, it is provided that a kind of pharmaceutical composition, it comprises at least one above-mentioned PI3K inhibitors of kinases of at least one pharmaceutically acceptable adjuvant, adjuvant or carrier and dose therapeutically effective.
According to a further aspect in the invention, it is provided that the application in the medicine of Prevention and/or the proliferative disease for the treatment of and/or auxiliary treatment PI3K zymogenesis of a kind of above-mentioned PI3K inhibitors of kinases or above-mentioned pharmaceutical composition.
Further, in above-mentioned application, the proliferative disease of PI3K zymogenesis is colorectal cancer, gastric cancer, breast carcinoma, pulmonary carcinoma, hepatocarcinoma, carcinoma of prostate, cancer of pancreas, thyroid carcinoma, bladder cancer, renal carcinoma, cerebroma, neck cancer, the cancer of CNS, glioblastoma, or myeloproliferative disease, and leukemia and lymphatic cancer.
According to a further aspect in the invention, it is provided that the application of a kind of above-mentioned PI3K inhibitors of kinases or above-mentioned pharmaceutical composition vitro inhibition cancer cell growth.
Application technical scheme, PI3K inhibitors of kinases provided by the present invention, the pharmaceutical composition comprising it can be used in suppressing PI3K kinases, and the proliferative disease of PI3K zymogenesis, it is possible to the treatment for the proliferative disease of PI3K zymogenesis provides effectiveness and the better inhibitor of selectivity.
Detailed description of the invention
Below in conjunction with the embodiment of the present invention, technical scheme being described in detail, but below embodiment is only understand the present invention, and can not limit the present invention, the multitude of different ways that the present invention can be defined by the claims and cover is implemented.
In order to realize providing more effectiveness and the better compound of selectivity for the treatment of tumor pointed by background section.Provide a kind of PI3K inhibitors of kinases in the present invention.This PI3K inhibitors of kinases includes having formula I pyrimidine compound, its stereoisomer, hydrate or pharmaceutically acceptable salt.Wherein, formula I structure is as follows:
In above-mentioned formula I, X, Y, Z, W are independently selected from N or-CH-.
R in above-mentioned formula I1, R2Independently selected from H, C1-C4Alkyl, C containing one or more substituent groups1-C4Alkyl, C1-C4Alkoxyl, C containing one or more substituent groups1-C4Alkoxyl, C3-C6Heterocyclic radical, C containing one or more substituent groups3-C6Heterocyclic radical, C4-C8Condense assorted bicyclic group or the C containing one or more substituent groups4-C8Condensing assorted bicyclic group, described substituent group is selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, C1-C4Alkyl, halo C1-C4Alkyl, hydroxyl C1-C4Alkyl, C1-C4Alkoxyl, halo C1-C4Alkoxyl, hydroxyl C1-C4Alkoxyl or C1-C4Alkoxy C1-C4Alkyl.
R in above-mentioned formula I3Selected from H ,-CN ,-CH3,-CF3Or-SO2NH2；Wherein preferred R3For-CF3。
R in above-mentioned formula I4Selected from H or halogen, it is preferred to H.
In one preferred embodiment of the invention, above-mentioned PI3K inhibitors of kinases includes the pyrimidine compound with formula II and/or general formula III, its stereoisomer, hydrate or pharmaceutically acceptable salt；Described formula II and general formula III structure are as follows:
In above-mentioned formula II and general formula III: R1, R2Independently selected from H, C1-C4Alkyl, C containing one or more substituent groups1-C4Alkyl, C1-C4Alkoxyl, C containing one or more substituent groups1-C4Alkoxyl, C3-C6Heterocyclic radical, C containing one or more substituent groups3-C6Heterocyclic radical, C4-C8Condense assorted bicyclic group or the C containing one or more substituent groups4-C8Condensing assorted bicyclic group, described substituent group is selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, C1-C4Alkyl, halo C1-C4Alkyl, hydroxyl C1-C4Alkyl, C1-C4Alkoxyl, halo C1-C4Alkoxyl, hydroxyl C1-C4Alkoxyl or C1-C4Alkoxy C1-C4Alkyl.
In one preferred embodiment of the invention, R in above-mentioned PI3K inhibitors of kinases formula of I formula II or general formula III1, R2Independently selected from following structure:
Wherein, A, B, C, D, E, F is independently selected from-CH2-,-O-,-S-or-NR11-；
R5, R6, R7, R8, R9, R10, R11Independently selected from H, halogen, hydroxyl, amino, C1-C4Alkyl, halo C1-C4Alkyl, hydroxyl C1-C4Alkyl, C1-C4Alkoxyl, halo C1-C4Alkoxyl, hydroxyl C1-C4Alkoxyl, or C1-C4Alkyl sulphonyl.
Preferably, R in above-mentioned PI3K inhibitors of kinases formula of I, formula II or general formula III1, R2Independently selected from following structure:
It is further preferable that R in above-mentioned PI3K inhibitors of kinases formula of I, formula II or general formula III1It is selected from structure:
It is further preferable that R in above-mentioned PI3K inhibitors of kinases formula of I, formula II or general formula III2It is selected from structure:
It is further preferable that pyrimidine compound is in above-mentioned PI3K inhibitors of kinases:
Rac-5-(6-morpholine-2-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two) [2,3-c] pyrroles-6 (3H)-Ji) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter referred to as ZJQ-04)；
5-(2-((1R, 4R)-2-oxygen-5-azabicyclo [2.2.1] heptane-5-base)-6-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter referred to as ZJQ-05)；
5-(2-((2R, 6S)-2,6-thebaine)-6-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter referred to as ZJQ-06)；
5-(2-((4RS, 7SR)-dihydro-2H-[1,4] two [2,3-c] pyrroles-6 (3H, 7H, 7aH)-Ji)-6-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter referred to as ZJQ-13)；
5-(6-((2R, 6S)-2,6-thebaine)-2-((4SR, 7RS)-tetrahydrochysene-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-Ji) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter referred to as ZJQ-14)；
5-(6-((2R, 6S)-2,6-thebaine)-2-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter referred to as ZJQ-10)；
5-(2-morpholine-6-((4SR, 7RS)-tetrahydrochysene-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-Ji) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter referred to as ZJQ-19)；
Rac-5-(2-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-Ji) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter referred to as ZJQ-20)；
(-)-5-(6-morpholine-2-((4RS, 7RS)-tetrahydrochysene)-2H-[1,4] two) [2,3-c] pyrroles-6 (3H)-Ji) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter referred to as ZJQ-22)；
(+)-5-(6-morpholine-2-((4SR, 7SR)-tetrahydrochysene)-2H-[1,4] two) [2,3-c] pyrroles-6 (3H)-Ji) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter referred to as ZJQ-23)；
Rac-6-morpholine-2-((4RS, 7RS)-tetrahydrochysene)-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-Ji)-[4,5 '-Sulfadiazine Compound]-2 '-amine (hereinafter referred to as ZJQ-24)；
5-(2-(4-(mesyl) piperazine-1-base)-6-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter referred to as ZJQ-26)
4-(6-amino-4-(trifluoromethyl) pyridin-3-yl)-6-morpholine-N-(2-morpholine ethyl) pyrimidine-2-amine (hereinafter referred to as ZJQ-27)；
4-(6-amino-4-(trifluoromethyl) pyridin-3-yl)-6-morpholine-N-(4-morpholinyl phenyl) pyrimidine-2-amine (hereinafter referred to as ZJQ-28)；
5-(4-((1R, 4R)-2-oxygen-5-azabicyclo [2.2.1] heptane-5-base)-6-morpholine-1,3,5-three nitrogen piperazine-2-base)-4-(trifluoromethyl) pyridine-2-amine (hereinafter referred to as ZJQ-07)；
5-(4-((1R, 4R)-2-oxygen-5-azabicyclo [2.2.1] heptane-5-base)-6-((2R, 6S)-2,6-thebaine)-1,3,5-tri-nitrogen piperazine-2-base)-4-(trifluoromethyl) pyridine-2-amine (hereinafter referred to as ZJQ-08)；
Rac-5-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-Ji)-1,3,5-tri-nitrogen piperazine-2-base)-4-(trifluoromethyl) pyridine-2-amine (hereinafter referred to as ZJQ-21)；
(-)-5-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-Ji)-1,3,5-tri-nitrogen piperazine-2-base)-4-(trifluoromethyl) pyridine-2-amine (hereinafter referred to as ZJQ-29)；Or
(+)-5-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-Ji)-1,3,5-tri-nitrogen piperazine-2-base)-4-(trifluoromethyl) pyridine-2-amine (hereinafter referred to as ZJQ-30).
PI3K inhibitors of kinases provided by the present invention can be used in suppressing PI3K kinases and the proliferative disease of PI3K zymogenesis, it is possible to the treatment for the proliferative disease of PI3K zymogenesis provides effectiveness and the better inhibitor of selectivity.
The PI3K inhibitors of kinases of the present invention can include pyrimidine compound pharmaceutically acceptable salt.Pharmaceutically acceptable salt refers to the form basic group in parent compound being converted to salt.Pharmaceutically acceptable salt include but not limited to, the inorganic or organic acid salt of basic group such as amine (ammonia) base.Pharmaceutically acceptable salt of the present invention can be synthesized by parent compound, and namely the basic group in parent compound reacts in a solvent system with the acid of 1-4 equivalent.P.1418 and JournalofPharmaceuticalScience suitable salt is set forth in Remington ' sPharmaceuticalSciences, 17thed., MackPublishingCompany, Easton, Pa., 1985, in 66,2 (1977).
In the present invention, compound basic group can become salt with acid, and these acid become the example of salt to include: with mineral acid, the salt that especially halogen acids (such as hydrochloric acid, hydrobromic acid, hydroiodic acid), nitric acid, sulphuric acid, phosphoric acid, carbonic acid etc. are formed；Lower alkanesulfonic acid, such as methanesulfonic acid, the salt that trifluoromethanesulfonic acid is formed；With aryl sulfonic acid, such as the salt that benzenesulfonic acid or p-methyl benzenesulfonic acid are formed；With organic acid, as acetic acid, fumaric acid, tartaric acid, oxalic acid, citric acid, maleic acid, malic acid or succinic acid formed salt；With aminoacid, such as the salt that aspartic acid or glutamic acid are formed.
The compound of the present invention and pharmaceutically acceptable salt also include the form of solvate or hydrate.In general, the form of solvate or hydrate is equal to non-solvated or non-hydrated form, and contains within the scope of the invention.Some compound in the present invention there may exist polycrystal or unbodied form.Generally speaking, all of physical form has equal purposes, and contains within the scope of the invention.
Additionally, unless other side shows, in the PI3K enzyme inhibitor of the present invention described in the invention, the structural formula of pyrimidine compound includes all of isomeric forms (such as enantiomerism, diastereo-isomerism, with geometrical isomerism (or conformational isomerism)): such as contain R, S configuration of asymmetric center, (Z), (E) isomer of double bond, and the conformer of (Z), (E).Therefore, the single three-dimensional chemical isomer of the compound of the present invention or its enantiomer, diastereomer, or the mixture of geometric isomer (or conformer) broadly fall into the scope of the present invention.
Unless other side shows, in PI3K inhibitors of kinases of the present invention, all tautomeric forms of pyrimidine compound are intended to be included within the scope.It addition, unless other side shows, the structural formula of compound described in the invention includes the enriched isotope of one or more different atom.
The exemplary of the present invention is described more fully below.But, these embodiments are only for illustration purpose, it is no intended to restriction the scope of the present invention.
If as it is used herein, for providing concrete restriction, the term of the present invention has following implication.
Term " alkyl " is the univalence hydrocarbyl including 1-20 carbon atom saturated straight chain or side chain, and wherein alkyl can be individually optionally replaced by one or more substituent groups described in the invention.Some of them embodiment is, alkyl group contains 1-10 carbon atom, and other embodiment is, alkyl group contains 1-8 carbon atom, and other embodiment is, alkyl group contains 1-6 carbon atom, other embodiment is, alkyl group contains 1-4 carbon atom.Alkyl group further example includes, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-pro-pyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,-CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), the tert-butyl group (t-Bu ,-C (CH3)3) etc..Term " alkyl " and its prefix " alkane " are being used herein as, and all comprise the saturated carbon chains of straight chain and side chain.
It is identical with the definition of aforementioned " alkyl " that term " alkoxyl " relates to the part of alkyl, and it is to be connected in the carbochain that " alkyl " is main by oxygen atom to be formed.
Term " haloalkyl " or " halogenated alkoxy " indicate that " alkyl " or " alkoxyl " can by the replaced situation of one or more identical or different halogen atoms.Wherein alkyl and alkoxy base have implication as aforesaid in the present invention, and such example includes, but are not limited to trifluoromethyl, trifluoromethoxy etc..
Term " hydroxy alkyl " or " hydroxy alkoxy base " indicate that " alkyl " or " alkoxyl " can be optionally substituted with one or more hydroxyl replaced situation.Wherein " alkyl " and " alkoxyl " group has implication as aforesaid in the present invention, and such example includes, but is not limited to methylol, 1-ethoxy, hydroxypropyl, 1,2-dihydroxypropyl, hydroxyl methoxyl group, 1-hydroxy ethoxy etc..
Term " halogen ", " halogen atom " or " halogen atom " includes fluorine, chlorine, bromine, iodine.
Term " heterocyclic radical " can be carbon back or hetero atom base." heterocyclic radical " equally also includes heterocyclic group and the saturated or unsaturated ring of part or heterocycle and closes the group formed.nullThe example of heterocycle includes，But it is not limited to，Pyrrolidinyl，Tetrahydrofuran base，Dihydrofuran base，Tetrahydro-thienyl，THP trtrahydropyranyl，Dihydro pyranyl，Tetrahydro thiapyran base，Piperidyl，Thiophene alkyl，Azelidinyl，Oxetanylmethoxy，Thietanyl，Piperidyl，Homopiperidinyl，Glycidyl，Azacycloheptyl，Oxepane base，Thia suberyl，N-morpholinyl，2-morpholinyl，Morpholinyl，Thio-morpholinyl，N-piperazinyl，2-piperazinyl，3-piperazinyl，Homopiperazine base，4-Methoxy-piperidin-1-base，1,2,3,6-tetrahydropyridine-1-base，Oxygen azatropylidene base，Diazepine base，Sulfur azatropylidene base，Pyrrolin-1-base，2-pyrrolinyl，3-pyrrolinyl，Indolinyl，2H-pyranose，4H-pyranose，Dioxacyclohexyl，1,3-dioxy amyl group，Pyrazolinyl，Dithiane base，Dithiode alkyl，Dihydro-thiophene base，Pyrazolidinyl imidazolinyl，Imidazolidinyl，1,2,3,4-tetrahydro isoquinolyl，1,2,6-thiadiazine alkane，1,1-dioxy-2-base，Quinolizinyl and N-pyridine radicals carbamide.And described heterocyclic radical can be substituted or non-substituted, wherein substituent group it may be that but be not limited to, oxo (=O), hydroxyl, amino, halogen, cyano group, heteroaryl, alkoxyl, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, the alkoxyl that hydroxyl replaces, alkyl-the C (=O) that hydroxyl replaces, alkyl-C (=O), Carboxyalkoxy etc..
Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base " or " condensed ring radical " represent saturated or undersaturated fused ring system, relate to the bicyclic system of non-aromatic.Such system can comprise independent or conjugation undersaturated condition, but its core texture does not comprise aromatic rings or heteroaromatic (but aromatic series can as substituent group thereon).Each ring in condensed-bicyclic or carbocyclic ring or assorted alicyclic, such example includes, but is not limited to, and 2,3,3a, 4,7,7a-hexahydro-1H-indenyl, 7-azabicyclo [2.2.1] heptane base, condensed-bicyclic [3.3.0] octyl, condensed-bicyclic [3.1.0] hexyl, 1,2,3,4,4a, 5,8,8a-octahydro naphthyls, these are included within the system of condensed-bicyclic.And described condensed-bicyclic base can be substituted or non-substituted, wherein substituent group is it may be that but be not limited to, halogen, hydroxyl, amino, cyano group, aryl, heteroaryl, alkoxyl, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group etc..
Term " condenses assorted bicyclic group " and represents saturated or undersaturated fused ring system, relates to the bicyclic system of non-aromatic.Such system can comprise independent or conjugation undersaturated condition, but its core texture does not comprise aromatic rings or heteroaromatic (but aromatic series can as substituent group thereon).And at least one member ring systems comprises one or more hetero atom, each of which member ring systems comprises 3-7 ring, namely comprises 1-6 carbon atom and selected from 1-3 the hetero atom of N, O, P, S, is optionally obtained picture SO, SO by one or more oxygen atoms are replaced at this S or P2, PO, PO2Group, such example includes, but is not limited to hexahydro-2H-[Isosorbide-5-Nitrae] dioxy [2,3-c] pyrrole radicals etc..And described in condense assorted bicyclic group can be substituted or non-substituted, wherein substituent group is it may be that but be not limited to, halogen, hydroxyl, amino, cyano group, aryl, heteroaryl, alkoxyl, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group etc..
In above-mentioned PI3K inhibitor provided by the present invention, pyrimidine compound can be prepared in several ways, and the suitable mode of lower searching that inspires of the structural formula that those skilled in the art provide in this application is prepared.In order to make it easy to understand, provide the preparation method about above-mentioned formula II and III in this application.
A kind of method preparing the pyrimidine compound with formula II: with 2,4,6-trichloropyrimidines (A) for raw material, the difference according to pyrimidine 2 and 4 reactivities, elder generation and R1NH occurs nucleophilic substitution to obtain intermediate (B), introduces R by substitution reaction subsequently2NH obtains intermediate (C), finally with 2-amino-4-trifluoromethyl pyridine-5-borate, Suzuki coupling reaction occurs again, obtains the target compound (D) with general formula II.
The reaction equation of said method is as follows:
A kind of method preparing the pyrimidine compound with general formula III: be similar to the synthesis of formula II, by successively introducing R1NH and R2NH, then occurs Suzuki to be obtained by reacting the target compound (H) with general structure III with pyrimidine boronic acid ester.
The reaction equation of said method is as follows:
Each substituent R in above-mentioned preparation process Chinese style A to formula H1And R2Definition with by formula I, substituent R in II and III1And R2Identical.
Meanwhile, additionally providing a kind of pharmaceutical composition in one embodiment of the invention, this pharmaceutical composition comprises at least one pharmaceutically acceptable adjuvant, adjuvant or carrier；And the above-mentioned PI3K inhibitors of kinases of at least one of dose therapeutically effective.
Term " therapeutically effective amount " refers to when needing the mammal of such treatment, it is sufficient to the effectively amount of the general formula compound for the treatment of.Therapeutically effective amount changes depending on the given activity of healing potion used, the age of patient, physiological situation, the existence of Other diseases state and nutriture.Additionally, the other medicines treatment that patient is likely to just accepting will affect the determination of the therapeutically effective amount of the healing potion to give.
Term " treatment " means for any treatment of disease in mammal body, including: (i) prevents disease, namely causes the clinical symptoms of disease not develop；(ii) disease is suppressed, i.e. stop the development of clinical symptoms；And/or (iii) palliates a disease, i.e. cause disappearing of clinical symptoms.
Term " pharmaceutically acceptable adjuvant, adjuvant or carrier " include any and whole solvent, disperse medium, coating, antibacterium and antifungal medicine, etc. blend absorption delay agent etc..Such medium and medicament are well known in the art for pharmaceutically active substances.Unless any conventional media or medicament and active component are incompatible, its application in therapeutic combination is expected.The active component supplemented can also be incorporated in compositions.
Said composition is preferably formulated as unit dosage forms.Term " unit dosage forms " refers to and is suitable for use as the physical discrete unit giving human experimenter and other mammiferous single doses, and per unit contains the predetermined amount calculating to produce required therapeutically effective active substance and relevant suitable pharmaceutical excipient (such as tablet, capsule, ampoule).In PI3K inhibitors of kinases, pyrimidine compound is effectively and generally give active drug amount in dosage range widely.Preferably for oral administration, each dosage unit comprises pyrimidine compound in the PI3K inhibitors of kinases of 10mg to 2g, it is more preferably 10 to 700mg, and for parenteral, it is preferred to pyrimidine compound in the PI3K inhibitors of kinases of 10 to 700mg, more preferably from about 50 to 200mg.But, it will be clear that, in the actual PI3K inhibitors of kinases given, the amount of pyrimidine compound will be determined by the situation that physician in view is relevant, including the disease to treat, the route of administration selected, the actual compound given and its relative activity, the age of each patient, body weight and reaction, the seriousness etc. of patients symptomatic.
In order to prepare solid composite such as tablet, carrying out mixing to form solid preformulation composition with drug excipient (or carrier) by main active component, it comprises the homogeneous mixture of compound of the present invention.When being uniform when claiming these preformulation composition, it refers to that active component is dispersed in whole compositions, so that compositions can easily be subdivided into identical effective unit dosage forms such as tablet, pill and capsule.
The tablet of the present invention or pill can applied or otherwise by compound to provide a kind of dosage form having and extending effect beneficial, or protection tablet or pill are from the effect of acid condition in stomach.Such as, tablet or pill can include interior dosage and external dose composition, and the latter has the form of the crust on the former.Can separating two kinds of compositions with enteric layer, in wherein enteric layer is used for stoping disintegrate under one's belt and allow, composition completely enters duodenum or is delayed by release.Various materials may be used for such enteric layer or coating, and above-mentioned material includes many polymer acids and polymer acid and the mixture of such material such as Lac, hexadecanol and cellulose acetate.
The solution in pharmaceutically acceptable aqueous solvent or organic solvent or its mixture and suspension and powder is included for the compositions of inhalation or insufflation.Liquid or solid compositions can comprise suitable pharmaceutical excipient as described above.Preferably, these compositionss are given to obtain locally or systemically effect by oral or nasal respiratory route.Can by using noble gas to be atomized the compositions in preferred pharmaceutically acceptable solvent.Directly can suck atomized soln from atomising device, or atomising device can be connected to face shield account shape thing or intermittent positive pressure breathing machine.Can by the device delivering dosage form in a suitable manner, it is preferable that oral or nose approach, give solution, suspensoid or powder composite.
In yet another aspect, present invention also offers a kind of above-mentioned P13K inhibitors of kinases or aforementioned pharmaceutical compositions application in the medicine of Prevention and/or the proliferative disease for the treatment of and/or auxiliary treatment PI3K zymogenesis.Wherein the proliferative disease of PI3K zymogenesis is cancer.This cancer includes the form of solid cancer and hematologic cancer.Preferably, the proliferative disease of this PI3K zymogenesis is colorectal cancer, gastric cancer, breast carcinoma, pulmonary carcinoma, hepatocarcinoma, carcinoma of prostate, cancer of pancreas, thyroid carcinoma, bladder cancer, renal carcinoma, cerebroma, neck cancer, the cancer of CNS, glioblastoma, or myeloproliferative disease, and leukemia and lymphatic cancer.
In yet another aspect, present invention also offers the application of a kind of above-mentioned P13K inhibitors of kinases or aforementioned pharmaceutical compositions vitro inhibition cancer cell growth.
By embodiment 1-24, the present invention will be further described below, but, these embodiments should not be taken as limiting the scope of the invention.
Unless other aspects show all of temperature and are decided to be degree Celsius in the embodiments described below.Reagent is bought in goods providers such as AlfaAesarChemicalCompany, lark prestige Science and Technology Ltd., and Aladdin reagent company limited, Beijing coupling Science and Technology Ltd. etc., all without through being further purified during use, unless other aspects show.General reagent is from Xi Long chemical plant, Shantou, and Guangzhou Chemical Reagent Factory, Tianjin Zhi Yuan chemical reagent company limited and Haiyang Chemical Plant, Qingdao etc. are commercially available.
In the embodiments described below, chromatographic column uses silicagel column, and silica gel (200-300 order) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum is with CDC13Or DMSO-d6For solvent (in units of ppm), with TMS (0ppm) or chloroform (7.26ppm) as reference standard.When multiplet occurs time, following abbreviation will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doubletofdoublets, quartet), dt (doubletoftriplets, double; two triplets).Coupling constant, represents with hertz (Hz).
In the embodiments described below, Algorithm (MS) data are by being equipped with what the spectrogrph of the Agilent6120 series LC-MS of G1311B quaternary pump and G1316BTCC (column temperature is maintained at 30 DEG C) measured, G1329B automatic sampler and G1315CDAD detector are applied to analyze, and ESI source is applied to LC-MS spectrogrph.
In the embodiments described below, volume injected is to be determined by sample concentration；Flow velocity is 0.5mL/min；The UV-Vis wavelength that the peak value of HPLC is by locating at 210nm and 254nm records reading.Mobile phase is isopropanol/normal hexane (40:60).
The embodiments described below is easy to statement, and part material can be described with its abbreviation, and these are called for short with its full name as follows as directed: DCM is CH2Cl2, i.e. dichloromethane；CHCl3For chloroform, i.e. chloroform；CDC13For deuterochloroform；PE is petroleum ether；EtOAc and EA is ethyl acetate；MeOH and CH3OH is methanol；EtOH and CH3CH2OH is ethanol；HCl is hydrochloric acid；AcOH and acetic acid are acetic acid；NH4OH and NH3·H2O is ammonia；Et3N and TEA is triethylamine；K2CO3For potassium carbonate；KI is potassium iodide；NBS is bromo-succinimide；NaHSO3For sodium sulfite；DIPEA is N, N-diisopropylethylamine；THF is oxolane；Pd(dppf)Cl2·CH2Cl2For [double; two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex；DMF is N,N-dimethylformamide；SOCl2For thionyl chloride；POCl3For phosphorus oxychloride；DMSO is dimethyl sulfoxide；DMSO-d6It is six deuterated dimethyl sulfoxides；H2O is water；ML is milliliter；Rt is retention time.
Embodiment 1: the synthesis of pyrimidine compound ZJQ-04.
The synthesis of step 1:5-bromo-4-(trifluoromethyl) pyridine-2-amine.
The structural formula of 5-bromo-4-(trifluoromethyl) pyridine-2-amine:
Synthetic method: 4-trifluoromethyl-PA (10g, 61.69mmol) is dissolved in CH2Cl2(100mL) in, being dividedly in some parts bromo-succinimide (NBS, 12.08g, 67.86mmol) under room temperature, lucifuge room temperature reaction is overnight.Reaction system CH2Cl2(100mL) dilution, uses saturated NaHSO3Washing twice, saturated NaCl aqueous solution is washed once, and anhydrous sodium sulfate dries.Decompression boils off solvent, residue column chromatographic isolation and purification, eluant: petrol ether/ethyl acetate=4/1, obtains target product 13.08g, brown solid, yield: 87.96%.
The nuclear magnetic data of product is1HNMR(400MHz,CDCl3) δ: 8.28 (s, 1H), 6.78 (s, 1H), 4.82 (s, 2H).Identical with ACSMed.Chem.Lett.2011,2,774 779 literary composition.By above-mentioned data it can be seen that through the product prepared by said method be target product 5-bromo-4-(trifluoromethyl) pyridine-2-amine.
The synthesis of step 2:5-(4,4,5,5-tetramethyl-1,3,2-dioxy borine-2-base)-4-(trifluoromethyl) pyridine-2-amine.
The structural formula of 5-(4,4,5,5-tetramethyl-1,3,2-dioxy borine-2-base)-4-(trifluoromethyl) pyridine-2-amine:
Synthetic method: by 5-bromo-4-(trifluoromethyl) pyridine-2-amine (6.54g of synthesis in step 1,27.26mmol) be dissolved in dioxane (100mL), then potassium acetate (8.03g it is sequentially added into, 81.77mmol), pinacol borate (7.62g, 29.98mmol), nitrogen is replaced, and 10min is stirred at room temperature, add Pd (dppf) Cl2·CH2Cl2(1.12g, 1.37mmol), is then warmed up to 115 DEG C of reaction 24h.Decompression boils off solvent, and residue is dissolved in ethyl acetate (200mL), washes twice, and saturated NaCl aqueous solution is washed once, and anhydrous sodium sulfate dries.Concentration, residue column chromatographic isolation and purification, eluant: petrol ether/ethyl acetate=3/1, obtain brown solid, solid is resuspended in normal hexane, filter, obtain target product 6.60g, white solid, yield: 84.04%.
The mass spectrometric data of product is LC-MS:289 (M+H).Identical with ACSMed.Chem.Lett.2011,2,774 779 literary composition.By above-mentioned data it can be seen that through the product prepared by said method be target product 5-(4,4,5,5-tetramethyl-1,3,2-dioxy borine-2-bases)-4-(trifluoromethyl) pyridine-2-amine.
The synthesis of step 3:6-oxygen-3-azabicyclo [3.1.0] hexane-3-benzyl carboxylate.
The structural formula of 6-oxygen-3-azabicyclo [3.1.0] hexane-3-benzyl carboxylate:
Synthetic method: by 2,5-pyrrolin alkane-1-benzyl formate (10g, 49.24mmol) be dissolved in dichloromethane (30mL), it is slowly added dropwise metachloroperbenzoic acid (10.55g, 61.14mmol) dichloromethane (70mL) mixed liquor in, be stirred at room temperature reaction 16h.Filtering, filtrate is respectively washed once with saturated sodium thiosulfate (100mL) and saturated sodium bicarbonate (100mL), and saturated NaCl aqueous solution is washed once, anhydrous Na2SO4Dry.Decompression boils off solvent, and the direct column chromatography for separation of residue, eluant: EA/PE=1/3 obtains target product 7.39g, yield: 68.49%.
The nuclear magnetic data of product is1HNMR(400MHz,CDCl3) δ: 7.41-7.29 (m, 5H), 5.16-5.04 (m, 2H), 3.86 (dd, J=19.1,12.8Hz, 2H), 3.73-3.63 (m, 2H), 3.38 (dd, J=12.7,6.0Hz, 2H).Identical with J.Med.Chem.2010,53,6730 6746 literary composition.By above-mentioned data it can be seen that through the product prepared by said method be target product 6-oxygen-3-azabicyclo [3.1.0] hexane-3-benzyl carboxylate.
The synthesis of step 4:rac-(3RS, 4RS)-3-(2-bromine oxethyl)-4-hydroxyl pyrrolidine-1-benzyl carboxylate.
The structural formula of rac-(3RS, 4RS)-3-(2-bromine oxethyl)-4-hydroxyl pyrrolidine-1-benzyl carboxylate:
Synthetic method: 6-oxygen-3-azabicyclo [3.1.0] hexane-3-benzyl carboxylate (3.16g that step 3 is synthesized, 14.42mmol) be dissolved in dry methylene chloride (20mL), add ethylene bromohyrin (1.97g, 15.87mmol), then diethyl ether solution (the 0.22g of boron trifluoride at room temperature it is slowly added to, 0.19mmol), stirred overnight at room temperature.Reaction system dichloromethane (30mL) dilutes, and once, saturated NaCl aqueous solution is washed once, and anhydrous sodium sulfate dries in washing, and decompression boils off solvent, residue column chromatography for separation, and eluant: EA/PE=2/1 obtains product 1.44g, yield: 29.03%.
The nuclear magnetic data of product is1HNMR(400MHz,CDCl3) δ: 7.32-7.16 (m, 5H), 5.03 (s, 2H), 4.16 (s, 1H), 3.78 (s, 1H), 3.73-3.66 (m, 1H), 3.56 (dd, J=14.9,12.0Hz, 2H), 3.41 (dd, J=23.8,12.8Hz, 2H), 3.32 (t, J=6.0Hz, 2H), 3.03 (s, 2H).13CNMR(100MHz,CDCl3) δ: 155.66 (s), 137.09 (s), 128.50 (s), 128.04 (s), 127.82 (s), 83.27 (s), 82.52 (s), 73.32 (s), 72.38 (s), 69.38 (s), 66.92 (s), 30.35 (s).By above-mentioned data it can be seen that through the product prepared by said method be target product rac-(3RS, 4RS)-3-(2-bromine oxethyl)-4-hydroxyl pyrrolidine-1-benzyl carboxylate.
The synthesis of step 5:rac-(4RS, 7RS)-tetrahydrochysene-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-benzyl carboxylate.
The structural formula of rac-(4RS, 7RS)-tetrahydrochysene-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-benzyl carboxylate:
Synthetic method: the rac-(3RS that step 4 is synthesized, 4RS)-3-(2-bromine oxethyl)-4-hydroxyl pyrrolidine-1-benzyl carboxylate (1.43g, 4.17mmol) it is dissolved in dehydrated alcohol (10mL), add potassium hydroxide (0.26g, dehydrated alcohol (3mL) solution 4.59mmol), is then heated to reflux 6h.Filtering, filter cake ethyl acetate (50mL) drip washing, merging filtrate, evaporated under reduced pressure, residue column chromatography for separation (eluant: EA/PE=1/1) obtains product 0.74g, yield: 67.27%.
The mass spectrometric data of product is LC-MS:264.1 (M+H).Nuclear magnetic data is1HNMR (400MHz, CDCl3) δ: 7.35 (d, J=4.6Hz, 5H), 5.13 (d, J=3.1Hz, 2H), 3.92-3.70 (m, 6H), 3.60 (s, 2H), 3.15 (dd, J=9.5,4.6Hz, 2H).13CNMR(100MHz,CDCl3) δ: 155.15 (s), 136.40 (s), 128.50 (s), 128.08 (s), 127.96 (s), 77.90 (s), 77.55 (s), 76.56 (s), 67.13 (s), 45.89 (s).By above-mentioned data it can be seen that through the product prepared by said method be target product rac-(4RS, 7RS)-tetrahydrochysene-2H-[Isosorbide-5-Nitrae] two [2,3-c] pyrroles-6 (3H)-benzyl carboxylate.
The synthesis of step 6:rac-(4RS, 7RS)-hexahydro-2H-[1,4] two [2,3-c] pyrroles.
The structural formula of rac-(4RS, 7RS)-hexahydro-2H-[1,4] two [2,3-c] pyrroles:
Synthetic method: by the rac-(4RS synthesized by step 5,7RS)-tetrahydrochysene-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-benzyl carboxylate (0.30g, 1.14mmol) it is dissolved in dry THF (10mL), add 10%Pd/C (0.10g), hydrogen exchange twice, room temperature hydrogenolysis 6h.Filtering, filtrate is evaporated and obtains product, is directly used in following step 8 and reacts.
The mass spectrometric data of product is LC-MS:130 (M+H).Identical with WO2004043472.By above-mentioned data it can be seen that through the product prepared by said method be target product rac-(4RS, 7RS)-hexahydro-2H-[Isosorbide-5-Nitrae] two [2,3-c] pyrroles.
The synthesis of step 7:4-(2,6-dichloro pyrimidine-4-base) morpholine.
The structural formula of 4-(2,6-dichloro pyrimidine-4-base) morpholine:
Synthetic method: by 2,4,6-trichloropyrimidine (1.0g, 5.45mmol) it is dissolved in dry dichloromethane (10mL), adds DIPEA (0.74g, 0.95mL), it is cooled to-5 DEG C, is slowly added dropwise into morpholine (0.47g, 5.45mmol).It is to slowly warm up to room temperature reaction 2h.Adding water in system, separate organic facies, saturated NaCl aqueous solution is washed once, and anhydrous sodium sulfate dries.Decompression boils off solvent, and residue column chromatography for separation (eluant: EA/PE=1/4) obtains product 1.02g, yield: 65.81%.
The nuclear magnetic data of product is1HNMR(400MHz,CDCl3) δ: 6.39 (d, J=4.5Hz, 1H), 3.88-3.49 (m, 8H).Identical with WO2006005918.By above-mentioned data it can be seen that through the product prepared by said method be target product 4-(2,6-dichloro pyrimidine-4-base) morpholine.
The synthesis of step 8:rac-(4RS, 7RS)-6-(the chloro-6-morpholine pyrimidine-2-base of 4-) hexahydro-2H-[1,4] two [2,3-c] pyrroles.
The structural formula of rac-(4RS, 7RS)-6-(the chloro-6-morpholine pyrimidine-2-base of 4-) hexahydro-2H-[1,4] two [2,3-c] pyrroles:
Synthetic method: 4-(2, the 6-dichloro pyrimidine-4-base) morpholine (0.42g, 1.80mmol) synthesized by step 7 is dissolved in THF/EtOH (1:1, in 12mL), add rac-(4RS, 7RS)-hexahydro-2H-[Isosorbide-5-Nitrae] two [2 synthesized in step 6,3-c] pyrroles (1.64mmol), triethylamine (0.20g, 1.97mmol), sodium iodide (246mg, 1.80mmol), heating reacts 12h to 60 DEG C.Decompression boils off solvent, ethyl acetate (50mL) dissolution residual substance, washes twice, and saturated NaCl aqueous solution is washed once, and anhydrous sodium sulfate dries.Boiling off solvent, column chromatographic isolation and purification (eluant: EA/PE=1/5) obtains product 0.28g, yield: 52.34%.
The mass spectrometric data of product is LC-MS:327.10 (M+H).Nuclear magnetic data is1HNMR(400MHz,CDCl3) δ: 5.87 (s, 1H), 3.96 (s, 2H), 3.90-3.81 (m, 5H), 3.77-3.64 (m, 7H), 3.58-3.51 (m, 4H).13CNMR(100MHz,CDCl3) δ: 163.26 (s), 160.39 (s), 159.46 (s), 91.00 (s), 78.14 (s), 67.24 (s), 66.31 (s), 46.39 (s), 44.35 (s).By above-mentioned data it can be seen that through the product prepared by said method be target product rac-(4RS, 7RS)-6-(the chloro-6-morpholine pyrimidine-2-base of 4-) hexahydro-2H-[Isosorbide-5-Nitrae] two [2,3-c] pyrroles.
Step 9: the synthesis of pyrimidine compound ZJQ-04 of the present invention.
Rac-5-(6-morpholine-2-((4RS, 7RS)-tetrahydrochysene)-2H-[1,4] two) [2,3-c] pyrroles-6 (3H)-Ji) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. the structural formula of compound ZJQ-04:
Synthetic method: by the rac-(4RS synthesized by step 8,7RS)-6-(the chloro-6-morpholine pyrimidine-2-base of 4-) hexahydro-2H-[1,4] two [2,3-c] pyrroles (200mg, 0.61mmol) it is dissolved in the dioxane (3.9mL) of deoxidation, it is sequentially added into the 5-(4,4,5 synthesized by step 2,5-tetramethyl-1,3,2-dioxy borine-2-bases)-4-(trifluoromethyl) pyridine-2-amine (0.35g, 1.23mmol), 2M wet chemical (1.05mL, 2.1mmol), pass into nitrogen 10min, be subsequently adding Pd (dppf) Cl2·CH2Cl2(25mg, 0.031mmol), seals, in 150 DEG C of microwave reaction 2.5h.Concentration removes solvent, and residue is dissolved in ethyl acetate (50mL), washes twice, and saturated NaCl aqueous solution is washed once, and anhydrous sodium sulfate dries.Decompression boils off solvent, residue column chromatographic isolation and purification, eluant: petrol ether/ethyl acetate=3/1-1/2, obtains yellow solid.This solid carries out secondary column chromatography purification, eluant: methylene chloride/methanol=50/1, obtains target product 47mg, white solid, yield: 16.97%, purity: 98.20%.
The high resolution mass spectrum data of product are HRMS (ESI): m/z [M+H]+calcd.for[C20H24F3N6O3]+: 453.1856, found:453.1852.Nuclear magnetic data is1HNMR(400MHz,CDCl3) δ: 8.25 (s, 1H), 6.76 (s, 1H), 5.95 (s, 1H), 5.29 (s, 1H), 4.82 (s, 2H), 4.01 (s, 2H), 3.87 (s, 3H), 3.79-3.70 (m, 6H), 3.63-3.56 (m, 4H), 3.26 (t, J=10.0Hz, 2H).13CNMR(100MHz,CDCl3) δ: 163.01 (s), 160.06 (s), 159.08 (s), 150.34 (s), 138.07 (s), 124.44 (s), 121.87 (s), 105.33 (s), 100.14 (s), 93.04 (s), 78.81 (s), 67.75 (s), 66.46 (s), 46.75 (s), 44.24 (s).From above-mentioned data, it is target product rac-5-(6-morpholine-2-((4RS through the product prepared by said method, 7RS)-tetrahydrochysene)-2H-[1,4] two) [2,3-c] pyrroles-6 (3H)-Ji) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. compound ZJQ-04.
Embodiment 2: the synthesis of pyrimidine compound ZJQ-05.
Step 1:(2R, 4R) the synthesis of-1-tert-butyl group-2-methyl-4-((t-butyldimethylsilyl) oxo) nafoxidine-1,2-dicarboxylic ester.
The structural formula of (2R, the 4R)-1-tert-butyl group-2-methyl-4-((t-butyldimethylsilyl) oxo) nafoxidine-1,2-dicarboxylic ester:
Synthetic method: by (2R, the 4R)-1-tert-butyl group-2-methyl 4-hydroxy-pyrrolidine-1,2-bis-carbonic ester (5g, 20.40mmol) be dissolved in dichloromethane (40mL), DIPEA (7.46mL, 44.87mmol), is cooled to-40 DEG C, dropping tert-butyl group dimethyl silyl triflate (5.63mL, 24.48mmol) continues stirring 3h afterwards.Adding a large amount of shrend to go out reaction, add dichloromethane and extract, anhydrous sodium sulfate dries, concentration, crosses column purification, eluant: PE/EA=3/1, obtains target product 6.63g, yield 90.45%.
The mass spectrometric data of product is LC-MS:360.2 (M+H).Identical with WO2009137130.By above-mentioned data it can be seen that through the product prepared by said method be target product (2R, the 4R)-1-tert-butyl group-2-methyl-4-((t-butyldimethylsilyl) oxo) nafoxidine-1,2-dicarboxylic ester.
Step 2:(2R, 4R) the synthesis of-tert-butyl group-4-((t-butyldimethylsilyl) oxo)-2-(methylol) nafoxidine-1-carboxylate.
The structural formula of (2R, 4R)-tert-butyl group-4-((t-butyldimethylsilyl) oxo)-2-(methylol) nafoxidine-1-carboxylate:
Synthetic method: by (2R synthesized in step 1, the 4R)-1-tert-butyl group-2-methyl-4-((t-butyldimethylsilyl) oxo) nafoxidine-1,2-dicarboxylic ester (6.63g, 18.46mmol) be dissolved in dry THF (50mL), it is cooled to 0 DEG C, after adding lithium borohydride (1.0g, 46.14mmol), recover stirred overnight at room temperature.It is cooled at 0 DEG C and is slowly added to methanol cancellation reaction, then filter, concentrated filtrate, cross post and be purified, obtain 3.80g target product, colourless oil liquid, yield: 62.19%.
The mass spectrometric data of product is LC-MS:276.2 (M-55).Nuclear magnetic data is1HNMR(400MHz,CDCl3) δ: 4.60 (s, 1H), 4.30 (d, J=25.1Hz, 1H), 4.08-3.92 (m, 1H), 3.86-45 (m, 3H), 3.32 (d, J=11.6Hz, 1H), 3.16 (dd, J=29.0,8.0Hz, 1H), 2.13 (s, 2H), 1.43 (s, 8H), 0.85 (s, 9H), 0.05 (d, J=4.5Hz, 6H).Identical with US20080081803.By above-mentioned data it can be seen that through the product prepared by said method be target product (2R, the 4R)-tert-butyl group-4-((t-butyldimethylsilyl) oxo)-2-(methylol) nafoxidine-1-carboxylate.
Step 3:(2R, 4R) synthesis of-tertiary butyl-4-hydroxy-2-((benzenesulfonyl oxo) methyl) nafoxidine-1-carboxylate
The structural formula of (2R, 4R)-tertiary butyl-4-hydroxy-2-((benzenesulfonyl oxo) methyl) nafoxidine-1-carboxylate:
Synthetic method the: by (2R synthesized by step 2, the 4R)-tert-butyl group-4-((t-butyldimethylsilyl) oxo)-2-(methylol) nafoxidine-1-carboxylate (3.80g, 11.47mmol) be dissolved in dry methylene chloride (50mL), add DIPEA (3.80mL, 22.94mmol) after be cooled to 0 DEG C, add methylsufonyl chloride (1.96g, 17.22mmol), then recover to stirred overnight at room temperature.Add shrend to go out reaction, organic facies washing once, saturated NaHCO3Washing once, then saturated NaCl washes once, and anhydrous sodium sulfate dries.Concentration, is made directly next step.Taking above-mentioned dissolving crude product in THF (25mL), 1h is stirred at room temperature after adding tetrabutyl ammonium fluoride (3.79g, 14.49mmol), add shrend and go out reaction, decompression boils off solvent, addition CH2Cl2(100mL) extracting, organic layer is washed, and saturated NaCl aqueous solution is washed once, and anhydrous sodium sulfate dries, and concentration is crossed column purification, obtained target product 2.90g, white solid, yield: 88.14%.
The nuclear magnetic data of product is1HNMR(400MHz,CDCl3) δ: 4.44 (dd, J=9.1,4.2Hz, 2H), 4.12 (s, 1H), 3.55 (s, 1H), 3.39 (d, J=12.0Hz, 1H), 3.02 (s, 3H), 2.24-1.98 (m, 4H), 1.46 (s, 9H).13CNMR(100MHz,CDCl3) δ: 177.95 (s), 69.86 (s), 64.05 (s), 55.47 (s), 37.16 (s), 36.07 (s), 28.32 (s), 27.90 (s), 18.78 (s).By above-mentioned data it can be seen that through the product prepared by said method be target product (2R, 4R)-tertiary butyl-4-hydroxy-2-((benzenesulfonyl oxo) methyl) nafoxidine-1-carboxylate.
Step 4:(1R, 4R) the synthesis of-tert-butyl group assorted bicyclo-of-2-oxa--5-[2.2.1]-heptane-5-carboxylate.
The structural formula of (1R, the 4R)-tert-butyl group assorted bicyclo-of-2-oxa--5-[2.2.1]-heptane-5-carboxylate:
Synthetic method: by (2R synthesized in step 3, 4R)-tertiary butyl-4-hydroxy-2-((benzenesulfonyl oxo) methyl) nafoxidine-1-carboxylate (1.28g, 4.33mmol) it is dissolved in dry THF (20mL), it is cooled to-10 DEG C, add 60%NaH (0.40g, 12.98mmol), then recover 24h is stirred at room temperature, after mixed liquor is cooled to 0 DEG C, it is slowly added to shrend go out reaction, add ethyl acetate to extract, anhydrous sodium sulfate dries organic layer, concentration, residue column chromatographic isolation and purification, eluant: petrol ether/ethyl acetate=5/1-3/1, obtain 0.84g target product, white solid, yield: 44.44%.
The nuclear magnetic data of product is1HNMR(400MHz,CDCl3) δ: 4.58-4.38 (m, 2H), 3.93-3.70 (m, 2H), 3.49-3.18 (m, 2H), 1.75 (d, J=47.0Hz, 2H), 1.45 (s, 9H).13CNMR(100MHz,CDCl3) δ: 154.19 (s), 74.31 (s), 57.43 (s), 56.27 (s), 54.68 (s), 54.17 (s), 36.47 (s), 29.45 (s).By above-mentioned data it can be seen that through the product prepared by said method be target product (1R, the 4R)-tert-butyl group assorted bicyclo-of-2-oxa--5-[2.2.1]-heptane-5-carboxylate.
Step 5:(1R, 4R) synthesis of the assorted bicyclo-of-2-oxa--5-[2.2.1]-heptane trifluoroacetate.
The structural formula of the assorted bicyclo-of (1R, 4R)-2-oxa--5-[2.2.1]-heptane trifluoroacetate:
Synthetic method: (1R, the 4R)-tert-butyl group assorted bicyclo-of-2-oxa--5-[2.2.1] synthesized by step 4-heptane-5-carboxylate (0.3g, 1.51mmol) is dissolved in dry CH2Cl2(10mL), in, trifluoroacetic acid (1mL) stirred overnight at room temperature is added.Decompression boils off solvent, is directly used in the next step.
Step 6:(1R, 4R) synthesis of-5-(the chloro-6-morpholine pyrimidine-2-base of 4-)-2-oxygen-5-azabicyclo [2.2.1] heptane.
The structural formula of (1R, 4R)-5-(the chloro-6-morpholine pyrimidine-2-base of 4-)-2-oxygen-5-azabicyclo [2.2.1] heptane:
Synthetic method: by 4-(2,6-dichloro pyrimidine-4-base) morpholine (0.38g, 1.65mmol) it is dissolved in THF/EtOH (1:1,12mL), adds (the 1R synthesized by above-mentioned steps 5,4R) the assorted bicyclo-of-2-oxa--5-[2.2.1]-heptane trifluoroacetate (1.51mmol), triethylamine (0.36g, 3.32mmol), sodium iodide (227mg, 1.51mmol), heating reacts 40h to 60 DEG C.Decompression boils off solvent, ethyl acetate (50mL) dissolution residual substance, washes twice, and saturated NaCl aqueous solution is washed once, and anhydrous sodium sulfate dries.Boiling off solvent, column chromatographic isolation and purification (eluant: EA/PE=1/5) obtains target product 0.96g, yield: 66.22%.
The mass spectrometric data of product is LC-MS:297.10 (M+H).Nuclear magnetic data is1HNMR(400MHz,CDCl3) δ: 5.84 (s, 1H), 4.96 (s, 1H), 4.64 (s, 1H), 3.84 (s, 2H), 3.73 (s, 4H), 3.54 (s, 6H), 1.89 (s, 2H).13CNMR(100MHz,CDCl3) δ: 163.29 (s), 160.35 (s), 159.75 (s), 91.09 (s), 73.92 (s), 66.58 (s), 56.90 (s), 55.51 (s), 44.31 (s), 36.60 (s).By above-mentioned data it can be seen that through the product prepared by said method be target product (1R, 4R)-5-(the chloro-6-morpholine pyrimidine-2-base of 4-)-2-oxygen-5-azabicyclo [2.2.1] heptane.
Step 7: the synthesis of pyrimidine compound ZJQ-05 of the present invention.
5-(2-((1R, 4R)-2-oxygen-5-azabicyclo [2.2.1] heptane-5-base)-6-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. the structural formula of compound ZJQ-05:
Synthetic method the: by (1R synthesized by step 6,4R)-5-(the chloro-6-morpholine pyrimidine-2-base of 4-)-2-oxygen-5-azabicyclo [2.2.1] heptane (221mg, 0.75mmol) it is dissolved in the dioxane (4.8mL) of deoxidation, the 5-(4 being sequentially added in embodiment 1 synthesized by step 2,4,5,5-tetramethyl-1,3,2-dioxy borine-2-bases)-4-(trifluoromethyl) pyridine-2-amine (0.43g, 1.49mmol), 2M wet chemical (1.13mL, 2.26mmol), pass into nitrogen 10min, be subsequently adding Pd (dppf) Cl2·CH2Cl2(31mg, 0.0375mmol), seals, in 150 DEG C of microwave reaction 2.5h.Concentration removes solvent, and residue is dissolved in ethyl acetate (50mL), washes twice, and saturated NaCl aqueous solution is washed once, and anhydrous sodium sulfate dries.Decompression boils off solvent, residue column chromatographic isolation and purification, eluant: petroleum ether: ethyl acetate=3/1-1/2, obtains a yellow solid.This solid carries out secondary column chromatography purification, eluant: methylene chloride/methanol=50/1, obtains target product 75mg, white solid, yield: 23.81%, purity: 93.71%.
The high resolution mass spectrum data of product are HRMS (ESI): m/z [M+H]+calcd.for[C19H22F3N6O2]+: 423.1751, found:423.1772.Nuclear magnetic data is1HNMR(400MHz,CDCl3) δ: 8.25 (s, 1H), 6.76 (s, 1H), 5.94 (s, 1H), 4.99 (s, 1H), 4.83 (s, 2H), 4.64 (s, 1H), 3.87 (dd, J=20.0,7.2Hz, 2H), 3.81-3.66 (m, 5H), 3.62-3.56 (m, 5H), 1.90 (s, 2H).13CNMR(100MHz,CDCl3) δ: 162.99 (s), 160.73 (s), 158.77 (s), 151.01 (s), 147.41 (s), 138.08 (s), 124.43 (s), 121.89 (s), 105.32 (s), 92.07 (s), 73.34 (s), 67.15 (s), 56.76 (s), 55.50 (s), 53.22 (s), 44.79 (s), 36.36 (s).From above-mentioned data, it is target product 5-(2-((1R through the product prepared by said method, 4R)-2-oxygen-5-azabicyclo [2.2.1] heptane-5-base)-6-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. compound ZJQ-05.
Embodiment 3: the synthesis of pyrimidine compound ZJQ-22.
(-)-5-(6-morpholine-2-((4RS, 7RS)-tetrahydrochysene)-2H-[1,4] two) [2,3-c] pyrroles-6 (3H)-Ji) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. the structural formula of compound ZJQ-22:
Synthetic method: the ZJQ-04 prepared by embodiment 1 is split, separation condition: anti-phase chiral preparatory column (lu5ucellose-2 of Fei Luomen), mobile phase: methanol/water=95/5；Purity: 99.90%；Retention time: 13.94min, obtains resolved product ZJQ-22.
The high resolution mass spectrum data of resolved product are HRMS (ESI): m/z [M+H]+calcd.for[C20H24F3N6O3]+: 453.1856, found:453.1845.Optically-active data are [a]3 D 0=-34.2 (c=0.20, CHCl3).From above-mentioned data, through the product prepared by said method be target product (-)-5-(6-morpholine-2-((4RS, 7RS)-tetrahydrochysene)-2H-[1,4] two) [2,3-c] pyrroles-6 (3H)-Ji) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. compound ZJQ-22.
Embodiment 4: the synthesis of pyrimidine compound ZJQ-23.
(+)-5-(6-morpholine-2-((4SR, 7SR)-tetrahydrochysene)-2H-[1,4] two) [2,3-c] pyrroles-6 (3H)-Ji) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. the structural formula of compound ZJQ-23:
Synthetic method: the ZJQ-04 prepared by embodiment 1 is split, separation condition: anti-phase chiral preparatory column (lu5ucellose-2 of Fei Luomen), mobile phase: methanol/water=95/5；Purity: 99.07%；Retention time: 14.67min, obtains resolved product ZJQ-23.
The high resolution mass spectrum data of resolved product are HRMS (ESI): m/z [M+H]+calcd.for[C20H24F3N6O3]+: 453.1856, found:453.1863.Optically-active data areFrom above-mentioned data, through the product prepared by said method be target product (+)-5-(6-morpholine-2-((4SR, 7SR)-tetrahydrochysene)-2H-[1,4] two) [2,3-c] pyrroles-6 (3H)-Ji) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. compound ZJQ-23.
Embodiment 5: the synthesis of pyrimidine compound ZJQ-07.
The synthesis of step 1:4-(4,6-bis-chloro-1,3,5-tri-nitrogen piperazine-2-base) morpholine.
The structural formula of 4-(4,6-bis-chloro-1,3,5-tri-nitrogen piperazine-2-base) morpholine:
Synthetic method: 2,4,6-tri-chloro-1,3,5-tri-nitrogen piperazines (5.0g, 27.33mmol) are dissolved in CH2Cl2(100mL) in, it is cooled to-5 DEG C, is slowly added dropwise the CH into DIPEA (4.10mL, 24.64mmol) Yu morpholine (2.15mL, 24.64mmol)2Cl2(20mL) mixed liquor, low-temp reaction 1h, rise to 0 DEG C of reaction overnight.Reaction system CH2Cl2(50mL) dilution, 1MHCl washes twice (50mL × 2), and saturated NaCl washes once, and anhydrous sodium sulfate dries.Column chromatographic isolation and purification, eluant: PE/EA=10/1-5/1, obtain target product 4.59g, white solid, yield: 59.74%.
The nuclear magnetic data of product is1HNMR(400MHz,CDCl3) δ: 3.97-3.80 (m, 4H), 3.80-3.65 (m, 4H).Identical with WO2011039735.By above-mentioned data it can be seen that through the product prepared by said method be target product 4-(4,6-bis-chloro-1,3,5-tri-nitrogen piperazine-2-base) morpholine.
Step 2:(1R, 4R) synthesis of-5-(4-chloro-6-morpholine-1,3,5-three nitrogen piperazine-2-base)-2-oxygen-5-azabicyclo [2.2.1] heptane
The structural formula of (1R, 4R)-5-(4-chloro-6-morpholine-1,3,5-three nitrogen piperazine-2-base)-2-oxygen-5-azabicyclo [2.2.1] heptane:
Synthetic method: by 4-(4 synthesized in step 1,6-bis-chloro-1,3,5-tri-nitrogen piperazine-2-bases) morpholine (0.36g, 1.51mmol) is dissolved in THF (1:1, in 12mL), add the assorted bicyclo-of (1R, 4R)-2-oxa--5-[the 2.2.1]-heptane trifluoroacetate (1.51mmol) synthesized by embodiment 2 step 5, potassium carbonate (0.32g, 2.27mmol), stirred overnight at room temperature.Decompression boils off solvent, ethyl acetate (50mL) dissolution residual substance, washes twice, and saturated NaCl aqueous solution is washed once, and anhydrous sodium sulfate dries.Boiling off solvent, column chromatographic isolation and purification (eluant: EA/PE=1/5) obtains product 0.39g, yield: 84.46%.
The mass spectrometric data of product is LC-MS:298.2 (M+H).Nuclear magnetic data is1HNMR(400MHz,CDCl3) δ: 5.02 (d, J=35.7Hz, 1H), 4.67 (s, 1H), 3.94-3.64 (m, 10H), 3.52 (dt, J=27.2,11.2Hz, 4H).13CNMR(100MHz,CDCl3) δ: 169.09 (s), 164.57 (s), 163.29 (s), 76.13 (s), 73.57 (s), 66.84 (s), 56.77 (s), 55.22 (s), 43.79 (s), 36.73 (s).By above-mentioned data it can be seen that through the product prepared by said method be target product (1R, 4R)-5-(chloro-6-morpholine-1 of 4-, 3,5-tri-nitrogen piperazine-2-bases)-2-oxygen-5-azabicyclo [2.2.1] heptane.
Step 3: the synthesis of pyrimidine compound ZJQ-07.
5-(4-((1R, 4R)-2-oxygen-5-azabicyclo [2.2.1] heptane-5-base)-6-morpholine-1,3,5-tri-nitrogen piperazine-2-bases)-4-(trifluoromethyl) pyridine-2-amine, i.e. the structural formula of compound ZJQ-07:
Synthetic method: by (1R synthesized in step 2, 4R)-5-(the chloro-6-morpholine-1 of 4-, 3, 5-tri-nitrogen piperazine-2-base)-2-oxygen-5-azabicyclo [2.2.1] heptane (250mg, 0.84mmol) it is dissolved in the dioxane (4.0mL) of deoxidation, it is sequentially added into the 5-(4 synthesized by embodiment 1 step 2, 4, 5, 5-tetramethyl-1, 3, 2-dioxy borine-2-base)-4-(trifluoromethyl) pyridine-2-amine (0.49g, 1.69mmol), 2M wet chemical (1.26mL, 2.52mmol), pass into nitrogen 10min, it is subsequently adding Pd (dppf) Cl2·CH2Cl2(35mg, 0.042mmol), seals, in 150 DEG C of microwave reaction 2.5h.Concentration removes solvent, and residue is dissolved in ethyl acetate (50mL), washes twice, and saturated NaCl aqueous solution is washed once, and anhydrous sodium sulfate dries.Decompression boils off solvent, residue column chromatographic isolation and purification, eluant: petrol ether/ethyl acetate=3/1-1/2, obtains a brown solid.This solid carries out secondary column chromatography purification, eluant: methylene chloride/methanol=50/1, obtains target product 60mg, white solid, yield: 16.85%, purity: 95.32%.
The high resolution mass spectrum data of product are HRMS (ESI): m/z [M+H]+calcd.for[C18H21F3N7O2]+: 424.1703, found:424.1692.Nuclear magnetic data is1HNMR(400MHz,CDCl3) δ: 8.71 (s, 1H), 6.77 (s, 1H), 5.06 (d, J=35.4Hz, 1H), 4.95 (s, 2H), 4.68 (s, 1H), 3.93-3.46 (m, 12H), 1.92 (q, J=10.0Hz, 1H), 1.84 (s, 1H).13CNMR(100MHz,CDCl3) δ: 169.47 (s), 164.57 (s), 163.59 (s), 159.39 (s), 152.58 (s), 138.38 (s), 122.47 (s), 121.50 (s), 105.32 (s), 74.35 (s), 66.80 (s), 56.59 (s), 54.90 (s), 43.56 (s), 36.59 (s).From above-mentioned data, it is target product 5-(4-((1R through the product prepared by said method, 4R)-2-oxygen-5-azabicyclo [2.2.1] heptane-5-base)-6-morpholine-1,3,5-tri-nitrogen piperazine-2-base)-4-(trifluoromethyl) pyridine-2-amine, i.e. compound ZJQ-07.
Embodiment 6: the synthesis of pyrimidine compound ZJQ-28.
The synthesis of step 1:4-chloro-6-morpholine-N-(4-morpholinyl phenyl) pyrimidine-2-amine.
The structural formula of 4-chloro-6-morpholine-N-(4-morpholinyl phenyl) pyrimidine-2-amine:
Synthetic method: by the 4-(2 synthesized by embodiment 1 step 7,6-dichloro pyrimidine-4-base) morpholine (0.50g, 2.15mmol) it is dissolved in n-butyl alcohol (20mL), add 4-morpholine aniline (0.38g, 2.15mmol), one hydration p-methyl benzenesulfonic acid (0.26g, 1.72mmol), heats to 100 DEG C of reaction 24h.Decompression boils off solvent, ethyl acetate (50mL) dissolution residual substance, saturated NaHCO3Aqueous solution is washed once, and saturated NaCl aqueous solution is washed once, and anhydrous sodium sulfate dries.Boil off solvent, column chromatographic isolation and purification (eluant: EA/PE=1/1, DCM/CH3OH=10/1, gradient elution) obtain product 0.43g, yield: 53.54%.
The mass spectrometric data of product is LC-MS:376.2 (M+H).Nuclear magnetic data is1HNMR(400MHz,CDCl3) δ: 7.45-7.36 (m, 2H), 6.89 (d, J=7.4Hz, 2H), 6.83 (s, 1H), 5.97 (d, J=1.5Hz, 1H), 3.89-3.82 (m, 4H), 3.78-3.72 (m, 4H), 3.57 (s, 4H), 3.14-3.07 (m, 4H).13CNMR(100MHz,CDCl3) δ: 163.66 (s), 160.29 (s), 159.10 (s), 147.23 (s), 132.18 (s), 121.19 (s), 116.44 (s), 92.62 (s), 66.94 (s), 66.44 (s), 50.05 (s), 44.53 (s).By above-mentioned data it can be seen that through the product prepared by said method be target product 4-chloro-6-morpholine-N-(4-morpholinyl phenyl) pyrimidine-2-amine.
Step 2: the synthesis of pyrimidine compound ZJQ-28.
4-(6-amino-4-(trifluoromethyl) pyridin-3-yl)-6-morpholine-N-(4-morpholinyl phenyl) pyrimidine-2-amine, i.e. the structural formula of compound ZJQ-28:
Synthetic method: by chloro-for the 4-synthesized by step 1 6-morpholine-N-(4-morpholinyl phenyl) pyrimidine-2-amine (0.30g, 0.80mmol) it is dissolved in the dioxane (3.60mL) of deoxidation, it is sequentially added into the 5-(4 synthesized by embodiment 1 step 2,4,5,5-tetramethyl-1,3,2-dioxy borine-2-base)-4-(trifluoromethyl) pyridine-2-amine (0.27g, 1.20mmol), 2M wet chemical (1.20mL, 2.40mmol), pass into nitrogen 10min, be subsequently adding Pd (dppf) Cl2·CH2Cl2(33mg, 0.04mmol), seals, in 150 DEG C of microwave reaction 43min.Concentration removes solvent, and residue is dissolved in ethyl acetate (50mL), washes twice, and saturated NaCl aqueous solution is washed once, and anhydrous sodium sulfate dries.Decompression boils off solvent, residue column chromatographic isolation and purification, eluant: methylene chloride/methanol=50/1, obtains target product 38mg, white solid, yield: 9.50%, purity: 98.30%.
The high resolution mass spectrum data of product are HRMS (ESI): m/z [M+H]+calcd.for[C24H27F3N7O2]+: 502.2173, found:502.2163.Nuclear magnetic data is1HNMR(400MHz,CDCl3) δ: 8.27 (s, 1H), 7.47 (d, J=7.7Hz, 2H), 6.92-6.85 (m, 3H), 6.76 (s, 1H), 6.06 (s, 1H), 4.84 (s, 2H), 3.88-3.83 (m, 4H), 3.81-3.76 (m, 4H), 3.62 (d, J=4.0Hz, 4H), 3.13-3.07 (m, 4H).13CNMR(100MHz,CDCl3) δ: 163.27 (s), 162.96 (s), 159.62 (s), 158.71 (s), 151.02 (s), 146.79 (s), 137.71 (s), 137.32 (s), 133.07 (s), 123.94 (s), 120.83 (s), 116.61 (s), 104.80 (s), 94.66 (s), 66.99 (s), 66.66 (s), 50.29 (s), 44.40 (s).By above-mentioned data it can be seen that through the product prepared by said method be target product 4-(6-amino-4-(trifluoromethyl) pyridin-3-yl)-6-morpholine-N-(4-morpholinyl phenyl) pyrimidine-2-amine, i.e. compound ZJQ-28.
Embodiment 7: the synthesis of pyrimidine compound ZJQ-26.
The synthesis of step 1:4-(the chloro-2-of 6-(4-(mesyl) piperazine-1-base) pyrimidine-4-yl) morpholine
The structural formula of 4-(the chloro-2-of 6-(4-(mesyl) piperazine-1-base) pyrimidine-4-yl) morpholine:
Synthetic method: by the 4-(2 synthesized by embodiment 1 step 7,6-dichloro pyrimidine-4-base) morpholine (0.40g, 1.72mmol) it is dissolved in THF/EtOH (1:1,20mL), adds N-first sulfo group piperazine (0.31g, 1.89mmol), DIPEA (0.34g, 2.58mmol), sodium iodide (258mg, 1.72mmol), heating reacts 24h to 70 DEG C.Decompression boils off solvent, ethyl acetate (100mL) dissolution residual substance, washes twice, and saturated NaCl aqueous solution is washed once, and anhydrous sodium sulfate dries.Boiling off solvent, column chromatographic isolation and purification (eluant: EA/PE=1/3-1/1) obtains product 0.31g, yield: 50.65%.
The mass spectrometric data of product is LC-MS:362.1 (M+H).Nuclear magnetic data is1HNMR(400MHz,CDCl3) δ: 5.89 (d, J=2.8Hz, 1H), 3.90 (d, J=3.6Hz, 4H), 3.80-3.70 (m, 4H), 3.55 (s, 4H), 3.24 (d, J=4.0Hz, 4H), 2.78 (d, J=2.8Hz, 3H).13CNMR(100MHz,CDCl3)δ:163.51(s),160.65(s),160.47(s),91.78(s),66.83(s),45.77(s),44.47(s),43.46(s),34.48(s).By above-mentioned data it can be seen that through the product prepared by said method be target product 4-(the chloro-2-of 6-(4-(mesyl) piperazine-1-base) pyrimidine-4-yl) morpholine.
Step 2: the synthesis of pyrimidine compound ZJQ-26.
5-(2-(4-(mesyl) piperazine-1-base)-6-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. the structural formula of compound ZJQ-26:
Synthetic method: by 4-(the chloro-2-of 6-(4-(mesyl) piperazine-1-base) pyrimidine-4-yl) morpholine (0.25g prepared in step 1; 0.69mmol) it is dissolved in the dioxane (3.0mL) of deoxidation; the 5-(4 being sequentially added in embodiment 1 synthesized by step 2; 4; 5; 5-tetramethyl-1; 3; 2-dioxy borine-2-base)-4-(trifluoromethyl) pyridine-2-amine (0.40g; 1.38mmol), 2M wet chemical (1.05mL, 2.07mmol); pass into nitrogen 10min, be subsequently adding Pd (dppf) Cl2·CH2Cl2(28mg, 0.035mmol), seals, in 150 DEG C of microwave reaction 2.5h.Concentration removes solvent, and residue is dissolved in ethyl acetate (50mL), washes twice, and saturated NaCl aqueous solution is washed once, and anhydrous sodium sulfate dries.Decompression boils off solvent, and residue column chromatographic isolation and purification (eluant: methylene chloride/methanol=50/1) obtains target product 49mg, white solid, yield: 14.54%, purity: 97.34%.
The high resolution mass spectrum data of product are HRMS (ESI): m/z [M-H]-calcd.for[C19H24F3N7O3S]+: 486.1507, found:486.1498.Nuclear magnetic data is1HNMR(400MHz,CDCl3)δ:8.23(s,1H),6.79(s,1H),5.98(s,1H),4.94(s,2H),3.99-3.89(m,4H),3.84-3.74(m,4H),3.66-3.53(m,4H),3.31-3.20(m,4H),2.77(s,3H)。13CNMR(100MHz,CDCl3)δ:163.32(s),162.93(s),160.91(s),158.84(s),150.69(s),144.28(s),137.71(s),124.13(s),105.44(s),92.70(s),66.64(s),45.77(s),44.28(s),43.57(s),34.33(s).From above-mentioned data; be target product 5-(2-(4-(mesyl) piperazine-1-base)-6-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine through the product prepared by said method, i.e. compound ZJQ-26.
Embodiment 8: the synthesis of pyrimidine compound ZJQ-21.
The synthesis of step 1:rac-(4RS, 7RS)-6-(4-chloro-6-morpholine-1,3,5-three nitrogen piperazine-2-base) hexahydro-2H-[1,4] two [2,3-c] pyrroles.
The structural formula of rac-(4RS, 7RS)-6-(4-chloro-6-morpholine-1,3,5-three nitrogen piperazine-2-base) hexahydro-2H-[1,4] two [2,3-c] pyrroles:
Synthetic method: by the 4-(4,6-bis-chloro-1,3 synthesized by embodiment 5 step 1,5-tri-nitrogen piperazine-2-base) morpholine (0.27g, 1.14mmol) it is dissolved in THF (10mL), adds rac-(4RS, 7RS)-hexahydro-2H-[1,4] two [2,3-c] pyrroles (0.18g, 1.14mmol), DIPEA (0.18g, 1.37mmol), stirred overnight at room temperature.Decompression boils off solvent, ethyl acetate (50mL) dissolution residual substance, washes twice, and saturated NaCl aqueous solution is washed once, and anhydrous sodium sulfate dries.Boiling off solvent, column chromatographic isolation and purification (eluant: EA/PE=1/5) obtains product 0.31g, yield: 82.23%.
The mass spectrometric data of product is LC-MS:328.1 (M+H).Nuclear magnetic data is1HNMR(400MHz,CDCl3) δ: 4.08-3.41 (m, 16H), 3.31-3.14 (m, 2H).13CNMR(100MHz,CDCl3) δ: 169.18 (s), 164.17 (s), 163.82 (s), 77.77 (s), 67.18 (s), 66.62 (s), 46.17 (s), 43.82 (s).By above-mentioned data it can be seen that through the product prepared by said method be target product rac-(4RS, 7RS)-6-(chloro-6-morpholine-1 of 4-, 3,5-tri-nitrogen piperazine-2-bases) hexahydro-2H-[Isosorbide-5-Nitrae] two [2,3-c] pyrroles.
Step 2: the synthesis of pyrimidine compound ZJQ-21.
Rac-5-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-Ji)-1,3,5-tri-nitrogen piperazine-2-base)-4-(trifluoromethyl) pyridine-2-amine, i.e. the structural formula of compound ZJQ-21:
Synthetic method: by the rac-(4RS synthesized by step 1, 7RS)-6-(the chloro-6-morpholine-1 of 4-, 3, 5-tri-nitrogen piperazine-2-base) hexahydro-2H-[1, 4] two [2, 3-c] pyrroles (250mg, 0.76mmol) it is dissolved in the dioxane (3.5mL) of deoxidation, it is sequentially added into the 5-(4 synthesized by embodiment 1 step 2, 4, 5, 5-tetramethyl-1, 3, 2-dioxy borine-2-base)-4-(trifluoromethyl) pyridine-2-amine (0.44g, 1.53mmol), 2M wet chemical (1.14mL, 2.28mmol), pass into nitrogen 10min, it is subsequently adding Pd (dppf) Cl2·CH2Cl2(31mg, 0.038mmol), seals, in 150 DEG C of microwave reaction 2.5h.Concentration removes solvent, and residue is dissolved in ethyl acetate (50mL), washes twice, and saturated NaCl aqueous solution is washed once, and anhydrous sodium sulfate dries.Decompression boils off solvent, residue column chromatographic isolation and purification, eluant: methylene chloride/methanol=50/1, obtains target product 35mg, white solid, yield: 10.12%, purity: 90.49%.
The mass spectrometric data of product is LC-MS:454.2 (M+H).Nuclear magnetic data is1HNMR(400MHz,CDCl3) δ: 8.72 (s, 1H), 6.77 (s, 1H), 4.90 (s, 2H), 4.16-3.60 (m, 16H), 3.26 (dt, J=14.9,10.0Hz, 2H).13CNMR(100MHz,CDCl3) δ: 169.73 (s), 164.52 (s), 163.88 (s), 159.75 (s), 152.72 (s), 138.10 (s), 122.28 (s), 105.32 (s), 99.74 (s), 78.01 (s), 67.27 (s), 66.80 (s), 45.82 (s), 43.58 (s).From above-mentioned data, it is target product rac-5-(4-morpholine-6-((4RS through the product prepared by said method, 7RS)-tetrahydrochysene-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-Ji)-1,3,5-tri-nitrogen piperazine-2-bases)-4-(trifluoromethyl) pyridine-2-amine, i.e. compound ZJQ-21.
Embodiment 9: the synthesis of pyrimidine compound ZJQ-29.
(-)-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-Ji)-1,3,5-tri-nitrogen piperazine-2-base)-4-(trifluoromethyl) pyridine-2-amine, i.e. the structural formula of compound ZJQ-29:
Synthetic method: prepared ZJQ-21 is split, separation condition: anti-phase chiral preparatory column (lu5ucellose-2 of Fei Luomen), mobile phase: methanol/water=95/5；Purity: 97.70%；Retention time: 12.25min, obtains resolved product ZJQ-29.
The mass spectrometric data of product is LC-MS:454.2 (M+H).Optically-active data are [a]3 D 0=-29.5 (c=0.21, CHCl3).From above-mentioned data, through the product prepared by said method be target product (-)-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-Ji)-1,3,5-tri-nitrogen piperazine-2-bases)-4-(trifluoromethyl) pyridine-2-amine, i.e. compound ZJQ-29.
Embodiment 10: the synthesis of pyrimidine compound ZJQ-30.
(+)-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-Ji)-1,3,5-tri-nitrogen piperazine-2-base)-4-(trifluoromethyl) pyridine-2-amine, i.e. the structural formula of compound ZJQ-30:
Synthetic method: prepared ZJQ-21 is split, separation condition: anti-phase chiral preparatory column (lu5ucellose-2 of Fei Luomen), mobile phase: methanol/water=95/5；Purity: 98.62%；Retention time: 14.25min, obtains resolved product ZJQ-30.
The mass spectrometric data of product is LC-MS:454.2 (M+H).Optically-active data areFrom above-mentioned data, through the product prepared by said method be target product (+)-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-Ji)-1,3,5-tri-nitrogen piperazine-2-bases)-4-(trifluoromethyl) pyridine-2-amine, i.e. compound ZJQ-30.
Also being prepared for other compound in table 1 below in the present invention, the synthetic method of these compounds is with reference to said method simultaneously.The sign data of these compounds, as shown in table 1 including nuclear magnetic data and high resolution mass spectrum data.
Table 1
External PI3K alpha kinase suppresses test:
The compounds of this invention suppresses PI3K alpha kinase activity, thus suppresses the transduction of cell-signaling pathways, thus affecting cell cycle and cell proliferation.The inhibitory action of PI3K alpha kinase is passed through following Kinase-GloLuminescentKinaseAssay method evaluation by this compounds.
Detection instrument: adopt Kinase-GloPlusLuminescentKinaseAssay (KinaseGloPlus kinases luminous detection) test kit to carry out test target compound kinase inhibiting activity.
Cleaning Principle: Kinase-GloPlusLuminescentKinaseAssay is the inactive detection method of a kind of homogenizing, and it is to carry out the kinase whose activity of quantitative assay purification by the content of ATP in system after detecting kinase reaction.The mensuration of ATP content is by by Mg2+, the light intensity that produces after aoxidizing of ATP and oxygen catalysis firefly luciferin (beetleluciferin) come quantitative.Reaction system adds a certain amount of ATP, kinase reaction needs to consume ATP, remaining ATP is luminous after can reacting with the LUC Photinus pyralis LUC Photinus pyralis FL in KinaseGlo reagent, such that it is able to the amount of the remaining ATP of detection by quantitative, kinase whose activity is reacted in indirect determination.
Detection method: test-compound is formulated as 100 × concentration of highest response inhibition concentration with 100% dimethyl sulfoxide (DMSO), draws in 100 μ L to 96 orifice plate one holes.Then hole-specifically carry out the Concentraton gradient dilution of 3 times with 100%DMSO, prepare 10 concentration." completely " and " blank " control wells 100%DMSO of 100 μ L replaces.Wherein, " completely " control wells is without compound group, and " blank " control wells is without kinases group.Subsequently, the preparation compound intermediate diluent containing 4%DMSO, compound method is add 4 μ L compounds and 96 μ L1 × kinases basis buffer in each hole of detection plate.2.5 μ L above-claimed cpd intermediate diluent are added Sptting plate, then kinases (is added 1 × kinases basis buffer (50mMHEPES, pH7.5,1mMEGTA, 100mMNaCl, 3mMMgCl by 2.5 μ L4 × kinase solution2, 2mMDTT, 0.03%CHAPS formulated) add to detection each hole of plate in.Incubated at room 10min.By 5 μ L2 × substrate solution (by PIP2 and ATP add 1 × kinases basis buffer formulated) add detection each hole of plate in.Incubated at room 1h.Add 10 μ L stop buffer (Kinase-Gloreagent) and terminate reaction.Vibration, centrifugal 1min, low-speed oscillation 15min, then Flexstation reading plate detects, and the reader finally according to RLU value and " completely " and " blank " control wells calculates the suppression ratio under each concentration of compound, and the mapping of binding compounds concentration calculates IC50Value.
Result of the test: in Table 2.
Table 2 target compound PI3K alpha kinase vitro inhibition activity
Compound IC50(nM) Compound IC50(nM)
ZJQ-04 31 ZJQ-20 375
ZJQ-05 60 ZJQ-21 32
ZJQ-06 91 ZJQ-22 61
ZJQ-07 59 ZJQ-23 35
ZJQ-08 9530 ZJQ-24 128
ZJQ-10 224 ZJQ-26 23
ZJQ-13 117 ZJQ-27 568
ZJQ-14 5751 ZJQ-28 26
ZJQ-19 896 ZJQ-29 68
NVP-BKM120 28 ZJQ-30 38
Be can be seen that PI3K alpha kinase is all had inhibitory activity by the compound that invention is protected by data in table 2, and wherein most has obvious PI3K alpha kinase inhibitory activity.And, compared with the Buparlisib (NVP-BKM120) with structural formula 1 of the compound N ovartis company exploitation coming into III clinical trial phase pointed out in current background technology, compound ZJQ-04 provided by the present invention, ZJQ-21, ZJQ-23, ZJQ-26, ZJQ-28 and compound ZJQ-30 have the inhibitory activity equal to or slightly better with it.As can be seen here, PI3K alpha kinase is had obvious inhibitory activity by compound provided by the invention, has further DEVELOPMENT PROSPECT.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.All within the spirit and principles in the present invention, any amendment of making, equivalent replacement, improvement etc., should be included within protection scope of the present invention.

Claims (5)

1. a PI3K inhibitors of kinases, it is characterised in that described PI3K inhibitors of kinases is any one pyrimidine compound following, the stereoisomer of described pyrimidine compound or pharmaceutically acceptable salt；And described pyrimidine compound is:
Rac-5-(6-morpholine-2-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two) [2,3-c] pyrroles-6 (3H)-Ji) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine；
5-(2-((1R, 4R)-2-oxygen-5-azabicyclo [2.2.1] heptane-5-base)-6-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine；
(-)-5-(6-morpholine-2-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two) [2,3-c] pyrroles-6 (3H)-Ji) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine；
(+)-5-(6-morpholine-2-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two) [2,3-c] pyrroles-6 (3H)-Ji) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine；
5-(4-((1R, 4R)-2-oxygen-5-azabicyclo [2.2.1] heptane-5-base)-6-morpholine-1,3,5-three nitrogen piperazine-2-base)-4-(trifluoromethyl) pyridine-2-amine；
Rac-5-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-Ji)-1,3,5-three nitrogen piperazine-2-base)-4-(trifluoromethyl) pyridine-2-amine；
(-)-5-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-Ji)-1,3,5-tri-nitrogen piperazine-2-base)-4-(trifluoromethyl) pyridine-2-amine；Or
(+)-5-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two [2,3-c] pyrroles-6 (3H)-Ji)-1,3,5-tri-nitrogen piperazine-2-base)-4-(trifluoromethyl) pyridine-2-amine.
2. a pharmaceutical composition, it is characterised in that comprise the PI3K inhibitors of kinases described at least one claim 1 of at least one pharmaceutically acceptable adjuvant, adjuvant or carrier and dose therapeutically effective.
3. the PI3K inhibitors of kinases described in a claim 1 or the pharmaceutical composition described in claim 2 application in the medicine of preparation prevention and/or the proliferative disease for the treatment of PI3K zymogenesis.
4. application according to claim 3, it is characterized in that, the proliferative disease of described PI3K zymogenesis is colorectal cancer, gastric cancer, breast carcinoma, pulmonary carcinoma, hepatocarcinoma, carcinoma of prostate, cancer of pancreas, thyroid carcinoma, bladder cancer, renal carcinoma, cerebroma, neck cancer, glioblastoma, myeloproliferative disease, leukemia or lymphatic cancer.
5. the PI3K inhibitors of kinases described in a claim 1 or the pharmaceutical composition described in claim 2 suppress the application of the non-treatment purpose in cancer cell growth in vitro.
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