CN103483345A - Phosphoinositide 3-kinase (P13K) inhibitor, pharmaceutical composition containing P13K inhibitor, and application of phosphoinositide kinase inhibitor and pharmaceutical composition - Google Patents
Phosphoinositide 3-kinase (P13K) inhibitor, pharmaceutical composition containing P13K inhibitor, and application of phosphoinositide kinase inhibitor and pharmaceutical composition Download PDFInfo
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- CN103483345A CN103483345A CN201310442704.XA CN201310442704A CN103483345A CN 103483345 A CN103483345 A CN 103483345A CN 201310442704 A CN201310442704 A CN 201310442704A CN 103483345 A CN103483345 A CN 103483345A
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- morpholine
- amine
- trifluoromethyl
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- pyridine
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- 0 C*1C(CC2)CN(C)C2C1 Chemical compound C*1C(CC2)CN(C)C2C1 0.000 description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N C1NCCNC1 Chemical compound C1NCCNC1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- WBXHZEKQFVTUCW-UHFFFAOYSA-N CS(N(CC1)CCN1I)(=O)=O Chemical compound CS(N(CC1)CCN1I)(=O)=O WBXHZEKQFVTUCW-UHFFFAOYSA-N 0.000 description 1
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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
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- 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
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- 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
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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
- C07D491/08—Bridged systems
Abstract
The invention discloses a phosphoinositide 3-kinase (P13K) inhibitor, a pharmaceutical composition containing the P13K inhibitor, and application of the P13K inhibitor and the pharmaceutical composition. The P13K inhibitor comprises a pyrimidine compound and a stereoisomer/hydrate/pharmaceutically-acceptable salt thereof. The pyrimidine compound has a general formula I of which the structure is shown in the specification. The P13K inhibitor and the pharmaceutical composition containing the same can be used for inhibiting PI3 Ks and treating proliferative diseases on which the PI3 Ks act. According to the invention, high-effectiveness and high-selectivity inhibitors for treating proliferative diseases on which PI3Ks act can be provided.
Description
Technical field
The present invention relates to medical technical field, more specifically refer to a kind of PI3K kinase inhibitor, the pharmaceutical composition that comprises it and application thereof.
Background technology
Malignant tumour is a class disease of serious threat human life health, and its M & M is the trend risen year by year, and the mortality ratio that the mankind cause because of cancer is only second to cardiovascular and cerebrovascular diseases and is at the second place.At present, the medicine for treatment of tumour is divided into conventional cell poison class medicine and novel molecular targeted drug clinically.The former due to Main Function in DNA, RNA and tubulin etc. and the life-and-death common constituent of cell, thereby non-specifically block cell fission and cause necrocytosis, in the kill tumor cell, also destroyed the human normal cell, cause that its selectivity is low, toxicity is large; The latter has relatively clear and definite target spot usually, the regulating cell growth that Main Function is huge in difference in normal cell and tumour cell, key molecule and the signal transduction pathway thereof of propagation, can grow and reduce Normocellular effect by inhibition tumor cell, thereby increased selectivity to tumour, reduced the toxicity of normal tissue, greatly improved treatment level.
Each drugmaker accelerates the development of anti-tumor drugs targeting, adds market sought-after to the antitumor drug of this classification, and molecular targeted agents has become fastest-rising part on global antitumor drug market.Phosphatidylinositol-3-kinase (phosphoinositide 3-kinase, PI3K) is signaling molecule crucial in many vital movements.The signal path (PI3K/Akt/m-TOR) of PI3K mediation controlling numerous in tumor development vital cytobiology process, comprise cell proliferation, apoptosis, transcribe, translation, metabolism, vasculogenesis and the regulation and control of cell cycle etc.In human tumor cells, this signal path is compared with other signal path, and producer changes as higher as the probability of transgenation, gene amplification, gene rearrangement, thereby closely related with genesis, transfer and the resistance of tumour.Therefore, the PI3K inhibitor has unique advantage at aspects such as inhibition tumor cell propagation, inducing apoptosis of tumour cell and reversing tumor cells resistances, separately medication or with other targeted drug drug combination.The antitumor drug research that key molecule is target spot in the PI3K signal path of take becomes one of focus of neoplasm targeted therapy.
PI3Ks has the phosphatidyl inositol kinase of the kinase whose activity of serine/threonine (Ser/Thr) in one class born of the same parents, can phosphorylation phosphatidylinositols (PtdIns), phosphatidylinositol-4phosphate (PtdIns4P), phosphatidylinositols-4,3 hydroxyls of 5-bisphosphate (PtdIns (4,5) P2).According to its constitutional features and effect substrate specificity, PI3Ks family can be divided into four classes: I type, II type, III type and IV type.Up to the present, most study be I type PI3K, according to the difference of catalytic subunit, be divided into: PI3K α, PI3K β, tetra-hypotypes of PI3K γ and PI3K δ (Nat.Rev.Drug Discov.2009,8,627-644).Although four kinds of hypotypes of I type PI3K have higher homology on structure forms, its physiological function has certain overlapping, due to the difference of its active pocket peripheral structure, causes them to play a different role in the genesis of function and cancer.
At present existing nearly 20 compounds enter clinical experimental stage, tens compounds are wherein arranged in II phase clinical stage, have 4 compounds to enter the III clinical trial phase.The compound that enters the III clinical trial phase is respectively the Rigosertib with structural formula 2 (ON-01910) of the Buparlisib with structural formula 1 (NVP-BKM120) of Novartis company exploitation, the exploitation of Onconova Therapeutics company, the Idelalisib (CAL-101, GS-1101) with structural formula 3 of ICOS company exploitation and the Perifosine with structural formula 4 (KRX-0401) of ASTA Medica company exploitation.1-4 is as follows for the said structure formula:
Yet, there is no so far the listing of PI3K inhibitor, the research staff also needs to research and develop more PI3K kinase inhibition agent molecule, so that the better compound of effectiveness of selection and selectivity is for the treatment of cancer.
Summary of the invention
The present invention aims to provide a kind of PI3K kinase inhibitor, the pharmaceutical composition that comprises it and application thereof, so that the better compound of effectiveness of selection and selectivity is for the treatment of cancer.
To achieve these goals, according to an aspect of the present invention, provide a kind of PI3K kinase inhibitor, comprised the pyrimidine compound with general formula I, its steric isomer, hydrate or pharmacy acceptable salt, described general formula I structure is as follows:
In described general formula I: X, Y, Z, W independently selected from N or-CH-; R
1, R
2independently selected from H, C
1-C
4alkyl, containing one or more substituent C
1-C
4alkyl, C
1-C
4alkoxyl group, containing one or more substituent C
1-C
4alkoxyl group, C
3-C
6heterocyclic radical, containing one or more substituent C
3-C
6heterocyclic radical, C
4-C
8condense assorted bicyclic group or contain one or more substituent C
4-C
8condense assorted bicyclic group, described substituting group is selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, C
1-C
4alkyl, halo C
1-C
4alkyl, hydroxyl C
1-C
4alkyl, C
1-C
4alkoxyl group, halo C
1-C
4alkoxyl group, hydroxyl C
1-C
4alkoxyl group or C
1-C
4alkoxy C
1-C
4alkyl; R
3be selected from H ,-CN ,-CH
3,-CF
3or-SO
2nH
2; R
4be selected from H or halogen.
Further, above-mentioned R
3for-CF
3;
Further, above-mentioned PI3K kinase inhibitor comprises the pyrimidine compound with general formula I I and/or general formula III, its steric isomer, hydrate or pharmacy acceptable salt; General formula I I and general formula III structure are as follows:
In described general formula I I and general formula III: R
1, R
2independently selected from H, C
1-C
4alkyl, containing one or more substituent C
1-C
4alkyl, C
1-C
4alkoxyl group, containing one or more substituent C
1-C
4alkoxyl group, C
3-C
6heterocyclic radical, containing one or more substituent C
3-C
6heterocyclic radical, C
4-C
8condense assorted bicyclic group or contain one or more substituent C
4-C
8condense assorted bicyclic group, described substituting group is selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, C
1-C
4alkyl, halo C
1-C
4alkyl, hydroxyl C
1-C
4alkyl, C
1-C
4alkoxyl group, halo C
1-C
4alkoxyl group, hydroxyl C
1-C
4alkoxyl group or C
1-C
4alkoxy C
1-C
4alkyl.
Further, R in above-mentioned general formula I or in general formula I I and III
1, R
2independently selected from following structure:
Wherein, A, B, C, D, E, F is independently selected from-CH
2-,-O-,-S-or-NR
11-; R
5, R
6, R
7, R
8, R
9, R
10, R
11independently selected from H, halogen, hydroxyl, amino, C
1-C
4alkyl, halo C
1-C
4alkyl, hydroxyl C
1-C
4alkyl, C
1-C
4alkoxyl group, halo C
1-C
4alkoxyl group, hydroxyl C
1-C
4alkoxyl group, or C
1-C
4alkyl sulphonyl;
R in general formula I I or general formula III further, in above-mentioned general formula I,
1, R
2independently selected from following structure:
Further, R in above-mentioned general formula I, general formula I I or general formula III
1be selected from following structure:
Further, R in above-mentioned general formula I, general formula I I or general formula III
2be selected from following structure:
Further, above-mentioned pyrimidine compound is:
Rac-5-(the 6-morpholine-2-(and (4RS, 7RS)-tetrahydrochysene-2H-[1,4] two Evil) [2,3-c] pyrroles-6 (3H)-yl) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine;
5-(2-((1R, 4R)-2-oxygen-5-azabicyclo [2.2.1] heptane-5-yl)-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 Evil [2,3-c] pyrroles-6 (3H, 7H, 7aH)-yl)-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 Evil [2,3-c] pyrroles-6 (3H)-yl) 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 Evil [2,3-c] pyrroles-6 (3H)-yl) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine;
Rac-5-(2-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two Evil [2,3-c] pyrroles-6 (3H)-yl) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine;
Rac-6-morpholine-2-((4RS, 7RS)-tetrahydrochysene)-2H-[1,4] two Evil [2,3-c] pyrroles-6 (3H)-yl)-[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-(the 6-morpholine-2-(and (4RS, 7RS)-tetrahydrochysene-2H-[1,4] two Evil) [2,3-c] pyrroles-6 (3H)-yl) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine;
(+)-5-(the 6-morpholine-2-(and (4RS, 7RS)-tetrahydrochysene-2H-[1,4] two Evil) [2,3-c] pyrroles-6 (3H)-yl) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine;
5-(4-((1R, 4R)-2-oxygen-5-azabicyclo [2.2.1] heptane-5-yl)-6-morpholine-1,3,5-tri-nitrogen piperazines-2-yl)-4-(trifluoromethyl) pyridine-2-amine;
5-(2-(4-(methylsulfonyl) piperazine-1-yl)-6-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine;
5-(4-((1R, 4R)-2-oxygen-5-azabicyclo [2.2.1] heptane-5-yl)-6-((2R, 6S)-2,6-thebaine)-1,3,5-tri-nitrogen piperazines-2-yl)-4-(trifluoromethyl) pyridine-2-amine;
Rac-5-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two Evil [2,3-c] pyrroles-6 (3H)-yl)-1,3,5-tri-nitrogen piperazines-2-yl)-4-(trifluoromethyl) pyridine-2-amine;
(-)-5-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two Evil [2,3-c] pyrroles-6 (3H)-yl)-1,3,5-tri-nitrogen piperazines-2-yl)-4-(trifluoromethyl) pyridine-2-amine; Perhaps
(+)-5-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two Evil [2,3-c] pyrroles-6 (3H)-yl)-1,3,5-tri-nitrogen piperazines-2-yl)-4-(trifluoromethyl) pyridine-2-amine.
According to a further aspect in the invention, provide a kind of pharmaceutical composition, at least one above-mentioned PI3K kinase inhibitor that it comprises at least one pharmaceutically acceptable auxiliary material, auxiliary or carrier and dose therapeutically effective.
According to a further aspect in the invention, a kind of above-mentioned PI3K kinase inhibitor or the above-mentioned application of pharmaceutical composition in the medicine of the proliferative disease of Prevention and/or treatment and/or assisting therapy PI3K zymogenesis are provided.
Further, in above-mentioned application, the proliferative disease of PI3K zymogenesis is colorectal cancer, cancer of the stomach, mammary cancer, lung cancer, liver cancer, prostate cancer, carcinoma of the pancreas, thyroid carcinoma, bladder cancer, kidney, brain tumor, the neck cancer, the cancer of CNS, glioblastoma, or myeloproliferative disease, and leukemia and lymphatic cancer.
The application of a kind of above-mentioned PI3K kinase inhibitor or above-mentioned pharmaceutical composition vitro inhibition cancer cell growth is provided according to a further aspect in the invention.
Apply technical scheme of the present invention, PI3K kinase inhibitor provided by the present invention, the pharmaceutical composition that comprises it can be used in and suppress the PI3K kinases, and the proliferative disease of PI3K zymogenesis, can provide validity and the better inhibitor of selectivity for the treatment of the proliferative disease of PI3K zymogenesis.
Embodiment
Below in conjunction with the embodiment of the present invention, technical scheme of the present invention is described in detail, but following embodiment to 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.
For realize the background technology part pointed provide more validity and the better compound of selectivity with the treatment for tumour.A kind of PI3K kinase inhibitor is provided in the present invention.This PI3K kinase inhibitor comprises having the general formula I pyrimidine compound, its steric isomer, hydrate or pharmacy acceptable salt.Wherein, the general formula I structure is as follows:
X in above-mentioned general formula I, Y, Z, W independently selected from N or-CH-.
R in above-mentioned general formula I
1, R
2independently selected from H, C
1-C
4alkyl, containing one or more substituent C
1-C
4alkyl, C
1-C
4alkoxyl group, containing one or more substituent C
1-C
4alkoxyl group, C
3-C
6heterocyclic radical, containing one or more substituent C
3-C
6heterocyclic radical, C
4-C
8condense assorted bicyclic group or contain one or more substituent C
4-C
8condense assorted bicyclic group, described substituting group is selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, C
1-C
4alkyl, halo C
1-C
4alkyl, hydroxyl C
1-C
4alkyl, C
1-C
4alkoxyl group, halo C
1-C
4alkoxyl group, hydroxyl C
1-C
4alkoxyl group or C
1-C
4alkoxy C
1-C
4alkyl.
R in above-mentioned general formula I
3be selected from H ,-CN ,-CH
3,-CF
3or-SO
2nH
2; Preferred R wherein
3for-CF
3.
R in above-mentioned general formula I
4be selected from H or halogen, be preferably H.
In a preferred embodiment of the present invention, above-mentioned PI3K kinase inhibitor comprises the pyrimidine compound with general formula I I and/or general formula III, its steric isomer, hydrate or pharmacy acceptable salt; Described general formula I I and general formula III structure are as follows:
In above-mentioned general formula I I and general formula III: R
1, R
2independently selected from H, C
1-C
4alkyl, containing one or more substituent C
1-C
4alkyl, C
1-C
4alkoxyl group, containing one or more substituent C
1-C
4alkoxyl group, C
3-C
6heterocyclic radical, containing one or more substituent C
3-C
6heterocyclic radical, C
4-C
8condense assorted bicyclic group or contain one or more substituent C
4-C
8condense assorted bicyclic group, described substituting group is selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, C
1-C
4alkyl, halo C
1-C
4alkyl, hydroxyl C
1-C
4alkyl, C
1-C
4alkoxyl group, halo C
1-C
4alkoxyl group, hydroxyl C
1-C
4alkoxyl group or C
1-C
4alkoxy C
1-C
4alkyl.
In a preferred embodiment of the present invention, R in above-mentioned PI3K kinase inhibitor formula of I general formula I I or general formula III
1, R
2independently selected from following structure:
Wherein, A, B, C, D, E, F is independently selected from-CH
2-,-O-,-S-or-NR
11-;
R
5, R
6, R
7, R
8, R
9, R
10, R
11independently selected from H, halogen, hydroxyl, amino, C
1-C
4alkyl, halo C
1-C
4alkyl, hydroxyl C
1-C
4alkyl, C
1-C
4alkoxyl group, halo C
1-C
4alkoxyl group, hydroxyl C
1-C
4alkoxyl group, or C
1-C
4alkyl sulphonyl.
Preferably, R in above-mentioned PI3K kinase inhibitor formula of I, general formula I I or general formula III
1, R
2independently selected from following structure:
More preferably, R in above-mentioned PI3K kinase inhibitor formula of I, general formula I I or general formula III
1be selected from following structure:
More preferably, R in above-mentioned PI3K kinase inhibitor formula of I, general formula I I or general formula III
2be selected from following structure:
More preferably, in above-mentioned PI3K kinase inhibitor, pyrimidine compound is:
Rac-5-(the 6-morpholine-2-(and (4RS, 7RS)-tetrahydrochysene-2H-[1,4] two Evil) [2,3-c] pyrroles-6 (3H)-yl) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter to be referred as ZJQ-04);
5-(2-((1R, 4R)-2-oxygen-5-azabicyclo [2.2.1] heptane-5-yl)-6-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter to be referred as ZJQ-05);
5-(2-((2R, 6S)-2,6-thebaine)-6-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter to be referred as ZJQ-06);
5-(2-((4RS, 7SR)-dihydro-2H-[1,4] two Evil [2,3-c] pyrroles-6 (3H, 7H, 7aH)-yl)-6-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter to be referred as ZJQ-13);
5-(6-((2R, 6S)-2, the 6-thebaine)-2-((4SR, 7RS)-tetrahydrochysene-2H-[1,4] two Evil [2,3-c] pyrroles-6 (3H)-yl) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter to be referred as ZJQ-14);
5-(6-((2R, 6S)-2,6-thebaine)-2-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter to be referred as ZJQ-10);
5-(2-morpholine-6-((4SR, 7RS)-tetrahydrochysene-2H-[1,4] two Evil [2,3-c] pyrroles-6 (3H)-yl) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter to be referred as ZJQ-19);
Rac-5-(2-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two Evil [2,3-c] pyrroles-6 (3H)-yl) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter to be referred as ZJQ-20);
(-)-5-(6-morpholine-2-((4RS, 7RS)-tetrahydrochysene)-2H-[1,4] two Evil) [2,3-c] pyrroles-6 (3H)-yl) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter to be referred as ZJQ-22);
(+)-5-(6-morpholine-2-((4SR, 7SR)-tetrahydrochysene)-2H-[1,4] two Evil) [2,3-c] pyrroles-6 (3H)-yl) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter to be referred as ZJQ-23);
Rac-6-morpholine-2-((4RS, 7RS)-tetrahydrochysene)-2H-[1,4] two Evil [2,3-c] pyrroles-6 (3H)-yl)-[4,5 '-Sulfadiazine Compound]-2 '-amine (hereinafter to be referred as ZJQ-24);
5-(2-(4-(methylsulfonyl) piperazine-1-yl)-6-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter to be referred as ZJQ-26)
4-(6-amino-4-(trifluoromethyl) pyridin-3-yl)-6-morpholine-N-(2-morpholine ethyl) pyrimidine-2-amine (hereinafter to be referred as ZJQ-27);
4-(6-amino-4-(trifluoromethyl) pyridin-3-yl)-6-morpholine-N-(4-morpholinyl phenyl) pyrimidine-2-amine (hereinafter to be referred as ZJQ-28);
5-(4-((1R, 4R)-2-oxygen-5-azabicyclo [2.2.1] heptane-5-yl)-6-morpholine-1,3,5-tri-nitrogen piperazines-2-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter to be referred as ZJQ-07);
5-(4-((1R, 4R)-2-oxygen-5-azabicyclo [2.2.1] heptane-5-yl)-6-((2R, 6S)-2,6-thebaine)-1,3,5-, tri-nitrogen piperazines-2-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter to be referred as ZJQ-08);
Rac-5-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two Evil [2,3-c] pyrroles-6 (3H)-yl)-1,3,5-tri-nitrogen piperazines-2-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter to be referred as ZJQ-21);
(-)-5-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two Evil [2,3-c] pyrroles-6 (3H)-yl)-1,3,5-tri-nitrogen piperazines-2-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter to be referred as ZJQ-29); Perhaps
(+)-5-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two Evil [2,3-c] pyrroles-6 (3H)-yl)-1,3,5-tri-nitrogen piperazines-2-yl)-4-(trifluoromethyl) pyridine-2-amine (hereinafter to be referred as ZJQ-30).
PI3K kinase inhibitor provided by the present invention can be used in and suppresses the PI3K kinases, and the proliferative disease of PI3K zymogenesis, can provide validity and the better inhibitor of selectivity for the treatment of the proliferative disease of PI3K zymogenesis.
PI3K kinase inhibitor of the present invention can comprise the pyrimidine compound pharmacy acceptable salt.Pharmacy acceptable salt refers to the form of the conversion of the basic group in parent compound salify.Pharmacy acceptable salt include but not limited to, and basic group is the inorganic or organic acid salt of amine (ammonia) base for example.Pharmacy acceptable salt of the present invention can be synthetic by parent compound, and the basic group in parent compound reacts in a solvent systems with the acid of 1-4 equivalent.Suitable salt is set forth in Remington ' s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418 with Journal of Pharmaceutical Science, in 66,2 (1977).
In the present invention the compound basic group can with sour salify, the example of these sour salifies comprises: with mineral acid, the salt that especially haloid acid (as spirit of salt, Hydrogen bromide, hydroiodic acid HI), nitric acid, sulfuric acid, phosphoric acid, carbonic acid etc. form; Low alkyl group sulfonic acid, as methylsulfonic acid, the salt that trifluoromethanesulfonic acid forms; With aryl sulfonic acid, as the salt of Phenylsulfonic acid or tosic acid formation; With organic acid, as the salt of acetic acid, fumaric acid, tartrate, oxalic acid, citric acid, toxilic acid, oxysuccinic acid or succsinic acid formation; With amino acid, as the salt of aspartic acid or L-glutamic acid formation.
Compound of the present invention and pharmacy acceptable salt also comprise the form of solvate or hydrate.In general, the form of solvate or hydrate and form non-solvated or non-hydrated are equal to, and contain within the scope of the invention.Some compound in the present invention likely exists polycrystal or unbodied form.Generally speaking, all physical form have equal purposes, and contain within the scope of the invention.
In addition, unless other side shows, in PI3K enzyme inhibitors of the present invention described in the invention, the structural formula of pyrimidine compound comprises that all isomeric forms are (as enantiomerism, diastereo-isomerism, and rotamerism (or conformational isomerism)): the R, the S configuration that for example contain asymmetric center, (Z) of two keys, (E) isomer, and (Z), the conformer of (E).Therefore, the single three-dimensional chemical isomer of compound of the present invention or its enantiomer, diastereomer, or the mixture of geometrical isomer (or conformer) all belongs to scope of the present invention.
Unless other side shows, within PI3K kinase inhibitor of the present invention, all tautomeric forms of pyrimidine compound are included in scope of the present invention.In addition, unless other side show, the structural formula of compound described in the invention comprises the enriched isotope of one or more different atoms.
Below will describe exemplary of the present invention in detail.Yet these embodiments only for the purpose of illustration, are not intended to limit the scope of the invention.
As used herein, concrete restriction is provided if, term of the present invention has following implication.
Term " alkyl " is the univalence hydrocarbyl that comprises 1-20 carbon atom saturated straight chain or side chain, and wherein alkyl can independently optionally be replaced by one or more substituting 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 that alkyl group contains 1-6 carbon atom, other embodiment is that alkyl group contains 1-4 carbon atom.Alkyl group further example comprises, but is not limited to methyl (Me ,-CH
3), ethyl (Et ,-CH
2cH
3), n-propyl (n-Pr ,-CH
2cH
2cH
3), sec.-propyl (i-Pr ,-CH (CH
3)
2), normal-butyl (n-Bu ,-CH
2cH
2cH
2cH
3), isobutyl-(i-Bu ,-CH
2cH (CH
3)
2), sec-butyl (s-Bu ,-CH (CH
3) CH
2cH
3), the tertiary butyl (t-Bu ,-C (CH
3)
3) etc.Term " alkyl " and its prefix " alkane " are used herein, all comprise the saturated carbon chains of straight chain and side chain.
The part that term " alkoxyl group " relates to alkyl is identical with the definition of aforementioned " alkyl ", and it is to be connected on " alkyl " main carbochain and to form by Sauerstoffatom.
Term " haloalkyl " or " halogenated alkoxy " mean that " alkyl " or " alkoxyl group " can be by the situation that one or more identical or different halogen atom replaced.Wherein alkyl and alkoxy base have implication as aforesaid as the present invention, and such example comprises, but is not limited to trifluoromethyl, trifluoromethoxy etc.
Term " hydroxyalkyl " or " hydroxy alkoxy base " mean that " alkyl " or " alkoxyl group " can be by the situation that one or more hydroxyl replaced.Wherein " alkyl " and " alkoxyl group " group has implication as aforesaid as the present invention, and such example comprises, but is not limited to methylol, 1-hydroxyethyl, hydroxypropyl, 1,2-dihydroxypropyl, hydroxyl methoxyl group, 1-hydroxy ethoxy etc.
Term " halogen ", " halogen atom " or " halogen atom " comprises fluorine, chlorine, bromine, iodine.
Term " heterocyclic radical " can be carbon back or heteroatoms base." heterocyclic radical " equally also comprises heterocyclic group and saturated or the unsaturated ring of part or heterocycle and closes formed group.The example of heterocycle comprises, but be not limited to, pyrrolidyl, tetrahydrofuran base, the dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, the thioxane base, azelidinyl, the oxa-cyclobutyl, the thia cyclobutyl, piperidyl, homopiperidinyl, epoxypropyl, the nitrogen heterocyclic heptyl, the oxepane base, the thia suberyl, the N-morpholinyl, the 2-morpholinyl, morpholinyl, thio-morpholinyl, the N-piperazinyl, the 2-piperazinyl, the 3-piperazinyl, the homopiperazine base, 4-methoxyl group-piperidin-1-yl, 1, 2, 3, 6-tetrahydropyridine-1-base, oxygen azatropylidene base, the diazepine base, sulphur azatropylidene base, pyrroline-1-base, the 2-pyrrolinyl, the 3-pyrrolinyl, indolinyl, the 2H-pyranyl, the 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxy amyl group, pyrazolinyl, the dithiane base, the dithiode alkyl, the dihydro-thiophene base, the pyrazolidyl imidazolinyl, imidazolidyl, 1, 2, 3, the 4-tetrahydro isoquinolyl, 1, 2, 6-thiadiazine alkane, 1, 1-dioxy-2-base, quinolizinyl and N-pyridyl urea.And described heterocyclic radical can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, oxo (=O), hydroxyl, amino, halogen, cyano group, heteroaryl, alkoxyl group, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, the alkoxyl group that hydroxyl replaces, alkyl-C (=O) that hydroxyl replaces, alkyl-C (=O), carboxyl alkoxyl group etc.
Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base " or " condensed ring radical " mean saturated or undersaturated condensed ring system, relate to the bicyclic system of non-aromatic.Such system can comprise independently or the undersaturated condition of conjugation, but its core texture does not comprise aromatic nucleus or fragrant heterocycle (but aromatic series can be used as the substituting group on it).Each ring in condensed-bicyclic or carbocyclic ring or assorted alicyclic, such example comprises, but is not limited to 2,3,3a, 4,7,7a-six hydrogen-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 naphthyl, within these are included in the system of condensed-bicyclic.And described condensed-bicyclic base can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, halogen, hydroxyl, amino, cyano group, aryl, heteroaryl, alkoxyl group, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy etc.
Term " condenses assorted bicyclic group " and means saturated or undersaturated condensed ring system, relates to the bicyclic system of non-aromatic.Such system can comprise independently or the undersaturated condition of conjugation, but its core texture does not comprise aromatic nucleus or fragrant heterocycle (but aromatic series can be used as the substituting group on it).And at least one member ring systems comprises one or more heteroatomss, wherein each member ring systems comprises the 3-7 ring, comprise 1-6 carbon atom and be selected from N, and O, P, the 1-3 of a S heteroatoms, optionally replaced and obtain picture SO, SO by one or more Sauerstoffatom at this S or P
2, PO, PO
2group, such example comprises, but is not limited to six hydrogen-2H-[1,4] bis-Yang Evil [2,3-c] pyrryl etc.And described to condense assorted bicyclic group can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, halogen, hydroxyl, amino, cyano group, aryl, heteroaryl, alkoxyl group, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy etc.
In above-mentioned PI3K inhibitor provided by the present invention can prepare by pyrimidine compound in several ways, finds suitable mode under the inspiration of the structural formula that those skilled in the art provided in this application and is prepared.For the ease of understanding, provide in this application the preparation method about above-mentioned general formula I I and III.
A kind of method for preparing the pyrimidine compound with general formula I I: with 2,4,6-trichloropyrimidine (A) for raw material, according to the difference of pyrimidine 2 and 4 reactive behavioies, elder generation and R
1nucleophilic substitution reaction occurs and obtains intermediate (B) in NH, introduces R by substitution reaction subsequently
2nH obtains intermediate (C), finally with 2-amino-4-5-flumethiazine-5-boric acid ester, the Suzuki linked reaction occurs again, obtains having the target compound (D) of general structure II.
The reaction formula of aforesaid method is as follows:
A kind of method for preparing the pyrimidine compound with general formula III: be similar to the synthetic of general formula I I, by priority, introduce R
1nH and R
2suzuki, then occur with the pyrimidine boric acid ester and react the target compound (H) that obtains having general structure III in NH.
The reaction formula of aforesaid method is as follows:
At above-mentioned preparation process Chinese style A to each substituent R in formula H
1and R
2definition with in general formula I, II and III substituent R
1and R
2identical.
Simultaneously, also provide in one embodiment of the invention a kind of pharmaceutical composition, this pharmaceutical composition comprises at least one pharmaceutically acceptable auxiliary material, auxiliary or carrier; And at least one above-mentioned PI3K kinase inhibitor of dose therapeutically effective.
Term " treatment significant quantity " refers to when needing the Mammals of such treatment, is enough to the effectively amount of the general formula compound for the treatment of.The treatment significant quantity will depend on given activity, the patient's of the healing potion used existence of age, physiological situation, Other diseases state and nutritional status and change.In addition, the treatment of the patient may just accept other medicines will affect treatment significant quantity definite of the healing potion that will give.
Term " treatment " means any treatment for disease in mammalian body, comprising: (i) prevent disease, cause the clinical symptom of disease not develop; (ii) suppress disease, that is, stop the development of clinical symptom; And/or (iii) palliate a disease, that is, cause disappearing of clinical symptom.
Term " pharmaceutically acceptable auxiliary material, auxiliary or carrier " comprise any and whole solvents, dispersion medium, dressing, 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 activeconstituents are incompatible, its application in therapeutic composition is expected.Supplementary activeconstituents also can be incorporated in composition.
Said composition preferably is formulated into unit dosage.Term " unit dosage " refers to and is suitable for use as the physics discrete unit that gives human experimenter and other mammiferous single doses, and per unit contains and calculates to produce the predetermined amount of the effective active substance of needed treatment and relevant suitable pharmaceutical excipient (as tablet, capsule, ampoule).In the PI3K kinase inhibitor, pyrimidine compound is the active drug amount that effectively and usually gives in dosage range widely.Preferably, for oral administration, pyrimidine compound in the PI3K kinase inhibitor that each dose unit comprises 10mg to 2g, more preferably 10 to 700mg, and, for administered parenterally, be preferably pyrimidine compound in 10 to 700mg PI3K kinase inhibitor, more preferably from about 50 to 200mg.Yet, should understand, in the actual PI3K kinase inhibitor given, the amount of pyrimidine compound will be determined according to relevant situation by the doctor, comprise the illness that will treat, the route of administration of selecting, the pragmatize compound given with and relative reactivity, each patient's age, body weight and reaction, the seriousness of patient's symptom etc.
In order to prepare solids composition as tablet, main active ingredient is mixed to form solid preformulation composition, the uniform mixture that it comprises compound of the present invention with drug excipient (or carrier).When claiming that these preformulation composition are uniform, it refers to that active ingredient is dispersed in whole composition, so that composition can easily be subdivided into identical effective unit dosage as tablet, pill and capsule.
Tablet of the present invention or pill can be applied or otherwise by compound so that a kind of formulation with prolongation effect advantage to be provided, or protection tablet or pill are avoided the effect of acidic conditions in stomach.For example, tablet or pill can comprise interior dosage and external dose composition, and the latter has the form of the crust on the former.Can separate two kinds of compositions with enteric layer, wherein enteric layer is used for stoping disintegration under one's belt and allows interior complete components to enter duodenum or be delayed release.Various materials can be for such enteric layer or coating, and above-mentioned materials comprises many polymer acids and polymer acid and the such material mixture as shellac, cetyl alcohol and cellulose acetate.
Be included in solution and the suspension of pharmaceutically acceptable water-containing solvent or organic solvent or its mixture for the composition of inhalation or insufflation, and powder.The liquid or solid composition can comprise suitable pharmaceutical excipient as described above.Preferably, give these compositions to obtain part or systemic effect by oral or nasal respiration approach.Can be by carry out the composition of atomization in the preferred acceptable solvent of pharmacy with rare gas element.Can directly from atomisation unit, suck atomized soln, or atomisation unit can be connected in face shield account shape thing or intermittent positive pressure breathing machine.Can be by the device of sending in a suitable manner formulation, preferred oral or nose approach, give solution, suspensoid or powder composite.
In yet another aspect, the present invention also provides a kind of above-mentioned P13K kinase inhibitor or the application of aforementioned pharmaceutical compositions in the medicine of the proliferative disease of Prevention and/or treatment and/or assisting therapy PI3K zymogenesis.Wherein the proliferative disease of PI3K zymogenesis is cancer.This cancer comprises the form of entity cancer and blood cancer.Preferably, the proliferative disease of this PI3K zymogenesis is colorectal cancer, cancer of the stomach, mammary cancer, lung cancer, liver cancer, prostate cancer, carcinoma of the pancreas, thyroid carcinoma, bladder cancer, kidney, brain tumor, the neck cancer, the cancer of CNS, glioblastoma, or myeloproliferative disease, and leukemia and lymphatic cancer.
In yet another aspect, the present invention also provides the application of a kind of above-mentioned P13K kinase inhibitor or the growth of aforementioned pharmaceutical compositions vitro inhibition cancer cell.
Below by embodiment 1-24, the present invention will be further described, yet these embodiment should be as the restriction to scope of the present invention.
Unless in the embodiments described below, other aspects show that all temperature are decided to be degree centigrade.Reagent is bought in goods providers as Alfa Aesar Chemical Company, lark prestige Science and Technology Ltd., and Aladdin reagent company limited, Beijing coupling Science and Technology Ltd.s etc., all do not have during use through being further purified, unless other aspects show.General reagent is from Xi Long chemical plant, Shantou, Guangzhou Chemical Reagent Factory, and Tianjin causes the purchases such as chemical reagent company limited far away and Haiyang Chemical Plant, Qingdao and obtains.
In the embodiments described below, chromatographic column is used silicagel column, and silica gel (200-300 order) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum is with CDCl
3or DMSO-d
6for solvent (take ppm as unit), use TMS (0ppm) or chloroform (7.26ppm) as reference standard.When multiplet occurring, following abbreviation: s (singlet, unimodal) will be used, d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet ofdoublets, quartet), dt (doublet of triplets, two triplets).Coupling constant, mean with hertz (Hz).
Algorithm in the embodiments described below (MS) data are measured by the spectrograph of the Agilent 6120 serial LC-MS of outfit G1311B quaternary pump and G1316B TCC (column temperature remains on 30 ℃), G1329B automatic sampler and G1315C DAD detector applies are in analysis, and the ESI source is applied to the LC-MS spectrograph.
In the embodiments described below, volume injected is to determine by sample concentration; Flow velocity is 0.5mL/min; The peak value of HPLC is to record and read by the UV-Vis wavelength at 210nm and 254nm place.Moving phase is Virahol/normal hexane (40: 60).
The embodiment the following describes is convenient to statement, and part material can be described with its abbreviation, and these abbreviations contrast and are described as follows with its full name: DCM is CH
2cl
2, i.e. methylene dichloride; CHCl
3for chloroform, i.e. trichloromethane; CDCl
3for deuterochloroform; PE is sherwood oil; EtOAc and EA are ethyl acetate; MeOH and CH
3oH is methyl alcohol; EtOH and CH
3cH
2oH is ethanol; HCl is hydrochloric acid; AcOH and acetic acid are acetic acid; NH
4oH and NH
3h
2o is ammoniacal liquor; Et
3n and TEA are triethylamine; K
2cO
3for salt of wormwood; KI is potassiumiodide; NBS is bromo-succinimide; NaHSO
3for sodium bisulfite; DIPEA is DIPEA; THF is tetrahydrofuran (THF); Pd (dppf) Cl
2cH
2cl
2for [1,1 '-bis-(diphenylphosphine) ferrocene] palladium chloride methylene dichloride complex compound; DMF is DMF; SOCl
2for thionyl chloride; POCl
3for phosphorus oxychloride; DMSO is methyl-sulphoxide; DMSO-d
6be six deuterated dimethyl sulfoxides; H
2o is water; ML is milliliter; Rt is retention time.
Embodiment 1: pyrimidine compound ZJQ-04's is synthetic.
Synthesizing of the bromo-4-of step 1:5-(trifluoromethyl) pyridine-2-amine.
The structural formula of the bromo-4-of 5-(trifluoromethyl) pyridine-2-amine:
Synthetic method: 4-trifluoromethyl-PA (10g, 61.69mmol) is dissolved in to CH
2cl
2(100mL) in, add bromo-succinimide (NBS, 12.08g, 67.86mmol) under room temperature, the lucifuge room temperature reaction spends the night in batches.Reaction system CH
2cl
2(100mL) dilution, use saturated NaHSO
3wash twice, the saturated NaCl aqueous solution is washed once, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent, the residue column chromatographic isolation and purification, eluent: petrol ether/ethyl acetate=4/1 obtains target product 13.08g, brown solid, yield: 87.96%.
The nuclear magnetic data of product is
1h NMR (400MHz, CDCl
3) δ: 8.28 (s, 1H), 6.78 (s, 1H), 4.82 (s, 2H).With ACS Med.Chem.Lett.2011, identical in 2,774-779 literary composition.From above-mentioned data, through aforesaid method, prepared product is the bromo-4-of target product 5-(trifluoromethyl) pyridine-2-amine.
Synthesizing of step 2:5-(4,4,5,5-tetramethyl--1,3,2-dioxy borine-2-yl)-4-(trifluoromethyl) pyridine-2-amine.
The structural formula of 5-(4,4,5,5-tetramethyl--1,3,2-dioxy borine-2-yl)-4-(trifluoromethyl) pyridine-2-amine:
Synthetic method: by the bromo-4-of 5-synthetic in step 1 (trifluoromethyl) pyridine-2-amine (6.54g, 27.26mmol) be dissolved in dioxane (100mL), then add successively Potassium ethanoate (8.03g, 81.77mmol), tetramethyl ethylene ketone boric acid ester (7.62g, 29.98mmol), nitrogen replacement, and, in stirring at room 10min, add Pd (dppf) Cl
2cH
2cl
2(1.12g, 1.37mmol), then be warmed up to 115 ℃ of reaction 24h.The pressure reducing and steaming solvent, residue is dissolved in ethyl acetate (200mL), washes twice, and the saturated NaCl aqueous solution is washed once, anhydrous sodium sulfate drying.Concentrated, the residue column chromatographic isolation and purification, eluent: petrol ether/ethyl acetate=3/1, obtain brown solid, the solid Eddy diffusion, in normal hexane, is filtered, obtain target product 6.60g, white solid, yield: 84.04%.
The mass-spectrometric data of product is LC-MS:289 (M+H).With ACS Med.Chem.Lett.2011, identical in 2,774-779 literary composition.From above-mentioned data, through aforesaid method, prepared product is target product 5-(4,4,5,5-tetramethyl--1,3,2-dioxy borine-2-yl)-4-(trifluoromethyl) pyridine-2-amine.
Synthesizing 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) is dissolved in methylene dichloride (30mL), slowly is added drop-wise to metachloroperbenzoic acid (10.55g, 61.14mmol) methylene dichloride (70mL) mixed solution in, stirring at room reaction 16h.Filter, filtrate is respectively washed once with saturated sodium thiosulfate (100mL) and saturated sodium bicarbonate (100mL), and the saturated NaCl aqueous solution is washed once, anhydrous Na
2sO
4dry.The pressure reducing and steaming solvent, the direct column chromatography for separation of residue, eluent: EA/PE=1/3 obtains target product 7.39g, yield: 68.49%.
The nuclear magnetic data of product is
1h NMR (400MHz, CDCl
3) 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).With J.Med.Chem.2010, identical in 53,6730-6746 literary composition.From above-mentioned data, through aforesaid method, prepared product is target product 6-oxygen-3-azabicyclo [3.1.0] hexane-3-benzyl carboxylate.
Synthesizing 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: the synthetic 6-oxygen by step 3-3-azabicyclo [3.1.0] hexane-3-benzyl carboxylate (3.16g, 14.42mmol) be dissolved in dry methylene chloride (20mL), add ethylene bromohyrin (1.97g, 15.87mmol), then diethyl ether solution (the 0.22g that at room temperature slowly adds boron trifluoride, 0.19mmol), stirred overnight at room temperature.Methylene dichloride for reaction system (30mL) dilution, once, the saturated NaCl aqueous solution is washed once in washing, anhydrous sodium sulfate drying, the pressure reducing and steaming solvent, the residue column chromatography for separation, eluent: EA/PE=2/1 obtains product 1.44g, yield: 29.03%.
The nuclear magnetic data of product is
1h NMR (400MHz, CDCl
3) 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).
13C?NMR(100MHz，CDCl
3)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)。From above-mentioned data, through aforesaid method, prepared product is target product rac-(3RS, 4RS)-3-(2-bromine oxethyl)-4-hydroxyl pyrrolidine-1-benzyl carboxylate.
Step 5:rac-(4RS, 7RS)-tetrahydrochysene-2H-[1,4] bis-Evil [2,3-c] pyrroles-6 (3H)-benzyl carboxylate synthetic.
Rac-(4RS, 7RS)-tetrahydrochysene-2H-[1, the structural formula of 4] bis-Evil [2,3-c] pyrroles-6 (3H)-benzyl carboxylate:
Synthetic method: the synthetic rac-(3RS by step 4,4RS)-3-(2-bromine oxethyl)-4-hydroxyl pyrrolidine-1-benzyl carboxylate (1.43g, 4.17mmol) be dissolved in dehydrated alcohol (10mL), add potassium hydroxide (0.26g, 4.59mmol) dehydrated alcohol (3mL) solution, reflux 6h then.Filter ethyl acetate for filter cake (50mL) drip washing, merging filtrate, evaporated under reduced pressure, residue column chromatography for separation (eluent: EA/PE=1/1) obtain product 0.74g, yield: 67.27%.
The mass-spectrometric data of product is LC-MS:264.1 (M+H).Nuclear magnetic data is
1h NMR (400MHz, CDCl
3) 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).
13C?NMR(100MHz，CDCl
3)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)。From above-mentioned data, through aforesaid method, prepared product is target product rac-(4RS, 7RS)-tetrahydrochysene-2H-[1,4] bis-Evil [2,3-c] pyrroles-6 (3H)-benzyl carboxylate.
Step 6:rac-(4RS, 7RS)-six hydrogen-2H-[1,4] bis-Evil [2,3-c] pyrroles' is synthetic.
Rac-(4RS, 7RS)-six hydrogen-2H-[1,4] bis-Evil [2,3-c] pyrroles' structural formula:
Synthetic method: by the rac-(4RS of step 5 synthesized, 7RS)-tetrahydrochysene-2H-[1,4] bis-Evil [2,3-c] pyrroles-6 (3H)-benzyl carboxylate (0.30g, 1.14mmol) be dissolved in dry THF (10mL), add 10%Pd/C (0.10g), hydrogen exchange twice, room temperature hydrogenolysis 6h.Filter, the filtrate evaporate to dryness obtains product, is directly used in reaction in following step 8.
The mass-spectrometric data of product is LC-MS:130 (M+H).With identical in WO 2004043472.From above-mentioned data, through aforesaid method, prepared product is target product rac-(4RS, 7RS)-six hydrogen-2H-[1,4] bis-Evil [2,3-c] pyrroles.
Synthesizing of step 7:4-(2,6-dichloro pyrimidine-4-yl) morpholine.
The structural formula of 4-(2,6-dichloro pyrimidine-4-yl) morpholine:
Synthetic method: 2,4,6-trichloropyrimidine (1.0g, 5.45mmol) is dissolved in dry methylene dichloride (10mL), adds DIPEA (0.74g, 0.95mL), be cooled to-5 ℃, slowly be added dropwise to morpholine (0.47g, 5.45mmol).Slowly be warming up to room temperature reaction 2h.Add water in system, separate organic phase, the saturated NaCl aqueous solution is washed once, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent, residue column chromatography for separation (eluent: EA/PE=1/4) obtain product 1.02g, yield: 65.81%.
The nuclear magnetic data of product is
1h NMR (400MHz, CDCl
3) δ: 6.39 (d, J=4.5Hz, 1H), 3.88-3.49 (m, 8H).With identical in WO 2006005918.From above-mentioned data, through aforesaid method, prepared product is target product 4-(2,6-dichloro pyrimidine-4-yl) morpholine.
Step 8:rac-(4RS, 7RS)-6-(the chloro-6-morpholine of 4-pyrimidine-2-base) six hydrogen-2H-[1,4] bis-Evil [2,3-c] pyrroles' is synthetic.
Rac-(4RS, 7RS)-6-(the chloro-6-morpholine of 4-pyrimidine-2-base) six hydrogen-2H-[1,4] bis-Evil [2,3-c] pyrroles' structural formula:
Synthetic method: the 4-of step 7 synthesized (2,6-dichloro pyrimidine-4-yl) morpholine (0.42g, 1.80mmol) is dissolved in to THF/EtOH (1: 1,12mL), add the rac-(4RS, 7RS) of synthesized in step 6-six hydrogen-2H-[1,4] bis-Evil [2,3-c] pyrroles (1.64mmol), triethylamine (0.20g, 1.97mmol), sodium iodide (246mg, 1.80mmol), be heated to 60 ℃ of reaction 12h.The pressure reducing and steaming solvent, ethyl acetate (50mL) dissolution residual substance, wash twice, and the saturated NaCl aqueous solution is washed once, anhydrous sodium sulfate drying.Boil off solvent, column chromatographic isolation and purification (eluent: EA/PE=1/5) obtain product 0.28g, yield: 52.34%.
The mass-spectrometric data of product is LC-MS:327.10 (M+H).Nuclear magnetic data is
1h NMR (400MHz, CDCl
3) 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).
13C?NMR(100MHz，CDCl
3)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)。From above-mentioned data, through aforesaid method, prepared product is target product rac-(4RS, 7RS)-6-(the chloro-6-morpholine of 4-pyrimidine-2-base) six hydrogen-2H-[1,4] bis-Evil [2,3-c] pyrroles.
Step 9: pyrimidine compound ZJQ-04's of the present invention is synthetic.
Rac-5-(6-morpholine-2-((4RS, 7RS)-tetrahydrochysene)-2H-[1,4] two Evil) [2,3-c] pyrroles-6 (3H)-yl) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. structural formula of compound ZJQ-04:
Synthetic method: by the rac-(4RS of step 8 synthesized, 7RS)-6-(the chloro-6-morpholine of 4-pyrimidine-2-base) six hydrogen-2H-[1,4] bis-Evil [2,3-c] pyrroles (200mg, 0.61mmol) be dissolved in the dioxane (3.9mL) of deoxidation, the 5-(4,4,5 that adds successively step 2 synthesized, 5-tetramethyl--1,3,2-dioxy borine-2-yl)-4-(trifluoromethyl) pyridine-2-amine (0.35g, 1.23mmol), 2M wet chemical (1.05mL, 2.1mmol), pass into nitrogen 10min, then add Pd (dppf) Cl
2cH
2cl
2(25mg, 0.031mmol), sealing, in 150 ℃ of microwave reaction 2.5h.Concentrated except desolventizing, residue is dissolved in ethyl acetate (50mL), washes twice, and the saturated NaCl aqueous solution is washed once, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent, the residue column chromatographic isolation and purification, eluent: petrol ether/ethyl acetate=3/1-1/2, obtain yellow solid.This solid carries out the secondary column chromatography purification, eluent: methylene chloride/methanol=50/1, obtain target product 47mg, and 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[C
20h
24f
3n
6o
3]
+: 453.1856, found:453.1852.Nuclear magnetic data is
1h NMR (400MHz, CDCl
3) 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).
13C?NMR(100MHz，CDCl
3)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, through aforesaid method, prepared product is target product rac-5-(6-morpholine-2-((4RS, 7RS)-tetrahydrochysene)-2H-[1,4] bis-Evil) [2,3-c] pyrroles-6 (3H)-yl) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. compound ZJQ-04.
Embodiment 2: pyrimidine compound ZJQ-05's is synthetic.
Step 1:(2R, 4R)-the 1-tertiary butyl-2-methyl-4-((t-butyldimethylsilyl) oxo) Pyrrolidine-1,2-dicarboxylic ester synthetic.
(2R, 4R)-1-tertiary butyl-2-methyl-4-((t-butyldimethylsilyl) oxo) Pyrrolidine-1, the structural formula of 2-dicarboxylic ester:
Synthetic method: by (2R, 4R)-1-tertiary butyl-2-methyl 4-hydroxy-pyrrolidine-1,2-bis-carbonic ether (5g, 20.40mmol) be dissolved in methylene dichloride (40mL), DIPEA (7.46mL, 44.87mmol), be cooled to-40 ℃, continue to stir 3h after dripping tertiary butyl dimethyl silyl triflate (5.63mL, 24.48mmol).Add a large amount of shrends reaction of going out, then add methylene dichloride to be extracted, anhydrous sodium sulfate drying, concentrated, cross column purification, eluent: PE/EA=3/1, obtain target product 6.63g, yield 90.45%.
The mass-spectrometric data of product is LC-MS:360.2 (M+H).With identical in WO 2009137130.From above-mentioned data, through aforesaid method, prepared product is target product (2R, the 4R)-1-tertiary butyl-2-methyl-4-((t-butyldimethylsilyl) oxo) Pyrrolidine-1, the 2-dicarboxylic ester.
Step 2:(2R, 4R)-tertiary butyl-4-((t-butyldimethylsilyl) oxo)-2-(methylol) Pyrrolidine-1-carboxylicesters synthetic.
The structural formula of (2R, the 4R)-tertiary butyl-4-((t-butyldimethylsilyl) oxo)-2-(methylol) Pyrrolidine-1-carboxylicesters:
Synthetic method the: by (2R of synthesized in step 1, the 4R)-1-tertiary butyl-2-methyl-4-((t-butyldimethylsilyl) oxo) Pyrrolidine-1,2-dicarboxylic ester (6.63g, 18.46mmol) be dissolved in dry THF (50mL), be cooled to 0 ℃, after adding lithium borohydride (1.0g, 46.14mmol), recover stirred overnight at room temperature.Be cooled under 0 ℃ and slowly add methyl alcohol cancellation reaction, then filter, concentrated filtrate, cross post and carry out purifying, obtains the 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 is
1h NMR (400MHz, CDCl
3) 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).With identical in US 20080081803.From above-mentioned data, through aforesaid method, prepared product is target product (2R, the 4R)-tertiary butyl-4-((t-butyldimethylsilyl) oxo)-2-(methylol) Pyrrolidine-1-carboxylicesters.
Step 3:(2R, 4R)-tertiary butyl-4-hydroxy-2-((benzenesulfonyl oxo) methyl) Pyrrolidine-1-carboxylicesters synthetic
The structural formula of (2R, 4R)-tertiary butyl-4-hydroxy-2-((benzenesulfonyl oxo) methyl) Pyrrolidine-1-carboxylicesters:
Synthetic method the: by (2R of step 2 synthesized, the 4R)-tertiary butyl-4-((t-butyldimethylsilyl) oxo)-2-(methylol) Pyrrolidine-1-carboxylicesters (3.80g, 11.47mmol) be dissolved in dry methylene chloride (50mL), add DIPEA (3.80mL, 22.94mmol) after be cooled to 0 ℃, add Methanesulfonyl chloride (1.96g, 17.22mmol), then return to stirred overnight at room temperature.Add the shrend reaction of going out, organic phase is washed once, saturated NaHCO
3wash once, then saturated NaCl washes once, anhydrous sodium sulfate drying.Concentrated, directly carry out next step.Get above-mentioned dissolving crude product in THF (25mL), add stirring at room 1h after tetrabutyl ammonium fluoride (3.79g, 14.49mmol), add the shrend reaction of going out, the pressure reducing and steaming solvent, add CH
2cl
2(100mL) extraction, the organic layer washing, the saturated NaCl aqueous solution is washed once, and anhydrous sodium sulfate drying is concentrated, crosses column purification, obtains target product 2.90g, white solid, yield: 88.14%.
The nuclear magnetic data of product is
1h NMR (400MHz, CDCl
3) 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).
13C?NMR(100MHz，CDCl
3)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)。From above-mentioned data, through aforesaid method, prepared product is target product (2R, 4R)-tertiary butyl-4-hydroxy-2-((benzenesulfonyl oxo) methyl) Pyrrolidine-1-carboxylicesters.
Step 4:(1R, 4R)-assorted two ring [2.2.1]-heptane-5-carboxylicesterss of the tertiary butyl-2-oxa--5-synthetic.
The structural formula of assorted two ring [2.2.1]-heptane-5-carboxylicesterss of (1R, 4R)-tertiary butyl-2-oxa--5-:
Synthetic method the: by (2R of synthesized in step 3, 4R)-tertiary butyl-4-hydroxy-2-((benzenesulfonyl oxo) methyl) Pyrrolidine-1-carboxylicesters (1.28g, 4.33mmol) be dissolved in dry THF (20mL), be cooled to-10 ℃, add 60%NaH (0.40g, 12.98mmol), then recover stirring at room 24h, after mixed solution is cooled to 0 ℃, slowly add the shrend reaction of going out, add ethyl acetate to be extracted, the anhydrous sodium sulfate drying organic layer, concentrated, the residue column chromatographic isolation and purification, eluent: petrol ether/ethyl acetate=5/1-3/1, obtain the 0.84g target product, white solid, yield: 44.44%.
The nuclear magnetic data of product is
1h NMR (400MHz, CDCl
3) 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).
13C?NMR(100MHz，CDCl
3)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)。From above-mentioned data, through aforesaid method, prepared product is assorted two ring [2.2.1]-heptane-5-carboxylicesterss of target product (1R, 4R)-tertiary butyl-2-oxa--5-.
Step 5:(1R, 4R)-assorted two ring [the 2.2.1]-heptane trifluoroacetates of 2-oxa--5-synthetic.
The structural formula of assorted two ring [the 2.2.1]-heptane trifluoroacetates of (1R, 4R)-2-oxa--5-:
Synthetic method: assorted two ring [2.2.1]-heptane-5-carboxylicesterss (0.3g, 1.51mmol) of (1R, the 4R) of step 4 synthesized-tertiary butyl-2-oxa--5-are dissolved in to dry CH
2cl
2(10mL), in, add trifluoroacetic acid (1mL) stirred overnight at room temperature.The pressure reducing and steaming solvent, be directly used in the next step.
Step 6:(1R, 4R)-5-(the chloro-6-morpholine of 4-pyrimidine-2-base)-2-oxygen-5-azabicyclo [2.2.1] heptane synthetic.
The structural formula of (1R, 4R)-5-(the chloro-6-morpholine of 4-pyrimidine-2-base)-2-oxygen-5-azabicyclo [2.2.1] heptane:
Synthetic method: by 4-(2,6-dichloro pyrimidine-4-yl) morpholine (0.38g, 1.65mmol) be dissolved in THF/EtOH (1: 1,12mL) in, add (the 1R of above-mentioned steps 5 synthesizeds, assorted two ring [the 2.2.1]-heptane trifluoroacetates (1.51mmol) of 4R)-2-oxa--5-, triethylamine (0.36g, 3.32mmol), sodium iodide (227mg, 1.51mmol), be heated to 60 ℃ of reaction 40h.The pressure reducing and steaming solvent, ethyl acetate (50mL) dissolution residual substance, wash twice, and the saturated NaCl aqueous solution is washed once, anhydrous sodium sulfate drying.Boil off solvent, column chromatographic isolation and purification (eluent: EA/PE=1/5) obtain target product 0.96g, yield: 66.22%.
The mass-spectrometric data of product is LC-MS:297.10 (M+H).Nuclear magnetic data is
1h NMR (400MHz, CDCl
3) 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，CDCl
3)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)。From above-mentioned data, through aforesaid method, prepared product is target product (1R, 4R)-5-(the chloro-6-morpholine of 4-pyrimidine-2-base)-2-oxygen-5-azabicyclo [2.2.1] heptane.
Step 7: pyrimidine compound ZJQ-05's of the present invention is synthetic.
5-(2-((1R, 4R)-2-oxygen-5-azabicyclo [2.2.1] heptane-5-yl)-6-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. structural formula of compound ZJQ-05:
Synthetic method the: by (1R of step 6 synthesized, 4R)-5-(the chloro-6-morpholine of 4-pyrimidine-2-base)-2-oxygen-5-azabicyclo [2.2.1] heptane (221mg, 0.75mmol) be dissolved in the dioxane (4.8mL) of deoxidation, the 5-(4 that adds successively step 2 synthesized in embodiment 1,4,5,5-tetramethyl--1,3,2-dioxy borine-2-yl)-4-(trifluoromethyl) pyridine-2-amine (0.43g, 1.49mmol), 2M wet chemical (1.13mL, 2.26mmol), pass into nitrogen 10min, then add Pd (dppf) Cl
2cH
2cl
2(31mg, 0.0375mmol), sealing, in 150 ℃ of microwave reaction 2.5h.Concentrated except desolventizing, residue is dissolved in ethyl acetate (50mL), washes twice, and the saturated NaCl aqueous solution is washed once, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent, the residue column chromatographic isolation and purification, eluent: sherwood oil: ethyl acetate=3/1-1/2, obtain a yellow solid.This solid carries out the secondary column chromatography purification, eluent: methylene chloride/methanol=50/1, obtain target product 75mg, and 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[C
19h
22f
3n
6o
2]
+: 423.1751, found:423.1772.Nuclear magnetic data is
1h NMR (400MHz, CDCl
3) 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).
13C?NMR(100MHz，CDCl
3)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, through aforesaid method, prepared product is target product 5-(2-((1R, 4R)-2-oxygen-5-azabicyclo [2.2.1] heptane-5-yl)-6-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. compound ZJQ-05.
Embodiment 3: pyrimidine compound ZJQ-22's is synthetic.
(-)-5-(6-morpholine-2-((4RS, 7RS)-tetrahydrochysene)-2H-[1,4] two Evil) [2,3-c] pyrroles-6 (3H)-yl) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. structural formula of compound ZJQ-22:
Synthetic method: the ZJQ-04 that embodiment 1 is prepared is split, separation condition: anti-phase chirality preparative column (the lu 5u cellose-2 of Fei Luomen), moving phase: methanol/water=95/5; Purity: 99.90%; Retention time: 13.94min, obtain resolved product ZJQ-22.
The high resolution mass spectrum data of resolved product are HRMS (ESI): m/z[M+H]
+calcd.for[C
20h
24f
3n
6o
3]
+: 453.1856, found:453.1845.The optically-active data are
from above-mentioned data, through aforesaid method, prepared product is target product (-)-5-(6-morpholine-2-((4RS, 7RS)-tetrahydrochysene)-2H-[1,4] bis-Evil) [2,3-c] pyrroles-6 (3H)-yl) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. compound ZJQ-22.
Embodiment 4: pyrimidine compound ZJQ-23's is synthetic.
(+)-5-(6-morpholine-2-((4SR, 7SR)-tetrahydrochysene)-2H-[1,4] two Evil) [2,3-c] pyrroles-6 (3H)-yl) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. structural formula of compound ZJQ-23:
Synthetic method: the ZJQ-04 that embodiment 1 is prepared is split, separation condition: anti-phase chirality preparative column (the lu 5u cellose-2 of Fei Luomen), moving phase: methanol/water=95/5; Purity: 99.07%; Retention time: 14.67min, obtain resolved product ZJQ-23.
The high resolution mass spectrum data of resolved product are HRMS (ESI): m/z[M+H]
+calcd.for[C
20h
24f
3n
6o
3]
+: 453.1856, found:453.1863.The optically-active data are
from above-mentioned data, through aforesaid method, prepared product is target product (+)-5-(6-morpholine-2-((4SR, 7SR)-tetrahydrochysene)-2H-[1,4] bis-Evil) [2,3-c] pyrroles-6 (3H)-yl) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. compound ZJQ-23.
Embodiment 5: pyrimidine compound ZJQ-07's is synthetic.
Step 1:4-(4,6-bis-chloro-1,3,5-tri-nitrogen piperazines-2-yl) morpholine synthetic.
The structural formula of 4-(4,6-bis-chloro-1,3,5-tri-nitrogen piperazines-2-yl) morpholine:
Synthetic method: 2,4,6-tri-is chloro-1,3, and 5-tri-nitrogen piperazines (5.0g, 27.33mmol) are dissolved in CH
2cl
2(100mL) in, be cooled to-5 ℃, slowly be added dropwise to the CH of DIPEA (4.10mL, 24.64mmol) and morpholine (2.15mL, 24.64mmol)
2cl
2(20mL) mixed solution, low-temp reaction 1h, rise to 0 ℃ of reaction and spend the night.Reaction system CH
2cl
2(50mL) dilution, 1M HCl washes (50mL * 2) twice, and saturated NaCl washes once, anhydrous sodium sulfate drying.Column chromatographic isolation and purification, eluent: PE/EA=10/1-5/1, obtain target product 4.59g, white solid, yield: 59.74%.
The nuclear magnetic data of product is
1h NMR (400MHz, CDCl
3) δ: 3.97-3.80 (m, 4H), 3.80-3.65 (m, 4H).With identical in WO 2011039735.From above-mentioned data, through aforesaid method, prepared product is target product 4-(4,6-bis-chloro-1,3,5-tri-nitrogen piperazines-2-yl) morpholine.
Step 2:(1R, 4R)-5-(the chloro-6-morpholine-1,3 of 4-, 5-tri-nitrogen piperazines-2-yl)-2-oxygen-5-azabicyclo [2.2.1] heptane synthetic
The structural formula of (1R, 4R)-5-(the chloro-6-morpholine-1,3 of 4-, 5-tri-nitrogen piperazines-2-yl)-2-oxygen-5-azabicyclo [2.2.1] heptane:
Synthetic method: by the 4-of synthesized in step 1 (4,6-bis-chloro-1,3,5-, tri-nitrogen piperazines-2-yl) morpholine (0.36g, 1.51mmol) is dissolved in THF (1: 1,12mL), assorted two ring [the 2.2.1]-heptane trifluoroacetates (1.51mmol) of (1R, 4R)-2-oxa--5-that add embodiment 2 step 5 synthesizeds, salt of wormwood (0.32g, 2.27mmol), stirred overnight at room temperature.The pressure reducing and steaming solvent, ethyl acetate (50mL) dissolution residual substance, wash twice, and the saturated NaCl aqueous solution is washed once, anhydrous sodium sulfate drying.Boil off solvent, column chromatographic isolation and purification (eluent: EA/PE=1/5) obtain product 0.39g, yield: 84.46%.
The mass-spectrometric data of product is LC-MS:298.2 (M+H).Nuclear magnetic data is
1h NMR (400MHz, CDCl
3) 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，CDCl
3)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)。From above-mentioned data, through aforesaid method, prepared product is target product (1R, 4R)-5-(the chloro-6-morpholine-1,3 of 4-, 5-tri-nitrogen piperazines-2-yl)-2-oxygen-5-azabicyclo [2.2.1] heptane.
Step 3: pyrimidine compound ZJQ-07's is synthetic.
5-(4-((1R, 4R)-2-oxygen-5-azabicyclo [2.2.1] heptane-5-yl)-6-morpholine-1,3,5-tri-nitrogen piperazines-2-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. structural formula of compound ZJQ-07:
Synthetic method the: by (1R of synthesized in step 2,4R)-5-(chloro-6-morpholine-1 of 4-, 3,5-tri-nitrogen piperazines-2-yl)-2-oxygen-5-azabicyclo [2.2.1] heptane (250mg, 0.84mmol) be dissolved in the dioxane (4.0mL) of deoxidation, the 5-(4,4,5 that adds successively embodiment 1 step 2 synthesized, 5-tetramethyl--1,3,2-dioxy borine-2-yl)-4-(trifluoromethyl) pyridine-2-amine (0.49g, 1.69mmol), 2M wet chemical (1.26mL, 2.52mmol), pass into nitrogen 10min, then add Pd (dppf) Cl
2cH
2cl
2(35mg, 0.042mmol), sealing, in 150 ℃ of microwave reaction 2.5h.Concentrated except desolventizing, residue is dissolved in ethyl acetate (50mL), washes twice, and the saturated NaCl aqueous solution is washed once, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent, the residue column chromatographic isolation and purification, eluent: petrol ether/ethyl acetate=3/1-1/2, obtain a brown solid.This solid carries out the secondary column chromatography purification, eluent: methylene chloride/methanol=50/1, obtain target product 60mg, and 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[C
18h
21f
3n
7o
2]
+: 424.1703, found:424.1692.Nuclear magnetic data is
1h NMR (400MHz, CDCl
3) 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).
13C?NMR(100MHz，CDCl
3)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, through aforesaid method, prepared product is target product 5-(4-((1R, 4R)-2-oxygen-5-azabicyclo [2.2.1] heptane-5-yl)-6-morpholine-1,3,5-tri-nitrogen piperazines-2-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. compound ZJQ-07.
Embodiment 6: pyrimidine compound ZJQ-28's is synthetic.
Synthesizing of the chloro-6-morpholine-N-of step 1:4-(4-morpholinyl phenyl) pyrimidine-2-amine.
The structural formula of the chloro-6-morpholine-N-of 4-(4-morpholinyl phenyl) pyrimidine-2-amine:
Synthetic method: by the 4-(2 of embodiment 1 step 7 synthesized, 6-dichloro pyrimidine-4-yl) morpholine (0.50g, 2.15mmol) be dissolved in propyl carbinol (20mL), add 4-morpholine aniline (0.38g, 2.15mmol), one hydration tosic acid (0.26g, 1.72mmol), be heated to 100 ℃ of reaction 24h.The pressure reducing and steaming solvent, ethyl acetate (50mL) dissolution residual substance, saturated NaHCO
3the aqueous solution is washed once, and the saturated NaCl aqueous solution is washed once, anhydrous sodium sulfate drying.Boil off solvent, column chromatographic isolation and purification (eluent: EA/PE=1/1, DCM/CH3OH=10/1, gradient elution) obtains product 0.43g, yield: 53.54%.
The mass-spectrometric data of product is LC-MS:376.2 (M+H).Nuclear magnetic data is
1h NMR (400MHz, CDCl
3) 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).
13C?NMR(100MHz，CDCl
3)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)。From above-mentioned data, through aforesaid method, prepared product is the chloro-6-morpholine-N-of target product 4-(4-morpholinyl phenyl) pyrimidine-2-amine.
Step 2: pyrimidine compound ZJQ-28's is synthetic.
4-(6-amino-4-(trifluoromethyl) pyridin-3-yl)-6-morpholine-N-(4-morpholinyl phenyl) pyrimidine-2-amine, i.e. structural formula of compound ZJQ-28:
Synthetic method: by the chloro-6-morpholine-N-of the 4-of step 1 synthesized (4-morpholinyl phenyl) pyrimidine-2-amine (0.30g, 0.80mmol) be dissolved in the dioxane (3.60mL) of deoxidation, the 5-(4 that adds successively embodiment 1 step 2 synthesized, 4,5,5-tetramethyl--1,3,2-dioxy borine-2-yl)-4-(trifluoromethyl) pyridine-2-amine (0.27g, 1.20mmol), 2M wet chemical (1.20mL, 2.40mmol), pass into nitrogen 10min, then add Pd (dppf) Cl
2cH
2cl
2(33mg, 0.04mmol), sealing, in 150 ℃ of microwave reaction 43min.Concentrated except desolventizing, residue is dissolved in ethyl acetate (50mL), washes twice, and the saturated NaCl aqueous solution is washed once, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent, the residue column chromatographic isolation and purification, eluent: methylene chloride/methanol=50/1, obtain 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[C
24h
27f
3n
7o
2]
+: 502.2173, found:502.2163.Nuclear magnetic data is
1h NMR (400MHz, CDCl
3) 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).
13C?NMR(100MHz，CDCl
3)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)。From above-mentioned data, through aforesaid method, prepared product is 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: pyrimidine compound ZJQ-26's is synthetic.
Synthesizing of step 1:4-(the chloro-2-of 6-(4-(methylsulfonyl) piperazine-1-yl) pyrimidine-4-yl) morpholine
The structural formula of 4-(the chloro-2-of 6-(4-(methylsulfonyl) piperazine-1-yl) pyrimidine-4-yl) morpholine:
Synthetic method: by the 4-(2 of embodiment 1 step 7 synthesized, 6-dichloro pyrimidine-4-yl) morpholine (0.40g, 1.72mmol) be dissolved in THF/EtOH (1: 1,20mL) in, add N-first sulfo group piperazine (0.31g, 1.89mmol), DIPEA (0.34g, 2.58mmol), sodium iodide (258mg, 1.72mmol), be heated to 70 ℃ of reaction 24h.The pressure reducing and steaming solvent, ethyl acetate (100mL) dissolution residual substance, wash twice, and the saturated NaCl aqueous solution is washed once, anhydrous sodium sulfate drying.Boil off solvent, column chromatographic isolation and purification (eluent: EA/PE=1/3-1/1) obtain product 0.31g, yield: 50.65%.
The mass-spectrometric data of product is LC-MS:362.1 (M+H).Nuclear magnetic data is
1h NMR (400MHz, CDCl
3) 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).
13C?NMR(100MHz，CDCl
3)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)。From above-mentioned data, through aforesaid method, prepared product is target product 4-(the chloro-2-of 6-(4-(methylsulfonyl) piperazine-1-yl) pyrimidine-4-yl) morpholine.
Step 2: pyrimidine compound ZJQ-26's is synthetic.
5-(2-(4-(methylsulfonyl) piperazine-1-yl)-6-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. structural formula of compound ZJQ-26:
Synthetic method: by 4-prepared in step 1 (the chloro-2-of 6-(4-(methylsulfonyl) piperazine-1-yl) pyrimidine-4-yl) morpholine (0.25g; 0.69mmol) be dissolved in the dioxane (3.0mL) of deoxidation; the 5-(4 that adds successively step 2 synthesized in embodiment 1; 4; 5; 5-tetramethyl--1; 3; 2-dioxy borine-2-yl)-4-(trifluoromethyl) pyridine-2-amine (0.40g; 1.38mmol), 2M wet chemical (1.05mL, 2.07mmol); pass into nitrogen 10min, then add Pd (dppf) Cl
2cH
2cl
2(28mg, 0.035mmol), sealing, in 150 ℃ of microwave reaction 2.5h.Concentrated except desolventizing, residue is dissolved in ethyl acetate (50mL), washes twice, and the saturated NaCl aqueous solution is washed once, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent, and the residue column chromatographic isolation and purification (eluent: methylene chloride/methanol=50/1) obtain 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[C
19h
24f
3n
7o
3s]
+: 486.1507, found:486.1498.Nuclear magnetic data is
1h NMR (400MHz, CDCl
3) 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).
13C?NMR(100MHz，CDCl
3)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, through aforesaid method, prepared product is target product 5-(2-(4-(methylsulfonyl) piperazine-1-yl)-6-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. compound ZJQ-26.
Embodiment 8: pyrimidine compound ZJQ-21's is synthetic.
Step 1:rac-(4RS, 7RS)-6-(the chloro-6-morpholine-1,3 of 4-, 5-tri-nitrogen piperazines-2-yl) six hydrogen-2H-[1,4] bis-Evil [2,3-c] pyrroles' is synthetic.
Rac-(4RS, 7RS)-6-(the chloro-6-morpholine-1,3 of 4-, 5-tri-nitrogen piperazines-2-yl) six hydrogen-2H-[1,4] bis-Evil [2,3-c] pyrroles' structural formula:
Synthetic method: by the 4-of embodiment 5 step 1 synthesizeds, (4,6-bis-chloro-1,3,5-tri-nitrogen piperazines-2-yl) morpholine (0.27g, 1.14mmol) be dissolved in THF (10mL), add rac-(4RS, 7RS)-six hydrogen-2H-[1,4] bis-Evil [2,3-c] pyrroles (0.18g, 1.14mmol), DIPEA (0.18g, 1.37mmol), stirred overnight at room temperature.The pressure reducing and steaming solvent, ethyl acetate (50mL) dissolution residual substance, wash twice, and the saturated NaCl aqueous solution is washed once, anhydrous sodium sulfate drying.Boil off solvent, column chromatographic isolation and purification (eluent: EA/PE=1/5) obtain product 0.31g, yield: 82.23%.
The mass-spectrometric data of product is LC-MS:328.1 (M+H).Nuclear magnetic data is
1h NMR (400MHz, CDCl
3) δ: 4.08-3.41 (m, 16H), 3.31-3.14 (m, 2H).
13C?NMR(100MHz，CDCl
3)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)。From above-mentioned data, through aforesaid method, prepared product is target product rac-(4RS, 7RS)-6-(the chloro-6-morpholine-1,3 of 4-, 5-tri-nitrogen piperazines-2-yl) six hydrogen-2H-[1,4] bis-Evil [2,3-c] pyrroles
Step 2: pyrimidine compound ZJQ-21's is synthetic.
Rac-5-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two Evil [2,3-c] pyrroles-6 (3H)-yl)-1,3,5-tri-nitrogen piperazines-2-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. structural formula of compound ZJQ-21:
Synthetic method: by the rac-(4RS of step 1 synthesized, 7RS)-6-(chloro-6-morpholine-1 of 4-, 3,5-tri-nitrogen piperazines-2-yl) six hydrogen-2H-[1,4] bis-Evil [2,3-c] pyrroles (250mg, 0.76mmol) be dissolved in the dioxane (3.5mL) of deoxidation, the 5-(4,4,5 that adds successively embodiment 1 step 2 synthesized, 5-tetramethyl--1,3,2-dioxy borine-2-yl)-4-(trifluoromethyl) pyridine-2-amine (0.44g, 1.53mmol), 2M wet chemical (1.14mL, 2.28mmol), pass into nitrogen 10min, then add Pd (dppf) Cl
2cH
2cl
2(31mg, 0.038mmol), sealing, in 150 ℃ of microwave reaction 2.5h.Concentrated except desolventizing, residue is dissolved in ethyl acetate (50mL), washes twice, and the saturated NaCl aqueous solution is washed once, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent, the residue column chromatographic isolation and purification, eluent: methylene chloride/methanol=50/1, obtain 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 is
1h NMR (400MHz, CDCl
3) 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，CDCl
3)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, through aforesaid method, prepared product is target product rac-5-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] bis-Evil [2,3-c] pyrroles-6 (3H)-yl)-1,3,5-, tri-nitrogen piperazines-2-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. compound ZJQ-21.
Embodiment 9: pyrimidine compound ZJQ-29's is synthetic.
(-)-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two Evil [2,3-c] pyrroles-6 (3H)-yl)-1,3,5-tri-nitrogen piperazines-2-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. structural formula of compound ZJQ-29:
Synthetic method: prepared ZJQ-21 is split to separation condition: anti-phase chirality preparative column (the lu 5u cellose-2 of Fei Luomen), moving phase: methanol/water=95/5; Purity: 97.70%; Retention time: 12.25min, obtain resolved product ZJQ-29.
The mass-spectrometric data of product is LC-MS:454.2 (M+H).The optically-active data are
from above-mentioned data, through aforesaid method, prepared product is target product (-)-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] bis-Evil [2,3-c] pyrroles-6 (3H)-yl)-1,3,5-, tri-nitrogen piperazines-2-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. compound ZJQ-29.
Embodiment 10: pyrimidine compound ZJQ-30's is synthetic.
(+)-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two Evil [2,3-c] pyrroles-6 (3H)-yl)-1,3,5-tri-nitrogen piperazines-2-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. structural formula of compound ZJQ-30:
Synthetic method: prepared ZJQ-21 is split to separation condition: anti-phase chirality preparative column (the lu 5ucellose-2 of Fei Luomen), moving phase: methanol/water=95/5; Purity: 98.62%; Retention time: 14.25min, obtain resolved product ZJQ-30.
The mass-spectrometric data of product is LC-MS:454.2 (M+H).The optically-active data are
from above-mentioned data, through aforesaid method, prepared product is target product (+)-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] bis-Evil [2,3-c] pyrroles-6 (3H)-yl)-1,3,5-, tri-nitrogen piperazines-2-yl)-4-(trifluoromethyl) pyridine-2-amine, i.e. compound ZJQ-30.
Also prepared as other compound in following table 1 in the present invention, the synthetic method of these compounds is with reference to aforesaid method simultaneously.The characterization data of these compounds, comprise that nuclear magnetic data and high resolution mass spectrum data are as shown in table 1.
Table 1
External PI3K alpha kinase suppresses test:
The compounds of this invention suppresses PI3K alpha kinase activity, suppresses thus the transduction of cell signal path, thereby affects cell cycle and cell proliferation.This compounds passes through following Kinase-Glo Luminescent Kinase Assay method evaluation to the restraining effect of PI3K alpha kinase.
Testing tool: adopt Kinase-Glo Plus Luminescent Kinase Assay (Kinase Glo Plus kinases luminous detection) test kit to carry out test target compound kinase inhibiting activity.
Detect principle: Kinase-Glo Plus Luminescent Kinase Assay is a kind of inactive detection method of homogeneous, and it is to carry out the kinase whose activity of quantitative assay purifying by detecting after kinase reaction the content of ATP in system.The mensuration of ATP content is by by Mg
2+, ATP and oxygen catalysis firefly luciferin (beetle luciferin) light intensity that occurs to produce after oxidation comes quantitative.Add a certain amount of ATP in reaction system, kinase reaction need to consume ATP, remaining ATP can with Kinase Glo reagent in Photinus pyralis LUC react rear luminous, thereby amount that can the remaining ATP of detection by quantitative, kinase whose activity is reacted in indirect measurement.
Detection method: 100% methyl-sulphoxide (DMSO) for test-compound is formulated as to 100 * concentration of highest response inhibition concentration, draws in 100 μ L to 96 orifice plate one holes.Then carry out the concentration gradient dilution of 3 times with 100%DMSO by hole, prepare 10 concentration." fully " and " blank " control wells replaces with the 100%DMSO of 100 μ L.Wherein, " fully " control wells is without the compound group, and " blank " control wells is without the kinases group.Subsequently, preparation is containing the compound intermediate diluent of 4%DMSO, and compound method for adding 4 μ L compounds and 96 μ L 1 * kinases basis damping fluid in each hole of check-out console.2.5 μ L above-claimed cpd intermediate diluent are added to Sptting plate, then 2.5 μ L 4 * kinase solution (are added to 1 * kinases basis damping fluid (50mM HEPES, pH 7.5,1mM EGTA, 100mM NaCl, 3mM MgCl by kinases
2, 2mM DTT, 0.03%CHAPS be formulated) be added in each hole of check-out console.Incubated at room 10min.By 5 μ L 2 * substrate solution (adding 1 * kinases basis damping fluid formulated PIP2 and ATP) add in each hole of check-out console.Incubated at room 1h.Add 10 μ L stop buffer (Kinase-Glo reagent) termination reactions.Vibration, centrifugal 1min, low-speed oscillation 15min, then Flexstation reads plate and is detected, and finally according to the reader of RLU value and " fully " and " blank " control wells, calculates the inhibiting rate under each concentration of compound, the binding compounds concentration calculating IC that maps
50value.
Test-results: in Table 2.
Table 2 target compound PI3K alpha kinase vitro inhibition activity
| Compound | IC 50(nM) | Compound | IC 50(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 |
Can find out that by data in table 2 compound that invention is protected all has and suppresses active the PI3K alpha kinase, and wherein major part has obvious PI3K alpha kinase inhibition activity.And, with the Buparlisib with structural formula 1 (NVP-BKM120) of the compound N ovartis company exploitation that enters the III clinical trial phase of pointing out in current background technology, compare, compound ZJQ-04 provided by the present invention, ZJQ-21, ZJQ-23, ZJQ-26, ZJQ-28 and compound ZJQ-30 have the inhibition activity equal to or slightly better with it.As can be seen here, compound provided by the invention has obvious inhibition active to the PI3K alpha kinase, 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.Within the spirit and principles in the present invention all, any modification of doing, be equal to replacement, improvement etc., within all should being included in protection scope of the present invention.
Claims (11)
1. a PI3K kinase inhibitor, is characterized in that, comprises the pyrimidine compound with formula I, its steric isomer, and hydrate or pharmacy acceptable salt, described formula I structure is as follows:
In described formula I:
X, Y, Z, W independently selected from N or-CH-;
R
1, R
2independently selected from H, C
1-C
4alkyl, containing one or more substituent C
1-C
4alkyl, C
1-C
4alkoxyl group, containing one or more substituent C
1-C
4alkoxyl group, C
3-C
6heterocyclic radical, containing one or more substituent C
3-C
6heterocyclic radical, C
4-C
8condense assorted bicyclic group or contain one or more substituent C
4-C
8condense assorted bicyclic group, described substituting group is selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, C
1-C
4alkyl, halo C
1-C
4alkyl, hydroxyl C
1-C
4alkyl, C
1-C
4alkoxyl group, halo C
1-C
4alkoxyl group, hydroxyl C
1-C
4alkoxyl group or C
1-C
4alkoxy C
1-C
4alkyl;
R
3be selected from H ,-CN ,-CH
3,-CF
3or-SO
2nH
2;
R
4be selected from H or halogen.
2. PI3K kinase inhibitor according to claim 1, is characterized in that, described R
3for-CF
3.
3. PI3K kinase inhibitor according to claim 2, is characterized in that, described PI3K kinase inhibitor comprises the pyrimidine compound with general formula II and/or general formula III, its steric isomer, hydrate or pharmacy acceptable salt; Described general formula II and general formula III structure are as follows:
In described general formula II and general formula III:
R
1, R
2independently selected from H, C
1-C
4alkyl, containing one or more substituent C
1-C
4alkyl, C
1-C
4alkoxyl group, containing one or more substituent C
1-C
4alkoxyl group, C
3-C
6heterocyclic radical, containing one or more substituent C
3-C
6heterocyclic radical, C
4-C
8condense assorted bicyclic group or contain one or more substituent C
4-C
8condense assorted bicyclic group, described substituting group is selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, C
1-C
4alkyl, halo C
1-C
4alkyl, hydroxyl C
1-C
4alkyl, C
1-C
4alkoxyl group, halo C
1-C
4alkoxyl group, hydroxyl C
1-C
4alkoxyl group or C
1-C
4alkoxy C
1-C
4alkyl.
4. according to the described PI3K kinase inhibitor of claim 1 or 3, it is characterized in that R in described formula I, described general formula II or described general formula III
1, R
2independently selected from following structure:
Wherein, A, B, C, D, E, F is independently selected from-CH
2-,-O-,-S-or-NR
11-;
R
5, R
6, R
7, R
8, R
9, R
10, R
11independently selected from H, halogen, hydroxyl, amino, C
1-C
4alkyl, halo C
1-C
4alkyl, hydroxyl C
1-C
4alkyl, C
1-C
4alkoxyl group, halo C
1-C
4alkoxyl group, hydroxyl C
1-C
4alkoxyl group, or C
1-C
4alkyl sulphonyl.
5. PI3K kinase inhibitor according to claim 4, is characterized in that, R in described formula I or in described general formula II and III
1, R
2independently selected from following structure:
6. PI3K kinase inhibitor according to claim 5, is characterized in that, in described formula I, in described general formula II or described general formula III,
R
1be selected from following structure:
R
2be selected from following structure:
7. PI3K kinase inhibitor according to claim 1, is characterized in that, pyrimidine compound is:
Rac-5-(the 6-morpholine-2-(and (4RS, 7RS)-tetrahydrochysene-2H-[1,4] two Evil) [2,3-c] pyrroles-6 (3H)-yl) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine;
5-(2-((1R, 4R)-2-oxygen-5-azabicyclo [2.2.1] heptane-5-yl)-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 Evil [2,3-c] pyrroles-6 (3H, 7H, 7aH)-yl)-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 Evil [2,3-c] pyrroles-6 (3H)-yl) 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 Evil [2,3-c] pyrroles-6 (3H)-yl) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine;
Rac-5-(2-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two Evil [2,3-c] pyrroles-6 (3H)-yl) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine;
Rac-6-morpholine-2-((4RS, 7RS)-tetrahydrochysene)-2H-[1,4] two Evil [2,3-c] pyrroles-6 (3H)-yl)-[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-(the 6-morpholine-2-(and (4RS, 7RS)-tetrahydrochysene-2H-[1,4] two Evil) [2,3-c] pyrroles-6 (3H)-yl) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine;
(+)-5-(the 6-morpholine-2-(and (4RS, 7RS)-tetrahydrochysene-2H-[1,4] two Evil) [2,3-c] pyrroles-6 (3H)-yl) pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine;
5-(4-((1R, 4R)-2-oxygen-5-azabicyclo [2.2.1] heptane-5-yl)-6-morpholine-1,3,5-tri-nitrogen piperazines-2-yl)-4-(trifluoromethyl) pyridine-2-amine;
5-(2-(4-(methylsulfonyl) piperazine-1-yl)-6-morpholine pyrimidine-4-yl)-4-(trifluoromethyl) pyridine-2-amine;
5-(4-((1R, 4R)-2-oxygen-5-azabicyclo [2.2.1] heptane-5-yl)-6-((2R, 6S)-2,6-thebaine)-1,3,5-tri-nitrogen piperazines-2-yl)-4-(trifluoromethyl) pyridine-2-amine;
Rac-5-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two Evil [2,3-c] pyrroles-6 (3H)-yl)-1,3,5-tri-nitrogen piperazines-2-yl)-4-(trifluoromethyl) pyridine-2-amine;
(-)-5-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two Evil [2,3-c] pyrroles-6 (3H)-yl)-1,3,5-tri-nitrogen piperazines-2-yl)-4-(trifluoromethyl) pyridine-2-amine; Perhaps
(+)-5-(4-morpholine-6-((4RS, 7RS)-tetrahydrochysene-2H-[1,4] two Evil [2,3-c] pyrroles-6 (3H)-yl)-1,3,5-tri-nitrogen piperazines-2-yl)-4-(trifluoromethyl) pyridine-2-amine.
8. a pharmaceutical composition, is characterized in that, the described PI3K kinase inhibitor of any one at least one claim 1 to 7 that comprises at least one pharmaceutically acceptable auxiliary material, auxiliary or carrier and dose therapeutically effective.
9. the described PI3K kinase inhibitor of any one or the application of pharmaceutical composition claimed in claim 8 in the medicine of the proliferative disease of Prevention and/or treatment and/or assisting therapy PI3K zymogenesis in a claim 1 to 7.
10. application according to claim 9, is characterized in that, the proliferative disease of described PI3K zymogenesis is colorectal cancer, cancer of the stomach, mammary cancer, lung cancer, liver cancer, prostate cancer, carcinoma of the pancreas, thyroid carcinoma, bladder cancer, kidney, brain tumor, neck cancer, the cancer of CNS, glioblastoma, or myeloproliferative disease, and leukemia and lymphatic cancer.
11. in a claim 1 to 7, the described PI3K kinase inhibitor of any one or pharmaceutical composition claimed in claim 8 suppress the application in the cancer cell growth in vitro.
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