CN103626783B

CN103626783B - Fused bicyclic heterocycle compound and purposes thereof and pharmaceutical composition

Info

Publication number: CN103626783B
Application number: CN201210301563.5A
Authority: CN
Inventors: 沈竞康; 丁健; 蒙凌华; 孟韬; 周华勇; 马兰萍; 胡定宇; 王昕�; 王艺; 陈奕
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2012-08-22
Filing date: 2012-08-22
Publication date: 2016-06-08
Anticipated expiration: 2032-08-22
Also published as: CN103626783A

Abstract

The present invention provides the fused bicyclic heterocycle compound or its isomer or its pharmacy acceptable salt and purposes thereof that the following general formula of a class (I) represents. Specifically, described compound can be used as PI3K inhibitor, therefore can be used for treating the disease caused by PI3K-AKT-mTOR signal path functional disorder and illness. The present invention also relates to containing the pharmaceutical composition of this compounds as PI3K inhibitor.

Description

Fused bicyclic heterocycle compound and purposes thereof and pharmaceutical composition

Technical field

The invention belongs to medical art, specifically, the present invention relates to acceptable salt and purposes thereof in a class fused bicyclic heterocycle compound or its isomer or its pharmaceutics. This compounds can be used as PI3K inhibitor, therefore can be used for treating the disease caused by PI3K-AKT-mTOR signal path functional disorder and illness. The present invention also relates to containing the pharmaceutical composition of this compounds as PI3K inhibitor.

Background technology

Phosphatidylinositol-3-kinase (Phosphoinositide3-kinases, PI3K) is a lipoid kinases. As the downstream effect device that receptor type tyrosine kinase and g protein coupled receptor are main, PI3K is by phosphorylation 4,5-bisphosphate phosphatidylinositols (PIP2) makes it be converted into 3,4,5-triphosphoric acid phosphatidylinositols (PIP3), and the signal of various somatomedin and cytokine is reached in cell. PIP3 can activate the effector of AKT (PKB) and other downstreams as second messenger in cell thus cause a series of biological effects. MTOR is one of important effector in AKT downstream, and it is serine/threonine kinase, belongs to phosphatidylinositol-3-kinase associated kinase (PIKK) family, and the catalytic domain of both mTOR and PI3K has the homology of height. (VivancoI, SawyersCL.Nat.Rev.Cancer2002; 2:489-501). MTOR also exists the different mixture of two kinds of structure and functions: mTORC1(mTOR mixture 1) and mTORC2(mTOR mixture 2).

Constructional feature according to PI3K is different with substrate specificity can be divided into I, II, III tri-class, wherein studies the most deep with I class. I class PI3K is heterodimer, by a catalytic subunit (molecular weight 110kDa, represent for p110) and a sub-base composition of adjustment, comprise PI3K ��, PI3K ��, PI3K �� and PI3K �� tetra-isoform, its catalytic subunit is respectively p110 ��, p110 ��, p110 �� and p110 �� (KongDX, YamoriT.Curr.Med.Chem.2009; 16:2839-2854).

PI3K once activation, can phosphorylation PIP2 be PIP3, PIP3 as second messenger important in cell, can be combined and they are raised to cytolemma with the PH structural domain of PDK1 and AKT. Then the T308 site of PDK1 phosphorylation AKT and the S473 site of mTORC2 phosphorylation AKT make AKT activate completely, AKT after activation again by signal transmission to the effector in downstream, such as mTORC1, thus regulating cell breed, survive, wither die, the biological procedures such as vasculogenesis. Tumor suppressor protein PTEN is as a phosphorus esterase, and its catalysis PIP3 dephosphorylation chemical conversion PIP2, thus the effect of anti-PI3K short of money, negativity regulates PI3K signal path. MTORC1 after being activated by AKT then can the multiple stream substrates of phosphorylation, such as S6K, 4EBP1 etc. thus regulate and control mRNA translation, albumen synthesis, Promote cell's growth and propagation.

PI3K-AKT-mTOR signal path regulates and controls cell survival, propagation, break up, wither die, numerous cell biological processes such as vasculogenesis, and these biological procedureses are relevant to the generation development of multiple disease and illness, particularly play a part most important in tumor development. These diseases and illness comprise proliferative disease (such as malignant tumour), immunological disease, cardiovascular disorder, virus infection, inflammation, metabolism/endocrine disorder and sacred disease. The example of metabolism/endocrine disorder comprises diabetes and obesity. The example of malignant tumour comprises malignant tumour (VivancoI, the SawyersCL.Nat.Rev.Cancer2002 of leukemia, brain tumor, kidney, stomach, skin, muscle, bladder, mammary gland, uterus, lung, colon, prostate gland, ovary and pancreas; 2:489-501).

The research of human tumor genomics in recent years shows, in multiple human tumor, PI3K-AKT-mTOR signal path due to many key node albumen wherein encoding gene exist sudden change and excessive activation, in kinds of tumors, the sudden change of gain-of-function in various degree, amplification or overexpression is there is as encoded the gene of PI3K, PTEN is general absence then, these make to suppress PI3K activity to become the Critical policies (LiuPX of oncotherapy, ChengHL, RobertsTM, ZhaoJJ.Nat.Rev.DrugDiscovery2009; 8:627-644). Existing several PI3K inhibitor enter the clinical study stage at present, this imply that the antitumor drug that PI3K inhibitor very likely becomes of new generation enters Clinical practice.

The present invention is just for PI3K target, and exploitation can treat the medicine of disease or the illness (particularly tumour) caused by PI3K-AKT-mTOR signal path functional disorder.

Summary of the invention

It is an object of the present invention to provide a class fused bicyclic heterocycle compound or its isomer or its pharmacy acceptable salt.

It is yet another object of the invention to provide this compounds or its isomer or its pharmacy acceptable salt as PI3K inhibitor in the purposes prepared in the medicine treating disease or the illness caused by PI3K-AKT-mTOR signal path functional disorder.

Another object of the present invention is to provide the pharmaceutical composition comprising this compounds or its isomer or its pharmacy acceptable salt as PI3K inhibitor.

Object according to the present invention, it provides there is fused bicyclic heterocycle compound or its isomer or its pharmacy acceptable salt that following general formula (I) represents:

Wherein,

Ring A is the 6 yuan of hetero-aromatic rings containing 1-3 atom N with the thick conjunction of ring B, 5 yuan or 6 yuan of hetero-aromatic rings that ring B is phenyl ring or is not necessarily replaced by C1-C6 alkyl containing 1-3 the heteroatoms being selected from N, O and S and heteroatoms,

Preferably, ring A is containing 1-2 atom N 6 yuan of hetero-aromatic rings, 5 yuan or 6 yuan of hetero-aromatic rings that ring B is phenyl ring or is not necessarily replaced by C1-C6 alkyl containing 1-2 the heteroatoms being selected from N, O and S and atom N,

More preferably, ring AB is the one being selected from following groups:

R⁵For H, amino or C1-C6 alkyl,

Preferably, R⁵For H, amino, methyl, ethyl, n-propyl or sec.-propyl;

R¹For the heteroatomic 6 yuan of heteroaryls being selected from N, O and S containing 1-3, the group that described heteroaryl is not necessarily selected from amino and C1-C6 alkyl by 1-3 replaces,

Preferably, R¹For the heteroatomic 6 yuan of heteroaryls being selected from N, O and S containing 1-2, the group that described heteroaryl is not necessarily selected from amino and C1-C4 alkyl by 1-2 replaces,

More preferably, R¹For

R²It is selected from hydrogen, amino and C1-C6 alkyl,

Preferably, R²For H, amino, methyl, ethyl, n-propyl or sec.-propyl;

More preferably, R²For H;

R³For-SO₂NHR⁴Or-NHSO₂R⁴, wherein R⁴For substituted or unsubstituted phenyl, the substituting group of described phenyl is halogen or C1-C6 alkyl,

Preferably, R³For-NHSO₂R⁴, wherein R⁴For the phenyl of halogen substiuted,

More preferably, R³For-NHSO₂R⁴, wherein R⁴For the phenyl that F replaces,

Most preferably, R³For

X is C1-C6 alkyl, C1-C6 alkoxyl group, halogen, amino, cyano group or hydroxyl,

Preferably, X is C1-C6 alkoxyl group,

More preferably, X is methoxyl group, oxyethyl group, positive propoxy or isopropoxy;

Most preferably, the fused bicyclic heterocycle compound that general formula (I) represents is one of following compounds:

The compound that general formula (I) represents has basic group, therefore " pharmacy acceptable salt " can be formed with mineral acid or organic acid, by processing the free alkali of general formula (I) compound with mineral acid or organic acid, pharmacy acceptable salt can be obtained, described mineral acid is hydrochloric acid, Hydrogen bromide, phosphoric acid or sulfuric acid etc., described organic acid is xitix, citric acid, tartrate, lactic acid, toxilic acid, propanedioic acid, fumaric acid, oxalic acid, oxysuccinic acid, oxyacetic acid, succsinic acid, propionic acid, acetic acid, methylsulfonic acid, trifluoromethanesulfonic acid, Phenylsulfonic acid or tosic acid etc.

The compound that general formula provided by the invention (I) represents can be prepared by the synthetic route shown in following reaction equation, R in route¹��R²And R³Definition as previously mentioned, and LG¹And LG²For Cl, Br, I or OTf etc. can participate in the leavings group of linked reaction.

According to leavings group LG¹And LG²Reactive behavior, work as LG¹Reactive behavior be better than LG²Time (such as embodiment 1 to embodiment 16), compound A first carries out the reaction of step a, i.e. compound A and R¹There is Suzuki linked reaction in the boric acid replaced, or compound A and R under palladium catalyst exists¹There is Stille linked reaction in the tri-n-butyl stannane replaced, obtain Compound C under palladium catalyst exists; Compound C carries out the Suzuki linked reaction of step b again with compound B; thus obtain the compound of general formula (I) structure; wherein; when the ring AB of compound A is azaindole ring, its 1 nitrogen-atoms can be replaced by protecting groups such as methoxycarbonyl (such as embodiment 2) or benzenesulfonyls (such as embodiment 5 and embodiment 11).

According to leavings group LG¹And LG²Reactive behavior, work as LG²Reactive behavior be better than LG¹Time (such as embodiment 17 to embodiment 20), compound A first carries out the reaction of step b, and namely compound A and compound B carries out Suzuki linked reaction, obtains Compound D; Compound D carries out the reaction of step a again, i.e. Compound D and R¹There is Suzuki linked reaction in the boric acid replaced, or Compound D and R under palladium catalyst exists¹There is Stille linked reaction in the tri-n-butyl stannane replaced, thus obtain the compound of general formula (I) structure under palladium catalyst exists.

In the synthetic route of the above-mentioned compound preparing general formula (I) structure:

The palladium catalyst used in Suzuki linked reaction is two (tri-butyl phosphine) palladium, three (dibenzalacetone) two palladium or [1, two (diphenylphosphine) ferrocene of 1'-] palladium chloride methylene dichloride complex compound, reaction solvent is 1,4-dioxane or 1,4-dioxane/water mixed solvent, temperature of reaction is between 80 DEG C-130 DEG C, can adopt conventional heating or microwave heating condition;

The palladium catalyst used in Stille linked reaction is tetrakis triphenylphosphine palladium, two (tri-butyl phosphine) palladiums or two (triphenylphosphine) palladium chloride, reaction solvent is 1,4-dioxane, N, dinethylformamide (DMF) or N-Methyl pyrrolidone (NMP), temperature of reaction is between 80 DEG C-130 DEG C, can adopt conventional heating or microwave heating condition.

Biology test shows that fused bicyclic heterocycle compound provided by the invention or its isomer or its pharmacy acceptable salt are PI3K inhibitor, therefore, fused bicyclic heterocycle compound that general formula provided by the invention (I) represents or its isomer or its pharmacy acceptable salt may be used for preparing the medicine of disease that treatment causes or illness by PI3K-AKT-mTOR signal path functional disorder. These diseases and illness comprise proliferative disease (such as malignant tumour), immunological disease, cardiovascular disorder, virus infection, inflammation, metabolism/endocrine disorder and sacred disease. The example of metabolism/endocrine disorder comprises diabetes and obesity. The example of the malignant tumour that the compounds of this invention treats can be used to comprise the cancer of leukemia, cerebral tumor, kidney, cancer of the stomach and skin, bladder, mammary gland, uterus, lung, colon, prostate gland, ovary and pancreas.

Present invention also offers a kind of pharmaceutical composition, it comprises the fused bicyclic heterocycle compound that represents of one or more general formulas (I) for the treatment of significant quantity or its isomer or its pharmacy acceptable salt as activeconstituents, and optionally can comprise pharmaceutically acceptable carrier, auxiliary agent or auxiliary material further.

Embodiment

Do not need to further describe, it is believed that those skilled in the art are by description above, it is possible to utilize the present invention to maximum degree. Therefore, the embodiment provided below is only illustrate the present invention further and oneself, and does not mean that and limit the scope of the invention by any way.

The structure of compound by nucleus magnetic resonance (¹H-NMR) and/or mass spectrum (MS) determine. It is by VarianAMX-300 type nuclear magnetic resonance analyser that NMR measures, and measuring solvent is deuterochloroform (CDCl₃) or deuterated dimethyl sulfoxide (DMSO-D₆), TMS is interior mark. The mensuration of MS ThermoFinniganLCQ-DecaXP type (ESI) liquid chromatograph-mass spectrometer. Column chromatographic isolation and purification product uses ISCORf75 combiflash companion instrument, carrier adopts the 200-300 order silica gel in Qingdao Haiyang chemical plant. Microwave heating uses BiotageInitiator Microwave synthesize instrument.

Preparation embodiment

Embodiment 1: the preparation of compound 1

Synthetic route is:

Reagent and condition: a) Stille linked reaction: 4-(tri-n-butyl tin) pyridazine (1.0eq.), tetrakis triphenylphosphine palladium (0.05eq.), cuprous iodide (0.1eq.), cesium fluoride (2.0eq.) (is two typical additives of Stille linked reaction, the carrying out of reaction can be promoted, see document Angew.Chem.Int.Ed.2004,43,1132 1136. ), N, dinethylformamide, room temperature; B) the fluoro-N-of Suzuki linked reaction: 2,4-bis-[2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-two oxygen is mixed boron heterocycle pentane-2-base)-3-pyridyl] benzsulfamide (compound B-1,1.2eq.), two (tri-butyl phosphine) palladium (0.03eq.), cesium fluoride (3.0eq.), 1,4-dioxane, 100 DEG C.

A) preparation of Compound C-1

The iodo-furo [2 of the chloro-2-of 4-, 3-b] synthesis of pyridine (compound A-1): by chloro-for 4-furo [2,3-b] pyridine (0.6g, 3.91mmol, according to document J.HeterocyclicChem., 1997, the method preparation described in 34:925-929) it is dissolved in anhydrous tetrahydro furan (10mL), dry ice-propanone bath is cooled to-78 DEG C, slowly drip the hexane solution (2.69mL adding 1.6M n-Butyl Lithium, 4.30mmol), slowly drip after stirring 30 minutes at continuing at-78 DEG C and add the solution that iodine (1.1g, 4.30mmol) is dissolved in anhydrous tetrahydro furan (8mL). Reactant drips after stirring 60 minutes at continuing at-78 DEG C and adds 10mL saturated aqueous ammonium chloride cancellation reaction. Reaction solution extracts with ethyl acetate (100mL), organic phase is washed with 5% hypo solution (50mL), saturated aqueous common salt (50mL) successively, anhydrous sodium sulfate drying, and filtration, concentrating under reduced pressure obtain compound A-1(1.0g, receipts rate 82%), it is beige solid. MS (ES): m/z280 [M+H]⁺.¹HNMR(300MHz,DMSO-d₆)��8.22(d,J=5.4Hz,1H),7.49(d,J=5.4Hz,1H),7.45(s,1H).

Step a(Stille linked reaction): by iodo-for chloro-for 4-2-furo [2; 3-b] pyridine (compound A-1:300mg; 1.07mmol); 4-(tri-n-butyl tin) pyridazine (396mg; 1.07mmol; purchased from Shanghai chemistry Science and Technology Ltd. of white unit); cesium fluoride (326mg; 2.15mmol); tetrakis triphenylphosphine palladium (62mg, 0.054mmol) and cuprous iodide (20.4mg, 0.107mmol) are dissolved in the anhydrous N of 5mL; in dinethylformamide, then stir under room temperature argon gas shielded and spend the night. Reaction solution is with the dilution of 150mL methylene dichloride, then washs with water successively (120mL �� 3), saturated aqueous common salt (120mL), anhydrous sodium sulfate drying, filtering, concentrating under reduced pressure, solid residue obtains Compound C-1(195mg with re-crystallizing in ethyl acetate, receipts rate 78%), it is tawny solid. MS (ESI): m/z232 [M+H]⁺.¹HNMR(300MHz,DMSO-d₆)��9.86(s,1H),9.41(d,J=4.7Hz,1H),8.41(d,J=5.4Hz,1H),8.21-8.14(m,2H),7.63(d,J=5.4Hz,1H)��

B) preparation of compound 1

2, the fluoro-N-of 4-bis-[2-methoxyl group-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-bis-oxygen is mixed boron heterocycle pentane-2-base)-3-pyridyl] preparation of benzsulfamide (compound B-1): by N-[the bromo-3-pyridyl of 2-methoxyl group-5-]-2, 4-bis-fluorobenzene sulphonamide (20g, 52.7mmol, according to document ACSMed.Chem.Lett., 2010, the method preparation described in 1:39 43), connection boric acid pinacol ester (15.4g, 60.7mmol), Potassium ethanoate (10.4g, 105mmol) and [1, two (diphenylphosphine) ferrocene of 1'-] palladium chloride methylene dichloride complex compound (2.2g, 2.64mmol) it is dissolved in 1, in 4-dioxane (200mL), then stir 48 hours in 120 degree of oil baths, reaction solution adds 300mL ethyl acetate again, filtering insolubles, filtrate decompression concentrates, residue is by quick silica gel chromatography, use petrol ether/ethyl acetate (V/V=2:1) wash-out, obtain compound B-1 (17g, receipts rate 76%), for white solid. MS (ESI): m/z427.1 [M+H]⁺,345.1[boronicacid,M⁺].¹HNMR(300MHz,DMSO-d₆)��10.18(s,1H),8.19(d,J=1.1Hz,1H),7.76-7.61(m,2H),7.62-7.46(m,1H),7.17(td,J=8.7,2.4Hz,1H),3.59(s,3H),1.27(s,12H)��

Step b(Suzuki linked reaction): by chloro-for 4-2-(4-pyridazinyl) furo [2, 3-b] pyridine (Compound C-1, 60mg, 0.259mmol), 2, the fluoro-N-of 4-bis-[2-methoxyl group-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-bis-oxygen is mixed boron heterocycle pentane-2-base)-3-pyridyl] benzsulfamide (compound B-1, 132mg, 0.311mmol), two (tri-butyl phosphine) palladium (4.0mg, 7.8 ��m of ol) and cesium fluoride (118mg, 0.78mmol) it is dissolved in 4mL anhydrous 1, in 4-dioxane, then stir under argon gas shielded in 100 DEG C of oil baths and spend the night. reaction solution is cooled to room temperature, dilute with 8mL methyl alcohol, then directly sample is mixed by thick silica gel dry method, by quick silica gel chromatography, use methylene chloride/methanol (V/V=95:5) wash-out, then with re-crystallizing in ethyl acetate, obtain compound 1(50mg, receipts rate 39%), it is buff white solid. MS (ESI): m/z496 [M+H]⁺.¹HNMR(400MHz,DMSO-d₆)��10.52(s,1H),9.86(dd,J=2.4,1.2Hz,1H),9.38(dd,J=5.5,1.2Hz,1H),8.57(d,J=2.3Hz,1H),8.50(d,J=5.1Hz,1H),8.32(s,1H),8.17(dd,J=5.4,2.4Hz,1H),8.09(d,J=2.3Hz,1H),7.80(td,J=8.6,6.3Hz,1H),7.64�C7.55(m,2H),7.22(td,J=8.4,2.6Hz,1H),3.74(s,3H).

Embodiment 2: the preparation of compound 2

Synthetic route is:

Reagent and condition: a) Stille linked reaction: 4-(tri-n-butyl tin) pyridazine (1.0eq.), tetrakis triphenylphosphine palladium (0.05eq.), cuprous iodide (0.1eq.), cesium fluoride (2.0eq.), N, dinethylformamide, room temperature; B) Suzuki linked reaction: 2, the fluoro-N-of 4-bis-[2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-bis-oxygen is mixed boron heterocycle pentane-2-base)-3-pyridyl] benzsulfamide (compound B-1,1.2eq.), three (dibenzalacetone) two palladium (0.02eq.), 2-dicyclohexyl phosphorus-2 ', 4 ', 6 '-tri isopropyl biphenyl (XPhos, 0.08eq.), potassiumphosphate (2.0eq.), 1,4-dioxane/water mixed liquid (v/v=4:1), 100 DEG C, 12 hours.

A) preparation of Compound C-2

The synthesis of the chloro-2-of 4-iodo-1H-pyrrolo-[2,3-b] pyridine-1-carboxylate methyl ester (compound A-2): by iodo-for chloro-for 4-2-1H-pyrrolo-[2,3-b] pyridine (100mg, 0.36mmol, method preparation according to describing in patent US20070129364) it is dissolved in anhydrous tetrahydro furan (5mL), ice-water bath cools, and slowly adds sodium hydride (Wt60%, 46mg, 1.1mmol), stir after 30 minutes, add methyl-chloroformate (0.033mL, 0.43mmol), stirring at room temperature is continued at 1 hour. Reaction solution, with ethyl acetate (20mL) dilution, washs with water (20mL), saturated aqueous common salt (20mL), anhydrous sodium sulfate drying successively, and filtration, concentrating under reduced pressure obtain compound A-2(120mg, receipts rate 99%), it is buff white solid.¹HNMR(300MHz,CDCl₃)��8.29(d,J=5.3Hz,1H),7.20(d,J=5.3Hz,1H),7.13(s,1H),4.15(s,3H).

Step a(Stille linked reaction): operation, with the step a in embodiment 1, is with compound A-2 alternative compounds A-1. Compound A-2 charging capacity is 120mg(0.36mmol), obtain Compound C-2(60mg, receipts rate 58%), it is buff white solid.¹HNMR(300MHz,DMSO-d₆)��9.50(dd,J=2.4,1.2Hz,1H),9.33(dd,J=5.4,1.2Hz,1H),8.48(d,J=5.3Hz,1H),7.93(dd,J=5.4,2.4Hz,1H),7.58(d,J=5.3Hz,1H),7.33(s,1H),3.94(s,3H).

B) preparation of compound 2

Step b(Suzuki linked reaction): by Compound C-2(60mg, 0.21mmol), compound B-1(115mg, 0.27mmol), three (dibenzalacetone) two palladium (3.8mg, 4.16 ��m of ol), 2-dicyclohexyl phosphorus-2 ', 4 ', 6 '-tri isopropyl biphenyl (XPhos, 7.93mg, 0.017mmol, for the Phosphine ligands of Suzuki linked reaction, effect is identical with Sphos, Xphos is more used to catalysis C-N key coupling) and potassiumphosphate (88mg, 0.416mmol) it is dissolved in 1, 4-dioxane/water mixed liquid (v/v=4:1, 4mL), then stirring reaction 12 hours under argon gas shielded in 100 DEG C of oil baths. reaction solution is cooled to room temperature, directly mixes sample by thick silica gel dry method, by quick silica gel chromatography, it may also be useful to methylene chloride/methanol (V/V=95:5) wash-out, obtains compound 2(55mg, receipts rate 53%), it is buff white solid. MS (ESI): m/z495.1 [M+H]⁺.¹HNMR(400MHz,DMSO-d₆)��12.82(s,1H),10.49(s,1H),9.85(d,J=1.2Hz,1H),9.30(d,J=5.5Hz,1H),8.55(d,J=2.2Hz,1H),8.43(d,J=4.9Hz,1H),8.17(dd,J=5.5,2.5Hz,1H),8.08(d,J=2.2Hz,1H),7.85-7.79(m,1H),7.66(s,1H),7.64-7.56(m,1H),7.29(d,J=5.0Hz,1H),7.27-7.19(m,1H),3.74(s,3H).

Embodiment 3: the preparation of compound 3

Synthetic route is:

A) preparation of Compound C-3

The synthesis of the chloro-2-of 4-iodo-1-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine (compound A-3): by iodo-for chloro-for 4-2-1H-pyrrolo-[2,3-b] pyridine (200mg, 0.72mmol, method preparation according to describing in patent US20070129364) it is dissolved in dry DMF (5mL), ice-water bath cools, and slowly adds sodium hydride (Wt60%, 41mg, 1.0mmol), stir after 30 minutes, add methyl iodide (0.054mL, 0.86mmol), stirring at room temperature is continued at 1 hour. Reaction solution, with ethyl acetate (40mL) dilution, washs with water (40mL), saturated aqueous common salt (40mL), anhydrous sodium sulfate drying successively, and filtration, concentrating under reduced pressure obtain compound A-3(210mg, receipts rate 100%), it is yellow solid.¹HNMR(300MHz,CDCl₃)��8.13(d,J=5.2Hz,1H),7.03(d,J=5.1Hz,1H),6.91(s,1H),3.86(s,3H).

Step a(Stille linked reaction): operation, with the step a in embodiment 1, is with compound A-3 alternative compounds A-1. Compound A-3 charging capacity is 200mg(0.68mmol), obtain Compound C-3(120mg, receipts rate 72%), it is buff white solid.¹HNMR(300MHz,DMSO-d₆)��9.67(dd,J=2.4,1.2Hz,1H),9.39(dd,J=5.4,1.2Hz,1H),8.37(d,J=5.1Hz,1H),8.09(dd,J=5.4,2.5Hz,1H),7.36(d,J=5.1Hz,1H),7.18(s,1H),3.98(s,3H).

B) preparation of compound 3

Step b(Suzuki linked reaction): operation, with the step b in embodiment 2, is with Compound C-3 alternative compounds C-2. Compound C-3 charging capacity is 100mg(0.41mmol), obtain compound 3(178mg, receipts rate 86%), it is buff white solid. MS (ESI): m/z509.1 [M+H]⁺.¹HNMR(400MHz,DMSO-d₆)��10.47(s,1H),9.66(dd,J=2.4,1.2Hz,1H),9.38(dd,J=5.4,1.2Hz,1H),8.52(d,J=2.3Hz,1H),8.48(d,J=4.9Hz,1H),8.08(dd,J=5.4,2.5Hz,1H),8.06(d,J=2.3Hz,1H),7.80(td,J=8.4,6.2Hz,1H),7.62�C7.53(m,1H),7.35(d,J=4.9Hz,1H),7.23�C7.16(m,2H),4.02(s,3H),3.73(s,3H).

Embodiment 4: the preparation of compound 4

Synthetic route is:

Reagent and condition: a) Stille linked reaction: 4-(tri-n-butyl tin) pyridazine (1.0eq.), tetrakis triphenylphosphine palladium (0.05eq.), cuprous iodide (0.1eq.), cesium fluoride (2.0eq.), N, N-METHYLFORMAMIDE, room temperature; B) the fluoro-N-of Suzuki linked reaction: 2,4-bis-[2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-two oxygen is mixed boron heterocycle pentane-2-base)-3-pyridyl] benzsulfamide (compound B-1,1.2eq.), two (tri-butyl phosphine) palladium (0.03eq.), cesium fluoride (3.0eq.), 1,4-dioxane, 100 DEG C.

A) preparation of Compound C-4

The iodo-thieno-[2 of the chloro-2-of 4-, 3-b] synthesis of pyridine (compound A-4): by chloro-for 4-thieno-[2,3-b] pyridine (1.0g, 5.9mmol, according to document J.HeterocyclicChem., 1977, the method preparation described in 14:807-812) it is dissolved in anhydrous tetrahydro furan (30mL), dry ice-propanone bath is cooled to-78 DEG C, slowly drip and add 2M diisopropylamine lithium solution (LDA, 3.6mL, 7.1mmol), slowly drip after stirring 30 minutes at continuing at-78 DEG C and add the solution that iodine (1.8g, 7.1mmol) is dissolved in anhydrous tetrahydro furan (20mL). Reactant drips after stirring 2 hours at continuing at-78 DEG C and adds 20mL saturated aqueous ammonium chloride cancellation reaction. Reaction solution extracts with ethyl acetate (150mL), organic phase is washed with 5% hypo solution (100mL), saturated aqueous common salt (100mL) successively, anhydrous sodium sulfate drying, and filtration, concentrating under reduced pressure obtain compound A-4(1.3g, receipts rate 71%), it is buff white solid. MS (ES): m/z296 [M+H]⁺.¹HNMR(300MHz,DMSO-d₆)��8.48(d,J=5.1Hz,1H),7.86(s,1H),7.56(d,J=5.1Hz,1H).

Step a(Stille linked reaction): operation, with the step a in embodiment 1, is with compound A-4 alternative compounds A-1. Compound A-4 charging capacity is 490mg(1.66mmol), obtain Compound C-4(180mg, receipts rate 44%), it is buff white solid. MS (ES): m/z248 [M+H]⁺.¹HNMR(300MHz,DMSO-d₆)��9.85(dd,J=2.5,1.1Hz,1H),9.38-9.30(m,1H),8.61(d,J=5.1Hz,1H),8.46(s,1H),8.13(dd,J=5.5,2.6Hz,1H),7.71(d,J=5.1Hz,1H).

B) preparation of compound 4

Step b(Suzuki linked reaction): operation, with the step b in embodiment 1, is with Compound C-4 alternative compounds C-1. Compound C-4 charging capacity is 54mg(0.22mmol), obtain compound 4(100mg, receipts rate 90%), it is buff white solid. MS (ESI): m/z512 [M+H]⁺.¹HNMR(400MHz,DMSO-d₆)��10.54(s,1H),9.77(dd,J=2.5,1.1Hz,1H),9.33(dd,J=5.5,1.1Hz,1H),8.71(d,J=4.9Hz,1H),8.44(d,J=2.3Hz,1H),8.35(s,1H),8.08-8.02(m,2H),7.84(td,J=8.6,6.3Hz,1H),7.63-7.54(m,2H),7.23(td,J=8.3,2.0Hz,1H),3.74(s,3H).

Embodiment 5: the preparation of compound 5

Synthetic route is:

Reagent and condition: a) Stille linked reaction: 4-(tri-n-butyl tin) pyridazine (1.0eq.), tetrakis triphenylphosphine palladium (0.05eq.), cuprous iodide (0.1eq.), cesium fluoride (2.0eq.), N, N-METHYLFORMAMIDE, room temperature; B) Suzuki linked reaction: 2, the fluoro-N-of 4-bis-[2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-bis-oxygen is mixed boron heterocycle pentane-2-base)-3-pyridyl] benzsulfamide (compound B-1,1.2eq.), three (dibenzalacetone) two palladium (0.02eq.), 2-dicyclohexyl phosphorus-2 ', 4 ', 6 '-tri isopropyl biphenyl (XPhos, 0.08eq.), potassiumphosphate (2.0eq.), 1,4-dioxane/water mixed liquid (v/v=4:1), 100 DEG C, 12 hours.

A) preparation of Compound C-5

Step a(Stille linked reaction): operation is with the step a in embodiment 1, and just with compound A-5(reference Tetrahedron, prepared by the method described in 2009,65:4814-4819) alternative compounds A-1. Compound A-5 charging capacity is 400mg(0.95mmol), obtain Compound C-5(40mg, receipts rate 18%), it is tawny solid.¹HNMR(400MHz,DMSO-d₆)��12.41(s,1H),9.92(s,1H),9.35(d,J=5.2Hz,1H),8.37(d,J=4.0Hz,1H),8.32(dd,J=5.5,2.4Hz,1H),7.69(d,J=1.9Hz,1H),7.40(d,J=5.0Hz,1H).

B) preparation of compound 5

Step b(Suzuki linked reaction): operation, with the step b in embodiment 2, is with Compound C-5 alternative compounds C-2. Compound C-5 charging capacity is 32mg(0.14mmol), obtain compound 5(8mg, receipts rate 12%), it is buff white solid. MS (ESI): m/z495 [M+H]⁺.¹HNMR(400MHz,DMSO-d₆)��11.81(s,1H),10.48(s,1H),9.87(dd,J=2.3,1.2Hz,1H),9.30(dd,J=5.5,1.1Hz,1H),8.48(d,J=4.7Hz,1H),8.47(d,J=2.2Hz,1H),8.23(dd,J=5.5,2.4Hz,1H),7.90(d,J=2.2Hz,1H),7.80(td,J=8.6,6.3Hz,1H),7.65(d,J=1.9Hz,1H),7.63�C7.56(m,1H),7.25�C7.16(m,2H),3.77(s,3H).

Embodiment 6: the preparation of compound 6

Synthetic route is:

A) preparation of Compound C-6

The chloro-2-of 4-iodo-1-methyl isophthalic acid H-pyrrolo-[3; 2-b] synthesis of pyridine (compound A-6): by iodo-for chloro-for 4-2-1H-pyrrolo-[3; 2-b] pyridine (compound A-10; 210mg; 0.75mmol; de-benzenesulfonyl method preparation by describing in compound A-5 referenced patent US20070129364) it is dissolved in dry DMF (5mL); ice-water bath cools; slowly add sodium hydride (Wt60%, 45mg, 1.1mmol); stir after 30 minutes; add methyl iodide (0.057mL, 0.9mmol), continue at stirring at room temperature 1 hour. Reaction solution, with ethyl acetate (40mL) dilution, washs with water (40mL), saturated aqueous common salt (40mL), anhydrous sodium sulfate drying successively, and filtration, concentrating under reduced pressure obtain compound A-6(208mg, receipts rate 94%), it is yellow solid.¹HNMR(400MHz,CDCl₃)��8.24(d,J=5.1Hz,1H),7.04(s,1H),7.03(d,J=5.1Hz,1H),4.13(s,3H).

Step a(Stille linked reaction): operation, with the step a in embodiment 1, is with compound A-6 alternative compounds A-1. Compound A-6 charging capacity is 200mg(0.68mmol), obtain Compound C-6(95mg, receipts rate 56%), it is buff white solid.¹HNMR(400MHz,DMSO-d₆)��9.59(s,1H),9.42(d,J=5.3Hz,1H),8.35(d,J=4.6Hz,1H),8.01(dd,J=5.3,2.4Hz,1H),7.37(d,J=5.0Hz,1H),7.20(s,1H),4.08(s,3H).

B) preparation of compound 6

Step b(Suzuki linked reaction): operation, with the step b in embodiment 2, is with Compound C-6 alternative compounds C-2. Compound C-6 charging capacity is 50mg(0.20mmol), obtain compound 6(95mg, receipts rate 91%), it is white solid. MS (ESI): m/z509.1 [M+H]⁺.¹HNMR(400MHz,DMSO-d₆)��10.43(s,1H),9.58(dd,J=2.4,1.2Hz,1H),9.39(dd,J=5.4,1.2Hz,1H),8.49(d,J=4.7Hz,1H),8.24(d,J=2.2Hz,1H),7.96(dd,J=5.4,2.4Hz,1H),7.86(d,J=2.2Hz,1H),7.77(td,J=8.6,6.2Hz,1H),7.63-7.53(m,1H),7.28(s,1H),7.22(td,J=8.3,2.4Hz,1H),7.10(d,J=4.7Hz,1H),3.70(s,3H),3.39(s,3H).

Embodiment 7: the preparation of compound 7

Synthetic route is:

A) preparation of Compound C-7

Step a(Stille linked reaction): operation, with the step a in embodiment 1, is just prepared according to the method described in patent WO2008124083 with compound A-7() alternative compounds A-1. Compound A-7 charging capacity is 400mg(1.43mmol), obtain Compound C-7(250mg, receipts rate 75%), it is rose pink solid. MS (ES): m/z232 [M+H]⁺.¹HNMR(300MHz,DMSO-d₆)��9.85(s,1H),9.43(d,J=5.4Hz,1H),8.58(d,J=5.2Hz,1H),8.29(s,1H),8.17(dd,J=5.4,2.3Hz,1H),7.67(d,J=5.2Hz,1H).

B) preparation of compound 7

Step b(Suzuki linked reaction): operation, with the step b in embodiment 1, is with Compound C-7 alternative compounds C-1. Compound C-7 charging capacity is 70mg(0.30mmol), obtain compound 7(100mg, receipts rate 67%), it is buff white solid. MS (ESI): m/z496 [M+H]⁺.¹HNMR(400MHz,DMSO-d₆)��10.53(s,1H),9.92(dd,J=2.3,1.2Hz,1H),9.43(dd,J=5.4,1.2Hz,1H),8.79(d,J=2.3Hz,1H),8.67(d,J=5.1Hz,1H),8.50(d,J=2.3Hz,1H),8.27(s,1H),8.23(dd,J=5.4,2.4Hz,1H),7.87-7.75(m,2H),7.65-7.53(m,1H),7.21(td,J=8.3,2.0Hz,1H),3.75(s,3H).

Embodiment 8: the preparation of compound 8

Synthetic route is:

A) preparation of Compound C-8

Step a(Stille linked reaction): operation is with the step a in embodiment 1, and just with compound A-8(according to document Org.Proc.Res.Dev., prepared by the method described in 2003,7:676 683) alternative compounds A-1. Compound A-8 charging capacity is 500mg(1.7mmol), obtain Compound C-8(400mg, receipts rate 95%), it is buff white solid. MS (ES): m/z248 [M+H]⁺.¹HNMR(300MHz,DMSO-d₆)��9.89-9.81(m,1H),9.37(d,J=5.4Hz,1H),8.74(d,J=5.1Hz,1H),8.64(s,1H),8.16(dd,J=5.4,2.5Hz,1H),7.70(d,J=5.1Hz,1H).

B) preparation of compound 8

Step b(Suzuki linked reaction): operation, with the step b in embodiment 1, is with Compound C-8 alternative compounds C-1. Compound C-8 charging capacity is 80mg(0.32mmol), obtain compound 8(100mg, receipts rate 58%), it is buff white solid. MS (ESI): m/z512 [M+H]⁺.¹HNMR(400MHz,DMSO-d₆)��10.57(s,1H),9.84(d,J=1.3Hz,1H),9.35(d,J=5.5Hz,1H),8.84(d,J=4.8Hz,1H),8.64(s,1H),8.52(d,J=2.3Hz,1H),8.08(dd,J=6.6,2.4Hz,2H),7.84(td,J=8.5,6.5Hz,1H),7.68-7.55(m,2H),7.25(td,J=8.7,2.4Hz,1H),3.77(s,3H).

Embodiment 9: the preparation of compound 9

Synthetic route is:

A) preparation of Compound C-9

Step a(Stille linked reaction): operation, with the step a in embodiment 1, is purchased from splendid scientific and technological (Shanghai) company limited of chemistry far away with compound A-9() alternative compounds A-1. Compound A-9 charging capacity is 300mg(1.24mmol), obtain Compound C-9(250mg, receipts rate 84%), it is buff white solid. MS (ES): m/z242 [M+H]⁺.¹HNMR(300MHz,DMSO-d₆)��9.84(s,1H),9.39(d,J=4.8Hz,1H),8.94(d,J=4.6Hz,1H),8.66(d,J=1.9Hz,1H),8.40(dd,J=8.8,2.0Hz,1H),8.29(d,J=8.8Hz,1H),8.24(dd,J=5.2,2.2Hz,1H),7.88(d,J=4.6Hz,1H).

B) preparation of compound 9

Step b(Suzuki linked reaction): operation, with the step b in embodiment 2, is with Compound C-9 alternative compounds C-2. Compound C-9 charging capacity is 100mg(0.41mmol), obtain compound 9(160mg, receipts rate 76%), it is off-white color solid. MS (ESI): m/z506 [M+H]⁺.¹HNMR(400MHz,DMSO-d₆)��10.50(s,1H),9.73(dd,J=2.5,1.2Hz,1H),9.31(dd,J=5.5,1.1Hz,1H),9.05(d,J=4.4Hz,1H),8.38�C8.26(m,4H),8.11(dd,J=5.5,2.6Hz,1H),7.96(d,J=2.3Hz,1H),7.82(td,J=8.7,6.4Hz,1H),7.63�C7.52(m,2H),7.27�C7.18(m,1H),3.72(s,3H).

Embodiment 10: the preparation of compound 10

Synthetic route is:

Reagent and condition: a) pyridine-4-boric acid (1.05eq.), salt of wormwood (3.0eq.), [1, two (diphenylphosphine) ferrocene of 1'-] palladium chloride methylene dichloride complex compound (0.05eq.), 1,4-dioxane-water (4:1), 100 DEG C, microwave, 30 minutes; B) the fluoro-N-of 2,4-bis-[2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-bis-oxygen is mixed boron heterocycle pentane-2-base)-3-pyridyl] benzsulfamide (compound B-1,1.2eq.), three (dibenzalacetone) two palladium (0.02eq.), 2-dicyclohexyl phosphorus-2 ', 4 ', 6 '-tri isopropyl biphenyl (XPhos, 0.08eq.), potassiumphosphate (2.0eq.), 1,4-dioxane/water mixed liquid (v/v=4:1), 100 DEG C, 12 hours.

A) preparation of Compound C-10

By iodo-for chloro-for 7-2-1H-pyrrolo-[3, 2-b] pyridine (compound A-10, 500mg, 1.795mmol, de-benzenesulfonyl method preparation by describing in compound A-5 referenced patent US20070129364), pyridine-4-boric acid (240mg, 1.97mmol) and salt of wormwood (744mg, 5.39mmol) be dissolved in 12mL dioxane-water (V/V=4:1), [1 is added again after logical bubbling argon number minute, two (diphenylphosphine) ferrocene of 1'-] palladium chloride methylene dichloride complex compound (73.3mg, 0.09mmol), then react 30 minutes in 100 DEG C, microwave. reaction solution is cooled to room temperature, separates upper strata dioxane layer, concentrating under reduced pressure, residue is by quick silica gel chromatography, it may also be useful to methylene chloride/methanol (V/V=95:5) wash-out, obtains Compound C-10(240mg, receipts rate 58%), it is buff white solid. MS (ESI): m/z230 [M+H]⁺.¹HNMR(400MHz,DMSO-d₆)��12.22(s,1H),8.69(dd,J=4.6,1.6Hz,2H),8.33(d,J=5.0Hz,1H),8.06(dd,J=4.5,1.6Hz,2H),7.47(d,J=2.2Hz,1H),7.34(d,J=5.1Hz,1H).

B) preparation of compound 10

Step b: operation, with the step b in embodiment 2, is with Compound C-10 alternative compounds C-2. Compound C-10 charging capacity is 65mg(0.28mmol), obtain compound 10(115mg, receipts rate 82%), it is white solid. MS (ESI): m/z494 [M+H]⁺.¹HNMR(400MHz,DMSO-d₆)��11.66(s,1H),10.48(s,1H),8.66(dd,J=4.6,1.6Hz,2H),8.44(t,J=3.5Hz,2H),7.98(dd,J=4.6,1.6Hz,2H),7.89(d,J=2.2Hz,1H),7.81(td,J=8.7,6.3Hz,1H),7.64�C7.54(m,1H),7.44(d,J=1.7Hz,1H),7.21(td,J=8.5,2.3Hz,1H),7.14(d,J=4.8Hz,1H),3.77(s,3H).

Embodiment 11: the preparation of compound 11

Synthetic route is:

Reagent and condition: a) pyridine-4-boric acid (1.05eq.), salt of wormwood (3.0eq.), [1, two (diphenylphosphine) ferrocene of 1'-] palladium chloride methylene dichloride complex compound (0.05eq.), 1,4-dioxane-water (4:1), 100 DEG C, microwave, 30 minutes; B) the fluoro-N-of 2,4-bis-[2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-bis-oxygen is mixed boron heterocycle pentane-2-base)-3-pyridyl] benzsulfamide (compound B-1,1.2eq.), three (dibenzalacetone) two palladium (0.02eq.), 2-dicyclohexyl phosphorus-2 ', 4 ', 6 '-tri isopropyl biphenyl (XPhos, 0.08eq.), potassiumphosphate (2.0eq.), 1,4-dioxane/water mixed liquid (v/v=4:1), 100 DEG C, 12 hours; Then, 5N potassium hydroxide aqueous solution (5.0eq), methyl alcohol, 110 DEG C, 1 hour.

A) preparation of Compound C-11

Step a: operation is with the step a in embodiment 10, and just with compound A-11(according to document Tetrahedron, prepared by the method described in 2009,65:4814-4819) alternative compounds A-10. Compound A-11 charging capacity is 900mg(2.15mmol), obtain Compound C-11(400mg, receipts rate 50%), it is buff white solid. MS (ES): m/z370 [M+H]⁺.¹HNMR(300MHz,CD₃OD)��8.67(d,J=5.5Hz,2H),8.33(d,J=5.2Hz,1H),7.83(d,J=8.2Hz,2H),7.69(d,J=4.9Hz,2H),7.62(t,J=7.5Hz,1H),7.49(t,J=7.7Hz,2H),7.37(d,J=5.3Hz,1H),6.98(s,1H).

B) preparation of compound 11

Step b: operation, with the step b in embodiment 2, just with Compound C-11 alternative compounds C-2, then sloughs benzenesulfonyl under potassium hydroxide effect. Compound C-11 charging capacity is 120mg(0.32mmol), obtain compound 11(70mg, receipts rate 43%), it is white solid. MS (ESI): m/z494 [M+H]⁺.¹HNMR(400MHz,DMSO-d₆)��12.65(s,1H),10.48(s,1H),8.66(d,J=6.1Hz,2H),8.51(d,J=2.3Hz,1H),8.38(d,J=4.9Hz,1H),8.08(d,J=2.3Hz,1H),7.95(dd,J=4.6,1.6Hz,2H),7.82(td,J=8.6,6.3Hz,1H),7.64�C7.54(m,1H),7.41(d,J=2.0Hz,1H),7.28�C7.18(m,2H),3.74(s,3H).

Embodiment 12: the preparation of compound 12

Synthetic route is:

A) preparation of Compound C-12

The iodo-3-methyl-thieno-[3 of the chloro-2-of 7-, 2-b] synthesis of pyridine (compound A-12): by chloro-for 7-3-methyl-thieno-[3,2-b] pyridine (1.5g, 8.2mmol, method preparation according to describing in patent WO2007117381) it is dissolved in anhydrous tetrahydro furan (40mL), dry ice-propanone bath is cooled to-78 DEG C, slowly drip the hexane solution (6.2mL adding 1.6M n-Butyl Lithium, 9.9mmol), slowly drip after stirring 30 minutes at continuing at-78 DEG C and add the solution that iodine (2.3g, 9.0mmol) is dissolved in anhydrous tetrahydro furan (10mL). Reactant drips after stirring 60 minutes at continuing at-78 DEG C and adds 80mL saturated aqueous ammonium chloride cancellation reaction. Reaction solution extracts with ethyl acetate (200mL), organic phase is washed with 5% hypo solution (50mL), saturated aqueous common salt (50mL) successively, anhydrous sodium sulfate drying, and filtration, concentrating under reduced pressure obtain compound A-12(2.4g, receipts rate 94%), it is tawny solid.¹HNMR(400MHz,DMSO-d₆)��8.61(d,J=5.1Hz,1H),7.55(d,J=5.1Hz,1H),2.38(s,3H).

Step a(Stille linked reaction): operation, with the step a in embodiment 1, is with compound A-12 alternative compounds A-1. Compound A-12 charging capacity is 400mg(1.3mmol), obtain Compound C-12(90mg, receipts rate 26%), it is buff white solid.¹HNMR(400MHz,DMSO-d₆)��9.61(s,1H),9.42(dd,J=5.5,0.9Hz,1H),8.79(d,J=5.0Hz,1H),8.03(dd,J=5.4,2.3Hz,1H),7.74(d,J=5.0Hz,1H),2.64(s,3H).

B) preparation of compound 12

Step b(Suzuki linked reaction): operation, with the step b in embodiment 2, is with Compound C-12 alternative compounds C-2. Compound C-12 charging capacity is 70mg(0.27mmol), obtain compound 12(120mg, receipts rate 85%), it is white solid. MS (ESI): m/z526 [M+H]⁺.¹HNMR(400MHz,DMSO-d₆)��10.55(s,1H),9.58(dd,J=2.5,1.2Hz,1H),9.41(dd,J=5.4,1.2Hz,1H),8.87(d,J=4.8Hz,1H),8.49(d,J=2.3Hz,1H),8.05(d,J=2.3Hz,1H),7.98(dd,J=5.4,2.5Hz,1H),7.82(td,J=8.6,6.3Hz,1H),7.63(d,J=4.8Hz,1H),7.62�C7.54(m,1H),7.21(td,J=8.2,2.2Hz,1H),3.77(s,3H),2.67(s,3H).

Embodiment 13: the preparation of compound 13

Synthetic route is:

A) preparation of Compound C-13

Step a(Stille linked reaction): operation, with the step a in embodiment 1, is just prepared according to the method described in patent WO2008150827 with compound A-13() alternative compounds A-1. Compound A-13 charging capacity is 180mg(0.58mmol), obtain Compound C-13(84mg, receipts rate 60%), it is lavender solid.¹HNMR(400MHz,DMSO-d₆)��10.12(s,1H),9.50(d,J=5.4Hz,1H),9.00(d,J=4.6Hz,1H),8.72(s,2H),8.54-8.50(m,1H),8.12(d,J=4.7Hz,1H).

B) preparation of compound 13

Step b(Suzuki linked reaction): operation, with the step b in embodiment 2, is with Compound C-13 alternative compounds C-2. Compound C-13 charging capacity is 40mg(0.16mmol), obtain compound 13(35mg, receipts rate 42%), it is buff white solid. MS (ESI): m/z507 [M+H]⁺.¹HNMR(400MHz,DMSO-d₆)��10.44(s,1H),10.01(dd,J=2.1,1.1Hz,1H),9.42(dd,J=5.4,1.0Hz,1H),9.12(d,J=4.5Hz,1H),8.77-8.65(m,2H),8.57(d,J=2.2Hz,1H),8.46(dd,J=5.4,2.4Hz,1H),8.26(d,J=2.2Hz,1H),7.93(d,J=4.4Hz,1H),7.83(td,J=8.5,6.5Hz,1H),7.64-7.52(m,1H),7.21(td,J=8.4,2.0Hz,1H),3.72(s,3H).

Embodiment 14: the preparation of compound 14

Synthetic route is:

A) preparation of Compound C-14

Step a(Stille linked reaction): operation is with the step a in embodiment 1, and just with compound A-14(according to document Bioorg.Med.Chem., prepared by the method described in 2006,14:6832-6846) alternative compounds A-1. Compound A-14 charging capacity is 300mg(1.23mmol), obtain Compound C-14(190mg, receipts rate 63%), it is tawny solid.¹HNMR(400MHz,DMSO-d₆)��9.59(dd,J=2.3,1.2Hz,1H),9.54(s,1H),9.51(dd,J=5.3,1.1Hz,1H),8.66(d,J=9.1Hz,1H),8.12-8.08(m,2H),8.02(d,J=2.1Hz,1H).

B) preparation of compound 14

Step b(Suzuki linked reaction): operation, with the step b in embodiment 2, is with Compound C-14 alternative compounds C-2. Compound C-14 charging capacity is 60mg(0.24mmol), obtain compound 14(95mg, receipts rate 75%), it is yellow solid. MS (ESI): m/z507 [M+H]⁺.¹HNMR(400MHz,DMSO-d₆)��10.39(s,1H),9.67(d,J=0.8Hz,1H),9.53-9.51(m,2H),8.70(d,J=8.9Hz,1H),8.54(d,J=2.3Hz,1H),8.36(dd,J=8.9,1.7Hz,1H),8.18(dd,J=5.3,2.3Hz,1H),8.11(d,J=1.3Hz,1H),8.08(d,J=2.2Hz,1H),7.76-7.70(m,1H),7.62-7.52(m,1H),7.21-7.17(m,1H),3.65(s,3H).

Embodiment 15: the preparation of compound 15

Synthetic route is:

A) preparation of Compound C-15

Step a(Stille linked reaction): operation, with the step a in embodiment 1, is just prepared by the method described in compound A-15(referenced patent WO2003070244) alternative compounds A-1. Compound A-15 charging capacity is 200mg(0.78mmol), obtain Compound C-15(180mg, receipts rate 90%), it is yellow solid.¹HNMR(400MHz,DMSO-d₆)��9.73(s,1H),9.27(d,J=5.2Hz,1H),8.35(d,J=1.8Hz,1H),8.11(m,2H),7.64(d,J=8.8Hz,1H),7.04(s,1H),6.97(s,2H).

B) preparation of compound 15

Step b(Suzuki linked reaction): operation, with the step b in embodiment 2, is with Compound C-15 alternative compounds C-2. Compound C-15 charging capacity is 60mg(0.23mmol), obtain compound 15(30mg, receipts rate 25%), it is yellow solid. MS (ESI): m/z521 [M+H]⁺.¹HNMR(400MHz,DMSO-d₆)��10.50(brs,1H),9.61(dd,J=2.5,1.1Hz,1H),9.19(dd,J=5.5,1.0Hz,1H),8.21(d,J=2.2Hz,1H),8.06(dd,J=8.7,2.1Hz,1H),7.99-7.92(m,2H),7.86-7.77(m,2H),7.68(d,J=8.7Hz,1H),7.61-7.52(m,1H),7.23(td,J=8.6,2.3Hz,1H),6.89(brs,2H),6.77(s,1H),3.70(s,3H).

Embodiment 16: the preparation of compound 16

Synthetic route is:

A) preparation of Compound C-16

Step a(Stille linked reaction): operation is with the step a in embodiment 1, and just with compound A-16(reference J.Med.Chem., prepared by the method described in 1989,32:1936-1942) alternative compounds A-1. Compound A-16 charging capacity is 200mg(0.78mmol), obtain Compound C-16(110mg, receipts rate 55%), it is tawny solid.¹HNMR(400MHz,DMSO-d₆)��9.82(s,1H),9.37(d,J=4.6Hz,1H),8.58(d,J=2.0Hz,1H),8.33(dd,J=8.8,2.1Hz,1H),8.21(dd,J=5.3,2.4Hz,1H),8.15(d,J=8.8Hz,1H),7.79(s,1H),2.69(s,3H).

B) preparation of compound 16

Step b(Suzuki linked reaction): operation, with the step b in embodiment 2, is with Compound C-16 alternative compounds C-2. Compound C-16 charging capacity is 50mg(0.19mmol), obtain compound 16(75mg, receipts rate 73%), it is yellow solid. MS (ESI): m/z520 [M+H]⁺.¹HNMR(400MHz,DMSO-d₆)��10.49(s,1H),9.71(s,1H),9.29(d,J=5.1Hz,1H),8.33-8.24(m,3H),8.19(d,J=8.6Hz,1H),8.09(dd,J=5.4,2.2Hz,1H),7.93(d,J=1.8Hz,1H),7.82(dd,J=15.3,8.5Hz,1H),7.57(t,J=9.0Hz,1H),7.50(s,1H),7.23(t,J=8.5Hz,1H),3.72(s,3H),2.75(s,3H).

Embodiment 17: the preparation of compound 17

Synthetic route is:

Reagent and condition: the fluoro-N-of b) Suzuki linked reaction: 2,4-bis-[2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-bis-oxygen is mixed boron heterocycle pentane-2-base)-3-pyridyl] benzsulfamide (compound B-1,1.0eq), salt of wormwood (3.0eq), [1, two (diphenylphosphine) ferrocene of 1'-] palladium chloride methylene dichloride complex compound (0.05eq), 1,4-dioxane/water mixed liquid (v/v=4:1), 100 DEG C, microwave, 30 minutes; A) Stille linked reaction: 4-(tri-n-butyl tin) pyridazine (1.2eq), two (tri-butyl phosphine) palladium (0.03eq), cesium fluoride (3.0eq), 1,4-dioxane, 100 DEG C.

B) preparation of Compound D-1

Step b(Suzuki linked reaction): by bromo-for the 2-chloro-pyrazoles of 7-also [1, 5-a] pyrimidine (compound A-17, 150mg, 0.645mmol, according to document J.Med.Chem., 2010, the method preparation described in 53:123-1249), 2, the fluoro-N-of 4-bis-[2-methoxyl group-5-(4, 4, 5, 5-tetramethyl--1, 3, 2-bis-oxygen is mixed boron heterocycle pentane-2-base)-3-pyridyl] benzsulfamide (compound B-1, 275mg, 0.645mmol) and salt of wormwood (268mg, 1.94mmol) it is dissolved in 6mL dioxane-water (V/V=4:1), [1 is added again after logical bubbling argon number minute, two (diphenylphosphine) ferrocene of 1'-] palladium chloride methylene dichloride complex compound (26.3mg, 0.032mmol), then react 30 minutes in 100 DEG C, microwave. reaction solution is cooled to room temperature, separates upper strata dioxane layer, concentrating under reduced pressure, residue is by quick silica gel chromatography, it may also be useful to petrol ether/ethyl acetate (V/V=1:2) wash-out, obtains Compound D-1(70mg, receipts rate 22%), it is buff white solid. MS (ES): m/z496,498 [M+H]⁺.¹HNMR(300MHz,DMSO-d₆)��10.53(s,1H),8.74(d,J=2.2Hz,1H),8.64(d,J=4.5Hz,1H),8.42(d,J=2.2Hz,1H),7.84(dd,J=14.8,8.6Hz,1H),7.59(t,J=9.9Hz,1H),7.36(d,J=4.5Hz,1H),7.23(t,J=7.2Hz,1H),7.05(s,1H),3.77(s,3H)��

A) preparation of compound 17

Step a(Stille linked reaction): by N-(5-(the bromo-pyrazoles of 2-also [1; 5-a] pyrimidin-7-yl)-2-methoxyl group-pyridin-3-yl)-2; fluoro-benzsulfamide (the Compound D-1 of 4-bis-; 60mg; 0.121mmol); 4-(tri-n-butyl tin) pyridazine (54mg; 0.145mmol); two (tri-butyl phosphine) palladium (2.5mg; 4.84 ��m of ol) and cesium fluoride (40mg; 0.27mmol) it is dissolved in the anhydrous 1,4-dioxane of 4mL, then stirs under argon gas shielded in 100 DEG C of oil baths and spend the night. Reaction solution is cooled to room temperature, dilute with 8mL methyl alcohol, then directly sample is mixed by thick silica gel dry method, by quick silica gel chromatography, use methylene chloride/methanol (V/V=95:5) wash-out, then with re-crystallizing in ethyl acetate, obtain compound 17(26mg, receipts rate 43%), it is off-white color solid. MS (ESI): m/z496 [M+H]⁺.¹HNMR(400MHz,DMSO-d₆)��10.56(s,1H),9.95(dd,J=2.3,1.3Hz,1H),9.38(dd,J=5.4,1.2Hz,1H),8.83(d,J=2.3Hz,1H),8.75(d,J=2.3Hz,1H),8.70(d,J=4.4Hz,1H),8.29(dd,J=5.4,2.3Hz,1H),7.80(td,J=8.6,6.3Hz,1H),7.72(s,1H),7.64�C7.53(m,1H),7.48(d,J=4.4Hz,1H),7.21(td,J=8.5,2.2Hz,1H),3.77(s,3H).

Embodiment 18: the preparation of compound 18

Synthetic route is:

Reagent and condition: the fluoro-N-of b) Suzuki linked reaction: 2,4-bis-[2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-bis-oxygen is mixed boron heterocycle pentane-2-base)-3-pyridyl] benzsulfamide (compound B-1,1.0eq), salt of wormwood (3.0eq), [1, two (diphenylphosphine) ferrocene of 1'-] palladium chloride methylene dichloride complex compound (0.05eq), 1,4-dioxane/water mixed liquid (v/v=4:1), 100 DEG C, microwave, 30 minutes; A) Stille linked reaction: 4-(tri-n-butyl tin) pyridazine (1.2eq), tetrakis triphenylphosphine palladium (0.05eq), 1,4-dioxane, 110 DEG C.

B) preparation of Compound D-2

Step b(Suzuki linked reaction): operation, with the step b in embodiment 17, is purchased from Shanghai Bi get Pharmaceutical Technology Co., Ltd with compound A-18() alternative compounds A-17. Compound A-18 charging capacity is 250mg(1.0mmol), obtain Compound D-2(285mg, receipts rate 54%), it is white solid. MS (EI): m/z506,508 [M]⁺.¹HNMR(400MHz,DMSO-d₆)��10.54(s,1H),9.40(s,1H),8.49(d,J=2.2Hz,1H),8.24(d,J=2.0Hz,1H),8.21(dd,J=8.9,2.2Hz,1H),8.10(d,J=2.2Hz,1H),8.06(d,J=8.9Hz,1H),7.83(td,J=8.6,6.3Hz,1H),7.66-7.55(m,1H),7.26(td,J=8.2,2.3Hz,1H),3.77(s,3H).

A) preparation of compound 18

Step a(Stille linked reaction): by Compound D-2(120mg; 0.24mmol); 4-(tri-n-butyl tin) pyridazine (105mg; 0.28mmol) and tetrakis triphenylphosphine palladium (14mg; 12 ��m of ol) it is dissolved in 4mL anhydrous 1; in 4-dioxane, then stir under argon gas shielded in 110 DEG C of oil baths and spend the night. Reaction solution is cooled to room temperature, then directly mixes sample by thick silica gel dry method, by quick silica gel chromatography, it may also be useful to methylene chloride/methanol (V/V=95:5) wash-out, obtains compound 18(95mg, receipts rate 79%), it is buff white solid. MS (ESI): m/z507 [M+H]⁺.¹HNMR(400MHz,DMSO-d₆)��10.55(s,1H),9.79(dd,J=2.4,1.1Hz,1H),9.43(s,1H),9.35(dd,J=5.5,0.9Hz,1H),8.61(d,J=2.2Hz,1H),8.58-8.56(m,2H),8.31-8.26(m,1H),8.23(d,J=2.2Hz,1H),8.18(dd,J=5.5,2.5Hz,1H),7.82(td,J=8.5,6.3Hz,1H),7.63-7.55(m,1H),7.24(td,J=8.6,2.3Hz,1H),3.76(s,3H).

Embodiment 19: the preparation of compound 19

Synthetic route is:

Reagent and condition: the fluoro-N-of b) Suzuki linked reaction: 2,4-bis-[2-methoxyl group-5-(4,4,5,5-tetramethyl--1,3,2-bis-oxygen is mixed boron heterocycle pentane-2-base)-3-pyridyl] benzsulfamide (compound B-1,1.0eq), salt of wormwood (3.0eq), [1, two (diphenylphosphine) ferrocene of 1'-] palladium chloride methylene dichloride complex compound (0.05eq), 1,4-dioxane/water mixed liquid (v/v=4:1), 100 DEG C, microwave, 30 minutes; A) Suzuki linked reaction: 6-aminopyridine-3-boric acid pinacol ester (compound B-2,1.2eq), salt of wormwood (3.0eq), [1, two (diphenylphosphine) ferrocene of 1'-] palladium chloride methylene dichloride complex compound (0.05eq), 1,4-dioxane/water mixed liquid (v/v=4:1), 100 DEG C, microwave, 30 minutes.

B) preparation of Compound D-3

Step b(Suzuki linked reaction): operation is with the step b in embodiment 17, and just with compound A-19(according to document ACSMed.Chem.Lett., prepared by the method described in 2010,1:39-43) alternative compounds A-17. Compound A-19 charging capacity is 1.5g(4.5mmol), obtain Compound D-3(1.6g, receipts rate 70%), it is buff white solid. MS (ESI): m/z506,508 [M+H]⁺��¹HNMR(400MHz,DMSO-d₆)��10.51(s,1H),9.01(d,J=4.4Hz,1H),8.22(d,J=2.2Hz,1H),8.11-8.05(m,1H),8.00-7.93(m,2H),7.90-7.80(m,2H),7.66-7.57(m,1H),7.56(d,J=4.4Hz,1H),7.27(td,J=8.4,2.1Hz,1H),3.75(s,3H)��

A) preparation of compound 19

Step a(Suzuki linked reaction): by Compound D-3(120mg, 0.237mmol), 6-aminopyridine-3-boric acid pinacol ester (compound B-2,63mg, 0.284mmol, purchased from Sigma-AldrichCo.LLC) and salt of wormwood (98mg, 0.711mmol) it is dissolved in 4mL dioxane-water (V/V=4:1), [1 is added again after logical bubbling argon number minute, two (diphenylphosphine) ferrocene of 1'-] palladium chloride methylene dichloride complex compound (9.7mg, 0.012mmol), then react 30 minutes in 100 DEG C, microwave. Reaction solution is cooled to room temperature, separates upper strata dioxane layer, concentrating under reduced pressure, and residue is by quick silica gel chromatography, it may also be useful to methylene chloride/methanol (V/V=95:5) wash-out, obtains compound 19(85mg, receipts rate 69%), it is white solid. MS (ESI): m/z520 [M+H]⁺.¹HNMR(400MHz,DMSO-d₆)��10.50(s,1H),8.91(d,J=4.4Hz,1H),8.38(d,J=2.5Hz,1H),8.26(d,J=2.1Hz,1H),8.14(d,J=8.7Hz,1H),8.09(d,J=8.8Hz,1H),7.93(s,1H),7.91(d,J=2.2Hz,1H),7.87�C7.75(m,2H),7.62�C7.53(m,1H),7.48(d,J=4.4Hz,1H),7.27�C7.17(m,1H),6.53(d,J=8.7Hz,1H),6.21(s,2H),3.72(s,3H).

Embodiment 20: the preparation of compound 20

Synthetic route is:

Reagent and condition: a) Suzuki linked reaction: 2-aminopyrimidine-5-boric acid pinacol ester (compound B-3,1.2eq), salt of wormwood (3.0eq), [1, two (diphenylphosphine) ferrocene of 1'-] palladium chloride methylene dichloride complex compound (0.05eq), 1,4-dioxane/water mixed liquid (v/v=4:1), 100 DEG C, microwave, 30 minutes.

Compound 20 adopts the method for embodiment 19 to prepare. Operation and charging capacity are identical with the step a in embodiment 19, just by 6-aminopyridine-3-boric acid pinacol ester (compound B-2) 2-aminopyrimidine-5-boric acid pinacol ester (compound B-3, purchased from splendid scientific and technological (Shanghai) company limited of chemistry far away) substitute, obtain compound 20(60mg, receipts rate 48%), it is buff white solid. MS (ESI): m/z521 [M+H]⁺.¹HNMR(400MHz,DMSO-d₆)��10.47(s,1H),8.94(d,J=4.4Hz,1H),8.71(s,2H),8.28(d,J=2.1Hz,1H),8.19-8.12(m,2H),8.00(s,1H),7.94(d,J=2.1Hz,1H),7.80(dd,J=15.0,8.3Hz,1H),7.57(t,J=8.7Hz,1H),7.51(d,J=4.4Hz,1H),7.24(t,J=8.3Hz,1H),6.92(s,2H),3.70(s,3H).

Pharmacological test example

Pharmacological test example 1:ELISA detection compound is on the impact (pAKT-S473ELISAAssay) of Rh30 cell AKT1S473 phosphorylation

AKT is one of important effect protein in PI3K downstream, and AKT phosphorylation level directly reflects the activity of PI3K in cell. In order to study the pharmacologically active of the compound of the present invention, establish the method at cell-based screening PI3K inhibitor, namely by the change of AKT phosphorylation in cell after detection compound effect, judge whether compound suppresses PI3K active.

Experimentation: human rhabdomyosarcoma cell Rh30(is provided by Shanghai Pharmaceutical Inst., Chinese Academy of Sciences) with 1 �� 10⁵Individual/hole/500 �� L trains liquid kind in 24 orifice plates, overnight incubation. 2nd day, change serum-free RPMI1640 after cleaning twice cell with D-PBS and cultivate 24 hours. Then add testing compound and DMSO comparison, act on 1 hour, within last 10 minutes, add, what act on, the type-1 insulin like growth factor (IGF1) that final concentration is 100ng/mL. Abandon liquid in most hole, add the lysate lysing cell of precooling, immediately cell pyrolysis liquid is proceeded to AKT antibody bag by and with BSA close enzyme plate hole in, add 50 �� L/ holes dilute after AKTpS473 antibody, let slip night for 4 DEG C. Exhaust AKTpS473 antibody in enzyme plate hole, with D-PBST clean plate hole 3 times, add 50 �� L/ holes dilute after the anti-rabbit antibody of HRP mark, incubated at room 2 hours in wet box on shaking table. With D-PBST clean plate hole 3 times, add TMB and develop the color liquid, 100 �� LL/ holes, be fixed on vibrator colour developing to blue obvious. Finally use 2MH₂SO₄50 �� L/ hole color development stopping, read OD450 value and calculate inhibiting rate.

Table 1 prepares the biological activity result that the compound in embodiment obtains in pharmacological test example 1 for part of the present invention, and the compound concentration of test is 10 ��Ms/L:

Table 1

Compound	Inhibiting rate (%)
		Compound 1	98
Compound 3	129
		Compound 4	111
Compound 6	124
		Compound 7	109
Compound 9	117
		Compound 17	105

Compound	Inhibiting rate (%)
		GSK2126458	101

Wherein: compound GSK2126458 is positive control drug (Knight, S.D.; Adams, N.D.; Burgess, J.L.; Etal.ACSMed.Chem.Lett.2010,1:39-43.).

Test result shows, part of the present invention prepares embodiment compound under 10 ��Ms/L concentration to the PI3K/mTOR inhibitor that the inhibiting rate of AKT phosphorylation and positive control drug GSK2126458(are known) quite, at cell levels, PI3K had inhibit activities significantly.

Pharmacological test example 2: sulphonyl rhodamine B (sulforhodamineB, SRB) protein staining method detection compound is to the inhibited proliferation of tumour cell

1) cell strain: human rhabdomyosarcoma cell Rh30, people glioblastoma cell U87MG(provide by Shanghai Pharmaceutical Inst., Chinese Academy of Sciences).

2) experimentation: the tumor cell inoculation that some amount is in logarithmic phase is in 96 well culture plates (90 �� L/ hole), overnight incubation, after cell attachment, add gradient concentration (0.1 respectively, 0.3,1,3,10 ��Ms/L) embodiment compound or positive control drug GSK2126458(10 �� L/ hole), each concentration establishes three wells. Treated with medicaments cell is after 72 hours, and incline nutrient solution, add 100 �� L ice-cold 10% solution of trichloroacetic acid fixed cell, place with distilled water wash 5 times after 1 hour for 4 DEG C, seasoning in air. Then sulphonyl Luo Dan bright B(sulforodamineB, the SRB of the 4mg/mL that 100 �� L are prepared is added by 1% Glacial acetic acid) solution, dyes 15 minutes in room temperature, removes staining fluid, wash 5 times with 1% Glacial acetic acid, dry air. Finally add the Tris solution (pH10.5) of the 10mM/L of 100 �� L, under 520nm wavelength, measure OD value by the wavelengthtunable orifice plate microplate reader (VersaMax) that declines, then the IC obtaining compound by calculating growth of tumour cell being suppressed₅₀Value.

3) result: see table 2.

Table 2

Compound	Rh30IC₅₀(��M)	U87MGIC₅₀(��M)
			Compound 1	0.60	3.59

Compound	Rh30IC₅₀(��M)	U87MGIC₅₀(��M)
			Compound 2	7.22	3.61
Compound 3	0.43	0.67
			Compound 4	2.82	3.24
Compound 5	2.84	>10
			Compound 6	0.98	7.15
Compound 8	0.80	4.21
			Compound 9	0.13	0.85
Compound 10	1.76	ND
			Compound 11	7.24	ND
Compound 17	0.51	1.03
			GSK2126458	0.04	0.04

Wherein: ND is that activity is not tested, and GSK2126458 is positive control drug.

Test result shows, human rhabdomyosarcoma cell Rh30 and people glioblastoma cell U87MG is had good inhibited proliferation by the compound of the present invention.

Pharmacological test example 3: the growth-inhibiting effect of human glioma's U87MG nude mouse subcutaneous transplantation knurl

1) test medicine: the compound (compound 3) of embodiment 3 and the compound (compound 9) of embodiment 9, all with 0.5% sodium carboxymethyl cellulose solution preparation.

2) laboratory animal: BALB/cA nude mouse, female, 4-5 week age, body weight 19 �� 2g, is provided by Shanghai Pharmaceutical Inst., Chinese Academy of Sciences, produce conformity certification numbering: SCXK(Shanghai) 2008-0017. Every treated animal number: negative control group 12, administration group 6.

3) cell strain: human glioma's U87MG cell strain (providing by Shanghai Pharmaceutical Inst., Chinese Academy of Sciences), inoculates armpit on the right side of nude mouse with this cell strain subcutaneous, and cell inoculum size is 5 �� 10⁶/ only, use after passing for 2 generations after forming transplanted tumor again in nude mouse body.

4) experimental technique: the tumor tissue getting growth animated period cuts into 1.5mm³Left and right, aseptically, is inoculated in armpit on the right side of nude mouse subcutaneous. Nude mouse subcutaneous transplantation knurl vernier caliper measurement transplanted tumor diameter, treats that tumor growth is to 100-200mm³After by animal random packet. Test medicine presses 10mg/kg group; Solvent control group to equivalent blank solvent, every day oral administration once, successive administration 21 days. In whole experimentation, measure transplanted tumor diameter 2 times weekly, weigh mouse body weight simultaneously. The calculation formula of gross tumor volume (tumorvolume, TV) is: TV=1/2 �� a �� b², wherein a, b represent length and width respectively. Result according to measuring calculates Relative tumor volume (relativetumorvolume, RTV), and calculation formula is: RTV=V_t/V₀. Wherein V₀For (d during sub-cage administration₀) measure gained gross tumor volume, V_tGross tumor volume during for measuring each time. The evaluation index of anti-tumor activity is Relative tumor proliferation rate T/C (%), and calculation formula is as follows: T/C (%)=(T_RTV/C_RTV) �� 100%, T_RTV: treatment group RTV; C_RTV: negative control group RTV.

5) experimental result: the compound (compound 3) of embodiment 3 and the compound (compound 9) of embodiment 9 are by 10mg/kg dosage, every day oral administration once, successive administration is after 21 days, the growth of mouse subcutaneous transplanting knurl has and significantly slows down, and within the 21st day, gained T/C percentage ratio is respectively 62.27% and 46.41%. Comparing with solvent control group, administration group shows certain Tumor growth inhibition effect.

Above-mentioned pharmacological evaluation test result shows, the compound of the present invention can be used for treating the disease, particularly malignant tumour that cause by the cell function of the exception relevant with PI3K.

Claims

1. one kind has fused bicyclic heterocycle compound or its pharmacy acceptable salt that following general formula (I) represents:

Wherein,

R²For H;

Ring AB is the one being selected from following groups:

R⁵For H, amino or C1-C6 alkyl,

R¹For

R³For-NHSO₂R⁴, wherein R⁴For the phenyl that F replaces,

X is methoxyl group, oxyethyl group, positive propoxy or isopropoxy.

2. fused bicyclic heterocycle compound according to claim 1 or its pharmacy acceptable salt, wherein,

R⁵For H, amino, methyl, ethyl, n-propyl or sec.-propyl;

R³For

3. fused bicyclic heterocycle compound according to claim 2 or its pharmacy acceptable salt, the compound that general formula I represents is one of following compounds:

4. a pharmaceutical composition, it comprises one or more fused bicyclic heterocycle compounds according to any one of claim 1-3 for the treatment of significant quantity or its pharmacy acceptable salt as activeconstituents, and optionally can comprise pharmaceutically acceptable carrier, auxiliary agent or auxiliary material further.

5. fused bicyclic heterocycle compound according to any one of claim 1-3 or its pharmacy acceptable salt or pharmaceutical composition according to claim 4 are caused by PI3K-AKT-mTOR signal path functional disorder in preparation treatment disease or the purposes of the medicine of illness.

6. purposes according to claim 5, wherein, described disease and illness be: proliferative disease, immunological disease, cardiovascular disorder, virus infection, inflammation, metabolism/endocrine disorder and/or sacred disease.

7. purposes according to claim 6, wherein, described proliferative disease is malignant tumour, described metabolism/endocrine disorder is diabetes or obesity, and described malignant tumour is the cancer of sarcoma, leukemia, cerebral tumor, kidney, cancer of the stomach and skin, bladder, mammary gland, uterus, lung, colon, prostate gland, ovary and pancreas.

8. purposes according to claim 7, wherein, described cerebral tumor is glioblastoma, and described sarcoma is human rhabdomyosarcoma.