CN106458969A

CN106458969A - (substituted phenyl) (substituted pyrimidine) amino derivative, preparation method therefor, and medication use

Info

Publication number: CN106458969A
Application number: CN201580023470.2A
Authority: CN
Inventors: 魏用刚; 李瑶; 张国彪; 邱关鹏; 胡仕红; 陈雷; 李升�; 张黔
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Sichuan Haisco Pharmaceutical Co Ltd
Priority date: 2014-08-25
Filing date: 2015-08-25
Publication date: 2017-02-22
Also published as: WO2016029839A1; CN113121575A

Abstract

Provided are a (substituted phenyl) (substituted pyrimidine) amino derivative as described in formula (I), an optical isomer, pharmaceutically acceptable salt or eutectic product thereof, preparation method therefor, and use thereof in preparing tumor medications. The compound of formula is (I).

Description

A kind of (substituted phenyl) (substituted pyrimidine) amido derivative and preparation method thereof and medicinal usage

Technical field

The present invention relates to (substituted phenyl) (substituted pyrimidine) amido derivative described in a kind of logical formula (I) and its optical isomer, pharmaceutically acceptable salt or eutectic, and preparation method and the purposes in tumour medicine is prepared.

Background technology

With the arrival of industrial age, the pollution of environment and living-pattern preservation cause the incidence of disease of cancer persistently to rise.At present, cancer has become the primary killers for threatening human life and health.According to IARC (IARC) report：8 years cancer new cases of global 200d are 1,2,660,000, and death is 7,560,000, accounts for the 13% of all death tolls.In coming few decades, pathogenesis of cancer number will rapid growth, it is contemplated that the year two thousand thirty the whole world will have 21,360,000 cancer new cases, death will be up to 13,150,000, and the market demand for the treatment of of cancer will maintain sustained and rapid growth.

Receptor tyrosine kinase superfamily in cell surface receptor is played an important role by extracellular growth factors to the regulation of cell signal.Receptor tyrosine kinase can catalytic phosphatase group be transferred to from ATP on the tyrosine group of substrate.When no ligand activation receptor tyrosine kinase, these kinases are in unphosphorylated free state, and its kinase domain is in inactive structure.When part is combined with the extracellular fragment of receptor tyrosine kinase, oligomerization, and autophosphorylation occur for acceptor, the binding site of signal protein are formd while the catalytic activity for increasing kinases, signal protein is in connection, so as to activate many signal paths.These signal paths are connected each other, propagation, existence, differentiation, function, migration and the apoptosis of regulating cell.When receptor tyrosine kinase loses regulation and control, during abnormal activation, cell can change into tumour cell, propagation, growth ability and resistance ability are improved, with stronger into vessel patency, invasiveness and transfer ability (Yarden and Sliwkowski, 2001, Nat Rev Mol Cell Biol, 2,127-137).

ErbB families belong to receptor tyrosine kinase, include four members：EGF-R ELISA (EGFR/HER1/ErbB1), HER2 (neu/ErbB2), HER3 (ErbB3) and HER4 (ErbB4) (Olayioye, Neve etc., 2000, EMBO J, 19,3159-3167；Yarden and Sliwkowski, 2001, Nat Rev Mol Cell Biol, 2,127-137).They are containing extracellular ligand binding domain, single transmembrane domain and intracellular EGFR-TK and regulation domain.Its function is that the phosphate for being catalyzed ATP is transferred on the tyrosine group of substrate protein.The receptor oligomerization of ligand-dependent causes the autophosphorylation in regulation domain, so as to occur intracellular signal transduction, finally causes cell to be bred.The occurrence and development of the signal path and tumour are closely related.In kinds of tumors, the ErbB receptor of superactivation, especially EGFR can cause the imbalance control of growth factor signal.EGFR activation be often as being overexpressed or continuous activation caused by being mutated or part from point Secrete expression.EGFR overexpression or mutation can be detected in the kinds cancers such as head and neck cancer, oophoroma, carcinoma of urinary bladder, cervical carcinoma, cancer of the esophagus, stomach cancer, breast cancer, endometrial carcinomas, colon cancer, lung cancer and brain tumor, generally indicate this bad prognosis.Therefore it is an antitumor strategy received much concern to suppress EGFR.The micromolecular inhibitor of many targeting EGFRs is developed in succession, and some of them have applied to clinical treatment.

The EGFR kinase inhibitor of the first generation such as Gefitinib, Erlotinib clinically can effectively treat non-small cell lung cancer, and especially those contain non-small cell lung cancer (Mok, Wu etc. that activated mutant occurs for EGFR kinase domains, 2009, N Engl J Med, 361,947-957；Rosell, Moran etc., 2009, N Engl J Med, 361,958-967).Most common EGFR activated mutants are L858R and delE746_A750, relative to the EGFR of wild type, these mutation can increase affinity of the acceptor to Gefitinib and Erlotinib, and reduce affinity (Carey of the acceptor to ATP, Garton etc., 2006, Cancer Res, 66,8163-8171；Yun, Boggon etc., 2007, Cancer Cell, 11,217-227).But, clinically, due to the appearance of acquired resistance, the utilization of Gefitinib and Erlotinib is finally restricted.Acquired resistance can all occur in patients with lung cancer more than 50%, wherein T790M containing EGFR guard the gate residue mutations (Kobayashi, Boggon etc., 2005, N Engl J Med, 352,786-792 more than 90%；Pao, Miller etc., 2005, PLoS Med, 2, e73).T790M mutation hinder the combination of medicine not from space conformation, but recover acceptor to ATP affinity, suitable with wild type (Yun, Mengwasser etc., 2008, Proc Natl Acad Sci U S A, 105,2070-2075).

The EGFR kinase inhibitor of the second generation generally has quinoline structure, is irreversible EGFR inhibitor.Different from Gefitinib, they contain Polarography, can occur Michael addition reaction with the cysteine residues (Cys 797) guarded in EGFR.The covalent property of these compounds makes them compared to reversible inhibitor, with the stronger ability for occupying ATP sites, therefore, although T790M mutation can increase ATP affinity, this kind of inhibitor is enough to suppress EGFR T790M (Engelman, Zejnullahu etc. in preclinical models, 2007, Cancer Res, 67,11924-11932；Li, Ambrogio etc., 2008, Oncogene, 27,4702-4711).But, existing irreversible inhibitor is on cell line model, suppress the ability of EGFR T790M mutation again below the ability for suppressing to only have EGFR activated mutants, and clinically under available concentration, this kind of compound can not suppress EGFR T790M (Yuza, Glatt etc. in vitro, 2007, Cancer Biol Ther, 6,661-667；Godin-Heymann, Ulkus etc., 2008, Mol Cancer Ther, 7,874-879).Because EGFR T790M are similar to ATP affinity to the EGFR of wild type to ATP affinity, the EGFR inhibitor of quinazoline ditosylate salt can also suppress the EGFR of wild type while EGFR T790M are suppressed.Clinically, suppressing Wild type EGFR simultaneously can cause patient fash and diarrhoea occur, this can limit the dosage of second generation EGFR inhibitor, so that the plasma concentration of medicine makes the Clinical efficacy of this kind of medicine by larger limitation with being not enough to suppress T790M.Such as CI-1033, HKI-272 and PF00299804, clinically the treatment for Gefitinib and the non-small cell lung cancer of Erlotinib resistance is very limited, and can occur dose-dependent diarrhoea and fash (Janne, von Pawel etc., 2007, J Clin Oncol, 25,3936-3944；Advani, Coiffier etc., 2010, J Clin Oncol, 28,2085-2093).

Suppressed in order to specificity for EGFR T790M, third generation EGFR Catastrophic selections inhibitor comes out.This kind of irreversible inhibitor has higher selectivity compared with second generation quinolines to EGFR T790M, may clinically have higher activity and more preferable tolerance.Such as covalent miazines EGFR inhibitor WZ4002, it is high to EGFR T790M selectivity 30-100 times compared to quinolines in testing in vitro, and then low 100 times is suppressed to Wild type EGFR.In animal lung cancer model derived from EGFR T790M, preferable drug effect (Zhou, Ercan etc., 2009, Nature, 462,1070-1074) is also shown.Another Catastrophic selection inhibitor co-1686 is high to Wild type EGFR to EGFR T790M selectivity ratios 10-25 times in vitro.EGFR mutation, including medicament-resistant mutation T790M and activated mutant (L858R, del19) can optionally be suppressed, and to Wild type EGFR unrestraint.In vitro, oral co-1686 can result in the tumor regression of T790M mutation, and further medicament-resistant mutation (Walter, Sjin etc., 2013, Cancer Discov, 3,1404-1415) does not occur for mediate tumor cell.In order to meet clinical demand, it is necessary to continue the EGFR inhibitor that research and development do not produce obvious toxic-side effects under the concentration that can effectively overcome T790M to be mutated.

Many document reports kinases inhibitor and its anti-tumor application are had at present.Such as：

WO2009051822 disclose can as EGFR inhibitor pyrimidine derivatives, and its in the purposes for the treatment of cancer.Wherein A, B are selected from carbocyclic ring or heterocycle etc., and structure is as follows：

WO2011140338 describe can as EGFR inhibitor Hete rocyclic derivatives, and be used as the purposes of antineoplastic.Wherein B is selected from 6 to 10 yuan of the single aryl or double heteroaryls containing at least one N atom, and X1 is selected from O, S or N, R²⁹、R^29aH, 5 to 6 yuan of non-heteroaryls, 5 to 6 yuan of non-heteroaryl methylenes or 5 to 6 yuan of non-Heteroarylcarbonyls are independently selected from R29b, structure is as follows：

WO2011090760, WO2009158571 describe can as kinases inhibitor pyrimidine derivatives, and as the purposes for treating a variety of disease medicaments, wherein A, B is independently selected from heterocycle or carbocyclic ring, and structure is as follows：

WO2013014448 disclose can as EGFR inhibitor pyrimidine derivatives, and its in the purposes for the treatment of cancer.Wherein G is selected from 4,5,6,7- tetrahydro-pyrazoles simultaneously [l, 5-a] pyridin-3-yl, lH- indol-3-yls, 1- methyl-lH-indol -3- bases or pyrazolo [l, 5-a] pyridin-3-yl, and R3 is N- dimethylaminoethyl-N- methylaminos etc., and structure is as follows：

It is an object of the invention to provide a kind of effect is good, better tolerance, selectivity be high or the low EGFR inhibitor of toxic side effect, and its purposes in treating cancer related drugs are prepared.Described cancer includes head and neck cancer, oophoroma, carcinoma of urinary bladder, cervical carcinoma, cancer of the esophagus, stomach cancer, breast cancer, endometrial carcinomas, colon cancer, lung cancer, brain tumor, non-small cell lung cancer, cancer of pancreas, entity tumor, colorectal carcinoma or glioblastoma etc..

The content of the invention

The present invention relates to the compound shown in a kind of logical formula (I) and its optical isomer, pharmaceutically acceptable salt or eutectic, wherein：

B is selected from 6 to 15 circle heterocycles, and described heterocycle contains 1 to 4 hetero atom for being selected from N, O, S or P；

R¹It is independently selected from F, Cl, Br, I, hydroxyl, cyano group, C_1-10Alkyl, C_1-10Alkoxy ,-NR^1aR^1b,-C (=O) C_1-10Alkyl ,-S (=O)₂-C_1-10Alkyl, the circle heterocycles of-C (=O) -3 to 15,-C (=O)-C_3-15Carbocyclic ring ,-(CH₂)_n- 3 to 15 circle heterocycles ,-(CH₂)_n-C_3-15Carbocyclic ring ,-O- (CH₂)_n-C_3-15Carbocyclic ring ,-O- (CH₂)_n- 3 to 15 circle heterocycles ,-O- (CH₂)_n- C (=O) C_1-6Alkyl ,-O- (CH₂)_n- O-C (=O) C_1-6Alkyl or-O- (CH₂)_n-O-C_1-10Alkyl, it is described CH₂, alkyl, alkoxy, carbocyclic ring or heterocycle be optionally further selected from F, Cl, Br, I ,=O, hydroxyl, amino, cyano group, nitro, C by 0 to 5_1-6Alkyl, C_1-6Alkoxy ,-(CH₂)_n-OH、-(CH₂)_n- F ,-C (=O) C_1-6Alkyl ,-O-C (=O) C_1-6Alkyl ,-C (=O) C_1-6Alkoxy ,-C (=O) C_3-15Carbocyclic ring ,-(CH₂)_n-C_3-10Carbocyclic ring or-(CH₂)_nThe substituent of -3 to 10 circle heterocycles is replaced, and the heterocycle contains 1 to 4 hetero atom for being selected from N, O, S or P；

R^1aAnd R^1bSelected from H or C_1-10Alkyl；

R²Selected from H, F, Cl, Br, I, cyano group, C_1-10Alkyl or C_1-10Alkoxy, described alkyl or alkoxy are optionally further selected from F, Cl, Br, I, C by 0 to 4_1-6Alkyl or C_1-6The substituent of alkoxy is replaced；

R³Selected from H, C_2-10Alkenyl, C_3-15Cycloalkyl, C_1-10Alkyl or C_1-10Alkoxy, the alkenyl, cycloalkyl, alkyl or alkoxy optionally further 0 to 4 is selected from F, Cl, Br, I, C_1-6Alkyl or C_1-6The substituent of alkoxy is replaced；

R⁴Selected from H, F, Cl, Br, I, nitro, amino, C_1-10Alkyl, 5 to 15 yuan of loop coils, 4 to 15 yuan and ring, 3 to 10 circle heterocycles ,-NR^4cR^4d、-Z-(CH₂)_nR^4a、-O-(CH₂)_nR^4b、-Z-(CH₂)_nNR^4cR^4dOr-O- (CH₂)_nNR^4cR^4d, the CH₂, loop coil and ring or heterocycle be optionally further selected from F, Cl, Br, I, hydroxyl, amino, C by 0 to 4_1-6Alkyl, C_1-6Alkoxy ,-(CH₂)_n- C (=O)-R^4e、-(CH₂)_n- O-C (=O)-R^4e、-NR^4cR^4d, by 0 to 4 R^4cSubstituted C_3-10Carbocyclic ring or by 0 to 4 R^4cThe substituent of 3 to 10 circle heterocycles of substitution is replaced, and the heterocycle contains 1 to 4 hetero atom for being selected from N, O or S；

Z is selected from-NH- or-N (C_1-6Alkyl)-；

R^4aSelected from C_3-15Carbocyclic ring or 3 to 15 circle heterocycles, the heterocycle contain 1 to 4 hetero atom for being selected from N, O or S, and the carbocyclic ring or heterocycle are optionally further selected from F, Cl, Br, I, amino, hydroxyl, C by 0 to 4_1-6Alkoxy, C_1-6Alkyl or by 1 to 2 C_1-6The substituent of alkyl-substituted amino is replaced；

R^4bSelected from-C (=O) C_1-6Alkyl ,-O-C (=O) C_1-6Alkyl, C_1-10Alkoxy, C_3-15Carbocyclic ring or 3 to 15 circle heterocycles, the alkyl, alkoxy, carbocyclic ring or heterocycle are optionally further selected from F, Cl, Br, I, amino ,-NR by 0 to 4^4cR^4d, hydroxyl, C_1-6Alkyl, C_1-6The C of alkoxy or halogen substitution_1-6The substituent of alkyl is replaced, and the heterocycle contains 1 to 4 hetero atom for being selected from N, O or S；

R^4cAnd R^4dSelected from H, C_1-10Alkyl ,-C (=O) C_1-6Alkyl or-C (=O) C_1-6Alkoxy；

R^4eSelected from amino, hydroxyl, C_1-10Alkyl, C_3-15Carbocyclic ring or 3 to 15 circle heterocycles, the amino, alkyl, carbocyclic ring or heterocycle are optionally further selected from F, Cl, Br, I, amino, hydroxyl, C by 0 to 4_1-6Alkyl, C_1-6Alkoxy ,-C (=O) C_1-6Alkyl ,-C (=O)-NH₂,-O-C (=O) C_1-6Alkyl or the C of halogen substitution_1-6The substituent of alkyl is replaced, and the heterocycle contains 1 to 4 hetero atom for being selected from N, O or S；

R⁵Selected from H, F, Cl, Br, I or 5 to 15 circle heterocycles, the heterocycle contains 1 to 4 and is selected from N, O or S Hetero atom, described heterocycle is optionally further selected from F, Cl, Br, I ,=O ,-C (=O) C by 0 to 4_1-6Alkyl, C_1-6Alkyl or C_1-6The substituent of alkoxy is replaced；

F is selected from 0,1,2,3,4,5 or 6；

N is selected from 0,1,2 or 3；

In each scheme of the present invention, as-B- (R¹)_fIt is selected from And R²Selected from H, F, Cl, methyl or cyano group, R³Selected from H, methoxyl group or methyl, f is 1, R⁵During for H, R⁴Be not H,

Preferred scheme of the present invention, compound and its optical isomer, pharmaceutically acceptable salt or eutectic shown in a kind of logical formula (I), wherein：

B is selected from 6 to 15 circle heterocycles, and described heterocycle contains 1 to 4 hetero atom for being selected from N, O or S；

R¹It is independently selected from F, Cl, Br, I, hydroxyl, cyano group, C_1-4Alkyl, C_1-4Alkoxy ,-NR^1aR^1b,-C (=O) C_1-4Alkyl ,-S (=O)₂-C_1-4Alkyl, the circle heterocycles of-C (=O) -3 to 7,-C (=O)-C_3-7Carbocyclic ring ,-(CH₂)_n-C_3-6Carbocyclic ring or 3 to 7 circle heterocycles, described CH₂, alkyl, alkoxy, carbocyclic ring or heterocycle be optionally further selected from F, Cl, Br, I ,=O, hydroxyl, C by 0 to 4_1-4Alkyl, C_1-4Alkoxy ,-C (=O) C_1-4Alkoxy ,-(CH₂)_n-OH、-(CH₂)_n- F ,-C (=O) C_3-6Carbocyclic ring ,-C (=O) C_1-4Alkyl ,-(CH₂)_n-C_3-6Carbocyclic ring or-(CH₂)_n- 3 to 6 circle heterocycles substituents are replaced, and the heterocycle contains 1 to 4 hetero atom for being selected from N, O or S；

R^1aAnd R^1bSelected from H or C_1-4Alkyl；

R²Selected from H, F, Cl, Br, I, cyano group, C_1-4Alkyl or C_1-4Alkoxy, described alkyl or alkoxy are optionally further selected from F, Cl, Br, I, C by 0 to 4_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

R³Selected from H, C_2-6Alkenyl, C_3-6Cycloalkyl, C_1-4Alkyl or C_1-4Alkoxy, the alkenyl, cycloalkyl, alkyl or alkoxy optionally further 0 to 4 is selected from F, Cl, Br, I, C_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

R⁴Selected from H, F, Cl, Br, I, 5 to 15 yuan of loop coils, 4 to 15 yuan and ring, 3 to 10 circle heterocycles ,-Z- (CH₂)_nR^4a、-O-(CH₂)_nR^4b、-Z-(CH₂)_nNR^4cR^4dOr-O- (CH₂)_nNR^4cR^4d, the heterocycle contain 1 to 4 be selected from N, O or S hetero atom, the CH₂, loop coil and ring or heterocycle optionally further by 0 to 4 selected from F, Cl, Br, I, Amino, hydroxyl, C_1-4Alkyl ,-NR^4cR^4d,-C (=O)-R^4eOr C_1-4The substituent of alkoxy is replaced；

Z is selected from-NH- or-N (C_1-4Alkyl)-；

R^4aSelected from C_3-6Carbocyclic ring or 3 to 7 circle heterocycles, the heterocycle contain 1 to 4 hetero atom for being selected from N, O or S, and the carbocyclic ring or heterocycle are optionally further selected from F, Cl, Br, I, amino, hydroxyl, C by 0 to 4_1-4Alkyl, by 1 to 2 C_1-4The substituent of alkyl-substituted amino is replaced；

R^4bSelected from C_3-6Carbocyclic ring or 3 to 7 circle heterocycles, the heterocycle contain 1 to 4 hetero atom for being selected from N, O, S, and the carbocyclic ring or heterocycle are optionally further selected from F, Cl, Br, I, amino, hydroxyl ,-NR by 0 to 4^4cR^4d、C_1-4Alkyl or the C replaced by 1 to 2 halogen_1-4The substituent of alkyl is replaced；

R^4cAnd R^4dSelected from H or C_1-4Alkyl；

R^4eSelected from amino, hydroxyl, C_1-4Alkyl, C_3-6Carbocyclic ring or 3 to 7 circle heterocycles, the amino, alkyl, carbocyclic ring or heterocycle are optionally further selected from F, Cl, Br, I, amino, hydroxyl, C by 0 to 4_1-4Alkyl, C_1-4The C of alkoxy or halogen substitution_1-4The substituent of alkyl is replaced, and the heterocycle contains 1 to 4 hetero atom for being selected from N, O or S；

R⁵Selected from H, F, Cl, Br, I or 5 to 6 circle heterocycles, the heterocycle contains 1 to 4 hetero atom for being selected from N, O, S, and described heterocycle is optionally further selected from H, F, Cl, Br, I ,=O ,-C (=O) C by 0 to 4_1-4Alkyl, C_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

F is selected from 0,1,2,3 or 4；

N is each independently selected from 0,1,2 or 3.

B is selected from 8 to 13 circle heterocycles, and the heterocycle contains 1 to 4 hetero atom for being selected from N, O or S；

R¹It is independently selected from F, Cl, Br, I, hydroxyl, cyano group ,-S (=O)₂-C_1-4Alkyl ,-C (=O)-C_3-6Carbocyclic ring, C_1-4Alkyl ,-(CH₂)_n-C_3-6Carbocyclic ring or-(CH₂)_n- 5 to 6 circle heterocycles, preferably H, F, Cl ,-S (=O)₂-C_1-4Alkyl, C_1-4Alkyl ,-C (=O)-C_3-6Carbocyclic ring ,-(CH₂)_n-C_3-6Carbocyclic ring or-(CH₂)_n- 5 to 6 circle heterocycles；Described CH₂, alkyl, carbocyclic ring or heterocycle be optionally further selected from F, Cl, Br, I ,=O, hydroxyl, C by 0 to 4_1-4Alkyl, C_1-4Alkoxy ,-CH₂- cyclopropyl, tertbutyloxycarbonyl ,-(CH₂)_n-OH、-(CH₂)_n- F ,-C (=O) C_1-4Alkyl ,-(CH₂)_n-C_3-6Carbocyclic ring or-(CH₂)_nThe substituent of -3 to 6 circle heterocycles is replaced, and is preferably further selected from F, hydroxyl, C by 0 to 4_1-4Alkyl or-C (=O) C_1-4The substituent of alkyl is replaced；The heterocycle contains 1 to 4 hetero atom for being selected from N, O or S；

R²Selected from H, F, Cl, C_1-4Alkyl or C_1-4Alkoxy, preferably H, F, Cl or C_1-4Alkoxy；

R³For H, C_2-4Alkenyl, C_3-4Cycloalkyl, C_1-4Alkyl or C_1-4Alkoxy, preferably H, C_1-4Alkyl or C_1-4Alkoxy；The alkoxy optionally further 0 to 4 substituent for being selected from F, Cl or Br is replaced；

R⁴Selected from H, F, Cl, 7 to 11 yuan of loop coils, 6 to 10 yuan and ring, 3 to 6 circle heterocycles ,-Z- (CH₂)_nR^4a、-Z-(CH₂)_nNR^4cR^4d、-O-(CH₂)_nR^4bOr-O- (CH₂)_nNR^4cR^4d, the heterocycle contain 1 to 4 be selected from N, O or S hetero atom, the CH₂, loop coil and ring or heterocycle be optionally further selected from F, Cl, Br, I, amino ,-NH (CH by 0 to 4₃)、-N(CH₃)₂, methyl or ethyl substituent replaced；

Z is selected from-NH- or-N (C_1-4Alkyl)-；

R^4aSelected from C_3-4Carbocyclic ring or 5 circle heterocycles, the heterocycle contain 1 to 4 hetero atom for being selected from N, O, S, and the carbocyclic ring or heterocycle are optionally further selected from F, Cl, Br, I, amino, hydroxyl ,-NHCH by 0 to 4₃、-N(CH₃)₂, methyl or ethyl substituent taken；

R^4bSelected from C_3-4Carbocyclic ring or 4 to 6 circle heterocycles, the heterocycle contain 1 to 4 hetero atom for being selected from N, O, S, and the carbocyclic ring or heterocycle are optionally further selected from F, Cl, Br, I, amino, hydroxyl ,-NH (CH by 0 to 4₃)、-N(CH₃)₂、-CH₂CH₂F, methyl or ethyl substituent are replaced；

R^4cAnd R^4dSelected from H, methyl or ethyl；

R⁵Selected from H, F, Cl or 5 to 6 circle heterocycles, the heterocycle contains 1 to 4 hetero atom for being selected from N, O, S, and described heterocycle is optionally further selected from F, Cl, Br, I ,=O ,-C (=O) C by 0 to 4_1-4Alkyl, C_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

N is selected from 0,1,2 or 3.

B is selected from It is preferred that OrFurther preferablyOr

R¹It is independently selected from F, Cl, Br, I ,-S (=O)₂CH₃,-C (=O)-cyclopropyl, hydroxyl, cyano group, methyl, ethyl, isopropyl, cyclopropyl ,-CH₂- cyclopropyl ,-CH (CH₃)-cyclopropyl, morpholinyl, piperazinyl, piperidyl or nafoxidine base, preferably H, F, Cl ,-S (=O)₂CH₃, methyl, ethyl, isopropyl, cyclopropyl ,-CH₂- cyclopropyl ,-CH₂(CH₃)-cyclopropyl ,-C (=O)-cyclopropyl, morpholinyl or piperazinyl；Described methyl, ethyl, morpholinyl, piperazinyl, piperidyl or nafoxidine base optionally further by 0 to 4 selected from F, Cl, Br, I ,=O, hydroxyl, Methyl, ethyl, methoxyl group, isopropyl, cyclopropyl ,-CH₂- cyclopropyl, ethoxy, 2- fluoro ethyls, tertbutyloxycarbonyl, oxetanylmethoxy ,-C (=O) CH₃Or-C (=O) CH₂CH₃Substituent replaced, preferably optionally further by 0 to 4 be selected from F, hydroxyl, methyl ,-CH₂- cyclopropyl, ethoxy, 2- fluoro ethyls, tertbutyloxycarbonyl or-C (=O) CH₃Substituent replaced；

R²Selected from H, F, Cl, methyl or methoxy, preferably H, F, Cl or methoxyl group；

R³Selected from H, methyl, ethyl, vinyl, cyclopropyl, methoxyl group, fluoro-methoxy, difluoro-methoxy or trifluoromethoxy, preferably H, ethyl, methoxyl group or difluoro-methoxy；

R⁴Selected from H, F, Cl, 7 to 11 yuan of loop coils, 3 to 6 circle heterocycles ,-Z- (CH₂)_nR^4a、-O-(CH₂)_nR^4b、-Z-(CH₂)_nNR^4cR^4dOr-O- (CH₂)_nNR^4cR^4d, preferably F, 7 to 11 yuan of loop coils, 3 to 6 circle heterocycles ,-Z- (CH₂)_nR^4a、-O-(CH₂)_nR^4b、-Z-(CH₂)_nNR^4cR^4dOr-O- (CH₂)_nNR^4cR^4d；The heterocycle contains 1 to 4 hetero atom for being selected from N, O or S, the CH₂, loop coil or heterocycle be optionally further selected from F, Cl, Br, I, methyl, ethyl or-N (CH by 0 to 4₃)₂Substituent replaced, preferably optionally further select the substituent of F or methyl to replace by 0 to 2；

Z is selected from-NH- or-N (CH₃)-；

R^4aSelected from substituted or unsubstituted cyclopropyl or nafoxidine base, when substituted, optionally further F, Cl, Br, I, amino, hydroxyl ,-NHCH are selected from by 1 to 4₃、-N(CH₃)₂, methyl or ethyl substituent replaced；

R^4bSelected from substituted or unsubstituted cyclopropyl,Nafoxidine base, piperazinyl, piperidyl or morpholinyl；When substituted, F, Cl, Br, I, amino, hydroxyl ,-NHCH further optionally are selected from by 1 to 4₃、-N(CH₃)₂、-CH₂CH₂F, methyl or ethyl substituent are replaced, and are preferably selected from amino or-CH by 1 to 4₂CH₂F substituent is replaced；

R^4cAnd R^4dSelected from H, methyl or ethyl, preferably H or methyl；

R⁵Selected from H, F, Cl or morpholinyl, preferably H, F or morpholinyl；

N is selected from 0,1,2 or 3.

B is selected fromIt is preferred that OrFurther preferablyOr

R¹It is independently selected from F, Cl ,-S (=O)₂CH₃, hydroxyl, cyano group, methyl, difluoromethyl, ethyl, -CH₂CH₂OH, isopropyl, cyclopropyl ,-CH₂- cyclopropyl, Morpholinyl, piperazinyl, piperidyl or nafoxidine base, preferably H, F, methyl, morpholinyl, piperazinyl,OrFurther preferred H, F, methyl or morpholinyl；

R³Selected from H, ethyl, methoxyl group or difluoro-methoxy, preferably H or methoxyl group；

R⁴Selected from H, F, Cl,

It is preferred that H,

R⁵Selected from H, F, Cl or morpholinyl, preferably H, F or morpholinyl；

F is selected from 0,1,2 or 3, preferably 0,1 or 2.

Preferred scheme of the present invention ,-B- (R¹)_fIt is selected from, but not limited to, one of following structure：

The present invention relates to the compound shown in a kind of logical formula (II) and its optical isomer, pharmaceutically acceptable salt or eutectic, wherein：

B is selected from 6 circle heterocycles, 7 circle heterocycles, 8 circle heterocycles, 9 circle heterocycles or 10 circle heterocycles, the heterocycle optionally further by 0,1,2,3 or 4 R¹Substitution, the hetero atom that described heterocycle contains 1,2,3 or 4 are selected from N, O, S；

R¹It is independently selected from H, F, Cl, Br, I, S (=O)₂-C_1-4Alkyl, C_1-4Alkyl, NR^1aR^1b,-C (=O) C_1-4Alkyl, the circle heterocycles of-C (=O) -3, the circle heterocycles of-C (=O) -4, the circle heterocycles of-C (=O) -5, the circle heterocycles of-C (=O) -6, the circle heterocycles of-C (=O) -7, C_1-4Alkoxy, C₃Carbocyclic ring, C₄Carbocyclic ring, C₅Carbocyclic ring, C₆Carbocyclic ring or 3 circle heterocycles, 4 circle heterocycles, 5 circle heterocycles, 6 circle heterocycles or 7 circle heterocycles, described alkyl, alkoxy, carbocyclic ring or heterocycle optionally further by 0,1,2,3 or 4 be selected from H, F, Cl, Br, I, (=O), C_1-4Alkyl, C_1-4Alkoxy ,-C (=O) C_1-4Alkyl, C₃Carbocyclic ring, C₄Carbocyclic ring, C₅Carbocyclic ring, C₆Carbocyclic ring or 3 circle heterocycles, 4 circle heterocycles, 5 circle heterocycles or 6 circle heterocycles substituents are replaced, the hetero atom that the heterocycle contains 1,2,3 or 4 are selected from N, O, S；

R^1aAnd R^1bSelected from H or C_1-4Alkyl；

R²Selected from H, F, Cl, Br, I, C_1-4Alkyl or C_1-4Alkoxy, described alkyl or alkoxy optionally further by 0,1,2,3 or 4 be selected from H, F, Cl, Br, I, C_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

R³For H, C_2-6Alkenyl, C₃Cycloalkyl, C₄Cycloalkyl, C₅Cycloalkyl, C₆Cycloalkyl, C_1-4Alkyl or C_1-4Alkoxy, the alkenyl, cycloalkyl, alkyl or alkoxy optionally further 0,1,2,3 or 4 be selected from H, F, Cl, Br, I, C_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

R⁴Selected from H, F, Cl, Br, I, 9 yuan of loop coils, Z- (CH₂)_nR^4a、O-(CH₂)_nR^4bOr O- (CH₂)_nNR^4cR^4d, The hetero atom that the loop coil contains 1,2,3 or 4 are selected from N, O, S, the loop coil optionally further by 0,1,2,3 or 4 be selected from H, F, Cl, Br, I, C_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

Alternatively, R is worked as⁴Selected from Z- (CH₂)_n- 6 circle heterocycles, 3 circle heterocycles, 4 circle heterocycles, 5 circle heterocycles, 6 circle heterocycles or N (CH₃)-(CH₂)_nNR^4cR^4dWhen, the heterocycle contains 1 to 4 hetero atom for being selected from N, O, S, and the heterocycle is optionally further by 0 to 4 H, F, Cl, Br, I, amino, C_1-4Alkyl or by 1 to 2 C_1-4The substituent of alkyl-substituted amino is replaced, other group definitions optionally one of following condition：

1)：R³Selected from ethyl or by 1, the C that 2 or 3 F, Cl, Br or I replace_1-4Alkyl,

2)：R²Selected from C_1-4Alkoxy or by 1, the C that 2 or 3 F, Cl, Br or I replace_1-4Alkoxy,

3)：B is selected from 6 circle heterocycles, 7 circle heterocycles, 8 circle heterocycles, 9 circle heterocycles or 10 circle heterocycles, the hetero atom that the heterocycle contains 1,2,3 or 4 are selected from N, O, S, the heterocycle optionally further by 1,2,3 or 4 be selected from H, F, Cl, Br, I, S (=O)₂-C_1-4Alkyl, C_1-4Alkyl, C_1-4Alkoxy, C₃Carbocyclic ring, C₄Carbocyclic ring, C₅Carbocyclic ring, C₆Carbocyclic ring, 3 circle heterocycles, 4 circle heterocycles, the substituent of 5 circle heterocycles or 6 circle heterocycles are replaced；

Z is selected from NH or N-C_1-4Alkyl；

R^4aSelected from C₃Carbocyclic ring, C₄Carbocyclic ring, C₅Carbocyclic ring, C₆Carbocyclic ring, 3 circle heterocycles, 4 circle heterocycles or 5 circle heterocycles, the hetero atom that the heterocycle contains 1,2,3 or 4 are selected from N, O, S, the carbocyclic ring or heterocycle optionally further by 0,1,2,3 or 4 be selected from H, F, Cl, Br, I, amino, C_1-4Alkyl or by 1 to 2 C_1-4The substituent of alkyl-substituted amino is replaced；

R^4bSelected from C₃Carbocyclic ring, C₄Carbocyclic ring, C₅Carbocyclic ring, C₆Carbocyclic ring, 3 circle heterocycles, 4 circle heterocycles, 5 circle heterocycles or 6 circle heterocycles, the hetero atom that the heterocycle contains 1,2,3 or 4 are selected from N, O, S, the carbocyclic ring or heterocycle optionally further by 0,1,2,3 or 4 be selected from H, F, Cl, Br, I, amino, C_1-4Alkyl or by 1 to 2 C_1-4The substituent of alkyl-substituted amino is replaced；

R^4cAnd R^4dSelected from H or C_1-4Alkyl；

R⁵Selected from H, F, Cl, Br, I ,-O-5 circle heterocycles ,-O-6 circle heterocycles ,-O-7 circle heterocycles, 5 circle heterocycles, 6 circle heterocycles or 7 circle heterocycles, the hetero atom that the heterocycle contains 1,2,3 or 4 are selected from N, O, S, described heterocycle optionally further by 0,1,2,3 or 4 be selected from H, F, Cl, Br, I, (=O) ,-C (=O) C_1-4Alkyl, C_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

Alternatively, R is worked as³And R⁴When being independently each H, R⁵Selected from 5 circle heterocycles or 6 circle heterocycles, the hetero atom that the heterocycle contains 1,2,3 or 4 are selected from N, O, S, described heterocycle optionally further by 0,1,2,3 or 4 be selected from H, F, Cl, Br, I, (=O) ,-C (=O) C_1-4Alkyl, C_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

N is selected from 0,1 or 2.

Preferred scheme of the present invention, compound and its optical isomer, pharmaceutically acceptable salt or eutectic shown in a kind of logical formula (II), wherein：

B is selected from 8 circle heterocycles, 9 circle heterocycles or 10 circle heterocycles, preferably 9 circle heterocycles, further preferred pyrido pyrazolyl or benzopyrrole base, the heterocycle optionally further by 0,1,2,3 or 4 R¹Substitution, the hetero atom that described heterocycle contains 1,2,3 or 4 are selected from N, O, S；

R¹It is independently selected from H, F, Cl, Br, I, S (=O)₂-C_1-4Alkyl, C_1-4Alkyl, NR^1aR^1b、C_1-4Alkoxy, C₃Carbocyclic ring, C₄Carbocyclic ring, C₅Carbocyclic ring, C₆Carbocyclic ring, 3 circle heterocycles, 4 circle heterocycles, 5 circle heterocycles or 6 circle heterocycles, preferably H, F, Cl, Br, I, S (=O)₂-C_1-4Alkyl, C_1-4Alkyl, C₅Carbocyclic ring, C₆Carbocyclic ring, 5 circle heterocycles or 6 circle heterocycles, further preferred H, F, Cl, Br, I, S (=O)₂-C_1-4Alkyl, C_1-4Alkyl, 5 circle heterocycles or 6 circle heterocycles, more preferably H, F, Cl, Br, I, S (=O)₂CH₃, methyl, isopropyl, cyclopropyl, morpholinyl, piperazinyl, piperidyl or nafoxidine base,

R^1aAnd R^1bSelected from H or C_1-4Alkyl；

Described alkyl, alkoxy, carbocyclic ring, heterocycle, methyl, morpholinyl, piperazinyl, piperidyl or nafoxidine base, optionally further by 0,1,2,3 or 4 be selected from H, F, Cl, Br, I, (=O), C_1-4Alkyl, C_1-4Alkoxy ,-C (=O) C_1-4Alkyl, C₃Carbocyclic ring, C₄Carbocyclic ring, C₅Carbocyclic ring, C₆Carbocyclic ring or 3 circle heterocycles, 4 circle heterocycles, 5 circle heterocycles or 6 circle heterocycles substituents are replaced, preferably by 0,1,2,3 or 4 be selected from H, F, Cl, Br, I, (=O), C_1-4Alkyl, C_1-4Alkoxy ,-C (=O) C_1-4Alkyl, C₃Carbocyclic ring, C₄Carbocyclic ring, C₅Carbocyclic ring, C₆Carbocyclic ring, 3 circle heterocycles, 4 circle heterocycles, the substituent of 5 circle heterocycles or 6 circle heterocycles are replaced, further preferably by 0,1,2,3 or 4 be selected from H, F, Cl, Br, I, (=O), methyl, methoxyl group, isopropyl, cyclopropyl ,-C (=O) CH₃Or-C (=O) CH₂CH₃Substituent replaced, the hetero atom that the heterocycle contains 1,2,3 or 4 are selected from N, O, S.

R⁴Selected from H, F, Cl, 9 yuan of loop coils, Z- (CH₂)_nR^4a、O-(CH₂)_nR^4bOr O- (CH₂)_nNR^4cR^4d, the hetero atom that the loop coil contains 1,2,3 or 4 are selected from N, O, S, the loop coil optionally further by 0,1,2,3 or 4 substituents selected from H, F, Cl, Br, I, methyl or ethyl replace；

Alternatively, R is worked as⁴Selected from Z- (CH₂)_n- 6 circle heterocycles, 3 circle heterocycles, 4 circle heterocycles, 5 circle heterocycles or 6 circle heterocycles or N (CH₃)-(CH₂)_nNR^4cR^4dWhen, the heterocycle contains 1 to 4 hetero atom for being selected from N, O, S, and the carbocyclic ring or heterocycle are optionally further selected from H, F, Cl, Br, I, amino, NHCH by 0 to 4₃、N(CH₃)₂, methyl or ethyl substituent replaced, other group definitions optionally one of following condition：

1)：R³Selected from ethyl or by 1, the C that 2 or 3 F, Cl, Br or I replace_1-4Alkyl, preferably by 1,2 or 3 The methyl of individual F substitutions,

2)：R²Selected from C_1-4Alkoxy or by 1, the C that 2 or 3 F, Cl, Br or I replace_1-4Alkoxy, preferably methoxyl group, fluoro-methoxy, difluoro-methoxy or trifluoromethoxy,

3)：B is selected from 9 circle heterocycles, the hetero atom that the heterocycle contains 1,2,3 or 4 are selected from N, O, S, the heterocycle optionally further by 1,2,3 or 4 be selected from H, F, Cl, Br, I, SO₂CH₃, methyl, the substituent of isopropyl or cyclopropyl replaced；

Z is selected from NH or NC_1-4Alkyl；

R^4aSelected from C₃Carbocyclic ring, C₄Carbocyclic ring or 5 circle heterocycles, preferably cyclopropyl or nafoxidine base, the hetero atom that the heterocycle contains 1,2,3 or 4 are selected from N, O, S, the carbocyclic ring or heterocycle optionally further by 0,1,2,3 or 4 be selected from H, F, Cl, Br, I, amino, NHCH₃、N(CH₃)₂, methyl or ethyl substituent taken；

R^4bSelected from C₃Carbocyclic ring, C₄Carbocyclic ring, 5 circle heterocycles or 6 circle heterocycles, it is preferred that cyclopropyl, nafoxidine base or piperazinyl, the hetero atom that the heterocycle contains 1,2,3 or 4 are selected from N, O, S, the carbocyclic ring or heterocycle optionally further by 0,1,2,3 or 4 be selected from H, F, Cl, Br, I, amino, NHCH₃、N(CH₃)₂, methyl or ethyl substituent replaced；

R^4cAnd R^4dSelected from H, methyl or ethyl.

B is selected from 8 circle heterocycles, 9 circle heterocycles or 10 circle heterocycles, the heterocycle optionally further by 0,1,2,3 or 4 R¹Substitution, the hetero atom that the heterocycle contains 1,2,3 or 4 are selected from N, O, S；

R¹It is independently selected from H, F, Cl, Br, I, C_1-4Alkyl, S (=O)₂-C_1-4Alkyl, C_3-6Carbocyclic ring, 5 circle heterocycles or 6 circle heterocycles, NR^1aR^1b,-C (=O) C_1-4Alkyl, the circle heterocycles of-C (=O) -3, the circle heterocycles of-C (=O) -4, the circle heterocycles of-C (=O) -5, the circle heterocycles of-C (=O) -6 or the circle heterocycles of-C (=O) -7, preferably H, F, Cl, Br, I, S (=O)₂-C_1-4Alkyl, C_1-4Alkyl or 5 circle heterocycles or 6 circle heterocycles；Described alkyl or heterocycle optionally further by 0,1,2,3 or 4 be selected from H, F, Cl, Br, I, (=O), C_1-4Alkyl, C_1-4Alkoxy ,-C (=O) C_1-4Alkyl, C3 carbocyclic rings, C4 carbocyclic rings, C5 carbocyclic rings, C6 carbocyclic rings, 3 circle heterocycles, 4 circle heterocycles, the substituent of 5 circle heterocycles or 6 circle heterocycles are replaced, the hetero atom that the heterocycle contains 1,2,3 or 4 are selected from N, O, S；

R^1aAnd R^1bSelected from H or C_1-4Alkyl；

R²Selected from H, F, Cl, C_1-4Alkyl or C_1-4Alkoxy；

R³For H, C_2-4Alkenyl, C_3-4Cycloalkyl, C_1-4Alkyl or C_1-4Alkoxy, the alkoxy optionally further 0,1,2,3 or 4 substituents for being selected from H, F, Cl or Br are replaced；

Z is selected from NH or NC_1-4Alkyl；

R^4aSelected from C₃Carbocyclic ring, C₄Carbocyclic ring or 5 circle heterocycles, the hetero atom that the heterocycle contains 1,2,3 or 4 are selected from N, O, S, the carbocyclic ring or heterocycle optionally further by 0,1,2,3 or 4 be selected from H, F, Cl, Br, I, amino, NHCH₃、N(CH₃)₂, methyl or ethyl substituent taken；

R^4bSelected from C₃Carbocyclic ring, C₄Carbocyclic ring, 5 circle heterocycles or 6 circle heterocycles, the hetero atom that the heterocycle contains 1,2,3 or 4 are selected from N, O, S, the carbocyclic ring or heterocycle optionally further by 0,1,2,3 or 4 be selected from H, F, Cl, Br, I, amino, NHCH₃、N(CH₃)₂, methyl or ethyl substituent replaced；

R^4cAnd R^4dSelected from H, methyl or ethyl；

R⁵Selected from H, F, Cl, 5 circle heterocycles, 6 circle heterocycles ,-O-5 circle heterocycles ,-O-6 circle heterocycles or-O-7 circle heterocycles, the hetero atom that the heterocycle contains 1,2,3 or 4 are selected from N, O, S, described heterocycle optionally further by 0,1,2,3 or 4 be selected from H, F, Cl, Br, I, (=O) ,-C (=O) C_1-4Alkyl, C_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

Alternatively, R is worked as³And R⁴When being independently each H, R⁵For 5 to 6 circle heterocycles, the hetero atom that the heterocycle contains 1,2,3 or 4 are selected from N, O, S, described heterocycle optionally further by 0,1,2,3 or 4 be selected from H, F, Cl, Br, I, (=O) ,-C (=O) C_1-4Alkyl, C_1-4Alkyl or C_1-4The substituent of alkoxy is replaced.

B is selected from 9 circle heterocycles, preferably pyrido pyrazolyl or benzopyrrole base, the heterocycle optionally further by 0,1,2, 3 or 4 R¹Substitution, the hetero atom that the heterocycle contains 1,2,3 or 4 are selected from N, O, S；

R¹It is independently selected from H, F, Cl, Br, I, methyl, S (=O)₂CH₃, isopropyl, cyclopropyl, NHCH₃、N(CH₃)₂、N(CH₃)(C₂H₅) ,-C (=O) C_1-4Alkyl,-C (=O)-ring propoxyl group,-C (=O)-cyclobutoxy group,-C (=O)-nafoxidine base,-C (=O)-morpholinyl,-C (=O)-piperazinyl,-C (=O)-piperidyl, the circle heterocycles of-C (=O) -7, morpholinyl, piperazinyl, piperidyl or nafoxidine base, preferably H, F, Cl, Br, I, S (=O)₂CH₃, methyl, isopropyl, cyclopropyl, morpholinyl, piperazinyl, piperidyl or nafoxidine；Described methyl, morpholinyl, piperazinyl, piperidyl or nafoxidine base optionally further by 0,1,2,3 or 4 be selected from H, F, Cl, Br, I, (=O), methyl, methoxyl group, isopropyl, cyclopropyl ,-C (=O) CH₃Or-C (=O) CH₂CH₃Substituent replaced；

R²Selected from H, F, Cl, methyl or methoxy；

R³Selected from H, methyl, ethyl, vinyl, cyclopropyl, methoxyl group, fluoro-methoxy, difluoro-methoxy or trifluoromethoxy, preferably H, methoxyl group, cyclopropyl or difluoro-methoxy；

Alternatively, R is worked as⁴Selected from Z- (CH₂)_n- 6 circle heterocycles, 3 circle heterocycles, 4 circle heterocycles, 5 circle heterocycles or 6 circle heterocycles or N (CH₃)-(CH₂)_nNR^4cR^4dWhen, the heterocycle contains 1 to 4 hetero atom for being selected from N, O, S, and the carbocyclic ring or heterocycle are optionally further selected from H, F, Cl, Br, I, amino, NHCH by 0 to 4₃、N(CH₃)₂, methyl or ethyl substituent taken, other group definitions optionally one of following condition：

1)：R³Selected from ethyl or by 1, the methyl that 2 or 3 F replace, preferably difluoro-methoxy,

2)：R²For methoxyl group, fluoro-methoxy, difluoro-methoxy or trifluoromethoxy, preferably methoxyl group,

3)：B is selected from 9 circle heterocycles, it is preferred that pyrido pyrazolyl or benzopyrrole base, the hetero atom that the heterocycle contains 1,2,3 or 4 are selected from N, O, S, the heterocycle, pyrido pyrazolyl or benzopyrrole base optionally further by 1,2,3 or 4 be selected from H, F, Cl, Br, I, SO₂CH₃, methyl, the substituent of isopropyl or cyclopropyl replaced；

Z is selected from NH or NCH₃；

R^4aSelected from substituted or unsubstituted cyclopropyl or nafoxidine base, when substituted, optionally further by 0,1,2,3 or 4 be selected from H, F, Cl, Br, I, amino, NHCH₃、N(CH₃)₂, methyl or ethyl substituent replaced；

R^4bSelected from substituted or unsubstituted cyclopropyl, nafoxidine base or piperazinyl, when substituted, optionally further by 0,1,2,3 or 4 be selected from H, F, Cl, Br, I, amino, NHCH₃、N(CH₃)₂, methyl or ethyl substituent replaced；

R^4cAnd R^4dSelected from H, methyl or ethyl；

R⁵Selected from H, F, Cl, morpholinyl, piperazinyl, piperidyl or nafoxidine base ,-O- nafoxidines base ,-O- piperazinyls ,-O- piperidyls ,-O- morpholinyls or-O-7 circle heterocycles, it is preferred that morpholinyl or piperazinyl, described morpholinyl, piperazinyl, piperidyl or nafoxidine base are optionally further selected from H, F, Cl, Br, I, (=O) ,-C (=O) CH by 0 to 4₃,-C (=O) CH₂CH₃, methyl, ethyl, the substituent of methoxyl group replaced；

Alternatively, R is worked as³And R⁴When being independently each H, R⁵For morpholinyl, piperazinyl, piperidyl or nafoxidine base, it is preferred that morpholinyl or piperazinyl, described morpholinyl, piperazinyl, piperidyl or nafoxidine base are optionally further selected from H, F, Cl, Br, I, (=O) ,-C (=O) CH by 0 to 4₃,-C (=O) CH₂CH₃, methyl, ethyl, the substituent of methoxyl group replaced.

Preferred scheme of the present invention, compound and its optical isomer, pharmaceutically acceptable salt or eutectic shown in a kind of logical formula (II), wherein

B is selected from one of substituted or unsubstituted following structure：When substituted optionally by 1 R¹Substitution；

R¹It is independently selected from H, F, Cl, S (=O)₂CH₃, isopropyl, cyclopropyl, morpholinyl, piperazinyl, piperidyl or nafoxidine；

R²Selected from H, F, Cl, methyl or methoxy；

R³Selected from H, methoxyl group or difluoro-methoxy；

R⁴Selected from one of H, F, Cl or following structure：

Alternatively, R is worked as⁴It is selected fromWhen, other group definitions optionally one of following condition：

1)：R³Selected from ethyl or by 1, the methyl that 2 or 3 F replace,

2)：R²For methoxyl group,

3)：B is selected fromOr by one of 1 F following structures replaced：

R⁵Selected from H, F, Cl, morpholinyl, piperazinyl, piperidyl or nafoxidine base；

Alternatively, R is worked as³And R⁴When being independently each H, R⁵For morpholinyl, piperazinyl, piperidyl or nafoxidine base.

Preferred scheme of the present invention, the compound described in a kind of logical formula (I) or logical formula (II), wherein compound is selected from, but not limited to, one of following structure：

The present invention relates to the compound shown in logical formula (I) or logical formula (II) and its optical isomer, pharmaceutically acceptable salt or eutectic, wherein described salt is selected from hydrochloride, sulfate, phosphate, acetate, trifluoroacetate, fumarate, benzoate, benzene sulfonate, mesylate, fluoroform sulphonate or combinations thereof.

The present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition contains compound and its optical isomer shown in the heretofore described any one for the treatment of effective dose, pharmaceutically acceptable salt or eutectic, and pharmaceutically acceptable carrier or excipient.

The invention further relates to the compounds of this invention and its optical isomer, pharmaceutically acceptable salt or eutectic, or pharmaceutical composition described above, the purposes in treating cancer related drugs are prepared.

Preferred scheme of the present invention, described cancer includes head and neck cancer, oophoroma, carcinoma of urinary bladder, cervical carcinoma, cancer of the esophagus, stomach cancer, breast cancer, endometrial carcinomas, colon cancer, lung cancer, brain tumor, non-small cell lung cancer, cancer of pancreas, entity tumor, colorectal carcinoma or glioblastoma.

The invention further relates to a kind of method for the treatment of cancer, methods described includes administration present invention compound indicated before or its optical isomer, pharmaceutically acceptable salt or eutectic, or pharmaceutical composition of the present invention.

Synthetic method

R⁶Selected from H, F, Cl, Br, I or OH,

B、f、R¹、R²、R³、R⁴Or R⁵Definition and logical formula (I) compound described in definition it is consistent；

If R⁴For H, F, Cl, Br or I, then R⁶With R⁴Identical, the nitro of formula (I-A) compound, which is reduced, obtains formula (I-B) compound, and described reducing agent is selected from H₂、Pt、Fe、Zn、LiAlH₄Or NaBH₄；

If R⁴For nitro, then：R in formula (I-A) compound⁶Formula (I-B`) compound is obtained for H and with nitrating agent (such as nitric acid) reaction, the nitro of formula (I-B`) compound, which is reduced, obtains formula (I-B) compound；

If R⁴For alkyl, then R in formula (I-A) compound⁶Formula (I-B`) compound is obtained for H and with the reaction such as grignard reagent or alkyl lithium reagents, the nitro of formula (I-B`) compound, which is reduced, obtains formula (I-B) compound；

Otherwise：Formula (I-A) compound and H-R⁴Reaction obtains formula (I-B`) compound in the presence of a base, the nitro of formula (I-B`) compound, which is reduced, obtains formula (I-B) compound, described alkali is selected from diisopropyl ethyl amine, diisopropylamine, triethylamine, potassium carbonate, sodium acid carbonate, sodium carbonate, sodium tert-butoxide, potassium tert-butoxide, potassium acetate, sodium acetate, sodium hydride or cesium carbonate etc., and described reducing agent is selected from H₂、Pt、Fe、Zn、LiAlH₄Or NaBH₄；

Formula (I-B) compound is reacted in the presence of a base with acryloyl halide (such as acryloyl chloride) or acrylic acid obtains logical formula (I) compound, and described alkali is selected from diisopropyl ethyl amine, diisopropylamine, triethylamine, potassium carbonate, sodium acid carbonate, sodium carbonate, sodium tert-butoxide, potassium tert-butoxide, potassium acetate, sodium acetate, sodium hydride or cesium carbonate etc.；

Formula (I-A) compound is by buying or being made with reference to literature methods such as WO2013014448.

Or,

R⁶Selected from H, F, Cl, Br, I or OH,

B、R¹、R²、R³、R⁴Or R⁵Definition and logical formula (II) compound described in definition it is consistent；

If R⁴For H, F, Cl, Br or I, then R⁶With R⁴Identical, the nitro of formula (I-A-1) compound, which is reduced, obtains formula (I-B-1) compound, and described reducing agent is selected from H₂、Pt、Fe、Zn、LiAlH₄Or NaBH₄；

If R⁴For nitro, then R in formula (I-A-1) compound⁶Formula (I-B`-1) compound is obtained for H and with nitrating agent (such as nitric acid) reaction；The nitro of formula (I-B`-1) compound, which is reduced, obtains formula (I-B-1) compound；

If R⁴For alkyl, then R in formula (I-A-1) compound⁶Formula (I-B`-1) compound is obtained for H and with the reaction such as grignard reagent or alkyl lithium reagents, the nitro of formula (I-B`-1) compound, which is reduced, obtains formula (I-B-1) compound；

Otherwise：Formula (I-A-1) compound and H-R⁴Reaction obtains formula (I-B`-1) compound in the presence of a base, the nitro of formula (I-B`-1) compound, which is reduced, obtains formula (I-B-1) compound, described alkali is selected from diisopropyl ethyl amine, diisopropylamine, triethylamine, potassium carbonate, sodium acid carbonate, sodium carbonate, sodium tert-butoxide, potassium tert-butoxide, potassium acetate, sodium acetate, sodium hydride or cesium carbonate etc., and described reducing agent is selected from H₂、Pt、Fe、Zn、LiAlH₄Or NaBH₄；

Formula (I-B-1) compound is reacted in the presence of a base with acryloyl halide (such as acryloyl chloride) or acrylic acid obtains logical formula (II) compound, and described alkali is selected from diisopropyl ethyl amine, diisopropylamine, triethylamine, potassium carbonate, sodium acid carbonate, sodium carbonate, sodium tert-butoxide, potassium tert-butoxide, potassium acetate, sodium acetate, sodium hydride or cesium carbonate etc.；

Formula (I-A-1) compound is by buying or being made with reference to literature methods such as WO2013014448.

Unless there are opposite statement, the term used in the specification and in the claims has following implications.

Involved carbon, hydrogen, oxygen, sulphur, nitrogen or halogen include their isotope in group of the present invention and compound, and involved carbon, hydrogen, oxygen, sulphur, nitrogen or halogen is optionally further substituted by their one or more corresponding isotopes in group of the present invention and compound, the isotope of wherein carbon includes¹²C、¹³C and¹⁴C, the isotope of hydrogen includes protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as superheavy hydrogen), and the isotope of oxygen includes¹⁶O、¹⁷O and¹⁸O, the isotope of sulphur includes³²S、³³S、³⁴S and³⁶S, the isotope of nitrogen includes¹⁴N and¹⁵N, the isotope of fluorine¹⁹F, the isotope of chlorine includes³⁵Cl and³⁷Cl, the isotope of bromine includes⁷⁹Br and⁸¹Br。

" alkyl " refers to the saturated aliphatic hydrocarbons group of straight chain and side chain, main chain includes 1 to 20 carbon atom, preferably 1 to 12 carbon atom, more preferably 1 to 8 carbon atom, more preferably 1 to 6 carbon atom, the straight chain and branched group of still further preferably 1 to 4 carbon atom, most preferably 1 to 2 carbon atom.The example of alkyl includes but is not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, 2- amyl groups, 3- amyl groups, 2- methyl -2- butyl, 3- methyl -2- butyl, 3- methyl isophthalic acids-butyl, 2-methyl-1-butene base, n-hexyl, 2- hexyls, 3- hexyls, 2- methyl -2- amyl groups, 3- methyl -2- amyl groups, 4- methyl -2- amyl groups, 3- methyl -3- amyl groups, 2- methyl -3- amyl groups, 2, 3- dimethyl -2- butyl, 3, 3- dimethyl -2- butyl, n-heptyl, 2- methylhexyls, 3- methylhexyls, 4- methylhexyls, 5- methylhexyls, 2, 2- dimethyl amyl groups, 2, 3- dimethyl amyl groups, 2, 4- dimethyl amyl groups, 3, 3- dimethyl amyl groups, 2- ethyl pentyl groups, 3- ethyl pentyl groups, n-octyl, 2, 2- dimethylhexanyls, 2, 3- dimethylhexanyls, 2, 4- dimethylhexanyls, 2, 5- dimethylhexanyls, 3, 3- dimethylhexanyls, 4, 4- dimethylhexanyls, 2- ethylhexyls, 3- ethylhexyls, 4- ethylhexyls, 2- first Base -2- ethyl pentyl groups, 2- methyl -3- ethyl pentyl groups, n-nonyl, 2- methyl -2- ethylhexyls and positive decyl etc..Alkyl can be substituted or unsubstituted, when substituted, substituent can be substituted on any workable tie point, and substituent is preferably selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano group, aryl, heteroaryl, heterocyclic radical, bridged ring base, loop coil base and ring group, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate ,-(CH₂)_r- C (=O)-R^a、-O-(CH₂)_r- C (=O)-R^a、-(CH₂)_r- C (=O)-NR^bR^c、-(CH₂)_rS (=O)_qR^a、-(CH₂)_r- alkenyl-R^a、OR^dOr-(CH₂)_r- alkynyl-R^a(wherein r, q are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR^bR^c, wherein R^bWith R^cIt is independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, sulfonyl or trifyl, it is alternatively that, R^bWith R^cFive or hexa-atomic cycloalkyl or Heterocyclylalkyl can be formed.R^aWith R^dIt is each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, Heterocyclylalkyl, carbonyl, ester group, bridged ring base, loop coil base or simultaneously ring group.

" alkylidene " refers to that abovementioned alkyl removes straight or branched alkane derived from two hydrogen atoms, including-(CH₂)_v- (v is 1 to 18 integer), alkylidene embodiment includes but is not limited to methylene, ethylidene and propylidene etc..Alkylidene can be substituted or unsubstituted, when substituted, substituent is preferably selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano group, aryl, heteroaryl, heterocyclic radical, bridged ring base, loop coil base and ring group, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate ,-(CH₂)_r- C (=O)-R^a、-O-(CH₂)_r- C (=O)-R^a、-(CH₂)_r- C (=O)-NR^bR^c、-(CH₂)_rS (=O)_qR^a、-(CH₂)_r- alkenyl-R^a、OR^dOr-(CH₂)_r- alkynyl-R^a(wherein r, q are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR^bR^c, wherein R^bWith R^cIt is independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, sulfonyl, trifyl, it is alternatively that, R^bWith R^cFive or hexa-atomic cycloalkyl or heterocyclic radical can be formed.R^aWith R^dIt is each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic radical, carbonyl, ester group, bridged ring base, loop coil base or simultaneously ring group.

" alkoxy " refers to-O- alkyl, the wherein for example hereinbefore definition of alkyl.Alkoxy can be substituted or unsubstituted, and alkoxy embodiment includes but is not limited to methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy and positive hexyloxy etc..When substituted, substituent is preferably 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano group, aryl, heteroaryl, heterocyclic radical, bridged ring base, loop coil base and ring group, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate-(CH₂)_r- C (=O)-R^a、-O-(CH₂)_r- C (=O)-R^a、-(CH₂)_r- C (=O)-NR^bR^c、-(CH₂)_rS (=O)_qR^a、-(CH₂)_r- alkenyl-R^a、OR^dOr-(CH₂)_r- alkynyl-R^a(wherein r, q are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR^bR^c, wherein R^bWith R^cIt is independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, sulfonyl, trifyl, it is alternatively that, R^bWith R^cFive or hexa-atomic cycloalkyl or heterocyclic radical, R can be formed^aWith R^dIt is each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic radical, carbonyl, ester group, bridged ring base, loop coil base or simultaneously ring group.

" alkenyl " refer at least composition containing carbon-to-carbon double bond such as the alkyl of hereinbefore definition, preferably comprise 2 to 20 carbon atoms, further preferred 2 to 12 carbon atoms more preferably have 2 to 8 carbon atoms on main chain, and alkenyl can be substituted or unsubstituted.Non-limiting example includes vinyl, pi-allyl, 1- acrylic, 2- acrylic, 1- cyclobutenyls, 2- cyclobutenyls, 3- cyclobutenyls, 1- pentenyls, 2- pentenyls, 3- pentenyls, 4- pentenyls, 1- methyl isophthalic acids-cyclobutenyl, 2-methyl-1-butene alkenyl, 2- methyl -3- cyclobutenyls, 1- hexenyls, 2- hexenyls, 3- hexenyls, 4- hexenyls, 5- hexenyls, 1- methyl-1-pentene alkenyls, 2- methyl-1-pentene alkenyls, 1- heptenyls, 2- heptenyls, 3- heptenyls, 4- heptenyls, 1- octenyls, 3- octenyls, 1- nonenyls, 3- nonenyls, 1- decene bases, 4- decene bases, 1, 3- butadiene, 1, 3- pentadienes, 1, 4- pentadienes, 1, 4- hexadienes, 3- hendecene bases, 4- laurylenes base and 4, 8, carbon trialkenyls of 12- 14 etc..When substituted, substituent is 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano group, aryl, heteroaryl, heterocyclic radical, bridged ring base, loop coil base and ring group, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate ,-(CH₂)_r- C (=O)-R^a、-O-(CH₂)_r- C (=O)-R^a、-(CH₂)_r- C (=O)-NR^bR^c、-(CH₂)_rS (=O)_qR^a、-(CH₂)_r- alkenyl-R^a、OR^dOr-(CH₂)_r- alkynyl-R^a(wherein r, q are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR^bR^c, wherein R^bWith R^cIt is independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, sulfonyl, trifyl, it is alternatively that, R^bWith R^cFive or hexa-atomic cycloalkyl or heterocyclic radical can be formed.R^aWith R^dIt is each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic radical, carbonyl, ester group, bridged ring base, loop coil base or simultaneously ring group.

" alkynyl " refers to, comprising at least one carbon-to-carbon triple bond composition such as alkyl of hereinbefore definition, preferably comprise 2 to 20 carbon atoms, further preferred 2 to 8 carbon atoms more preferably have the alkynyl of 2 to 4 carbon atoms on main chain.Alkynyl can be substituted or unsubstituted.Non-limiting example includes acetenyl, 1- propinyls, 2-propynyl, butynyl, 2- butynyls, 3- butynyls, 1- methyl -2-propynyl, 4- pentynyls, 3- pentynyls, 1- methyl -2- butynyls, 2- hexin bases, 3- hexin bases, 2- heptynyls, 3- heptynyls, 4- heptynyls, 3- octynyls, 3- n-heptylacetylenes base, 4- decynyls, 3- undecynes base and 4- dodecyne bases etc.；When substituted, substituent is preferably one or more following groups, independently selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano group, aryl, heteroaryl, heterocyclic radical, bridged ring base, loop coil base and ring group, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate ,-(CH₂)_r- C (=O)-R^a、-O-(CH₂)_r- C (=O)-R^a、-(CH₂)_r- C (=O)-NR^bR^c、-(CH₂)_rS (=O)_qR^a、-(CH₂)_r- alkenyl-R^a、OR^dOr-(CH₂)_r- alkynyl-R^a(wherein r, q are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR^bR^c, wherein R^bWith R^cBe independently selected from including H, hydroxyl, amino, carbonyl, Alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, sulfonyl, trifyl, it is alternatively that, R^bWith R^cFive or hexa-atomic cycloalkyl or heterocyclic radical can be formed.R^aWith R^dIt is each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic radical, carbonyl, ester group, bridged ring base, loop coil base or simultaneously ring group.

" alkylthio group " refers to-S- alkyl or-S- (unsubstituted cycloalkyl), and non-limiting example includes methyl mercapto, ethylmercapto group, rosickyite base and butylthio etc..

" amino " refers to-NH₂。

" acyl group " or " carbonyl " refers to-C (=O)-R^aGroup, wherein R^aIt is as defined above.

" aldehyde " refers to-C (=O)-H.

" thio " refers to=S.

" halogen " refers to fluorine, chlorine, bromine, iodine.

" hydroxyl " refers to-OH.

" cyano group " refers to-C ≡ N.

" isocyano group " refers to-N ≡ C.

" nitro " refers to-NO₂。

" carboxylic acid " refers to-C (=O)-OH.

" carboxylate " refers to-C (=O)-O-R^d, R^dSelected from alkyl, cycloalkyl or heterocyclic radical.

" sulfydryl " refers to-SH.

" mercaptan " refers to the hydrocarbon that one or more of alkyl hydrogen atom is replaced by sulfydryl, and non-limiting example includes methyl mercaptan, ethyl mercaptan, the mercaptan of 1,2- bis-.

" carbocyclic ring " refers to substituted or unsubstituted saturation or undersaturated aromatic rings or non-aromatic ring, aromatic rings or it is non-aromatic can be monocyclic, bicyclic, three rings or multi-loop system, non-limiting example includes cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclohexenyl group, suberyl, cyclopentene, cyclohexadiene, cycloheptatriene, phenyl, naphthyl, benzo cyclopenta, two rings [3.2.1] octyl, two rings [5.2.0] nonyl, three rings [5.3.1.1] dodecyl, adamantyl or spiral shell [3.3] heptane base etc..When substituted, substituent is independently selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano group, aryl, heteroaryl, heterocyclic radical, bridged ring base, loop coil base and ring group, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate ,-(CH₂)_r- C (=O)-R^a、-O-(CH₂)_r- C (=O)-R^a、-(CH₂)_r- C (=O)-NR^bR^c、-(CH₂)_rS (=O)_qR^a、-(CH₂)_r- alkenyl-R^a、OR^dOr-(CH₂)_r- alkynyl-R^a(wherein r, q are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR^bR^c, wherein R^bWith R^cIt is independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, sulfonyl, trifyl, it is alternatively that, R^bWith R^cFive or hexa-atomic cycloalkyl or heterocyclic radical can be formed. R^aWith R^dIt is each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic radical, carbonyl, ester group, bridged ring base, loop coil base or simultaneously ring group.

" heterocycle " refers to substituted or unsubstituted saturation or undersaturated aromatic rings, non-aromatic ring, and is constituted comprising at least one hetero atom for being selected from N, O, P or S, and N, S, the P selectively replaced in the ring of heterocycle can be oxidized to various oxidation state.Aromatic rings, non-aromatic ring can be monocyclic, it is bicyclic, three rings or multi-loop system, non-limiting example includes, oxirane, aziridinyl, oxetanyl, azetidinyl, 1, 3- dioxolanes, 1, 4- dioxolanes, 1, 3- dioxane, azacycloheptyl, pyridine radicals, furyl, thienyl, pyranose, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, piperidyl, piperazine stings base, morpholinyl, thio-morpholinyl, 1, 3- dithiane, dihydrofuran, dihydropyran, the ring of two thiophene penta, tetrahydrofuran, nafoxidine, imidazolidine, tetrahydro-thiazoles, oxinane, benzimidazole, benzo pyridine, pyrrolopyridine, coumaran, azabicyclic [3.2.1] octyl, azabicyclic [5.2.0] nonyl, oxatricyclo [5.3.1.1] dodecyl, azaadamantane base, oxa- spiroheptane base,Deng；When substituted, substituent is preferably 1 to 5, substituent independently selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano group, aryl, heteroaryl, heterocyclic radical, bridged ring base, loop coil base and ring group, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate ,-(CH2)_r- C (=O)-R^a、-O-(CH2)_r- C (=O)-R^a、-(CH2)_r- C (=O)-NR^bR^c、-(CH2)_rS (=O)_qR^a、-(CH2)_r- alkenyl-R^a、OR^dOr-(CH2)_r- alkynyl-R^a(wherein r, q are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR^bR^c, wherein R^bWith R^cIt is independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, sulfonyl, trifyl, it is alternatively that, R^bWith R^cFive or hexa-atomic cycloalkyl or heterocyclic radical can be formed.R^aWith R^dIt is each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic radical, carbonyl, ester group, bridged ring base, loop coil base or simultaneously ring group.

" cycloalkyl " refers to saturation or undersaturated monocyclic cycloalkyl, can be substituted or unsubstituted, ring carbon atom includes 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, further preferred 3 to 8 carbon atoms, non-limiting reality Applying example includes cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl, cyclopropanyl, cyclobutane base, cyclopentenyl, cyclohexenyl group, cycloheptenyl, 1,5- cyclo-octadiene base, 1,4- cyclohexadienyls and cycloheptatriene base etc..When substituted, substituent is 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano group, aryl, heteroaryl, heterocyclic radical, bridged ring base, loop coil base and ring group, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate ,-(CH₂)_r- C (=O)-R^a、-O-(CH₂)_r- C (=O)-R^a、-(CH₂)_r- C (=O)-NR^bR^c、-(CH₂)_rS (=O)_qR^a、-(CH₂)_r- alkenyl-R^a、OR^dOr-(CH₂)_r- alkynyl-R^a(wherein r, q are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR^bR^c, wherein R^bWith R^cIt is independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, sulfonyl, trifyl, it is alternatively that, R^bWith R^cFive or hexa-atomic cycloalkyl or heterocyclic radical can be formed.R^aWith R^dIt is each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic radical, carbonyl, ester group, bridged ring base, loop coil base or simultaneously ring group.

" loop coil " refer to it is substituted or unsubstituted it is monocyclic between share 5 to 20 yuan of polycyclic moieties of a carbon atom (title spiro-atom), it can be selected from N, O, P or S (=O) comprising 0 to 5 double bond containing 0 to 5_nHetero atom (n be 0,1 or 2).Preferably 6 to 14 yuan, more preferably 6 to 12 yuan, 6 to 10 yuan are more selected, its non-limiting example includesWhen substituted, substituent is 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano group, aryl, heteroaryl, heterocyclic radical, bridged ring base, loop coil base and ring group, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate ,-(CH₂)_r- C (=O)-R^a、-O-(CH₂)_r- C (=O)-R^a、-(CH₂)_r- C (=O)-NR^bR^c、-(CH₂)_rS (=O)_qR^a、-(CH₂)_r- alkenyl-R^a、OR^dOr-(CH₂)_r- alkynyl-R^a(wherein r, q are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR^bR^c, wherein R^bWith R^cIt is independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, sulfonyl, trifyl, it is alternatively that, R^bWith R^cFive or hexa-atomic cycloalkyl or heterocyclic radical can be formed.R^aWith R^dIt is each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic radical, carbonyl, ester group, bridged ring base, loop coil base or simultaneously ring group.

" and ring " refers to the polycyclic moiety of each ring and shared a pair of the carbon atoms adjoined of other rings in system in system, and wherein one or more rings can contain 0 or multiple double bonds, and can be substitutions or unsubstituted, and in member ring systems Each ring can contain 0 to 5 and be selected from N, S (=O)_nOr O hetero atom.Preferably 5 to 20 yuan, more preferably 5 to 14 yuan, more select 5 to 12 yuan, still further preferably 5 to 10 yuan.Non-limiting example includes When substituted, substituent is 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano group, aryl, heteroaryl, heterocyclic radical, bridged ring base, loop coil base and ring group, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate ,-(CH₂)_r- C (=O)-R^a、-O-(CH₂)_r- C (=O)-R^a、-(CH₂)_r- C (=O)-NR^bR^c、-(CH₂)_rS (=O)_qR^a、-(CH₂)_r- alkenyl-R^a、OR^dOr-(CH₂)_r- alkynyl-R^a(wherein r, q are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR^bR^c, wherein R^bWith R^cIt is independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, sulfonyl, trifyl, it is alternatively that, R^bWith R^cFive or hexa-atomic cycloalkyl or heterocyclic radical can be formed.R^aWith R^dIt is each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic radical, carbonyl, ester group, bridged ring base, loop coil base or simultaneously ring group.

" bridged ring " refers to the polycyclic moiety for the carbon atom that any two is not directly connected, and can contain 0 or multiple double bonds, and can be substituted or unsubstituted, and any ring in member ring systems can contain 0 to 5 and be selected from N, S (=O)_nOr O hetero atoms or group (wherein n is 1,1,2).Annular atom includes 5 to 20 atoms, preferably 5 to 14 atoms, further preferred 5 to 12, at further preferred 5 to 10.Non-limiting example includesAnd adamantane.When substituted, substituent is 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano group, aryl, heteroaryl, heterocyclic radical, bridged ring base, loop coil base and ring group, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate ,-(CH₂)_r- C (=O)-R^a、-O-(CH₂)_r- C (=O)-R^a、-(CH₂)_r- C (=O)-NR^bR^c、-(CH₂)_rS (=O)_qR^a、-(CH₂)_r- alkenyl-R^a、OR^dOr -(CH₂)_r- alkynyl-R^a(wherein r, q are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR^bR^c, wherein R^bWith R^cIt is independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, sulfonyl, trifyl, it is alternatively that, R^bWith R^cFive or hexa-atomic cycloalkyl or heterocyclic radical can be formed.R^aWith R^dIt is each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic radical, carbonyl, ester group, bridged ring base, loop coil base or simultaneously ring group.

" benzyl " refers to-CH₂- phenyl, the phenyl is substituted or unsubstituted, and its non-limiting example includes-CH₂- phenyl ,-CH₂- p-methylphenyl etc..

" aryl " refers to substituted or unsubstituted 6 to 14 yuan of cyclic aromatic groups, including mono-cyclic aromatic base and polycyclic aromatic base.It is preferred that 6 to 14 yuan of aromatic rings, further preferred 6 to 10 yuan of aromatic rings, its non-limiting examples include phenyl, naphthyl, anthryl and phenanthryl etc..The aryl rings can be condensed on heteroaryl, heterocyclic radical or cycloalkyl ring, wherein the ring linked together with precursor structure is aryl rings, non-limiting example is included：

When substituted, substituent is 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano group, aryl, heteroaryl, heterocyclic radical, bridged ring base, loop coil base and ring group, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate ,-(CH₂)_r- C (=O)-R^a、-O-(CH₂)_r- C (=O)-R^a、-(CH₂)_r- C (=O)-NR^bR^c、-(CH₂)_rS (=O)_qR^a、-(CH₂)_r- alkenyl-R^a、OR^dOr-(CH₂)_r- alkynyl-R^a(wherein r, q are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR^bR^c, wherein R^bWith R^cIt is independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, sulfonyl, trifyl, it is alternatively that, R^bWith R^cFive or hexa-atomic cycloalkyl or heterocyclic radical can be formed.R^aWith R^dIt is each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic radical, carbonyl, ester group, bridged ring base, loop coil base and ring group.

" heteroaryl " refers to substituted or unsubstituted 5 to 14 yuan of aromatic rings, and is selected from N, O or S (=O) containing 1 to 5_nHetero atom or group, preferably 5 to 10 yuan miscellaneous aromatic rings, further preferred 5 to 6 yuan.The non-limiting example of heteroaryl includes but is not limited to pyridine radicals, furyl, thienyl, pyridine radicals, pyranose, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, piperidyl, morpholine, thiomorpholine, 1,3- dithiane, benzimidazole, piperazine and stings base, benzimidazole, benzo pyridine, pyrrolopyridine etc..The heteroaryl ring can be condensed on aryl, heterocyclic radical or cycloalkyl ring, wherein the ring linked together with precursor structure is heteroaryl ring, non-limiting example is included

When substituted, substituent is 1 to 5 selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxyl, nitro, sulfydryl, amino, cyano group, isocyano group, aryl, heteroaryl, heterocyclic radical, bridged ring base, loop coil base and ring group, hydroxy alkyl ,=O, carbonyl, aldehyde, carboxylic acid, carboxylate ,-(CH₂)_r- C (=O)-R^a、-O-(CH₂)_r- C (=O)-R^a、-(CH₂)_r- C (=O)-NR^bR^c、-(CH₂)_rS (=O)_qR^a、-(CH₂)_r- alkenyl-R^a、OR^dOr-(CH₂)_r- alkynyl-R^a(wherein r, q are 0,1 or 2), artyl sulfo, thiocarbonyl, silylation or-NR^bR^c, wherein R^bWith R^cIt is independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, sulfonyl, trifyl, it is alternatively that, R^bWith R^cFive or hexa-atomic cycloalkyl or heterocyclic radical can be formed.R^aWith R^dIt is each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic radical, carbonyl, ester group, bridged ring base, loop coil base or simultaneously ring group.

" artyl sulfo " refers to-S- aryl or-S- heteroaryls as defined herein.Artyl sulfo example includes but is not limited to thiophenyl, pyridinylthio, furyl sulfenyl, thienyl sulfenyl, pyrimidine-based sulfur-base etc..

" silylation " refers to that one or more of silicomethane hydrogen atom is replaced formed group by alkyl, and embodiment includes but is not limited to trimethyl silicon substrate, triethyl group silicon substrate, t-Butyldimethylsilyl and tert-butyl diphenyl silicon substrate etc..

" optional " or " optionally " refer to event described later or environment can with but necessarily occur, the explanation includes the occasion that the event or environment occur or do not occurred.Such as：" alkyl optionally replaced by F " refer to alkyl can with but necessarily replaced by F, illustrate to include the situation that alkyl is not replaced by the F situations replaced and alkyl by F.

" pharmaceutically acceptable salt " or " its pharmaceutically acceptable salt " refers to keeping the biological effectiveness and characteristic of free acid or free alkali, and described free acid by with nontoxic inorganic base or organic base, or described free acid passes through those salt with nontoxic inorganic acid or organic acid reaction acquisition, including alkali metal salt, such as sodium salt, sylvite, lithium salts；Alkali salt, such as calcium salt, magnesium salts；Other metal salts, such as molysite, mantoquita, cobalt salt；Organic alkali salt, such as ammonium salt, triethylamine salt, pyridiniujm, picoline salt, 2, 6- lutidines salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, ethylenediamine salt, guanidinesalt, isopropyl amine salt, trismethylamine salt, tripropyl amine salt, triethanolamine salt, diethanolamine salt, ethanolamine salt, dimethyl ethanol amine salt, dicyclohexyl amine salt, coffee alkali salt, procaine salt, choline salt, beet alkali salt, Benethamine Penicillin salt, glucose amine salt, N-METHYL-ALPHA-L-GLUCOSAMINE salt, cocoa alkali salt, amino butanetriol salt, purine salt, piperazine salt, alkylbenzyldimethylasaltsum saltsum, piperidinium salt, N-ethylpiperidine salt, tetramethyl amine salt, dibenzyl amine salt and phenylglycine alkyl ester salt etc.；Halogen acid salt, such as hydrofluoride, hydrochloride, hydriodate, hydrobromate；Inorganic acid salt, such as hydrochloride, nitrate, sulfate, perchlorate, phosphate；Rudimentary alkyl sulfonate, such as mesylate, fluoroform sulphonate, esilate；Arylsulphonate, such as benzene sulfonate, tosilate；Acylate, such as acetate, benzoate, fumarate, formates, trifluoroacetate, furoate, gluconate, glutamic acid Salt, glycollate, isethionate, lactate, maleate, malate, mandelate, mucus hydrochlorate, embonate, pantothenate, stearate, succinate, sulfanilate, tartrate, malonate, 2 hydroxy propanoic acid salt, citrate, salicylate, oxalates, oxyacetate, glucuronate salt, galacturonic hydrochlorate, citrate, lysine salt, arginine salt, aspartate, cinnamate etc..

" pharmaceutical composition " represents compound described in one or more texts or its physiology/pharmaceutically acceptable salt and the mixture of other constituents, wherein other components include physiology/pharmaceutically acceptable carrier and excipient.

" carrier " refers to that obvious stimulation will not be produced to organism and will not eliminate the bioactivity of given compound and the carrier of characteristic or diluent.

" excipient " refers to being added in pharmaceutical composition further relying on the inert substance of compound administration.The example of excipient includes but is not limited to calcium carbonate, calcium phosphate, various sugared and different types of starch, cellulose derivative (including microcrystalline cellulose), gelatin, vegetable oil, polyethylene glycols, diluent, granulating agent, lubricant, adhesive, disintegrant etc..

" prodrug " refers to that the compound of the compounds of this invention with bioactivity can be converted into physiological conditions or by solvolysis.The prodrug of the present invention is prepared by modifying the group of the phenolic group in the compound, operation or be removed in vivo that the modification can be routinely, and obtains parent compound.When the pro-drug of the present invention is delivered to mammalian subject, pro-drug is isolated and forms free hydroxyl respectively.The example of prodrug includes, but are not limited to the phenolic hydroxyl group of the compounds of this invention and phosphoric acid into sodium salt derivative.

" eutectic " or " eutectic " refers to active pharmaceutical ingredient (active pharmaceutical ingredient,) and eutectic formation (cocrystal former API, CCF) the crystal being combined into the presence of hydrogen bond or other non-covalent bonds, wherein API and CCF pure state is the presence of fixed stoichiometric proportion between solid, and each component at room temperature.Eutectic is a kind of multicomponent crystal, both comprising the binary eutectic formed between two kinds of neutral solids, also the multi-element eutectic comprising neutral solid and the formation of salt or solvate." the eutectic formation " includes but is not limited to various pharmaceutically acceptable acid, alkali, non-ionic compound, water, amino acid, alcohol or other solvents, its non-limiting examples include alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), proline (Pro), phenylalanine (Phe), tryptophan (Trp), methionine (Met), glycine (Gly), serine (Ser), threonine (Thr), cysteine (Cys), tyrosine (Tyr), asparagine (Asn), glutamine (Gln), lysine (Lys), arginine (Arg), histidine (His), aspartic acid (Asp), glutamic acid (Glu), pyroglutamic acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzene sulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, vinyl sulfonic acid, formic acid, fumaric acid, furancarboxylic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, stearic acid, butanedioic acid, sulfanilic acid, tartaric acid, p-methyl benzenesulfonic acid, malonic acid, 2 hydroxy propanoic acid, oxalic acid, glycolic, glucuronic acid, galacturonic acid, Chinese holly Rafter acid, lysine, arginine, L-aminobutanedioic acid, cinnamic acid, p-methyl benzenesulfonic acid, methanesulfonic acid, ethyl sulfonic acid or trifluoromethanesulfonic acid, ammonia, isopropylamine, Trimethylamine, diethylamine, triethylamine, tripropylamine, diethanol amine, monoethanolamine, triethanolamine, dimethylethanolamine, DMAE, 2- DEAE diethylaminoethanols, dicyclohexylamine, caffeine, procaine, choline, glycine betaine, Benethamine Penicillin, ethylenediamine, gucosamine, methylglucosamine, theobromine, tromethamine, purine, piperazine, piperidines, N-ethylpiperidine, methanol, ethanol, butynediols, 1, 2- propane diols, (R) 1, 2- propane diols, (S) 1, 2- propane diols or 1- methyl isophthalic acids, 2- ethylene glycol.

" effective dose " has guided the amount of the compound of tissue, system or subject physiologic or medical science translation, this amount is sought, is included in the one or more of symptoms generation for being enough to prevent treated illness or illness when being applied with subject or it is mitigated to the amount of compound to a certain degree.

" solvate " refers to the compounds of this invention or its salt, and they also include the stoichiometry combined with non-covalent intermolecular forces or non-stoichiometric solvent.Then it is hydrate when solvent is water.

“IC₅₀" refer to half-inhibition concentration, refer to concentration when reaching maximum suppression effect half.

Embodiment

Technical scheme is described in detail below in conjunction with drawings and Examples, but protection scope of the present invention includes but is not limited to this.

The structure of compound by nuclear magnetic resonance (NMR) or (and) mass spectrum (MS) determines.NMR displacements (δ) are with 10^-6(ppm) unit is provided.NMR measure is to use (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic resonance spectrometer, and measure solvent is deuterated dimethyl sulfoxide (DMSO-d₆), deuterochloroform (CDCl₃), deuterated methanol (CD₃OD), inside it is designated as tetramethylsilane (TMS).

MS measure uses (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

HPLC measure uses Agilent 1260DAD high pressure liquid chromatographs (100 × 4.6mm of Zorbax SB-C18).

Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, and the specification that the silica gel plate that thin-layered chromatography (TLC) is used is used is 0.15mm~0.20mm, and the specification that thin-layer chromatography isolates and purifies product use is 0.4mm~0.5mm.

Column chromatography is carrier typically using the mesh silica gel of Yantai Huanghai Sea silica gel 200~300.

Oneself initiation material known of the present invention can be used or synthesized according to methods known in the art, or be can purchase in the smooth science and technology of Thailand, pacified the companies such as silent resistance to Jilin Chemical, Shanghai moral, the imperial chemical industry of Chengdu section, splendid remote chemistry science and technology, lark prestige science and technology.

Blanket of nitrogen refers to that reaction bulb connects the nitrogen balloon of an about 1L volume.

Nitrogen atmosphere refers to that reaction bulb connects the hydrogen balloon of an about 1L volume.

Hydrogenation is generally vacuumized, and is filled with hydrogen, is operated 3 times repeatedly.

Without specified otherwise in embodiment, reaction is carried out under nitrogen atmosphere.

Without specified otherwise in embodiment, solution refers to the aqueous solution.

Without specified otherwise in embodiment, the temperature of reaction is room temperature.

Room temperature is optimum reaction temperature, is 20 DEG C~30 DEG C.

Boc:Tertbutyloxycarbonyl；

n-Bu:Normal-butyl；

t-Bu:The tert-butyl group；

TBS:T-Butyldimethylsilyl；

TIPS:Triisopropylsilyl.

Intermediate 1

5- (difluoro-methoxy)-N¹- (2- (dimethylamino) ethyl)-N¹- methyl -2- nitrobenzene -1,4- diamines (intermediate 1)

5-(difluoromethoxy)-N¹-(2-(dimethylamino)ethyl)-N¹-methyl-2-nitrobenzene-1,4-diamine

The first step：(4- fluoro-2-hydroxyphenyls) t-butyl carbamate (1b)

tert-butyl(4-fluoro-2-hydroxyphenyl)carbamate

Added into reaction bulb after 2- amino-5-fluorine phenol 1a (5g, 39.4mmol) and tetrahydrofuran (100mL), stirring and dissolving, add di-tert-butyl dicarbonate (17.2g, 78.7mmol), reaction two days is stirred at room temperature.It is concentrated under reduced pressure into dry, water (150mL) is added into residue, ethyl acetate (200mL), stirring point liquid, water layer is extracted with ethyl acetate (150mL × 2), merges organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, residue silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=20:1) off-white powder (4- fluoro-2-hydroxyphenyls) t-butyl carbamate (1b) (6g, yield 67%) is obtained.

¹H NMR(400MHz,CDCl₃)δ8.55(s,1H),6.95(dd,1H),6.69(dd,1H),6.56(ddd,2H),1.52(s,9H)。

Second step：(2- (difluoro-methoxy) -4- fluorophenyls) t-butyl carbamate (1c)

tert-butyl(2-(difluoromethoxy)-4-fluorophenyl)carbamate

(4- fluoro-2-hydroxyphenyls) t-butyl carbamate (1b) (4g is added into reaction bulb, 17.6mmol) with acetonitrile (40mL), ice bath is cooled down, add potassium hydroxide (19.7g, water (40mL) solution 352mmol), is cooled to -78 DEG C, and bromine methyl fluoride diethyl phosphate (11.8g is added dropwise, 44.1mmol), drip off and be warmed to room temperature reaction 30 minutes.Ethyl acetate (100mL) is added into reaction solution, stirring point liquid, water layer is extracted with ethyl acetate (50mL × 2), merge organic phase, organic phase anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, residue silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=20:1) yellow liquid (2- (difluoro-methoxy) -4- fluorophenyls) t-butyl carbamate (1c) (3g, yield 61%) is obtained.

¹H NMR(400MHz,CDCl₃)δ8.09(t,1H),6.95-6.83(m,2H),6.72(s,1H),6.52(t,1H),1.52(s,9H)。

3rd step：The fluoro- 5- nitroanilines (1d) of 2- (difluoro-methoxy) -4-

2-(difluoromethoxy)-4-fluoro-5-nitroaniline

The concentrated sulfuric acid (10mL) and water (0.7mL) are added into reaction bulb, ice bath is cooled down, add (2- (difluoro-methoxy) -4- fluorophenyls) t-butyl carbamate (1c) (2.7g, 9.8mmol), add stirring 10 minutes, potassium nitrate (0.98g, 9.8mmol) is slowly added to, ice bath is added and reacts 1 hour.Reaction solution is poured into frozen water (50mL), ice bath is cooled down, with ammoniacal liquor regulation system pH value to 9, extracted with ethyl acetate (50mL × 3), merge organic phase, organic phase anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, residue silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=20:1-10:1) the fluoro- 5- nitroanilines (1d) (370mg, yield 17%) of brown solid 2- (difluoro-methoxy) -4- are obtained.

¹H NMR(400MHz,DMSO-d₆)δ7.50(d,1H),7.32(s,1H),7.29(t,1H),6.52(t,1H),5.59(s,2H)。

4th step：5- (difluoro-methoxy)-N¹- (2- (dimethylamino) ethyl)-N¹- methyl -2- nitrobenzene -1,4- diamines (intermediate 1)

Fluoro- 5- nitroanilines (the 1d) (250mg of 2- (difluoro-methoxy) -4- are added into reaction bulb, 1.15mmol), N, N, N'- trimethyls ethylenediamine (18A) (118mg, 1.15mmol), diisopropyl ethyl amine (375mg, 2.9mmol) and N, N'- dimethyl acetamide (5mL), 140 DEG C of microwave reacts 1 hour.Reaction solution is concentrated under reduced pressure into dry, residue silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=50:1) brown oil 5- (difluoro-methoxy)-N is obtained¹- (2- (dimethylamino) ethyl)-N¹- methyl -2- nitrobenzene-Isosorbide-5-Nitrae-diamines (intermediate 1) (120mg, yield 34%).

MS m/z(ESI):305.3[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ7.25(t,1H),7.13(d,2H),5.40(s,2H),3.08(t,2H),2.67(t,2H),2.63(s,3H),2.39(s,6H)。

Intermediate 2

3- (2- chlorine pyrimidine-4-yl) -1- Methyl-1H-indoles (intermediate 2)

3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole

The first step：3- (2- chlorine pyrimidine-4-yl) -1H- indoles (2b)

3-(2-chloropyrimidin-4-yl)-1H-indole

Added into reaction bulb after indoles (4g, 34.1mmol) and 1,2- dichloroethanes (114mL), stirring and dissolving, 3mol/L methyl-magnesium-bromides tetrahydrofuran solution (11.4mL, 34.1mmol) is added dropwise in ice bath cooling.Drip off insulation reaction 15 minutes, add 2,4- dichloro pyrimidines (2a) (5.6g, 37.6mmol), be slowly increased to room temperature reaction 3 hours.Ice bath cools down reaction solution, and methanol (10mL) is added dropwise, and stirs 15 minutes, is concentrated under reduced pressure, residue silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=4:1-2:1) yellow solid 3- (2- chlorine pyrimidine-4-yl) -1H- indoles (2b) (2.9g, yield 37%) is obtained.

MS m/z(ESI):230.1[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ12.07(s,1H),8.58–8.47(m,2H),8.47–8.36(m,1H),7.91(d,1H),7.51(dd,1H),7.31–7.15(m,2H)。

Second step：3- (2- chlorine pyrimidine-4-yl) -1- Methyl-1H-indoles (intermediate 2)

3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole

3- (2- chlorine pyrimidine-4-yl) -1H- indoles (2b) (2.5g is added into reaction bulb, 10.9mmol) with tetrahydrofuran (77mL), after stirring and dissolving, ice bath is cooled down, and sodium hydride (0.48g, 12mmol) is added portionwise, add insulation reaction 30 minutes, iodomethane (0.75mL, 12mmol) is added dropwise, insulation reaction is dripped off 2 hours.Saturated sodium bicarbonate aqueous solution (100mL) is added into reaction solution, ethyl acetate (200mL), stirring point liquid, organic layer is washed with saturated sodium bicarbonate aqueous solution (50mL × 1) and saturated aqueous common salt (50mL × 1) successively, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, residue is beaten (10mL × 1) with dichloromethane, obtain faint yellow solid 3- (2- chlorine pyrimidine-4-yl) -1- Methyl-1H-indoles (intermediate 2) (2.3g, yield 85%).

MS m/z(ESI):244.1[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ8.45(d,1H),8.32(dd,1H),7.98(s,1H),7.51(d,1H),7.45–7.30(m,3H),3.90(s,3H)。

Intermediate 3

5- ((4- (1- methyl indol -3- bases) pyrimidine -2-base) amino) fluoro- 1- nitrobenzene (intermediate 3) of -4- methoxyl groups -2-

5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitrobenzene

Prepared with reference to the synthetic method of WO2013014448 intermediates 129.

Intermediate 4

The chloro- N- of 5- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (intermediate 4)

5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

The first step：3- (2,5- dichloro pyrimidine -4- bases) -1H- indoles (4b)

3-(2,5-dichloropyrimidin-4-yl)-1H-indole

By indoles 4a (12.78g; 109mmol) it is dissolved in tetrahydrofuran (60mL); under nitrogen protection, 0 DEG C is cooled to, methyl-magnesium-bromide (36.4mL is added dropwise; 109mmol); continue to stir 0.5 hour, add trichloropyrimidine (10g, 54.5mmol); react at room temperature 1 hour, then 60 DEG C are reacted 1.5 hours.Reaction solution is cooled to room temperature, acetic acid (6.34mL) is added dropwise, stirring 10 minutes, add (100mL) water and tetrahydrofuran (30mL), 60 DEG C are stirred 30 minutes, divide liquid, normal heptane (100mL) is added in organic phase, separate out yellow solid, filtering, filter cake is washed with normal heptane (100mL), and dry cake obtains yellow solid 3- (2,5- dichloro pyrimidine -4- bases) -1H- indoles (4b) (13g, yield 91%).

MS m/z:264.0[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ12.26(s,1H),8.73(s,2H),8.53(s,1H),7.57(s,1H), 7.28(s,2H)。

Second step：3- (2,5- dichloro pyrimidine -4- bases) -1- Methyl-1H-indoles (4c)

3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-indole

By 3- (2,5- dichloro pyrimidine -4- bases) -1H- indoles (4b) (6g, 22.8mmol) it is dissolved in tetrahydrofuran (100mL), 0 DEG C is cooled to, sodium hydride (1.1g, 27.4mmol) is added, continue to react 30 minutes, iodomethane (4.26mL, 68.4mmol) is added, reaction 2 hours is warmed to room temperature.Reaction solution is concentrated, residue is washed with water (50mL) and tetrahydrofuran (50mL), filtering, filtration cakes torrefaction obtains compound 3- (2,5- dichloro pyrimidine -4- bases) -1- Methyl-1H-indoles (4c), yellow solid (4.7g, yield 75%).

MS m/z:278.0[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ8.75(d,2H),8.55(d,1H),7.61(d,1H),7.43–7.22(m,2H),3.96(s,3H)。

3rd step：The fluoro- 2- methoxyl groups -5- nitroanilines (4e) of 4-

4-fluoro-2-methoxy-5-nitroaniline

Under ice bath, the fluoro- 2- aminoanisoles (4d) (17.1g, 0.1mmol) of 4- are dissolved in the concentrated sulfuric acid (100mL), potassium nitrate (10.1g, 0.1mmol) is slowly added to, 10 DEG C are reacted 2 hours.Reaction solution is poured into trash ice, add ammoniacal liquor and adjust pH to 8, add ethyl acetate (400mL × 2) extraction, merge organic phase, organic phase anhydrous sodium sulfate drying, concentration, obtains the fluoro- 2- methoxyl groups -5- nitroanilines (4e) of 4-, yellow solid (18.6g, crude product).

¹H NMR(400MHz,DMSO-d₆)δ7.34(d,1H),7.03(d,1H),5.22(s,2H),3.90(s,3H)。

4th step：The chloro- N- of 5- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (intermediate 4)

By 3- (2,5- dichloro pyrimidine -4- bases) -1- Methyl-1H-indoles (4c) (1g, 3.6mmol) it is dissolved in 2- amylalcohols (100mL), add fluoro- 2- methoxyl groups -5- nitroanilines (the 4e) (672mg of 4-, 3.6mmol) with p-methyl benzenesulfonic acid (822mg, 4.32mmol), 120 DEG C, back flow reaction 2 days are heated to.Reaction solution is cooled to room temperature, add acetonitrile (50mL), filtering, filter cake is washed with acetonitrile (50mL) and water (50mL) successively, filter cake dries to obtain the chloro- N- of 5- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (intermediate 4), celadon solid (1.48g, 97%).

MS m/z:428.0[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ8.74(s,1H),8.66(d,1H),8.58(s,1H),8.47(s,1H),8.33(d,1H),7.53(d,1H),7.38(t,1H),7.27(t,1H),7.06(t,1H),3.97(s,3H),3.92(s,3H)。

Intermediate 5

5- ((the chloro- 4- of 5- (pyrazolo [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) fluoro- 1- nitrobenzene (intermediate 5) of -4- methoxyl groups -2-

5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-fluoro- 1-nitrobenzene

The first step：(E) -4- (2- vinyl butyl ethers base) -2,5- dichloro pyrimidines (5b)

(E)-4-(2-butoxyvinyl)-2,5-dichloropyrimidine

By 2; 4; 5- trichloropyrimidines (5a) (5g; 27.3mmol), 1- vinyl butyl ethers (2.85g; 28.5mmol), triethylamine (2.88g, 28.5mmol) and palladium (0.21g, 0.95mmol) are added in polyethylene glycol (30mL); under nitrogen protection, 50 DEG C of 5 hours of reaction.Reaction solution is cooled to room temperature, water (50mL) is added, is extracted with ethyl acetate (50mL × 3), merges organic phase, organic phase anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (petroleum ether：Ethyl acetate (v/v)=50:1) title compound (E) -4- (2- vinyl butyl ethers base) -2,5- dichloro pyrimidines (5b), yellow solid (0.6g, yield 9%) are obtained.

¹H NMR(400MHz,CDCl₃)δ8.32(s,1H),8.07(d,1H),6.09(d,1H),4.03(t,2H),1.76–1.70(m,2H),1.48–1.43(m,2H),0.97(t,3H)。

Second step：3- (2,5- dichloro pyrimidine -4- bases) pyrazolo [1,5-a] pyridine (5c)

3-(2,5-dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine

By (E) -4- (2- vinyl butyl ethers base) -2,5- dichloro pyrimidines (5b) (0.6g, 2.4mmol), 1- amino-pyridines -1- (0.6g, 2.4mmol) with potassium carbonate (0.84g, 6.0mmol) it is added to N, in dinethylformamide (30mL), room temperature to 110 DEG C of 5 hours of reaction.Room temperature is cooled to, water (20mL) is added into reaction solution, is extracted with ethyl acetate (50mL × 3), merge organic phase, organic phase is washed with water (50mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (petroleum ether：Ethyl acetate (v/v)=10:1) title compound 3- (2,5- dichloro pyrimidine -4- bases) pyrazolo [1,5-a] pyridine (5c), yellow solid (0.1g, yield 16%) are obtained.

¹H NMR(400MHz,DMSO-d₆)δ9.08(s,1H),8.96(d,1H),8.80(s,1H),8.57(d,1H),7.75–7.71(m,1H),7.27(td,1H)。

MS m/z:265.1[M+1]⁺。

3rd step：5- ((the chloro- 4- of 5- (pyrazolo [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) fluoro- 1- nitrobenzene (intermediate 5) of -4- methoxyl groups -2-

5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitrobenzene

By 3- (2,5- dichloro pyrimidine -4- bases) pyrazolo [1,5-a] pyridine (5c) (1g, 3.7mmol), the fluoro- 2- methoxyl groups -5- nitroanilines (0.84g of 4-, 4.5mmol) with p-methyl benzenesulfonic acid (1.08g, 5.6mmol) it is added in 2- amylalcohols (30mL), is warming up to 120 DEG C of 12 hours of reaction.It is cooled to room temperature, methanol (50mL) is added into reaction solution, filtering, filter cake is washed with ether (30mL), dry cake obtains title compound 5- ((5- chloro- 4- (pyrazolos [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) the fluoro- 1- nitrobenzene (intermediate 5) of -4- methoxyl groups -2-, yellow solid (1g, yield 64%).

MS m/z:415.1[M+1]⁺。

Intermediate 6

5- ((4- (indol-3-yl) -5- chlorine pyrimidine -2-base) amino) fluoro- 1- nitrobenzene (intermediate 6) of -4- methoxyl groups -2-

5-((4-(indol-3-yl)-5-chloropyrimidin-2-yl)amino)-4-methoxy-2-fluoro-1-nitrobenzene

Prepared with reference to the synthetic method of WO2013014448 intermediates 68.

Intermediate 7

The chloro- 4- of 5- (the fluoro- 1H- indol-3-yls of 4-)-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) pyrimidine -2- amine (intermediate 7)

5-chloro-4-(4-fluoro-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine

The first step：The fluoro- 1H- indoles (7b) of 3- (2,5- dichloro pyrimidine -4- bases) -4-

3-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1H-indole

Fluoro- 1H- indoles (the 7a) (15g of 4- are added into reaction bulb, 0.11mol) with tetrahydrofuran (90mL), ice salt bath is cooled down, and 3mol/L methyl-magnesium-bromide tetrahydrofuran solution (37mL) is added dropwise, and keeps interior temperature to be less than -5 DEG C, drip off insulation reaction 30 minutes, add 2,4,5- trichloropyrimidines (10.2g, 0.06mol), add be warming up to 60 DEG C react 1 hour.Reaction solution is cooled to room temperature, add acetic acid (10mL), water (90mL), tetrahydrofuran (50mL), is warming up to 60 DEG C and reacts 1 hour, be cooled to room temperature, separate organic layer, anhydrous sodium sulfate drying, is concentrated under reduced pressure into dry, silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=8:1-6:1) the fluoro- 1H- indoles (7b) (3.7g, yield 24%) of yellow solid tert-butyl group 3- (2,5- dichloro pyrimidine -4- bases) -4- are obtained.

MS m/z(ESI):280.1[M-1]^-。

¹H NMR(400MHz,DMSO-d₆)δ12.26(s,1H),8.87(s,1H),8.14(d,1H),7.37(d,1H),7.23(td,1H),6.93(dd,1H)。

Second step：The chloro- 4- of 5- (the fluoro- 1H- indol-3-yls of 4-)-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) pyrimidine -2- amine (intermediate 7)

3- (2 is added into reaction bulb, 5- dichloro pyrimidine -4- bases) fluoro- 1H- indoles (the 7b) (2.6g of -4-, 9.1mmol), fluoro- 2- methoxyl groups -5- nitroanilines (the 4e) (1.3g of 4-, 9.1mmol), p-methyl benzenesulfonic acid (1.2g, 11.1mmol) with 2- amylalcohols (55mL), it is heated to 120 DEG C and reacts 9 hours.Reaction solution is cooled to room temperature, filtering, respectively filter cake is washed with acetonitrile (5mL × 1) and dichloromethane (5mL × 1), collect filter cake, petroleum ether (30mL) is added into filtrate, stirring, filtering, filter cake is with acetonitrile (5mL × 1) and dichloromethane (15mL × 1), collect solid, the chloro- 4- of brown solid 5- (the fluoro- 1H- indol-3-yls of 4-)-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) pyrimidine -2- amine (intermediate 7) (2.2g, yield 55%) is obtained twice.

MS m/z(ESI):430.1[M-1]^-。

Intermediate 8

4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 7-)-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) pyrimidine -2- amine (intermediate 8)

4-(7-fluoro-1-methyl-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine

The first step：The fluoro- 1H- indoles (8b) of 3- (2- chlorine pyrimidine-4-yl) -7-

3-(2-chloropyrimidin-4-yl)-7-fluoro-1H-indole

7- fluoro indoles (10g is added into reaction bulb, 74mmol) with 1,2- dichloroethanes (270mL), after stirring and dissolving, ice bath is cooled down, 3mol/L methyl-magnesium-bromides tetrahydrofuran solution (24.7mL, 74mmol) is added dropwise, insulation reaction is dripped off 15 minutes, add 2,4- dichloro pyrimidines (2a) (16g, 110mmol), are slowly increased to 45 DEG C and react 24 hours.Ice bath cools down reaction solution, and methanol (100mL) is added dropwise, and stirs 15 minutes, is concentrated under reduced pressure, silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=5:1-1:1) the fluoro- 1H- indoles (8b) (8.4g, yield 46.6%) of yellow solid 3- (2- chlorine pyrimidine-4-yl) -7- are obtained.

MS m/z(ESI):246.1[M-1]^-。

¹H NMR(400MHz,DMSO-d₆)δ12.59(s,1H),8.61–8.54(m,2H),8.25(d,1H),7.97(d,1H),7.21(td,1H),7.09(dd,1H)。

Second step：The fluoro- 1- Methyl-1H-indoles (8c) of 3- (2- chlorine pyrimidine-4-yl) -7-

3-(2-chloropyrimidin-4-yl)-7-fluoro-1-methyl-1H-indole

Fluoro- 1H- indoles (the 8b) (280mg of 3- (2- chlorine pyrimidine-4-yl) -7- are added into reaction bulb, 1.13mmol) with tetrahydrofuran (14mL), after stirring and dissolving, sodium hydride (58mg is added portionwise in ice bath cooling, 2.4mmol), add insulation reaction 30 minutes, iodomethane (0.15mL, 2.4mmol) is added dropwise, drip off insulation reaction 30 minutes, be heated to 40 DEG C and react 3 hours.Ice bath cools down reaction solution, adds water (10mL), is extracted with ethyl acetate (20mL × 2), merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=3:1) the fluoro- 1- Methyl-1H-indoles (8c) (260mg, yield 88%) of yellow solid 3- (2- chlorine pyrimidine-4-yl) -7- are obtained.

MS m/z(ESI):262.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ8.43(d,1H),8.08(d,1H),7.80(s,1H),7.42(d,1H),7.17(td,1H),6.97(dd,1H),4.05(d,3H)。

3rd step：4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 7-)-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) pyrimidine -2- amine (intermediate 8)

Fluoro- 1- Methyl-1H-indoles (the 8c) (260mg of 3- (2- chlorine pyrimidine-4-yl) -7- are added into reaction bulb, 1mmol), the fluoro- 2- methoxyl groups -5- nitroanilines (186mg of 4-, 1mmol), p-methyl benzenesulfonic acid (132mg, 1.2mmol) with 2- amylalcohols (5mL), it is heated to 105 DEG C and reacts 3 hours.Reaction solution is cooled to room temperature, filtering, filter cake is washed with acetonitrile (10mL × 1), collect filter cake, obtain faint yellow solid 4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 7-)-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) pyrimidine -2- amine (intermediate 8) (280mg, yield 68%).

MS m/z(ESI):410.2[M-1]^-。

Intermediate 9

N- (the fluoro- 2- methoxyl groups -5- nitro-phenyls of 4-) -5- methoxyl group -4- pyrazolos [1,5-a] pyridin-3-yl-pyrimidine -2- amine (intermediate 9)

N-(4-fluoro-2-methoxy-5-nitro-phenyl)-5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-amine

The first step：(trans) -4- (2- n-butoxies vinyl) -2- chloro-5-methoxyls pyrimidine (9b)

(E)-4-(2-butoxyvinyl)-2-chloro-5-methoxypyrimidine

Weigh 2,4- dichloro-5-methoxy pyrimidines (9a) (10.74g, 60mmol), it is placed in 500mL round-bottomed flasks, polyethylene glycol 400 (150mL), triethylamine (12.5mL, 90.00mmol), vinyl n-butyl ether (11.6mL is sequentially added into reaction bulb, 90.00mmol) with palladium (0.67g, 3mmol), 80 DEG C are warming up to, is stirred 16 hours.Reaction solution is cooled to room temperature, add water (200mL), extracted with ethyl acetate (250mL × 2), merge organic phase, organic phase is washed with saturated aqueous common salt (150mL), column chromatography for separation purifies (petrol ether/ethyl acetate (v/v)=5 after anhydrous sodium sulfate drying, concentration:1) (trans) -4- (2- n-butoxies vinyl) -2- chloro-5-methoxyls pyrimidine (9b) (6.64g, yield 46%) of yellow liquid is obtained.

¹H NMR(400MHz,CDCl₃)δ7.98-7.94(m,2H),6.04-6.01(d,1H),3.98-3.95(m,2H),3.90(s,3H),1.75-1.68(m,2H),1.45-1.41(m,2H),0.97-0.93(m,3H)。

Second step：3- (2- chloro-5-methoxyls-pyrimidine-4-yl) pyrazolo [1,5-a] pyridine (9c)

3-(2-chloro-5-methoxy-pyrimidin-4-yl)pyrazolo[1,5-a]pyridine

Weigh (trans) -4- (2- n-butoxies vinyl) -2- chloro-5-methoxyls pyrimidine (9b) (9.0g, 37.3mmol), it is placed in 250mL round-bottomed flasks, N is sequentially added into reaction bulb, N- dimethyl acetamides (100mL), 1- amido pyridine iodides (8.2g, 37.3mmol) with potassium carbonate (12.9g, 92.5mmol), it is warming up at 110 DEG C and stirs 24 hours.Reaction solution is cooled to room temperature, add water (100mL), extracted with ethyl acetate (150mL × 2), merge organic phase, organic phase is washed with saturated aqueous common salt (50mL × 2), column chromatography for separation purifies (petrol ether/ethyl acetate (v/v)=3 after anhydrous sodium sulfate drying, concentration:1) 3- (2- chloro-5-methoxyls-pyrimidine-4-yl) pyrazolo [1,5-a] pyridine (9c) (3.9g, yield 40%) of yellow solid is obtained.

¹H NMR(400MHz,CDCl₃)δ8.81-8.78(m,2H),8.57-8.56(d,1H),8.15(s,1H), 7.46-7.44(m,1H),7.02-6.99(m,1H),4.08(s,3H)。

3rd step：N- (the fluoro- 2- methoxyl groups -5- nitro-phenyls of 4-) -5- methoxyl group -4- pyrazolos [1,5-a] pyridin-3-yl-pyrimidine -2- amine (intermediate 9)

Weigh 3- (2- chloro-5-methoxyls-pyrimidine-4-yl) pyrazolo [1,5-a] pyridine (9c) (1.04g, 4mmol), it is placed in 50mL round-bottomed flasks, 2- amylalcohols (15mL), the fluoro- 2- methoxyl groups -5- nitroanilines (0.74g, 4mmol) of 4- are sequentially added into reaction bulb, p-methyl benzenesulfonic acid (0.84g, 4.4mmol).Reaction system is warming up to stirring at 120 DEG C and is cooled to room temperature after 48 hours.Acetonitrile (20mL), ammoniacal liquor (20mL) are added into reaction bulb.Filtering, filter cake is washed with acetonitrile (10mL × 2), water (10mL × 2) is washed, collect filter cake, it is dried to obtain N- (the fluoro- 2- methoxyl groups -5- nitro-phenyls of 4-) -5- methoxyl group -4- pyrazolos [1 of yellow solid, 5-a] pyridin-3-yl-pyrimidine -2- amine (intermediate 9) (0.6g, yield 37%).

Intermediate 10

N- (3,4- difluoro-2-methoxyl -5- nitrobenzene) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (intermediate 10)

N-(3,4-difluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

The first step：N- (3,4- difluoro-2-methoxyl -5- nitrobenzene) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (intermediate 10)

By 3- (2- chlorine pyrimidine-4-yl) -1- Methyl-1H-indoles (intermediate 2) (3g, 12mmol), 3,4- difluoro-2-methoxyl -5- nitroanilines (10a) (3g, 14mmol) with p-methyl benzenesulfonic acid (3.5g, 18mmol) it is added in 2- amylalcohols (30mL), 120 DEG C of 12 hours of reaction.Reaction solution is cooled to room temperature, add methanol (50mL), filtering, filter cake is washed with ether (30mL), filtration cakes torrefaction obtains title compound N- (3,4- difluoro-2-methoxyl -5- nitrobenzene) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (intermediate 10), yellow solid (3g, yield 62.5%).

MS m/z:494.3[M+1]⁺。

Embodiment 1

N- (5- ((5- chloro- 4- (pyrazolos [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) -4- methoxyl groups -2- (1- methyl isophthalic acids, 7- diaza spiros [4.4] nonane -7- bases) phenyl) acrylamide (compound 1)

N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diazaspiro[4.4]nonan-7-yl)phenyl)acrylamide

The first step：5- ((5- chloro- 4- (pyrazolos [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) -4- methoxyl groups -2- (1- methyl isophthalic acids, 7- diaza spiros [4.4] nonane -7- bases) -1- nitrobenzene (1B)

5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diazaspiro[4.4]nonan-7-yl)-1-nitrobenzene

By 5- ((5- chloro- 4- (pyrazolos [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) fluoro- 1- nitrobenzene (the intermediate 5) (0.3g of -4- methoxyl groups -2-, 0.72mmol), 1- methyl isophthalic acids, 7- diaza spiros [4.4] nonane (1A) (0.15g, 10.8mmol) and N, N- diisopropylethylamine (i.e. DIPEA) (0.28g, 2.17mmol) it is added to N, in dinethylformamide (3mL), 1.5 hours of 140 DEG C of microwave reactions.It is cooled to room temperature, water (20mL) is added into reaction solution, extracted with ethyl acetate (50mL × 3), merge organic phase, organic phase is washed with water (50mL × 2), anhydrous sodium sulfate drying, concentration, obtain title compound 5- ((5- chloro- 4- (pyrazolos [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) -4- methoxyl groups -2- (1- methyl isophthalic acids, 7- diaza spiros [4.4] nonane -7- bases) -1- nitrobenzene (1B), red solid (0.3g, yield 79%).

¹H NMR(400MHz,DMSO-d₆)δ8.94(s,1H),8.84(d,1H),8.68(s,1H),8.41(s,2H),8.06(s,1H),7.32(m,1H),7.13(m,1H),6.56(s,1H),3.90(s,3H),3.43–3.41(m,2H),3.26-3.24(m,1H),2.77–2.64(m,3H),2.31(s,3H),2.12-2.09(m,1H),1.79–1.66(m,5H)。

MS m/z:535.3[M+1]⁺。

Second step：5- ((the chloro- 4- of 5- (pyrazolo [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) -4- methoxyl groups -2- (1- methyl isophthalic acids, 7- diaza spiros [4.4] nonane -7- bases) aniline (1C)

5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diazaspiro[4.4]nonan-7-yl)aniline

By 5- ((5- chloro- 4- (pyrazolos [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) -4- methoxyl groups -2- (1- methyl isophthalic acids, 7- diaza spiros [4.4] nonane -7- bases) -1- nitrobenzene (1B) (0.6g, 1.12mmol), iron powder (0.378g, 6.7mmol) it is added to ammonium chloride in the mixed solution of ethanol (20mL) and water (5mL), 90 DEG C are reacted 4 hours.It is cooled to room temperature, water (20mL) is added into reaction solution, extracted with dichloromethane (50mL × 3), merge organic phase, organic phase is washed with water (50mL × 2), anhydrous sodium sulfate drying, concentration, obtain title compound 5- ((5- chloro- 4- (pyrazolos [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) -4- methoxyl groups -2- (1- methyl isophthalic acids, 7- diaza spiros [4.4] nonane -7- bases) aniline (1C), red solid (0.56g, crude product).

¹H NMR(400MHz,DMSO-d₆)δ8.94(s,1H),8.82(d,1H),8.44–8.36(m,3H),7.32(m,1H),7.12(m,1H),6.94(s,1H),6.69(s,1H),4.26(s,2H),3.66(s,3H),3.21(d,1H),3.13(s,1H),3.07–3.01(m,1H),2.70–2.64(m,3H),2.34(s,3H),2.10–2.03(m,1H),1.93–1.83(m,2H),1.80–1.61(m,3H)。

MS m/z；505.3[M+1]⁺。

3rd step：N- (5- ((5- chloro- 4- (pyrazolos [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) -4- methoxyl groups -2- (1- methyl isophthalic acids, 7- diaza spiros [4.4] nonane -7- bases) phenyl) acrylamide (compound 1)

By 5- ((5- chloro- 4- (pyrazolos [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) -4- methoxyl groups -2- (1- methyl isophthalic acids, 7- diaza spiros [4.4] nonane -7- bases) aniline (1C) (0.6g, 1.1mmol), N- ethyl diisopropylamines (0.3g, 2.2mmol) add in tetrahydrofuran (20mL), acryloyl chloride (0.1g is added dropwise under the conditions of -40 DEG C, 1.1mmol) tetrahydrofuran (5mL) solution, half an hour is reacted at this temperature.Water (10mL) is added into reaction solution, is extracted with ethyl acetate (50mL × 3), merges organic phase, organic phase is washed with water (50mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=50:1) title compound N- (5- ((5- chloro- 4- (pyrazolos [1 are obtained, 5-a] pyridin-3-yl) pyrimidine -2-base) amino) -4- methoxyl groups -2- (1- methyl isophthalic acids, 7- diaza spiros [4.4] nonane -7- bases) phenyl) acrylamide (compound 1), yellow solid (0.18g, yield 27%).

¹H NMR(400MHz,CDCl₃)δ9.10(s,1H),8.93(s,1H),8.54–8.51(m,2H),8.41(s,1H),8.18(s,1H),7.40(s,1H),7.31(m,1H),6.90(t,1H),6.71(s,1H),6.35–6.31(m,2H),5.72–5.69(m,1H),3.89(s,3H),3.25(s,2H),3.06(d,1H),2.78(s,3H),2.50(s,3H),2.22(s,1H),2.00(s,2H),1.87(s,3H)。

MS m/z:559.4[M+1]⁺。

Embodiment 2

(S)-N- (5- ((the chloro- 4- of 5- (pyrazolo [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) -4- methoxyl groups -2- (1- methyl isophthalic acids, 7- Diaza spiro [4.4] nonane -7- bases) phenyl) acrylamide (compound 2)

(S)-N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diazaspiro[4.4]nonan-7-yl)phenyl)acrylamide

Embodiment 3

(R)-N- (5- ((5- chloro- 4- (pyrazolos [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) -4- methoxyl groups -2- (1- methyl isophthalic acids, 7- diaza spiros [4.4] nonane -7- bases) phenyl) acrylamide (compound 3)

(R)-N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diazaspiro[4.4]nonan-7-yl)phenyl)acrylamide

The method for splitting of embodiment 2 and embodiment 3 is as follows：

Take N- (5- ((5- chloro- 4- (pyrazolos [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) -4- methoxyl groups -2- (1- methyl isophthalic acids, 7- diaza spiros [4.4] nonane -7- bases) phenyl) acrylamide (compound 1) (100mg) is for splitting, and preparation condition is：Instrument GX-281C0630, (0.1% diethylamine+n-hexane)/isopropanol=70/30,10.0mL/min, 254nm, 40 DEG C of column temperature (AD-H20*250mm 5um H-37)；Obtain two optical isomers：Isomers 1 (peak 1,50mg, yellow solid, ee%=100%, t=33.97min), isomers 2 (peak 2,50mg, yellow solid, ee%=100%, t=40.78min).

Isomers 1

¹H NMR(400MHz,CDCl₃)δ9.11(s,1H),8.93(s,1H),8.53(d,2H),8.42(s,1H),8.16(s,1H),7.40(s,1H),7.30(d,1H),6.90(t,1H),6.72(s,1H),6.40–6.16(m,2H),5.71(d,1H),3.89(s,3H),3.24(d,2H),3.07(d,1H),2.77(s,3H),2.48(s,3H),2.21(s,1H),2.05–1.78(m,5H)。

MS m/z:559.3[M+1]⁺。

Isomers 2

¹H NMR(400MHz,CDCl₃)δ9.11(s,1H),8.93(s,1H),8.53(d,2H),8.42(s,1H),8.16(s,1H),7.40(s,1H),7.30(d,1H),6.90(t,1H),6.72(s,1H),6.35–6.25(m,2H),5.71(d,1H),3.89(s,3H),3.34–3.13(m,2H),3.08–3.06(m,1H),2.95–2.64(m,3H),2.48(s,3H),2.21 (s,1H),2.09–1.78(m,5H)。

MS m/z:559.3[M+1]⁺。

Embodiment 4

N- (5- ((4- (1- methyl indol -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- (1- methyl isophthalic acids, 7- diaza spiros [4.4] nonane -7- bases) phenyl) acrylamide trifluoroacetate (compound 4)

N-(5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diazaspiro[4.4]nonan-7-yl)phenyl)acrylamide triflouro

The first step：5- ((4- (1- methyl indol -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- (1- methyl isophthalic acids, 7- diaza spiros [4.4] nonane -7- bases) -1- nitrobenzene (4B)

5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diazaspiro[4.4]nonan-7-yl)-1-nitrobenzene

By 5- ((4- (1- methyl indol -3- bases) pyrimidine -2-base) amino) fluoro- 1- nitrobenzene (the intermediate 3) (1.0g of -4- methoxyl groups -2-, 2.5mmol) and N, N- diisopropylethylamine (0.65g, 5.0mmol) it is added to N, in dinethylformamide (3mL), 1.5 hours of 140 DEG C of microwave reactions.It is cooled to room temperature, water (20ml) is added into reaction solution, extracted with dichloromethane (50mL × 3), merge organic phase, organic phase is washed with water (50mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=50:1) title compound 5- ((the chloro- 4- of 5- (1- methyl indol -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- (1- methyl isophthalic acids are obtained, 7- diaza spiros [4.4] nonane -7- bases) -1- nitrobenzene (4B), yellow solid (0.5g, yield 38.4%).

¹H NMR(400MHz,DMSO-d₆)δ8.54(s,1H),8.36(d,1H),8.34–8.25(m,2H),8.04(s, 1H),7.51(d,1H),7.24(t,1H),7.18(d,1H),7.10(t,1H),6.57(s,1H),3.96(s,3H),3.87(s,3H),3.42(d,2H),3.25(d,1H),2.78–2.68(m,3H),2.31(s,3H),2.11–2.09(m,1H),1.83–1.65(m,5H)。

MS m/z:514.3[M+1]⁺。

Second step：5- ((4- (1- methyl indol -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- (1- methyl isophthalic acids, 7- diaza spiros [4.4] nonane -7- bases) aniline (4C)

5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diazaspiro[4.4]nonan-7-yl)aniline

By 5- ((4- (1- methyl indol -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- (1- methyl isophthalic acids, 7- diaza spiros [4.4] nonane -7- bases) -1- nitrobenzene (4B) (0.5g, 0.97mmol), iron powder (0.32g, 5.8mmol) with ammonium chloride (0.52g, in the mixed solution for 9.7mmol) being added to ethanol (5mL)/water (2mL), 90 DEG C of 4 hours of reaction.It is cooled to room temperature, water (20mL) is added into reaction solution, extracted with dichloromethane (50mL × 3), merge organic phase, organic phase is washed with water (50mL × 2), anhydrous sodium sulfate drying, it is concentrated to give title compound 5- ((4- (1- methyl indol -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- (1- methyl isophthalic acids, 7- diaza spiros [4.4] nonane -7- bases) aniline (4C), yellow solid (0.4g, yield 85%).

MS m/z:484.4[M+1]⁺。

3rd step：N- (5- ((4- (1- methyl indol -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- (1- methyl isophthalic acids, 7- diaza spiros [4.4] nonane -7- bases) phenyl) acrylamide (4D)

N-(5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diazaspiro[4.4]nonan-7-yl)phenyl)acrylamide

By 5- ((4- (1- methyl indol -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- (1- methyl isophthalic acids, 7- diaza spiros [4.4] nonane -7- bases) aniline (4C) (0.5g, 1mmol), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (i.e. EDCI) (0.149g, 2.0mmol) with acrylic acid (0.79g, 4mmol) add in pyridine (5mL), react at room temperature 2 hours.Water (10mL) is added into reaction solution, is extracted with dichloromethane (50mL × 3), merges organic phase, organic phase is washed with water (50mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=50:1) title compound N- (5- ((4- (1- methyl indol -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- (1- methyl isophthalic acids are obtained, 7- diaza spiros [4.4] nonane -7- bases) phenyl) acrylamide (4D), yellow solid (0.2g, yield 36%).

¹H NMR(400MHz,DMSO-d₆)δ9.29(s,1H),8.40(s,1H),8.33(d,1H),8.27(d,1H),8.15(s,1H),7.78(s,1H),7.51(d,1H),7.27–7.11(m,3H),6.59(s,1H),6.56–6.49(m,1H),6.21(dd,1H),5.75–5.69(m,1H),3.89–3.86(m,6H),3.37(d,1H),3.25–3.22(m,2H),2.77–2.59(m,3H),2.31(s,3H),2.05–2.02(m,1H),1.81–1.58(m,5H)。

MS m/z:538.1[M+1]⁺。

4th step：N- (5- ((4- (1- methyl indol -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- (1- methyl isophthalic acids, 7- diaza spiros [4.4] nonane -7- bases) phenyl) acrylamide trifluoroacetate (compound 4)

N-(5-((4-(1-methylindol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(1-methyl-1,7-diazaspiro[4.4]nonan-7-yl)phenyl)acrylamide triflouroacetate

By N- (5- ((4- (1- methyl indol -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- (1- methyl isophthalic acids, 7- diaza spiros [4.4] nonane -7- bases) phenyl) acrylamide (4D) (50mg, 0.09mmol) it is dissolved in dichloromethane (10mL), add trifluoroacetic acid (15mg), it is stirred at room temperature 30 minutes, concentration, obtain N- (5- ((4- (1- methyl indol -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- (1- methyl isophthalic acids, 7- diaza spiros [4.4] nonane -7- bases) phenyl) acrylamide trifluoroacetate (compound 4), yellow solid (57mg).

¹H NMR(400MHz,DMSO-d₆)δ10.14(s,1H),9.31(d,1H),8.54(d,1H),8.31–8.27(m,3H),7.54(d,1H),7.25–7.18(m,3H),6.77(d,1H),6.66–6.45(m,1H),6.23(d,1H),5.74(d,1H),3.91(s,3H),3.88(s,3H),3.75–3.51(m,3H),3.18–3.13(m,3H),2.88(s,3H),2.38–1.90(m,6H)。

MS m/z:538.2[M+1]⁺。

Embodiment 5

N- (2- ((1- amino cyclopropyl) methoxyl group) -5- ((the chloro- 4- of 5- (pyrazolo [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide trifluoroacetate (compound 5)

N-(2-((1-aminocyclopropyl)methoxy)-5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide trifluoroacetate

The first step：(1- ((4- ((the chloro- 4- of 5- (pyrazolo [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) -5- methoxyl group -2- nitrobenzene Epoxide) methyl) cyclopropyl) carbamate (5B)

tert-butyl(1-((4-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenoxy)methyl)cyclopropyl)carbamate

Take the chloro- N- of 5- (the fluoro- 2- methoxyl groups -5- nitro-phenyls of 4-) -4- pyrazolos [1,5-a] pyridin-3-yl-pyrimidine -2- amine (intermediate 5) (0.41g, 1.00mmol) it is placed in round-bottomed flask, tetrahydrofuran (20mL) is added into reaction bulb, it is cooled to 0 DEG C, sodium hydride (0.08g is added into reaction bulb, 1.1mmol, wt%=60%), stirring 5 minutes, add (1- methylols cyclopropyl)-t-butoxycarbonyl amino (5A) (0.21g, 1.1mmol).Reaction is warmed to room temperature lower reaction and terminated for 4 hours.Water (20mL) is added into reaction bulb, aqueous phase is extracted with ethyl acetate (50mL × 2), organic phase after merging is washed with saturated aqueous common salt (30mL), column chromatography for separation purifies (petrol ether/ethyl acetate (v/v)=1 after anhydrous sodium sulfate drying, concentration:1) (1- ((4- ((the 5- chloro- 4- (pyrazolos [1 of yellow solid are obtained, 5-a] pyridin-3-yl) pyrimidine -2-base) amino) -5- methoxyl group -2- nitro-phenoxies) methyl) cyclopropyl) carbamate (5B) (0.56g, yield 97%).

¹H NMR(400MHz,CDCl₃)δ8.60(s,1H),8.58(s,1H),8.46-8.42(m,1H),8.40-8.35(m,1H),8.32(s,1H),8.25(br,1H),7.43-7.39(m,1H),7.05-7.02(m,1H),5.25(br,1H),4.19(s,2H),4.01(s,3H),1.42(s,9H),097(s,4H)。

Second step：(1- ((2- amino -4- ((the chloro- 4- of 5- (pyrazolo [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) -5- methoxyphenoxies) methyl) cyclopropyl) carbamate (5C)

tert-butyl(1-((2-amino-4-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-5-methoxyphenoxy)methyl)cyclopropyl)carbamate

Weigh (1- ((4- ((5- chloro- 4- (pyrazolos [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) -5- methoxyl group -2- nitro-phenoxies) methyl) cyclopropyl) carbamate (5B) (0.58g, 1.0mmol), it is placed in 100mL round-bottomed flasks, ethanol (21mL), water (7mL), reduced iron powder (0.34g are sequentially added into reaction bulb, 6.0mmol) with ammonium chloride (0.037g, 0.7mmol), temperature rising reflux is reacted, and post processing is entered after 6 hours.By reacting liquid filtering, filter cake is washed with dichloromethane (10mL × 2) and methanol (10mL × 2) successively, merging filtrate, and concentration, residue uses column chromatography purification (petrol ether/ethyl acetate (v/v)=1:1) (1- ((2- amino -4- ((the 5- chloro- 4- (pyrazolos [1 of gray solid shape are obtained, 5-a] pyridin-3-yl) pyrimidine -2-base) amino) -5- methoxyphenoxies) methyl) cyclopropyl) carbamate (5C) (0.37g, yield 67%).

3rd step：(1- ((2- acrylamidos -4- ((the chloro- 4- of 5- (pyrazolo [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) -5- methoxyphenoxies) methyl) cyclopropyl) carbamate (5D)

tert-butyl(1-((2-acrylamido-4-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-5-methoxyphenoxy)methyl)cyclopropyl)carbamate

Weigh (1- ((2- amino -4- ((the chloro- 4- of 5- (pyrazolo [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) -5- methoxybenzene oxygen Base) methyl) cyclopropyl) carbamate (5C) (0.37g, 0.67mmol), it is placed in 100mL round-bottomed flasks, tetrahydrofuran (15mL) and diisopropyl ethyl amine (0.12mL, 0.74mmol) are sequentially added into reaction bulb, 0 DEG C is cooled to, acryloyl chloride (0.055mL is added dropwise, 0.70mmol), after completion of dropping, temperature reaction 1 hour.Reaction solution is concentrated under reduced pressure, dichloromethane (50mL) and saturated sodium bicarbonate aqueous solution (30mL) are added into residue, divide liquid, aqueous phase is extracted with dichloromethane (50mL), merge organic phase, organic phase is washed with saturated aqueous common salt (30mL), anhydrous sodium sulfate drying, it is concentrated under reduced pressure, residue uses column chromatography purification (methylene chloride/methanol (v/v)=10:1) (1- ((2- acrylamidos -4- ((the 5- chloro- 4- (pyrazolos [1 of yellow solid are obtained, 5-a] pyridin-3-yl) pyrimidine -2-base) amino) -5- methoxyphenoxies) methyl) cyclopropyl) carbamate (5D) (0.20g, yield 49%).

4th step：N- (2- ((1- amino cyclopropyl) methoxyl group) -5- ((the chloro- 4- of 5- (pyrazolo [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide trifluoroacetate (compound 5)

N-(2-((1-aminocyclopropyl)methoxy)-5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide 2,2,2-trifluoroacetate

Weigh (1- ((2- acrylamidos -4- ((5- chloro- 4- (pyrazolos [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) -5- methoxyphenoxies) methyl) cyclopropyl) carbamate (5D) (0.2g, 0.33mmol), it is placed in 100mL round-bottomed flasks, dichloromethane (15mL) and trifluoroacetic acid (5mL) are sequentially added into reaction bulb, is reacted at room temperature 1 hour.N- (2- ((1- amino cyclopropyl) methoxyl group) -5- ((5- chloro- 4- (pyrazolos [1 of yellow solid are obtained after being concentrated under reduced pressure, 5-a] pyridin-3-yl) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide trifluoroacetate (compound 5) (0.03g, yield 15%).

MS m/z(ESI):506.3[(M-M_TFA)+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ9.23(s,1H),8.84(s,1H),8.78-8.76(d,1H),8.69(s,1H),8.48(br,3H),8.38(m,2H),8.22(s,1H),7.33-7.31(m,1H),7.11-7.08(m,1H),6.88(s,1H),6.57-6.55(m,1H),6.23-6.20(d,1H),5.78-5.75(d,1H),4.24(s,2H),3.77(s,3H),1.12-1.09(m,2H),1.03-1.00(m,2H)。

Embodiment 6

N- (2- (((1- amino cyclopropyl) methyl) (methyl) amino) -5- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide trifluoroacetate (compound 6)

N-(2-(((1-aminocyclopropyl)methyl)(methyl)amino)-5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide trifluoroacetate

The first step：(1- (((4- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -5- methoxyl group -2- nitrobenzophenones) (methyl) amino) methyl) cyclopropyl) t-butyl carbamate (6B)

tert-butyl-(1-(((4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenyl)(methyl)amino)methyl)cyclopropyl)carbamate

By 5- ((4- (indol-3-yl) -5- chlorine pyrimidine -2-base) amino) fluoro- 1- nitrobenzene (the intermediate 6) (1.0g of -4- methoxyl groups -2-, 2.4mmol), (1- ((methylamino) methyl) cyclopropyl) t-butyl carbamate (6A) (0.96g, 4.8mmol) and N, N- diisopropylethylamine (0.62g, 4.8mmol) it is added in trifluoroethanol (3mL), 1.5 hours of 140 DEG C of microwave reactions.Reaction solution is cooled down to room temperature, water (20mL) is added, is extracted with dichloromethane (50mL × 3), merge organic phase, organic phase is washed with water (50mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=50:1) title compound (1- (((4- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -5- methoxyl group -2- nitrobenzophenones) (methyl) amino) methyl) cyclopropyl) t-butyl carbamate (6B) is obtained, red solid (0.5g, yield 34.97%).

MS m/z:594.3[M+1]⁺。

Second step：(1- (((4- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -5- methoxyl group -2- aminophenyls) (methyl) amino) methyl) cyclopropyl) t-butyl carbamate (6C)

tert-butyl-(1-(((4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2-aminophenyl)(methyl)amino)methyl)cyclopropyl)carbamate

(1- (((4- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -5- methoxyl group -2- nitrobenzophenones) (methyl) amino) methyl) cyclopropyl) t-butyl carbamate (6B) (0.27g, 0.45mmol), iron powder (0.15g, 2.7mmol) with ammonium chloride (0.24g, 4.5mmol) it is added in ethanol (5mL) and water (2mL), 90 DEG C of 4 hours of reaction.It is cooled to room temperature, water (20mL) is added into reaction solution, extracted with dichloromethane (50mL × 3), merge organic phase, organic phase is washed with water (50mL × 2), anhydrous sodium sulfate drying, concentration, title compound (1- (((4- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -5- methoxyl group -2- aminophenyls) (methyl) amino) methyl) cyclopropyl) t-butyl carbamate (6C) is obtained, it is yellow Color solid (0.18g, yield 70.3%).

MS m/z:564.2[M+1]⁺。

3rd step：N- (2- (((1- (tert-butoxycarbonyl) amino cyclopropyl) methyl) (methyl) amino) -5- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (6D)

N-(2-(((1-(tert-butoxycarbonyl)aminocyclopropyl)methyl)(methyl)amino)-5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

By (1- (((4- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -5- methoxyl group -2- aminophenyls) (methyl) amino) methyl) cyclopropyl) t-butyl carbamate (6C) (0.16g, 0.28mmol), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (0.21g, 1.1mmol) with acrylic acid (40.9mg, 0.56mmol) it is added in pyridine (5mL), 2 hours is reacted under room temperature.Water (10mL) is added into reaction solution, and is extracted (50mL × 3) with dichloromethane, merges organic phase, organic phase is washed with water (50mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=50:1) title compound N- (2- (((1- (tert-butoxycarbonyl) amino cyclopropyl) methyl) (methyl) amino) -5- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (6D) is obtained, yellow solid (0.15g, yield 88%).

MS m/z:618.2[M+1]⁺。

4th step：N- (2- (((1- amino cyclopropyl) methyl) (methyl) amino) -5- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide trifluoroacetate (compound 6)

By N- (2- (((1- (tert-butoxycarbonyl) amino cyclopropyl) methyl) (methyl) amino) -5- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (6D) (0.15g, 0.24mmol) be added to dichloromethane (2mL) and trifluoroacetic acid (1mL) in, under room temperature react 2 hours.Reaction solution is concentrated to give title compound N- (2- (((1- amino cyclopropyl) methyl) (methyl) amino) -5- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide trifluoroacetate (compound 6), yellow solid (0.1g, yield 88%).

¹H NMR(400MHz,DMSO-d₆)δ11.85(s,1H),9.21(s,1H),8.50–8.49(m,2H),8.43(s,1H),8.36(s,1H),8.35–8.22(m,4H),7.45(m,1H),7.15(m,1H),7.00(m,1H),6.95(s,1H),6.71–6.64(m,1H),6.23(d,1H),5.76(d,1H),3.77(s,3H),3.16(s,1H),2.65(s,3H),1.04(s,2H),0.85(s,2H)。

MS m/z:518.1[M+1]⁺。

Embodiment 7

N- (2- ((1- amino cyclopropyl) methoxyl group) -5- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxybenzenes Base) acrylamide (compound 7)

N-(2-((1-aminocyclopropyl)methoxy)-5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

The first step：(1- ((2- nitros -4- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -5- methoxyphenoxies) methyl) cyclopropyl) t-butyl carbamate (7B)

tert-butyl(1-((4-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenoxy)methyl)cyclopropyl)carbamate

By the chloro- N- of 5- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (intermediate 4) (650mg, 1.52mmol) it is dissolved in tetrahydrofuran (50mL), sodium hydride (121.6mg is added under ice bath, 3.04mmol, wt%=60%), stirring 30 minutes, (1- (methylol) cyclopropyl) t-butyl carbamate (313.1mg is added dropwise, 1.67mmol), room temperature reaction is stayed overnight.Water (100mL) and ethyl acetate (150mL) are added into reaction solution, divide liquid, aqueous phase is extracted with ethyl acetate (100mL), merge organic phase, organic phase anhydrous sodium sulfate drying, it is concentrated to give compound (1- ((2- nitros -4- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -5- methoxyphenoxies) methyl) cyclopropyl) t-butyl carbamate (7B), yellow solid (903mg).

MS m/z:595.1[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ8.58(d,2H),8.40(s,1H),8.39–8.22(m,2H),7.51(d,1H),7.25(dd,9.8Hz,2H),7.01(s,2H),4.29(s,2H),3.94(s,3H),3.91(s,3H),1.99(s,1H),1.37(s,9H),0.87(s,2H),0.77(s,2H)。

Second step：(1- ((2- amino -4- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -5- methoxyphenoxies) methyl) cyclopropyl) t-butyl carbamate (7C)

tert-butyl(1-((2-amino-4-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxyphenoxy)methyl)cyclopropyl)carbamate

(1- ((2- nitros -4- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -5- methoxyphenoxies) methyl) cyclopropyl) t-butyl carbamate (7B) (900mg will be changed, 1.52mmol) it is dissolved in ethanol (30mL), add water (10mL), iron powder (509mg, 9.12mmol) with ammonium chloride (57mg, 10.6mmol), it is warming up to 90 DEG C, back flow reaction 4 hours.Reaction solution is cooled to room temperature, filtered, concentration.With silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=1:0~20:1), obtain compound (1- ((2- amino -4- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -5- methoxyphenoxies) methyl) cyclopropyl) t-butyl carbamate (7C), greenish yellow solid (800mg, yield 93%).

MS m/z:565.2[M+1]⁺。

3rd step：N- (2- ((1- (tert-butoxycarbonyl) amino cyclopropyl) methoxyl group) -5- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (7D)

N-(2-((1-(tert-butoxycarbonyl)aminocyclopropyl)methoxy)-5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

By (1- ((2- amino -4- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -5- methoxyphenoxies) methyl) cyclopropyl) t-butyl carbamate (7C) (800mg, 1.4mmol) it is dissolved in tetrahydrofuran (30mL), add N, N- diisopropylethylamine (0.278mg, 1.68mmol), reaction solution is cooled down to 0 DEG C, acryloyl chloride (0.17mL is added dropwise, tetrahydrofuran (5mL) solution 2.1mmol), is warmed to room temperature reaction 4 hours.Saturated sodium bicarbonate aqueous solution (100mL) and dichloromethane (100mL) are added into reaction solution, point liquid concentrates organic phase, residue silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=25:1), obtain compound N-(2- ((1- (tert-butoxycarbonyl) amino cyclopropyl) methoxyl group) -5- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (7D), red solid (450mg, yield 52%).

MS m/z:619.2[M+1]⁺。

4th step：N- (2- ((1- amino cyclopropyl) methoxyl group) -5- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 7)

By N- (2- ((1- (tert-butoxycarbonyl) amino cyclopropyl) methoxyl group) -5- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (7D) (450mg, 0.73mmol) it is dissolved in dichloromethane (12mL), trifluoroacetic acid (3mL) is added, is reacted at room temperature 2 hours.Water (50mL) is added into reaction solution, pH to 8 is adjusted with saturated sodium bicarbonate aqueous solution, ethyl acetate (100mL) is added, point liquid concentrates organic phase, and residue prepares N- (2- ((1- Amino cyclopropyl) methoxyl group) -5- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 7), faint yellow solid (70mg, yield 19%).

MS m/z:519.1[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ9.32(s,1H),8.41(d,2H),8.33(d,2H),7.41(s,1H),7.36(d,1H),7.29(d,1H),7.21(t,1H),6.57(s,1H),6.38(dd,1H),6.34–6.25(m,1H),5.70(d,1H),3.90(s,5H),3.87(s,3H),1.25(s,1H),0.75(t,2H),0.67(t,2H)。

Embodiment 8

N- (5- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyl groups -2- (methyl (2- (nafoxidine -1- bases) ethyl) amino) phenyl) acrylamide (compound 8)

N-(5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)phenyl)acrylamide

The first step：5- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyl groups -2- (methyl (2- (nafoxidine -1- bases) ethyl) amino) -1- nitrobenzene (8B)

5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)-nitrobenzene

By 5- ((4- (indol-3-yl) -5- chlorine pyrimidine -2-base) amino) fluoro- 1- nitrobenzene (the intermediate 6) (1.0g of -4- methoxyl groups -2-, 2.4mmol), N- methyl -2- (nafoxidine -1- bases) ethylamine (8A) (0.60g, 4.8mmol) and N, N- diisopropylethylamine (0.6g, 4.8mmol) it is added to N, in N- dimethyl acetamides (3mL), 140 DEG C of microwave reactions 1.5 hours.Reaction solution is cooled down to room temperature, water (20mL) is added, is extracted with dichloromethane (50mL × 3), merge organic phase, organic phase is washed with water (50mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloro Methane：Methanol (v/v)=50:1) title compound 5- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyl groups -2- (methyl (2- (nafoxidine -1- bases) ethyl) amino) -1- nitrobenzene (8B) is obtained, red solid (0.5g, yield 40%).

¹H NMR(400MHz,CDCl₃)δ9.17(s,1H),9.04(s,1H),8.45(m,1H),8.39(s,1H),8.29(s,1H),7.51(s,1H),7.41(m,1H),7.34–7.19(m,2H),6.65(s,1H),3.93(s,3H),3.36–3.25(m,2H),2.86(s,3H),2.81–2.72(m,2H),2.58(s,4H),1.77(s,4H)。

5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)aniline

By 5- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyl groups -2- (methyl (2- (nafoxidine -1- bases) ethyl) amino) -1- nitrobenzene (8B) (0.5g, 0.95mmol), iron powder (0.32g, 5.7mmol) with ammonium chloride (0.51g, 9.5mmol) it is added in ethanol (5mL) and water (2mL), 90 DEG C are reacted 4 hours.Reaction solution is cooled to room temperature, water (20mL) is added into reaction solution, extracted with dichloromethane (50mL × 3), merge organic phase, organic phase is washed with water (50mL × 2), anhydrous sodium sulfate drying, concentration, obtain title compound 5- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyl groups -2- (methyl (2- (nafoxidine -1- bases) ethyl) amino) aniline (8C), red solid (0.4g, yield 85%).

MS m/z:492.4[M+1]⁺。

3rd step：N- (5- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyl groups -2- (methyl (2- (nafoxidine -1- bases) ethyl) amino) phenyl) acrylamide (compound 8)

By 5- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyl groups -2- (methyl (2- (nafoxidine -1- bases) ethyl) amino) aniline (8C) (0.4g, 0.8mmol), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (0.31g, 1.6mmol) with acrylic acid (0.12g, 1.6mmol) it is added in pyridine (5mL), reacts 2 hours at room temperature.Water (10mL) is added into reaction solution, is extracted with dichloromethane (50mL × 3), merges organic phase, organic phase is washed with water (50mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=50:1) title compound N- (5- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyl groups -2- (methyl (2- (nafoxidine -1- bases) ethyl) amino) phenyl) acrylamide (compound 8) is obtained, yellow solid (0.12g, yield 27%).

¹H NMR(400MHz,CDCl₃)δ9.85(s,1H),9.44(s,1H),9.32(s,1H),8.51–8.48(m,1H),8.28–8.25(m,2H),7.55(s,1H),7.35–7.32(m,1H),7.22–7.17(m,2H),6.79(s,1H),6.42–6.39(m,2H),5.72–5.69(m,1H),3.88(s,3H),2.99(s,2H),2.71(s,3H),257–2.40(m,6H),1.85(s,4H)。

MS m/z:546.3[M+1]⁺。

Embodiment 9

N- (4- methoxyl groups -2- (methyl (2- (pyrrolidin-1-yl) ethyl) amino) -5- ((4- (1- Methyl-1H-indole -3- bases) pyridine -2- bases) amino) phenyl) acrylamide (compound 9)

N-(4-methoxy-2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

The first step：2- methoxyl groups-N⁴- methyl-N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -5- nitros-N⁴- (2- (pyrrolidin-1-yl) ethyl) phenyl -1,4- diamines (9B)

2-methoxy-N⁴-methyl-N¹-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-nitro-N⁴-(2-(pyrrolidin-1-yl)ethyl)benzene-1,4-diamine

By 5- ((4- (1- methyl indol -3- bases) pyrimidine -2-base) amino) fluoro- 1- nitrobenzene (the intermediate 3) (1.0g of -4- methoxyl groups -2-, 2.5mmol), N- methyl -2- (pyrrolidin-1-yl) ethylamine (9A) (650mg, 5.1mmol), N, N- diisopropylethylamine (660mg, 5.1mmol) and N, accelerine (5mL) is placed in 25mL microwave reaction pipes, 140 DEG C of microwave reactions 1.5 hours.Reaction solution adds water (50mL) and dichloromethane (50mL), divide liquid, organic phase washed with water (50mL × 2), washed with saturated aqueous common salt (50mL × 1), anhydrous sodium sulfate drying, concentration, with silica gel column chromatography separating-purifying, (eluant, eluent first uses petroleum ether:Ethyl acetate (v/v)=1:1~0:1, then use dichloromethane:Methanol (v/v)=32:1~9:1) title compound 2- methoxyl groups-N is obtained⁴- methyl-N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -5- nitros-N⁴- (2- (pyrrolidin-1-yl) ethyl) phenyl-Isosorbide-5-Nitrae-diamines (9B), yellow solid (820mg, yield 66%).

¹H NMR(400MHz,CDCl₃)δ9.56(s,1H),8.39(d,1H),8.26(s,1H),8.17(m,1H),7.54(s,1H),7.43–7.37(m,1H),7.35–7.27(m,2H),7.19(d,1H),6.70(s,1H),3.99(s,3H),3.94(s,3H),3.41–3.34(m,2H),2.91(s,3H),2.88–2.78(m,2H),2.64(br,4H),1.81(br,4H)。

MS m/z:502.2[M+1]⁺。

Second step：5- methoxyl groups-N¹- methyl-N⁴- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base)-N¹- (2- (pyrrolidin-1-yl) ethyl) benzene -1,2,4- triamines (9C)

5-methoxy-N¹-methyl-N⁴-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N¹-(2-(pyrrolidin-1-yl)ethyl)benzene-1,2,4-triamine

By 2- methoxyl groups-N⁴- methyl-N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -5- nitros-N⁴- (2- (pyrrolidin-1-yl) ethyl) phenyl -1,4- diamines (9B) (820mg, 1.63mmol) it is dissolved in ethanol (30mL) and water (10mL), add iron powder (546mg, 9.78mmol) with ammonium chloride (872mg, 16.3mmol), 95 DEG C of back flow reactions 3 hours.Reaction solution adds water (50mL) and dichloromethane (50mL), divide liquid, organic phase washed with water (30mL × 2) and saturated aqueous common salt (30mL × 1) washing, anhydrous sodium sulfate drying, concentration, with silica gel column chromatography separating-purifying, (eluant, eluent first uses petroleum ether:Ethyl acetate (v/v)=1:1~0:1, then use dichloromethane:Methanol (v/v)=32:1~9:1) title compound 5- methoxyl groups-N, is obtained¹- methyl-N⁴- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base)-N¹- (2- (pyrrolidin-1-yl) ethyl) benzene -1,2,4- triamines (9C), brown solid (410mg, yield 53%).

¹H NMR(400MHz,CDCl₃)δ8.48(dd,1H),8.33(d,1H),8.16(s,1H),7.80(s,1H),7.60(s,1H),7.41–7.35(m,1H),7.35–7.27(m,2H),7.03(d,1H),6.69(s,1H),3.88(s,3H),3.85(s,3H),3.23(t,2H),2.95(m,6H),2.70(s,3H),1.98(br,4H)。

MS m/z:472.3[M+1]⁺。

3rd step：N- (4- methoxyl groups -2- (methyl (2- (pyrrolidin-1-yl) ethyl) amino) -5- ((4- (1- Methyl-1H-indole -3- bases) pyridine -2- bases) amino) phenyl) acrylamide (compound 9)

By 5- methoxyl groups-N¹- methyl-N⁴- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base)-N¹- (2- (pyrrolidin-1-yl) ethyl) benzene -1,2,4- triamines (9C) (410mg, 0.87mmol) it is dissolved in 15mL pyridines, add acrylic acid (313mg, 4.35mmol) with 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (834mg, 4.35mmol), react at room temperature 4 hours.Water (50mL) and dichloromethane (50mL) are added to reaction solution, divide liquid, organic phase is washed with 10% sodium hydroxide solution (50mL × 2), water (50mL × 2) and saturated aqueous common salt (50mL × 1) successively, anhydrous sodium sulfate drying, concentration, with silica gel column chromatography separating-purifying, (eluant, eluent first uses petroleum ether:Ethyl acetate (v/v)=1:1~0:1, then use dichloromethane:Methanol (v/v)=32:1~19:1), obtain title compound N- (4- methoxyl groups -2- (methyl (2- (pyrrolidin-1-yl) ethyl) amino) -5- ((4- (1- Methyl-1H-indole -3- bases) pyridine -2- bases) amino) phenyl) acrylamide (compound 9), yellow solid (190mg, yield 42%).

¹H NMR(400MHz,DMSO-d₆)δ9.84(s,1H),9.08(s,1H),8.65(s,1H),8.33(d,1H), 8.25(d,1H),7.89(s,1H),7.52(d,1H),7.24(t,2H),7.15(t,1H),7.03(s,1H),6.50(s,1H),6.26(dd,1H),5.77(d,1H),3.91(s,3H),3.87(s,3H),2.98(s,2H),2.71(s,3H),2.55–2.45(m,6H),1.75(br,4H)。

MS m/z:526.2[M+1]⁺。

Embodiment 10

N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- (2- (4- methylpiperazine-1-yls) ethyoxyl) phenyl) acrylamide (compound 10)

N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)acrylamide

The first step：The chloro- N- of 5- (2- methoxyl groups -4- (2- (4- methylpiperazine-1-yls) ethyoxyl) -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (10B)

5-chloro-N-(2-methoxy-4-(2-(4-methylpiperazin-1-yl)ethoxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

By the chloro- N- of 5- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (intermediate 4) (854.1mg, 2mmol) it is dissolved in tetrahydrofuran (50mL), sodium hydride (80mg is added under ice bath, 2.2mmol, wt%=60%), stir 30 minutes, 2- (4- methylpiperazine-1-yls) ethanol (576.5mg is added dropwise, 4mmol), room temperature reaction is stayed overnight.Reaction terminates, add 100mL water and 100mL ethyl acetate, divide liquid, organic phase anhydrous sodium sulfate drying, it is concentrated to give the chloro- N- of compound 5- (2- methoxyl groups -4- (2- (4- methylpiperazine-1-yls) ethyoxyl) -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (10B), yellow solid (800mg, yield 80%).

MS m/z:552.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ9.20(s,1H),8.46(d,1H),8.38(s,1H),8.21(s,1H),7.50(s,1H),7.38(d,1H),7.36–7.30(m,1H),7.29–7.23(m,1H),6.61(s,1H),4.24(t,2H),3.99(s,3H),3.90(d,3H),2.89(t,2H),2.77–2.64(m,4H),2.50(s,4H),2.31(s,3H)。

Second step：N¹- (the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -6- methoxyl groups -4- (2- (4- methylpiperazine-1-yls) ethyoxyl) phenyl -1,3- diamines (10C)

N¹-(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-(2-(dimethylamino)ethoxy)-6-methoxybenzene-1,3-diamine

By the chloro- N- of 5- (2- methoxyl groups -4- (2- (4- methylpiperazine-1-yls) ethyoxyl) -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (10B) (800mg, 1.45mmol) it is dissolved in ethanol (15mL), add water (5mL), iron powder (486.3mg, 8.7mmol) with ammonium chloride (54mg, 1mmol), it is warming up to 90 DEG C, back flow reaction 4 hours.Reaction solution is cooled to room temperature, filtered, concentration.With silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=1:0~10:1) compound N, is obtained¹- (the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -6- methoxyl groups -4- (2- (4- methylpiperazine-1-yls) ethyoxyl) phenyl -1,3- diamines (10C), yellow solid (200mg, yield 26.5%).

MS m/z:522.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ8.63(d,1H),8.31(s,1H),8.22(s,1H),8.06(s,1H),7.51(s,1H),7.40(d,1H),7.34(dd,1H),7.28(dd,4.0Hz,1H),6.57(s,1H),4.11(t,2H),3.90(s,3H),3.84(s,3H),2.79(t,2H),2.66(s,4H),2.60–2.44(m,4H),2.32(d,3H)。

3rd step：N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- (2- (4- methylpiperazine-1-yls) ethyoxyl) phenyl) acrylamide (compound 10)

By N¹- (the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -6- methoxyl groups -4- (2- (4- methylpiperazine-1-yls) ethyoxyl) phenyl -1,3- diamines (10C) (150mg, 0.288mmol) it is dissolved in tetrahydrofuran (10mL), add N, N- diisopropylethylamine (0.057mL, 0.345mmol), it is cooled to 0 DEG C, acryloyl chloride (0.028mL is added dropwise, tetrahydrofuran (5mL) solution 0.345mmol), is warmed to room temperature reaction 1 hour.Saturated sodium bicarbonate aqueous solution (50mL) and ethyl acetate (50mL) are added into reaction solution, divide liquid, concentration is prepared into compound N-(5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- (2- (4- methylpiperazine-1-yls) ethyoxyl) phenyl) acrylamide (compound 10), faint yellow solid (40mg, yield 24.1%).

MS m/z:576.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ9.32(s,1H),8.41(s,1H),8.40(s,1H),8.31(s,1H),7.41(s,1H),7.36(d,1H),7.29(d,1H),7.21(t,1H),6.61(s,1H),6.41–6.35(m,2H),5.71(dd,1H),4.18(t,2H),3.90(s,3H),3.87(s,3H),2.72(t,2H),2.62(s,4H),2.53(s,4H),2.33(s,3H)。

Embodiment 11

N- (4- methoxyl groups -2- (methyl (1- methyl nafoxidine -3- bases) amino) -5- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) phenyl) acrylamide (compound 11)

N-(5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(1-methylpyrrolidin-3-yl)amino)phenyl)acrylamide

The first step：N¹- (the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) -2- methoxyl groups-N⁴- methyl-N⁴- (1- methyl nafoxidine -3- bases) -5- nitrobenzene -1,4- diamines (11B)

N1-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)-2-methoxy-N4-methyl-N4-(1-methylpyrrolidin-3-yl)-5-nitrobenzene-1,4-diamine

By 5- ((4- (indol-3-yl) -5- chlorine pyrimidine -2-base) amino) fluoro- 1- nitrobenzene (the intermediate 6) (1.0g of -4- methoxyl groups -2-, 2.4mmol), N, 1- dimethyl tetrahydros pyrroles -3- amine (11A) (0.55g, 4.8mmol) and N, N- diisopropylethylamine (DIPEA) (0.6g, 4.8mmol) it is added to N, in N- dimethyl acetamides (3mL), 1.5 hours of 140 degree of microwave reactions.It is cooled to room temperature, water (20mL) is added into reaction solution, extracted with dichloromethane (50mL × 3), merge organic phase, organic phase is washed with water (50mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=50:1) title compound N, is obtained¹- (the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) -2- methoxyl groups-N⁴- methyl-N⁴- (1- methyl nafoxidine -3- bases) -5- nitrobenzene-Isosorbide-5-Nitrae-diamines (11B), red solid (0.5g, yield 42%).

MS m/z:508.3[M+1]⁺。

Second step：N⁴- (the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) -5- methoxyl groups-N¹- methyl-N¹- (1- methyl nafoxidine -3- bases) benzene -1,2,4- triamines (11C)

N4-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy-N1-methyl-N1-(1-methylpyrrolidin-3-yl)benzene-1,2,4-triamine

By N¹- (the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) -2- methoxyl groups-N⁴- methyl-N⁴- (1- methyl nafoxidine -3- bases) -5- nitrobenzene -1,4- diamines (11B) (0.5g, 0.98mmol), iron powder (0.33g, 5.9mmol) and ammonium chloride (0.52g, 9.8mmol) it is added in ethanol (5mL) and water (2mL), 90 DEG C of 4 hours of reaction.Reaction solution is cooled to room temperature, water (20ml) is added, is extracted with dichloromethane (50mL × 3), merges organic phase, organic phase is washed with water (50mL × 2), anhydrous sodium sulfate drying, concentration obtains title compound N⁴- (the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) -5- methoxyl groups-N¹- methyl-N¹- (1- methyl nafoxidine -3- bases) benzene -1,2,4- triamines (11C), red solid (0.3g, yield 64%).

MS m/z:478.3[M+1]⁺。

3rd step：N- (4- methoxyl groups -2- (methyl (1- methyl nafoxidine -3- bases) amino) -5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 11)

N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(1-methylpyrrolidin-3-yl)amino)phenyl)acrylamide

By N⁴- (the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) -5- methoxyl groups-N¹- methyl-N¹- (1- methyl nafoxidine -3- bases) benzene -1,2,4- triamines (11C) (0.3g, 0.62mmol), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (i.e. EDCI) (0.48g, 2.5mmol) with acrylic acid (0.09g, 1.2mmol) it is added in pyridine (5mL), 2 hours is reacted under room temperature.Water (10mL) is added into reaction solution, is extracted with dichloromethane (50mL × 3), merges organic phase, organic phase is washed with water (50mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=50:1) title compound N- (4- methoxyl groups -2- (methyl (1- methyl nafoxidine -3- bases) amino) -5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 11) is obtained, yellow solid (0.07g, yield 21%).

¹H NMR(400MHz,CDCl₃)δ9.50(s,1H),9.22(d,2H),8.49–8.47(m,1H),8.29–8.28(m,2H),7.56(s,1H),7.35–7.33(m,1H),7.21–7.18(m,2H),6.74(s,1H),6.40-6.38(m,2H),5.73(d,1H),3.88(s,3H),3.59(s,1H),2.79(s,1H),2.60(br,6H),2.32(s,3H),2.07–1.98(m,1H),1.82(s,1H)。

MS m/z:546.2[M+1]⁺。

Embodiment 12

N- (4- methoxyl groups -2- (methyl (1- methyl nafoxidine -3- bases) amino) -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 12)

N-(4-methoxy-2-(methyl(1-methylpyrrolidin-3-yl)amino)-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

The first step：N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -2- methoxyl groups-N⁴- methyl-N⁴- (1- methyl nafoxidine -3- bases) -5- nitrobenzene -1,4- diamines (12B)

N1-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-methoxy-N4-methyl-N4-(1-methylpyrrolidin-3-yl)-5-nitrobenzene-1,4-diamine

By 5- ((4- (1- methyl indol -3- bases) pyrimidine -2-base) amino) fluoro- 1- nitrobenzene (the intermediate 3) (1.0g of -4- methoxyl groups -2-, 2.5mmol), N, 1- dimethyl pyrrolidine -3- amine (11A) (580mg, 5.1mmol), N, N- diisopropylethylamine (660mg, 5.1mmol), trifluoroethanol (5mL) is placed in 25mL microwave reaction pipes, 140 DEG C of microwave reactions 1.5 hours.Water (50mL) and dichloromethane (50mL) are added into reaction solution, divide liquid, organic phase is washed with water (50mL × 2), washed with saturated aqueous common salt (50mL × 1), anhydrous sodium sulfate drying, concentration, with silica gel column chromatography separating-purifying (petroleum ether：Ethyl acetate (v/v)=1:1~0:1；Dichloromethane：Methanol (v/v)=32:1~9:1) title compound N is obtained¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -2- methoxyl groups-N⁴- methyl-N⁴- (1- methyl nafoxidine -3- bases) -5- nitrobenzene-Isosorbide-5-Nitrae-diamines (12B), yellow solid (370mg, yield 31%).

¹H NMR(400MHz,CDCl₃)δ9.52(s,1H),8.39(d,1H),8.22(s,1H),8.18(dd,1H),7.57(s,1H),7.44–7.36(m,1H),7.35–7.28(m,2H),7.19(d,1H),6.66(s,1H),4.03(dd,1H),3.98(s,3H),3.93(s,3H),2.95–2.85(m,1H),2.84(d,3H),2.79–2.62(m,3H),2.45(s,3H),2.18(m,1H),2.07–1.93(m,1H)。

MS m/z:488.4[M+1]⁺。

Second step：N⁴- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -5- methoxyl groups-N¹- methyl-N¹- (1- methyl nafoxidine -3- bases) benzene -1,2,4- triamines (12C)

N4-(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy-N1-methyl-N1-(1-methylpyrrolidin-3-yl)benzene-1,2,4-triamine

By N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -2- methoxyl groups-N⁴- methyl-N⁴- (1- methyl nafoxidine -3- bases) -5- nitrobenzene -1,4- diamines (12B) (0.37g, 0.75mmol), iron powder (0.25g, 4.5mmol) with ammonium chloride (0.4g, 7.59mmol) it is added in ethanol (5mL) and (2mL) water mixed solution, 90 DEG C of 4 hours of reaction.Reaction solution is cooled to room temperature, water (20mL) is added, is extracted with dichloromethane (50mL × 3), merges organic phase, organic phase is washed with water (50mL × 2), anhydrous sodium sulfate drying, concentration obtains title compound N⁴- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -5- methoxyl groups-N¹- methyl-N¹- (1- methyl nafoxidine -3- bases) benzene -1,2,4- triamines (12C), black solid (0.3g, Yield 88%).

MS m/z:458.4[M+1]⁺。

3rd step：N- (4- methoxyl groups -2- (methyl (1- methyl nafoxidine -3- bases) amino) -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 12)

By N⁴- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -5- methoxyl groups-N¹- methyl-N¹- (1- methyl nafoxidine -3- bases) benzene -1,2,4- triamines (12C) (0.4g, 88mmol), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDCI) (0.67,3.5mmol) with acrylic acid (0.127g, 1.7mmol) it is added in pyridine (5mL), 2 hours is reacted at room temperature.Water (10mL) is added into reaction solution, is extracted with dichloromethane (50mL × 3), merges organic phase, organic phase is washed with water (50mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=50:1) title compound N- (4- methoxyl groups -2- (methyl (1- methyl nafoxidine -3- bases) amino) -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 12) is obtained, yellow solid (0.012g, yield 83%).

¹H NMR(400MHz,DMSO-d₆)δ9.39(s,1H),9.07(s,1H),8.65(s,1H),8.33(d,1H),8.24(d,1H),7.89(s,1H),7.52(d,1H),7.26–7.22(m,2H),7.15(t,1H),7.00(s,1H),6.65-5.59(m,1H),6.26(d,1H),5.76(d,1H),3.91(s,3H),3.86(s,3H),3.60(s,1H),2.59(s,5H),2.42(s,2H),2.23(s,3H),1.92(s,1H),1.74(s,1H)。

MS m/z:512.2[M+1]⁺。

Embodiment 13

(R)-N- (5- ((the chloro- 4- of 5- (pyrazolo [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) -4- methoxyl groups -2- ((1- methyl nafoxidine -3- bases) epoxide) phenyl) acrylamide (compound 13)

(R)-N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpyrrolidin-3-yl)oxy)phenyl)acrylamide

The first step：(R) the chloro- N- of -5- (2- methoxyl groups -4- ((1- methyl nafoxidine -3- bases) epoxide) -5- nitrobenzophenones) -4- (pyrazolo [1,5-a] pyridin-3-yl) pyrimidine -2- diamines (13B)

(R)-5-chloro-N-(2-methoxy-4-((1-methylpyrrolidin-3-yl)oxy)-5-nitrophenyl)-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine

Sodium hydride (0.09g is added in reaction bulb, 2.25mmol), it is cooled to 0 DEG C, add tetrahydrofuran (5mL) and 5- ((5- chloro- 4- (pyrazolos [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) fluoro- 1- nitrobenzene (the intermediate 5) (0.413g of -4- methoxyl groups -2-, 2.25mmol), (R)-(-) -1- methyl -3- hydroxyl pyrrolidines (0.118g is added dropwise, tetrahydrofuran (5mL) solution 1.17mmol), at room temperature reaction is stayed overnight.Reaction solution is cooled down to 0 DEG C, middle addition saturated ammonium chloride solution (10mL), reaction is quenched, added water (10mL), and point liquid, aqueous phase is extracted with ethyl acetate (50mL × 3), merge organic phase, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (petroleum ether:Ethyl acetate (v/v)=2:1, methanol:Dichloromethane (v/v)=1:2) the chloro- N- of title compound (R) -5- (2- methoxyl groups -4- ((1- methyl nafoxidine -3- bases) epoxide) -5- nitrobenzophenones) -4- (pyrazolos [1 are obtained, 5-a] pyridin-3-yl) pyrimidine -2- diamines (13B), yellow solid (0.22g, yield 44%).

¹H NMR(400MHz,DMSO-d₆)δ8.95(s,1H),8.86-8.84(d,1H),8.81(s,1H),8.46(s,1H),8.30(s,1H),7.38-7.34(dt,1H),7.17-7.13(dt,1H),6.87(s,1H),5.25(s,1H),3.95(s,3H)。

MS m/z:496.2[M+1]⁺。

Second step：(R)-N¹- (the chloro- 4- of 5- (pyrazolo [1,5-a] pyridin-3-yl) pyrimidine -2-base) -6- methoxyl groups -4- ((1- methyl nafoxidine -3- bases) epoxide) phenyl -1,3- diamines (13C)

(R)-N1-(5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)-6-methoxy-4-((1-methylpyrrolidin-3-yl)oxy)benzene-1,3-diamine

By the chloro- N- of (R) -5- (2- methoxyl groups -4- ((1- methyl nafoxidine -3- bases) epoxide) -5- nitrobenzophenones) -4- (pyrazolos [1,5-a] pyridin-3-yl) pyrimidine -2- diamines (13B) (0.20g, 0.40mmol), iron powder (0.145g, 2.60mmol) with ammonium chloride (0.04g, the in the mixed solvent of absolute ethyl alcohol (9mL) and water (3mL) 0.75mmol) is dissolved in, 90 DEG C is warming up to and reacts 4.5 hours.Reaction solution is cooled to room temperature, suction filtration concentrates filtrate, residue silica gel column chromatography separating-purifying (methanol:Dichloromethane (v/v)=1:2) title compound (R)-N, is obtained¹- (5- chloro- 4- (pyrazolos [1,5-a] pyridin-3-yl) pyrimidine -2-base) -6- methoxyl groups -4- ((1- methyl nafoxidine -3- bases) epoxide) phenyl -1,3- diamines (13C), greenish yellow solid (0.07g, yield 38%).

¹H NMR(400MHz,CDCl₃)δ8.93(s,1H),8.62-8.55(m,2H),8.35(s,1H),7.90(s,1H),7.44(s,1H),7.38-7.36(dt,1H),6.98-6.94(dt,1H),6.49(s,1H),4.93(s,1H),3.84(s,3H),3.49(s,1H),3.20-3.06(m,4H),2.66(s,3H),2.43-2.35(m,2H)。

MS m/z:466.3[M+1]⁺。

3rd step：(R)-N- (5- ((the chloro- 4- of 5- (pyrazolo [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) -4- methoxyl group -2- ((1- Methyl nafoxidine -3- bases) epoxide) phenyl) acrylamide (compound 13)

By (R)-N¹- (5- chloro- 4- (pyrazolos [1,5-a] pyridin-3-yl) pyrimidine -2-base) -6- methoxyl groups -4- ((1- methyl nafoxidine -3- bases) epoxide) phenyl -1,3- diamines (13C) (0.07g, 0.15mmol) it is dissolved in the tetrahydrofuran (3mL) newly steamed, reaction solution is cooled down to 0 DEG C, new steaming tetrahydrofuran (9.7mL) solution of diisopropyl ethyl amine (0.3mL) and new steaming tetrahydrofuran (0.87mL) solution of acryloyl chloride (0.13mL) is added dropwise, reacts 1.5 hours at room temperature.Saturated sodium bicarbonate solution (50mL) is added into reaction solution, reaction is quenched, aqueous phase is extracted with ethyl acetate (50mL × 3), merges organic phase, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (methanol:Dichloromethane (v/v)=1:2~1:1), title compound (R)-N- (5- ((5- chloro- 4- (pyrazolos [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) -4- methoxyl groups -2- ((1- methyl nafoxidine -3- bases) epoxide) phenyl) acrylamide (compound 13), yellow solid (0.03g, yield 41%).

¹H NMR(400MHz,DMSO-d₆)δ9.27(s,1H),8.93(s,1H),8.82-8.81(d,1H),8.65(s,1H),8.37(s,1H),8.14(s,1H),7.30-7.28(dt,1H),7.11-7.08(dt,1H),6.79(s,1H),6.61-6.50(m,1H),6.19-6.14(dd,1H),5.70-5.67(dd,1H),4.98(s,1H),3.82(s,1H),3.76(s,3H),2.84-2.66(m,4H),2.39-2.36(m,2H),2.30(s,3H)。

MS m/z:520.3[M+1]⁺。

Embodiment 14

N- (5- ((the chloro- 4- of 5- (pyrazolo [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) -2- (2- (dimethylamino) ethyoxyl) -4- methoxyphenyls) acrylamide (compound 14)

N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)ethoxy)-4-methoxyphenyl)acrylamide

The first step：The chloro- N- of 5- (4- (2- dimethylaminos) ethyoxyl) -2- methoxyl group -5- nitrobenzophenones) -4- pyrazolos [1,5-a] pyridin-3-yl) pyrimidine -2- amine (14B)

5-chloro-N-(4-(2-(dimethylamino)ethoxy)-2-methoxy-5-nitrophenyl)-4-(pyrazolo[1,5-a]p yridin-3-yl)pyrimidin-2-amine

By 5- ((5- chloro- 4- (pyrazolos [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) fluoro- 1- nitrobenzene (the intermediate 5) (0.41g of -4- methoxyl groups -2-, 1.00mmol) it is dissolved in tetrahydrofuran (20mL), reaction solution is cooled down to 0 DEG C, add sodium hydride (0.08g, 1.1mmol, wt%=60%), after stirring 5 minutes, add N, N- dimethylethanolamines (14A) (0.11mL, 1.1mmol), reaction is warmed to room temperature lower reaction 4 hours.Water (20mL) is added into reaction bulb, aqueous phase is extracted with ethyl acetate (50mL × 2), merge organic phase, organic phase is washed with saturated aqueous common salt (30mL), column chromatography for separation purifies (methylene chloride/methanol (v/v)=15 after anhydrous sodium sulfate drying, concentration:1) the chloro- N- of 5- (4- (2- dimethylaminos) ethyoxyl) -2- methoxyl group -5- nitrobenzophenones of yellow solid are obtained) -4- pyrazolos [1,5-a] pyridin-3-yl) pyrimidine -2- amine (14B) (0.36g, yield 75%).

¹H NMR(400MHz,CDCl₃)δ9.06(s,1H),8.93(s,1H),8.55-8.47(m,2H),8.41(s,1H),7.48(s,1H),7.37-7.35(m,1H),6.96-6.94(m,1H),6.67(s,1H),4.27-4.24(m,2H),4.01(s,3H),2.91-2.88(m,2H),2.42(s,6H)。

Second step：N¹- (chloro- 4- pyrazolos [1,5-a] pyridin-3-yl-pyrimidine -2-bases of 5-) -4- (2- dimethylamino ethoxies) -6- methoxyl groups-phenyl -1,3- diamines (14C)

N1-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)-4-(2-dimethylaminoethyloxy)-6-methoxy-benzene-1,3-diamine

Weigh the chloro- N- of 5- (4- (2- dimethylaminos) ethyoxyl) -2- methoxyl group -5- nitrobenzophenones) -4- pyrazolos [1,5-a] pyridin-3-yl) pyrimidine -2- amine (14B) (0.36g, 0.74mmol), it is placed in 100mL round-bottomed flasks, ethanol (21mL), water (7mL), reduced iron powder (0.25g are sequentially added into reaction bulb, 4.44mmol) with ammonium chloride (0.028g, 0.52mmol), temperature rising reflux reacts 6 hours.By reacting liquid filtering, filter cake is washed with dichloromethane (10mL × 2), methanol (10mL × 2) successively, merging filtrate, and concentration, residue uses column chromatography purification (methylene chloride/methanol (v/v)=15:1) N of gray solid shape is obtained¹- (chloro- 4- pyrazolos [1,5-a] pyridin-3-yl-pyrimidine -2-bases of 5-) -4- (2- dimethylamino ethoxies) -6- methoxyl groups-phenyl -1,3- diamines (14C) (0.30g, yield 88%).

¹H NMR(400MHz,CDCl₃)δ8.94(s,1H),8.60-8.55(m,2H),8.35(s,1H),7.87(s,1H),7.42-7.37(m,2H),6.96-6.93(m,1H),6.59(s,1H),4.19-4.17(m,2H),3.85(s,3H),2.91-2.88(m,2H),2.42(s,6H)。

3rd step：N- (5- ((the chloro- 4- of 5- (pyrazolo [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) -2- (2- (dimethylamino) ethyoxyl) -4- methoxyphenyls) acrylamide (compound 14)

N-[5-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)amino]-2-(2-dimethylaminoethyloxy)-4-methoxy-phenyl]prop-2-enamide

Weigh N¹- (the chloro- 4- pyrazolos [1 of 5-, 5-a] pyridin-3-yl-pyrimidine -2-base) -4- (2- dimethylamino ethoxies) -6- methoxyl groups-phenyl -1,3- diamines (14C) (0.2g, 0.43mmol), it is placed in 100mL round-bottomed flasks, is sequentially added into reaction bulb Tetrahydrofuran (15mL) and diisopropyl ethyl amine (0.09mL, 0.56mmol), are cooled to 0 DEG C, are added dropwise after acryloyl chloride (0.04mL, 0.52mmol), completion of dropping, temperature reaction 1 hour.Be concentrated under reduced pressure reaction solution, dichloromethane (50mL) is added into residue, saturated sodium bicarbonate aqueous solution (30mL), divide liquid, aqueous phase is extracted with dichloromethane (50mL), merges organic phase, and organic phase is washed with saturated aqueous common salt (30mL), anhydrous sodium sulfate drying, column chromatography for separation purifies (methylene chloride/methanol (v/v)=15 after being concentrated under reduced pressure:1), obtain N- (5- ((the 5- chloro- 4- (pyrazolos [1 of yellow solid, 5-a] pyridin-3-yl) pyrimidine -2-base) amino) -2- (2- (dimethylamino) ethyoxyl) -4- methoxyphenyls) acrylamide (compound 14) (0.08g, yield 48%).

MS m/z(ESI):517.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ10.02(s,1H),9.53(s,1H),8.82(s,1H),8.76-8.74(d,1H),8.53-8.51(d,1H),8.25(s,1H),7.36(s,1H),7.28-7.26(m,1H),6.91-6.89(m,1H),6.77(s,1H),6.38-6.36(m,2H),5.68-5.65(m,1H),3.98(s,3H),3.87(s,3H),2.82-2.80(m,2H),2.72(s,3H),2.34-2.30(m,8H)。

Embodiment 15

N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- ((dimethylamino) ethyoxyl) -4- methoxyphenyls) acrylamide (compound 15)

N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)ethoxy)-4-methoxyphenyl)acrylamide

The first step：The chloro- N- of 5- (4- (2- (dimethylamino) ethyoxyl) -2- methoxyl group -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (15B)

5-chloro-N-(4-(2-(dimethylamino)ethoxy)-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

By the chloro- N- of 5- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (intermediate 4) (500mg, 1.17mmol) it is dissolved in tetrahydrofuran (50mL), sodium hydride (51.5mg is added under ice bath, 1.28mmol), stirring 30 minutes, dimethylethanolamine (14A) (0.24mL, 2.34mmol) is added dropwise, reacts at room temperature 4 hours.To reaction solution Middle addition water (100mL) and ethyl acetate (150mL), divide liquid, organic phase anhydrous sodium sulfate drying, it is concentrated to give the chloro- N- of compound 5- (4- (2- (dimethylamino) ethyoxyl) -2- methoxyl group -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (15B), yellow solid (500mg, yield 86.2%).

MS m/z:497.1[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ8.58(d,2H),8.40(s,1H),8.33(s,1H),8.27(d,1H),7.51(d,1H),7.25(t,1H),7.09–6.97(m,2H),4.34(t,2H),3.96(d,3H),3.91(d,3H),2.72(t,2H),2.25(d,6H)。

Second step：N¹- (the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -4- (2- (dimethylamino) ethyoxyl) -6- methoxyphenyl -1,3- diamines (15C)

N1-(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-(2-(dimethylamino)ethoxy)-6-methoxybenzene-1,3-diamine

By the chloro- N- of 5- (4- (2- (dimethylamino) ethyoxyl) -2- methoxyl group -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (15B) (500mg, in the mixed solution for 1mmol) being dissolved in ethanol (15mL) and water (5mL), add iron powder (335mg, 6mmol) with ammonium chloride (37.4mg, 0.7mmol), it is warming up to 90 DEG C, back flow reaction 4 hours.Reaction solution is cooled to room temperature, filtered, concentration, residue silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=1:0~50:1) compound N, is obtained¹- (the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -4- (2- (dimethylamino) ethyoxyl) -6- methoxyphenyls -1,3- diamines (15C), yellow solid (350mg, yield 75.1%).

MS m/z:467.2[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ8.53(s,1H),8.36(d,1H),8.30(s,1H),8.25(s,1H),7.50(d,1H),7.24(t,1H),7.07(t,1H),6.98(s,1H),6.74(s,1H),5.75(s,1H),4.23(s,2H),3.90(s,3H),3.68(s,3H),3.05(d,3H),2.67(s,6H)。

3rd step：N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- ((dimethylamino) ethyoxyl) -4- methoxyphenyls) acrylamide (compound 15)

By N¹- (the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -4- (2- (dimethylamino) ethyoxyl) -6- methoxyphenyls -1,3- diamines (15C) (350mg, 0.75mmol) it is dissolved in tetrahydrofuran (28mL), add N, N- diisopropylethylamine (i.e. DIPEA) (0.15mL, 0.9mmol), it is cooled to 0 DEG C, acryloyl chloride (0.073mL is added dropwise, tetrahydrofuran (5mL) solution 0.9mmol), is warmed to room temperature reaction 3 hours.Saturated sodium bicarbonate aqueous solution (100mL) and dichloromethane (100mL) are added into reaction solution, divide liquid, concentrate organic phase, it is prepared into N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- ((dimethylamino) ethyoxyl) -4- methoxyphenyls) acrylamide (compound 15), white solid (40mg, 10.3%).

MS m/z:521.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ9.65(s,1H),9.38(s,1H),8.39(d,2H),8.33(s,1H),7.45(s,1H),7.35(d,1H),7.29(d,1H),7.22(dd,1H),6.63(s,1H),6.44–6.26(m,2H),5.68(d,1H),4.17–4.10(m,2H),3.90(s,3H),3.87(s,3H),2.63(s,2H),2.39(s,6H)。

Embodiment 16

N- (5- ((the chloro- 4- of 5- (1- methyl -6- morpholinyl -1H- indol-3-yls) pyrimidine -2-base) amino) the fluoro- 4- methoxyphenyls of -2-) acrylamide (compound 16)

N-(5-((5-chloro-4-(1-methyl-6-morpholino-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)acrylamide

The first step：1- (6- nitro -1H- indoles -1- bases) ethyl ketone (16B)

1-(6-nitro-1H-indol-1-yl)ethanone

6- nitroindolines (16A) (16.2g, 0.1mol) are dissolved in pyridine (40mL), acetic anhydride (40.8g, 0.4mol) are added, room temperature reaction is stayed overnight.Reaction solution is concentrated, saturated aqueous common salt (200mL) and ethyl acetate (200mL) are added into residue, point liquid, organic phase anhydrous sodium sulfate drying is concentrated to give target compound 1- (6- nitro -1H- indoles -1- bases) Ethyl ketone (16B), yellow solid (6g, yield 30%).

MS m/z:205.1[M+1]⁺。

Second step：1- (6- amino -1H- indoles -1- bases) ethyl ketone (16C)

1-(6-amino-1H-indol-1-yl)ethanone

By 1- (6- nitro -1H- indoles -1- bases) ethyl ketone (16B) (20g, 0.1mol) it is dissolved in methanol (50mL) and tetrahydrofuran (50mL), add palladium carbon (2g, 10%) with ammonium formate (40.3g, 6.4mol), 60 DEG C are reacted 2 hours.Reaction terminates, filtering, and filter cake is washed with ethyl acetate (100mL), merging filtrate, ethyl acetate (150mL) and saturated aqueous common salt (150mL) are added in concentration, residue, point liquid, aqueous phase is washed with ethyl acetate (150mL), merge organic phase, organic phase anhydrous sodium sulfate drying is concentrated to give 1- (6- amino -1H- indoles -1- bases) ethyl ketone (16C), yellow solid (9.3g, yield 53.4%).

3rd step：4- (1H- indoles -6- bases) morpholine (16D)

4-(1H-indol-6-yl)morpholine

By 1- (6- amino -1H- indoles -1- bases) ethyl ketone (16C) (8g, 60.1mmol) with 2, bromodiethyl ether (the 9mL of 2'- bis-, 72mmol) it is dissolved in N, in dinethylformamide (100mL), DIPEA (i.e. DIP ethyl acetate) (29.7mL is added, 180mmol), 90 DEG C of reactions are stayed overnight.Reaction solution is cooled to room temperature, add ethyl acetate (200mL) and saturated aqueous common salt (200mL), divide liquid, aqueous phase is washed with ethyl acetate (200mL), merge organic phase, organic phase anhydrous sodium sulfate drying is concentrated to give 4- (1H- indoles -6- bases) morpholine (16D), yellow solid (9.2g, yield 76%).

MS m/z:203.1[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ8.04(s,1H),7.53(d,1H),7.09(dd,1H),6.98–6.80(m,2H),6.46(ddd,1H),4.00–3.83(m,4H),3.25–3.08(m,4H)。

4th step：4- (3- (2,5- dichloro pyrimidine -4- bases) -1H- indoles -6- bases) morpholine (16E)

4-(3-(2,5-dichloropyrimidin-4-yl)-1H-indol-6-yl)morpholine

By 4- (1H- indoles -6- bases) morpholine (16D) (4.5g; 22.3mmol) it is dissolved in tetrahydrofuran (100mL); under nitrogen protection, 0 DEG C is cooled to, methyl-magnesium-bromide (7.5mL is added dropwise; 22.3mmol); continue to stir 0.5 hour, add trichloropyrimidine (2.05g, 22.3mmol); room temperature reaction 1 hour, is warming up to 60 DEG C and reacts 1 hour.Reaction solution is cooled to room temperature, acetic acid (6.34mL) is added dropwise and stirs 10 minutes, water (100mL) is added, 60 DEG C are stirred 30 minutes, point liquid, organic phase addition normal heptane (100mL), concentration, residue silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~50:1) compound 4- (3- (2,5- dichloro pyrimidine -4- bases) -1H- indoles -6- bases) morpholine (16E), greenish yellow solid (3g, yield 39%), is obtained.

MS m/z:349.0[M+1]⁺。

5th step：4- (3- (2,5- dichloro pyrimidine -4- bases) -1- Methyl-1H-indole -6- bases) morpholine (16F)

4-(3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-indol-6-yl)morpholine

By 4- (3- (2,5- dichloro pyrimidine -4- bases) -1H- indoles -6- bases) morpholine (16E) (3g, 8.6mmol) it is dissolved in tetrahydrofuran (50mL), 0 DEG C is cooled to, sodium hydride (460mg, 11.5mmol) is added, reaction 30 minutes, iodomethane (1.6mL, 25.8mmol) is added, reaction 3 hours is warmed to room temperature.Reaction solution is concentrated, residue is washed with water (50mL) and tetrahydrofuran (20mL), filtering, filtration cakes torrefaction obtains 4- (3- (2,5- dichloro pyrimidine -4- bases) -1- Methyl-1H-indole -6- bases) morpholine (16F), faint yellow solid (1.9g, yield 61.3%).

MS m/z:363.0[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ8.59(d,1H),8.41(s,1H),8.29(s,1H),7.07(d,1H),6.82(s,1H),3.99–3.89(m,4H),3.85(s,3H),3.30–3.20(m,4H)。

6th step：The chloro- N- of 5- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2- amine (16G)

5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-6-morpholino-1H-indol-3-yl)pyrimidin-2-amine

By 4- (3- (2,5- dichloro pyrimidine -4- bases) -1- Methyl-1H-indole -6- bases) morpholine (16F) (724g, 2mmol) it is dissolved in 2- amylalcohols (20mL), add the fluoro- 2- methoxyl groups -5- nitroanilines (372mg of 4-, 2mmol) with p-methyl benzenesulfonic acid (456.5mg, 2.4mmol), 120 DEG C, back flow reaction 2 days are heated to.Reaction solution is cooled to room temperature, add acetonitrile (50mL), filtering, filter cake is washed with water (50mL), dry-chloro- N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2- amine (16G), gray solid (800mg, yield 80%).

MS m/z:513.1[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ9.35(d,1H),8.39(s,1H),8.34(d,1H),8.14(s,1H),7.56(s,1H),6.97(d,1H),6.80(s,1H),6.75(d,1H),4.02(s,3H),3.93(s,4H),3.84(s,3H),3.23(s,4H)。

7th step：N¹- (the chloro- 4- of 5- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2-base) the fluoro- 6- methoxybenzenes -1,3- diamines (16H) of -4-

N1-(5-chloro-4-(1-methyl-6-morpholino-1H-indol-3-yl)pyrimidin-2-yl)-4-fluoro-6-methoxybenzene-1,3-diamine

General-chloro- N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2- amine (16G) (600mg, 1.17mmol) it is dissolved in ethanol (30mL) and water (10mL), add iron powder (392mg, 7.03mmol) with ammonium chloride (43.8mg, 0.82mmol), it is warming up to 90 DEG C, back flow reaction 4 hours.Reaction solution is cooled to room temperature, filtered, filter cake is washed with methanol (50mL), merging filtrate, concentration, residue silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~50:1) N is obtained¹- (the chloro- 4- of 5- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2-base) fluoro- 6- methoxybenzenes -1, the 3- diamines (16H) of -4-, brown solid (150mg, yield 26.6%).

MS m/z:483.1[M+1]⁺。

8th step：N- (5- ((the chloro- 4- of 5- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2-base) amino) the fluoro- 4- methoxyphenyls of -2-) acrylamide (compound 16)

By N¹- (the chloro- 4- of 5- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2-base) the fluoro- 6- methoxybenzenes -1 of -4-, 3- diamines (16H) (150mg, 0.31mmol) it is dissolved in tetrahydrofuran (10mL), add N, N- diisopropylethylamine (0.06mL, 0.37mmol), it is cooled to 0 DEG C, acryloyl chloride (0.03mL is added dropwise, tetrahydrofuran (5mL) solution 0.37mmol), is warmed to room temperature reaction 1.5 hours.Saturated sodium bicarbonate aqueous solution (100mL) and dichloromethane (100mL) are added into reaction solution, divide liquid, concentration prepares N- (5- ((the chloro- 4- of 5- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2-base) amino) the fluoro- 4- methoxyphenyls of -2-) acrylamide (compound 16), faint yellow solid (20mg, yield 12%).

MS m/z:537.1[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ9.14(s,1H),8.37(s,1H),8.35(s,1H),8.22(s,1H),7.50(d,1H),7.19(s,1H),6.99(s,1H),6.73(d,1H),6.40(dd,1H),6.26(dd,1H),5.75(d,1H),3.96(s,4H),3.90(s,3H),3.86(s,3H),3.26(s,4H)。

Embodiment 17

(R)-N- (5- ((the chloro- 4- of 5- (the fluoro- 1H- indol-3-yls of 4-) pyrimidine -2-base) amino) -2- (3- (dimethylamino) nafoxidine -1- bases) -4- methoxyphenyls) acrylamide (compound 17)

(R)-N-(5-((5-chloro-4-(4-fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide

The first step：(R) the chloro- N- of -5- (4- (3- (dimethylamino) nafoxidine -1- bases) -2- methoxyl group -5- nitrobenzophenones) -4- (the fluoro- 1H- indol-3-yls of 4-) pyrimidine -2- amine (17B)

(R)-5-chloro-N-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxy-5-nitrophenyl)-4-(4-fluoro-1H-indol-3-yl)pyrimidin-2-amine

5- chloro- 4- (the fluoro- 1H- indol-3-yls of 4-)-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) pyrimidine -2- amine is added into reaction bulb (intermediate 7) (1.1g, 2.5mmol), (R)-N, N- dimethyl pyrrole -3- amine (17A) (0.5g, 2.8mmol), diisopropyl ethyl amine (1.5g, 11.5mmol) and N, N'- dimethyl acetamides (10mL), 140 DEG C of microwave reacts 1 hour.Reaction solution is concentrated under reduced pressure into dry, residue silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=100:1) the chloro- N- of brown oil (R) -5- (4- (3- (dimethylamino) nafoxidine -1- bases) -2- methoxyl group -5- nitrobenzophenones) -4- (the fluoro- 1H- indol-3-yls of 4-) pyrimidine -2- amine (17B) (0.5g, yield 38%) is obtained.

MS m/z(ESI):526.3[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ12.00(s,1H),8.48(d,2H),8.26(s,1H),7.85(d,1H),7.32(d,1H),7.17(m,1H),6.84(dd,1H),6.51(s,1H),3.94(s,3H),3.40(dd,1H),3.27–3.19(m,1H),3.17(d,1H),3.11(d,2H),2.23(s,6H),2.16–2.12(m,1H),1.80(m,1H)。

Second step：(R)-N¹- (the chloro- 4- of 5- (the fluoro- 1H- indol-3-yls of 4-) pyrimidine -2-base) -4- (3- (dimethylamino) nafoxidine -1- bases) -6- methoxybenzene -1,3- diamines (17C)

(R)-N1-(5-chloro-4-(4-fluoro-1H-indol-3-yl)pyrimidin-2-yl)-4-(3-(dimethylamino)pyrrolidin-1-yl)-6-methoxybenzene-1,3-diamine

(R) -5- chloro- N- (4- (3- (dimethylamino) nafoxidine -1- bases) -2- methoxyl group -5- nitrobenzophenones) -4- (the fluoro- 1H- indol-3-yls of 4-) pyrimidine -2- amine (17B) (0.5g is added into reaction bulb, 0.95mmol), iron powder (0.32g, 5.7mmol), ammonium chloride (51mg, 0.95mmol) with ethanol/water (27mL/9.5mL), back flow reaction is heated to 2 hours.By reacting liquid filtering, filter cake is washed with ethanol (10mL × 3), merging filtrate, concentration, residue silica gel column chromatography separating-purifying (dichloromethane/ammonia methanol (v/v)=80:1-30:1) brown solid (R)-N is obtained¹- (the chloro- 4- of 5- (the fluoro- 1H- indol-3-yls of 4-) pyrimidine -2-base) -4- (3- (dimethylamino) nafoxidine -1- bases) -6- methoxybenzenes -1,3- diamines (17C) (0.2g, yield 42.6%).

MS m/z(ESI):496.4[M+1]⁺。

3rd step：(R)-N- (5- ((the chloro- 4- of 5- (the fluoro- 1H- indol-3-yls of 4-) pyrimidine -2-base) amino) -2- (3- (dimethylamino) nafoxidine -1- bases) -4- methoxyphenyls) acrylamide (compound 17)

(R)-N is added into reaction bulb¹- (the chloro- 4- of 5- (the fluoro- 1H- indol-3-yls of 4-) pyrimidine -2-base) -4- (3- (dimethylamino) nafoxidine -1- bases) -6- methoxybenzenes -1,3- diamines (17C) (0.18g, 0.36mmol), diisopropyl ethyl amine (52mg, 0.4mmol) with dichloromethane (4.6mL), ice bath is cooled down, acryloyl chloride (33mg is added dropwise, dichloromethane (1mL) 0.36mmol), ice bath reacts 2 hours.The saturated common salt aqueous solution (10mL) is added into reaction solution, stirring point liquid, water layer is extracted with dichloromethane (30mL × 3), merge organic phase, organic phase anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, residue silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=50:1-25:1) faint yellow solid (R)-N- (5- ((the chloro- 4- of 5- (the fluoro- 1H- indol-3-yls of 4-) pyrimidine -2-base) amino) -2- (3- (dimethylamino) nafoxidine -1- bases) -4- are obtained Methoxyphenyl) acrylamide (compound 17) (50mg, yield 25.5%).

MS m/z(ESI):550.3[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ11.95(s,1H),9.28(s,1H),8.42(s,1H),8.11(s,1H),7.87(s,1H),7.84(s,1H),7.31(d,1H),7.15(m,1H),6.83(dd,1H),6.53(s,2H),6.19(d,1H),5.68(d,1H),3.83(s,3H),3.23(m,5H),2.32(s,6H),2.11(s,1H),1.82(s,1H)。

Embodiment 18

N- (5- ((the chloro- 4- of 5- (the fluoro- 1H- indol-3-yls of 4-) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (compound 18)

N-(5-((5-chloro-4-(4-fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

The first step：N¹- (the chloro- 4- of 5- (the fluoro- 1H- indol-3-yls of 4-) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro benzene -1,4- diamines (18B)

N1-(5-chloro-4-(4-fluoro-1H-indol-3-yl)pyrimidin-2-yl)-N4-(2-(dimethylamino)ethyl)-2-methoxy-N4-methyl-5-nitrobenzene-1,4-diamine

5- chloro- 4- (the fluoro- 1H- indol-3-yls of 4-)-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) pyrimidine -2- amine (intermediate 7) (1g is added into reaction bulb, 2.5mmol), N, N, N'- trimethyls ethylenediamine (18A) (0.28g, 2.8mmol), diisopropyl ethyl amine (1.3g, 10.4mmol) and N, N'- dimethyl acetamide (10mL), 140 DEG C of microwave reacts 1 hour.Reaction solution is concentrated under reduced pressure into dry, residue silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=50:1) brown oil N is obtained¹- (the chloro- 4- of 5- (the fluoro- 1H- indol-3-yls of 4-) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro benzene-Isosorbide-5-Nitrae-diamines (18B) (0.55g, yield 45.8%).

MS m/z(ESI):514.3[M+1]⁺。

Second step：N⁴- (the chloro- 4- of 5- (the fluoro- 1H- indol-3-yls of 4-) pyrimidine -2-base)-N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- aminomethyl phenyl -1,2,4- triamines (18C)

N⁴-(5-chloro-4-(4-fluoro-1H-indol-3-yl)pyrimidin-2-yl)-N¹-(2-(dimethylamino)ethyl)-5-methoxy-N¹-methylbenzene-1,2,4-triamine

N is added into reaction bulb¹- (the chloro- 4- of 5- (the fluoro- 1H- indol-3-yls of 4-) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro benzene -1,4- diamines (18B) (0.52g, 1mmol), iron powder (0.34g, 6.1mmol), ammonium chloride (54mg, 1mmol) with ethanol/water (28mL/10mL), back flow reaction is heated to 2 hours.By reacting liquid filtering, filter cake is washed with ethanol (10mL × 3), merging filtrate, concentration, residue silica gel column chromatography separating-purifying (dichloromethane/ammonia methanol (v/v)=100:1-50:1) yellow solid N is obtained⁴- (the chloro- 4- of 5- (the fluoro- 1H- indol-3-yls of 4-) pyrimidine -2-base)-N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- aminomethyl phenyl -1,2,4- triamines (18C) (350mg, yield 71.5%).

MS m/z(ESI):484.3[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ11.96(s,1H),8.45(s,1H),7.97(s,1H),7.86(s,1H),7.42(s,1H),7.33(d,1H),7.17(m,1H),6.87(dd,1H),6.72(s,1H),4.50(s,2H),3.73(s,3H),2.84(t,2H),2.59(s,3H),2.32(t,2H),2.15(s,6H)。

3rd step：N- (5- ((the chloro- 4- of 5- (the fluoro- 1H- indol-3-yls of 4-) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (compound 18)

N is added into reaction bulb⁴- (the chloro- 4- of 5- (the fluoro- 1H- indol-3-yls of 4-) pyrimidine -2-base)-N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- aminomethyl phenyl -1,2,4- triamines (18C) (0.32g, 0.66mmol), diisopropyl ethyl amine (94mg, 0.73mmol) with dichloromethane (8.6mL), ice bath is cooled down, and the dichloromethane solution (2mL) of acryloyl chloride (60mg, 0.66mmol) is added dropwise, reacted 2 hours under completion of dropping, ice bath.Sodium bicarbonate aqueous solution (10mL) is added into reaction solution, stirring, divide liquid, water layer is extracted with dichloromethane (30mL × 3), merges organic phase, and organic phase is washed with saturated aqueous common salt (20mL), anhydrous sodium sulfate drying, filtering, concentration, residue silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=50:1-30:1) faint yellow solid N- (5- ((the chloro- 4- of 5- (the fluoro- 1H- indol-3-yls of 4-) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (compound 18) (140m g, yield 39.4%) is obtained.

MS m/z(ESI):538.3[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ11.98(s,1H),10.03(s,1H),8.81(s,1H),8.46(s,1H),8.22(s,1H),7.93(d,1H),7.31(d,1H),7.15(m,1H),6.98(s,1H),6.83(dd,1H),6.38(dd,1H),6.26(dd,1H),5.74(d,1H),3.82(s,3H),2.96–2.78(m,2H),2.68(s,3H),2.31(m,2H),2.20(s,6H)。

Embodiment 19

N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 7-) pyrimidine -2-base) ammonia Base) -4- methoxyphenyls) acrylamide (compound 19)

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(7-fluoro-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

The first step：N¹- (2- (dimethylamino) ethyl)-N⁴- (4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 7-) pyrimidine -2-base) -5- methoxyl groups-N¹- methyl -2- nitrobenzene -1,4- diamines (19B)

N1-(2-(dimethylamino)ethyl)-N4-(4-(7-fluoro-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy-N1-methyl-2-nitrobenzene-1,4-diamine

4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 7-)-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) pyrimidine -2- amine (intermediate 8) (280mg is added into reaction bulb, 0.68mmol), N, N, N'- trimethyls ethylenediamine (18A) (69mg, 0.68mmol), diisopropyl ethyl amine (219mg, 1.7mmol) and N, N'- dimethyl acetamide (4.5mL), 140 DEG C of microwave reacts 1.5 hours.Reaction solution is cooled to room temperature, add water (10mL), extracted with ethyl acetate (20mL × 2), merge organic phase, organic phase anhydrous sodium sulfate drying, filtering, concentration, residue silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=100:1-20:1) brown solid N is obtained¹- (2- (dimethylamino) ethyl)-N⁴- (4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 7-) pyrimidine -2-base) -5- methoxyl groups-N¹- methyl -2- nitrobenzene-Isosorbide-5-Nitrae-diamines (19B) (120mg, yield 36%).

¹H NMR(400MHz,DMSO-d₆)δ8.58(s,1H),8.33(d,1H),8.30(s,1H),8.18(t,1H)8.13(s,1H),7.20(d,1H),7.03(m,2H),6.84(s,1H),4.03(d,3H),3.95(s,3H),3.27(t,2H),2.86(s,3H),2.49(t,2H),2.16(s,6H)。

Second step：N¹- (2- (dimethylamino) ethyl)-N⁴- (4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 7-) pyrimidine -2-base) -5- methoxyl groups-N¹- methylbenzene -1,2,4- triamines (19C)

N1-(2-(dimethylamino)ethyl)-N4-(4-(7-fluoro-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy-N1-methylbenzene-1,2,4-triamine

MS m/z(ESI):464.6[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ8.29(m,2H),8.25(d,1H),7.83(s,1H),7.41(s,1H), 7.13(d,1H),7.09-6.99(m,2H),6.76(s,1H),4.04(d,2H),3.73(s,3H),2.89(t,3H),2.63(s,3H),2.37(t,2H),2.18(s,6H)。

3rd step：N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 7-) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 19)

N is added into reaction bulb¹- (2- (dimethylamino) ethyl)-N⁴- (4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 7-) pyrimidine -2-base) -5- methoxyl groups-N¹- methylbenzene -1,2,4- triamines (19C) (0.36g, 0.78mmol), diisopropyl ethyl amine (111mg, 0.86mmol) with dichloromethane (10mL), acryloyl chloride (70mg is added dropwise in ice bath cooling, dichloromethane solution (2mL) 0.78mmol), drips off ice bath and reacts 2 hours.Sodium bicarbonate aqueous solution (10mL) is added into reaction solution, stirring point liquid, water layer is extracted (20mL × 2) with dichloromethane, merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, residue silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=30:1-20:1) brown oil N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (the fluoro- 1- Methyl-1H-indoles -3- bases of 7-) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 19) (360mg, yield 90%) is obtained.

MS m/z(ESI):518.3[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ10.13(s,1H),9.07(s,1H),8.63(s,1H),8.35(d,1H),8.07(d,1H),7.96(s,1H),7.22(d,1H),7.14–6.96(m,3H),6.49(dd,1H),6.27(dd,1H),5.77(d,1H),4.08(m,3H),3.86(s,3H),2.94(br,2H),2.71(s,3H),2.40(br,2H),2.27(s,6H)。

Embodiment 20

N- (2- ((2- dimethylaminos) ethyl) (methyl) amino) -4- methoxyl groups -5- ((5- methoxyl groups -4- (pyrazolo [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) phenyl) acrylamide (compound 20)

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((5-methoxy-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

The first step：N⁴- (2- dimethylamino ethyls) -2- methoxyl groups-N¹- (5- methoxyl group -4- pyrazolos [1,5-a] pyridin-3-yl-pyrimidine - 2- bases)-N⁴- methyl-5-nitro-phenyl -1,4- diamines (20B)

N4-(2-dimethylaminoethyl)-2-methoxy-N1-(5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)-N4-methyl-5-nitro-benzene-1,4-diamine

Weigh N- (the fluoro- 2- methoxyl groups -5- nitro-phenyls of 4-) -5- methoxyl group -4- pyrazolos [1,5-a] pyridin-3-yl-pyrimidine -2- amine (intermediate 9) (0.41g, 1mmol), it is placed in 10mL microwave reaction pipes, N is sequentially added into reaction tube, N- dimethyl acetamides (2mL), N, N, N'- trimethyls ethylenediamine (18A) (0.16mL, 1.2mmol) with diisopropyl ethyl amine (0.2mL, 1.2mmol), it is warming up under 140 DEG C of microwaves and reacts 1 hour.Reaction solution is concentrated under reduced pressure, residue uses column chromatography purification (methylene chloride/methanol (v/v)=15:1) N of red solid is obtained⁴- (2- dimethylamino ethyls) -2- methoxyl groups-N¹- (5- methoxyl group -4- pyrazolos [1,5-a] pyridin-3-yl-pyrimidine -2-base)-N⁴- methyl-5-nitro-phenyl -1,4- diamines (20B) (0.22g, yield 45%).

¹H NMR(400MHz,CDCl₃)δ9.00(s,1H),8.82(s,1H),8.68-8.66(d,1H),8.54-8.53(d,1H),8.17(s,1H),7.41-7.34(m,2H),6.94-6.91(m,1H),6.75(s,1H),4.01(s,3H),4.00(s,3H),3.33-3.30(m,2H),2.88(s,3H),2.66-2.63(m,2H),2.37(s,6H)。

Second step：N¹- (2- dimethylamino ethyls) -5- methoxyl groups-N⁴- (5- methoxyl group -4- pyrazolos [1,5-a] pyridin-3-yl-pyrimidine -2-base)-N¹- methylphenyl -1,2,4- triamines (20C)

N¹-(2-dimethylaminoethyl)-5-methoxy-N⁴-(5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)-N¹-methyl-benzene-1,2,4-triamine

Weigh N⁴- (2- dimethylamino ethyls) -2- methoxyl groups-N¹- (5- methoxyl group -4- pyrazolos [1,5-a] pyridin-3-yl-pyrimidine -2-base)-N⁴- methyl-5-nitro-phenyl -1,4- diamines (20B) (0.22g, 0.45mmol), it is placed in 100mL round-bottomed flasks, ethanol (21mL), water (7mL), reduced iron powder (0.15g are sequentially added into reaction bulb, 2.70mmol) with ammonium chloride (0.017g, 0.32mmol), temperature rising reflux reacts 6 hours.By reacting liquid filtering, filter cake is washed with dichloromethane (10mL × 2), methanol (10mL × 2) successively, merging filtrate, and concentration, residue uses column chromatography purification (methylene chloride/methanol (v/v)=15:1) N of gray solid shape is obtained¹- (2- dimethylamino ethyls) -5- methoxyl groups-N⁴- (5- methoxyl group -4- pyrazolos [1,5-a] pyridin-3-yl-pyrimidine -2-base)-N¹- methylphenyl -1,2,4- triamines (20C) (0.20g, yield 98%).

¹H NMR(400MHz,CDCl₃)δ8.82-8.80(m,2H),8.55-8.53(d,2H),8.11(s,1H),7.94(s,1H),7.37-7.36(m,2H),6.92-6.90(m,2H),6.71(s,1H),4.96(br,1H),3.95(s,3H),3.85(s,3H),3.02-3.00(m,2H),2.67(s,3H),2.50-2.46(m,2H),2.42(s,6H)。

3rd step：N- (2- ((2- dimethylaminos) ethyl) (methyl) amino) -4- methoxyl groups -5- ((5- methoxyl groups -4- (pyrazolo [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) phenyl) acrylamide (compound 20)

Weigh N¹- (2- dimethylamino ethyls) -5- methoxyl groups-N⁴- (5- methoxyl group -4- pyrazolos [1,5-a] pyridin-3-yl-pyrimidine -2- Base)-N¹- methylphenyl -1,2,4- triamines (20C) (0.2g, 0.43mmol), are placed in 100mL round-bottomed flasks, sequentially add tetrahydrofuran (15mL) and diisopropyl ethyl amine (0.09mL, 0.56mmol), 0 DEG C is cooled to, acryloyl chloride (0.04mL is added dropwise, 0.52mmol), it is warmed to room temperature reaction 1 hour.Be concentrated under reduced pressure reaction solution, dichloromethane (50mL) is added into residue, saturated sodium bicarbonate aqueous solution (30mL), divide liquid, aqueous phase is extracted with dichloromethane (50mL), merges organic phase, and organic phase is washed with saturated aqueous common salt (30mL), anhydrous sodium sulfate drying, column chromatography for separation purifies (methylene chloride/methanol (v/v)=15 after being concentrated under reduced pressure:1) N- (2- ((2- dimethylaminos) ethyl) (methyl) amino) -4- methoxyl groups -5- ((5- methoxyl groups -4- (pyrazolos [1 of yellow solid are obtained, 5-a] pyridin-3-yl) pyrimidine -2-base) amino) phenyl) acrylamide (compound 20) (0.08g, yield 48%).

MS m/z(ESI):517.2[M+1]⁺。

Embodiment 21

N- (2- ((2- dimethylaminos) ethyl) (methyl) amino) -5- ((5- methoxyl groups -4- (pyrazolo [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) phenyl) acrylamide (compound 21)

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((5-methoxy-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

The first step：N- (the fluoro- 3- nitro-phenyls of 4-) -5- methoxyl group -4- pyrazolos [1,5-a] pyridin-3-yl-pyrimidine -2- amine (21B)

N-(4-fluoro-3-nitro-phenyl)-5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-amine

Weigh 3- (2- chloro-5-methoxyls-pyrimidine-4-yl) pyrazolo [1,5-a] pyridine (9c) (0.52g, 2mmol), it is placed in 50mL round-bottomed flasks, the fluoro- 3- nitroanilines (0.31g of 2- amylalcohols (15mL), 4- is sequentially added into reaction bulb, 2mmol) with p-methyl benzenesulfonic acid (0.46g, 2.4mmol), it is warming up to 120 DEG C and reacts 48 hours.Reaction solution is cooled to room temperature, add acetonitrile (20mL) and ammoniacal liquor (20mL), filtering, filter cake is washed with acetonitrile (10mL × 2), water (10mL × 2), collect filter cake, it is dried to obtain N- (the fluoro- 3- nitro-phenyls of 4-) -5- methoxyl group -4- pyrazolos [1,5-a] pyridin-3-yl-pyrimidine -2- amine (21B) (0.68g, yield 89%) of yellow solid.

¹H NMR(400MHz,DMSO-d₆)δ9.82(s,1H),8.88-8.75(m,4H),8.37(s,1H),8.03-8.01(m,1H),7.51-7.47(m,2H),7.18-7.16(m,1H),4.02(s,3H)。

Second step：N¹- (2- dimethylamino ethyls)-N⁴- (5- methoxyl group -4- pyrazolos [1,5-a] pyridin-3-yl-pyrimidine -2-base)-N¹- methyl -2- nitro-phenyl -1,4- diamines (21C)

N1-(2-dimethylaminoethyl)-N4-(5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)-N1-methyl-2-nitro-benzene-1,4-diamine

Weigh N- (the fluoro- 3- nitro-phenyls of 4-) -5- methoxyl group -4- pyrazolos [1,5-a] pyridin-3-yl-pyrimidine -2- amine (21B) (0.38g, 1mmol), it is placed in 10mL microwave reaction pipes, N is sequentially added into reaction tube, N- dimethyl acetamides (2mL), N, N, N'- trimethyls ethylenediamine (18A) (0.16mL, 1.2mmol) with diisopropyl ethyl amine (0.2mL, 1.2mmol), it is warming up under 140 DEG C of microwaves and reacts 1 hour.Reaction solution is concentrated under reduced pressure, residue uses column chromatography purification (methylene chloride/methanol (v/v)=15:1) N of red solid is obtained¹- (2- dimethylamino ethyls)-N⁴- (5- methoxyl group -4- pyrazolos [1,5-a] pyridin-3-yl-pyrimidine -2-base)-N¹- methyl -2- nitro-phenyl -1,4- diamines (21C) (0.46g).

¹H NMR(400MHz,CDCl₃)δ8.82(s,1H),8.64-8.62(m,1H),8.57-8.53(m,1H),8.30(s,1H),8.14(s,1H),7.51-7.49(m,1H),7.40-7.38(m,1H),7.24-7.22(d,1H),7.04(s,1H),6.97-6.93(m,1H),4.01(s,3H),3.33-3.30(m,2H),2.84-2.79(m,5H),2.55(s,6H)。

3rd step：N¹- (2- dimethylamino ethyls)-N⁴- (5- methoxyl group -4- pyrazolos [1,5-a] pyridin-3-yl-pyrimidine -2-base)-N¹- methylphenyl -1,2,4- triamines (21D)

N1-(2-dimethylaminoethyl)-N4-(5-methoxy-4-pyrazolo[1,5-a]pyridin-3-yl-pyrimidin-2-yl)-N1-methyl-benzene-1,2,4-triamine

Weigh N¹- (2- dimethylamino ethyls)-N⁴- (5- methoxyl group -4- pyrazolos [1,5-a] pyridin-3-yl-pyrimidine -2-base)-N¹- methyl -2- nitro-phenyls -1,4- diamines (21C) (0.8g, 1.73mmol), it is placed in 100mL round-bottomed flasks, ethanol (30mL), water (10mL), reduced iron powder (0.58g are sequentially added into reaction bulb, 10.4mmol) with ammonium chloride (0.065g, 1.21mmol), temperature rising reflux reacts 6 hours.By reacting liquid filtering, filter cake is washed with dichloromethane (10mL × 2), and methanol (10mL × 2) washing, merging filtrate, concentration, residue uses column chromatography purification (methylene chloride/methanol (v/v)=15:1) To the N of gray solid shape¹- (2- dimethylamino ethyls)-N⁴- (5- methoxyl group -4- pyrazolos [1,5-a] pyridin-3-yl-pyrimidine -2-base)-N¹- methylphenyl -1,2,4- triamines (21D) (0.63g, yield 84%).

¹H NMR(400MHz,CDCl₃)δ8.81(s,1H),8.78-8.75(d,1H),8.55-8.53(d,1H),8.11(s,1H),7.79-7.77(d,2H),7.28(s,1H),7.20-7.17(m,3H),3.98(s,3H),3.18-3.15(m,2H),2.90-2.87(m,2H),2.64(s,6H)。

4th step：N- (2- ((2- dimethylaminos) ethyl) (methyl) amino) -5- ((5- methoxyl groups -4- (pyrazolo [1,5-a] pyridin-3-yl) pyrimidine -2-base) amino) phenyl) acrylamide (compound 21)

Weigh N¹- (2- dimethylamino ethyls)-N⁴- (5- methoxyl group -4- pyrazolos [1,5-a] pyridin-3-yl-pyrimidine -2-base)-N¹- methylphenyl -1,2,4- triamines (21D) (0.63g, 1.46mmol), it is placed in 100mL round-bottomed flasks, tetrahydrofuran (15mL) and diisopropyl ethyl amine (0.29mL, 1.75mmol) are sequentially added into reaction bulb, cooling reaction solution is to 0 DEG C, acryloyl chloride (0.14mL is added dropwise, 1.75mmol), after completion of dropping, temperature reaction 1 hour.Be concentrated under reduced pressure reaction solution, dichloromethane (50mL) is added into residue, saturated sodium bicarbonate aqueous solution (30mL), divide liquid, aqueous phase is extracted with dichloromethane (50mL), merges organic phase, organic phase is washed with saturated aqueous common salt (30mL), anhydrous sodium sulfate drying, is concentrated under reduced pressure, and residue uses column chromatography purification (methylene chloride/methanol (v/v)=15:1) N- (2- ((2- dimethylaminos) ethyl) (methyl) amino) -5- ((5- methoxyl groups -4- (pyrazolos [1 of yellow solid are obtained, 5-a] pyridin-3-yl) pyrimidine -2-base) amino) phenyl) acrylamide (compound 21) (0.15g, yield 48%).

MS m/z(ESI):487.3[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ8.82(s,1H),8.77-8.73(m,1H),8.56-8.53(m,2H),8.21(s,1H),8.02(s,1H),7.78-7.76(d,1H),7.72-7.70(m,1H),7.30-7.28(m,1H),7.23-7.21(m,2H),7.01(s,1H),6.45-6.41(m,1H),5.73-5.70(m,1H),3.99(s,3H),2.82-2.80(m,2H),2.72(s,3H),2.34-2.30(m,8H)。

Embodiment 22

N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) fluoro- 4- methoxyl groups -5- of -3- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) phenyl) acrylamides (compound 22)

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-3-fluoro-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

The first step：N⁴- (2- (dimethylamino) ethyl) the fluoro- 2- methoxyl groups-N of -3-⁴- methyl-N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -5- nitrobenzene -1,4- diamines (22B)

N⁴-(2-(dimethylamino)ethyl)-3-fluoro-2-methoxy-N⁴-methyl-N¹-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-nitrobenzene-1,4-diamine

By N- (3,4- difluoro-2-methoxyl -5- nitrobenzene) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (intermediate 10) (1.4g, 3.4mmol), N, N, N'- trimethyl ethylenediamine (18A) (0.69g, 6.8mmol) and N, N- diisopropylethylamine (0.87g, 6.8mmol) it is added in DMF (3mL), 140 DEG C of microwave reactions 1.5 hours.Reaction solution is cooled to room temperature, water (20mL) is added into reaction solution, extracted with dichloromethane (50mL × 3), merge organic phase, organic phase is washed with water (50mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=50:1) title compound N is obtained⁴- (2- (dimethylamino) ethyl) the fluoro- 2- methoxyl groups-N of -3-⁴- methyl-N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -5- nitrobenzene-Isosorbide-5-Nitrae-diamines (22B), red solid (0.25g, yield 15%).

¹H NMR(400MHz,DMSO-d₆)δ8.62(s,1H),8.56(s,1H),8.42–8.38(m,2H),8.35(s,1H),7.54(d,1H),7.32(d,1H),7.30–7.22(m,2H),7.16(t,1H),4.02(s,3H),3.88(s,3H),3.20(t,2H),2.82(s,3H),2.65(s,2H),2.35(s,6H)。

MS m/z:494.3[M+1]⁺。

Second step：N¹- (2- (dimethylamino) ethyl) the fluoro- 5- methoxyl groups-N of -6-¹- methyl-N⁴- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) benzene -1,2,4- triamines (22C)

N¹-(2-(dimethylamino)ethyl)-6-fluoro-5-methoxy-N¹-methyl-N⁴-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)benzene-1,2,4-triamine

By N⁴- (2- (dimethylamino) ethyl) the fluoro- 2- methoxyl groups-N of -3-⁴- methyl-N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -5- nitrobenzene -1,4- diamines (22B) (0.25g, 5mmol), iron powder (0.17g, 30mmol) with ammonium chloride (0.27g, in the mixed solution for 50mmol) being added to ethanol (5mL) and water (2mL), it is warming up to 90 DEG C and reacts 4 hours.Reaction solution is cooled to room temperature, water (20mL) is added, is extracted with dichloromethane (50mL × 3), merges organic phase, organic phase is washed with water (50mL × 2), anhydrous sodium sulfate drying, concentration obtains title compound N¹- (2- (dimethylamino) ethyl) the fluoro- 5- methoxyl groups-N of -6-¹- methyl-N⁴- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) benzene -1,2,4- triamines (22C), red solid (0.22g, yield 96%).

MS m/z:464.4[M+1]⁺。

3rd step：N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) fluoro- 4- methoxyl groups -5- of -3- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) phenyl) acrylamides (compound 22)

By N¹- (2- (dimethylamino) ethyl) the fluoro- 5- methoxyl groups-N of -6-¹- methyl-N⁴- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) phenyl -1,2,4- triamines (22C) (0.27g, 0.55mmol), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDCI) (0.42g, 2.19mmol) with acrylic acid (0.078g, 1.09mmol) it is added in pyridine (5mL), 2 hours is reacted under room temperature.Water (10mL) is added into reaction solution, is extracted with dichloromethane (50mL × 3), merges organic phase, organic phase is washed with water (50mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=50:1) title compound N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) fluoro- 4- methoxyl groups -5- of -3- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) phenyl) acrylamides (compound 22) are obtained, yellow solid (40mg, yield 14%).

¹H NMR(400MHz,DMSO-d₆)δ10.58(s,1H),9.04(s,1H),8.68(s,1H),8.37(d,1H),8.24(d,1H),8.20(s,1H),7.53(d,1H),7.29(d,1H),7.25(m,1H),7.14(m,1H),6.41–6.25(m,2H),5.83(m,1H),3.92(s,3H),3.86(s,3H),3.06(s,2H),2.81(s,3H),2.28(s,2H),2.22(s,6H)。

MS m/z:518.4[M+1]⁺。

Embodiment 23

N- (4- (difluoro-methoxy) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 23)

N-(4-(difluoromethoxy)-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

The first step：2- (difluoro-methoxy)-N⁴- (2- (dimethylamino) ethyl)-N⁴- methyl-N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -5- nitrobenzene -1,4- diamines (23B)

2-(difluoromethoxy)-N⁴-(2-(dimethylamino)ethyl)-N⁴-methyl-N¹-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-nitrobenzene-1,4-diamine

5- (difluoro-methoxy)-N- (2- (dimethylamino) ethyl)-N- methyl -2- nitrobenzene -1 is added into reaction bulb, 4- diamines (intermediate 1) (120mg, 0.39mmol), 3- (2- chlorine pyrimidine-4-yl) -1- Methyl-1H-indoles (intermediate 2) (115mg, 0.47mmol), p-methyl benzenesulfonic acid (94mg, 0.86mmol) with 2- amylalcohols (2mL), it is heated to 110 DEG C and reacts 3 hours.Reaction solution is concentrated under reduced pressure into dry, residue silica gel column chromatography separating-purifying (dichloromethane/ammonia methanol (v/v)=50:1) brown oil 2- (difluoro-methoxy)-N is obtained⁴- (2- (dimethylamino) ethyl)-N⁴- methyl-N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -5- nitrobenzene-Isosorbide-5-Nitrae-diamines (23B) (150mg, yield 75%).

MS m/z(ESI):512.3[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ8.56(d,2H),8.37–8.29(m,3H),7.50(dd,1H),7.39(t,1H),7.30–7.22(m,2H),7.20(s,1H),7.17–7.07(m,1H),3.88(s,3H),3.41(t,2H),2.98(s,2H),2.83(s,3H),2.56(s,6H)。

Second step：5- (difluoro-methoxy)-N¹- (2- (dimethylamino) ethyl)-N¹- methyl-N⁴- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) benzene -1,2,4- triamines (23C)

5-(difluoromethoxy)-N¹-(2-(dimethylamino)ethyl)-N¹-methyl-N⁴-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)benzene-1,2,4-triamine

2- (difluoro-methoxy)-N is added into reaction bulb⁴- (2- (dimethylamino) ethyl)-N⁴- methyl-N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -5- nitrobenzene -1,4- diamines (23B) (150mg, 0.29mmol), iron powder (99mg, 1.76mmol), ammonium chloride (11mg, 0.2mmol) with ethanol/water (5mL/1.5mL), back flow reaction is heated to 2 hours.Reaction solution is concentrated under reduced pressure into dry, residue silica gel column chromatography separating-purifying (dichloromethane/ammonia methanol (v/v)=50:1) 5- (difluoro-methoxy)-N of brown solid is obtained¹- (2- (dimethylamino) ethyl)-N¹- methyl-N⁴- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) benzene -1,2,4- triamines (23C) (100mg, yield 72%).

MS m/z(ESI):482.4[M+1]⁺。

3rd step：N- (4- (difluoro-methoxy) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 23)

5- (difluoro-methoxy)-N is added into reaction bulb¹- (2- (dimethylamino) ethyl)-N¹- methyl-N⁴- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) benzene -1,2,4- triamines (23C) (110mg, 0.23mmol), diisopropyl ethyl amine (39mg, 0.3mmol) with dichloromethane (3mL), acryloyl chloride (23mg, 0.25mmol) is added dropwise in ice bath cooling, drips off rear ice bath and reacts 1 hour.Dichloromethane (20mL) and saturated aqueous common salt (20mL) are added into reaction solution, divide liquid, water layer is extracted with dichloromethane (10mL × 4), merge organic phase, organic phase anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=30:1) pale yellow oil N- (4- (difluoro-methoxy) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 23) (45m g, yield 37%) is obtained.

MS m/z(ESI):536.3[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ10.21(s,1H),8.94(s,1H),8.50(s,1H),8.35–8.28(m,2H),8.24(d,1H),7.51(d,1H),7.28–7.15(m,3H),7.10(d,1H),7.07(t,1H),6.55–6.38(m,1H),6.27(d,1H),5.80(d,1H),3.89(s,3H),2.90(s,2H),2.71(s,3H),2.40(m,2H),2.26(s,6H)。

Embodiment 24

N- (3- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -5- morpholines benzene) acrylamide (compound 24)

N-(3-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-morpholinophenyl)acrylamide

The first step：4- (the iodo- 5- nitrobenzophenones of 3-) morpholine (24B)

4-(3-iodo-5-nitrophenyl)morpholine

By iodo- 5- nitrobenzene (the 24A) (5.0g of the fluoro- 3- of 1-, 18.7mmol) with morpholine (3.4g, 39.3mmol) it is dissolved in dimethyl sulfoxide (DMSO) (15mL), reacted at 90 DEG C 17 hours and terminate reaction, add 30mL water, extracted with dichloromethane (30mL × 2), 30mL water washings, 30mL saturated common salt water washings, anhydrous sodium sulfate drying, it is concentrated under reduced pressure to give yellow solid 4- (the iodo- 5- nitrobenzophenones of 3-) morpholine (24B) (6.0g, yield 96.8%).

¹H NMR(400MHz,CDCl₃)δ7.99–7.95(m,1H),7.64(t,1H),7.45(dd,1H),3.86(dd,4H),3.24(dd,4H)。

LC-MS(m/z):335.1[M+1]⁺。

Second step：Morpholinyl -5- nitroanilines (24C)

3-morpholino-5-nitroaniline

By 4- (the iodo- 5- nitrobenzophenones of 3-) morpholine (24B) (1.0g, 3.0mmol) it is dissolved in N, in dinethylformamide (2mL), add ammoniacal liquor (51mg, 30mmol), copper powder (190mg, 3.0mmol), 100 DEG C of enclosed system reactions are stayed overnight.Reaction terminates, and adds 60mL water, dichloromethane extraction (60mL × 2), water (60mL) is washed, saturated aqueous common salt (60mL) washing, anhydrous sodium sulfate drying, it is concentrated under reduced pressure, silica gel column chromatography separation (ethyl acetate/petroleum ether=1:10~1:1) red solid morpholinyl -5- nitroanilines (24C) (0.35g, yield 52.23%), are obtained.

¹H NMR(400MHz,CDCl₃)δ7.14(t,1H),7.01(t,1H),6.42(t,1H),3.87–3.83(m,4H),3.22–3.16(m,4H)。

3rd step：4- (1- Methyl-1H-indole -3- bases)-N- (morpholinyl -5- nitrobenzophenones) pyrimidine -2- amine (24D)

4-(1-methyl-1H-indol-3-yl)-N-(3-morpholino-5-nitrophenyl)pyrimidin-2-amine

By 3- (2- chlorine pyrimidine-4-yl) -1- Methyl-1H-indoles (intermediate 2) (0.4g, 1.6mmol), 3- morpholino -5- nitroanilines (0.37g, 1.6mmol), p-methyl benzenesulfonic acid (0.31g, 1.6mmol) it is added in 40mL 2- amylalcohols, 120 DEG C of reactions are stayed overnight.Reaction terminates, and reaction solution is cooled down, and separates out solid, filtering, dry cake, obtains yellow solid 4- (1- Methyl-1H-indole -3- bases)-N- (morpholinyl -5- nitrobenzophenones) pyrimidine -2- amine (24D) (0.3g, yield 53.5%).

LC-MS(m/z):431.1[M+1]⁺。

4th step：N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -5- morpholine benzene -1,3- diamines (24E)

N¹-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-morpholinobenzene-1,3-diamine

By 4- (1- Methyl-1H-indole -3- bases)-N- (3- morpholine -5- nitrobenzene) pyrimidine -2- amine (24D) (0.4g, 0.93mmol) it is dissolved in the in the mixed solvent of ethanol (20ml) and water (10ml), add iron powder (311mg, 5.6mmol) with ammonium chloride (497.5mg, 9.3mmol).90 DEG C are reacted 2 hours.Water (30ml) is added into reaction solution, extracted with dichloromethane (30mL × 2), merge organic phase, organic phase washed with water (30mL) and saturated aqueous common salt (30mL) washing, anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain title compound N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -5- morpholine benzene -1,3- diamines (24E), brown solid (250mg, yield 68%).

¹H NMR(400MHz,CDCl₃)δ8.45(dd,1H),8.28(d,1H),7.82(s,1H),7.44–7.35(m,2H),7.35–7.27(m,2H),7.02(d,1H),6.77(m,1H),6.71(m,1H),5.99(m,1H),3.87(s,3H),3.83–3.79(m,4H),3.17–3.12(m,4H)。

MS m/z(ESI):401.1[M+1]⁺。

5th step：N- (3- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -5- morpholines benzene) acrylamide (compound 24)

By N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -5- morpholines benzene -1,3- diamines (24E) (250mg, 0.625mmol) it is dissolved in 5mL pyridines, add acrylic acid (90mg, 1.25mmol), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (2.5mmol, 478mg) are added, are reacted at room temperature 2 hours.Add 60mL dichloromethane, washed successively with water (60mL × 2), saturated sodium bicarbonate (60mL × 2), saturated aqueous common salt (30mL), anhydrous sodium sulfate drying, it is concentrated under reduced pressure, residue is with silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=100/1-100/3), obtain N- (3- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -5- morpholines benzene) acrylamide (compound 24) (150mg, yield 52.8%) of light red solid shape.

¹H NMR(400MHz,CDCl₃)δ8.36(d,1H),8.27(d,1H),7.96(s,1H),7.62(s,1H),7.50(d,2H),7.37(d,1H),7.31(m,1H),7.23(d,1H),7.17(s,1H),7.03(d,1H),6.87(s,1H),6.41(d,1H),6.23(dd,1H),5.73(d,1H),3.85(s,3H),3.83–3.76(m,4H),3.20–3.12(m,4H)。

MS m/z(ESI):455.2[M+1]⁺。

Embodiment 25

N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- ethylphenyls) acrylamide (compound 25)

N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-ethylphenyl)acrylamide

The first step：The fluoro- 5- nitroanilines (25B) of 2- ethyls -4-

2-ethyl-4-fluoro-5-nitroaniline

Added in reaction bulb and 2- ethyl -4- fluoroanilines (25A) (3.88g, 27.9mmol) are added dropwise at concentrated sulfuric acid 25mL, 0 DEG C, adding potassium nitrate, ((2.82g, 27.9mmol), 0 DEG C is reacted 1 hour.Ice cube (100mL) is added into saturated sodium bicarbonate solution (300ml), reaction system is poured slowly into above-mentioned solution, sodium bicarbonate solid is added to there is no bubble generation.Divide liquid, aqueous phase is extracted with ethyl acetate (150mL × 4), merge organic phase, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (petroleum ether:Ethyl acetate (v/v)=10:1~2:1) the fluoro- 5- nitroanilines (25B) (3.33g, yield 55%) of title compound orange solids 2- ethyls -4- are obtained.

MS m/z:185.1[M+1]⁺。

Second step：The chloro- N- of 5- (the fluoro- 5- nitrobenzophenones of 2- ethyls -4-) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (25C)

5-chloro-N-(2-ethyl-4-fluoro-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

By fluoro- 5- nitroanilines (the 25B) (1.31g of 2- ethyls -4-, 7.1mmol) with 3- (2,5- dichloro pyrimidine -4- bases) -1- Methyl-1H-indoles (4c) (1.97g, 7.1mmol) it is dissolved in 1, in 4- dioxane (70mL), add the double diphenylphosphine -9.9- dimethyl xanthenes (0.46g of 4.5-, 0.79mmol), cesium carbonate (4.85g, 14.9mmol) with palladium (0.10g, 0.47mmol), liquid nitrogen is cooled down, nitrogen displacement 0.5 hour, and 120 DEG C of reactions are stayed overnight after being warmed to room temperature.Room temperature is cooled to, solid is leached out, concentrated, residue silica gel column chromatography separating-purifying (petroleum ether:Ethyl acetate (v/v)=10:1~3:1) the chloro- N- of title compound greenish yellow solid 5- (the fluoro- 5- nitrobenzophenones of 2- ethyls -4-) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (25C) (0.59g, yield 20%), is obtained.

MS m/z:426.1[M+1]⁺。

3rd step：N¹- (the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- ethyls-N⁴- methyl-5-nitro benzene -1,4- diamines (25D)

N¹-(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N⁴-(2-(dimethylamino)ethyl)-2-ethyl-N⁴-methyl-5-nitrobenzene-1,4-diamine

5- chloro- N- (the fluoro- 5- nitrobenzophenones of 2- ethyls -4-) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (25C) (0.56g is added in microwave reaction pipe, 1.32mmol), add N, N- dimethyl acetamides (8mL) dissolve, add diisopropyl ethyl amine (0.26mL, 1.59mmol), N, N, N '-trimethyl ethylenediamine (18A) (0.21mL, 1.59mmol), 140 DEG C of microwave reactions 1 hour.Reaction system is cooled to after room temperature and concentrated, residue silica gel column chromatography separating-purifying (petroleum ether:Ethyl acetate (v/v)=4:1~2:1~dichloromethane:Methanol (v/v)=15:1~5:1) title compound orange solids N, is obtained¹- (the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- ethyls-N⁴- methyl-5-nitro benzene-Isosorbide-5-Nitrae-diamines (25D) (0.49g, yield 73%).

MS m/z=509.2 [M+1]⁺。

4th step：N⁴- (the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base)-N¹- (2- (dimethylamino) ethyl) -5- ethyls-N¹- aminomethyl phenyl -1,2,4- triamines (25E)

N⁴-(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N¹-(2-(dimethylamino)ethyl)-5-ethyl-N¹-methylbenzene-1,2,4-triamine

By N¹- (the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- ethyls-N⁴- methyl-5-nitro benzene -1,4- diamines (25D) (0.46g, 0.91mmol), iron powder (0.30g, the in the mixed solvent of absolute ethyl alcohol (12mL) and water (4mL) 5.43mmol) is added with ammonium chloride (0.04g, 0.75mmol), 90 DEG C of reactions is warming up to and stays overnight, add iron powder (0.15g, continue to react 2 hours 2.72mmol) with ammonium chloride (0.02g, 0.37mmol), at 90 DEG C.Room temperature is cooled to, solid is leached out, concentrated, residue silica gel column chromatography separating-purifying (petroleum ether:Ethyl acetate (v/v)=1:1~ethyl acetate~ethyl acetate:Methanol (v/v)=10:1~3:1) title compound orange solids N, is obtained⁴- (the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base)-N¹- (2- (dimethylamino) ethyl) -5- ethyls-N¹- aminomethyl phenyl -1,2,4- triamines (25E) (0.43g, yield 92%).

MS m/z:479.2[M+1]⁺。

5th step：N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- ethylphenyls) acrylamide (compound 25)

Diisopropyl ethyl amine (1.7mL) is added in the tetrahydrofuran (8.3mL) newly steamed, solution 1 is obtained；Acryloyl chloride (0.75mL) is added in the tetrahydrofuran (9.25mL) newly steamed, solution 2 is obtained.By N⁴- (the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base)-N¹- (2- (dimethylamino) ethyl) -5- ethyls-N¹- aminomethyl phenyl -1,2,4- triamines (25E) (0.40g, 0.84mmol) are dissolved in the tetrahydrofuran (10mL) newly steamed, solution 1 (1mL) and solution 2 (1mL) are added dropwise at 0 DEG C, reacts 1.5 hours at room temperature.Water (80mL) is added into reaction solution reaction is quenched, aqueous phase is extracted with ethyl acetate (70mL × 5), merge organic phase, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (petroleum ether:Ethyl acetate (v/v)=1:1~ethyl acetate:Methanol (v/v)=10:1~1:1), obtain title compound white solid N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyridine -2- bases) N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- ethylphenyls) acrylamides (compound 25) (0.07g, yield 16%).

¹H NMR(400MHz,DMSO-d₆)δ10.12(s,1H),8.88(s,1H),8.53(s,2H),7.46-7.44(m,1H),7.23(s,1H),7.18-7.15(m,1H),6.89-6.86(m,1H),6.43-6.36(m,1H),6.21-6.16(m,1H),5.74-5.72(m,1H),5.33-5.31(m,1H),3.87(s,3H),3.17-3.16(m,2H),2.75(s,3H),2.58-2.52(m,2H),2.37-2.34(m,2H),2.21(s,6H),1.09-1.05(t,3H)。

MS m/z:533.2[M+1]⁺。

Embodiment 26

4- (3- (2- ((5- acrylamide -2- methoxyphenyls) amino) -5- chlorine pyrimidine-4-yl) -1- Methyl-1H-indole -6- bases) piperazine - 1- carboxylates (compound 26)

tert-butyl 4-(3-(2-((5-acrylamido-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)-1-methyl-1H-indol-6-yl)piperazine-1-carboxylate

The first step：6- bromo- 1- (triisopropylsilyl) -1 hydrogen-indoles (26B)

6-bromo-1-(triisopropylsilyl)-1H-indole

In the round-bottomed flask that tetrahydrofuran (250mL) is added to 2L, at 0 DEG C, sodium hydride (24.5g is added into reaction bulb, 0.612mol, w/w=60%), tetrahydrofuran (500mL) solution of 6- bromo indoles (100.0g, 0.510mol) is added dropwise.Completion of dropping, is stirred 30 minutes at 0 DEG C, and tetrahydrofuran (250mL) solution of tri isopropyl chlorosilane (100g, 0.518mol) is added dropwise.Completion of dropping, reaction continues to stir 30 minutes at 0 DEG C.Reaction dissolvent is removed under reduced pressure, residue is poured into ethyl acetate (3000mL), organic phase washed with water (1000mL), saturated common salt washing (500mL) washing, anhydrous sodium sulfate drying, column chromatography for separation (petrol ether/ethyl acetate (v/v)=15 after being concentrated under reduced pressure:1) 6- bromo- 1- (triisopropylsilyl) -1 hydrogen-indoles (26B) (160g, yield 93%) of white solid is obtained.

¹H NMR(400MHz,CDCl₃)δ7.63(s,1H),7.49-7.47(d,1H),7.20-7.18(m,2H),6.59-6.58(d,1H),1.71-1.64(m,3H),1.16-1.14(m,18H)。

Second step：4- (1 hydrogen-indoles -6- bases) piperidines -1- carboxylates (26C)

tert-butyl 4-(1H-indol-6-yl)piperazine-1-carboxylate

6- bromo- 1- (triisopropylsilyl) -1 hydrogen-indoles (26B) (1.2g, 3.6mmol) is added in 100mL round-bottomed flasks, Ortho-xylene (40mL), 1- tert-butoxycarbonyl-piperazines (1.0g are sequentially added into reaction bulb, 5.4mmol), sodium tert-butoxide (0.51g, 5.4mmol), tri-tert phosphorus (0.11g, 0.54mmol) with palladium (0.04g, 0.18mmol), the displacement of nitrogen ball is multiple, stirs 30 minutes at room temperature, is warming up to reaction at 120 DEG C and continues 2 hours.By reacting liquid filtering, filter cake is washed with ethyl acetate (50mL × 2), and filtrate is washed (20mL) with saturated common salt, anhydrous sodium sulfate drying, and be concentrated under reduced pressure to obtain crude product.The crude product is dissolved in 100mL tetrahydrofurans, tetrabutyl ammonium fluoride (1.9g, 7.2mmol) is added thereto, is reacted 1 hour at room temperature.Reaction dissolvent, column chromatography for separation (petrol ether/ethyl acetate (v/v)=2 is removed under reduced pressure:1) 4- (1 hydrogen-indoles -6- bases) piperidines -1- carboxylates (26C) (0.65g, yield of white solid is obtained：60%).

¹H NMR(400MHz,CDCl₃)δ8.09(br,1H),7.55-7.53(d,1H),6.96(s,1H),6.95-6.89(m,2H),6.47(s,1H),3.65(s,4H),3.13(s,4H),1.50(s,9H)。

3rd step：4- (3- (2,5- dichloro pyrimidine -4- bases) -1 hydrogen-indoles -6- bases) piperidines -1- carboxylate (26D) tert-butyl 4- (3- (2,5-dichloropyrimidin-4-yl) -1H-indol-6-yl) piperazine-1-carboxylate

4- (1 hydrogen-indoles -6- bases) piperidines -1- carboxylates (26C) (0.3g, 1mmol) are added in 50mL round-bottomed flasks, and tetrahydrofuran (5mL) is added into reaction bulb.At 0 DEG C, it is added dropwise after the diethyl ether solution (0.5mL, 1.5mmol, 3mol/L) of methyl-magnesium-bromide, completion of dropping, reaction is warmed to room temperature stirring 1 hour.At 0 DEG C, 2,4,5- trichloropyrimidines (0.2g, 1.1mmol) are added into reaction bulb.It is warming up to back flow reaction 2 hours.Reaction solution is cooled to room temperature, add water (20mL) and reaction is quenched, residue is extracted with ethyl acetate (50mL × 2), merge organic phase, washed with saturated common salt (30mL), anhydrous sodium sulfate drying, column chromatography (petrol ether/ethyl acetate (v/v)=2 after being concentrated under reduced pressure:1) 4- (3- (2,5- dichloro pyrimidine -4- bases) -1 hydrogen-indoles -6- bases) piperidines -1- carbonic acid tertiary butyl ester (26D) (0.1g, yield 20%) of isolated yellow solid.

¹H NMR(400MHz,CDCl₃)δ9.15(s,1H),8.58-8.57(d,1H),8.56-8.41(m,2H),7.08-7.06(d,1H),6.96(s,1H),3.67-3.65(m,4H),3.17(s,4H),1.51(s,9H)。

MS m/z:448.0[M+1]⁺。

4th step：4- (3- (2,5- dichloro pyrimidine -4- bases) -1- methyl isophthalic acids hydrogen-indoles -6- bases) piperidines -1- carboxylates (26E)

tert-butyl 4-(3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-indol-6-yl)piperazine-1-carboxylate

By 4- (3- (2,5- dichloro pyrimidine -4- bases) -1 hydrogen-indoles -6- bases) piperidines -1- carboxylates (26D) (1.1g, 2.4mmol) add in 100mL round-bottomed flasks, DMF (20mL) is added into reaction bulb.At 0 DEG C, sodium hydride (0.14g, 5.9mol, 60%) is added into reaction bulb, continues to react 30 minutes at 0 DEG C.Iodomethane (1.0g, 7.1mmol) is added into reaction solution, reaction is warmed to room temperature lower stirring 2 hours.Reaction solution is poured into water (100mL), separate out a large amount of solids, filtering is precipitated and washed successively with petroleum ether (20mL × 2), water (20mL × 2), naturally dry, obtain the 4- (3- (2 of yellow solid, 5- dichloro pyrimidine -4- bases) -1- methyl isophthalic acids hydrogen-indoles -6- bases) piperidines -1- carboxylates (26E) (1.1g, yield 99%).

5th step：4- (3- (the chloro- 2- of 5- ((2- methoxyl group -5- nitrobenzophenones) amido) pyrimidine-4-yl) -1- methyl isophthalic acids hydrogen-indoles -6- bases) Piperidines -1- carboxylates (26F)

tert-butyl 4-(3-(5-chloro-2-((2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indol-6-yl)piperazine-1-carboxylate

By 4- (3- (2,5- dichloro pyrimidine -4- bases) -1- methyl isophthalic acids hydrogen-indoles -6- bases) piperidines -1- carboxylates (26E) (0.46g, 1.0mmol) add in 100mL round-bottomed flasks, 1 is sequentially added into reaction bulb, 4- dioxane (20mL), 2- amino -4- Nitroanisoles (0.2g, 1.2mmol) with sodium tert-butoxide (0.24g, 2.5mmol).With reaction system with nitrogen 10 minutes, double diphenylphosphine -9, the 9- dimethyl xanthenes (0.063g, 0.11mmol) of 4,5- and palladium (0.022g, 0.1mmol) are added, reaction system nitrogen displacement again.Back flow reaction is warming up to stir 6 hours.Question response is cooled to after room temperature, water (20mL) is added into reaction system reaction is quenched, residue is extracted with ethyl acetate (50mL × 2), merge organic phase, washed with saturated aqueous common salt (20mL), anhydrous sodium sulfate drying, column chromatography for separation (petrol ether/ethyl acetate (v/v)=2 after being concentrated under reduced pressure:1) 4- (3- (the chloro- 2- of 5- ((2- methoxyl group -5- nitrobenzophenones) amido) pyrimidine-4-yl) -1- methyl isophthalic acids hydrogen-indoles -6- bases) piperidines -1- carboxylates (26F) (0.25g, yield 42%) of yellow solid are obtained.

¹H NMR(400MHz,CDCl₃)δ9.49(s,1H),8.43-8.39(m,2H),8.17(s,1H),7.92-7.90(d,1H),7.77(s,1H),7.02-6.94(m,3H),4.05(s,3H),3.86(s,3H),3.68(s,4H),3.21(s,4H),1.50(s,9H)。

6th step：4- (3- (2- ((5- amido -2- methoxyphenyls) amido) the chloro- pyrimidine-4-yls of -5-) -1- methyl isophthalic acids hydrogen-indoles -6- bases) piperidines -1- carboxylates (26G)

tert-butyl 4-(3-(2-((5-amino-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)-1-methyl-1H-indol-6-yl)piperazine-1-carboxylate

By 4- (3- (the chloro- 2- of 5- ((2- methoxyl group -5- nitrobenzophenones) amido) pyrimidine-4-yl) -1- methyl isophthalic acids hydrogen-indoles -6- bases) piperidines -1- carbonic acid tertiary butyl ester (26F) (0.12g, 0.2mmol) add in 100mL round-bottomed flasks, sequentially add ethanol (15mL), water (5mL), reduced iron powder (0.067g, 1.2mmol) with ammonium chloride (0.007g, 0.14mmol), it is warming up to back flow reaction 4 hours.Reaction solution is cooled to room temperature, filtered, filter cake is washed with dichloromethane (10mL × 2), methanol (10mL × 2).Filtrate is concentrated, column chromatography for separation purification (petrol ether/ethyl acetate (v/v)=1:1) 4- (3- (2- ((5- amido -2- methoxyphenyls) amido) the chloro- pyrimidine-4-yls of -5-) -1- methyl isophthalic acids hydrogen-indoles -6- bases) piperidines -1- carboxylates (26G) (0.06g, yield 55%) of yellow solid are obtained.

¹H NMR(400MHz,CDCl₃)δ8.56-8.54(d,1H),8.31(s,1H),8.14-8.11(m,1H),7.74(s,1H),7.04-7.02(d,1H),6.79(s,1H),6.75-6.72(d,1H),6.32-6.29(m,1H),3.84(s,3H),3.81(s,3H),3.65-3.63(m,4H),3.19-3.16(m,4H),1.50(s,9H)。

7th step：4- (3- (2- ((5- acrylamide -2- methoxyphenyls) amino) -5- chlorine pyrimidine-4-yl) -1- Methyl-1H-indole -6- bases) piperazine -1- carboxylates (compound 26)

4- (3- (2- ((5- amido -2- methoxyphenyls) amido) the chloro- pyrimidine-4-yls of -5-) -1- methyl isophthalic acids hydrogen-indoles -6- bases) piperidines -1- carboxylates (26G) (0.65g, 1.2mmol) are added in 50mL round-bottomed flasks.Pyridine (10mL), acrylic acid (0.17g, 2.4mmol) and 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (0.88g, 4.8mmol) are added into reaction bulb successively.Reaction stirring 6 hours at room temperature.Reaction dissolvent is removed under reduced pressure, add saturated sodium bicarbonate aqueous solution (40mL), residue is extracted with ethyl acetate (50mL × 2), merge organic phase, washed with saturated common salt (40mL), anhydrous sodium sulfate drying, 4- (3- (2- ((5- acrylamide -2- methoxyphenyls) amino) -5- chlorine pyrimidine-4-yl) -1- Methyl-1H-indole -6- bases) piperazine -1- carboxylates (compound 26) (0.50g, yield 70%) of column chromatography (ethyl acetate) isolated yellow solid after being concentrated under reduced pressure.

¹H NMR(400MHz,CDCl₃)δ8.51-8.49(m,2H),8.31(s,1H),8.35(s,1H),8.17(s,1H),7.79-7.77(m,2H),7.15(s,1H),7.02-7.00(m,1H),6.90-6.88(d,1H),6.39-6.35(d,1H),6.08-6.06(m,1H),5.69-5.66(m,1H),3.93(s,3H),3.86(s,3H),3.69(s,4H),3.22(s,4H),1.50(s,9H)。

MS m/z:618.1[M+1]⁺。

Embodiment 27

N- (3- ((the chloro- 4- of 5- (1- methyl -6- (4- methylpiperazine-1-yls) indol-3-yl) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 27)

N-(3-((5-chloro-4-(1-methyl-6-(4-methylpiperazin-1-yl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

The first step：N- (3- ((the chloro- 4- of 5- (1- methyl -6- (4- methylpiperazine-1-yls) indol-3-yl) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 27)

4- [3- [the chloro- 2- of 5- [2- methoxyl groups -5- (acrylamido) anilino-] pyrimidine-4-yl] -1- Methvl-indole -6- bases] piperidines -1- carboxylates (compound 26) (0.40g, 0.65mmol) are added in 50mL round-bottomed flasks.At 0 DEG C, dichloromethane (10mL) and trifluoroacetic acid (5mL) are sequentially added, lower reaction stirring 2 hours is warmed to room temperature.Dichloromethane (50mL), saturated sodium bicarbonate aqueous solution (20mL) are added into reaction solution, layering, aqueous phase is extracted with dichloromethane (50mL), merge organic phase, with anhydrous sodium sulfate drying, it is concentrated under reduced pressure, obtained crude product.At 0 DEG C, dichloromethane (10mL), acetic acid (2mL), formalin (1mL) are sequentially added in addition crude product, stirred 30 minutes.Sodium triacetoxy borohydride (0.29g, 1.3mmol) is added into reaction solution, reaction is warmed to room temperature stirring 3 hours.Saturated sodium bicarbonate aqueous solution (30mL) is added dropwise into reaction bulb reaction is quenched, extracted with dichloromethane (50mL × 2), merge organic phase, washed with saturated aqueous common salt (40mL), anhydrous sodium sulfate drying, it is concentrated under reduced pressure, column chromatography (methylene chloride/methanol (v/v)=15:1) N- (3- ((the chloro- 4- of 5- (1- methyl -6- (4- methylpiperazine-1-yls) indol-3-yl) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 27) (0.20g, 56%) of isolated yellow solid.

¹H NMR(400MHz,CDCl₃)δ8.54-8.53(m,1H),8.49-8.47(d,1H),8.35(s,1H),8.13(s,1H),7.83-7.82(m,1H),7.77(s,1H),7.12(s,1H),6.97-6.83(m,3H),6.38-6.34(d,1H),6.06-6.03(m,1H),5.71-5.68(d,1H),3.93(s,3H),3.86(s,3H),3.37(s,4H),2.79(s,4H),2.50(s,3H)。

MS m/z:532.1[M]。

Embodiment 28

N- (2- ((1- amino cyclopropyl) methoxyl group) -4- methoxyl groups -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 28)

N-(2-((1-aminocyclopropyl)methoxy)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

The first step：(1- ((5- methoxyl groups -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- nitro-phenoxies) methyl) cyclopropyl) carbamate (28A)

tert-butyl(1-((5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-nitrophenoxy)methyl)cyclopropyl)carbamate

By 5- ((4- (1- methyl indol -3- bases) pyrimidine -2-base) amino) fluoro- 1- nitrobenzene (the intermediate 3) (1g of -4- methoxyl groups -2-, 2.54mmol) it is dissolved in tetrahydrofuran (20mL), sodium hydride (203mg is added under ice bath, 5.08mmol), stirring 30 minutes, (1- methylols cyclopropyl)-t-butoxycarbonyl amino (951mg, 5.08mmol) is added dropwise, reacts at room temperature 8 hours.Reaction terminates, and adds 150mL water and 150mL ethyl acetate, point liquid.Aqueous phase is extracted with 100mL ethyl acetate, merge organic phase, anhydrous sodium sulfate drying, it is concentrated to give yellow solid compound (1- ((5- methoxyl groups -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- nitro-phenoxies) methyl) cyclopropyl) carbamate (28A) (1g, yield 71.4%).

MS m/z:561.1[M+1]⁺。

Second step：(1- ((2- amino -5- methoxyl groups -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenoxy group) methyl) cyclopropyl) carbamate (28B)

tert-butyl(1-((2-amino-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenoxy)methyl)cyclopropyl)carbamate

By (1- ((5- methoxyl groups -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- nitro-phenoxies) methyl) cyclopropyl) carbamate (28A) (1.1g, 2.1mmol) it is dissolved in 20mL ethanol, sequentially add 7mL water, iron powder (356mg, 6.4mmol) with ammonium chloride (78.6mg, 1.5mmol), 90 DEG C of back flow reactions are warming up to 6 hours.Reaction solution is cooled to room temperature, filtered, concentration.Silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain brown solid compound (1- ((2- amino -5- methoxyl groups -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenoxy group) methyl) cyclopropyl) carbamate (28B) (750mg, yield 68.2%).

MS m/z:531.1[M+1]⁺。

3rd step：(1- ((2- acrylamido -5- methoxyl groups -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenoxy group) methyl) cyclopropyl) carbamate (28C)

tert-butyl(1-((2-acrylamido-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenoxy)methyl)cyclopropyl)carbamate

By (1- ((2- amino -5- methoxyl groups -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenoxy group) methyl) cyclopropyl) carbamate (28B) (750mg, 1.4mmol) it is dissolved in 20mL pyridines, sequentially add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (1.2g, 6.3mmol) with acrylic acid (0.15mL, 2.1mmol), react at room temperature 4 hours.It is spin-dried for removing pyridine, adds 100mL water and 100mL dichloromethane, point liquid.Organic phase is washed with 4mol/L sodium hydrate aqueous solutions (100mL).Organic phase anhydrous sodium sulfate drying.Silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain white solid (1- ((2- acrylamido -5- methoxyl groups -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenoxy group) methyl) cyclopropyl) carbamate (28C) (730mg, yield 89.4%).

MS m/z:585.2[M+1]⁺。

4th step：N- (2- ((1- amino cyclopropyl) methoxyl group) -4- methoxyl groups -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 28)

By (1- ((2- acrylamido -5- methoxyl groups -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenoxy group) methyl) cyclopropyl) carbamate (28C) (730mg, 1.25mmol) it is dissolved in 20mL dichloromethane, 10mL trifluoroacetic acids are added, are reacted at room temperature 2 hours.Reaction terminates, and is spin-dried for removing solvent, and pH value of solution is adjusted to 8 with saturated sodium bicarbonate aqueous solution.100mL dichloromethane is added, point liquid, organic phase anhydrous sodium sulfate drying.Silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain compound as white solid N- (2- ((1- amino cyclopropyl) methoxyl group) -4- methoxyl groups -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 28) (130mg, 21.5%).

MS m/z:485.1[M+1]⁺。

Embodiment 29

N- (4- methoxyl groups -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (2- morpholines ethyoxyl) phenyl) acrylamide (compound 29)

N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(2-morpholinoethoxy)phenyl)acrylamide

The first step：N- (2- methoxyl groups -4- (2- morpholines ethyoxyl) -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (29A)

N-(2-methoxy-4-(2-morpholinoethoxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

By 5- ((4- (1- methyl indol -3- bases) pyrimidine -2-base) amino) fluoro- 1- nitrobenzene (the intermediate 3) (1.2g of -4- methoxyl groups -2-, 3.05mmol) it is dissolved in 30mL tetrahydrofurans, sodium hydride (244.2mg is added under ice bath, 6.1mmol), stirring 30 minutes, 2- morpholine ethanols (800.8mg, 6.1mmol) are added dropwise, react at room temperature 6 hours.Reaction terminates, and adds 150mL water and 150mL ethyl acetate, point liquid.Aqueous phase is extracted with 100mL ethyl acetate, organic phase anhydrous sodium sulfate drying, it is concentrated to give yellow solid compound N- (2- methoxyl groups -4- (2- morpholines ethyoxyl) -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (29A) (1g, yield 66.7%).

Second step：6- methoxyl groups-N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -4- (2- morpholines ethyoxyl) benzene -1,3- diamines (29B)

6-methoxy-N1-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-(2-morpholinoethoxy)benzene-1,3-diamine

By N- (2- methoxyl groups -4- (2- morpholines ethyoxyl) -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (29A) (1g, 2mmol) it is dissolved in 30mL ethanol, sequentially add 10mL water, iron powder (672mg, 12mmol) with ammonium chloride (74.2mg, 1.4mmol), 90 DEG C of back flow reactions are warming up to 8 hours.Reaction solution is cooled to room temperature, filtered, concentration.With silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1) brown solid compound 6- methoxyl groups-N, is obtained¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -4- (2- morpholines ethyoxyl) benzene -1,3- diamines (29B) (600mg, yield 63.3%).

3rd step：N- (4- methoxyl groups -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (2- morpholines ethyoxyl) phenyl) acrylamide (compound 29)

By 6- methoxyl groups-N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -4- (2- morpholines ethyoxyl) benzene -1,3- diamines (29B) (600mg, 1.26mmol) it is dissolved in 10mL pyridines, sequentially add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (722mg, 3.78mmol), acrylic acid (0.13mL, 1.89mmol), react at room temperature 4 hours.It is spin-dried for removing pyridine, adds 100mL water and 100mL dichloromethane, point liquid.Organic phase is washed with 4mol/L sodium hydrate aqueous solutions (100mL).Organic phase anhydrous sodium sulfate drying.Silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain compound as white solid N- (4- methoxyl groups -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (2- morpholines ethyoxyl) phenyl) acrylamide (compound 29) (65mg, yield 7.8%).

MS m/z:529.1[M+1]⁺。

Embodiment 30

N- (5- ((4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (compound 30)

N-(5-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

The first step：3- (2- chlorine pyrimidine-4-yl) -1- (difluoromethyl) -1H- indoles (30A)

3-(2-chloropyrimidin-4-yl)-1-(difluoromethyl)-1H-indole

By 3- (2- chlorine pyrimidine-4-yl) -1H- indoles (2b) (1g, 4.35mmol) it is dissolved in 15mL acetonitriles, add potassium hydroxide (4.88g, 87mmol) with 10mL water, it is cooled to 0 DEG C, bromine methyl fluoride diethyl phosphonate (2.32g, 8.7mmol) is added dropwise, is warmed to room temperature continuation and reacts 2 hours.Reaction solution is poured into 50mL water, ethyl acetate (50mL) extraction, organic phase is washed with water (50mL), and anhydrous sodium sulfate drying is concentrated to give brown solid compound 3- (2- chlorine pyrimidines -4- Base) -1- (difluoromethyl) -1H- indoles (30A) (1.2g, crude product).

MS m/z=280.0 [M+1]⁺。

Second step：4- (1- (difluoromethyl) -1H- indol-3-yls)-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) pyrimidine -2- amine (30B)

4-(1-(difluoromethyl)-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine

By 3- (2- chlorine pyrimidine-4-yl) -1- (difluoromethyl) -1H- indoles (30A) (0.1g, 0.36mmol) it is dissolved in 2- amylalcohols (10mL), add fluoro- 2- methoxyl groups -5- nitroanilines (the 4e) (67mg of 4-, 0.36mmol) with p-methyl benzenesulfonic acid (83mg, 0.43mmol), 120 DEG C of back flow reactions are heated to 1 day.Reaction solution is cooled to room temperature, filtering, filter cake is washed with water (50mL), dry to obtain yellow solid 4- (1- (difluoromethyl) -1H- indol-3-yls)-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) pyrimidine -2- amine (30B) (0.1g, yield 66.7%).

MS m/z=430.0 [M+1]⁺。

3rd step：N¹- (4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro benzene -1,4- diamines (30C)

N¹-(4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N⁴-(2-(dimethylamino)ethyl)-2-methoxy-N⁴-methyl-5-nitrobenzene-1,4-diamine

By 4- (1- (difluoromethyl) -1H- indol-3-yls)-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) pyrimidine -2- amine (30B) (0.6g, 1.4mmol) it is dissolved in N, in N- dimethyl acetamides (5mL), add DIPEA (220mg, 1.7mmol) and N, N, N'- trimethyls ethylenediamine (18A) (172mg, 1.7mmol), 140 DEG C of microwave reacts 1 hour.Reaction terminates, and adds 150mL water and 150mL ethyl acetate, point liquid.Organic phase anhydrous sodium sulfate drying, is concentrated to give brown oil compound N¹- (4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro benzene-Isosorbide-5-Nitrae-diamines (30C) (0.7g, yield 97.9%).

MS m/z=512.1 [M+1]⁺。

4th step：N⁴- (4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base)-N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methylbenzene -1,2,4- triamines (30D)

N⁴-(4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N¹-(2-(dimethylamino)ethyl)-5-methoxy-N¹-methylbenzene-1,2,4-triamine

By N¹- (4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro benzene -1,4- diamines (30C) (0.9g, 1.76mmol) it is dissolved in 30mL ethanol, sequentially add 10mL water, iron powder (295mg, 5.28mmol) with ammonium chloride (66mg, 1.23mmol), 90 DEG C of back flow reactions are warming up to 4 hours, concentration.With silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1) brown solid compound N, is obtained⁴- (4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base)-N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methylbenzene -1,2,4- triamines (30D) (350mg, yield 41.3%).

MS m/z=482.1 [M+1]⁺。

5th step：N- (5- ((4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (compound 30)

By N⁴- (4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base)-N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methylbenzene -1,2,4- triamines (30D) (350mg, 0.73mmol) it is dissolved in 10mL pyridines, sequentially add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (416mg, 2.18mmol) with acrylic acid (0.075mL, 1.09mmol), react at room temperature 4 hours.Pyridine is spin-dried for, 150mL water and 150mL dichloromethane is added, point liquid.Organic phase is washed with 4mol/L sodium hydrate aqueous solutions 100mL.Organic phase anhydrous sodium sulfate drying.Silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain white solid N- (5- ((4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (compound 30) (170mg, yield 43.6%).

MS m/z:536.1[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ9.76(s,1H),9.43(s,1H),8.46(d,1H),8.04(dd,1H),7.79(dd,2H),7.38–7.32(m,2H),6.75(s,1H),6.40(d,1H),5.77(d,1H),3.90(s,3H),2.74(s,3H),1.55(s,6H)。

Embodiment 31

N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (1- isopropyl -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 31)

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(1-isopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

The first step：3- (2- chlorine pyrimidine-4-yl) -1- isopropyl -1H- indoles (31A)

3-(2-chloropyrimidin-4-yl)-1-isopropyl-1H-indole

By 3- (2- chlorine pyrimidine-4-yl) -1H- indoles (2b) (2g, 8.7mmol) it is dissolved in 30mL tetrahydrofurans, 0 DEG C adds sodium hydride (836mg, 10.4mmol), reaction 30 minutes, Iso-Propyl iodide (5.24mL, 26.3mmol) is added, reaction 32 hours is warmed to room temperature.Reaction terminates, and adds 150mL dichloromethane and 100mL water, point liquid.Aqueous phase is extracted with 100mL dichloromethane, organic phase anhydrous sodium sulfate drying.With silica gel column chromatography separating-purifying (petroleum ether:Ethyl acetate (v/v)=1:0~2:1) brown solid compound 3- (2- chlorine pyrimidine-4-yl) -1- isopropyl -1H- indoles (31A) (0.75g, yield 32.6%) is obtained.

MS m/z=272.1 [M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ8.44–8.39(m,1H),8.36(d,1H),8.02(s,1H),7.38(dd,1H),7.27(dt,2H),7.22(d,1H),4.64(dt,1H),1.59–1.45(m,6H)。

Second step：N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1- isopropyl -1H- indol-3-yls) pyrimidine -2- amine (31B)

N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-isopropyl-1H-indol-3-yl)pyrimidin-2-amine

By 3- (2- chlorine pyrimidine-4-yl) -1- isopropyl -1H- indoles (31A) (0.75g, 2.77mmol) it is dissolved in 2- amylalcohols (40mL), add fluoro- 2- methoxyl groups -5- nitroanilines (the 4e) (515mg of 4-, 2.77mmol) with p-methyl benzenesulfonic acid (632mg, 3.33mmol), 120 DEG C of back flow reactions are heated to 3 days.Reaction solution is cooled to room temperature, solid is separated out, filter cake uses 20mL acetonitriles and 100mL water washings successively.Filter cake is dried into obtain yellow solid N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1- isopropyl -1H- indol-3-yls) pyrimidine -2- amine (31B) (0.6g, yield 51.3%).

¹H NMR(400MHz,CDCl₃)δ9.15(d,1H),8.51(s,1H),8.46–8.26(m,3H),7.63(d,1H),7.39(dd,2H),7.25(t,1H),7.14(t,1H),4.98–4.78(m,1H),4.02(s,3H),1.54(d,6H)。

3rd step：N¹- (2- (dimethylamino) ethyl)-N⁴- (4- (1- isopropyl -1H- indol-3-yls) pyrimidine -2-base) -5- methoxyl groups-N¹- methyl -2- nitrobenzene -1,4- diamines (31C)

N¹-(2-(dimethylamino)ethyl)-N⁴-(4-(1-isopropyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy-N¹-methyl-2-nitrobenzene-1,4-diamine

By N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1- isopropyl -1H- indol-3-yls) pyrimidine -2- amine (31B) (0.6g, 1.4mmol) it is dissolved in N, in N- dimethyl acetamides (10mL), sequentially add DIPEA (221mg, 1.71mmol) and N, N, N'- trimethyls ethylenediamine (18A) (175mg, 1.71mmol), 140 DEG C of microwave reacts 1 hour.Reaction terminates, concentration.With silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~30:1) red solid compound N is obtained¹- (2- (dimethylamino) ethyl)-N⁴- (4- (1- isopropyl -1H- indol-3-yls) pyrimidine -2-base) -5- methoxyl groups-N¹- methyl -2- nitrobenzene-Isosorbide-5-Nitrae-diamines (31C) (0.6g, yield 85.2%).

MS m/z:504.3[M+1]⁺。

4th step：N¹- (2- (dimethylamino) ethyl)-N⁴- (4- (1- isopropyl -1H- indol-3-yls) pyrimidine -2-base) -5- methoxyl groups-N¹- methylbenzene -1,2,4- triamines (31D)

N1-(2-(dimethylamino)ethyl)-N4-(4-(1-isopropyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy-N1-methylbenzene-1,2,4-triamine

By N¹- (2- (dimethylamino) ethyl)-N⁴- (4- (1- isopropyl -1H- indol-3-yls) pyrimidine -2-base) -5- methoxyl groups-N¹- methyl -2- nitrobenzene-Isosorbide-5-Nitrae-diamines (31C) (0.6g, 1.2mmol) is dissolved in 15mL ethanol, sequentially add 5mL water, iron powder (201mg, 3.6mmol) and ammonium chloride (45mg, 0.84mmol), 90 DEG C of back flow reactions are warming up to 4 hours.Reaction solution is cooled to room temperature, filtered, concentration.With silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~30:1) brown solid compound N, is obtained¹- (2- (dimethylamino) ethyl)-N⁴- (4- (1- isopropyl -1H- indol-3-yls) pyrimidine -2-base) -5- methoxyl groups-N¹- methylbenzene -1,2,4- triamines (31D) (550mg, yield 96.8%).

MS m/z:474.3[M+1]⁺。

5th step：N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (1- isopropyl -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 31)

By N¹- (2- (dimethylamino) ethyl)-N⁴- (4- (1- isopropyl -1H- indol-3-yls) pyrimidine -2-base) -5- methoxyl groups-N¹- methylbenzene -1,2,4- triamines (31D) (550mg, 1.16mmol) it is dissolved in 10mL pyridines, add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (997mg, 5.22mmol), acrylic acid (0.12mL, 1.74mmol), is reacted at room temperature 4 hours.Pyridine is spin-dried for, sodium hydrate aqueous solution (100mL, 4mol/L) and 100mL ethyl acetate is added, point liquid.Organic phase 100mL saturated common salt water washings, anhydrous sodium sulfate drying.Silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain compound as white solid N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (1- isopropyl -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 31) (400mg, yield 65.5%).

MS m/z:528.2[M+1]⁺。

Embodiment 32

N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (1- ethyl -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 32)

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(1-ethyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

The first step：3- (2- chlorine pyrimidine-4-yl) -1- ethyl -1H- indoles (32A)

3-(2-chloropyrimidin-4-yl)-1-ethyl-1H-indole

3- (2- chlorine pyrimidine-4-yl) -1H- indoles (2b) (2g, 8.7mmol) is dissolved in 30mL tetrahydrofurans, 0 DEG C is cooled to, sodium hydride (0.836g, 10.4mmol) is added, 0 DEG C is reacted 30 minutes.Iodoethane (4.1g, 26.3mmol) is added, continuation is warmed to room temperature and reacts 4 hours, reaction terminates, and is spin-dried for solvent.Solid is washed with 100mL water and 20mL tetrahydrofurans.Solid drying is obtained into yellow solid compound 3- (2- chlorine pyrimidine-4-yl) -1- ethyl -1H- indoles (32A) (2.1g, yield 95.5%).

MS m/z:258.0[M+1]⁺。

Second step：4- (1- ethyl -1H- indol-3-yls)-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) pyrimidine -2- amine (32B)

4-(1-ethyl-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine

By 3- (2- chlorine pyrimidine-4-yl) -1- ethyl -1H- indoles (32A) (0.257g, 1mmol) it is dissolved in 2- amylalcohols (10mL), add fluoro- 2- methoxyl groups -5- nitroanilines (the 4e) (186mg of 4-, 1mmol) with p-methyl benzenesulfonic acid (228mg, 1.2mmol), 120 DEG C of back flow reactions are heated to 1 day.Reaction solution is cooled to room temperature, filtering, filter cake 50mL water washings, dry to obtain yellow solid 4- (1- ethyl -1H- indol-3-yls)-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) pyrimidine -2- amine (32B) (0.3g, yield 73.7%).

MS m/z:408.0[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ9.15(d,1H),8.48–8.35(m,3H),8.27(s,1H),7.59(d,1H),7.39–7.33(m,2H),7.26(t,1H),7.15(t,1H),4.30(q,2H),4.03(s,3H),1.46(t,3H)。

3rd step：N¹- (2- (dimethylamino) ethyl)-N⁴- (4- (1- ethyl -1H- indol-3-yls) pyrimidine -2-base) -5- methoxyl groups-N¹- methyl -2- nitrobenzene -1,4- diamines (32C)

N1-(2-(dimethylamino)ethyl)-N4-(4-(1-ethyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy- N1-methyl-2-nitrobenzene-1,4-diamine

By 4- (1- ethyl -1H- indol-3-yls)-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) pyrimidine -2- amine (32B) (1g, 2.46mmol) it is dissolved in 12mL N, in N- dimethyl acetamides, DIPEA (387.8mg is added, 3mmol), and N, N, N'- trimethyl ethylenediamine (18A) (300mg, 3mmol), 140 DEG C of microwave reacts 1 hour.Reaction terminates, and adds 150mL water and 150mL dichloromethane, point liquid.Organic phase anhydrous sodium sulfate drying, is concentrated to give red solid compound N¹- (2- (dimethylamino) ethyl)-N⁴- (4- (1- ethyl -1H- indol-3-yls) pyrimidine -2-base) -5- methoxyl groups-N¹- methyl -2- nitrobenzene-Isosorbide-5-Nitrae-diamines (32C) (1g, yield 83.3%).

MS m/z:490.1[M+1]⁺。

4th step：N¹- (2- (dimethylamino) ethyl)-N⁴- (4- (1- ethyl -1H- indol-3-yls) pyrimidine -2-base) -5- methoxyl groups-N¹- methylbenzene -1,2,4- triamines (32D)

N1-(2-(dimethylamino)ethyl)-N4-(4-(1-ethyl-1H-indol-3-yl)pyrimidin-2-yl)-5-methoxy-N1-methylbenzene-1,2,4-triamine

By N¹- (2- (dimethylamino) ethyl)-N⁴- (4- (1- ethyl -1H- indol-3-yls) pyrimidine -2-base) -5- methoxyl groups-N¹- methyl -2- nitrobenzene-Isosorbide-5-Nitrae-diamines (32C) (1g, 2mmol) is dissolved in 15mL ethanol, sequentially add 5mL water, iron powder (335mg, 6mmol) and ammonium chloride (75mg, 1.4mmol), 90 DEG C of back flow reactions are warming up to 6 hours.Reaction solution is concentrated, with silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1) brown solid compound N, is obtained¹- (2- (dimethylamino) ethyl)-N⁴- (4- (1- ethyl -1H- indol-3-yls) pyrimidine -2-base) -5- methoxyl groups-N¹- methylbenzene -1,2,4- triamines (32D) (800mg, yield 87.1%).

MS m/z:460.1[M+1]⁺。

5th step：N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (1- ethyl -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 32)

By N¹- (2- (dimethylamino) ethyl)-N⁴- (4- (1- ethyl -1H- indol-3-yls) pyrimidine -2-base) -5- methoxyl groups-N¹- methylbenzene -1,2,4- triamines (32D) (800mg, 1.74mmol) it is dissolved in 15mL pyridines, sequentially add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (999mg, 5.2mmol) with acrylic acid (0.18mL, 2.61mmol), react at room temperature 4 hours.Pyridine is spin-dried for, 100mL water and 100mL dichloromethane is added, point liquid.Organic phase is washed with sodium hydrate aqueous solution (100mL, 4mol/L).Organic phase anhydrous sodium sulfate drying.Silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain compound as white solid N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (1- ethyl -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 32) (110mg, yield 12.3%).

MS m/z:514.2[M+1]⁺。

Embodiment 33

N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (1- (2- hydroxyethyls) -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 33)

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(1-(2-hydroxyethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

Second step：1- (2- ((t-Butyldimethylsilyl) epoxide) ethyl) -3- (2- chlorine pyrimidine-4-yl) -1H- indoles (33A)

1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(2-chloropyrimidin-4-yl)-1H-indole

3- (2- chlorine pyrimidine-4-yl) -1H- indoles (2b) (1g, 4.35mmol) is dissolved in 25mL tetrahydrofurans, 0 DEG C is cooled to, sodium hydride (125.3mg, 5.22mmol) is added, 0 DEG C is reacted 30 minutes.(2- bromine oxethyls)-t-butyldimethyl silane (2.5g, 8.7mmol) is added, continuation is warmed to room temperature and reacts 1 day.Reaction terminates, it is spin-dried for solvent, solid 100mL water washings, solid drying is obtained into yellow solid compound 1- (2- ((t-Butyldimethylsilyl) epoxide) ethyl) -3- (2- chlorine pyrimidine-4-yl) -1H- indoles (33A) (1.3g, yield 77.4%).

¹H NMR(400MHz,CDCl₃)δ8.79(d,1H),8.76–8.72(m,1H),8.38(s,1H),7.81(d,1H),7.79–7.74(m,1H),7.70–7.65(m,2H),4.65(t,2H),4.32(t,2H),1.20–1.17(m,9H),0.23–0.21(m,6H)。

Second step：2- (3- (2- ((the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) amino) pyrimidine-4-yl) -1H- indoles -1- bases) ethanol (33B)

2-(3-(2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-indol-1-yl)ethanol

By 1- (2- ((t-Butyldimethylsilyl) epoxide) ethyl) -3- (2- chlorine pyrimidine-4-yl) -1H- indoles (33A) (1.3g, 3.36mmol) it is dissolved in 2- amylalcohols (50mL), sequentially add fluoro- 2- methoxyl groups -5- nitroanilines (the 4e) (625mg of 4-, 3.36mmol) with p-methyl benzenesulfonic acid (774mg, 4.03mmol), 120 DEG C of back flow reactions are heated to 2 days.Reaction solution is cooled to room temperature, filtering, filter cake 100mL water washings, dry to obtain yellow solid 2- (3- (2- ((the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) amino) pyrimidine-4-yl) -1H- indoles -1- bases) ethanol (33B) (1.1g, yield 78.6%).

MS m/z:424.0[M+1]⁺。

3rd step：2- (3- (2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenones) amino) pyrimidine-4-yl) -1H- indoles -1- bases) ethanol (33C)

2-(3-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-indol-1-yl)ethanol

By 2- (3- (2- ((the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) amino) pyrimidine-4-yl) -1H- indoles -1- bases) ethanol (33B) (1g, 2.4mmol) it is dissolved in 10mLN, in N- dimethyl acetamides, sequentially add DIPEA (366mg, 2.8mmol) and N, N, N'- trimethyls ethylenediamine (18A) (290mg, 2.8mmol), 140 DEG C of microwave reacts 1 hour.Reaction terminates, and adds 150mL water and 150mL ethyl acetate, point liquid.Organic phase 100mL water washings, anhydrous sodium sulfate drying, filtering, it is concentrated to give Red oil compound 2- (3- (2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenones) amino) pyrimidine-4-yl) -1H- indoles -1- bases) ethanol (33C) (1g, yield 83.3%).

4th step：N¹- (4- (1- (2- ((t-Butyldimethylsilyl) epoxide) ethyl) -1H- indol-3-yls) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro benzene -1,4- diamines (33D)

N¹-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N⁴-(2-(dimethylamino)ethyl)-2-methoxy-N⁴-methyl-5-nitrobenzene-1,4-diamine

By 2- (3- (2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenones) amino) pyrimidine-4-yl) -1H- indoles -1- bases) ethanol (33C) (1g, 1.98mmol) it is dissolved in 20mL dichloromethane, add triethylamine (600mg, 5.94mmol), tert-butyl chloro-silicane (448mg is added dropwise, 2.97mmol), react at room temperature 4 hours.Reaction terminates, and adds 10mL water, stirs 30 minutes.100mL water and 100mL dichloromethane are added into reaction solution, point liquid.Aqueous phase is extracted with 100mL dichloromethane, the washing of 150mL saturated sodium-chlorides.It is concentrated to give Red oil N¹- (4- (1- (2- ((t-Butyldimethylsilyl) epoxide) ethyl) -1H- indol-3-yls) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro benzene-Isosorbide-5-Nitrae-diamines (33D) (1g, yield 83.3%).

MS m/z:620.0[M+1]⁺。

5th step：N⁴- (4- (1- (2- ((t-Butyldimethylsilyl) epoxide) ethyl) -1H- indol-3-yls) pyrimidine -2- Base)-N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methylbenzene -1,2,4- triamines (33E)

By N¹- (4- (1- (2- ((t-Butyldimethylsilyl) epoxide) ethyl) -1H- indol-3-yls) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro benzene-Isosorbide-5-Nitrae-diamines (33D) (1g, 1.6mmol) is dissolved in 30mL ethanol, sequentially add 10mL water, iron powder (270mg, 4.8mmol) and ammonium chloride (60mg, 1.1mmol), 90 DEG C of back flow reactions are warming up to 6 hours.Reaction solution is concentrated, with silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1) brown solid compound N, is obtained⁴- (4- (1- (2- ((t-Butyldimethylsilyl) epoxide) ethyl) -1H- indol-3-yls) pyrimidine -2-base)-N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methylbenzene -1,2,4- triamines (33E) (1.1g, crude product).

6th step：N- (5- ((4- (1- (2- ((t-Butyldimethylsilyl) epoxide) ethyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (33F)

N-(5-((4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

By N⁴- (4- (1- (2- ((t-Butyldimethylsilyl) epoxide) ethyl) -1H- indol-3-yls) pyrimidine -2-base)-N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methylbenzene -1,2,4- triamines (33E) (943mg, 1.6mmol) it is dissolved in 15mL pyridines, sequentially add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (917mg, 4.8mmol), acrylic acid (0.17mL, 2.4mmol), react at room temperature 4 hours.Reaction solution is spin-dried for remove pyridine, 150mL water and 150mL ethyl acetate is added, point liquid.Organic phase is washed with sodium hydrate aqueous solution (100mL, 4mol/L), anhydrous sodium sulfate drying, is filtered, concentration.Residue silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain brown solid compound N-(5- ((4- (1- (2- ((t-Butyldimethylsilyl) epoxide) ethyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (33F) (360mg, yield 35%).

MS m/z:644.2[M+1]⁺。

7th step：N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (1- (2- hydroxyethyls) -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 33)

By N- (5- ((4- (1- (2- ((t-Butyldimethylsilyl) epoxide) ethyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (33F) (0.36g, 0.52mmol) it is dissolved in 10mL dichloromethane, add tetrabutyl ammonium fluoride (293mg, 1.12mmol), react at room temperature 6 hours.Reaction terminates, and adds 100mL water and 100mL dichloromethane, point liquid.Aqueous phase is extracted with 100mL dichloromethane, is closed And organic phase, organic phase washed with 150mL saturated sodium-chlorides.Organic phase is concentrated, silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain brown solid compound N-(2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (1- (2- hydroxyethyls) -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 33) (0.25g, yield 84.6%).

MS m/z:530.1[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ9.69(s,1H),9.08(s,1H),8.38(d,1H),8.08–8.00(m,1H),7.72(s,1H),7.46–7.40(m,1H),7.27(d,1H),7.23(t,1H),6.75(s,1H),6.38(d,1H),5.76(d,1H),4.45(t,2H),4.06(t,2H),3.89(s,3H),3.06(d,2H),2.70(s,3H),2.43(s,2H),1.60(s,6H)。

Embodiment 34

N- (5- ((4- (1- (Cvclopropvlmethvl) -1H- indol-3-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (compound 34)

N-(5-((4-(1-(cyclopropylmethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

The first step：N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1H- indol-3-yls) pyrimidine -2- amine (34A)

N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine

By 3- (2- chlorine pyrimidine-4-yl) -1H- indoles (2b) (3g, 13.1mmol) it is dissolved in 2- amylalcohols (10mL), add fluoro- 2- methoxyl groups -5- nitroanilines (the 4e) (2.44g of 4-, 13.1mmol) with p-methyl benzenesulfonic acid (3.02g, 15.7mmol), 120 DEG C of back flow reactions are heated to 3 days.Reaction solution is cooled to room temperature, 200mL ammoniacal liquor is added, solid is separated out, filtered, filter cake 250mL water and 100mL petroleum ethers dry to obtain celadon solid N- (the fluoro- 2- methoxyl groups -5- nitrobenzene of 4- Base) -4- (1H- indol-3-yls) pyrimidine -2- amine (34A) (4g, yield 80.5%).

MS m/z=380.1 [M+1]⁺。

Second step：N¹- (4- (1H- indol-3-yls) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro benzene -1,4- diamines (34B)

N¹-(4-(1H-indol-3-yl)pyrimidin-2-yl)-N⁴-(2-(dimethylamino)ethyl)-2-methoxy-N⁴-methyl-5-nitrobenzene-1,4-diamine

By N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1H- indol-3-yls) pyrimidine -2- amine (34A) (2g, 5.3mmol) it is dissolved in 15mL N, in N- dimethyl acetamides, add DIPEA (1.02g, 7.9mmol) and N, N, N'- trimethyls ethylenediamine (18A) (809mg, 7.9mmol), 120 DEG C of microwave reacts 1.5 hours.Reaction terminates, and reaction solution is cooled into room temperature, adds 200mL water and 200mL ethyl acetate, point liquid.Organic phase 100mL saturated common salt water washings, anhydrous sodium sulfate drying is concentrated to give red brown solid compound N¹- (4- (1H- indol-3-yls) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro benzene-Isosorbide-5-Nitrae-diamines (34B) (1.8g, yield 75%).

3rd step：N¹- (4- (1- (Cvclopropvlmethvl) -1H- indol-3-yls) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro benzene -1,4- diamines (34C)

N¹-(4-(1-(cyclopropylmethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N⁴-(2-(dimethylamino)ethyl)-2-methoxy-N⁴-methyl-5-nitrobenzene-1,4-diamine

By N¹- (4- (1H- indol-3-yls) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro benzene-Isosorbide-5-Nitrae-diamines (34B) (2g, 4.3mmol) is dissolved in 20mL dimethylformamides, is cooled to 0 DEG C, adds sodium hydride (0.26g, 6.5mmol), and 0 DEG C is reacted 30 minutes.Bromomethyl cyclopropane (0.585g, 4.3mmol) is added, continuation is warmed to room temperature and reacts 6 hours.Reaction terminates, and adds 100mL water and 100mL ethyl acetate, point liquid.Aqueous phase is extracted with 100mL ethyl acetate.Merge organic phase, organic phase anhydrous sodium sulfate drying is concentrated to give brown solid compound N¹- (4- (1- (Cvclopropvlmethvl) -1H- indol-3-yls) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro benzene-Isosorbide-5-Nitrae-diamines (34C) (2g, yield 90.9%).

MS m/z:516.1[M+1]⁺。

4th step：N⁴- (4- (1- (Cvclopropvlmethvl) -1H- indol-3-yls) pyrimidine -2-base)-N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methylbenzene -1,2,4- triamines (34D)

N⁴-(4-(1-(cyclopropylmethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N¹-(2-(dimethylamino)ethyl)-5-methoxy-N¹-methylbenzene-1,2,4-triamine

By N¹- (4- (1- (Cvclopropvlmethvl) -1H- indol-3-yls) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro benzene-Isosorbide-5-Nitrae-diamines (34C) (2g, 3.88mmol) is dissolved in 24mL ethanol, sequentially add 8mL water, iron powder (1.3g, 23.3mmol) and ammonium chloride (145mg, 2.7mmol), 92 DEG C of back flow reactions are warming up to 5 hours. Reaction solution is concentrated, with silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=1:0~10:1) brown solid compound N, is obtained⁴- (4- (1- (Cvclopropvlmethvl) -1H- indol-3-yls) pyrimidine -2-base)-N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methylbenzene -1,2,4- triamines (34D) (1.1g, yield 58.5%).

MS m/z:486.1[M+1]⁺。

5th step：N- (5- ((4- (1- (Cvclopropvlmethvl) -1H- indol-3-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (compound 34)

By N⁴- (4- (1- (Cvclopropvlmethvl) -1H- indol-3-yls) pyrimidine -2-base)-N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methylbenzene -1,2,4- triamines (34D) (1g, 2.06mmol) it is dissolved in 25mL pyridines, sequentially add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (1.18g, 6.2mmol) and acrylic acid (0.213mL, 3.1mmol), react at room temperature 4 hours.Reaction solution is spin-dried for remove pyridine, add 150mL ethyl acetate and sodium hydrate aqueous solution (100mL, 4mol/L), liquid is divided, aqueous phase is extracted with 100mL ethyl acetate, merge organic phase, 150mL saturated sodium-chlorides are washed, anhydrous sodium sulfate drying, filtering, it is spin-dried for, with silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain compound as white solid N- (5- ((4- (1- (Cvclopropvlmethvl) -1H- indol-3-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (compound 34) (250mg, yield 22.7%).

MS m/z=540.4 [M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ10.09(s,1H),9.83(s,1H),9.07(s,1H),8.38(d,1H),8.08(dd,1H),7.71(s,1H),7.51–7.42(m,1H),7.28–7.24(m,3H),7.22(d,1H),6.79(s,1H),6.40(s,2H),5.74–5.67(m,1H),4.21(d,2H),3.88(s,3H),3.48(s,1H),2.89(dd,2H),2.70(s,3H),2.28(s,8H),1.44(dtd,1H),0.61–0.52(m,2H),0.50–0.42(m,2H)。

Embodiment 35

N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((5- methoxyl groups -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 35)

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((5-methoxy-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

The first step：3- (2- chloro-5-methoxyls pyrimidine-4-yl) -1H- indoles (35A)

3-(2-chloro-5-methoxypyrimidin-4-yl)-1H-indole

Indoles (4a) (2.34g, 20mmol) is dissolved in 40mL tetrahydrofurans, under nitrogen protection, 0 DEG C is cooled to, methyl-magnesium-bromide (6.7mL, 20mmol) is added dropwise, continues to stir 0.5 hour.2,4- dichloro-5-methoxy pyrimidines (3.58g, 20mmol) are added, are reacted at room temperature 1 hour, 65 DEG C is warming up to and reacts 4 hours.150mL water and 150mL dichloromethane are added into reaction solution, point liquid.Organic phase anhydrous sodium sulfate drying, filtering, is spin-dried for, silica gel column chromatography separating-purifying (petroleum ether:Ethyl acetate (v/v)=10:1~2:1) yellow solid 3- (2- chloro-5-methoxyls pyrimidine-4-yl) -1H- indoles (35A) (2.81g, yield 55.1%), is obtained.

MS m/z=260.0 [M+1]⁺。

Second step：3- (2- chloro-5-methoxyls pyrimidine-4-yl) -1- Methyl-1H-indoles (35B)

3-(2-chloro-5-methoxypyrimidin-4-yl)-1-methyl-1H-indole

By 3- (2- chloro-5-methoxyls pyrimidine-4-yl) -1H- indoles (35A) (1.4g, 5.4mmol) it is dissolved in 25mL tetrahydrofurans, is cooled to 0 DEG C, adds sodium hydride (0.261g, 10.9mmol), 0 DEG C is reacted 30 minutes.Iodomethane (2.3g, 16.2mmol) is added, continuation is warmed to room temperature and reacts 4 hours, reaction terminates, 10mL water quenchings is added and goes out reaction, be spin-dried for solvent.With silica gel column chromatography separating-purifying (petroleum ether:Ethyl acetate (v/v)=1:0~2:1) yellow solid compound 3- (2- chloro-5-methoxyls pyrimidine-4-yl) -1- Methyl-1H-indoles (35B) (0.3g, yield 20.4%), are obtained.

MS m/z=274.0 [M+1]⁺。

3rd step：N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -5- methoxyl groups -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (35C)

N-(4-fluoro-2-methoxy-5-nitrophenyl)-5-methoxy-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

By 3- (2- chloro-5-methoxyls pyrimidine-4-yl) -1- Methyl-1H-indoles (35B) (0.3g, 1.1mmol) it is dissolved in 2- amylalcohols (20mL), add fluoro- 2- methoxyl groups -5- nitroanilines (the 4e) (204mg of 4-, 1.1mmol) with p-methyl benzenesulfonic acid (253mg, 1.32mmol), 120 DEG C of back flow reactions are heated to 18 hours.Reaction solution is cooled to room temperature, 150mL water and 150mL ethyl acetate is added, point liquid.Organic phase anhydrous sodium sulfate drying, silica gel column chromatography separating-purifying (dichloromethane： Methanol (v/v)=1:0~10:1) red solid N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -5- methoxyl groups -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (35C) (0.55g, yield 45.8%), is obtained.

4th step：N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N⁴- (5- methoxyl groups -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base)-N¹- methyl -2- nitrobenzene -1,4- diamines (35D)

N¹-(2-(dimethylamino)ethyl)-5-methoxy-N⁴-(5-methoxy-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N¹-methyl-2-nitrobenzene-1,4-diamine

By N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -5- methoxyl groups -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (35C) (1g, 2.36mmol) it is dissolved in 10mL N, in N- dimethyl acetamides, DIPEA (367mg is added, 2.84mmol), and N, N, N'- trimethyl ethylenediamine (18A) (290mg, 2.84mmol), 125 DEG C of microwave reacts 1 hour.Reaction terminates, and DMA is removed in rotation, adds 150mL water and 150mL dichloromethane, point liquid.Aqueous phase is extracted with 100mL dichloromethane, merges organic phase.Organic phase anhydrous sodium sulfate drying, filtering, is concentrated to give red solid compound N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N⁴- (5- methoxyl groups -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base)-N¹- methyl -2- nitrobenzene-Isosorbide-5-Nitrae-diamines (35D) (1g, yield 83.3%).

MS m/z:490.1[M+1]⁺。

5th step：N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N⁴- (5- methoxyl groups -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base)-N¹- methylbenzene -1,2,4- triamines (35E)

N¹-(2-(dimethylamino)ethyl)-5-methoxy-N⁴-(5-methoxy-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N¹-methylbenzene-1,2,4-triamine

By N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N⁴- (5- methoxyl groups -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base)-N¹- methyl -2- nitrobenzene-Isosorbide-5-Nitrae-diamines (35D) (3.5g, 6.93mmol) is dissolved in 30mL ethanol, sequentially add 10mL water, iron powder (2.32g, 41.6mmol) and ammonium chloride (260mg, 4.85mmol), 90 DEG C of back flow reactions are warming up to 6 hours.Reaction solution is concentrated, silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1) brown solid compound N, is obtained¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N⁴- (5- methoxyl groups -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base)-N¹- methylbenzene -1,2,4- triamines (35E) (2g, yield 60.6%).

MS m/z:476.1[M+1]⁺。

6th step：N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((5- methoxyl groups -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 35)

By N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N⁴- (5- methoxyl groups -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base)-N¹- methylbenzene -1,2,4- triamines (35E) (350mg, 1.05mmol) are dissolved in 10mL pyridines, add EDCI (600 Mg, 3.14mmol) and acrylic acid (0.11mL, 1.57mmol), react at room temperature 4 hours.Reaction solution is spin-dried for remove pyridine, 100mL water and 100mL dichloromethane is added, point liquid.Organic phase is washed with sodium hydrate aqueous solution (100mL, 4mol/L), anhydrous sodium sulfate drying.Silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain brown solid compound N-(2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((5- methoxyl groups -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 35) (210mg, yield 37.8%).

MS m/z:530.1[M+1]⁺。

Embodiment 36

N- (4- methoxyl groups -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (3- morpholines propoxyl group) phenyl) acrylamide (compound 36)

N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(3-morpholinopropoxy)phenyl)acrylamide

The first step：N- (2- methoxyl groups -4- (3- morpholines propoxyl group) -5- nitrobenzene) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (36A)

N-(2-methoxy-4-(3-morpholinopropoxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

By 5- ((4- (1- methyl indol -3- bases) pyrimidine -2-base) amino) fluoro- 1- nitrobenzene (the intermediate 3) (1g of -4- methoxyl groups -2-, 2.54mmol) it is dissolved in 50mL tetrahydrofurans, sodium hydride (122mg is added under ice bath, 3.1mmol), stir 30 minutes.3- morpholine propyl group -1- alcohol (552mg, 3.8mmol) is added dropwise, room temperature reaction is stayed overnight.Reaction terminates, add 100mL water and 150mL ethyl acetate, divide liquid, organic phase anhydrous sodium sulfate drying, filtering, it is concentrated to give yellow solid compound N- (2- methoxyl groups -4- (3- morpholines propoxyl group) -5- nitrobenzene) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (36A) (1g, yield 71.4%).

MS m/z:519.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ9.66(d,1H),8.39(dd,1H),8.24(d,1H),8.15(dd,1H),7.51(s,1H),7.43–7.37(m,1H),7.35–7.28(m,2H),7.19(d,1H),6.56(s,1H),4.18(t,2H),4.01(s,1H),4.00(s,3H),3.93(d,3H),3.83–3.78(m,1H),3.75–3.68(m,4H),3.48(s,1H),2.67–2.59(m,3H),2.56–2.45(m,4H),2.11–1.98(m,2H),1.73(dt,1H)。

Second step：6- methoxyl groups-N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -4- (3- morpholines propoxyl group) benzene -1,3- diamines (36B)

6-methoxy-N¹-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-(3-morpholinopropoxy)benzene-1,3-diamine

By N- (2- methoxyl groups -4- (3- morpholines propoxyl group) -5- nitrobenzene) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (36A) (1g, 1.93mmol) it is dissolved in 30mL ethanol, 10L water, iron powder (646.5g successively, 11.58mol) with ammonium chloride (72.3g, 1.35mol), 90 DEG C of back flow reactions are warming up to 4 hours.Reaction solution is cooled to room temperature, filtered, concentration, with silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1) brown solid compound 6- methoxyl groups-N, is obtained¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -4- (3- morpholines propoxyl group) benzene -1,3- diamines (36B) (600mg, yield 63.7%).

MS m/z:489.2[M+1]⁺。

3rd step：N- (4- methoxyl groups -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (3- morpholines propoxyl group) phenyl) acrylamide (compound 36)

By 6- methoxyl groups-N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -4- (3- morpholines propoxyl group) benzene -1,3- diamines (36B) (600mg, 1.23mmol) it is dissolved in 10mL pyridines, sequentially add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (703mg, 3.68mmol) with acrylic acid (0.127mL, 1.84mmol), react at room temperature 3 hours.Reaction solution is spin-dried for remove pyridine, 4mol/L sodium hydrate aqueous solution 150mL and 150mL dichloromethane is added, point liquid.Organic phase 100mL saturated common salt water washings, anhydrous sodium sulfate drying.Silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain faint yellow solid compound N-(4- methoxyl groups -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (3- morpholines propoxyl group) phenyl) acrylamide (compound 36) (120mg, yield 18%).

MS m/z=543.2 [M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ9.68(s,1H),8.87(s,1H),8.34(d,1H),8.09(d,1H),7.97(s,1H),7.65(s,1H),7.39(d,1H),7.32–7.22(m,1H),7.17(d,1H),6.55(s,1H),6.44(d,1H),5.76(d,1H),4.13(t,2H),3.96(s,3H),3.90(s,5H),2.75(s,4H),2.20(s,2H),1.62(s,4H)。

Embodiment 37

N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- (3- morpholines propoxyl group) phenyl) acrylamide (compound 37)

N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(3-morpholinopropoxy)phenyl)acrylamide

The first step：The chloro- N- of 5- (2- methoxyl groups -4- (3- morpholines propoxyl group) -5- nitrobenzene) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (37A)

5-chloro-N-(2-methoxy-4-(3-morpholinopropoxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

By the chloro- N- of 5- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (intermediate 4) (1g, 2.34mmol) it is dissolved in 50mL tetrahydrofurans, sodium hydride (103mg is added under ice bath, 2.57mmol), stir 30 minutes.3- morpholine propyl group -1- alcohol (680mg, 4.68mmol) is added dropwise, room temperature reaction is stayed overnight.Reaction terminates, add 100mL water and 100mL ethyl acetate, divide liquid, organic phase anhydrous sodium sulfate drying, filtering, it is concentrated to give the chloro- N- of yellow oily compounds 5- (2- methoxyl groups -4- (3- morpholines propoxyl group) -5- nitrobenzene) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (37A) (1.2g, yield 85.7%).

¹H NMR(400MHz,DMSO-d₆)δ8.60(s,1H),8.55(s,1H),8.40(s,1H),8.32(s,1H),8.25(d,1H),7.51(d,1H),7.28–7.21(m,1H),7.01(t,1H),6.97(s,1H),4.46(s,1H),4.30(t,2H),3.94(s,3H),3.89(d,3H),3.43(t,4H),2.39(d,4H),2.29(s,1H),2.00–1.91(m,2H),1.61–1.51(m,4H)。

Second step：N¹- (the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -6- methoxyl groups -4- (3- morpholines propoxyl group) benzene -1,3- diamines (37B)

N1-(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-(3-morpholinopro poxy)benzene-1,3-diamine

By the chloro- N- of 5- (2- methoxyl groups -4- (3- morpholines propoxyl group) -5- nitrobenzene) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (37A) (1g, 1.8mmol) it is dissolved in 30mL ethanol, sequentially add 10mL water, iron powder (606.7mg, 10.06mmol) with ammonium chloride (67.8mg, 1.27mmol), 90 DEG C of back flow reactions are warming up to 4 hours.Reaction solution is cooled to room temperature, filtered, concentration, silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1) black solid compound N, is obtained¹- (the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -6- methoxyl groups -4- (3- morpholines propoxyl group) benzene -1,3- diamines (37B) (900mg, yield 95.3%).

MS m/z:523.2[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ8.52(s,1H),8.34(d,1H),8.29(s,1H),8.24(s,1H),7.49(d,1H),7.23(t,1H),7.05(t,1H),6.96(s,1H),6.68(s,1H),4.05(t,2H),3.90(s,3H),3.66(s,4H),3.65(s,4H),3.44(t,2H),2.65(d,6H),2.04–1.92(m,2H)。

3rd step：N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- (3- morpholines propoxyl group) phenyl) acrylamide (compound 37)

By N¹- (the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -6- methoxyl groups -4- (3- morpholines propoxyl group) benzene -1,3- diamines (37B) (900mg, 1.72mmol) it is dissolved in 30mL tetrahydrofurans, add N, N- diisopropylethylamine (0.34mL, 2.06mmol), acryloyl chloride (0.17mL is added dropwise at 0 DEG C, tetrahydrofuran solution 5mL 2.06mmol), is warmed to room temperature reaction 4 hours.100mL saturated sodium bicarbonate aqueous solutions and 100mL ethyl acetate are added, point liquid.Silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain yellow solid compound N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- (3- morpholines propoxyl group) phenyl) acrylamide (compound 37) (330mg, yield 41.4%).

MS m/z:577.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ9.27(s,1H),8.41(d,1H),8.38(s,1H),8.29(s,1H),7.65(s,1H),7.35(d,2H),7.29(d,1H),7.20(t,1H),6.57(s,1H),6.36(dd,1H),6.26(dd,1H),5.71(d,1H),4.11(t,2H),3.89(s,3H),3.88(s,3H),3.77–3.71(m,4H),2.56(d,2H),2.49(s,4H),2.04(dd,2H)。

Embodiment 38

N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- (3- morpholines propoxyl group) phenyl) acrylamide mesylate (compound 38)

N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(3-morp holinopropoxy)phenyl)acrylamide methanesulfonate

The first step：N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- (3- morpholines propoxyl group) phenyl) acrylamide mesylate (compound 38)

N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(3-morpholinopropoxy)phenyl)acrylamide methanesulfonate

By N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- (3- morpholines propoxyl group) phenyl) acrylamide (compound 37) (120mg, 0.208mmol) it is dissolved in 20mL ethanol, add 10mL ethyl acetate, methanesulfonic acid (0.0135mL is added dropwise at 70 DEG C, ethyl acetate (5mL) solution 0.208mmol), reacts 2 hours.Reaction solution is spin-dried for obtaining yellow solid compound N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- (3- morpholines propoxyl group) phenyl) acrylamide mesylate (compound 38) (140mg).

MS m/z:577.2[M+1]⁺。

Embodiment 39

N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base) amino) phenyl) acrylamide (compound 39)

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

The first step：3- (2- chlorine pyrimidine-4-yl) -1H- pyrrolo-es [2,3-b] pyridine (39B)

3-(2-chloropyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine

1H- pyrrolo-es [2,3-b] pyridine (39A) (10g, 85.2mmol) is dissolved in 1; in 2- dichloroethanes (50mL), under nitrogen protection, 0 DEG C is cooled to; methyl-magnesium-bromide (28.6mL, 85.2mmol) is added dropwise, continues to stir 0.5 hour.2,4- dichloro pyrimidines (15.26g, 102.4mmol) are added, are reacted at room temperature 4 hours.50mL methanol is added into reaction solution, solvent is spin-dried for, with silica gel column chromatography separating-purifying (petroleum ether:Ethyl acetate (v/v)=1:0~2:1) 3- (2- chlorine pyrimidine-4-yl) -1H- pyrrolo-es [2,3-b] pyridine (39B), yellow solid (10g, yield 51.3%), are obtained.

MS m/z=230.1 [M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ12.07(s,1H),8.52(dd,2H),8.47–8.37(m,1H),7.91(d,1H),7.51(dd,1H),7.29–7.19(m,2H)。

Second step：3- (2- chlorine pyrimidine-4-yl) -1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine (39C)

3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole

By 3- (2- chlorine pyrimidine-4-yl) -1H- pyrrolo-es [2,3-b] pyridine (39B) (2g, 8.7mmol) it is dissolved in 10mL tetrahydrofurans, 0 DEG C adds sodium hydride (418mg, 10.4mmol), continue to react 30 minutes, add iodomethane (1.63mL, 26.2mmol), it is warmed to room temperature reaction 4 hours.It is spin-dried for solvent and obtains solid, solid is washed with 50mL water and 50mL tetrahydrofurans, filters, be dried to obtain compound 3- (2- chlorine pyrimidine-4-yl) -1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine (39C), yellow solid (2.1g).

MS m/z:244.1[M+1]⁺。

3rd step：N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2- amine (39D)

N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

By 3- (2- chlorine pyrimidine-4-yl) -1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridine (39C) (1g, 4.1mmol) it is dissolved in 2- amylalcohols (20mL), add fluoro- 2- methoxyl groups -5- nitroanilines (the 4e) (765mg of 4-, 4.1mmol) with p-methyl benzenesulfonic acid (939mg, 4.9mmol), 120 DEG C of back flow reactions are heated to 2 days.Reaction solution is cooled to room temperature, add 30mL acetonitriles, filtering, filter cake with 50mL water washings once, dry to obtain N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2- amine (39D), yellow solid (1.2g, yield 75%).

4th step：N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl-N⁴- (4- (1- methyl isophthalic acid H- pyrrolo-es [2,3-b] Pyridin-3-yl) pyrimidine -2-base) -2- nitrobenzene -1,4- diamines (39E)

N¹-(2-(dimethylamino)ethyl)-5-methoxy-N¹-methyl-N⁴-(4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine

By N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2- amine (39D) (1g, 2.54mmol) it is dissolved in 20mL tetrahydrofurans, sodium hydride (203mg, 5.08mmol) is added under ice bath, stirring 30 minutes, N, N, N'- trimethyls ethylenediamine (18A) (733mg is added dropwise, 5.08mmol), react at room temperature 8 hours.Reaction terminates, and adds 150mL water and 150mL ethyl acetate, point liquid.Aqueous phase is extracted once with 100mL ethyl acetate, merges organic phase.Organic phase anhydrous sodium sulfate drying, filtering, is concentrated to give compound N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl-N⁴- (4- (1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base) -2- nitrobenzene-Isosorbide-5-Nitrae-diamines (39E), yellow solid (1.1g, yield 84.6%).

MS m/z:518.1[M+1]⁺。

5th step：N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl-N⁴- (4- (1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base) benzene -1,2,4- triamines (39F)

N¹-(2-(dimethylamino)ethyl)-5-methoxy-N¹-methyl-N⁴-(4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)benzene-1,2,4-triamine

By N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl-N⁴- (4- (1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base) -2- nitrobenzene -1,4- diamines (39E) (1.1g, 2.18mmol) it is dissolved in 15mL ethanol, sequentially add 5mL water, iron powder (356mg, 6.4mmol) and ammonium chloride (78.7mg, 1.55mmol), 90 DEG C of back flow reactions are warming up to 4 hours.Reaction solution is cooled to room temperature, filtered, concentration.Silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=1:0~10:1) compound N, is obtained¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl-N⁴- (4- (1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base) benzene -1,2,4- triamines (39F), brown solid (550mg, yield 51.9%).

6th step：N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base) amino) phenyl) acrylamide (compound 39)

By N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl-N⁴- (4- (1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base) benzene -1,2,4- triamines (39F), brown solid (550mg, 1mmol) is dissolved in 15mL pyridines, sequentially add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDCI) (573mg, 3mmol) with acrylic acid (0.103mL, 1.5mmol), react at room temperature 4 hours.Reaction solution is spin-dried for remove pyridine, 100mL water and 100mL dichloromethane is added, point liquid.Organic phase washed once with sodium hydrate aqueous solution (100mL, 4mol/L).Organic phase anhydrous sodium sulfate drying.Silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1) N- (2- ((2- (diformazans, are obtained Base amino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base) amino) phenyl) acrylamide (compound 39), white solid (65mg, yield 12%).

MS m/z:542.1[M+1]⁺。

Embodiment 40

N- (5- ((the chloro- 4- of 5- (1- methyl -6- morpholinyl -1H- indol-3-yls) pyrimidine -2-base) amino) the fluoro- 4- methoxyphenyls of -2-) acrylamide (compound 40)

The first step：1- (6- nitro -1H- indoles -1- bases) ethyl ketone (40B)

1-(6-nitro-1H-indol-1-yl)ethanone

6- nitro -1H- indoles (40A) (16.2g, 0.1mol) is dissolved in 40mL pyridines, acetic anhydride (40.8g, 0.4mol) is added, room temperature reaction is stayed overnight.Reaction terminates, and is spin-dried for, and adds 200mL saturated aqueous common salts and 200mL ethyl acetate, divide liquid, organic phase anhydrous sodium sulfate drying, filtering, it is spin-dried for obtaining 1- (6- nitro -1H- indoles -1- bases) ethyl ketone (40B), yellow solid (6g, yield 30%).

MS m/z:205.1[M+1]⁺。

Second step：1- (6- amino -1H- indoles -1- bases) ethyl ketone (40C)

1-(6-amino-1H-indol-1-yl)ethanone

By 1- (6- nitro -1H- indoles -1- bases) ethyl ketone (40B) (20g, 0.1mol) it is dissolved in 50mL methanol and 50mL tetrahydrofurans, adds palladium carbon (2g, 10%) and ammonium formate (40.3g, 6.4mol), 60 DEG C are reacted 2 hours.Reaction terminates, filtering, is washed with 100mL ethyl acetate, is spin-dried for filtrate, adds 150mL ethyl acetate and 150mL saturated aqueous common salts, point liquid.Aqueous phase washed once with 150mL ethyl acetate.Merge organic phase anhydrous sodium sulfate drying and obtain 1- (6- amino -1H- indoles -1- bases) ethyl ketone (40C), yellow solid (9.3g, yield 53.4%).

3rd step：4- (1H- indoles -6- bases) morpholine (40D)

4-(1H-indol-6-yl)morpholine

By 1- (6- amino -1H- indoles -1- bases) ethyl ketone (40C) (8g, 60.1mmol) with 2, bromodiethyl ether (the 9mL of 2'- bis-, 72mmol) it is dissolved in 100mLN, in dinethylformamide, DIPEA (DIPEA) (29.7mL is added, 180mmol), 90 DEG C of reactions are stayed overnight.Reaction terminates, and is cooled to room temperature and adds 200mL ethyl acetate and 200mL saturated aqueous common salts, point liquid.Aqueous phase washed once with 200mL ethyl acetate.Merge organic phase anhydrous sodium sulfate drying, concentration obtains compound 4- (1H- indoles -6- bases) morpholine (40D), yellow solid (9.2g, yield 76%).

MS m/z:203.1[M+1]⁺。

4th step：4- (3- (2,5- dichloro pyrimidine -4- bases) -1H- indoles -6- bases) morpholine (40E)

4-(3-(2,5-dichloropyrimidin-4-yl)-1H-indol-6-yl)morpholine

4- (1H- indoles -6- bases) morpholine (40D) (4.5g, 22.3mmol) is dissolved in 100mL tetrahydrofurans, under nitrogen protection; it is cooled to 0 DEG C; methyl-magnesium-bromide (7.5mL, 22.3mmol) is added dropwise, continues to stir 0.5 hour.Trichloropyrimidine (2.05g, 22.3mmol) is added, is reacted at room temperature 1 hour, 60 DEG C is risen to and continues to react 1 hour.Reaction solution is cooled to room temperature, 6.34mL acetic acid is added dropwise and stirs 10 minutes.100mL water is added, 60 DEG C are stirred 30 minutes, and point liquid, organic phase is spin-dried for, with silica gel column chromatography separating-purifying (dichloromethane with 100mL normal heptanes are added:Methanol (v/v)=1:0~50:1) 4- (3- (2,5- dichloro pyrimidine -4- bases) -1H- indoles -6- bases) morpholine (40E), greenish yellow solid (3g, yield 39%), is obtained.

MS m/z:349.0[M+1]⁺。

5th step：4- (3- (2,5- dichloro pyrimidine -4- bases) -1- Methyl-1H-indole -6- bases) morpholine (40F)

4-(3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-indol-6-yl)morpholine

By 4- (3- (2,5- dichloro pyrimidine -4- bases) -1H- indoles -6- bases) morpholine (40E) (3g, 8.6mmol) is dissolved in 50mL tetrahydrofurans, and 0 DEG C adds sodium hydride (460mg, 11.5mmol), react 30 minutes.Iodomethane (1.6mL, 25.8mmol) is added, reaction 3 hours is warmed to room temperature.It is spin-dried for, is washed with 50mL water and 20mL tetrahydrofurans, is filtered, drying is concentrated to give 4- (3- (2,5- dichloro pyrimidine -4- bases) -1- Methyl-1H-indole -6- bases) morpholine (40F), faint yellow solid (1.9g, yield 61.3%).

MS m/z:363.0[M+1]⁺。

6th step：The chloro- N- of 5- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2- amine (40G)

By 4- (3- (2,5- dichloro pyrimidine -4- bases) -1- Methyl-1H-indole -6- bases) morpholine (40F) (724g, 2mmol) it is dissolved in 2- amylalcohols (20mL), add the fluoro- 2- methoxyl groups -5- nitroanilines (372mg of 4-, 2mmol) with p-methyl benzenesulfonic acid (456.5mg, 2.4mmol), 120 DEG C of back flow reactions are heated to 2 days.Reaction solution is cooled to room temperature, add 50mL acetonitriles, filtering, filter cake 50mL water washings, dry to obtain the chloro- N- of 5- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2- amine (40G), gray solid (800mg, yield 80%).

MS m/z:513.1[M+1]⁺。

7th step：N¹- (the chloro- 4- of 5- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2-base) the fluoro- 6- methoxyphenyls -1,3- diamines (40H) of -4-

N¹-(5-chloro-4-(1-methyl-6-morpholino-1H-indol-3-yl)pyrimidin-2-yl)-4-fluoro-6-methoxybenzene-1,3-diamine

By the chloro- N- of 5- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2- amine (40G) (600mg, 1.17mmol) it is dissolved in addition 10mL water in 30mL ethanol, sequentially add iron powder (392mg, 7.03mmol) with ammonium chloride (43.8mg, 0.82mmol), it is warming up to 90 DEG C, back flow reaction 4 hours.Reaction solution is cooled to room temperature, filters, washed once with 50mL methanol, is concentrated.With silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=1:0~50:1) N, is obtained¹- (the chloro- 4- of 5- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2-base) fluoro- 6- methoxyphenyls -1, the 3- diamines (40H) of -4-, brown solid (150mg, yield 26.6%).

MS m/z:483.1[M+1]⁺。

8th step：N- (5- ((the chloro- 4- of 5- (1- methyl -6- morpholinyl -1H- indol-3-yls) pyrimidine -2-base) amino) the fluoro- 4- methoxyphenyls of -2-) acrylamide (compound 40)

By N¹- (the chloro- 4- of 5- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2-base) the fluoro- 6- methoxyphenyls -1,3- diamines of -4- (40H) (150mg, 0.31mmol) it is dissolved in 10mL tetrahydrofurans, add N, N- diisopropylethylamine (0.06mL, 0.37mmol), tetrahydrofuran (5mL) solution of acryloyl chloride (0.03mL, 0.37mmol) is added dropwise at 0 DEG C, reaction 1.5 hours is warmed to room temperature.100mL saturated sodium bicarbonate aqueous solutions and 100mL dichloromethane are added into reaction solution, point liquid.Silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain N- (5- ((the chloro- 4- of 5- (1- methyl -6- morpholinyl -1H- indol-3-yls) pyrimidine -2-base) amino) the fluoro- 4- methoxyphenyls of -2-) acrylamide (compound 40), faint yellow solid (20mg, yield 12%).

MS m/z=537.1 [M+1]⁺。

Embodiment 41

N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- (2- (4- methylpiperazine-1-yls) ethyoxyl) phenyl) acrylamide (compound 41)

The first step：The chloro- N- of 5- (2- methoxyl groups -4- (2- (4- methylpiperazine-1-yls) ethyoxyl) -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (41A)

By the chloro- N- of 5- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (intermediate 4) (854.1mg, 2mmol) it is dissolved in 50mL tetrahydrofurans, sodium hydride (80mg is added under ice bath, 2.2mmol), stir Mix 30 minutes, 2- (4- methylpiperazine-1-yls) ethanol (576.5mg, 4mmol) is added dropwise, room temperature reaction is stayed overnight.Reaction terminates, add 100mL water and 100mL ethyl acetate, divide liquid, organic phase anhydrous sodium sulfate drying, come over, it is concentrated to give the chloro- N- of compound 5- (2- methoxyl groups -4- (2- (4- methylpiperazine-1-yls) ethyoxyl) -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (41A), yellow solid (800mg, yield 80%).

MS m/z:552.2[M+1]⁺。

Second step：N¹- (the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -6- methoxyl groups -4- (2- (4- methylpiperazine-1-yls) ethyoxyl) benzene -1,3- diamines (41B)

By the chloro- N- of 5- (2- methoxyl groups -4- (2- (4- methylpiperazine-1-yls) ethyoxyl) -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (41A) (800mg, 1.45mmol) it is dissolved in 15mL ethanol, sequentially add 5mL water, iron powder (486.3mg, 8.7mmol) with ammonium chloride (54mg, 1mmol), it is warming up to 90 DEG C, back flow reaction 4 hours.Reaction solution is cooled to room temperature, filtered, concentration, silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1) compound N, is obtained¹- (the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -6- methoxyl groups -4- (2- (4- methylpiperazine-1-yls) ethyoxyl) benzene -1,3- diamines (41B), yellow solid (200mg, yield 26.5%).

MS m/z:522.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ8.63(d,1H),8.31(s,1H),8.22(s,1H),8.06(s,1H),7.51(s,1H),7.40(d,1H),7.34(dd,1H),7.28(dd,1H),6.57(s,1H),4.11(t,2H),3.90(s,3H),3.84(s,3H),2.79(t,2H),2.66(s,4H),2.60–2.44(m,4H),2.32(d,3H)。

3rd step：N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- (2- (4- methylpiperazine-1-yls) ethyoxyl) phenyl) acrylic acid amides (compound 41)

By N¹- (the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -6- methoxyl groups -4- (2- (4- methylpiperazine-1-yls) ethyoxyl) benzene -1,3- diamines (41B) (150mg, 0.288mmol) it is dissolved in 10mL tetrahydrofurans, add DIPEA (0.057mL, 0.345mmol), acryloyl chloride (0.028mL is added dropwise at 0 DEG C, tetrahydrofuran solution 5mL 0.345mmol), is warmed to room temperature reaction 1 hour.50mL saturated sodium bicarbonate aqueous solutions and 50mL ethyl acetate are added, point liquid.Silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1) compound N-(5- ((the chloro- 4- of 5- (1- Methyl-1H-indoles -3-, are obtained Base) pyrimidine -2-base) amino) -4- methoxyl groups -2- (2- (4- methylpiperazine-1-yls) ethyoxyl) phenyl) acrylic acid amides (compound 41), faint yellow solid (40mg, yield 24.1%).

MS m/z=576.2 [M+1]⁺。

Embodiment 42

N- (3- ((the chloro- 4- of 5- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 42)

N-(3-((5-chloro-4-(1-methyl-6-morpholino-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

The first step：The chloro- N- of 5- (2- methoxyl group -5- nitrobenzophenones) -4- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2- amine (42A)

5-chloro-N-(2-methoxy-5-nitrophenyl)-4-(1-methyl-6-morpholino-1H-indol-3-yl)pyrimidin-2-amine

By 4- (3- (2,5- dichloro pyrimidine -4- bases) -1- Methyl-1H-indole -6- bases) morpholine (40F) (724g, 2mmol) it is dissolved in 2- amylalcohols (20mL), add 2- methoxyl group -5- nitroanilines (336.3mg, 2mmol) with p-methyl benzenesulfonic acid (456.5mg, 2.4mmol), 120 DEG C of back flow reactions are heated to 3 days.Reaction solution is cooled to room temperature, add 50mL acetonitriles, filtering, filter cake 50mL water washings, dry to obtain the chloro- N- of 5- (2- methoxyl group -5- nitrobenzophenones) -4- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2- amine (42A), celadon solid (990mg).

MS m/z:495.1[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ8.87(s,1H),8.70(s,1H),8.56(s,1H),8.51(s,1H),8.33(d,1H),8.07(d,1H),7.48(d,2H),7.36(s,1H),7.32(d,1H),7.11(d,2H),7.02(d,1H), 3.99(s,3H),3.90(s,8H),3.73(s,19H),2.29(s,3H)。

Second step：N¹- (the chloro- 4- of 5- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2-base) -6- methoxybenzene -1,3- diamines (42B)

N¹-(5-chloro-4-(1-methyl-6-morpholino-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxybenzene-1,3-diamine

By the chloro- N- of 5- (2- methoxyl group -5- nitrobenzophenones) -4- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2- amine (42A) (990mg, 2mmol) it is dissolved in 30mL ethanol, sequentially add 10mL water, iron powder (670mg, 12mmol) with ammonium chloride (75mg, 1.4mmol), 90 DEG C of back flow reactions are warming up to stay overnight.Reaction solution is cooled to room temperature, filters, washed once with 50mL methanol, is concentrated, silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1) compound N, is obtained¹- (the chloro- 4- of 5- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2-base) -6- methoxybenzenes -1,3- diamines (42B), brown solid (340mg, yield 36.6%).

MS m/z:465.1[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ8.56(d,1H),8.33(s,1H),8.16(d,1H),8.13(s,1H),7.75(s,1H),7.03(dd,1H),6.82(d,1H),6.74(d,1H),6.31(dd,1H),3.97–3.91(m,4H),3.85(s,3H),3.85(s,3H),3.26–3.19(m,4H)。

3rd step：N- (3- ((the chloro- 4- of 5- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 42)

By N¹- (the chloro- 4- of 5- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2-base) -6- methoxybenzenes -1,3- diamines (42B) (280mg, 0.6mmol) it is dissolved in 30mL tetrahydrofurans, add N, N- diisopropylethylamine (DIPEA) (0.12mL, 0.72mmol), acryloyl chloride (0.059mL is added dropwise at 0 DEG C, tetrahydrofuran solution 5mL 0.72mmol), is warmed to room temperature reaction 4 hours.100mL saturated sodium bicarbonate aqueous solutions and 100mL ethyl acetate are added, point liquid.Silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain compound N-(3- ((the chloro- 4- of 5- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 42), faint yellow solid (120mg, yield 38.7%).

MS m/z:519.1[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ8.52(dd,2H),8.35(s,1H),8.15(s,1H),7.83(d,1H),7.78(s,1H),7.12(s,1H),6.98(d,1H),6.89(d,1H),6.37(d,1H),6.09(dd,10.2Hz,1H),5.69(d,1H),3.93(s,7H),3.87(s,3H),3.25(s,4H)。

Embodiment 43

N- (5- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -2- (2- (dimethylamino) ethyoxyl) -4- methoxyphenyls) acrylamide (compound 43)

N-(5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)ethoxy)-4-methoxyphenyl)acrylamide

The first step：The chloro- N- of 5- (4- (2- (dimethylamino) ethyoxyl) -2- methoxyl group -5- nitrobenzophenones) -4- (1H- indol-3-yls) pyrimidine -2- amine (43A)

By the chloro- N- of 5- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (intermediate 4) (620mg, 1.5mmol) it is dissolved in 30mL tetrahydrofurans, sodium hydride (66mg is added under ice bath, 1.65mmol), stirring 30 minutes, dimethylethanolamine (0.3mL, 3mmol) is added dropwise, reacts at room temperature 4 hours.Reaction terminates, add 100mL water and 100mL ethyl acetate, divide liquid, organic phase anhydrous sodium sulfate drying, it is concentrated to give the chloro- N- of compound 5- (4- (2- (dimethylamino) ethyoxyl) -2- methoxyl group -5- nitrobenzophenones) -4- (1H- indol-3-yls) pyrimidine -2- amine (43A), brown solid (660mg, yield 91.3%).

Second step：N¹- (the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) -4- (2- (dimethylamino) ethyoxyl) -6- methoxyl group -1,3- diamines (43B)

N¹-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)-4-(2-(dimethylamino)ethoxy)-6-methoxybenzene-1,3-diamine

By the chloro- N- of 5- (4- (2- (dimethylamino) ethyoxyl) -2- methoxyl group -5- nitrobenzophenones) -4- (1H- indol-3-yls) pyrimidine -2- amine (43A) (650mg, 1.35mmol) it is dissolved in 30mL ethanol, sequentially add 10mL water, iron powder (452mg, 8.1mmol) With ammonium chloride (50.5mg, 0.95mmol), 90 DEG C are warming up to, back flow reaction is stayed overnight.Reaction solution is cooled to room temperature, filtered, concentration, silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~20:1) compound N, is obtained¹- (the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) -4- (2- (dimethylamino) ethyoxyl) -6- methoxyl groups -1,3- diamines (43B), yellow solid (200mg, yield 32.8%).

MS m/z=453.1 [M+1]⁺。

3rd step：N- (5- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -2- (2- (dimethylamino) ethyoxyl) -4- methoxyphenyls) acrylamide (compound 43)

By N¹- (the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) -4- (2- (dimethylamino) ethyoxyl) -6- methoxyl groups -1,3- diamines (43B) (200mg, 0.44mmol) it is dissolved in 15mL tetrahydrofurans, add N, N- diisopropylethylamine (DIPEA) (0.088mL, 0.53mmol), acryloyl chloride (0.043mL is added dropwise at 0 DEG C, tetrahydrofuran (5mL) solution 0.53mmol), is warmed to room temperature reaction 4 hours.100mL saturated sodium bicarbonate aqueous solutions and 100mL ethyl acetate are added into reaction solution, point liquid.Silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain compound N-(5- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -2- (2- (dimethylamino) ethyoxyl) -4- methoxyphenyls) acrylamide (compound 43), buff white solid (20mg, yield 9.0%).

MS m/z=507.1 [M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ9.83(s,1H),9.33(s,1H),9.18(s,1H),8.48(d,1H),8.29(d,1H),8.26(s,1H),7.41(s,1H),7.33(d,1H),7.24–7.14(m,2H),6.65(s,1H),6.41(d,1H),6.27(dd,1H),5.71(d,1H),4.20–4.09(m,2H),3.88(s,3H),2.62–2.52(m,2H),2.37(s,6H)。

Embodiment 44

(S)-N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- ((1- methylpyrrole -3- bases) epoxide) phenyl) acrylamide (compound 44)

(S)-N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpyrrolidin-3-yl)oxy)phenyl)acrylamide

The first step：(S) the chloro- N- of -5- (2- methoxyl groups -4- ((1- methylpyrrole -3- bases) epoxide) -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (44A)

(S)-5-chloro-N-(2-methoxy-4-((1-methylpyrrolidin-3-yl)oxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

By the chloro- N- of 5- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (intermediate 4) (854.1mg, 2mmol) it is dissolved in 30mL tetrahydrofurans, sodium hydride (160mg is added under ice bath, 4mmol), stirring 30 minutes, (S)-(+) -1- methyl -3- hydroxyl pyrrolidines (242.76mg, 2.4mmol) are added dropwise, room temperature reaction is stayed overnight.Reaction terminates, add 150mL water and 150mL ethyl acetate, divide liquid, organic phase anhydrous sodium sulfate drying, it is concentrated to give the chloro- N- of compound (S) -5- (2- methoxyl groups -4- ((1- methylpyrrole -3- bases) epoxide) -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (44A), yellow solid (1g, yield 99%).

MS m/z:509.1[M+1]⁺。

Second step：(S)-N¹- (the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -6- methoxyl groups -4- ((1- methylpyrrole -3- bases) epoxide) benzene -1,3- diamines (44B)

(S)-N¹-(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-((1-methylpyrrolidin-3-yl)oxy)benzene-1,3-diamine

By the chloro- N- of (S) -5- (2- methoxyl groups -4- ((1- methylpyrrole -3- bases) epoxide) -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (44A) (1g, 2mmol) it is dissolved in 30mL ethanol, sequentially add 10mL water, iron powder (659.3mg, 11.8mmol) with ammonium chloride (73.7mg, 1.38mmol), 90 DEG C are warming up to, back flow reaction is stayed overnight.Reaction solution is cooled to room temperature, filtered, concentration, silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=1:0~10:1) compound (S)-N, is obtained¹- (the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -6- methoxyl groups -4- ((1- methylpyrrole -3- bases) epoxide) benzene -1,3- diamines (44B), brown solid (410mg, yield 42.9%).

3rd step：(S)-N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- ((1- methylpyrrole -3- bases) epoxide) phenyl) acrylamide (compound 44)

(S)-N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-((1- methylpyrrolidin-3-yl)oxy)phenyl)acrylamide

By (S)-N¹- (the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -6- methoxyl groups -4- ((1- methylpyrrole -3- bases) epoxide) benzene -1,3- diamines (44B) (400mg, 0.84mmol) it is dissolved in 30mL tetrahydrofurans, add N, N- diisopropylethylamine (DIPEA) (0.165mL, 1mmol), acryloyl chloride (0.08mL is added dropwise at 0 DEG C, tetrahydrofuran solution (5mL) 1mmol), is warmed to room temperature reaction 4 hours.100mL saturated sodium bicarbonate aqueous solutions and 100mL ethyl acetate are added into reaction solution, point liquid.Silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain compound (S)-N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- ((1- methylpyrrole -3- bases) epoxide) phenyl) acrylamide (compound 44), greenish yellow solid (80mg, yield 17.9%).

MS m/z:533.1[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ9.33(s,1H),8.39(d,2H),8.32(s,1H),7.42(s,1H),7.36(d,1H),7.29(d,1H),7.21(t,1H),6.53(s,1H),6.37(s,2H),5.74–5.65(m,1H),4.81(s,1H),3.90(s,3H),3.86(s,3H),3.18(d,2H),2.51(s,3H),2.39–2.26(m,2H),2.20(d,2H)。

Embodiment 45

(R)-N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- ((1- methylpyrrole -3- bases) epoxide) phenyl) acrylamide (compound 45)

(R)-N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpyrrolidin-3-yl)oxy)phenyl)acrylamide

The first step：(R) the chloro- N- of -5- (2- methoxyl groups -4- ((1- methylpyrrole -3- bases) epoxide) -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (45A)

(R)-5-chloro-N-(2-methoxy-4-((1-methylpyrrolidin-3-yl)oxy)-5-nitrophenyl)-4-(1-methyl -1H-indol-3-yl)pyrimidin-2-amine

By the chloro- N- of 5- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (intermediate 4) (1mg, 2.3mmol) it is dissolved in 30mL tetrahydrofurans, sodium hydride (184mg is added under ice bath, 4.6mmol), stirring 30 minutes, (R)-(-) -1- methyl -3- hydroxyl pyrrolidines (284mg, 2.8mmol) are added dropwise, room temperature reaction is stayed overnight.Reaction terminates, add 150mL water and 150mL ethyl acetate, divide liquid, organic phase anhydrous sodium sulfate drying, filtering, concentration, obtains the chloro- N- of compound (R) -5- (2- methoxyl groups -4- ((1- methylpyrrole -3- bases) epoxide) -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (45A), yellow solid (1.1g).

MS m/z:509.0[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ9.19(s,1H),8.46(d,1H),8.39(s,1H),8.23(d,1H),7.49(s,1H),7.38(d,1H),7.34(dd,1H),7.30(dd,1H),6.52(s,1H),4.92(ddd,1H),3.99(s,3H),3.91(s,1H),3.90(s,3H),3.10(dd,1H),2.83–2.74(m,2H),2.72–2.64(m,1H),2.44(s,3H),2.32(dt,2H),2.19–2.10(m,1H)。

Second step：(R)-N¹- (the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -6- methoxyl groups -4- ((1- methylpyrrole -3- bases) epoxide) benzene -1,3- diamines (45B)

(R)-N1-(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-((1-methylpyrrolidin-3-yl)oxy)benzene-1,3-diamine

By the chloro- N- of (R) -5- (2- methoxyl groups -4- ((1- methylpyrrole -3- bases) epoxide) -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (45A) (1.1g, 2.16mmol) it is dissolved in 30mL ethanol, sequentially add 10mL water, iron powder (725mg, 13mmol) with ammonium chloride (81mg, 1.5mmol), it is warming up to 90 DEG C, back flow reaction 4 hours.Reaction solution is cooled to room temperature, filtered, concentration.Silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1) compound (R)-N, is obtained¹- (the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -6- methoxyl groups -4- ((1- methylpyrrole -3- bases) epoxide) benzene -1,3- diamines (45B), green solid (900mg, yield 90%).

¹H NMR(400MHz,CDCl₃)δ8.63(d,1H),8.32(s,1H),8.21(s,1H),8.09(s,1H),7.52(s,1H),7.39(d,1H),7.33(t,1H),7.27(dd,1H),6.48(s,1H),4.88(t,1H),3.90(s,3H),3.85(d,3H),3.16–2.98(m,6H),2.84(s,1H),2.58(s,3H),2.35(dt,1H),2.20(dd,1H)。

3rd step：(R)-N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- ((1- methylpyrrole -3- bases) epoxide) phenyl) acrylamide (compound 45)

By (R)-N¹- (the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -6- methoxyl groups -4- ((1- methylpyrrole -3- bases) epoxide) benzene -1,3- diamines (45B) (900mg, 1.88mmol) it is dissolved in 20mL tetrahydrofurans, add DIPEA (0.23mL, 2.26mmol), the tetrahydrofuran solution 5mL of acryloyl chloride (0.183mL, 2.26mmol) is added dropwise at 0 DEG C, is warmed to room temperature anti- Answer 4 hours.Saturated sodium bicarbonate aqueous solution is added into reaction solution and is adjusted to alkalescence, 100mL ethyl acetate and 150mL saturated aqueous common salts is added, point liquid.Organic phase anhydrous sodium sulfate drying.Silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain compound (R)-N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- ((1- methylpyrrole -3- bases) epoxide) phenyl) acrylamide (compound 45), faint yellow solid (180mg, yield 16%).

MS m/z=533.2 [M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ9.38(s,1H),8.90(s,1H),8.39(d,2H),8.32(s,1H),7.42(s,1H),7.35(d,1H),7.31–7.26(m,1H),7.23–7.18(m,1H),6.55(s,1H),6.35(qd,2H),5.68(dd,1H),4.76(s,1H),3.90(s,3H),3.86(s,3H),3.16(t,1H),3.00(d,1H),2.43(s,3H),2.34(dd,2H),2.31–2.25(m,1H),2.13(dd,1H),1.25(s,1H)。

Embodiment 46

N- (3- ((the chloro- 4- of 5- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide hydrochloride (compound 46)

N-(3-((5-chloro-4-(1-methyl-6-morpholino-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide hydrochloride

By N- (3- ((the chloro- 4- of 5- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 42) (86mg, 0.166mmol) it is dissolved in 1, in 4- dioxane (30mL), hydrochloric acid (0.083mL is added dropwise at 0 DEG C, 0.332mmol) 1,4- dioxane solutions, are warmed to room temperature reaction 2 hours.Reaction solution is spin-dried for obtain N- (3- ((the chloro- 4- of 5- (1- methyl -6- morpholine -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide hydrochloride (compound 46), yellow solid (90mg, yield 97.8%).

MS m/z:519.1[M+1]⁺。

Embodiment 47

(S)-N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- ((1- methylpyrrole -3- bases) epoxide) phenyl) acrylamide mesylate (compound 47)

(S)-N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-((1-methylpyrrolidin-3-yl)oxy)phenyl)acrylamide methanesulfonate

By (S)-N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- ((1- methylpyrrole -3- bases) epoxide) phenyl) acrylamide (compound 44) (40mg, 0.075mmol) it is dissolved in 10mL ethanol, add 5mL ethyl acetate, methanesulfonic acid (0.048mL is added dropwise at 70 DEG C, ethyl acetate solution (3mL) 0.075mmol), reacts 2 hours.Reaction solution is spin-dried for (S)-N- (5- ((the chloro- 4- of 5- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups -2- ((1- methylpyrrole -3- bases) epoxide) phenyl) acrylamide mesylate (compound 47), brown solid (47mg, yield 99.8%).

MS m/z:533.1[M+1]⁺。

Embodiment 48

N- (2- (2- (dimethylamino) ethyoxyl) -4- methoxyl groups -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 48)

N-(2-(2-(dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

The first step：N- (4- (2- (dimethylamino) ethyoxyl) -2- methoxyl group -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (48A)

N-(4-(2-(dimethylamino)ethoxy)-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

By 5- ((4- (1- methyl indol -3- bases) pyrimidine -2-base) amino) fluoro- 1- nitrobenzene (the intermediate 3) (1g of -4- methoxyl groups -2-, 2.54mmol) it is dissolved in 50mL tetrahydrofurans, sodium hydride (103mg is added under ice bath, 2.57mmol), stirring 30 minutes, 2- (dimethylamino) ethanol (417.2mg, 4.68mmol) is added dropwise, reacts at room temperature 4 hours.Reaction terminates, and adds 200mL water and 200mL ethyl acetate, point liquid.Organic phase anhydrous sodium sulfate drying, filtering, it is concentrated to give compound N-(4- (2- (dimethylamino) ethyoxyl) -2- methoxyl group -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (48A), yellow solid (1.05g, yield 91.3%).

MS m/z:463.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ9.67(s,1H),8.38(d,1H),8.26(s,1H),8.15(dd,1H),7.52(s,1H),7.40(dd,1H),7.34–7.27(m,2H),7.19(d,1H),6.63(s,1H),4.23(t,2H),3.99(d,3H),3.93(s,3H),3.48(s,3H),2.85(t,2H),2.40(s,6H)。

Second step：4- (2- (dimethylamino) ethyoxyl) -6- methoxyl groups-N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) benzene -1,3- diamines (48B)

4-(2-(dimethylamino)ethoxy)-6-methoxy-N¹-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)benzene-1,3-diamine

By N- (4- (2- (dimethylamino) ethyoxyl) -2- methoxyl group -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (48A) (1g, 2.16mmol) it is dissolved in 30mL ethanol, sequentially add 10mL water, iron powder (725mg, 13mmol) with ammonium chloride (81mg, 1.5mmol), 90 DEG C of back flow reactions are warming up to stay overnight.Reaction solution is cooled to room temperature, filtered, concentration.Silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=1:0~10:1) compound 4- (2- (dimethylamino) ethyoxyl) -6- methoxyl groups-N, is obtained¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) benzene -1,3- diamines (48B), brown solid (930mg, yield 99.7%).

MS m/z:433.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ8.52–8.47(m,1H),8.31(d,1H),8.13(s,1H),7.77(s,1H),7.47(s,1H),7.37(dd,1H),7.30(ddd,2H),6.99(d,1H),6.58(s,1H),4.09(t,2H),3.86(s,3H),3.84(s,3H),2.72(t,2H),2.35(s,6H)。

3rd step：N- (2- (2- (dimethylamino) ethyoxyl) -4- methoxyl groups -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 48)

By 4- (2- (dimethylamino) ethyoxyl) -6- methoxyl groups-N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) benzene -1,3- diamines (48B) (600mg, 1.38mmol) it is dissolved in 10mL pyridines, sequentially add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (794mg, 4.16mmol) with acrylic acid (0.143mL, 2.08mmol), react at room temperature 3 hours.Reaction solution is spin-dried for, sodium hydrate aqueous solution (150mL, 4mol/L) and 150mL dichloromethane is added, point liquid.Organic phase with 100mL water washings once.Organic phase anhydrous sodium sulfate drying.Silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain N- (2- (2- (dimethylamino) ethyoxyl) -4- methoxyl groups -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 48), yellow solid (330mg, yield 49.1%).

MS m/z:487.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ9.80(d,2H),8.99(s,1H),8.37(d,1H),8.10–8.03(m,1H),7.63(s,1H),7.39(dd,1H),7.19(d,1H),6.64(s,1H),6.49(d,0H),6.44(d,1H),6.38(d,1H),5.72(dd,1H),4.17–4.09(m,2H),3.98(d,3H),3.88(s,3H),2.59(d,2H),2.37(s,6H)。

Embodiment 49

(S)-N- (4- methoxyl groups -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- ((1- methylpyrrole -3- bases) epoxide) phenyl) acrylamide (compound 49)

(S)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((1-methylpyrrolidin-3-yl)oxy)phenyl)acrylamide

The first step：(S)-N- (2 methoxyl group -4- ((1- methylpyrrole -3- bases) epoxide) -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (49A)

(S)-N-(2-methoxy-4-((1-methylpyrrolidin-3-yl)oxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

By 5- ((4- (1- methyl indol -3- bases) pyrimidine -2-base) amino) fluoro- 1- nitrobenzene (the intermediate 3) (1g of -4- methoxyl groups -2-, 2.54mmol) it is dissolved in 30mL tetrahydrofurans, sodium hydride (203mg is added under ice bath, 5.08mmol), stirring 30 minutes, (S) -1- methylpyrrole -3- alcohol (308mg is added dropwise, tetrahydrofuran solution (5mL) 3.05mmol), is reacted at room temperature 4 hours.Reaction terminates, 100mL water and 150mL ethyl acetate are added into reaction solution, divide liquid, organic phase anhydrous sodium sulfate drying, filtering, it is concentrated to give (S)-N- (2 methoxyl group -4- ((1- methylpyrrole -3- bases) epoxide) -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (49A), yellow solid (1g, yield 83.3%).

MS m/z:475.2[M+1]⁺。

Second step：(S) -6- methoxyl groups-N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -4- ((1- methylpyrrole -3- bases) epoxide) benzene -1,3- diamines (49B)

(S)-6-methoxy-N¹-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-((1-methylpyrrolidin-3-yl)oxy)benzene-1,3-diamine

By (S)-N- (2 methoxyl group -4- ((1- methylpyrrole -3- bases) epoxide) -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (49A) (1g, 2.11mmol) it is dissolved in 30mL ethanol, sequentially add 10mL water, iron powder (707mg, 12.65mmol) with ammonium chloride (78.6mg, 1.47mmol), it is warming up to 90 DEG C, back flow reaction 4 hours.Reaction solution is cooled to room temperature, filtered, concentration.With silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=1:0~10:1) compound (S) -6- methoxyl groups-N, is obtained¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -4- ((1- methylpyrrole -3- bases) epoxide) benzene -1,3- diamines (49B), brown solid (500mg, yield 53.6%).

MS m/z:445.2[M+1]⁺。

3rd step：(S)-N- (4- methoxyl groups -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- ((1- methylpyrrole -3- bases) epoxide) phenyl) acrylamide (compound 49)

By (S) -6- methoxyl groups-N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -4- ((1- methylpyrrole -3- bases) epoxide) benzene -1,3- diamines (49B) (500mg, 1.13mmol) it is dissolved in 15mL pyridines, sequentially add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (646mg, 3.38mmol) with acrylic acid (0.116mL, 1.69mmol), react at room temperature 4 hours.Reaction solution is spin-dried for, 150mL water and 200mL dichloromethane is added, point liquid.Organic phase washed once with 4mol/L sodium hydrate aqueous solutions 150mL.Organic phase anhydrous sodium sulfate drying, filtering and concentrating, silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain (S)-N- (4- methoxyl groups -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- ((1- methylpyrrole -3- bases) epoxide) phenyl) acrylamide (compound 49), faint yellow solid (210mg, yield 37.3%).

MS m/z:499.2[M+1]⁺。

Embodiment 50

N- (4- methoxyl groups -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (2- (piperidin-1-yl) ethyoxyl) phenyl) acrylamide (compound 50)

N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(2-(piperidin-1-yl)ethoxy)phenyl)acrylamide

The first step：N- (2- methoxyl group -5- nitros -4- (2- (piperidin-1-yl) ethyoxyl) phenyl) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (50A)

N-(2-methoxy-5-nitro-4-(2-(piperidin-1-yl)ethoxy)phenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

By 5- ((4- (1- methyl indol -3- bases) pyrimidine -2-base) amino) fluoro- 1- nitrobenzene (the intermediate 3) (1g of -4- methoxyl groups -2-, 2.54mmol) it is dissolved in 50mL tetrahydrofurans, sodium hydride (122mg is added under ice bath, 3.1mmol), 2- (piperidin-1-yl) ethanol (656mg is added dropwise again after stirring 30min, 5.08mmol), room temperature reaction is stayed overnight.Reaction terminates, and adds 150mL water and 100mL ethyl acetate, point liquid.Aqueous phase is extracted with 100mL ethyl acetate, merge organic phase, anhydrous sodium sulfate drying, filtering, it is concentrated to give compound N-(2- methoxyl group -5- nitros -4- (2- (piperidin-1-yl) ethyoxyl) phenyl) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (50A), yellow solid (1.2g, yield 94.5%).

MS m/z:503.1[M+1]⁺。

Second step：6- methoxyl groups-N¹- (4- (1- methyl l-1H- indol-3-yls) pyrimidine -2-base) -4- (2- (piperidin-1-yl) ethyoxyl) benzene -1,3- diamines (50B)

6-methoxy-N1-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-(2-(piperidin-1-yl)ethoxy)benzene-1,3-diamine

By N- (2- methoxyl group -5- nitros -4- (2- (piperidin-1-yl) ethyoxyl) phenyl) -4- (1- Methyl-1H-indole -3- bases) pyrimidine - 2- amine (50A) (1.2g, 2.39mmol) is dissolved in 15mL ethanol, sequentially adds 5mL water, iron powder (400mg, 7.17mmol) with ammonium chloride (89.5mg, 1.67mmol), 90 DEG C, back flow reaction 6 hours are warming up to.Reaction solution is cooled to room temperature, filtered, concentration, silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=1:0~10:1) compound 6- methoxyl groups-N, is obtained¹- (4- (1- methyl l-1H- indol-3-yls) pyrimidine -2-base) -4- (2- (piperidin-1-yl) ethyoxyl) benzene -1,3- diamines (50B), brown solid (750mg, yield 68.2%).

MS m/z:473.3[M+1]⁺。

3rd step：N- (4- methoxyl groups -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (2- (piperidin-1-yl) ethyoxyl) phenyl) acrylamide (compound 50)

By 6- methoxyl groups-N¹- (4- (1- methyl l-1H- indol-3-yls) pyrimidine -2-base) -4- (2- (piperidin-1-yl) ethyoxyl) benzene -1,3- diamines (50B) (750mg, 1.59mmol) it is dissolved in 10mL pyridines, add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (911mg, 4.71mmol) with acrylic acid (0.164mL, 2.38mmol), react at room temperature 4 hours.Reaction solution is spin-dried for, 4mol/L sodium hydrate aqueous solution 100mL and 100mL ethyl acetate is added, point liquid.Organic phase washed once with 100mL saturated aqueous common salts.Organic phase anhydrous sodium sulfate drying.Silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain N- (4- methoxyl groups -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (2- (piperidin-1-yl) ethyoxyl) phenyl) acrylamide (compound 50), white solid (300mg, yield 35.8%).

MS m/z：527.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ9.60(s,1H),9.40(s,1H),8.83(s,1H),8.33(d,1H),8.07(d,1H),7.39(d,1H),7.33–7.23(m,1H),7.17(d,1H),6.51(s,1H),6.45(dd,1H),5.72(d,1H),4.33(s,2H),3.94(s,2H),3.87(d,2H),3.62(s,2H),3.33(d,2H),2.68(s,2H),2.33(s,2H),1.84(s,3H),1.55(s,3H)。

Embodiment 51

N- (4- methoxyl groups -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (2- (4- methylpiperazine-1-yls) ethyoxyl) phenyl) acrylamide (compound 51)

N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)acrylamide

The first step：N- (2- methoxyl groups -4- (2- (4- methylpiperazine-1-yls) ethyoxyl) -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (51A)

N-(2-methoxy-4-(2-(4-methylpiperazin-1-yl)ethoxy)-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

By 5- ((4- (1- methyl indol -3- bases) pyrimidine -2-base) amino) fluoro- 1- nitrobenzene (the intermediate 3) (1g of -4- methoxyl groups -2-, 2.54mmol) it is dissolved in 20mL tetrahydrofurans, sodium hydride (203mg is added under ice bath, 5.08mmol), stirring 30 minutes, 1- (2- ethoxys) -4- methyl piperazines (733mg, 5.08mmol) are added dropwise, react at room temperature 8 hours.Reaction terminates, and 150mL water and 150mL ethyl acetate are added into reaction solution, point liquid.Aqueous phase is extracted with 100mL ethyl acetate, merge organic phase, anhydrous sodium sulfate drying, filtering, it is concentrated to give N- (2- methoxyl groups -4- (2- (4- methylpiperazine-1-yls) ethyoxyl) -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (51A), yellow solid (1.1g, yield 84.6%).

MS m/z:518.1[M+1]⁺。

Second step：6- methoxyl groups-N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -4- (2- (4- methylpiperazine-1-yls) ethyoxyl) benzene -1,3- diamines (51B)

6-methoxy-N¹-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzene-1,3-diamine

By N- (2- methoxyl groups -4- (2- (4- methylpiperazine-1-yls) ethyoxyl) -5- nitrobenzophenones) -4- (1- Methyl-1H-indole -3- bases) pyrimidine -2- amine (51A) (1.1g, 2.18mmol) it is dissolved in 15mL ethanol, sequentially add 5mL water, add iron powder (356mg, 6.4mmol) with ammonium chloride (78.7mg, 1.55mmol), 90 DEG C, back flow reaction 4 hours are warming up to.Reaction solution is cooled to room temperature, filtered, concentration, silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=1:0~10:1) 6- methoxyl groups-N, is obtained¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -4- (2- (4- methylpiperazine-1-yls) ethyoxyl) benzene -1,3- diamines (51B), brown solid (550mg, yield 51.9%).

3rd step：N- (4- methoxyl groups -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (2- (4- methylpiperazine-1-yls) ethyoxyl) phenyl) acrylamide (compound 51)

By 6- methoxyl groups-N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -4- (2- (4- methylpiperazine-1-yls) ethyoxyl) benzene -1,3- diamines (51B) (550mg, 1mmol) it is dissolved in 15mL pyridines, add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (573mg, 3mmol) with acrylic acid (0.103mL, 1.5mmol), react at room temperature 4 hours.Reaction solution is spin-dried for, 100mL water and 100mL dichloromethane is added, point liquid.Organic phase washed once with 4mol/L sodium hydrate aqueous solutions 100mL.Organic phase anhydrous sodium sulfate drying.Silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain N- (4- methoxyl groups -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- (2- (4- methylpiperazine-1-yls) ethyoxyl) phenyl) acrylamide (compound 51), white solid (65mg, 12%).

MS m/z:542.1[M+1]⁺。

Embodiment 52

(R)-N- (4 methoxyl group -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- ((1- methylpyrrole -3- bases) amino) phenyl) acrylamide (compound 52)

(R)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((1-methylpyrrolidin-3-yl)amino)phenyl)acrylamide

The first step：(R)-tert-butyl group 3- ((tertbutyloxycarbonyl) amino) pyrroles -1- formic acid esters (52B)

(R)-tert-butyl 3-((tert-butoxycarbonyl)amino)pyrrolidine-1-carboxylate

By (R)-tert-butyl group 3- amino-pyrroles -1- formic acid esters (52A) (2g, 10.74mmol) it is dissolved in 25mL dichloromethane, add triethylamine (2.17g, 21.5mmol) with di-tert-butyl dicarbonate (2.46g, 11.28mmol), react at room temperature 3 hours.100mL water and 100mL dichloromethane are added into reaction solution, point liquid.Organic phase anhydrous sodium sulfate drying, filtering It is concentrated to give (R)-tert-butyl group 3- ((tertbutyloxycarbonyl) amino) pyrroles -1- formic acid esters (52B), colorless oil (3g).

Second step：(R)-N, 1- dimethyl pyrrole -3- amine (52C)

(R)-N,1-dimethylpyrrolidin-3-amine

By (R)-tert-butyl group 3- ((tertbutyloxycarbonyl) amino) pyrroles -1- formic acid esters (52B) (3g, 10.74mmol) it is dissolved in 50mL tetrahydrofurans, Lithium Aluminium Hydride (4g is slowly added under ice bath, 107.4mmol), room temperature reaction 1 hour, rises to 60 DEG C and continues to react 3 hours.Reaction terminates, and adds 50mL acetone, and drop adds water to reaction solution bubble-free and emerged.Filtering, is washed with 50mL tetrahydrofurans, is concentrated to give (R)-N, 1- dimethyl pyrrole -3- amine (52C), yellow liquid (1.65g).

MS m/z:115.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ3.65(t,1H),3.23–3.15(m,1H),2.68–2.60(m,1H),2.48–2.39(m,1H),2.37(s,3H),2.33(s,3H),2.14(dd,1H),1.70–1.64(m,1H),1.57(d,1H)。

3rd step：(R) -2- methoxyl groups-N⁴- methyl-N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base)-N⁴- (1- methylpyrrole -3- bases) -5- nitrobenzene -1,4- diamines (52D)

(R)-2-methoxy-N4-methyl-N1-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N4-(1-methylpyrrolidin-3-yl)-5-nitrobenzene-1,4-diamine

By 5- ((4- (1- methyl indol -3- bases) pyrimidine -2-base) amino) fluoro- 1- nitrobenzene (the intermediate 3) (1g of -4- methoxyl groups -2-, 2.54mmol) it is dissolved in 10mL N, in N- dimethyl acetamides, sequentially add N, N- diisopropylethylamine (DIPEA) (0.51mL, 3.05mmol) with (R)-N, 1- dimethyl pyrrole -3- amine (52C) (348mg, 3.05mmol), 140 DEG C of microwave reacts 1 hour.Reaction terminates, and reaction solution is concentrated, silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=1:0~10:1) compound (R) -2- methoxyl groups-N, is obtained⁴- methyl-N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base)-N⁴- (1- methylpyrrole -3- bases) -5- nitrobenzene-Isosorbide-5-Nitrae-diamines (52D), red solid (0.5g, yield 40.3%).

MS m/z:488.1[M+1]⁺。

4th step：(R) -5- methoxyl groups-N¹- methyl-N⁴- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base)-N¹- (1- methylpyrrole -3- bases) benzene -1,2,4- triamines (52E)

(R)-5-methoxy-N1-methyl-N4-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N1-(1-methylpyrrolidin-3-yl)benzene-1,2,4-triamine

By (R) -2- methoxyl groups-N⁴- methyl-N¹- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base)-N⁴- (1- methylpyrrole -3- bases) -5- nitrobenzene -1,4- diamines (52D) (1.24g, 2.5mmol) it is dissolved in 20mL ethanol, add 7mL water, iron powder (419mg, 7.5mmol) with ammonium chloride (94mg, 1.75mmol), 90 DEG C, back flow reaction 6 hours are warming up to.Reaction solution is cooled to room temperature, filtered, concentration, silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1) compound (R) -5- methoxyl groups-N, is obtained¹- methyl-N⁴- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base)-N¹- (1- methylpyrrole -3- bases) benzene -1,2,4- triamines (52E), brown solid (350mg, yield 30.7%).

MS m/z:458.1[M+1]⁺。

5th step：(R)-N- (4- methoxyl groups -2- (methyl (1- methylpyrrole -3- bases) amino) -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 52)

(R)-N-(4-methoxy-2-(methyl(1-methylpyrrolidin-3-yl)amino)-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

By (R) -5- methoxyl groups-N¹- methyl-N⁴- (4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base)-N¹- (1- methylpyrrole -3- bases) benzene -1,2,4- triamines (52E) (350mg, 0.76mmol) it is dissolved in 10mL pyridines, add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDCI) (436mg, 2.28mmol) with acrylic acid (0.08mL, 1.14mmol), react at room temperature 4 hours.Reaction solution is spin-dried for, 100mL water and 100mL dichloromethane is added, point liquid.Organic phase washed once with 4mol/L sodium hydrate aqueous solutions 100mL.Organic phase anhydrous sodium sulfate drying, is filtered, concentration, silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain (R)-N- (4- methoxyl groups -2- (methyl (1- methylpyrrole -3- bases) amino) -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 52), brown solid (80mg, yield 20.6%).

MS m/z:512.2[M+1]⁺。

Embodiment 53

N- (5- ((4- (1- (1- cyclopropylethyls) -1H- indol-3-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (compound 53)

N-(5-((4-(1-(1-cyclopropylethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acryamide

The first step：N¹- (4- (1- (1- cyclopropylethyls) -1H- indol-3-yls) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro benzene -1,4- diamines (53A)

N1-(4-(1-(1-cyclopropylethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N4-(2-(dimethylamino)ethyl)-2-methoxy-N4-methyl-5-nitrobenzene-1,4-diamine

By N¹- (4- (1H- indol-3-yls) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro benzene -1; 4- diamines (34B) (0.065g; 0.14mmol) it is dissolved in 10mL dichloromethane; add triphenylphosphine (0.074g; 0.28mmol) with 1- cyclopropyl-ethanols (0.012g; 0.14mmol); 0 DEG C is cooled under nitrogen protection; diisopropyl azodiformate (i.e. DIAD) (56.6mg is added dropwise; 0.28mmol), reaction 4 hours is warmed to room temperature, reaction terminates; reaction solution is spin-dried for, silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=1:0~20:1) compound N, is obtained¹- (4- (1- (1- cyclopropylethyls) -1H- indol-3-yls) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro benzene-Isosorbide-5-Nitrae-diamines (53A), brown solid (0.03g, yield 40.5%).

MS m/z:530.1[M+1]+。

Second step：N⁴- (4- (1- (1- cyclopropylethyls) -1H- indol-3-yls) pyrimidine -2-base)-N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methylbenzene -1,2,4- triamines (53B)

N⁴-(4-(1-(1-cyclopropylethyl)-1H-indol-3-yl)pyrimidin-2-yl)-N1-(2-(dimethylamino)ethyl)-5-methoxy-N¹-methylbenzene-1,2,4-triamine

By N¹- (4- (1- (1- cyclopropylethyls) -1H- indol-3-yls) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro benzene-Isosorbide-5-Nitrae-diamines (53A) (0.85g, 1.6mmol) is dissolved in 30mL ethanol, sequentially add 10mL water, iron powder (0.538g, 9.6mmol) and ammonium chloride (60mg, 1.1mmol), it is warming up to 90 DEG C, back flow reaction 6 hours.Reaction solution is concentrated, silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=1:0~10:1) compound N, is obtained⁴- (4- (1- (1- cyclopropylethyls) -1H- indol-3-yls) pyrimidine -2-base)-N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methylbenzene -1,2,4- triamines (53B), brown solid (0.3g, yield 37.5%).

MS m/z:500.1[M+1]⁺。

3rd step：N- (5- ((4- (1- (1- cyclopropylethyls) -1H- indol-3-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (compound 53)

N-(5-((4-(1-(1-cyclopropylethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

By N⁴- (4- (1- (1- cyclopropylethyls) -1H- indol-3-yls) pyrimidine -2-base)-N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methylbenzene -1,2,4- triamines (53B) (0.3g, 0.6mmol) it is dissolved in 10mL pyridines, add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (0.344g, 1.8mmol) with acrylic acid (0.062mL, 0.9mmol), react at room temperature 4 hours.Reaction solution is spin-dried for, 150mL ethyl acetate and 4mol/L sodium hydrate aqueous solution 100mL is added, point liquid, aqueous phase is extracted with water 100mL ethyl acetate, merges organic phase, 150mL saturated sodium-chlorides washed once.Organic phase anhydrous sodium sulfate drying, filtering and concentrating, silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=1:0~20:1), obtain compound N-(5- ((4- (1- (1- cyclopropylethyls) -1H- indol-3-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (compound 53), yellow solid (170mg, yield 51.2%).

MS m/z:554.2[M+1]⁺。

Compound 53 is split by efficient liquid phase, two optical isomers are obtained：Compound 53-1 (peak 1, t=4.50min), compound 53-2 (peak 2, t=5.07min).Splitting condition：Detection wavelength：254nM, column temperature：30 DEG C, mobile phase：Acetonitrile and water (0.1% ammoniacal liquor), acetonitrile/water=81%:19% Gradient elution.

Embodiment 54

N- (2- (((1- amino cyclopropyl) methyl) (methyl) amino) -4- methoxyl groups -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 54)

N-(2-(((1-aminocyclopropyl)methyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

The first step：(1- ((tertbutyloxycarbonyl) amino) cyclopropyl) methylmethanesulfonate ester (54B)

(1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl methanesulfonate

By (1- (hydroxymethyl) cyclopropyl) carbamate (54A) (5g, 26.7mmol) it is dissolved in 30mL dichloromethane, triethylamine (5.4g is added under ice bath, 53.4mmol), mesyl chloride (3.36g is added dropwise, 29.4mmol), low-temp reaction 2 hours, are warmed to room temperature continuation and react 6 hours.Reaction terminates, and 150mL water and 150mL dichloromethane are added into reaction solution, point liquid.Aqueous phase is extracted once with 100mL dichloromethane, merges organic phase, is washed with 150mL saturated common salts Wash once, anhydrous sodium sulfate drying, filter, be concentrated to give (1- ((tertbutyloxycarbonyl) amino) cyclopropyl) methylmethanesulfonate ester (54B), white solid (4g, yield 89.3%).

MS m/z:288.1[M+23]⁺。

Second step：(1- ((methylamino) methyl) cyclopropyl) carbamate (54C)

tert-butyl(1-((methylamino)methyl)cyclopropyl)carbamate

By (1- ((tertbutyloxycarbonyl) amino) cyclopropyl) methylmethanesulfonate ester (54B) (3.5g, 13.2mmol) it is dissolved in 50mL tetrahydrofurans, methylamine (615mg, 19.8mmol) is added, 50 DEG C are reacted 6 hours.Reaction terminates, and is spin-dried for solvent.150mL water and 200mL ethyl acetate are added, point liquid.Organic phase anhydrous sodium sulfate drying, filtering and concentrating obtains compound (1- ((methylamino) methyl) cyclopropyl) carbamate (54C), white solid (1.1g, yield 42.3%).

MS m/z:201.2[M+1]⁺。

3rd step：(1- (((5- methoxyl groups -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- nitrobenzophenones) (methyl) amino) methyl) cyclopropyl) carbamate (54D)

tert-butyl(1-(((5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-nitrophenyl)(methyl)amino)methyl)cyclopropyl)carbamate

By 5- ((4- (1- methyl indol -3- bases) pyrimidine -2-base) amino) fluoro- 1- nitrobenzene (the intermediate 3) (1g of -4- methoxyl groups -2-, 2.54mmol) it is dissolved in 15mL N, in N- dimethyl acetamides, add N, N- diisopropylethylamine (0.63mL, 3.82mmol) with the tert-butyl group (1- ((methylamino) methyl) cyclopropyl) carbamate (54C) (764mg, 3.82mmol), 140 DEG C of microwave reacts 1 hour.Reaction terminates, add 100mL dichloromethane and 100mL water, divide liquid, aqueous phase is extracted once with 100mL dichloromethane, merge organic phase, 200mL saturated aqueous common salts washed once, anhydrous sodium sulfate drying, filtering and concentrating obtains brown solid compound (1- (((5- methoxyl groups -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- nitrobenzophenones) (methyl) amino) methyl) cyclopropyl) carbamate (54D) (1.1g, yield 91.6%).

MS m/z:574.2[M+1]⁺。

4th step：(1- (((2- amino -5- methoxyl groups -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) (methyl) amino) methyl) cyclopropyl) carbamate (54E)

tert-butyl(1-(((2-amino-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)methyl)cyclopropyl)carbamate

By (1- (((5- methoxyl groups -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- nitrobenzophenones) (methyl) amino) methyl) cyclopropyl) carbamate (54D) (1.1g, 1.92mmol) it is dissolved in 60mL ethanol, sequentially add 20mL water, iron powder (643mg, 11.5mmol) with ammonium chloride (72mg, 1.34mmol), it is warming up to 90 DEG C, back flow reaction 4 hours.Reaction solution is cooled to room temperature, filtered, concentration, silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=1:0~10:1) brown solid compound (1- (((2- amino -5- methoxyl groups -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) benzene, is obtained Base) (methyl) amino) methyl) cyclopropyl) carbamate (54E) (900mg, yield 90%).

MS m/z:544.2[M+1]⁺。

5th step：(1- (((2- acrylamido -5- methoxyl groups -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) (methyl) amino) methyl) cyclopropyl) carbamate (54F)

tert-butyl(1-(((2-acrylamido-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)methyl)cyclopropyl)carbamate

By (1- (((2- amino -5- methoxyl groups -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) (methyl) amino) methyl) cyclopropyl) carbamate (54E) (900mg, 1.66mmol) it is dissolved in 15mL pyridines, add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDCI) (955mg, 5mmol) with acrylic acid (0.17mL, 2.48mmol), react at room temperature 2 hours.Reaction solution is spin-dried for, 100mL water and 100mL dichloromethane is added, point liquid.Organic phase washed once with 4mol/L sodium hydrate aqueous solutions 100mL, anhydrous sodium sulfate drying.It is concentrated to give yellow oil (1- (((2- acrylamido -5- methoxyl groups -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) (methyl) amino) methyl) cyclopropyl) carbamate (54F) (600mg, yield 60.5%).

MS m/z:598.2[M+1]⁺。

6th step：N- (2- (((1- amino cyclopropyl) methyl) (methyl) amino) -4- methoxyl groups -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 54)

By (1- (((2- acrylamido -5- methoxyl groups -4- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) (methyl) amino) methyl) cyclopropyl) carbamate (54F) (600mg, 1mmol) it is dissolved in 20mL dichloromethane, 10mL trifluoroacetic acids are added, are reacted at room temperature 3 hours.Reaction solution is spin-dried for, 100mL water is added, pH value of solution is adjusted to 8 with saturated sodium bicarbonate, adds 150mL dichloromethane, point liquid.Aqueous phase is extracted once with 100mL dichloromethane, merges organic phase, and 150mL saturated aqueous common salts washed once, anhydrous sodium sulfate drying, filtering and concentrating, silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=1:0~10:1), obtain brown solid N- (2- (((1- amino cyclopropyl) methyl) (methyl) amino) -4- methoxyl groups -5- ((4- (1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 54) (450mg, yield 90.5%).

MS m/z:498.1[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ9.88(s,1H),9.65(s,1H),9.07(s,1H),8.38(d,1H),8.07(d,1H),7.68(s,1H),7.39(d,1H),7.20(d,1H),6.72(s,1H),6.48(dd,2H),5.70(d,1H),3.99(s,3H),3.88(s,3H),2.80(s,3H),2.73(d,2H),1.55(m,4H)。

Embodiment 55

N- (5- ((4- (1- (cyclopropyl carbonyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (compound 55)

N-(5-((4-(1-(cyclopropanecarbonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

The first step：Cyclopropyl (3- (2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenones) amino) pyrimidine-4-yl) -1H- indoles -1- bases) ketone (55A)

cyclopropyl(3-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-indol-1-yl)methanone

By N¹- (4- (1H- indol-3-yls) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro benzene -1; 4- diamines (34B) (1g; 2.17mmol) it is dissolved in 20mL tetrahydrofurans, adds DIPEA (0.42g; 3.25mmol); 0 DEG C is cooled under nitrogen protection, then the formyl chloride of ring third (0.3mL, 3.25mmol) is added dropwise; 0 DEG C is reacted 1 hour, is warmed to room temperature continuation and is reacted 1 hour.Reaction terminates, and adds 10mL water quenchings and goes out reaction, reaction solution is spin-dried for, add 100mL water and 100mL dichloromethane, divides liquid.Aqueous phase is extracted once with 100mL dichloromethane.Merge organic phase, it washed once with 100mL saturated aqueous common salts, anhydrous sodium sulfate drying, filtering and concentrating obtains compound cyclopropyl (3- (2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenones) amino) pyrimidine-4-yl) -1H- indoles -1- bases) ketone (55A), brown solid (1g, yield 87%).

MS m/z=530.1 [M+1]⁺。

Second step：(3- (2- ((5- amino -4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) amino) pyrimidine-4-yl) -1H- indoles -1- bases) (cyclopropyl) ketone (55B)

(3-(2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)py rimidin-4-yl)-1H-indol-1-yl)(cyclopropyl)methanone

By cyclopropyl (3- (2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenones) amino) pyrimidine-4-yl) -1H- indoles -1- bases) ketone (55A) (1g, 1.89mmol) it is dissolved in 30mL ethanol, sequentially add 10mL water, enter iron powder (0.633g, 11.3mmol) with ammonium chloride (71mg, 1.32mmol), it is warming up to 90 DEG C, back flow reaction 6 hours.Reaction solution is concentrated, silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=1:0~10:1), obtain compound (3- (2- ((5- amino -4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) amino) pyrimidine-4-yl) -1H- indoles -1- bases) (cyclopropyl) ketone (55B), brown solid (0.5g, yield 53%).

3rd step：N- (5- ((4- (1- (cyclopropyl carbonyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (compound 55)

By (3- (2- ((5- amino -4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) amino) pyrimidine-4-yl) -1H- indoles -1- bases) (cyclopropyl) ketone (55B) (0.5g, 1mmol) it is dissolved in 10mL pyridines, add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (0.573g, 3mmol), add acrylic acid (0.103mL, 1.5mmol), react at room temperature 3 hours.Reaction solution is spin-dried for, 150mL ethyl acetate and 4mol/L sodium hydrate aqueous solution 100mL is added, point liquid, aqueous phase is extracted once with 100mL ethyl acetate.Merge organic phase, saturated nacl aqueous solution 150mL washed once, anhydrous sodium sulfate drying, filtering, silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=1:0~10:1), obtain N- (5- ((4- (1- (cyclopropyl carbonyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (compound 55), faint yellow solid (60mg, yield 11.3%).

MS m/z:554.4[M+1]⁺。

Embodiment 56

N- (3- ((the chloro- 4- of 5- (6- (4- (2- hydroxyethyls) piperazine -1- bases) -1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 56)

N-(3-((5-chloro-4-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

The first step：N- (3- ((the chloro- 4- of 5- (1- methyl -6- (piperazine -1- bases) -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (56A)

N-(3-((5-chloro-4-(1-methyl-6-(piperazin-1-yl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

4- (3- (2- ((5- acrylamide -2- methoxyphenyls) amino) -5- chlorine pyrimidine-4-yl) -1- Methyl-1H-indole -6- bases) piperazine -1- carboxylates (compound 26) (0.40g, 0.65mmol) are placed in 50mL round-bottomed flasks.At 0 DEG C, dichloromethane (10mL), trifluoroacetic acid (5mL) are sequentially added into reaction bulb.Reaction is warmed to room temperature lower stirring 2 hours.Dichloromethane (50mL) is added into residue, saturated sodium bicarbonate aqueous solution (20mL), layering, aqueous phase is extracted with dichloromethane (50mL), merge organic phase, anhydrous sodium sulfate drying, it is concentrated under reduced pressure, obtains yellow oily N- (3- ((the chloro- 4- of 5- (1- methyl -6- (piperazine -1- bases) -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (56A) (0.335g).

Second step：N- (3- ((the chloro- 4- of 5- (6- (4- (2- hydroxyethyls) piperazine -1- bases) -1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 56)

By N- (3- ((the chloro- 4- of 5- (1- methyl -6- (piperazine -1- bases) -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (56A) (0.16g, 0.31mmol) it is dissolved in 40mL acetonitriles, add potassium carbonate (86mg, 0.62mmol), bromoethanol (58.1mg, 0.47mmol), 60 DEG C are reacted 3 hours.Reaction terminates, and is spin-dried for solvent, adds 100mL water and 100mL dichloromethane, and point liquid, aqueous phase is extracted with 100mL dichloromethane, merges organic phase, with 150mL saturated common salt water washings, anhydrous sodium sulfate drying.Concentration, residue silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain yellow solid N- (3- ((the chloro- 4- of 5- (6- (4- (2- hydroxyethyls) piperazine -1- bases) -1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 56) (150mg, yield 86.2%).

LC-MS m/z:562.3[M+1]⁺。

Embodiment 57

N- (5- ((4- (1H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (compound 57)

N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

The first step：3- (2- chlorine pyrimidine-4-yl) -1H- pyrrolo-es [2,3-b] pyridine (57B)

3-(2-chloropyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine

7- azaindoles (57A) (6g, 50.8mmol) are dissolved in 100mL tetrahydrofurans, under nitrogen protection, 0 DEG C is cooled to, methyl-magnesium-bromide (17mL, 50.8mmol) is added dropwise, continue to stir 0.5 hour.2,4- dichloro pyrimidines (7.6g, 50.8mmol) are added, are reacted at room temperature 1 hour, 60 DEG C is warming up to and continues to react 2 hours.30mL methanol and 20mL acetic acid are added into reaction solution, solvent, 200mL water washings is spin-dried for, 10mL tetrahydrofurans are washed, dry to obtain yellow solid 3- (2- chlorine pyrimidine-4-yl) -1H- pyrrolo-es [2,3-b] pyridine (57B) (10g, yield 86.2%).

LC-MS(m/z):231.0[M+1]⁺。

Second step：N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2- amine (57C)

N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-amine

By 3- (2- chlorine pyrimidine-4-yl) -1H- pyrrolo-es [2,3-b] pyridine (57B) (2g, 8.7mmol) it is dissolved in 20mL 2- amylalcohols, add fluoro- 2- methoxyl groups -5- nitroanilines (the 4e) (1.62g of 4-, 8.7mmol) with p-methyl benzenesulfonic acid monohydrate (2g, 10.4mmol), 120 DEG C of back flow reactions are heated to 18 hours.Reaction solution is cooled to room temperature, 50mL ammoniacal liquor, filtering, filter cake 100mL water washings is added.Dry to obtain yellow solid N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2- amine (57C) (2.3g, yield 69.7%).

LC-MS(m/z):381.0[M+1]⁺。

3rd step：N¹- (4- (1H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro phendioxin, 4- diamines (57D)

N¹-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)-N⁴-(2-(dimethylamino)ethyl)-2-methoxy-N⁴-methyl-5-nitrobenzene-1,4-diamine

By N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (1H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2- amine (57C) (2.5g, 6.58mmol) is dissolved in 15mL DMAs, add N, N- diisopropylethylamine (1.02g, 7.9mmol), and N, N, N'- trimethyls ethylenediamine (18A) (807mg, 7.89mmol), 120 DEG C of microwave reacts 1.5 hours.Reaction terminates, and is spin-dried for solvent.With silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=1:0~10:1) red brown solid N, is obtained¹- (4- (1H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro phendioxin, 4- diamines (57D) (1g, yield 33.3%).

LC-MS(m/z):463.1[M+1]⁺。

4th step：N⁴- (4- (1H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base)-N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl benzo -1,2,4- triamines (57E)

N⁴-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)-N¹-(2-(dimethylamino)ethyl)-5-methoxy-N¹-methylbenzene-1,2,4-triamine

By N¹- (4- (1H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro phendioxin, 4- diamines (57D) (1g, 2.11mmol) is dissolved in 30mL ethanol, sequentially add 10mL water, iron powder (362mg, 6.44mmol) and ammonium chloride (81mg, 1.5mmol), 90 DEG C of back flow reactions are warming up to 6 hours.Reaction solution is cooled to room temperature, filtered, concentration.With silica gel column chromatography separating-purifying (dichloromethane：Methanol (v/v)=1:0~10:1) brown solid N, is obtained⁴- (4- (1H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base)-N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl benzo -1,2,4- triamines (57E) (933mg).

LC-MS(m/z):433.1[M+1]⁺。

5th step：N- (5- ((4- (1H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (compound 57)

By N⁴- (4- (1H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base)-N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl phendioxin, 2,4- triamines (57E) (500mg, 1.16mmol) it is dissolved in 15mL pyridines, add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (665mg, 3.48mmol), acrylic acid (0.12mL, 1.74mmol), is reacted at room temperature 6 hours.Pyridine is spin-dried for, 100mL water and 100mL dichloromethane is added, point liquid.Organic phase is washed with 4mol/L sodium hydrate aqueous solution (100mL), anhydrous sodium sulfate drying.With silica gel column chromatography separating-purifying (dichloromethane/ Methanol (v/v)=1:0~10:1), obtain white solid N- (5- ((4- (1H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (compound 57) (330mg, yield 58.5%).

LC-MS(m/z):487.1[M+1]⁺。

1H NMR(400MHz,DMSO-d₆)δ10.07(s,1H),9.03(s,1H),8.88(s,1H),8.37–8.32(m,1H),8.31(d,1H),8.01(dd,1.7Hz,1H),7.18(dd,4.7Hz,1H),7.01(s,1H),6.76(s,1H),6.64(d,1H),6.43(dd,10.1Hz,1H),6.25(dd,1.9Hz,1H),5.80–5.71(m,1H),3.87(d,3H),2.88(t,2H),2.75–2.67(m,3H),2.32(t,2H),2.19(d,6H)。

Embodiment 58

N- (3- ((4- (1H- pyrrolo-es [2,3-b] pyridin-3-yl) pyridine -2- bases) amino) -4- methoxyphenyls) acrylamide (compound 58)

N-(3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

The first step：N- (2- methoxyl group -5- nitrobenzophenones) -4- (1H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2- amine (58A)

N-(2-methoxy-5-nitrophenyl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-amine

By 3- (2- chlorine pyrimidine-4-yl) -1H- pyrroles [2,3-b] pyridine (57B) (2g, 8.7mmol) it is dissolved in 2- amylalcohols (30mL), add compound 2- methoxyl group -5- nitroanilines (1.46g, 8.7mmol) with p-methyl benzenesulfonic acid (2g, 10.44mmol), 120 DEG C of back flow reactions are heated to 18 hours.Reaction solution is cooled to room temperature, add 50mL ammoniacal liquor, filtering, filter cake 100mL water washings, dry to obtain yellow solid N- (2- methoxyl group -5- nitrobenzophenones) -4- (1H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2- amine (58A) (2.5g, yield 80.6%).

LC-MS(m/z):363.1[M+1]⁺。

Second step：N¹- (4- (1H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base) -6- methoxyl group benzo -1,3- triamines (58B)

N¹-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)-6-methoxybenzene-1,3-diamine

By N- (2- methoxyl group -5- nitrobenzophenones) -4- (1H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2- amine (58A) (0.5g, 1.38 Mmol) it is dissolved in 100mL methanol, adds palladium carbon (0.15g, 30%), nitrogen atmosphere is replaced three times, is reacted at room temperature 8 hours.Reaction terminates, and reaction solution is filtered with diatomite, dichloromethane (50mL) and methanol (50mL) washing, concentration, obtains red brown solid N¹- (4- (1H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base) -6- methoxyl group benzo -1,3- triamines (58B) (0.458g).

3rd step：N- (3- ((4- (1H- pyrrolo-es [2,3-b] pyridin-3-yl) pyridine -2- bases) amino) -4- methoxyphenyls) acrylamide (compound 58)

By N¹- (4- (1H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base) -6- methoxyl group phendioxins, 3- triamines (58B) (0.458mg, 1.38mmol) it is dissolved in 15mL pyridines, add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (527mg, 2.76mmol) with acrylic acid (0.14mL, 2.07mmol), react at room temperature 6 hours.Pyridine is spin-dried for, 100mL water and 100mL dichloromethane is added, point liquid.Organic phase is washed with 4mol/L sodium hydrate aqueous solutions (100mL), anhydrous sodium sulfate drying, filtering and concentrating, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=1:0~10:1), obtain white solid N- (3- ((4- (1H- pyrrolo-es [2,3-b] pyridin-3-yl) pyridine -2- bases) amino) -4- methoxyphenyls) acrylamide (compound 58) (230mg, yield 43.2%).

LC-MS(m/z):387.0[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ9.96(s,1H),9.11(s,1H),8.62(s,1H),8.38–8.32(m,1H),8.27(d,1H),8.02(dd,1H),7.34(dd,1H),7.19(dd,1H),7.06(d,1H),6.84(d,,1H),6.67(d,1H),6.46(dd,1H),6.26(dd,1H),5.75(dd,1H),3.85(s,3H)。

Embodiment 59

N- (4- methoxyl groups -3- ((4- (1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base) amino) phenyl) acrylamide (compound 59)

N-(4-methoxy-3-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

The first step：N- (2- methoxyl group -5- nitrobenzophenones) -4- (1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2- amine (59A)

N-(2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-amine

By N- (2- methoxyl group -5- nitrobenzophenones) -4- (1H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2- amine (58A) (0.4g, 1.1mmol) it is dissolved in 20mL tetrahydrofurans, it is cooled to 0 DEG C, adds sodium hydride (0.053g, 2.2mmol), reaction 30 minutes, iodomethane (0.2mL, 3.3mmol) is added, is reacted at room temperature 4 hours.Reaction terminates, add 60mL water, separate out solid, solid 100mL water and 50mL petroleum ethers, drying, obtain yellow solid N- (2- methoxyl group -5- nitrobenzophenones) -4- (1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2- amine (59A) (0.413g).

Second step：N¹- (4- (1H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base) -6- methoxyl group benzo -1,3- diamines (59B)

By N- (2- methoxyl group -5- nitrobenzophenones) -4- (1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2- amine (59A) (0.5g, 1.33mmol) it is dissolved in 50mL methanol, add palladium carbon (0.15g, 30%), nitrogen atmosphere is replaced three times, is reacted at room temperature 1 day.Reaction terminates, and reaction solution is filtered with diatomite, dichloromethane (100mL) and methanol (100mL) washing, is concentrated to give yellow solid N¹- (4- (1H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base) -6- methoxyl group benzo -1,3- diamines (59B) (0.46g).

LC-MS(m/z):347.1[M+1]⁺。

3rd step：N- (4- methoxyl groups -3- ((4- (1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base) amino) phenyl) acrylamide (compound 59)

By N¹- (4- (1H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base) -6- methoxyl group phendioxins, 3- diamines (59B) (0.46mg, 1.33mmol) it is dissolved in 15mL pyridines, add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (762mg, 4mmol) with acrylic acid (0.14mL, 2mmol), react at room temperature 6 days.Pyridine is spin-dried for, 100mL water and 100mL dichloromethane is added, point liquid.Organic phase is washed with 4mol/L sodium hydrate aqueous solutions (100mL), anhydrous sodium sulfate drying, filtering and concentrating, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=1:0~10:1), obtain brown solid N- (4- methoxyl groups -3- ((4- (1- methyl isophthalic acid H- pyrrolo-es [2,3-b] pyridin-3-yl) pyrimidine -2-base) amino) phenyl) acrylamide (compound 59) (400mg, yield 75.2%).

LC-MS(m/z):401.1[M+1]⁺。

Embodiment 60

N- (5- ((4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyl groups -2- (2- (4- methylpiperazine-1-yls) ethyoxyl) phenyl) acrylamide (compound 60)

N-(5-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)acrylamide

The first step：4- (1- (difluoromethyl) -1H- indol-3-yls)-N- (2- methoxyl groups -4- (2- (4- methylpiperazine-1-yls) ethyoxyl) -5- nitrobenzophenones) pyrimidine -2- amine (60A)

4-(1-(difluoromethyl)-1H-indol-3-yl)-N-(2-methoxy-4-(2-(4-methylpiperazin-1-yl)ethoxy)-5-nitrophenyl)pyrimidin-2-amine

By 4- (1- (difluoromethyl) -1H- indol-3-yls)-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) pyrimidine -2- amine (30B) (1g, 2.33mmol) it is dissolved in 30mL tetrahydrofurans, it is slowly added to sodium hydride (112mg, 4.66mmol), stirring 30 minutes, 2- (4- methylpiperazine-1-yls) ethanol (672mg, 4.66mmol) is added, is reacted at room temperature 4 hours.Reaction terminates, and adds 150mL water and 150mL dichloromethane, point liquid.Organic phase anhydrous sodium sulfate drying, it is concentrated to give yellow solid 4- (1- (difluoromethyl) -1H- indol-3-yls)-N- (2- methoxyl groups -4- (2- (4- methylpiperazine-1-yls) ethyoxyl) -5- nitrobenzophenones) pyrimidine -2- amine (60A) (1.2g, yield 93.0%).

LC-MS (m/z)=554.3 [M+1]⁺。

Second step：N¹- (4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) -6- methoxyl groups -4- (2- (4- methylpiperazine-1-yls) ethyoxyl) phendioxin, 3- diamines (60B)

N¹-(4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzene-1,3-diamine

By 4- (1- (difluoromethyl) -1H- indol-3-yls)-N- (2- methoxyl groups -4- (2- (4- methylpiperazine-1-yls) ethyoxyl) -5- nitrobenzophenones) pyrimidine -2- amine (60A) (1.2g, 2.17mmol) it is dissolved in 30mL ethanol, add 10mL water, iron powder (727mg, 13mmol) with ammonium chloride (81.3mg, 1.52mmol), 90 DEG C of back flow reactions are warming up to 4 hours.Reaction solution is concentrated, silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1) brown solid N, is obtained¹- (4- (1- (difluoro first Base) -1H- indol-3-yls) pyrimidine -2-base) -6- methoxyl groups -4- (2- (4- methylpiperazine-1-yls) ethyoxyl) phendioxin, 3- diamines (60B) (740mg, yield 65.5%).

3rd step：N- (5- ((4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyl groups -2- (2- (4- methylpiperazine-1-yls) ethyoxyl) phenyl) acrylamide (compound 60)

By N¹- (4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) -6- methoxyl groups -4- (2- (4- methylpiperazine-1-yls) ethyoxyl) phendioxin, 3- diamines (60B) (740mg, 1.4mmol) it is dissolved in 20mL pyridines, add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (802mg, 4.2mmol), acrylic acid (0.146mL, 2.1mmol), react at room temperature 4 hours.Pyridine in reaction solution is spin-dried for, 150mL water and 150mL dichloromethane is added, point liquid.Organic phase is washed with 4mol/L sodium hydrate aqueous solutions (100mL), anhydrous sodium sulfate drying, is filtered, concentration, silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain white solid N- (5- ((4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyl groups -2- (2- (4- methylpiperazine-1-yls) ethyoxyl) phenyl) acrylamide (compound 60) (200mg, yield 24.8%).

LC-MS (m/z)=578.3 [M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ9.68(s,1H),9.34(s,1H),8.59(s,1H),8.44(d,1H),8.04(dd,1H),7.78(s,1H),7.67(s,1H),7.35(dd,2H),7.22(d,1H),6.62(s,1H),6.43(m,2H),5.79(d,1H),4.19(t,2H),3.90(s,3H),2.80–2.74(m,2H),2.69(s,4H),2.62(s,4H),2.38(s,3H)。

Embodiment 61

N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (7- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 61)

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(7-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

The first step：3- (2- chlorine pyrimidine-4-yl) -7- Methyl-1H-indoles (61B)

3-(2-chloropyrimidin-4-yl)-7-methyl-1H-indole

7- methyl indols (61A) (10g, 76.2mmol) are dissolved in 100mL 1,2- dichloroethanes, nitrogen protection is cooled to 0 DEG C, methyl-magnesium-bromide (25.4mL, 76.2mmol) is added dropwise, and continues to stir 0.5 hour.2,4- dichloro pyrimidines (11.4g, 76.2mmol) are added, are reacted at room temperature 40 minutes, 60 DEG C is risen to and reacts 8 hours.Add 20mL methanol and 20mL acetic acid, reaction 20 minutes, it is spin-dried for solvent, separate out solid, solid 200mL water and 50mL petroleum ethers, filter cake is dried with infrared lamp, obtains yellow solid 3- (2- chlorine pyrimidine-4-yl) -7- Methyl-1H-indoles (61B) (12g, yield 64.9%).

LC-MS(m/z):244.0[M+1]⁺。

Second step：N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (7- Methyl-1H-indole -3- bases) pyrimidine -2- amine (61C)

N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(7-methyl-1H-indol-3-yl)pyrimidin-2-amine

By 3- (2- chlorine pyrimidine-4-yl) -7- Methyl-1H-indoles (61B) (4.2g, 17.28mmol) it is dissolved in 80mL 2- amylalcohols, add fluoro- 2- methoxyl groups -5- nitroanilines (the 4e) (3.2g of 4-, 17.28mmol) with p-methyl benzenesulfonic acid monohydrate (3.98g, 20.7mmol), 120 DEG C of back flow reactions are heated to 3 days.Room temperature is cooled to, 200mL ammoniacal liquor is added, solid, filtering, filter cake 200mL water and 100mL petroleum ethers is separated out.Dry to obtain dark green solid N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (7- Methyl-1H-indole -3- bases) pyrimidine -2- amine (61C) (4.5g, yield 66.3%).

LC-MS(m/z):394.1[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ11.85(s,1H),9.15(d,1H),8.39(d,1H),8.36(d,1H),8.23(s,1H),8.19(d,1H),7.41(d,1H),7.38–7.32(m,1H),7.04–6.96(m,2H),4.07–4.00(m,3H),3.31(s,3H),2.50(d,6H)。

3rd step：N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl-N⁴- (4- (7- Methyl-1H-indole -3- bases) pyrimidine -2-base) -2- nitro benzo -1,4- diamines (61D)

N¹-(2-(dimethylamino)ethyl)-5-methoxy-N¹-methyl-N⁴-(4-(7-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine

By N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (7- Methyl-1H-indole -3- bases) pyrimidine -2- amine (61C) (2.5g, 6.35mmol) it is dissolved in N, in N- dimethyl acetamides (10mL), add DIPEA (986mg, 7.63mmol) and N, N, N'- trimethyls ethylenediamine (18A) (780mg, 7.63mmol), 120 DEG C of microwave reacts 1.5 hours.Reaction terminates, concentration, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=1:0~10:1) brown solid N, is obtained¹- (2- (diformazans Base amino) ethyl) -5- methoxyl groups-N¹- methyl-N⁴- (4- (7- Methyl-1H-indole -3- bases) pyrimidine -2-base) -2- nitros benzo-Isosorbide-5-Nitrae-diamines (61D) (2.1g, yield 70%).

LC-MS(m/z):476.3[M+1]⁺。

4th step：N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl-N⁴- (4- (7- Methyl-1H-indole -3- bases) pyrimidine -2-base) phendioxin, 2,4- triamines (61E)

N¹-(2-(dimethylamino)ethyl)-5-methoxy-N¹-methyl-N⁴-(4-(7-methyl-1H-indol-3-yl)pyrimidin-2-yl)benzene-1,2,4-triamine

By N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl-N⁴- (4- (7- Methyl-1H-indole -3- bases) pyrimidine -2-base) -2- nitro phendioxins, 4- diamines (61D) (1.3g, 2.74mmol) it is dissolved in 30mL ethanol, add 10mL water, iron powder (0.918g, 16.4mmol) and ammonium chloride (102.7mg, 1.92mmol), 90 DEG C of back flow reactions are warming up to 4 hours.Reaction solution is concentrated, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=1:0~10:1) brown solid N, is obtained¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl-N⁴- (4- (7- Methyl-1H-indole -3- bases) pyrimidine -2-base) phendioxin, 2,4- triamines (61E) (0.8g, yield 66.7%).

LC-MS(m/z):446.1[M+1]⁺。

5th step：N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (7- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 61)

By N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl-N⁴- (4- (7- Methyl-1H-indole -3- bases) pyrimidine -2-base) phendioxin, 2,4- triamines (61E) (0.8g, 1.mmol) it is dissolved in 15mL pyridines, sequentially add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (1.03g, 5.4mmol) with acrylic acid (0.19mL, 2.7mmol), react at room temperature 4 hours.It is spin-dried for pyridine, add 150mL dichloromethane and 4mol/L sodium hydrate aqueous solutions (100mL), divide liquid, aqueous phase is extracted once with 150mL dichloromethane, merge organic phase, 200mL saturated sodium-chlorides washed once, anhydrous sodium sulfate drying, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=1:0~10:1), obtain yellow solid N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (7- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 61) (400mg, yield 44.5%).

LC-MS(m/z):500.2[M+1]⁺。

¹H NMR(400MHz,CDCl3)δ10.21(s,1H),9.81(s,1H),9.25(s,1H),8.89(s,1H),8.37(d,1H),7.95(d,1H),7.69(s,1H),7.16(d,1H),7.14–7.08(m,1H),6.80(s,1H),6.51(dd,1.4Hz,1H),6.37(s,1H),5.69(d,1H),3.88(d,3H),2.91(s,2H),2.84(s,2H),2.71(s,3H),2.49(s,3H),2.26(s,6H),1.73(s,2H)。

Embodiment 62

N- (5- ((4- (1,7- dimethyl -1H- indol-3-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (compound 62)

N-(5-((4-(1,7-dimethyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

The first step：3- (2- chlorine pyrimidine-4-yl) -1,7- dimethyl -1H- indoles (62A)

3-(2-chloropyrimidin-4-yl)-1,7-dimethyl-1H-indole

By 3- (2- chlorine pyrimidine-4-yl) -7- Methyl-1H-indoles (61B) (10g, 41.1mmol) it is dissolved in 100mL tetrahydrofurans, it is cooled to 0 DEG C, add sodium hydride (3.3g, 82.2mmol), 0 DEG C is reacted 30 minutes, adds iodomethane (17.5g, 123.4mmol), continuation is warmed to room temperature to react 1 hour.Reaction terminates, and is spin-dried for solvent, and solid 200mL water and 50mL petroleum ethers, drying obtain red brown solid 3- (2- chlorine pyrimidine-4-yl) -1,7- dimethyl -1H- indoles (62A) (10g, yield 95.2%).

Second step：4- (1,7- dimethyl -1H- indol-3-yls)-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) pyrimidine -2- amine (62B)

4-(1,7-dimethyl-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine

By 3- (2- chlorine pyrimidine-4-yl) -1,7- dimethyl -1H- indoles (62A) (5g, 19.4mmol) it is dissolved in 100mL2- amylalcohols, add fluoro- 2- methoxyl groups -5- nitroanilines (the 4e) (3.62g of 4-, 19.4mmol) with p-methyl benzenesulfonic acid monohydrate (4.47g, 23.3mmol), 120 DEG C of back flow reactions are heated to 3 days.It is cooled to room temperature, add 200mL ammoniacal liquor, separate out solid, filtering, filter cake uses 200mL water and 100mL petroleum ethers successively, and drying obtains yellow solid 4- (1,7- dimethyl -1H- indol-3-yls)-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) pyrimidine -2- amine (62B) (6g, yield 75.9%).

LC-MS(m/z):408.0[M+1]⁺。

¹H NMR(400MHz,DMSO-d₆)δ9.11(d,1H),8.38(d,1H),8.24(d,3H),7.34(d,1H),7.27(d,1H),7.01–6.92(m,2H),4.14(s,3H),4.02(s,3H),2.76(s,3H)。

3rd step：N¹- (4- (1,7- dimethyl -1H- indol-3-yls) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro phendioxin, 4- amine (62C)

N¹-(4-(1,7-dimethyl-1H-indol-3-yl)pyrimidin-2-yl)-N⁴-(2-(dimethylamino)ethyl)-2-methoxy-N⁴-methyl-5-nitrobenzene-1,4-diamine

By 4- (1,7- dimethyl -1H- indol-3-yls)-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) pyrimidine -2- amine (62B) (3g, 7.37mmol) it is dissolved in 10mL DMAs, adds N, N- diisopropylethylamine (1.14g, 8.84mmol) and N, N, N'- trimethyl ethylenediamine (18A) (904mg, 8.84mmol), 120 DEG C of microwave reacts 1.5 hours.Reaction terminates, and adds 150mL water and 150mL dichloromethane, point liquid.Aqueous phase is extracted with 150mL dichloromethane, merges organic phase, with 200mL saturated common salt water washings.Organic phase anhydrous sodium sulfate drying, is concentrated to give brown solid N¹- (4- (1,7- dimethyl -1H- indol-3-yls) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro phendioxin, 4- amine (62C) (3.6g).

LC-MS(m/z):490.2[M+1]⁺。

4th step：N⁴- (4- (1,7- dimethyl -1H- indol-3-yls) pyrimidine -2-base)-N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl benzo -1,2,4- triamines (62D)

N⁴-(4-(1,7-dimethyl-1H-indol-3-yl)pyrimidin-2-yl)-N¹-(2-(dimethylamino)ethyl)-5-methoxy-N¹-methylbenzene-1,2,4-triamine

By N¹- (4- (1,7- dimethyl -1H- indol-3-yls) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro phendioxin, 4- amine (62C) (3.6g, 7.36mmol) is dissolved in 30mL ethanol, add 10mL water, iron powder (, 2.46g, 44.1mmol) and ammonium chloride (273mg, 5.1mmol), 90 DEG C of back flow reactions are warming up to 4 hours.Reaction solution is concentrated, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=1:0~10:1) yellow solid N, is obtained⁴- (4- (1,7- dimethyl -1H- indol-3-yls) pyrimidine -2-base)-N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl phendioxin, 2,4- triamines (62D) (2.3mg, yield 69.7%).

LC-MS(m/z):460.1[M+1]⁺。

5th step：N- (5- ((4- (1,7- dimethyl -1H- indol-3-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (compound 62)

By N⁴- (4- (1,7- dimethyl -1H- indol-3-yls) pyrimidine -2-base)-N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl phendioxin, 2,4- triamines (62D) (1.66g, 3.62mmol) are dissolved in 30mL pyridines, sequentially add 1- (3- diformazans Aminopropyl) -3- ethyl-carbodiimide hydrochlorides (2.07g, 10.85mmol) and acrylic acid (0.38mL, 5.43mmol), react at room temperature 6 hours.Pyridine is spin-dried for, 4mol/L sodium hydrate aqueous solutions (200mL) and 200mL dichloromethane is added, point liquid.Organic phase washed once with 100mL saturated sodium-chloride water solutions, anhydrous sodium sulfate drying, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=1:0~10:1), obtain brown solid N- (5- ((4- (1,7- dimethyl -1H- indol-3-yls) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (compound 62) (1g, yield 53.8%).

LC-MS(m/z):514.2[M+1]⁺。

Embodiment 63

N- (4- methoxyl groups -3- ((4- (2- methyl isophthalic acid H- benzos [d] imidazoles -1- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 63)

N-(4-methoxy-3-((4-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

The first step：1- (2- chlorine pyrimidine-4-yl) -2- methyl isophthalic acid H- benzos [d] imidazoles (63B)

1-(2-chloropyrimidin-4-yl)-2-methyl-1H-benzo[d]imidazole

By 2- tolimidazoles (63A) (6.6g; 50mmol) it is dissolved in 100mL DMFs, under nitrogen protection; it is cooled to 0 DEG C; sodium hydride (2.4g, 60mmol) is added, continues to stir 0.5 hour; add 2; 4- dichloro pyrimidines (7.5g, 50mmol), are reacted at room temperature 10 hours.250mL water is added, solid is separated out, filtered, filter cake 200mL water and 100mL petroleum ethers dry to obtain white solid 1- (2- chlorine pyrimidine-4-yl) -2- methyl isophthalic acid H- benzos [d] imidazoles (63B) (23g).

LC-MS(m/z):245.0[M+1]⁺。

¹H NMR(400MHz,CDCl3)δ8.69(d,1H),8.36–8.27(m,1H),7.76–7.68(m,1H),7.36–7.31(m,2H),7.26(s,1H),2.99(s,3H)。

Second step：N- (2- methoxyl group -5- nitrobenzophenones) -4- (2- methyl isophthalic acid H- benzos [d] imidazoles -1- bases) pyrimidine -2- amine (63C)

N-(2-methoxy-5-nitrophenyl)-4-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine

By 1- (2- chlorine pyrimidine-4-yl) -2- methyl isophthalic acid H- benzos [d] imidazoles (63B) (2.44g, 10mmol) it is dissolved in 30mL 2- amylalcohols, add the nitroaniline (1.68g of 2- methoxyl groups -5,10mmol) with p-methyl benzenesulfonic acid (1.92g, 10mmol), 120 DEG C of back flow reactions are heated to 3 days.It is cooled to room temperature, add 100mL ammoniacal liquor, separate out solid, filtering, filter cake 250mL water and 100mL petroleum ethers, dry to obtain yellow solid N- (2- methoxyl group -5- nitrobenzophenones) -4- (2- methyl isophthalic acid H- benzos [d] imidazoles -1- bases) pyrimidine -2- amine (63C) (2.7g, yield 71.8%).

LC-MS(m/z):377.0[M+1]⁺。

3rd step：N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl-N⁴- (4- (2- methyl isophthalic acid H- benzos [d] imidazoles -1- bases) pyrimidine -2-base) -2- nitro benzo -1,4- diamines (63D)

N¹-(2-(dimethylamino)ethyl)-5-methoxy-N¹-methyl-N⁴-(4-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine

By N- (2- methoxyl group -5- nitrobenzophenones) -4- (2- methyl isophthalic acid H- benzos [d] imidazoles -1- bases) pyrimidine -2- amine (63C) (1g, 2.6mmol) it is dissolved in 20mL methanol, add palladium carbon (0.334g, 30%), nitrogen atmosphere is replaced three times, room temperature reaction reaction 3 hours.Reaction terminates, diatomite filtering, is washed with 50mL methanol.Filtrate is concentrated, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=1:0~50:1) yellow solid N, is obtained¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl-N⁴- (4- (2- methyl isophthalic acid H- benzos [d] imidazoles -1- bases) pyrimidine -2-base) -2- nitros benzo-Isosorbide-5-Nitrae-diamines (63D) (0.6g, yield 65.9%).

LC-MS(m/z):347.1[M+1]⁺。

4th step：N- (4- methoxyl groups -3- ((4- (2- methyl isophthalic acid H- benzos [d] imidazoles -1- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 63)

By N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl-N⁴- (4- (2- methyl isophthalic acid H- benzos [d] imidazoles -1- bases) pyrimidine -2-base) -2- nitro phendioxins, 4- diamines (63D) (0.6g, 1.73mmol) it is dissolved in 15mL pyridines, sequentially add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (0.993g, 5.2mmol) with acrylic acid (0.18mL, 2.6mmol), react at room temperature 4 hours.Pyridine is spin-dried for, 100mL ethyl acetate and 4mol/L sodium hydrate aqueous solution 100mL is added, point liquid, organic phase anhydrous sodium sulfate drying is filtered, concentration, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=1:0~50:1), obtain white solid N- (4- methoxyl groups -3- ((4- (2- methyl isophthalic acid H- benzos [d] imidazoles -1- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 63) (150mg, yield 21.7%).

LC-MS(m/z):401.1[M+1]⁺。

¹H NMR(400MHz,CDCl3)δ8.39(d,1H),8.33(s,1H),8.18–8.14(m,1H),7.72(dd,1H),7.66–7.59(m,1H),7.51(d,1H),7.40(d,1H),6.94–6.89(m,1H),6.73–6.66(m,1H),6.40–6.32(m,1H),6.15(dd,1H),5.71(d,1H),3.92(s,3H),2.92(d,3H)。

Embodiment 64

N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (2- methyl isophthalic acid H- benzos [d] imidazoles -1- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 64)

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

The first step：N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (2- methyl isophthalic acid H- benzos [d] imidazoles -1- bases) pyrimidine -2- amine (64A)

N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine

By 1- (2- chlorine pyrimidine-4-yl) -2- methyl isophthalic acid H- benzos [d] imidazoles (63B) (0.244g, 1mmol) it is dissolved in 30mL 2- amylalcohols, add fluoro- 2- methoxyl groups -5- nitroanilines (the 4e) (0.186g of 4-, 1mmol) with p-methyl benzenesulfonic acid monohydrate (0.192g, 1mmol), 120 DEG C of back flow reactions are heated to 1 day.Reaction solution is cooled to room temperature, 200mL ammoniacal liquor is added, solid, filtering, filter cake 250mL water and 100mL petroleum ethers is separated out.Dry to obtain brown solid N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (2- methyl isophthalic acid H- benzos [d] imidazoles -1- bases) pyrimidine -2- amine (64A) (3.7g, yield 93.9%).

LC-MS(m/z):395.1[M+1]⁺。

Second step：N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl-N⁴- (4- (2- methyl isophthalic acid H- benzos [d] imidazoles -1- bases) pyrimidine -2-base) -2- nitrobenzene -1,4- diamines (64B)

By N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (2- methyl isophthalic acid H- benzos [d] imidazoles -1- bases) pyrimidine -2- amine (64A) (2g, 5mmol) it is dissolved in N, in N- dimethyl acetamides (12mL), add DIPEA (0.775g, 6mmol) and N, N, N'- trimethyls ethylenediamine (18A) (613mg, 6mmol), 120 DEG C of microwave reacts 2 hours.Reaction terminates, and reaction solution is concentrated, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=1:0~20:1) red brown solid N1- (2- (dimethylamino) ethyl) -5- methoxyl groups-N, is obtained¹- methyl-N⁴- (4- (2- methyl isophthalic acid H- benzos [d] imidazoles -1- bases) pyrimidine -2-base) -2- nitrobenzene-Isosorbide-5-Nitrae-diamines (64B) (0.87g, yield 39.5%).

3rd step：N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl-N⁴- (4- (2- methyl isophthalic acid H- benzos [d] imidazoles -1- bases) pyrimidine -2-base) benzene -1,2,4- triamines (64C)

N¹-(2-(dimethylamino)ethyl)-5-methoxy-N¹-methyl-N⁴-(4-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)benzene-1,2,4-triamine

By N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl-N⁴- (4- (2- methyl isophthalic acid H- benzos [d] imidazoles -1- bases) pyrimidine -2-base) -2- nitrobenzene -1,4- diamines (64B) (0.87g, 1.95mmol) it is dissolved in 30mL ethanol, sequentially add 10mL water, iron powder (0.653g, 11.7mmol) with ammonium chloride (73mg, 1.37mmol), 90 DEG C of back flow reactions are warming up to 4 hours.Reaction solution is concentrated, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=1:0~20:1) brown solid N, is obtained¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl-N⁴- (4- (2- methyl isophthalic acid H- benzos [d] imidazoles -1- bases) pyrimidine -2-base) benzene -1,2,4- triamines (64C) (0.6g, yield 73.6%).

4th step：N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (2- methyl isophthalic acid H- benzos [d] imidazoles -1- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 64)

By N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl-N⁴- (4- (2- methyl isophthalic acid H- benzos [d] imidazoles -1- bases) pyrimidine -2-base) phendioxin, 2,4- triamines (64C) (0.6g, 1.34mmol) it is dissolved in 20mL pyridines, sequentially add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (0.764g, 4mmol) with acrylic acid (0.14mL, 2mmol), react at room temperature 3 hours.It is spin-dried for removing pyridine, add 150mL ethyl acetate and 4mol/L sodium hydrate aqueous solutions (100mL), divide liquid, aqueous phase is extracted with 100mL ethyl acetate, merge organic phase, washed with 150mL saturated sodium-chlorides, anhydrous sodium sulfate drying, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=1:0~20:1) faint yellow solid, is obtained N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (2- methyl isophthalic acid H- benzos [d] imidazoles -1- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 64) (300mg, yield 44.8%).

LC-MS(m/z):501.1[M+1]⁺。

¹H NMR(400MHz,CDCl3)δ8.76(s,1H),8.44(d,1H),8.23–8.12(m,1H),7.74–7.63(m,1H),7.28(d,1H),7.24(d,1H),7.07(s,1H),6.93(d,1H),6.83(s,1H),6.43(d,1H),5.72(d,1H),3.87(s,3H),2.92(s,5H),2.75(s,3H),2.32(s,8H)。

Embodiment 65

N- (3- ((the chloro- 4- of 5- (6- (2,6- Dimethyl-morpholins) -1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups-phenyl) acrylamide (compound 65)

N-(3-((5-chloro-4-(6-(2,6-dimethylmorpholino)-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

The first step：6- bromo- 1- (triisopropylsilyl) -1H- indoles (65B)

6-bromo-1-(triisopropylsilyl)-1H-indole

By 6- bromo indoles (65A) (30g, 153.02mmol) it is dissolved in 200mL tetrahydrofurans, sodium hydride (4.04g is slowly added under ice bath, 168.32mmol), stirring 30 minutes, tri isopropyl chlorosilane (35.4g, 183.6mmol) is added dropwise, reacts at room temperature 1 hour.Add 20mL water quenchings into reaction solution to go out reaction, addition 200mL water and 500mL ethyl acetate, Divide liquid, aqueous phase is extracted with 500mL ethyl acetate.Organic phase anhydrous sodium sulfate drying, is spin-dried for solvent, silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=50:1~20:1) white solid 6- bromo- 1- (triisopropylsilyl) -1H- indoles (65B) (46g, yield 87.9%), is obtained.

Second step：2,6- dimethyl -4- (1- (triisopropylsilyl) -1H- indoles -6- bases) morpholine (65C)

2,6-dimethyl-4-(1-(triisopropylsilyl)-1H-indol-6-yl)morpholine

By 6- bromo- 1- (triisopropylsilyl) -1H- indoles (65B) (1g, 3mmol) it is dissolved in 30mL ortho-xylenes, sequentially adds 2,6- thebaines (518mg, 4.5mmol), sodium tert-butoxide (577mg, 6mmol), double diphenylphosphine -9, the 9- dimethyl xanthene (173.6mg of 4,5-, 0.3mmol) with palladium (67.4mg, 0.3mmol), it is cooled to -20 DEG C, nitrogen displacement 30 minutes.120 DEG C are risen to react 4 hours.Reaction terminates, and adds 10mL water, is filtered with diatomite, the washing of 100mL ethyl acetate, adds 100mL water in filtrate, point liquid.Aqueous phase is extracted with 100mL ethyl acetate, merge organic phase, anhydrous sodium sulfate drying is concentrated to give brown solid 2,6- dimethyl -4- (1- (triisopropylsilyl) -1H- indoles -6- bases) morpholine (65C) (1.1g, yield 94.8%).

LC-MS(m/z):387.1[M+1]⁺。

3rd step：4- (1H- indoles -6- bases) -2,6- Dimethyl-morpholins (65D)

4-(1H-indol-6-yl)-2,6-dimethylmorpholine

Under ice bath, by 2,6- dimethyl -4- (1- (triisopropylsilyl) -1H- indoles -6- bases) morpholine (65C) (1.1g, 2.8mmol) it is dissolved in 20mL tetrahydrofurans, add tetrabutyl ammonium fluoride (2.8mL, 2.8mmol), react at room temperature 2 hours.Reaction terminates, and adds 10mL water quenchings and goes out reaction, concentrates, silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=1:0~2:1) yellow solid 4- (1H- indoles -6- bases) -2,6- Dimethyl-morpholins (65D) (0.6g, yield 93.2%), are obtained.

LC-MS(m/z):231.1[M+1]⁺。

4th step：4- (3- (2,5- dichloro pyrimidine -4- bases) -1H- indoles -6- bases) -2,6- Dimethyl-morpholins (65E)

4-(3-(2,5-dichloropyrimidin-4-yl)-1H-indol-6-yl)-2,6-dimethylmorpholine

4- (1H- indoles -6- bases) -2,6- Dimethyl-morpholins (65D) (0.6g, 2.6mmol) are dissolved in 30mL tetrahydrofurans; under nitrogen protection; it is cooled to 0 DEG C, methyl-magnesium-bromide (0.87mL, 2.6mmol) is added dropwise; reaction 30 minutes; add 2,4,5- trichloropyrimidines (0.477g; 2.6mmol), 65 DEG C are reacted 6 hours.Reaction terminates, and adds 150mL water and 150mL ethyl acetate, point liquid.Organic phase anhydrous sodium sulfate drying, is filtered, concentration, silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=1:0~2:1) yellow solid 4- (3- (2,5- dichloro pyrimidine -4- bases) -1H- indoles -6- bases) -2,6- Dimethyl-morpholins (65E) (0.64g, yield 65.5%), are obtained.

LC-MS(m/z):377.0[M+1]⁺。

5th step：4- (3- (2,5- dichloro pyrimidine -4- bases) -1- Methyl-1H-indole -6- bases) -2,6- Dimethyl-morpholins (65F)

4-(3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-indol-6-yl)-2,6-dimethylmorpholine

By 4- (3- (2,5- dichloro pyrimidine -4- bases) -1H- indoles -6- bases) -2,6- Dimethyl-morpholins (65E) (1.44g, 3.8mmol) it is dissolved in 30mL tetrahydrofurans, sodium hydride (306.5mg, 7.6mmol) is added under ice bath, stirring 30 minutes, iodomethane (0.72mL, 11.5mmol) is added dropwise, reacts at room temperature 1 hour.Reaction terminates, 20mL water quenchings are added to go out reaction, it is spin-dried for solvent, solid 100mL water washings, drying obtains yellow solid 4- (3- (2,5- dichloro pyrimidine -4- bases) -1- Methyl-1H-indole -6- bases) -2,6- Dimethyl-morpholins (65F) (1.3g, yield 87.8%).

6th step：The chloro- 4- of 5- (6- (2,6- Dimethyl-morpholins) -1- Methyl-1H-indole -3- bases)-N- (2- methoxyl group -5- nitrobenzophenones) pyrimidine -2- amine (65G)

5-chloro-4-(6-(2,6-dimethylmorpholino)-1-methyl-1H-indol-3-yl)-N-(2-methoxy-5-nitrophenyl)pyrimidin-2-amine

By 4- (3- (2,5- dichloro pyrimidine -4- bases) -1- Methyl-1H-indole -6- bases) -2,6- Dimethyl-morpholins (65F) (1.3g, 3.33mmol) it is dissolved in 30mL2- amylalcohols, add 2- methoxyl group -5- nitroanilines (561mg, 3.33mmol) and p-methyl benzenesulfonic acid (768mg, 4mmol), 120 DEG C of back flow reactions are heated to 3 days.Reaction solution is cooled to room temperature, add 150mL ammoniacal liquor, separate out solid, filtering, filter cake 200mL water and 100mL petroleum ethers, dry to obtain the chloro- 4- of brown solid 5- (6- (2,6- Dimethyl-morpholin) -1- Methyl-1H-indole -3- bases)-N- (2- methoxyl group -5- nitrobenzophenones) pyrimidine -2- amine (65G) (1g, yield 58.8%).

LC-MS(m/z):523.0[M+1]⁺。

7th step：N1- (the chloro- 4- of 5- (6- (2,6- Dimethyl-morpholins) -1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -6- methoxyl group benzo -1,3- diamines (65H)

N1-(5-chloro-4-(6-(2,6-dimethylmorpholino)-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxybenzene-1,3-diamine

By the chloro- 4- of 5- (6- (2,6- Dimethyl-morpholins) -1- Methyl-1H-indole -3- bases)-N- (2- methoxyl group -5- nitrobenzophenones) pyrimidine -2- amine (65G) (1g, 1.9mmol) it is dissolved in 30mL ethanol, sequentially add 10mL water, iron powder (642mg, 11.5mmol) with ammonium chloride (71mg, 1.33mmol), it is warming up to 90 DEG C of back flow reactions 6 hours, it is cooled to room temperature, filtering, filtrate is concentrated, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=1:0~50:1), obtain yellow solid N1- (the chloro- 4- of 5- (6- (2,6- Dimethyl-morpholins) -1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -6- methoxyl group phendioxins, 3- diamines (65H) (800mg, yield 85.6%).

LC-MS(m/z):493.0[M+1]⁺。

8th step：N- (3- ((the chloro- 4- of 5- (6- (2,6- Dimethyl-morpholins) -1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups-phenyl) acrylamide (compound 65)

By N1- (the chloro- 4- of 5- (6- (2,6- Dimethyl-morpholins) -1- Methyl-1H-indole -3- bases) pyrimidine -2-base) -6- methoxyl group phendioxins, 3- diamines (65H) (800mg, 1.6mmol) it is dissolved in 15mL pyridines, sequentially add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (917mg, 4.8mmol) and acrylic acid (0.17mL, 2.44mmol), react at room temperature 4 hours.Pyridine is spin-dried for, 4mol/L sodium hydrate aqueous solutions (150mL) and 150mL ethyl acetate is added, point liquid.Aqueous phase is extracted once with 1000mL ethyl acetate, merges organic phase, with 150mL water washings once.Organic phase anhydrous sodium sulfate drying, filtering and concentrating, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=1:0~20:1), obtain white solid N- (3- ((the chloro- 4- of 5- (6- (2,6- Dimethyl-morpholins) -1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -4- methoxyl groups-phenyl) acrylamide (compound 65) (400mg, yield 45.8%).

LC-MS(m/z):547.1[M+1]⁺。

Embodiment 66

N- (5- ((4- (5,6- dihydro -4H- pyrrolo-es [3,2,1-ij] quinoline -1- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (compound 66)

N-(5-((4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

The first step：3- (2- chlorine pyrimidine-4-yl) -7- Methyl-1H-indoles (66B)

3-(2-chloropyrimidin-4-yl)-7-methyl-1H-indole

By 5,6- dihydro -4H- pyrrolo-es [3,2; 1-IJ] quinoline (66A) (0.78g; 5mmol) it is dissolved in 10mL 1,2- dichloroethanes, under nitrogen protection; it is cooled to 0 DEG C; add 2,4- dichloro pyrimidines (0.745g, 5mmol); add alchlor (0.667g 5mmol) react at room temperature 40 minutes, rise to 80 DEG C and react 6 hours.10mL water is added into reaction solution, filtering, filter cake is washed with methanol (3mL × 3), infrared lamp drying obtains yellow solid 3- (2- chlorine pyrimidine-4-yl) -7- Methyl-1H-indoles (66B) (1.0g, yield 75%).

¹H NMR(400MHz,CDCl3)δ8.40(d,1H),7.99(m,2H),7.47(d,1H),7.22(t,1H),7.03(d,1H),4.22(t,2H),3.02(t,2H),2.27(m,2H)。

Second step：4- (5,6- dihydro -4H- pyrrolo-es [3,2,1-ij] quinoline -1- bases)-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) pyrimidine -2- amine (66C)

4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidin-2-amine

By 3- (2- chlorine pyrimidine-4-yl) -7- Methyl-1H-indoles (66B) (0.54g, 2.0mmol) it is dissolved in 8mL 2- amylalcohols, add fluoro- 2- methoxyl groups -5- nitroanilines (the 4e) (0.37g of 4-, 2.0mmol) with p-methyl benzenesulfonic acid monohydrate (0.46g, 2.4mmol), 120 DEG C of back flow reactions are heated to 8 hours.Room temperature is cooled to, 200mL ammoniacal liquor is added, solid, filtering, filter cake 200mL water and 100mL petroleum ethers is separated out.Dry to obtain light yellow solid 4- (5,6- dihydro -4H- pyrrolo-es [3,2,1-ij] quinoline -1- bases)-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) pyrimidine -2- amine (66C) (0.6g, yield 71.6%).

LC-MS(m/z):420.1[M+1]⁺。

¹H NMR(400MHz,CDCl3)δ9.85(d,1H),8.40(d,1H),8.29(s,1H),7.88(d,1H),7.66(s,1H),7.18-7.26(m,1H),7.01(d,1H),6.74(d,1H),4.74(br,1H),4.31(t,2H),4.02(s,3H),3.04(t,2H),2.29(t,2H)。

3rd step：N¹- (4- (5,6- dihydro -4H- pyrrolo-es [3,2,1-ij] quinoline -1- bases) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro benzene -1,4- diamines (66D)

N¹-(4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrimidin-2-yl)-N⁴-(2-(dimethylamino)ethyl)-2-methoxy-N⁴-methyl-5-nitrobenzene-1,4-diamine

By 4- (5,6- dihydro -4H- pyrrolo-es [3,2,1-ij] quinoline -1- bases)-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) pyrimidine -2- amine (66C) (0.6g, 1.43mmol) it is dissolved in 10mL DMAs, adds N, N- diisopropylethylamine (278mg, 2.15mmol) and N, N, N'- trimethyl ethylenediamine (18A) (219mg, 2.15mmol), 130 DEG C of microwave reacts 1.5 hours.Reaction terminates, and reaction solution is concentrated.100mL water and 100mL ethyl acetate are added, point liquid, aqueous phase is extracted with 100mL ethyl acetate, merge organic phase, 100mL saturated common salt water washings, anhydrous sodium sulfate drying, filtering and concentrating obtains red solid N¹- (4- (5,6- dihydro -4H- pyrrolo-es [3,2,1-ij] quinoline -1- bases) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro benzene -1,4- diamines (66D) (716mg).

LC-MS(m/z):502.3[M+1]⁺。

4th step：N⁴- (4- (5,6- dihydro -4H- pyrrolo-es [3,2,1-ij] quinoline -1- bases) pyrimidine -2-base)-N¹- (2- (dimethylamino) Ethyl) -5- methoxyl groups-N¹- methylbenzene -1,2,4- triamines (66E)

N⁴-(4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrimidin-2-yl)-N¹-(2-(dimethylamino)ethyl)-5-methoxy-N¹-methylbenzene-1,2,4-triamine

By N¹- (4- (5,6- dihydro -4H- pyrrolo-es [3,2,1-ij] quinoline -1- bases) pyrimidine -2-base)-N⁴- (2- (dimethylamino) ethyl) -2- methoxyl groups-N⁴- methyl-5-nitro benzene-Isosorbide-5-Nitrae-diamines (66D) (716mg, 1.43mmol) is dissolved in 15mL ethanol, sequentially add 5mL water, iron powder (0.479g, 8.58mmol) and ammonium chloride (53.5mg, 1mmol), 90 DEG C of back flow reactions are warming up to 6 hours.Reaction terminates, and reaction solution is concentrated, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=1:0~10:1) brown solid N, is obtained⁴- (4- (5,6- dihydro -4H- pyrrolo-es [3,2,1-ij] quinoline -1- bases) pyrimidine -2-base)-N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methylbenzene -1,2,4- triamines (66E) (0.43g, yield 63.9%).

LC-MS(m/z):472.4[M+1]⁺。

¹H NMR(400MHz,CDCl3)δ8.32(d,1H),8.17(s,1H),8.12(d,1H),7.87(s,1H),7.67(s,1H),7.23–7.16(m,1H),7.06(d,1H),7.01(d,1H),6.66(s,1H),4.30–4.21(m,2H),3.85(s,3H),3.48(s,2H),3.34(t,2H),3.11–2.99(m,4H),2.83(s,6H),2.72(s,3H),2.34–2.23(m,2H)。

5th step：N- (5- ((4- (5,6- dihydro -4H- pyrrolo-es [3,2,1-ij] quinoline -1- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups-phenyl) acrylamide (compound 66)

By N⁴- (4- (5,6- dihydro -4H- pyrrolo-es [3,2,1-ij] quinoline -1- bases) pyrimidine -2-base)-N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methylbenzene -1,2,4- triamines (66E) (430mg, 0.91mmol) it is dissolved in 15mL pyridines, add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (0.523g, 2.74mmol) and acrylic acid (0.094mL, 1.37mmol), react at room temperature 4 hours.Pyridine is spin-dried for, 100mL dichloromethane and 4mol/L sodium hydrate aqueous solutions (100mL) is added, point liquid, aqueous phase is extracted with 100mL dichloromethane, merges organic phase, is washed with 150mL saturated sodium-chlorides.Organic phase anhydrous sodium sulfate drying, filtering and concentrating, with silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=1:0~10:1), obtain yellow solid N- (5- ((4- (5,6- dihydro -4H- pyrrolo-es [3,2,1-ij] quinoline -1- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups-phenyl) acrylamide (compound 66) (140mg, yield 29.3%).

LC-MS(m/z):526.3[M+1]⁺。

¹H NMR(400MHz,CDCl3)δ10.21(s,1H),9.81(s,1H),9.25(s,1H),8.89(s,1H),8.37(d,1H),7.95(d,1H),7.69(s,1H),7.16(d,1H),7.14–7.08(m,1H),6.80(s,1H),6.51(dd,1H),6.37(s,1H),5.69(d,1H),3.88(d,3H),2.91(s,2H),2.84(s,2H),2.71(s,3H),2.49(s,3H),2.26(s,6H),1.73(s,2H)。

Embodiment 67

N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (spiral shell [cyclopropyl -1,3'- indoles] -1'- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 67)

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(spiro[cyclopropane-1,3'-indolin]-1'-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

The first step：3- (2- ethoxys) indol-2-one (67B)

3-(2-hydroxyethyl)indolin-2-one

By 2- indolones (67A) (5g, 37.6mmol) it is dissolved in 100mL 1.2- ethylene glycol, 200 DEG C are reacted 10 hours in autoclave, reaction terminates, and reaction solution is cooled into room temperature, diatomite filtering, 50mL methanol is washed, most of solvent is removed in rotation, adds 100mL ethyl acetate and 100mL water, point liquid.Aqueous phase is extracted with 100mL ethyl acetate, merges organic phase, with 150mL saturated common salt water washings, anhydrous sodium sulfate drying, is filtered, concentration, obtain yellow oily 3- (2- ethoxys) indol-2-one (67B) (4.5g, yield 68.2%).

LC-MS(m/z):178.1[M+1]⁺。

Second step：Spiral shell [cyclopropyl -1,3'- indoles] -2'- ketone (67C)

spiro[cyclopropane-1,3'-indolin]-2'-one

By 3- (2- ethoxys) indol-2-one (67B) (3g, 16.9mmol) it is dissolved in 60mL dichloromethane, add triethylamine (6.5mL, 46.8mmol), it is cooled to 0 DEG C, mesyl chloride (1.51mL, 82.2mmol) is added dropwise, is warmed to room temperature continuation reaction and stays overnight.Reaction terminates, and adds 100mL water and 60mL dichloromethane, point liquid, aqueous phase 100mL dichloromethane Extraction, merges organic phase, and anhydrous sodium sulfate drying is spin-dried for solvent, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=1:0~20:1) red solid spiral shell [cyclopropyl -1,3'- indoles] -2'- ketone (67C) (1.6g, yield 59.7%), is obtained.

LC-MS(m/z):160.2[M+1]⁺。

3rd step：Spiral shell [cyclopropyl -1,3'- indoles] (67D)

spiro[cyclopropane-1,3'-indoline]

Spiral shell [cyclopropyl -1,3'- indoles] -2'- ketone (67C) is dissolved in 50mL tetrahydrofurans, lithium aluminium hydride reduction (1.25g, 33mmol) is slowly added to, reacted at room temperature 30 minutes, 65 DEG C is risen to and reacts 4 hours.Reaction terminates, and pours into 100mL ice-water baths, and pH to 8 is adjusted with sodium hydrate aqueous solution, adds 100mL ethyl acetate, point liquid.Aqueous phase is extracted with 100mL ethyl acetate, merges organic phase, with 200mL saturated common salt water washings, organic phase anhydrous sodium sulfate drying is spin-dried for solvent, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=1:0~50:1) brown oil spiral shell [cyclopropyl -1,3'- indoles] (67D) (0.8g, yield 55.2%), is obtained.

LC-MS(m/z):146.2[M+1]⁺。

4th step：1'- (2- chlorine pyrimidine-4-yl) spiral shell [cyclopropyl -1,3'- indoles] (67E)

1'-(2-chloropyrimidin-4-yl)spiro[cyclopropane-1,3'-indoline]

Spiral shell [cyclopropyl -1,3'- indoles] (67D) (145.09mg, mmol) is dissolved in 10mL DMSOs, add potassium carbonate (276.4mg, 2mmol) and 2,4- dichloro pyrimidine (149mg, 1mmol), 80 DEG C are risen to react 1.5 hours.Reaction terminates, and adds 100mL water and 100mL ethyl acetate, point liquid.Aqueous phase is extracted with 100mL ethyl acetate, merge organic phase, saturated aqueous common salt (150mL) is washed, anhydrous sodium sulfate drying, it is spin-dried for solvent, obtain yellow solid 1'- (2- chlorine pyrimidine-4-yl) spiral shell [cyclopropyl -1,3'- indoles] (67E) (0.2g, yield 77.8%).

LC-MS(m/z):258.1[M+1]⁺。

5th step：N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (spiral shell [cyclopropyl -1,3'- indoles] -1'- bases) pyrimidine -2- amine (67F)

N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(spiro[cyclopropane-1,3'-indolin]-1'-yl)pyrimidin-2-amine

By 1'- (2- chlorine pyrimidine-4-yl) spiral shell [cyclopropyl -1,3'- indoles] (67E) (1g, 3.89mmol) it is dissolved in 60mL 2- amylalcohols, add fluoro- 2- methoxyl groups -5- nitroanilines (the 4e) (724mg of 4-, 3.89mmol) with p-methyl benzenesulfonic acid (0.887g, 4.67mmol), 130 DEG C of back flow reactions are heated to 6 hours.Reaction terminates, it is spin-dried for solvent, add 150mL water and 150mL ethyl acetate, divide liquid, aqueous phase is extracted with 150mL ethyl acetate, merges organic phase, saturated aqueous common salt (200mL) washing, anhydrous sodium sulfate drying, silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=4:1~methylene chloride/methanol=10:1) brown solid N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (spiral shell [cyclopropyl -1,3'- indoles] -1'- bases) pyrimidine -2- amine (67F) (1.2g, yield 95.2%), is obtained.

LC-MS(m/z):408.3[M+1]⁺。

6th step：N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl -2- nitros-N⁴- (4- (spiral shell [cyclopropyl -1,3'- indoles] -1'- bases) pyrimidine -2-base) benzene -1,4- diamines (67G)

N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-2-nitro-N4-(4-(spiro[cyclopropane-1,3'-indolin]-1'-yl)pyrimidin-2-yl)benzene-1,4-diamine

By N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) -4- (spiral shell [cyclopropyl -1,3'- indoles] -1'- bases) pyrimidine -2- amine (67F) (1.2g, 2.95mmol) it is dissolved in 5mL DMAs, adds N, N- diisopropylethylamine (0.571g, 4.42mmol) and N, N, N'- trimethyl ethylenediamine (18A) (452mg, 4.42mmol), 130 DEG C of microwave reacts 1.5 hours.Reaction terminates, and adds 150mL water and 150mL dichloromethane, point liquid.Aqueous phase is extracted with 150mL dichloromethane, merges organic phase, and saturated aqueous common salt (200mL) washing, anhydrous sodium sulfate drying is concentrated to give brown solid N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl -2- nitros-N⁴- (4- (spiral shell [cyclopropyl -1,3'- indoles] -1'- bases) pyrimidine -2-base) benzene-Isosorbide-5-Nitrae-diamines (67G) (1.2g, yield 85.7%).

LC-MS(m/z):490.3[M+1]⁺。

7th step：N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl-N⁴- (4- (spiral shell [cyclopropyl -1,3'- indoles] -1'- bases) pyrimidine -2-base) benzene -1,2,4-, triamine (67H)

N¹-(2-(dimethylamino)ethyl)-5-methoxy-N¹-methyl-N⁴-(4-(spiro[cyclopropane-1,3'-indolin]-1'-yl)pyrimidin-2-yl)benzene-1,2,4-triamine

By N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl -2- nitros-N⁴- (4- (spiral shell [cyclopropyl -1,3'- indoles] -1'- bases) pyrimidine -2-base) benzene -1,4- diamines (67G) (1.2g, 2.45mmol) it is dissolved in 24mL ethanol, sequentially add 8mL water, iron powder (0.822g, 14.7mmol) and ammonium chloride (92mg, 1.7mmol), 90 DEG C of back flow reactions are warming up to 4 hours.Reaction solution is concentrated, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=1:0~10:1) brown solid N, is obtained¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl-N⁴- (4- (spiral shell [cyclopropyl -1,3'- indoles] -1'- bases) pyrimidine -2-base) benzene -1,2,4-, triamine (67H) (440mg, yield 40%).

LC-MS(m/z):460.4[M+1]⁺。

8th step：N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (spiral shell [cyclopropyl -1,3'- indoles] -1'- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 67)

By N¹- (2- (dimethylamino) ethyl) -5- methoxyl groups-N¹- methyl-N⁴- (4- (spiral shell [cyclopropyl -1,3'- indoles] -1'- bases) pyrimidine -2-base) benzene -1,2,4-, triamine (67H) (0.44g, 0.96mmol) is dissolved in 15mL pyridines, sequentially add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (0.55g, 2.88mmol) with acrylic acid (0.1mL, 1.44mmol), react at room temperature 4 hours.Pyridine is spin-dried for, 4mol/L sodium hydrate aqueous solutions (100mL) and 100mL dichloromethane is added, point liquid, Aqueous phase is extracted with dichloromethane (100mL), merges organic phase, saturated sodium-chloride water solution (100mL) washing, anhydrous sodium sulfate drying, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=1:0~10:1), obtain yellow solid N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (spiral shell [cyclopropyl -1,3'- indoles] -1'- bases) pyrimidine -2-base) amino) phenyl) acrylamide (compound 67) (100mg, yield 20.3%).

LC-MS(m/z):514.3[M+1]⁺。

¹H NMR(400MHz,CDCl3)δ9.97(s,1H),9.45(s,1H),8.16(d,1H),7.80(s,1H),7.45(s,1H),7.16–7.07(m,1H),6.89(t,1H),6.77(s,1H),6.70–6.65(m,1H),6.43(s,1H),6.37(d,2H),5.71–5.62(m,1H),4.33(s,2H),3.87(s,3H),2.91(s,2H),2.70(s,3H),2.29(s,6H),1.58(s,4H)。

Embodiment 68

N- (5- ((4- (6- cyano group -1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (compound 68)

N-(5-((4-(6-cyano-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

The first step：1- Methyl-1H-indole -6- formonitrile HCNs (68B)

1-methyl-1H-indole-6-carbonitrile

6- cyano-indols (68A) (5g, 35.17mmol) are dissolved in 30mL tetrahydrofurans, sodium hydride (1.69g is slowly added to, 70.34mmol), react at room temperature 20 minutes, add iodomethane (14.97g, 105.5mmol), react at room temperature 3 hours.Reaction terminates, and adds 100mL water quenchings and goes out reaction.Most of solvent is removed, 100mL ethyl acetate and 100mL water is added, point liquid.Aqueous phase is extracted with 100mL ethyl acetate, merges organic phase, and saturated aqueous common salt (150mL) washing is anhydrous Sodium sulphate is dried, concentration, obtains yellow solid 1- Methyl-1H-indole -6- formonitrile HCNs (68B) (5.4g).

Second step：3- (2- chlorine pyrimidine-4-yl) -1- Methyl-1H-indole -6- formonitrile HCNs (68C)

3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole-6-carbonitrile

1- Methyl-1H-indole -6- formonitrile HCNs (68B) (5.4g, 34.6mmol) are dissolved in 40mL glycol dimethyl ethers, 2 are added, 4- dichloro pyrimidines (5.15g, 34.6mmol) with alchlor (4.61g, 34.6mmol), rise to 80 DEG C and react 4 hours.Reaction terminates, and adds 100mL water, separates out solid, and filtering, 150mL water washing filter cakes, infrared lamp drying obtains yellow solid 3- (2- chlorine pyrimidine-4-yl) -1- Methyl-1H-indole -6- formonitrile HCNs (68C) (9g, yield 97.8%).

LC-MS(m/z):269.1[M+1]⁺。

3rd step：3- (2- ((the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) amino) pyrimidine-4-yl) -1- Methyl-1H-indole -6- formonitrile HCNs (68D)

3-(2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-6-carbonitrile

By 3- (2- chlorine pyrimidine-4-yl) -1- Methyl-1H-indole -6- formonitrile HCNs (68C) (8g, 29.8mmol) it is dissolved in 150mL2- amylalcohols, add fluoro- 2- methoxyl groups -5- nitroanilines (the 4e) (5.55g of 4-, 29.8mmol) with p-methyl benzenesulfonic acid monohydrate (6.82g, 35.9mmol), 120 DEG C of back flow reactions are heated to 2 days.Room temperature is cooled to, 200mL ammoniacal liquor is added, solid, filtering, filter cake 200mL water and 100mL petroleum ethers is separated out.Dry to obtain brown solid 3- (2- ((the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) amino) pyrimidine-4-yl) -1- Methyl-1H-indole -6- formonitrile HCNs (68D) (10g, yield 80.6%).

LC-MS(m/z):419.0[M+1]⁺。

4th step：3- (2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenones) amino) pyrimidine-4-yl) -1- Methyl-1H-indole -6- formonitrile HCNs (68E)

3-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-6-carbonitrile

By 3- (2- ((the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) amino) pyrimidine-4-yl) -1- Methyl-1H-indole -6- formonitrile HCNs (68D) (10g, 23.9mmol) it is dissolved in 60mL N, in N- dimethyl acetamides, add DIPEA (4.64g, 35.87mmol) and N, N, N'- trimethyls ethylenediamine (18A) (3.67g, 35.87mmol), 130 DEG C of microwave reacts 1.5 hours.Reaction terminates, concentration.Add 200mL water and 200mL ethyl acetate, divide liquid, aqueous phase is extracted with 200mL ethyl acetate, merge organic phase, saturated aqueous common salt (400mL) is washed, anhydrous sodium sulfate drying, it is concentrated to give yellow solid 3- (2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenones) amino) pyrimidine-4-yl) -1- Methyl-1H-indole -6- formonitrile HCNs (68E) (10g, yield 84%).

LC-MS(m/z):501.1[M+1]⁺。

5th step：3- (2- ((5- amino -4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) amino) pyrimidine-4-yl) -1- Methyl-1H-indole -6- formonitrile HCNs (68F)

3-(2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-6-carbonitrile

By 3- (2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl group -5- nitrobenzophenones) amino) pyrimidine-4-yl) -1- Methyl-1H-indole -6- formonitrile HCNs (68E) (11g, 22mmol) it is dissolved in 100mL ethanol, sequentially add 33mL water, iron powder (7.37g, 132mmol) with ammonium chloride (824mg, 15.4mmol), 90 DEG C of back flow reactions are warming up to 6 hours.Reaction terminates, and reaction solution is concentrated, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=1:0~10:1), obtain brown solid 3- (2- ((5- amino -4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) amino) pyrimidine-4-yl) -1- Methyl-1H-indole -6- formonitrile HCNs (68F) (6g, yield 58.3%).

LC-MS(m/z):471.1[M+1]⁺。

6th step：N- (5- ((4- (6- cyano group -1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (compound 68)

By 3- (2- ((5- amino -4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyls) amino) pyrimidine-4-yl) -1- Methyl-1H-indole -6- formonitrile HCNs (68F) (6g, 12.7mmol) it is dissolved in 50mL pyridines, add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (7.3g, 38.2mmol) with acrylic acid (1.3mL, 19.1mmol), react at room temperature 4 hours.Pyridine is spin-dried for, 200mL dichloromethane and 4mol/L sodium hydrate aqueous solutions (200mL) is added, point liquid.Aqueous phase is extracted with 200mL dichloromethane, merges organic phase, saturated sodium-chloride (400mL) washing, anhydrous sodium sulfate drying, silica gel column chromatography separating-purifying (methylene chloride/methanol (v/v)=1:0~10:1), obtain yellow solid N- (5- ((4- (6- cyano group -1- Methyl-1H-indole -3- bases) pyrimidine -2-base) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyphenyls) acrylamide (compound 68) (1.2g, yield 18.2%).

LC-MS(m/z):525.2[M+1]⁺。

Embodiment 69

N- (5- ((4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyl groups -2- (2- morpholines base oxethyl) phenyl) acrylamide (compound 69)

N-(5-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(2-morpholinoethoxy)phenyl)acrylamide

The first step：4- (1- (difluoromethyl) -1H- indol-3-yls)-N- (2- methoxyl groups -4- (2- morpholines ethyoxyl) -5- nitrobenzophenones) pyrimidine -2- amine (69A)

4-(1-(difluoromethyl)-1H-indol-3-yl)-N-(2-methoxy-4-(2-morpholinoethoxy)-5-nitrophenyl)pyrimidin-2-amine

By 4- (1- (difluoromethyl) -1H- indol-3-yls)-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) pyrimidine -2- amine (30B) (1g, 2.33mmol) it is dissolved in 30mL tetrahydrofurans, it is slowly added to sodium hydride (112mg, 4.66mmol), stirring 30 minutes, 2- morpholine ethanols (611mg, 4.66mmol) are added, are reacted at room temperature 4 hours.Reaction terminates, and adds 150mL water and 150mL dichloromethane, point liquid.Organic phase anhydrous sodium sulfate drying, filtering, it is concentrated to give yellow solid 4- (1- (difluoromethyl) -1H- indol-3-yls)-N- (2- methoxyl groups -4- (2- morpholines ethyoxyl) -5- nitrobenzophenones) pyrimidine -2- amine (69A) (1.1g, yield 88%).

LC-MS(m/z):541.3[M+1]⁺。

Second step：N¹- (4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) -6- methoxyl groups -4- (2- morpholines base oxethyl) benzene -1,3- diamines (69B)

N¹-(4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-(2-morpholinoethoxy)benzene-1,3-diamine

By 4- (1- (difluoromethyl) -1H- indol-3-yls)-N- (2- methoxyl groups -4- (2- morpholines ethyoxyl) -5- nitrobenzophenones) pyrimidine -2- amine (69A) (1.1g, 2.03mmol) it is dissolved in addition 10mL water in 30mL ethanol, add iron powder (682mg, 12.2mmol) with ammonium chloride (76mg, 1.42mmol), it is warming up to 90 DEG C, back flow reaction 4h, concentration.With silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1) brown solid N, is obtained¹- (4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) -6- methoxyl groups -4- (2- morpholines base oxethyl) benzene -1,3- diamines (69B) (1g, yield 97.1%).

3rd step：N- (5- ((4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyl groups -2- (2- morpholines base oxethyl) phenyl) acrylamide (compound 69)

By N¹- (4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) -6- methoxyl groups -4- (2- morpholines base oxethyl) benzene - 1,3- diamines (69B) (1g, 1.96mmol) it is dissolved in 30mL pyridines, add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (1.12g, 5.88mmol), acrylic acid (0.202mL, 2.94mmol), is reacted at room temperature 4 hours.Pyridine in reaction solution is spin-dried for, 150mL water and 150mL dichloromethane is added, point liquid.Organic phase is washed with 4mol/L sodium hydrate aqueous solutions (100mL), anhydrous sodium sulfate drying, is filtered, concentration, silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain white solid N- (5- ((4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyl groups -2- (2- morpholines base oxethyl) phenyl) acrylamide (compound 69) (400mg, yield 36.4%).

LC-MS(m/z):565.3[M+1]⁺。

Embodiment 70

N- (2- ((1- amino cyclopropyl) methoxyl group) -5- ((4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 70)

N-(2-((1-aminocyclopropyl)methoxy)-5-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

The first step：(1- ((4- ((4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -5- methoxyl group -2- nitro-phenoxies) methyl) cyclopropyl) carbamate (70A)

tert-butyl(1-((4-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenoxy)methyl)cyclopropyl)carbamate

By 4- (1- (difluoromethyl) -1H- indol-3-yls)-N- (the fluoro- 2- methoxyl groups -5- nitrobenzophenones of 4-) pyrimidine -2- amine (30B) (1g, 2.33mmol) it is dissolved in 30mL tetrahydrofurans, it is slowly added to sodium hydride (112mg, 4.66mmol), stirring 30 minutes (1- methylols cyclopropyl)-t-butoxycarbonyl amino (873mg, 4.66mmol) is added, is reacted at room temperature 4 hours.Reaction terminates, and adds 150mL water and 150mL dichloromethane, point liquid.Organic phase anhydrous sodium sulfate drying, filtering, it is concentrated to give yellow solid (1- ((4- ((4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -5- methoxyl group -2- nitro-phenoxies) methyl) cyclopropyl) carbamate (70A) (1g, yield 72.5%).

LC-MS(m/z):597.3[M+1]⁺。

Second step：(1- ((2- amino -4- ((4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -5- methoxyphenyls) methyl) cyclopropyl) carbamate (70B)

tert-butyl(1-((2-amino-4-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxyphenoxy)methyl)cyclopropyl)carbamate

By (1- ((4- ((4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -5- methoxyl group -2- nitro-phenoxies) methyl) cyclopropyl) carbamate (70A) (1g, 1.68mmol) it is dissolved in 30mL ethanol, add 10mL water, iron powder (562mg, 10mmol) with ammonium chloride (63mg, 1.2mmol), 90 DEG C of back flow reactions are warming up to 4 hours.Reaction solution is concentrated, silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1) brown solid (1- ((2- amino -4- ((4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -5- methoxyphenyls) methyl) cyclopropyl) carbamate (70B) (951mg), is obtained.

LC-MS(m/z):567.3[M+1]⁺。

3rd step：(1- ((2- acrylamidos -4- ((4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -5- methoxyphenyls) methyl) cyclopropyl) carbamate (70C)

tert-butyl(1-((2-acrylamido-4-((4-(1-(difluoromethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxyphenoxy)methyl)cyclopropyl)carbamate

By (1- ((2- amino -4- ((4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -5- methoxyphenyls) methyl) cyclopropyl) carbamate (70B) (951mg, 1.68mmol) it is dissolved in 30mL pyridines, add 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (963mg, 5.04mmol) with acrylic acid (0.173mL, 2.52mmol), react at room temperature 4 hours.Pyridine in reaction solution is spin-dried for, 150mL water and 150mL dichloromethane is added, point liquid.Organic phase is washed with 4mol/L sodium hydrate aqueous solutions (100mL), anhydrous sodium sulfate drying, is filtered, concentration, silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain yellow solid (1- ((2- acrylamidos -4- ((4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -5- methoxyphenyls) methyl) cyclopropyl) carbamate (70C) (800mg, yield 76.9%).

LC-MS(m/z):621.3[M+1]⁺。

4th step：N- (2- ((1- amino cyclopropyl) methoxyl group) -5- ((4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 70)

By (1- ((2- acrylamidos -4- ((4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -5- methoxyphenyls) methyl) cyclopropyl) carbamate (70C) (0.8g, 1.29mmol) it is dissolved in 50mL dichloromethane, 20mL trifluoroacetic acids are added, are reacted at room temperature 4 hours.Most of solvent is removed in rotation, adds 100mL water, with saturated sodium bicarbonate aqueous solution bar pH value to 8, adds 150mL dichloromethane, point liquid.Aqueous phase is extracted with 100mL dichloromethane, is merged organic phase, is washed with 150mL saturated sodium-chloride water solutions.Organic phase anhydrous sodium sulfate drying, is filtered, concentration, silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=1:0~10:1), obtain white solid N- (2- ((1- amino cyclopropyl) methoxyl group) -5- ((4- (1- (difluoromethyl) -1H- indol-3-yls) pyrimidine -2-base) amino) -4- methoxyphenyls) acrylamide (compound 70) (370mg, yield 55.1%).

LC-MS(m/z):521.2[M+1]⁺。

¹H NMR(400MHz,CDCl₃)δ9.75(s,1H),9.37(s,1H),8.78(s,1H),8.44(d,1H),8.05(dd,1H),7.82–7.75(m,1H),7.69(s,1H),7.35(dd,2H),7.22(d,1H),6.60(s,1H),6.40(d,2H),5.77(t,1H),1.26(s,3H),0.88(s,2H),0.74(d,2H),0.68(t,2H)。

Test case 1：Growth of cancer cells is tested to suppress

Continuous passage tumour cell is suspended from after culture medium, counting and planted into 96 porocyte culture plates through Trypsin Induced.Non-small cell lung cancer cell NCI-H1975 is per 10000, hole cell, and human epithelial cells cancer cell A431 cell lines are per 10000, hole cell, in 37 DEG C, 5%CO₂In incubator, overnight incubation.Second day every kind of cell takes 6 holes to add 30 μ l50% trichloroacetic acids and fixed；Remaining each hole is separately added into compound to be tested.Testing compound is configured to solution with DMSO, 10 μM of maximum concentration, as follows 5 times of dilutions, 10 concentration to be measured.It is to be measured with the culture medium gradient dilution containing 0.1%FBS for NCI-H1975, A431 cell line, and it is 2 times of final concentration.The 96 porocyte culture plates culture mediums for planting NCI-H1975, A431 cell are changed to the fresh culture medium (per hole 100ul) containing 0.1%FBS, testing compounds of the 100ul containing 2 times of final concentrations is added.Each 96 porocyte culture plates are in 37 DEG C, 5%CO₂Cell culture incubator is incubated 72 hours.Then the trichloroacetic acids of 50 μ l 50% are added per hole, is placed in 4 DEG C of refrigerators and fixes 1 hour.

Trichloroacetic acid in each hole is discarded, washed 5 times with 300 μ l distilled waters.After drying at room temperature, 50 μ l 0.4%SRB (Sulforhodamine-B) dye solutions (1% acetic acid/0.4%SRB) are added per hole, 15min is reacted.The dye solution in each hole is discarded, is washed 6-7 times with 1% acetic acid, drying at room temperature.Each hole adds 200 μ l 10mM Tris solution (pH=10.5), vibration dissolving.Each hole 490nm absorbances are determined with ELIASA.It is control by the reading in 0 hole of testing compound concentration, half effect inhibition concentration (IC of testing compound is calculated and analyzed using origin7.5₅₀)。

Experiment of the anti-tumour cell proliferative activity of the compounds of this invention more than is measured, the IC measured₅₀Value is shown in Table 1.

The anti-tumour cell proliferative activity result of the test of table 1

Conclusion：The compounds of this invention has the growth inhibitory activity of significant growth inhibition effect, particularly compound 20, compound 33 etc. equal to non-small cell lung cancer cell NCI-H1975<1nM.The compounds of this invention have obvious selectivity, particularly compound 16,27,30,38,40,46,47 etc. to be had a surplus to 100 times of human epithelial cells cancer cell A431 growth inhibitory activities to non-small cell lung cancer cell NCI-H1975 growth inhibitory activities to non-small cell lung cancer cell NCI-H1975.

Claims

Compound and its optical isomer, pharmaceutically acceptable salt or eutectic shown in a kind of logical formula (I), wherein：

B is selected from 6 to 15 circle heterocycles, and described heterocycle contains 1 to 4 hetero atom for being selected from N, O, S or P；

R¹It is independently selected from F, Cl, Br, I, hydroxyl, cyano group, C_1-10Alkyl, C_1-10Alkoxy ,-NR^1aR^1b,-C (=O) C_1-10Alkyl ,-S (=O)₂-C_1-10Alkyl, the circle heterocycles of-C (=O) -3 to 15,-C (=O)-C_3-15Carbocyclic ring ,-(CH₂)_n- 3 to 15 circle heterocycles ,-(CH₂)_n-C_3-15Carbocyclic ring ,-O- (CH₂)_n-C_3-15Carbocyclic ring ,-O- (CH₂)_n- 3 to 15 circle heterocycles ,-O- (CH₂)_n- C (=O) C_1-6Alkyl ,-O- (CH₂)_n- O-C (=O) C_1-6Alkyl or-O- (CH₂)_n-O-C_1-10Alkyl, described CH₂, alkyl, alkoxy, carbocyclic ring or heterocycle be optionally further selected from F, Cl, Br, I ,=O, hydroxyl, amino, cyano group, nitro, C by 0 to 5_1-6Alkyl, C_1-6Alkoxy ,-(CH₂)_n-OH、-(CH₂)_n- F ,-C (=O) C_1-6Alkoxy ,-C (=O) C_1-6Alkyl ,-C (=O) C_3-15Carbocyclic ring ,-O-C (=O) C_1-6Alkyl ,-(CH₂)_n-C_3-10Carbocyclic ring or-(CH₂)_nThe substituent of -3 to 10 circle heterocycles is replaced, and the heterocycle contains 1 to 4 hetero atom for being selected from N, O, S or P；

R^1aAnd R^1bSelected from H or C_1-10Alkyl；

R²Selected from H, F, Cl, Br, I, cyano group, C_1-10Alkyl or C_1-10Alkoxy, described alkyl or alkoxy are optionally further selected from F, Cl, Br, I, C by 0 to 4_1-6Alkyl or C_1-6The substituent of alkoxy is replaced；

R³Selected from H, C_2-10Alkenyl, C_3-15Cycloalkyl, C_1-10Alkyl or C_1-10Alkoxy, the alkenyl, cycloalkyl, alkyl or alkoxy optionally further 0 to 4 is selected from F, Cl, Br, I, C_1-6Alkyl or C_1-6The substituent of alkoxy is replaced；

R⁴Selected from H, F, Cl, Br, I, nitro, amino, C_1-10Alkyl, 5 to 15 yuan of loop coils, 4 to 15 yuan and ring, 3 to 10 circle heterocycles ,-NR^4cR^4d、-Z-(CH₂)_nR^4a、-O-(CH₂)_nR^4b、-Z-(CH₂)_nNR^4cR^4dOr-O- (CH₂)_nNR^4cR^4d, the CH₂, loop coil and ring or heterocycle be optionally further selected from F, Cl, Br, I, hydroxyl, amino, C by 0 to 4_1-6Alkyl, C_1-6Alkoxy ,-(CH₂)_n- C (=O)-R^4e、-(CH₂)_n- O-C (=O)-R^4e、-NR^4cR^4d, by 0 to 4 R^4cSubstituted C_3-10Carbocyclic ring or by 0 to 4 R^4cThe substituent of 3 to 10 circle heterocycles of substitution is replaced, and the heterocycle contains 1 to 4 hetero atom for being selected from N, O or S；

Z is selected from-NH- or-N (C_1-6Alkyl)-；

R^4aSelected from C_3-15Carbocyclic ring or 3 to 15 circle heterocycles, the heterocycle contain 1 to 4 miscellaneous original for being selected from N, O or S Son, the carbocyclic ring or heterocycle are optionally further selected from F, Cl, Br, I, amino, hydroxyl, C by 0 to 4_1-6Alkoxy, C_1-6Alkyl or by 1 to 2 C_1-6The substituent of alkyl-substituted amino is replaced；

R^4bSelected from-C (=O) C_1-6Alkyl ,-O-C (=O) C_1-6Alkyl, C_1-10Alkoxy, C_3-15Carbocyclic ring or 3 to 15 circle heterocycles, the alkyl, alkoxy, carbocyclic ring or heterocycle are optionally further selected from F, Cl, Br, I, amino ,-NR by 0 to 4^4cR^4d, hydroxyl, C_1-6Alkyl, C_1-6The C of alkoxy or halogen substitution_1-6The substituent of alkyl is replaced, and the heterocycle contains 1 to 4 hetero atom for being selected from N, O or S；

R^4cAnd R^4dSelected from H, C_1-10Alkyl ,-C (=O) C_1-6Alkyl or-C (=O) C_1-6Alkoxy；

R^4eSelected from amino, hydroxyl, C_1-10Alkyl, C_3-15Carbocyclic ring or 3 to 15 circle heterocycles, the amino, alkyl, carbocyclic ring or heterocycle are optionally further selected from F, Cl, Br, I, amino, hydroxyl, C by 0 to 4_1-6Alkyl, C_1-6Alkoxy ,-C (=O) C_1-6Alkyl ,-C (=O)-NH₂,-O-C (=O) C_1-6Alkyl or the C of halogen substitution_1-6The substituent of alkyl is replaced, and the heterocycle contains 1 to 4 hetero atom for being selected from N, O or S；

R⁵Selected from H, F, Cl, Br, I or 5 to 15 circle heterocycles, the heterocycle contains 1 to 4 hetero atom for being selected from N, O or S, and described heterocycle is optionally further selected from F, Cl, Br, I ,=O ,-C (=O) C by 0 to 4_1-6Alkyl, C_1-6Alkyl or C_1-6The substituent of alkoxy is replaced；

F is selected from 0,1,2,3,4,5 or 6；

N is selected from 0,1,2 or 3；

Condition is, as-B- (R¹)_fIt is selected fromAnd R²Selected from H, F, Cl, methyl or cyano group, R³Selected from H, methoxyl group or methyl, f is 1, R⁵During for H, R⁴Be not H,
Compound and its optical isomer, pharmaceutically acceptable salt or eutectic according to claim 1, wherein：

B is selected from 6 to 15 circle heterocycles, and described heterocycle contains 1 to 4 hetero atom for being selected from N, O or S；

R¹It is independently selected from F, Cl, Br, I, hydroxyl, cyano group, C_1-4Alkyl, C_1-4Alkoxy ,-NR^1aR^1b _、- C (=O) C_1-4Alkyl ,-S (=O)₂-C_1-4Alkyl, the circle heterocycles of-C (=O) -3 to 7,-C (=O)-C_3-7Carbocyclic ring ,-(CH₂)_n-C_3-6Carbocyclic ring or-(CH₂)_n- 3 to 7 circle heterocycles, described CH₂, alkyl, alkoxy, carbocyclic ring or heterocycle be optionally further by 0 to 4 Selected from F, Cl, Br, I ,=O, hydroxyl, C_1-4Alkyl, C_1-4Alkoxy ,-(CH₂)_n-OH、-(CH₂)_n- F ,-C (=O) C_1-4Alkoxy ,-C (=O) C_3-6Carbocyclic ring ,-C (=O) C_1-4Alkyl ,-(CH₂)_n-C_3-6Carbocyclic ring or-(CH₂)_n- 3 to 6 circle heterocycles substituents are replaced, and the heterocycle contains 1 to 4 hetero atom for being selected from N, O or S；

R^1aAnd R^1bSelected from H or C_1-4Alkyl；

R²Selected from H, F, Cl, Br, I, cyano group, C_1-4Alkyl or C_1-4Alkoxy, described alkyl or alkoxy are optionally further selected from F, Cl, Br, I, C by 0 to 4_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

R³Selected from H, C_2-6Alkenyl, C_3-6Cycloalkyl, C_1-4Alkyl or C_1-4Alkoxy, the alkenyl, cycloalkyl, alkyl or alkoxy optionally further 0 to 4 is selected from F, Cl, Br, I, C_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

R⁴Selected from H, F, Cl, Br, I, 5 to 15 yuan of loop coils, 4 to 15 yuan and ring, 3 to 10 circle heterocycles ,-Z- (CH₂)_nR^4a、-O-(CH₂)_nR^4b、-Z-(CH₂)_nNR^4cR^4dOr-O- (CH₂)_nNR^4cR^4d, the heterocycle contain 1 to 4 be selected from N, O or S hetero atom, the CH₂, loop coil and ring or heterocycle be optionally further selected from F, Cl, Br, I, amino, hydroxyl, C by 0 to 4_1-4Alkyl ,-NR^4cR^4d,-C (=O)-R^4eOr C_1-4The substituent of alkoxy is replaced；

Z is selected from-NH- or-N (C_1-4Alkyl)-；

R^4aSelected from C_3-6Carbocyclic ring or 3 to 7 circle heterocycles, the heterocycle contain 1 to 4 hetero atom for being selected from N, O or S, and the carbocyclic ring or heterocycle are optionally further selected from F, Cl, Br, I, amino, hydroxyl, C by 0 to 4_1-4Alkyl, by 1 to 2 C_1-4The substituent of alkyl-substituted amino is replaced；

R^4bSelected from C_3-6Carbocyclic ring or 3 to 7 circle heterocycles, the heterocycle contain 1 to 4 hetero atom for being selected from N, O, S, and the carbocyclic ring or heterocycle are optionally further selected from F, Cl, Br, I, amino, hydroxyl ,-NR by 0 to 4^4cR^4d、C_1-4Alkyl or the C replaced by 1 to 2 halogen_1-4The substituent of alkyl is replaced；

R^4cAnd R^4dSelected from H or C_1-4Alkyl；

R^4eSelected from amino, hydroxyl, C_1-4Alkyl, C_3-6Carbocyclic ring or 3 to 7 circle heterocycles, the amino, alkyl, carbocyclic ring or heterocycle are optionally further selected from F, Cl, Br, I, amino, hydroxyl, C by 0 to 4_1-4Alkyl, C_1-4The C of alkoxy or halogen substitution_1-4The substituent of alkyl is replaced, and the heterocycle contains 1 to 4 hetero atom for being selected from N, O or S；

R⁵Selected from H, F, Cl, Br, I or 5 to 6 circle heterocycles, the heterocycle contains 1 to 4 hetero atom for being selected from N, O, S, and described heterocycle is optionally further selected from F, Cl, Br, I ,=O ,-C (=O) C by 0 to 4_1-4Alkyl, C_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

F is selected from 0,1,2,3 or 4；

N is each independently selected from 0,1,2 or 3.
Compound and its optical isomer, pharmaceutically acceptable salt or eutectic according to claim 2, wherein：

B is selected from 8 to 13 circle heterocycles, and the heterocycle contains 1 to 4 hetero atom for being selected from N, O or S；

R¹It is independently selected from F, Cl, Br, I, hydroxyl, cyano group ,-S (=O)₂-C_1-4Alkyl, C_1-4Alkyl ,-C (=O)-C_3-6Carbocyclic ring ,-(CH₂)_n-C_3-6Carbocyclic ring or-(CH₂)_n- 5 to 6 circle heterocycles, described CH₂, alkyl, carbocyclic ring or heterocycle be optionally further selected from F, Cl, Br, I ,=O, hydroxyl, C by 0 to 4_1-4Alkyl, C_1-4Alkoxy ,-CH₂- cyclopropyl, tertbutyloxycarbonyl ,-(CH₂)_n-OH、-(CH₂)_n- F ,-C (=O) C_1-4Alkyl ,-(CH₂)_n-C_3-6Carbocyclic ring or-(CH₂)_nThe substituent of -3 to 6 circle heterocycles is replaced, and the heterocycle contains 1 to 4 hetero atom for being selected from N, O or S；

R²Selected from H, F, Cl, C_1-4Alkyl or C_1-4Alkoxy；

R³For H, C_2-4Alkenyl, C_3-4Cycloalkyl, C_1-4Alkyl or C_1-4Alkoxy, the alkoxy optionally further 0 to 4 substituent for being selected from F, Cl or Br is replaced；

R⁴Selected from H, F, Cl, 7 to 11 yuan of loop coils, 6 to 10 yuan and ring, 3 to 6 circle heterocycles ,-Z- (CH₂)_nR^4a、-Z-(CH₂)_nNR^4cR^4d、-O-(CH₂)_nR^4bOr-O- (CH₂)_nNR^4cR^4d, the heterocycle contain 1 to 4 be selected from N, O or S hetero atom, the CH₂, loop coil and ring or heterocycle be optionally further selected from F, Cl, Br, I, amino ,-NH (CH by 0 to 4₃)、-N(CH₃)₂, methyl or ethyl substituent replaced；

Z is selected from-NH- or-N (C_1-4Alkyl)-；

R^4aSelected from C_3-4Carbocyclic ring or 5 circle heterocycles, the heterocycle contain 1 to 4 hetero atom for being selected from N, O, S, and the carbocyclic ring or heterocycle are optionally further selected from F, Cl, Br, I, amino, hydroxyl ,-NHCH by 0 to 4₃、-N(CH₃)₂, methyl or ethyl substituent taken；

R^4bSelected from C_3-4Carbocyclic ring or 4 to 6 circle heterocycles, the heterocycle contain 1 to 4 hetero atom for being selected from N, O, S, and the carbocyclic ring or heterocycle are optionally further selected from F, Cl, Br, I, amino, hydroxyl ,-NH (CH by 0 to 4₃)、-N(CH₃)₂、-CH₂CH₂F, methyl or ethyl substituent are replaced；

R^4cAnd R^4dSelected from H, methyl or ethyl；

R⁵Selected from H, F, Cl or 5 to 6 circle heterocycles, the heterocycle contains 1 to 4 hetero atom for being selected from N, O, S, and described heterocycle is optionally further selected from F, Cl, Br, I ,=O ,-C (=O) C by 0 to 4_1-4Alkyl, C_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

N is selected from 0,1,2 or 3.
Compound and its optical isomer, pharmaceutically acceptable salt or eutectic according to claim 3, wherein：

B is selected from

R¹It is independently selected from F, Cl, Br, I ,-S (=O)₂CH₃,-C (=O)-cyclopropyl, hydroxyl, cyano group, methyl, ethyl, isopropyl, cyclopropyl ,-CH₂- cyclopropyl ,-CH (CH₃)-cyclopropyl, morpholinyl, piperazinyl, piperidyl or nafoxidine base, described methyl, ethyl, morpholinyl, piperazinyl, piperidyl or nafoxidine base are optionally further selected from F, Cl, Br, I ,=O, hydroxyl, methyl, ethyl, methoxyl group, isopropyl, cyclopropyl ,-CH by 0 to 4₂- cyclopropyl, ethoxy, 2- fluoro ethyls, tertbutyloxycarbonyl, oxetanylmethoxy ,-C (=O) CH₃Or-C (=O) CH₂CH₃Substituent replaced；

R²Selected from H, F, Cl, methyl or methoxy；

R³Selected from H, methyl, ethyl, vinyl, cyclopropyl, methoxyl group, fluoro-methoxy, difluoro-methoxy or trifluoromethoxy；

R⁴Selected from H, F, Cl, 7 to 11 yuan of loop coils, 3 to 6 circle heterocycles ,-Z- (CH₂)_nR^4a、-O-(CH₂)_nR^4b、-Z-(CH₂)_nNR^4cR^4dOr-O- (CH₂)_nNR^4cR^4d, the heterocycle contain 1 to 4 be selected from N, O or S hetero atom, the CH₂, loop coil or heterocycle be optionally further selected from F, Cl, Br, I, methyl, ethyl or-N (CH by 0 to 4₃)₂Substituent replaced；

Z is selected from-NH- or-N (CH₃)-；

R^4aSelected from substituted or unsubstituted cyclopropyl or nafoxidine base, when substituted, optionally further F, Cl, Br, I, amino, hydroxyl ,-NHCH are selected from by 1 to 4₃、-N(CH₃)₂, methyl or ethyl substituent replaced；

R^4bSelected from substituted or unsubstituted cyclopropyl,Nafoxidine base, piperazinyl, piperidyl or morpholinyl, when substituted, are optionally further selected from F, Cl, Br, I, amino, hydroxyl ,-NHCH by 1 to 4₃、-N(CH₃)₂、-CH₂CH₂F, methyl or ethyl substituent are replaced；

R^4cAnd R^4dSelected from H, methyl or ethyl；

R⁵Selected from H, F, Cl or morpholinyl；

N is selected from 0,1,2 or 3.
Compound and its optical isomer, pharmaceutically acceptable salt or eutectic according to claim 4, wherein：

B is selected from

R¹It is independently selected from F, Cl ,-S (=O)₂CH₃, hydroxyl, cyano group, methyl, difluoromethyl, ethyl, -CH₂CH₂OH, isopropyl, cyclopropyl ,-CH₂- cyclopropyl, Morpholinyl, piperazinyl, piperidyl or nafoxidine base；

R²Selected from H, F, Cl, methyl or methoxy；

R³Selected from H, ethyl, methoxyl group or difluoro-methoxy；

R⁴Selected from H, F, Cl,

R⁵Selected from H, F, Cl or morpholinyl；

F is selected from 0,1,2 or 3.
Compound according to claim 1 and its optical isomer, pharmaceutically acceptable salt or eutectic, the wherein compound are selected from one of following structure：
Compound and its optical isomer, pharmaceutically acceptable salt or eutectic shown in claim 1~6 any one, wherein described salt is selected from hydrochloride, sulfate, phosphate, acetate, trifluoroacetate, fumarate, benzoate, benzene sulfonate, mesylate, fluoroform sulphonate or combinations thereof.
A kind of pharmaceutical composition, described pharmaceutical composition contains the compound according to any one of claim 1~6 or its optical isomer, pharmaceutically acceptable salt or eutectic for the treatment of effective dose, and pharmaceutically acceptable carrier or excipient.
Compound and its optical isomer, pharmaceutically acceptable salt or eutectic shown in any one of claim 1~7, or the pharmaceutical composition described in claim 8, the purposes in treating cancer related drugs are prepared.
Purposes according to claim 9, described cancer includes head and neck cancer, oophoroma, carcinoma of urinary bladder, uterine neck Cancer, cancer of the esophagus, stomach cancer, breast cancer, endometrial carcinomas, colon cancer, lung cancer, brain tumor, non-small cell lung cancer, cancer of pancreas, entity tumor, colorectal carcinoma or glioblastoma.
A kind of method for the treatment of cancer, methods described includes the compound or its optical isomer, pharmaceutically acceptable salt or eutectic shown in administration any one of claim 1~7, or the pharmaceutical composition described in claim 8.
Method according to claim 11, described cancer includes head and neck cancer, oophoroma, carcinoma of urinary bladder, cervical carcinoma, cancer of the esophagus, stomach cancer, breast cancer, endometrial carcinomas, colon cancer, lung cancer, brain tumor, non-small cell lung cancer, cancer of pancreas, entity tumor, colorectal carcinoma or glioblastoma.