CN104211639A - Alkynyl heterocyclic compounds and application thereof - Google Patents

Alkynyl heterocyclic compounds and application thereof Download PDF

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Publication number
CN104211639A
CN104211639A CN201310224333.8A CN201310224333A CN104211639A CN 104211639 A CN104211639 A CN 104211639A CN 201310224333 A CN201310224333 A CN 201310224333A CN 104211639 A CN104211639 A CN 104211639A
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alkyl
halogen
replace
group
alkoxyl group
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胡有洪
耿美玉
刘杨
丁健
艾菁
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Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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Priority to CN201310224333.8A priority Critical patent/CN104211639A/en
Priority to PCT/CN2014/000557 priority patent/WO2014194667A1/en
Publication of CN104211639A publication Critical patent/CN104211639A/en
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The invention relates to alkynyl heterocyclic compounds represented by the formula (I), a preparation method thereof, and an application of the compounds in the preparation of antitumor drugs.

Description

One class alkynyl heterocyclic compound and application thereof
Technical field
The invention belongs to pharmaceutical synthesis field, be specifically related to a class novel alkynyl heterocyclic compound and preparing the purposes in anti-tumor drug.
Background technology
Receptor tyrosine kinase (RTKs) participates in a series of cell biological events such as propagation, migration, differentiation, apoptosis of regulating cell, and the generation of its process LAN or excessive activation and tumour develops closely related, is the crucial target spot of oncotherapy.Fibroblast growth factor receptor (fibroblast growth factor receptors, FGFRs) is receptor tyrosine kinase family (RTKs) important member.FGFR family mainly comprises FGFR1, FGFR2, FGFR3 and FGFR4 tetra-kinds of hypotypes.(Turner N., Grose R., Fibroblast growth factor signalling:from development to cancer, Nature ReviewsCancer. (2010) 10:116-129.Dieci M.V., Arnedos M., Andre F., Soria J.C., Fibroblast GrowthFactor Receptor Inhibitors as a Cancer Treatment:From a Biologic Rationale to MedicalPerspectives, Cancer Discovery. (2013) 3:264-279.) in tumour, due to gene amplification, sudden change, the reasons such as fusion or part induction, the each member's sustained activation of FGFR, inducing tumor cell is bred, invasion and attack, migration, promote vasculogenesis.FGFRs is high expression level or abnormal activation in kinds of tumors, closely related with the poor prognosis of tumour patient, as nonsmall-cell lung cancer, mammary cancer, cancer of the stomach, bladder cancer, carcinoma of endometrium, prostate cancer, cervical cancer, colorectal carcinoma, the esophageal carcinoma, cutin blastoma, myelomatosis, rhabdosarcoma etc.(Dieci MV, Arnedos M, Andre F, Soria JC:Fibroblast growthfactor receptor inhibitors as a cancer treatment:from a biologic rationale to medical perspectives.Cancer discovery, 2013, 3,264-79, Turner N, Grose R:Fibroblast growth factor signalling:fromdevelopment to cancer.Nat.Rev.Cancer, 2010, 10, 116-29.) research display, FGFR1 amplification accounts for 20% of nonsmall-cell lung cancer squama cancer, and by the lung cancer cell line in-vitro multiplication to FGFR1 amplification, the research such as signal path display FGFR selective depressant very effectively can suppress the activation of FGFR1 signal path and propagation (the Frequent andFocal FGFR1Amplification Associates with Therapeutically Tractable FGFR1Dependency inSquamous Cell Lung Cancer (vol3 of cell, 66er5, 2011), Sci Transl Med. (2010), Inhibitor-SensitiveFGFR1Amplification in Human Non-Small Cell Lung Cancer, PLoS ONE. (2011) 6:e20351.).FGFR2 gene amplification or sudden change cause the abnormal activation of FGFR2 signal path to contribute to the progression of cancer of the stomach.In stomach organization, the amplification rate of FGFR2 is 5%-10%(Matsumoto K, Arao T, Hamaguchi T, Shimada Y, Kato K, Oda I, Taniguchi H, Koizumi F, Yanagihara K, Sasaki H, Nishio K, Yamada Y:FGFR2geneamplification and clinicopathological features in gastric cancer.Br.J.Cancer, 2012,106,727-32.).To 313 routine stomach organization analysis displays, the amplification of FGFR2 and tumor size, local infiltration degree, the generation significant correlation of nodus lymphoideus transferring rate situation and far-end transfer, and the cancer of the stomach with FGFR2 amplification is generally evolving tumor, there is poor prognosis, relatively low (the Jung EJ of patient's overall survival rate, Jung EJ, Min SY, Kim MA, Kim WH:Fibroblast growth factor receptor2gene amplification status and its clinicopathologicsignificance in gastric carcinoma.Human pathology, 2012, 43, 1559-66.).In liver cancer, the FGFR of multiple hypotype and part FGFs thereof has abnormal expression and activation, as FGFR2, FGFR3, FGFR4, FGF19, FGF2, FGF5, FGF8, FGF9 etc.Multinomial clinical before and clinical study all show the importance of FGF/FGFR axis abnormal activation in liver cancer (Cheng AL, Shen YC, Zhu AX:Targeting Fibroblast Growth Factor Receptor Signalingin Hepatocellular Carcinoma.Oncology-Basel, 2011,81,372-80.).In non-invasive bladder cancer, FGFR3 sudden change accounts for 50%-60%, and in aggressive bladder cancer, FGFR3 sudden change accounts for 10%-15%.FGFR3t (4 in multiple myeloma; 14) (p16.3; Q32) gene rearrangement accounts for 15-20%, and this fusion gene can cause high expression level and the sustained activation of FGFR3, causes the bulk deposition of Clonal plasmocyte in bone and marrow thus affects normal hemopoietic function.(Fibroblast growth factor receptor inhibitors as a cancer treatment:from a biologic rationale tomedical perspectives.) the present invention is directed to FGFR1 and FGFR2 is target spot, synthesized a series of novel alkynyl heterocyclic compound with good FGFR1 and FGFR2 inhibit activities, and this series compound shows good inhibit activities on FGFR2 dependent stomach cancer cell line KATOIII.
Summary of the invention
The present inventor has synthesized the alkynyl heterocyclic compound of series of new, and measure these compounds there is inhibit activities on the molecular level of good FGFR1 and FGFR2, and effectively can suppress in nM level the growth of the dependent stomach cancer cell line KATOIII of FGFR2, there is significant anti-tumor activity.This is significant for developing the antitumor drug made new advances.
Therefore, an object of the present invention is to provide a class novel alkynyl heterocyclic compound.
Another object of the present invention is to provide above-mentioned novel alkynyl heterocyclic compound and is preparing the purposes in anti-tumor drug.
Another object of the present invention is to provide a kind of pharmaceutical composition with anti-tumor activity, and it comprises one or more above-mentioned novel alkynyl heterocyclic compounds and the pharmaceutically acceptable auxiliary material for the treatment of significant quantity.
According to first object of the present invention, the invention provides the alkynyl heterocyclic compound that a class general formula Ι represents,
Wherein, M and Y is CH or N independently of one another;
W is C or N; Wherein, when W is N, R 1do not exist;
L be-C (O) NH-or-NHC (O)-;
R 1be selected from:
1) H, hydroxyl;
2) C 1-C 6alkyl;
3) C 1-C 6alkoxyl group;
4) C 3-C 6cycloalkyl;
5) carboxyl ,-C (=O) O (C 1-C 6alkyl) ,-C (=O) NH (C 1-C 6alkyl);
6) do not replace or be selected from halogen, C by 1-5 1-C 6the C of alkyl, halogen substiuted 1-C 6alkyl, C 1-C 6the C that substituting group in alkoxyl group replaces 6-C 10aryl;
7) do not replace or be selected from halogen, C 1-C 6the C of alkyl, halogen substiuted 1-C 6alkyl, C 1-C 6the heteroatomic 5-8 unit heteroaryl be selected from containing 1-3 in N, O and S that substituting group in alkoxyl group replaces;
8) do not replace or be selected from halogen, C 1-C 6the C of alkyl, halogen substiuted 1-C 6alkyl, C 1-C 6the heteroatomic 4-7 unit heterocyclic radical be selected from containing 1-3 in N, O and S that substituting group in alkoxyl group replaces;
9）(Q 1)(Q 2)N-；
10) R 1phenyl ring, 5-6 unit's hetero-aromatic ring containing 1-2 atom N or the first heterocycle of the 5-6 containing 1-2 atom N can be formed with A ring Y position; Wherein, described phenyl ring, hetero-aromatic ring or heterocycle can be selected from halogen, C 1-C 6the C of alkyl, halogen substiuted 1-C 6alkyl, C 1-C 6alkoxyl group, carboxyl ,-C (=O) O (C 1-C 6alkyl) ,-C (=O) NH (C 1-C 6alkyl) in substituting group replace;
R 2be selected from:
1) H, halogen, hydroxyl;
2) oxo group;
3) C 1-C 6alkyl;
4) C 1-C 6alkoxyl group;
5) C 3-C 6cycloalkyl;
6) do not replace or be selected from halogen, C by 1-5 1-C 6the C of alkyl, halogen substiuted 1-C 6alkyl, C 1-C 6the C that substituting group in alkoxyl group replaces 6-C 10aryl;
7) do not replace or be selected from halogen, C 1-C 6the C of alkyl, halogen substiuted 1-C 6alkyl, C 1-C 6the heteroatomic 5-8 unit heteroaryl be selected from containing 1-3 in N, O and S that substituting group in alkoxyl group replaces;
8) do not replace or be selected from halogen, C 1-C 6the C of alkyl, halogen substiuted 1-C 6alkyl, C 1-C 6the heteroatomic 4-7 unit heterocyclic radical be selected from containing 1-3 in N, O and S that substituting group in alkoxyl group replaces;
9）(Q 1)(Q 2)N-；
10) R 2and R 1and adjacent atom can form the 5-6 unit's hetero-aromatic ring containing 1-2 atom N or contain the 5-6 unit heterocycle of 1-2 atom N; Wherein, described hetero-aromatic ring or heterocycle can be selected from halogen, oxo group, C 1-C 6the C of alkyl, halogen substiuted 1-C 6alkyl, C 1-C 6substituting group in alkoxyl group replaces;
11) R 2the 5-6 unit's hetero-aromatic ring containing 1-2 atom N can be formed with adjacent atom N or contain the 5-6 unit heterocycle of 1-2 atom N; Wherein, described hetero-aromatic ring or heterocycle can be selected from halogen, oxo group, C 1-C 6the C of alkyl, halogen substiuted 1-C 6alkyl, C 1-C 6substituting group in alkoxyl group replaces;
R 3be selected from:
1）H;
2) halogen;
3) not replace or the C of halogen substiuted 1-C 6alkyl;
4) C 1-C 6alkoxyl group;
5) C 3-C 6cycloalkyl;
R 4, R 5and R 6be selected from independently of one another:
1）H；
2) not replace or the C of halogen substiuted 1-C 6alkyl;
3）(CH 2) nNR 7R 8；
Wherein, n is 0 or 1;
R 7and R 8be independently of one another:
1）H；
2) not replace or the C of halogen substiuted 1-C 6alkyl;
3) C 3-C 6cycloalkyl;
4) R 7and R 8ring Het can be formed with the atom N be connected 1, wherein, Het 1for being selected from the heteroatomic 5-8 unit hetero-aromatic ring in N, O and S containing 1-3; The heteroatomic 4-10 unit heterocycle in N, O and S is selected from containing 1-3; Wherein, described hetero-aromatic ring or heterocycle can be selected from halogen, oxo group, C 1-C 6the C of alkyl, halogen substiuted 1-C 6alkyl, C 1-C 6substituting group in alkoxyl group replaces;
Wherein, Q 1and Q 2be hydrogen independently of one another; C 1-C 6alkyl; C 3-C 6cycloalkyl; C 1-C 6alkyloyl; Do not replace or be selected from halogen, C by 1-5 1-C 6the C of alkyl, halogen substiuted 1-C 6alkyl, C 1-C 6the phenyl that substituting group in alkoxyl group replaces;
B ring is phenyl ring; Or the heteroatomic 5-6 unit hetero-aromatic ring be selected from containing 1-3 in N, O and S.
Preferably, M and Y is CH or N independently of one another;
Preferably, W is C or N; Wherein, when W is N, R 1do not exist;
Preferably, L be-C (O) NH-or-NHC (O)-;
Preferably, R 1be selected from:
1) H, hydroxyl;
2) C 1-C 4alkyl;
3) C 1-C 4alkoxyl group;
4) C 3-C 6cycloalkyl;
5) carboxyl ,-C (=O) O (C 1-C 4alkyl) ,-C (=O) NH (C 1-C 4alkyl);
6) do not replace or be selected from halogen, C by 1-5 1-C 4the C of alkyl, halogen substiuted 1-C 4alkyl, C 1-C 4the phenyl that substituting group in alkoxyl group replaces;
7) do not replace or be selected from halogen, C 1-C 4the C of alkyl, halogen substiuted 1-C 4alkyl, C 1-C 4the heteroatomic 5-6 unit heteroaryl be selected from containing 1-3 in N, O and S that substituting group in alkoxyl group replaces;
8) do not replace or be selected from halogen, C 1-C 4the C of alkyl, halogen substiuted 1-C 4alkyl, C 1-C 4the heteroatomic 4-6 unit heterocyclic radical be selected from containing 1-3 in N, O and S that substituting group in alkoxyl group replaces;
9) (Q 1) (Q 2) N-; Wherein, Q 1and Q 2be hydrogen independently of one another; C 1-C 4alkyl; C 3-C 6cycloalkyl; C 1-C 4alkyloyl; Do not replace or be selected from halogen, C by 1-5 1-C 4the C of alkyl, halogen substiuted 1-C 4alkyl, C 1-C 4the phenyl that substituting group in alkoxyl group replaces;
10) R 1phenyl ring, 5-6 unit's hetero-aromatic ring containing 1-2 atom N or the first heterocycle of the 5-6 containing 1-2 atom N can be formed with A ring Y position; Wherein, described phenyl ring, hetero-aromatic ring or heterocycle can be selected from halogen, C 1-C 4the C of alkyl, halogen substiuted 1-C 4alkyl, C 1-C 4alkoxyl group, carboxyl ,-C (=O) O (C 1-C 4alkyl) ,-C (=O) NH (C 1-C 4alkyl) in substituting group replace;
Preferably, R 2be selected from:
1) H, halogen, hydroxyl;
2) oxo group;
3) C 1-C 4alkyl;
4) C 1-C 4alkoxyl group;
5) C 3-C 6cycloalkyl;
6) do not replace or be selected from halogen, C by 1-5 1-C 4the C of alkyl, halogen substiuted 1-C 4alkyl, C 1-C 4the phenyl that substituting group in alkoxyl group replaces;
7) do not replace or be selected from halogen, C 1-C 4the C of alkyl, halogen substiuted 1-C 4alkyl, C 1-C 4the heteroatomic 5-6 unit heteroaryl be selected from containing 1-3 in N, O and S that substituting group in alkoxyl group replaces;
8) do not replace or be selected from halogen, C 1-C 4the C of alkyl, halogen substiuted 1-C 4alkyl, C 1-C 4the heteroatomic 4-6 unit heterocyclic radical be selected from containing 1-3 in N, O and S that substituting group in alkoxyl group replaces;
9) (Q 1) (Q 2) N-; Wherein, Q 1and Q 2be hydrogen independently of one another; C 1-C 4alkyl; C 3-C 6cycloalkyl; C 1-C 4alkyloyl; Do not replace or be selected from halogen, C by 1-5 1-C 4the C of alkyl, halogen substiuted 1-C 4alkyl, C 1-C 4the phenyl that substituting group in alkoxyl group replaces;
10) R 2and R 1and adjacent atom can form the 5-6 unit's hetero-aromatic ring containing 1-2 atom N or contain the 5-6 unit heterocycle of 1-2 atom N; Wherein, described hetero-aromatic ring or heterocycle can be selected from halogen, oxo group, C 1-C 4the C of alkyl, halogen substiuted 1-C 4alkyl, C 1-C 4substituting group in alkoxyl group replaces;
11) R 2with adjacent atom N can be formed 5-6 unit's hetero-aromatic ring containing 1-2 atom N or containing 1-2 atom N the first heterocycle of 5-6; Wherein, described fragrant heterocycle or heterocycle can be selected from halogen, oxo group, C 1-C 4the C of alkyl, halogen substiuted 1-C 4alkyl, C 1-C 4substituting group in alkoxyl group replaces;
Further preferably, R 1be selected from:
1) hydrogen;
2) methyl, ethyl, sec.-propyl, the tertiary butyl;
3) hydroxyl, methoxyl group, oxyethyl group, isopropoxy, tert.-butoxy;
4) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
5) do not replace or to be selected from halogen by 1-4, phenyl that methyl, methoxyl group, trifluoromethyl replace;
6) do not replace or methyl substituted pyrazolyl, not replace or methyl substituted imidazolyl, pyrimidyl;
7) azelidinyl, pyrrolidyl, piperidyl, morpholinyl, do not replace or methyl substituted piperazinyl;
8) carboxyl ,-C (=O) OMe ,-C (=O) OEt ,-C (=O) NHMe ,-C (=O) NHEt;
9) amino; Methylamino-; Dimethylamino; Tert-butylamino; Cyclopropylamino; Kharophen; The phenyl amino not replacing or replaced by halogen, methyl, methoxyl group, trifluoromethyl;
Preferably, R 1the fused ring of following structure can be formed with A ring with A ring Y position:
Wherein, R 1 ', R 1 ", R 2be selected from independently of one another:
1）H；
2）F、Cl、Br；
3) methyl, ethyl, sec.-propyl, isobutyl-, trifluoromethyl;
4) cyclopropyl;
5) hydroxyl, methoxyl group, oxyethyl group, isopropoxy, tert.-butoxy;
6) carboxyl ,-C (=O) OMe ,-C (=O) OEt ,-C (=O) NHMe ,-C (=O) NHEt;
7) amino, methylamino-, dimethylamino, tert-butylamino, cyclopropylamino, kharophen;
Further preferably, R 2be selected from:
1）H；
2）F、Cl、Br；
3) oxo group;
4) methyl, ethyl, sec.-propyl, the tertiary butyl;
5) hydroxyl, methoxyl group, oxyethyl group, isopropoxy, tert.-butoxy;
6) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
7) do not replace or to be selected from halogen by 1-4, phenyl that methyl, methoxyl group, trifluoromethyl replace;
8) amino; Methylamino-; Dimethylamino; Tert-butylamino; Cyclopropylamino; Kharophen; The phenyl amino not replacing or replaced by halogen, methyl, methoxyl group, trifluoromethyl;
Preferably, R 2and R 1and adjacent atom can form the fused ring of following structure with A ring:
More preferably, R 2and R 1and adjacent atom can form the fused ring of following structure with A ring:
Preferably, R 2the fused ring of following structure can be formed with A ring with adjacent atom N:
Preferably, R 3for:
1）H；
2) halogen;
3) not replace or the C of halogen substiuted 1-C 4alkyl;
4) C 1-C 4alkoxyl group;
5) C 3-C 4cycloalkyl;
Further preferably, R 3for:
1）H；
2）F、Cl、Br；
3) methyl, ethyl, sec.-propyl, the tertiary butyl;
4) cyclopropyl;
5) trifluoromethyl;
6) methoxyl group, oxyethyl group, tert.-butoxy;
Preferably, B ring is the divalent group of following structure:
And when B ring is phenyl ring, R 1and R 2form ring E, and the fused ring that E ring and A ring are formed be not following structure:
Preferably, R 4, R 5and R 6be selected from:
1）H；
2）CF 3；
3）(CH 2) nNR 7R 8；
Wherein, n is 0 or 1;
R 7and R 8be independently of one another:
1）H；
2) not replace or the C of halogen substiuted 1-C 4alkyl;
3) C 3-C 6cycloalkyl.
4) R 7and R 8ring Het can be formed with the atom N be connected 1, wherein, Het 1for being selected from the heteroatomic 5-6 unit hetero-aromatic ring in N, O and S containing 1-3; The heteroatomic 4-10 unit heterocycle in N, O and S is selected from containing 1-3; Wherein, described hetero-aromatic ring or heterocycle can be selected from halogen, oxo group, C 1-C 4the C of alkyl, halogen substiuted 1-C 4alkyl, C 1-C 4substituting group in alkoxyl group replaces;
More preferably, R 4, R 5and R 6be selected from:
1）H；
2）CF 3；
3）
4）(CH 2) n-Het 1；
Wherein, n is 1; Het 1for following structure:
Preferably, C ring for following structure:
Wherein, Het 1for following structure:
Preferred, described alkynyl heterocyclic compound is selected from following compound:
Another object of the present invention is to provide the preparation method of the alkynyl heterocyclic compound that general formula I represents, the above-mentioned preparation method containing alkynyl heterocyclic compound comprise be selected from following synthetic route I, II and III any one:
Synthetic route I
Synthetic route I comprises the steps:
Step 1: add compound Ι-1, NBS, AIBN and CCl in round-bottomed flask 4, react with oil bath heating, temperature of reaction is 70 ~ 120 DEG C; After reaction terminates, purifying can obtain Compound I-2; The equivalence ratio of compound Ι-1, NBS and AIBN is 1:1.1:0.2; Type of heating is oil bath; Temperature is 100 DEG C; Reaction times is 36 hours.
Step 2: add compound Ι-2, Ι-3, CH in round-bottomed flask 2cl 2and Et 3n, reacts under room temperature; After reaction terminates, purifying can obtain Compound I-4; Compound Ι-2, compound Ι-3 and Et 3the equivalence ratio of N is 1:1.1:1.2; Temperature is room temperature; Reaction times is 12 hours.
Step 3: add compound Ι-4, reduction Fe powder, EtOH and NH in round-bottomed flask 4cl, react with oil bath heating, temperature of reaction is 70 ~ 120 DEG C; After reaction terminates, purifying can obtain Compound I-5; Compound Ι-4, reduction Fe powder and NH 4the equivalence ratio of Cl is 1:4:2; Type of heating is oil bath; Temperature is 100 DEG C; Reaction times is 10 hours.
Step 4: add compound Ι-6, SOCl in round-bottomed flask 2, DMF, with oil bath heating react, temperature of reaction is 80 ~ 120 DEG C; After reaction terminates, purifying can obtain Compound I-7; The equivalence ratio of compound Ι-6, DMF is 1:0.05, SOCl 2for solvent; Type of heating is oil bath; Temperature is 100 DEG C; Reaction times is 8 hours.
Step 5: add compound Ι-5, I-7, DMF and Et in round-bottomed flask 3n, reacts under room temperature; After reaction terminates, purifying can obtain Compound I-8; Compound Ι-5, Compound I-7 and Et 3the equivalence ratio of N is 1:1:1.1; Temperature is room temperature; Reaction times is 4 hours.
Step 6: add compound Ι-8, trimethyl silicane ethyl-acetylene, Pd (PPh in round-bottomed flask 3) 4, CuI, DMF and DIPEA, react with oil bath heating or microwave irradiation, temperature of reaction is 80 ~ 120 DEG C; After reaction terminates, purifying can obtain Compound I-9; Compound Ι-8, trimethyl silicane ethyl-acetylene, Pd (PPh 3) 4, CuI and DIPEA equivalence ratio be 1:1.5:0.05:0.1:3; Type of heating selects microwave irradiation, and power is 150 watts, and the time is 20 minutes; Temperature of reaction is 80 DEG C.
Step 7: add compound Ι-9, salt of wormwood and methyl alcohol in round-bottomed flask, reacts under room temperature; After reaction terminates, purifying can obtain Compound I-10.The equivalence ratio of compound Ι-9 and salt of wormwood is 1:10, and methyl alcohol is solvent, and chambers temp is room temperature; Reaction times is 3 hours.
Step 8: add compound Ι-10, compound Ι-11, Pd (PPh in round-bottomed flask 3) 4, CuI, DMF and DIPEA, react with oil bath heating or microwave irradiation, temperature of reaction is 80 ~ 120 DEG C; After reaction terminates, purifying can obtain Compound I-12.Compound Ι-10, compound Ι-11, Pd (PPh 3) 4, CuI and DIPEA equivalence ratio be 1:1.5:0.05:0.1:3; Type of heating selects microwave irradiation, and power is 150 watts, and the time is 20 minutes; Temperature of reaction is 90 DEG C.
Synthetic route Π
Synthetic route II comprises the steps:
Step 1: add Compound II per-1, PBr in round-bottomed flask 3and toluene, react under room temperature; After reaction terminates, purifying can obtain Compound II per-2; Compound II per-1 and PBr 3equivalence ratio be 1:2, toluene is solvent; Temperature is room temperature; Reaction times is 12 hours.
Step 2: add Compound II per-2, II-3, CH in round-bottomed flask 2cl 2and Et 3n, reacts under room temperature; After reaction terminates, purifying can obtain Compound II per-4; Compound II per-2, Compound II per-3 and Et 3the equivalence ratio of N is 1:1:1.1; Temperature is room temperature; Reaction times is 12 hours.
Step 3: add Compound II per-4, reduction Fe powder, EtOH and NH in round-bottomed flask 4cl, react with oil bath heating, temperature of reaction is 70 ~ 120 DEG C; After reaction terminates, purifying can obtain Compound II per-5; Compound II per-4, reduction Fe powder and NH 4the equivalence ratio of Cl is 1:4:2; Type of heating is oil bath; Temperature is 100 DEG C; Reaction times is 10 hours.
Step 4: add Compound II per-6, SOCl in round-bottomed flask 2, DMF, with oil bath heating react, temperature of reaction is 80 ~ 120 DEG C; After reaction terminates, purifying can obtain Compound II per-7; The equivalence ratio of Compound II per-6 and DMF is 1:0.05, SOCl 2for solvent; Type of heating is oil bath; Temperature is 100 DEG C; Reaction times is 8 hours.
Step 5: add Compound II per-5, II-7, DMF and Et in round-bottomed flask 3n, reacts under room temperature; After reaction terminates, purifying can obtain Compound II per-8; Compound II per-5, Compound II per-7 and Et 3the equivalence ratio of N is 1:1:1.1; Temperature is room temperature; Reaction times is 4 hours.
Step 6: add Compound II per-8, trimethyl silicane ethyl-acetylene, Pd (PPh in round-bottomed flask 3) 4, CuI, DMF and DIPEA, react with oil bath heating or microwave irradiation, temperature of reaction is 80 ~ 120 DEG C; After reaction terminates, purifying can obtain Compound II per-9; Compound II per-8, trimethyl silicane ethyl-acetylene, Pd (PPh 3) 4, CuI and DIPEA equivalence ratio be 1:1.5:0.05:0.1:3; Type of heating selects microwave irradiation, and power is 150 watts, and the time is 20 minutes; Temperature of reaction is 80 DEG C.
Step 7: add Compound II per-9, salt of wormwood and methyl alcohol in round-bottomed flask, reacts under room temperature; After reaction terminates, purifying can obtain Compound II per-10.The equivalence ratio of Compound II per-9 and salt of wormwood is 1:10, and methyl alcohol is solvent, and chambers temp is room temperature; Reaction times is 3 hours.
Step 8: add Compound II per-10, Compound II per-11, Pd (PPh in round-bottomed flask 3) 4, CuI, DMF and DIPEA, react with oil bath heating or microwave irradiation, temperature of reaction is 80 ~ 120 DEG C; After reaction terminates, purifying can obtain Compound II per-12.Compound II per-10, Compound II per-11, Pd (PPh 3) 4, CuI and DIPEA equivalence ratio be 1:1.5:0.05:0.1:3; Type of heating selects microwave irradiation, and power is 150 watts, and the time is 20 minutes; Temperature of reaction is 90 DEG C.
Synthetic route Ш
Synthetic route III comprises the steps:
Step 1: add compound Ш-1, NaBrO in round-bottomed flask 3, NaHSO 3, H 2o and EtOAc, reacts under room temperature; After reaction terminates, purifying can obtain compound Ш-2; Compound Ш-1, NaBrO 3and NaHSO 3equivalence ratio be 1:3:3, solvent H 2the solvent ratio of O and EtOAc is 1:1; Temperature is room temperature; Reaction times is 12 hours.
Step 2: add compound Ш-2, Ш-3, CH in round-bottomed flask 2cl 2and Et 3n, reacts under room temperature; After reaction terminates, purifying can obtain compound Ш-4; Compound Ш-2, compound Ш-3 and Et 3the equivalence ratio of N is 1:1:1.1, and temperature is room temperature; Reaction times is 12 hours.
Step 3: add compound Ш-4, Ш-5, DMF and Et in round-bottomed flask 3n, reacts under room temperature; After reaction terminates, purifying can obtain compound Ш-6; Compound Ш-4, compound Ш-5 and Et 3the equivalence ratio of N is 1:1:1.1, and temperature is room temperature; Reaction times is 4 hours.
Step 4: add compound Ш-6, trimethyl silicane ethyl-acetylene, Pd (PPh in round-bottomed flask 3) 4, CuI, DMF and DIPEA, react with oil bath heating or microwave irradiation, temperature of reaction is 80 ~ 120 DEG C; After reaction terminates, purifying can obtain compound Ш-7; Compound Ш-6, trimethyl silicane ethyl-acetylene, Pd (PPh 3) 4, CuI and DIPEA equivalence ratio be 1:1.5:0.05:0.1:3; Type of heating selects microwave irradiation, and power is 150 watts, and the time is 20 minutes; Temperature of reaction is 80 DEG C.
Step 5: add compound Ш-7, salt of wormwood and methyl alcohol in round-bottomed flask, reacts under room temperature; After reaction terminates, purifying can obtain compound Ш-8; The equivalence ratio of compound Ш-7 and salt of wormwood is 1:10, and methyl alcohol is solvent, and chambers temp is room temperature; Reaction times is 3 hours.
Step 6: add compound Ш-8, compound Ш-9, Pd (PPh in round-bottomed flask 3) 4, CuI, DMF and DIPEA, react with oil bath heating or microwave irradiation, temperature of reaction is 80 ~ 120 DEG C; After reaction terminates, purifying can obtain compound Ш-10.Compound Ш-9, compound Ш-8, Pd (PPh 3) 4, CuI and DIPEA equivalence ratio be 1:1.5:0.05:0.1:3; Type of heating selects microwave irradiation, and power is 150 watts, and the time is 20 minutes; Temperature of reaction is 90 DEG C.
Wherein, M, Y, W, R 1, R 2, R 3, R 7, R 8the same with the definition of B ring.
According to another object of the present invention, the invention provides the alkynyl heterocyclic compound that above-mentioned general formula (I) represents and preparing the purposes in anti-tumor drug.
According to an also object of the present invention, the invention provides a kind of pharmaceutical composition with anti-tumor activity, the alkynyl heterocyclic compound that its one or more above-mentioned general formulas (I) comprising treatment significant quantity represent and pharmaceutically acceptable auxiliary material.
Described tumour is any one in nonsmall-cell lung cancer, small cell lung cancer, lung squamous cancer, adenocarcinoma of lung, carcinoma of the pancreas, mammary cancer, prostate cancer, liver cancer, cancer of the stomach, skin carcinoma, cell carcinoma, nasopharyngeal carcinoma, lymphatic cancer, gastrointestinal stromal tumor, leukemia etc.
In this application, the implication of abbreviation is as follows:
NBS:N-bromo-succinimide;
MeOH: methyl alcohol
DMF:N, dinethylformamide;
EtOH: ethanol;
AIBN: Diisopropyl azodicarboxylate;
CCl 4: tetracol phenixin;
CH 2cl 2: methylene dichloride;
Et 3n: triethylamine;
NH 4cl: ammonium chloride;
Fe: iron;
SOCl 2: thionyl chloride;
PBr 3: phosphorus tribromide
H 2o: water
K 2cO 3: salt of wormwood
NaBrO 3: sodium bromate
NaHSO 3: sodium bisulfite
EtOAc: ethyl acetate
Pd (PPh 3) 4: four triphenyl phosphorus palladiums;
CuI: cuprous iodide;
DIPEA: diisopropylethylamine
Rt: room temperature
Boc: tertbutyloxycarbonyl.
Embodiment
The embodiment of following elaboration limits the present invention absolutely not.
Compound prepares embodiment
Embodiment 1
Step one:
In round-bottomed flask, add 1g(5mMol) 2-methyl-5-nitro phenylfluoroform, 980mg(5.5mMol) NBS, 164mg(1mMol) CCl of AIBN and 20 milliliter 4, react 36 hours at heating 100 DEG C with oil bath; Be cooled to room temperature, evaporated under reduced pressure solvent after reaction terminates, column chromatography obtains product 2-trifluoromethyl-4-nitrobenzyl bromine 1.04g(productive rate: 71%).
Step 2:
In round-bottomed flask, add 849mg(3mMol) 2-trifluoromethyl-4-nitrobenzyl bromine, 330mg(3.3mMol) N methyl piperazine, 364mg(3.6mMol) Et 3n and 10 milliliter CH 2cl 2, react 12 hours under room temperature; After reaction terminates, evaporated under reduced pressure solvent, column chromatography obtains product 1-methyl-4-(4-nitro-2-(trifluoromethyl) benzyl) piperazine 901mg(productive rate: 99%).
Step 3:
In round-bottomed flask, add 901mg(be about 3mMol) 1-methyl-4-(4-nitro-2-(trifluoromethyl) benzyl) piperazine, 672mg(12mMol) reduce Fe powder, 318mg(6mMol) NH 4cl and 15 milliliter EtOH, reacts 10 hour at heating 100 DEG C with oil bath; After reaction terminates, pad suction filtered through kieselguhr, evaporated under reduced pressure filtrate, column chromatography obtains product 4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) aniline 754mg(productive rate: 92.3%).
Step 4:
In round-bottomed flask, add 1.31g(5mMol) the iodo-4-tolyl acid of 3-, 15 milliliters of SOCl 2and 18mg(0.25mMol) dry DMF, react 8 hours at heating 100 DEG C with oil bath; After reaction terminates, evaporated under reduced pressure solvent obtains the iodo-4-methyl benzoyl chloride of product 3-, is directly used in next step reaction.
Step 5:
In round-bottomed flask, add 550mg(2mMol) 4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) aniline, 560mg(2mMol) the iodo-4-methyl benzoyl chloride of 3-, 223mg(2.2mMol) Et 3n and 15 milliliter DMF, reacts 4 hours under room temperature; After reaction terminates, evaporated under reduced pressure solvent, column chromatography obtains the iodo-4-methyl of product 3--N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide 786mg(productive rate: 76%).
Step 6:
In round-bottomed flask, add 517mg(1mMol) the iodo-4-methyl of 3--N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide, 147mg(1.5mMol) trimethyl silicane ethyl-acetylene, 60mg(0.05mMol) Pd (PPh 3) 4, 20mg(0.1mMol) CuI, 390mg(3mMol) DIPEA and 1 milliliter DMF, with power be 150 watts, temperature is the microwave irradiation 20 minutes of 90 DEG C; After reaction terminates, evaporated under reduced pressure solvent, column chromatography obtains product 4-methyl-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl)-3-((trimethyl silicon based) ethynyl) benzamide 307mg(productive rate: 63%).
Step 7:
In round-bottomed flask, add 307mg(0.63mMol) 4-methyl-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl)-3-((trimethyl silicon based) ethynyl) benzamide, 870mg(6.7mMol) salt of wormwood and 10 ml methanol, react 3 hours under room temperature; After reaction terminates, core filters, evaporated under reduced pressure filtrate, column chromatography obtains product 3-ethynyl-4-methyl-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide 252mg(productive rate: 96%).
Step 8
In round-bottomed flask, add 208mg(0.5mMol) 3-ethynyl-4-methyl-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide, 70mg(0.33mMol) 4-bromo-isoquinoline, 30mg(0.025mMol) Pd (PPh 3) 4, 10mg(0.05mMol) CuI, 195mg(1.5mMol) DIPEA and 1 milliliter DMF, with power be 150 watts, temperature is the microwave irradiation 20 minutes of 90 DEG C; After reaction terminates, evaporated under reduced pressure solvent, column chromatography obtains end product 3-(isoquinoline 99.9-4-ethynyl)-4-methyl-N-(4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide 157mg(productive rate: 58%) [M+1]: 543; 1hNMR [(400MHz, d-DMSO)]: δ 10.75 (lH, s), 9.53 (lH, s), 8.92 (lH, s), 8.41 (lH, d, J=8.3Hz), 8.27-8.38 (3H, m), 8.17 (lH, d, J=7.8Hz), 8.08 (lH, t, J=7.3Hz), 8.01 (lH, d, J=8.3Hz), 7.80-7.94 (2H, m), 7.59 (lH, d, J=8.3Hz), 3.78 (2H, s), 3.05-3.25 (4H, m), 2.73-2.85 (4H, m), 2.65 (3H, s), 2.45 (3H, s).
Embodiment 2
Except replacing beyond 4-bromo-isoquinoline with bromo-1 hydrogen of 4--pyrroles a pair of horses going side by side [2,3-c] pyridine, synthetic method is as embodiment 1.
[M+1]：532； 1HNMR[(400MHz,d-DMSO)]:δ12.39(lH,s),10.73(lH,s),8.80(lH,s),8.47(lH,s),8.22-8.27(2H,m),8.08(lH,dd,J=1.9Hz,J=8.6Hz),7.94(lH,dd,J=1.9Hz,J=8.0Hz),7.77(lH,s),7.71(lH,d,J=8.9Hz),7.54(lH,d,J=8.3Hz),6.69(lH,d,J=2.8Hz),3.57(2H,s),2.73-3.15(8H,m),2.63(3H,s),2.16(3H,s).
Embodiment 3
Except replacing beyond 4-bromo-isoquinoline with the bromo-1-methyl isophthalic acid hydrogen of 4--pyrroles a pair of horses going side by side [2,3-c] pyridine, synthetic method is as embodiment 1.
[M+1]：546； 1HNMR[(400MHz,d-DMSO)]:δ10.69(lH,s),8.83(lH,s),8.51(lH,s),8.25-8.31(2H,m),8.11(lH,dd,J=1.9Hz,J=8.6Hz),7.97(lH,dd,J=1.9Hz,J=8.0Hz),7.79(lH,s),7.73(lH,d,J=8.6Hz),7.53(lH,d,J=8.3Hz),6.67(lH,d,J=2.8Hz),3.59(2H,s),2.71-3.11(8H,m),2.67(3H,s),2.56(3H,s),2.18(3H,s).
Embodiment 4
Except replacing beyond 4-bromo-isoquinoline with the bromo-1-methyl isophthalic acid hydrogen of 4--pyrazoles a pair of horses going side by side [3,4-c] pyridine, synthetic method is as embodiment 1.
[M+1]：547； 1HNMR[(400MHz,d-DMSO)]:δ10.60(lH,s),9.24(lH,s),8.49(lH,s),8.37(lH,s),8.28(lH,d,J=1.8Hz),8.23(lH,d,J=1.8Hz),8.10(lH,dd,J=1.5Hz,J=8.5Hz),7.96(lH,dd,J=1.9Hz,J=8.0Hz),7.71(lH,d,J=8.5Hz),7.56(lH,d,J=8.2Hz),6.67(lH,d,J=2.8Hz),4.23(3H,s),3.64(2H,s),3.21-3.39(4H,m),2.88-3.08(4H,m),2.63(6H,s).
Embodiment 5
Except replacing beyond 4-bromo-isoquinoline with the bromo-1-sec.-propyl of 4--1 hydrogen-pyrroles a pair of horses going side by side [2,3-c] pyridine, synthetic method is as embodiment 1.
[M+1]：574； 1HNMR[(400MHz,d-DMSO)]:δ10.67(lH,s),8.81(lH,s),8.47(lH,s),8.26-8.33(2H,m),8.12(lH,dd,J=1.9Hz,J=8.6Hz),7.97(lH,dd,J=1.9Hz,J=8.0Hz),7.77(lH,s),7.71(lH,d,J=8.6Hz),7.55(lH,d,J=8.3Hz),6.69(lH,d,J=2.8Hz),5.13(lH,m),3.57(2H,s),3.17-3.31(4H,m),2.89-3.05(4H,m),2.67(3H,s),2.21(3H,s),1.61(6H,d,J=7.2Hz).
Embodiment 6
Except replacing beyond 4-bromo-isoquinoline with the bromo-1-isobutyl-of 4--1 hydrogen-pyrroles a pair of horses going side by side [2,3-c] pyridine, synthetic method is as embodiment 1.
[M+1]：588； 1HNMR[(400MHz,d-DMSO)]:δ10.65(lH,s),8.83(lH,s),8.45(lH,s),8.23-8.31(2H,m),8.13(lH,dd,J=1.9Hz,J=8.6Hz),7.99(lH,dd,J=1.9Hz,J=8.0Hz),7.75(lH,s),7.73(lH,d,J=8.6Hz),7.57(lH,d,J=8.3Hz),6.67(lH,d,J=2.8Hz),3.87(lH,m),3.57(2H,s),3.15-3.31(4H,m),2.87-3.03(4H,m),2.67(3H,s),2.21(3H,s),1.55-1.67(5H,m),1.01(3H,t,J=7.8Hz).
Embodiment 7
Except replacing beyond 4-bromo-isoquinoline with the bromo-1-cyclopropyl of 4--1 hydrogen-pyrroles a pair of horses going side by side [2,3-c] pyridine, synthetic method is as embodiment 1.
[M+1]：572； 1HNMR[(400MHz,d-DMSO)]:δ10.67(lH,s),8.81(lH,s),8.43(lH,s),8.21-8.31(2H,m),8.12(lH,dd,J=1.9Hz,J=8.6Hz),7.95(lH,dd,J=1.9Hz,J=8.0Hz),7.71(lH,s),7.72(lH,d,J=8.6Hz),7.56(lH,d,J=8.3Hz),6.66(lH,d,J=2.8Hz),3.65(2H,s),3.05-3.23(4H,m),2.83-3.05(4H,m),2.46-2.57(4H,m),2.23(3H,s),0.85-1.01(4H,m).
Embodiment 8
Except replacing beyond 4-bromo-isoquinoline with bromo-1 hydrogen of 4--pyrroles a pair of horses going side by side [2,3-c] pyridine-3-carboxylic acid, synthetic method is as embodiment 1.
[M+1]：576； 1HNMR[(400MHz,d-DMSO)]:δ12.37(lH,s),10.71(lH,s),8.83(lH,s),8.41(lH,s),8.22-8.27(2H,m),8.03(lH,s),7.77(lH,s),7.71(lH,d,J=8.3Hz),7.54(lH,d,J=8.3Hz),6.68(lH,d,J=2.9Hz),3.59(2H,s),2.75-3.14(8H,m),2.61(3H,s),2.19(3H,s).
Embodiment 9
Except replacing beyond 4-bromo-isoquinoline with bromo-1 hydrogen of 4--pyrroles a pair of horses going side by side [2,3-c] pyridine-3-carboxylic acid ethyl ester, synthetic method is as embodiment 1.
[M+1]：604； 1HNMR[(400MHz,d-DMSO)]:δ12.35(lH,s),10.73(lH,s),8.81(lH,s),8.43(lH,s),8.20-8.28(2H,m),8.05(lH,s),7.79(lH,s),7.70(lH,d,J=8.5Hz),7.54(lH,d,J=8.5Hz),6.65(lH,d,J=2.8Hz),4.23(2H,q,J=8.1Hz),3.56(2H,s),2.81-3.03(4H,m),2.47-2.67(7H,m),2.17(3H,s),1.33(3H,t,J=8.1Hz).
Embodiment 10
Except replacing beyond 4-bromo-isoquinoline with fluoro-1 hydrogen of the bromo-3-of 4--pyrroles a pair of horses going side by side [2,3-c] pyridine, synthetic method is as embodiment 1.
[M+1]：550； 1HNMR[(400MHz,d-DMSO)]:δ12.37(lH,s),10.74(lH,s),8.80(lH,s),8.47(lH,s),8.21-8.27(2H,m),8.03(lH,s),7.75(lH,s),7.69(lH,d,J=8.3Hz),7.53(lH,d,J=8.3Hz),6.67(lH,d,J=2.9Hz),3.59(2H,s),2.72-3.11(8H,m),2.65(3H,s),2.15(3H,s).
Embodiment 11
Except replacing beyond 4-bromo-isoquinoline with the bromo-3-methyl isophthalic acid hydrogen of 4--pyrroles a pair of horses going side by side [2,3-c] pyridine, synthetic method is as embodiment 1.
[M+1]：546； 1HNMR[(400MHz,d-DMSO)]:δ12.39(lH,s),10.71(lH,s),8.83(lH,s),8.46(lH,s),8.22-8.29(2H,m),7.89(lH,s),7.73(lH,s),7.67(lH,d,J=8.5Hz),7.51(lH,d,J=8.5Hz),6.69(lH,d,J=2.7Hz),3.61(2H,s),2.71-3.09(8H,m),2.63(3H,s),2.17(3H,s)，2.09(3H,s).
Embodiment 12
Except replacing beyond 4-bromo-isoquinoline with the bromo-7-methoxyl group of 4--1 hydrogen-pyrroles a pair of horses going side by side [2,3-c] pyridine, synthetic method is as embodiment 1.
[M+1]：532； 1HNMR[(400MHz,d-DMSO)]:δ12.37(lH,s),10.71(lH,s),8.78(lH,s),8.26(lH,s),8.21(lH,s),8.05(lH,dd,J=1.9Hz,J=8.6Hz),7.91(lH,dd,J=1.9Hz,J=8.1Hz),7.75(lH,s),7.70(lH,d,J=8.5Hz),7.51(lH,d,J=8.1Hz),6.67(lH,d,J=2.9Hz),3.97(3H,s),3.57(2H,s),2.71-3.10(8H,m),2.61(3H,s),2.19(3H,s).
Embodiment 13
Except replacing beyond 4-bromo-isoquinoline with chloro-1 hydrogen of the bromo-7-of 4--pyrroles a pair of horses going side by side [2,3-c] pyridine, synthetic method is as embodiment 1.
[M+1]：566； 1HNMR[(400MHz,d-DMSO)]:δ12.39(lH,s),10.70(lH,s),8.77(lH,s),8.28(lH,s),8.22(lH,s),8.07(lH,dd,J=1.8Hz,J=8.5Hz),7.90(lH,dd,J=1.8Hz,J=8.0Hz),7.73(lH,s),7.69(lH,d,J=8.5Hz),7.50(lH,d,J=8.1Hz),6.69(lH,d,J=2.7Hz),3.61(2H,s),2.73-3.15(8H,m),2.65(3H,s),2.21(3H,s).
Embodiment 14
Except replacing except 4-bromo-isoquinoline with 1-chlorine phthalazines, synthetic method is as embodiment 1.
[M+1]：544； 1HNMR[(400MHz,d-DMSO)]:δ10.75(lH,s),9.43(lH,s),8.43(lH,d,J=8.1Hz),8.25-8.33(3H,m),8.15(lH,d,J=7.6Hz),8.05(lH,t,J=7.3Hz),8.01(lH,d,J=8.1Hz),7.78-7.91(2H,m),7.53(lH,d,J=8.1Hz),3.71(2H,s),3.03-3.27(4H,m),2.71-2.89(4H,m),2.61(3H,s),2.35(3H,s).
Embodiment 15
Except replacing except 4-bromo-isoquinoline by 4-bromo-isoquinoline 1 (2H)-one, synthetic method is as embodiment 1.
[M+1]：559； 1HNMR[(400MHz,d-DMSO)]:δ10.75(lH,s),9.93(lH,s),8.45(lH,s),8.41(lH,d,J=8.1Hz),8.23-8.37(3H,m),8.15(lH,d,J=7.4Hz),8.07(lH,t,J=7.1Hz),8.02(lH,d,J=8.1Hz),7.78-7.91(2H,m),7.55(lH,d,J=8.2Hz),3.68(2H,s),3.03-3.27(4H,m),2.71-2.89(4H,m),2.63(3H,s),2.37(3H,s).
Embodiment 16
Except replacing beyond 4-bromo-isoquinoline by bromo-6,7-dimethoxy-isoquinoline 1 (2H)-one of 4-, synthetic method is as embodiment 1.
[M+1]：619； 1HNMR[(400MHz,d-DMSO)]:δ10.75(lH,s),10.01(lH,s),8.47(lH,s),8.27(lH,s),8.15(lH,s),8.07(lH,s),8.02(lH,d,J=8.1Hz),7.78-7.97(3H,m),7.55(lH,d,J=8.1Hz),3.93,(6H,s),3.63(2H,s),3.01-3.23(4H,m),2.70-2.86(4H,m),2.61(3H,s),2.29(3H,s).
Embodiment 17
Except replacing except 4-bromo-isoquinoline with the chloro-4-bromo-isoquinoline of 1-, synthetic method is as embodiment 1.
[M+1]：577； 1HNMR[(400MHz,d-DMSO)]:δ10.75(lH,s),8.75(lH,s),8.47(lH,d,J=8.3Hz),8.25-8.39(3H,m),8.19(lH,d,J=7.6Hz),8.09(lH,t,J=7.4Hz),8.05(lH,d,J=8.3Hz),7.71-7.90(2H,m),7.53(lH,d,J=8.1Hz),3.65(2H,s),3.01-3.25(4H,m),2.73-2.89(4H,m),2.61(3H,s),2.32(3H,s).
Embodiment 18
Except replacing beyond 4-bromo-isoquinoline with bromo-6, the 7-dimethoxy-isoquinolines of the chloro-4-of 1-, synthetic method is as embodiment 1.
[M+1]：637； 1HNMR[(400MHz,d-DMSO)]:δ10.73(lH,s),8.72(lH,s),8.35(lH,s),8.21(lH,s),8.09(lH,s),8.03(lH,d,J=8.4Hz),7.73-7.94(3H,m),7.52(lH,d,J=8.4Hz),3.91,(6H,s),3.61(2H,s),3.03-3.25(4H,m),2.71-2.85(4H,m),2.59(3H,s),2.19(3H,s).
Embodiment 19
Except replacing except 4-bromo-isoquinoline with the bromo-4-bromo-isoquinoline of 1-, synthetic method is as embodiment 1.
[M+1]：622； 1HNMR[(400MHz,d-DMSO)]:δ10.75(lH,s),8.73(lH,s),8.46(lH,d,J=8.5Hz),8.21-8.37(3H,m),8.17(lH,d,J=7.4Hz),8.11(lH,t,J=7.2Hz),8.06(lH,d,J=8.5Hz),7.70-7.92(2H,m),7.51(lH,d,J=8.2Hz),3.61(2H,s),3.01-3.22(4H,m),2.71-2.83(4H,m),2.63(3H,s),2.30(3H,s).
Embodiment 20
Except replacing except 4-bromo-isoquinoline with 1-methoxyl group-4-bromo-isoquinoline, synthetic method is as embodiment 1.
[M+1]：573； 1HNMR[(400MHz,d-DMSO)]:δ10.81(lH,s),8.67(lH,s),8.42(lH,d,J=8.3Hz),8.22-8.39(3H,m),8.15(lH,d,J=7.2Hz),8.10(lH,t,J=7.2Hz),8.03(lH,d,J=8.3Hz),7.75-7.97(2H,m),7.49(lH,d,J=8.4Hz),3.95(3H,s),3.57(2H,s),2.99-3.18(4H,m),2.69-2.81(4H,m),2.62(3H,s),2.26(3H,s).
Embodiment 21
Except replacing except 4-bromo-isoquinoline with 1-tert.-butoxy-4-bromo-isoquinoline, synthetic method is as embodiment 1.
[M+1]：615； 1HNMR[(400MHz,d-DMSO)]:δ10.79(lH,s),8.63(lH,s),8.47(lH,d,J=8.1Hz),8.21-8.34(3H,m),8.13(lH,d,J=7.3Hz),8.09(lH,t,J=7.3Hz),8.01(lH,d,J=8.1Hz),7.71-7.95(2H,m),7.43(lH,d,J=8.3Hz),3.59(2H,s),3.05-3.19(4H,m),2.71-2.86(4H,m),2.63(3H,s),2.28(3H,s),1.55(9H,s).
Embodiment 22
Except replacing except 4-bromo-isoquinoline with 1-methylamino-4-bromo-isoquinoline, synthetic method is as embodiment 1.
[M+1]：572； 1HNMR[(400MHz,d-DMSO)]:δ10.71(lH,s),8.65(lH,s),8.41(lH,d,J=8.1Hz),8.21-8.37(3H,m),8.13(lH,d,J=7.4Hz),8.11(lH,t,J=7.4Hz),8.01(lH,d,J=8.1Hz),7.71-7.93(3H,m),7.43(lH,d,J=8.2Hz),3.59(2H,s),2.99-3.18(4H,m),2.69-2.81(7H,m),2.61(3H,s),2.23(3H,s).
Embodiment 23
Except replacing beyond 4-bromo-isoquinoline with 1-N, N-dimethylamino-4-bromo-isoquinoline, synthetic method is as embodiment 1.
[M+1]：586； 1HNMR[(400MHz,d-DMSO)]:δ10.77(lH,s),8.69(lH,s),8.43(lH,d,J=8.2Hz),8.22-8.38(3H,m),8.11(lH,d,J=7.3Hz),8.07(lH,t,J=7.3Hz),8.02(lH,d,J=8.2Hz),7.73-7.95(2H,m),7.41(lH,d,J=8.3Hz),3.61(2H,s),2.97-3.15(10H,m),2.69-2.81(4H,m),2.63(3H,s),2.18(3H,s).
Embodiment 24
Except replacing except 4-bromo-isoquinoline with 1-tert-butylamino-4-bromo-isoquinoline, synthetic method is as embodiment 1.
[M+1]：614； 1HNMR[(400MHz,d-DMSO)]:δ10.70(lH,s),8.63(lH,s),8.40(lH,d,J=8.3Hz),8.20-8.35(3H,m),8.15(lH,d,J=7.1Hz),8.12(lH,t,J=7.1Hz),8.02(lH,d,J=8.3Hz),7.70-7.94(3H,m),7.45(lH,d,J=8.4Hz),3.61(2H,s),2.97-3.16(4H,m),2.67-2.83(4H,m),2.62(3H,s),2.21(3H,s),1.35(9H,s).
Embodiment 25
Except replacing except 4-bromo-isoquinoline with 1-cyclopropylamino-4-bromo-isoquinoline, synthetic method is as embodiment 1.
[M+1]：598； 1HNMR[(400MHz,d-DMSO)]:δ10.73(lH,s),8.61(lH,s),8.45(lH,d,J=8.5Hz),8.19-8.33(3H,m),8.14(lH,d,J=7.4Hz),8.10(lH,t,J=7.4Hz),8.03(lH,d,J=8.5Hz),7.71-7.95(3H,m),7.43(lH,d,J=8.2Hz),3.62(2H,s),2.98-3.19(4H,m),2.70-2.85(4H,m),2.65(3H,s),2.23(3H,s),1.37(1H,m),0.71-0.95(4H,m).
Embodiment 26
Except replacing beyond 4-bromo-isoquinoline with chloro-1,2,4-triazole a pair of horses going side by side [4, the 3-B] pyridazine of 6-, synthetic method is as embodiment 1.
[M+1]：534； 1HNMR[(400MHz,d-DMSO)]:δ10.67(lH,s),9.15(lH,s),8.42(lH,d,J=7.3Hz),8.23(1H,s),8.10(1H,s),7.91(lH,d,J=8.3Hz),7.78(lH,d,J=7.3Hz),7.49-7.57(2H,m),7.33(lH,d,J=8.3Hz),3.59(2H,s),2.95-3.16(4H,m),2.71-2.84(4H,m),2.61(3H,s),2.17(3H,s).
Embodiment 27
Except replacing beyond 4-bromo-isoquinoline with the chloro-3-methyl of 6-[1,2,4] triazole a pair of horses going side by side [4,3-B] pyridazine, synthetic method is as embodiment 1.
[M+1]：548； 1HNMR[(400MHz,d-DMSO)]:δ10.73(lH,s),8.45(lH,d,J=7.2Hz),8.24(1H,s),8.12(1H,s),7.92(lH,d,J=8.4Hz),7.75(lH,d,J=7.2Hz),7.47-7.59(2H,m),7.31(lH,d,J=8.4Hz),3.63(2H,s),2.91-3.12(4H,m),2.70-2.85(4H,m),2.63(3H,s),2.49(3H,s),2.19(3H,s).
Embodiment 28
Except replacing beyond 4-bromo-isoquinoline with 6-chloro-3-hydroxyl [1,2,4] triazole a pair of horses going side by side [4,3-B] pyridazine, synthetic method is as embodiment 1.
[M+1]：550； 1HNMR[(400MHz,d-DMSO)]:δ10.65(lH,s),8.43(lH,d,J=7.2Hz),8.21(1H,s),8.13(1H,s),7.92(lH,d,J=8.4Hz),7.83(lH,s),7.76(lH,d,J=7.1Hz),7.47-7.55(2H,m),7.31(lH,d,J=8.4Hz),3.61(2H,s),2.92-3.11(4H,m),2.70-2.82(4H,m),2.57(3H,s),2.19(3H,s).
Embodiment 29
Except replacing beyond 4-bromo-isoquinoline with 3-chloro-7H-pyrroles a pair of horses going side by side [2,3-C] pyridazine, synthetic method is as embodiment 1.
[M+1]：533； 1HNMR[(400MHz,d-DMSO)]:δ12.39(lH,s),10.73(lH,s),8.43(lH,s),8.21-8.25(2H,m),8.07(lH,dd,J=1.8Hz,J=8.4Hz),7.92(lH,dd,J=1.8Hz,J=8.1Hz),7.76(lH,s),7.72(lH,d,J=8.6Hz),7.51(lH,d,J=8.4Hz),6.67(lH,d,J=2.5Hz),3.61(2H,s),2.71-3.13(8H,m),2.61(3H,s),2.19(3H,s).
Embodiment 30
Except replacing except 4-bromo-isoquinoline with the bromo-5-pyridone of 3-, synthetic method is as embodiment 1.
[M+1]：509； 1HNMR[(400MHz,d-DMSO)]:δ10.73(lH,s),8.67(lH,s),8.35(lH,s),8.31(lH,s),8.24(1H,s),8.01(lH,d,J=8.2Hz),7.92(lH,d,J=8.4Hz),7.85(lH,s),7.73(lH,s),7.68(lH,d,J=8.4Hz),7.52(lH,d,J=8.2Hz),3.63(2H,s),2.70-3.14(8H,m),2.63(3H,s),2.17(3H,s).
Embodiment 31
Except replacing except 4-bromo-isoquinoline with the bromo-5-methoxypyridine of 3-, synthetic method is as embodiment 1.
[M+1]：523； 1HNMR[(400MHz,d-DMSO)]:δ10.68(lH,s),8.60(lH,s),8.31(lH,s),8.27(lH,s),8.14(1H,s),7.99(lH,d,J=8.4Hz),7.90(lH,d,J=8.6Hz),7.71(lH,s),7.63(lH,d,J=8.6Hz),7.55(lH,d,J=8.4Hz),3.94(3H,s),3.61(2H,s),2.69-3.11(8H,m),2.65(3H,s),2.13(3H,s).
Embodiment 32
Except replacing except 4-bromo-isoquinoline with the bromo-5-methoxypyridine of 3-, synthetic method is as embodiment 1.
[M+1]：523； 1HNMR[(400MHz,d-DMSO)]:δ10.69(lH,s),8.63(lH,s),8.32(lH,s),8.25(lH,s),8.16(1H,s),8.01(lH,d,J=8.3Hz),7.92(lH,d,J=8.5Hz),7.73(lH,s),7.65(lH,d,J=8.5Hz),7.51(lH,d,J=8.3Hz),3.63(2H,s),2.71-3.13(8H,m),2.61(3H,s),2.15(3H,s),1.36(9H,s).
Embodiment 33
Except replacing except 4-bromo-isoquinoline by the bromo-5-aminopyridine of 3-, synthetic method is as embodiment 1.
[M+1]：509； 1HNMR[(400MHz,d-DMSO)]:δ10.75(lH,s),8.59(lH,s),8.30(lH,s),8.26(lH,s),8.21(1H,s),8.03(lH,d,J=8.3Hz),7.91(lH,d,J=8.1Hz),7.70(lH,s),7.66(lH,d,J=8.1Hz),7.52(3H,m),3.57(2H,s),2.69-3.12(8H,m),2.61(3H,s),2.15(3H,s).
Embodiment 34
Except replacing except 4-bromo-isoquinoline with the bromo-5-dimethylaminopyridine of 3-, synthetic method is as embodiment 1.
[M+1]：522； 1HNMR[(400MHz,d-DMSO)]:δ10.65(lH,s),8.63(lH,s),8.34(lH,s),8.26(lH,s),8.15(1H,s),8.01(lH,d,J=8.3Hz),7.92(lH,d,J=8.5Hz),7.73(lH,s),7.65(lH,d,J=8.5Hz),7.56(2H,m),3.63(2H,s),2.71-3.14(8H,m),2.67(3H,s),2.56(3H,s),2.13(3H,s).
Embodiment 35
Except replacing except 4-bromo-isoquinoline with 3-bromo-5-tert-butylamino pyridine, synthetic method is as embodiment 1.
[M+1]：564； 1HNMR[(400MHz,d-DMSO)]:δ10.67(lH,s),8.65(lH,s),8.37(lH,s),8.25(lH,s),8.16(1H,s),8.03(lH,d,J=8.4Hz),7.93(lH,d,J=8.6Hz),7.75(lH,s),7.63(lH,d,J=8.6Hz),7.55(2H,m),3.65(2H,s),2.72-3.11(8H,m),2.65(3H,s),2.15(3H,s),1.36(9H,s).
Embodiment 36
Except replacing except 4-bromo-isoquinoline with 3-bromo-5-cyclopropylamino pyridine, synthetic method is as embodiment 1.
[M+1]：564； 1HNMR[(400MHz,d-DMSO)]:δ10.69(lH,s),8.67(lH,s),8.36(lH,s),8.24(lH,s),8.17(1H,s),8.02(lH,d,J=8.1Hz),7.95(lH,d,J=8.4Hz),7.71(lH,s),7.65(lH,d,J=8.4Hz),7.57(lH,d,J=8.1Hz),7.51(1H,s),3.61(2H,s),2.70-3.09(8H,m),2.61(3H,s),2.15(3H,s),1.35(1H,m),0.73-0.98(4H,m).
Embodiment 37
Except replacing except 4-bromo-isoquinoline with the bromo-5-of 3-(azetidin-1-base) pyridine, synthetic method is as embodiment 1.
[M+1]：548； 1HNMR[(400MHz,d-DMSO)]:δ10.67(lH,s),8.63(lH,s),8.37(lH,s),8.22(lH,s),8.15(1H,s),8.01(lH,d,J=8.3Hz),7.93(lH,d,J=8.5Hz),7.72(lH,s),7.67(lH,d,J=8.5Hz),7.55(lH,d,J=8.3Hz),3.63(2H,s),3.19-3.33(4H,m),2.71-3.13(8H,m),2.63(3H,s),2.23-2.29(2H,m),2.17(3H,s).
Embodiment 38
Except replacing except 4-bromo-isoquinoline with the bromo-5-of 3-(nitrogen heterocyclic penta-1-base) pyridine, synthetic method is as embodiment 1.
[M+1]：562； 1HNMR[(400MHz,d-DMSO)]:δ10.65(lH,s),8.65(lH,s),8.36(lH,s),8.23(lH,s),8.16(1H,s),8.03(lH,d,J=8.4Hz),7.94(lH,d,J=8.6Hz),7.70(lH,s),7.66(lH,d,J=8.6Hz),7.53(lH,d,J=8.4Hz),3.61(2H,s),3.29-3.43(4H,m),2.73-3.16(8H,m),2.63(3H,s),1.95-2.29(7H,m).
Embodiment 39
Except replacing except 4-bromo-isoquinoline with the bromo-5-of 3-(azepine hexamethylene-1-base) pyridine, synthetic method is as embodiment 1.
[M+1]：562； 1HNMR[(400MHz,d-DMSO)]:δ10.67(lH,s),8.66(lH,s),8.35(lH,s),8.21(lH,s),8.17(1H,s),8.01(lH,d,J=8.3Hz),7.92(lH,d,J=8.4Hz),7.68(lH,s),7.65(lH,d,J=8.4Hz),7.51(lH,d,J=8.3Hz),3.66(2H,s),2.73-3.27(12H,m),2.61(3H,s),2.19(3H,s),1.53-1.72(6H,m).
Embodiment 40
Except replacing except 4-bromo-isoquinoline with the bromo-5-of 3-(4-methylpiperazine-1-yl) pyridine, synthetic method is as embodiment 1.
[M+1]：562； 1HNMR[(400MHz,d-DMSO)]:δ10.65(lH,s),8.63(lH,s),8.36(lH,s),8.23(lH,s),8.15(1H,s),8.02(lH,d,J=8.1Hz),7.93(lH,d,J=8.5Hz),7.69(lH,s),7.63(lH,d,J=8.5Hz),7.49(lH,d,J=8.1Hz),3.67(2H,s),2.75-3.23(16H,m),2.64(3H,s),2.61(3H,s),2.15(3H,s).
Embodiment 41
Except replacing except 4-bromo-isoquinoline with 3-bromo-5-morpholinyl pyridine, synthetic method is as embodiment 1.
[M+1]：562； 1HNMR[(400MHz,d-DMSO)]:δ10.69(lH,s),8.65(lH,s),8.38(lH,s),8.25(lH,s),8.17(1H,s),8.04(lH,d,J=8.3Hz),7.95(lH,d,J=8.6Hz),7.73(lH,s),7.65(lH,d,J=8.6Hz),7.53(lH,d,J=8.3Hz),3.63(2H,s),3.55-3.63(4H,m),2.75-3.23(12H,m),2.64(3H,s),2.17(3H,s).
Embodiment 42
Except replacing except 4-bromo-isoquinoline with the bromo-5-phenylpyridine of 3-, synthetic method is as embodiment 1.
[M+1]：562； 1HNMR[(400MHz,d-DMSO)]:δ10.71(lH,s),8.69(lH,s),8.43(lH,s),8.23(lH,s),8.15(1H,s),8.02(lH,d,J=8.1Hz),7.91(lH,d,J=8.4Hz),7.73(lH,s),7.61(lH,d,J=8.4Hz),7.43-7.58(6H,m),3.61(2H,s),2.75-3.14(8H,m),2.61(3H,s),2.13(3H,s).
Embodiment 43
Except replacing except 4-bromo-isoquinoline with the bromo-5-of 3-(4-trifluoromethyl) pyridine, synthetic method is as embodiment 1.
[M+1]：637； 1HNMR[(400MHz,d-DMSO)]:δ10.73(lH,s),8.67(lH,s),8.45(lH,s),8.21(lH,s),8.17(1H,s),8.01(lH,d,J=8.2Hz),7.93(lH,d,J=8.5Hz),7.75(lH,s),7.61-7.69(3H,m),7.52(lH,d,J=8.2Hz),7.41(2H,d,J=7.8Hz),3.63(2H,s),2.77-3.15(8H,m),2.63(3H,s),2.15(3H,s).
Embodiment 44
Except replacing except 4-bromo-isoquinoline with the bromo-5-of 3-(4-p-methoxy-phenyl) pyridine, synthetic method is as embodiment 1.
[M+1]：599； 1HNMR[(400MHz,d-DMSO)]:δ10.71(lH,s),8.65(lH,s),8.43(lH,s),8.23(lH,s),8.15(1H,s),8.03(lH,d,J=8.3Hz),7.91(lH,d,J=8.5Hz),7.73(lH,s),7.62(lH,d,J=8.3Hz),7.49-7.56(3H,m),7.08(2H,d,J=7.9Hz),3.93(3H,s),3.61(2H,s),2.76-3.13(8H,m),2.61(3H,s),2.19(3H,s).
Embodiment 45
Except replacing beyond 4-bromo-isoquinoline with the bromo-5-of 3-(3,4,5-trimethoxyphenyl) pyridine, synthetic method is as embodiment 1.
[M+1]：659； 1HNMR[(400MHz,d-DMSO)]:δ10.69(lH,s),8.61(lH,s),8.39(lH,s),8.21(lH,s),8.13(1H,s),8.02(lH,d,J=8.1Hz),7.92(lH,d,J=8.4Hz),7.71(lH,s),7.61(lH,d,J=8.4Hz),7.53(lH,d,J=8.1Hz),6.67(2H,s),3.89(9H,s),3.59(2H,s),2.73-3.10(8H,m),2.63(3H,s),2.17(3H,s).
Embodiment 46
Except replacing beyond 4-bromo-isoquinoline with the bromo-5-of 3-(chloro-3, the 5-Dimethoxyphenyls of 2,6-bis-) pyridine, synthetic method is as embodiment 1.
[M+1]：697； 1HNMR[(400MHz,d-DMSO)]:δ10.67(lH,s),8.63(lH,s),8.41(lH,s),8.20(lH,s),8.15(1H,s),8.04(lH,d,J=8.2Hz),7.93(lH,d,J=8.5Hz),7.70(lH,s),7.63(lH,d,J=8.5Hz),7.51(lH,d,J=8.2Hz),6.61(1H,s),3.90(6H,s),3.62(2H,s),2.75-3.11(8H,m),2.62(3H,s),2.19(3H,s).
Embodiment 47
Except replacing except 4-bromo-isoquinoline with the bromo-5-of 3-(1-methyl isophthalic acid H-pyrazoles-4-base) pyridine, synthetic method is as embodiment 1.
[M+1]：573； 1HNMR[(400MHz,d-DMSO)]:δ10.71(lH,s),8.65(lH,s),8.43(lH,s),8.23(lH,s),8.17(1H,s),8.05(lH,s),8.01(lH,d,J=8.1Hz),7.96(lH,s),7.91(lH,d,J=8.6Hz),7.76(lH,s),7.60(lH,d,J=8.6Hz),7.53(lH,d,J=8.1Hz),3.87(3H,s),3.61(2H,s),2.76-3.13(8H,m),2.57(3H,s),2.17(3H,s).
Embodiment 48
Except replacing except 4-bromo-isoquinoline with the bromo-5-of 3-(pyrimidine-5-base) pyridine, synthetic method is as embodiment 1.
[M+1]：571； 1HNMR[(400MHz,d-DMSO)]:δ10.69(lH,s),8.67(lH,s),8.61(lH,s),8.42(lH,s),8.33(2H,s),8.21(lH,s),8.12(1H,s),8.02(lH,d,J=8.3Hz),7.93(lH,d,J=8.5Hz),7.75(lH,s),7.67(lH,d,J=8.5Hz),7.51(lH,d,J=8.3Hz),3.65(2H,s),2.72-3.11(8H,m),2.62(3H,s),2.16(3H,s).
Embodiment 49
Except replacing except 4-bromo-isoquinoline with the bromo-5-of 3-(1H-imidazoles-1-base) pyridine, synthetic method is as embodiment 1.
[M+1]：559； 1HNMR[(400MHz,d-DMSO)]:δ10.73(lH,s),8.63(lH,s),8.41(lH,s),8.25(lH,s),8.13(1H,s),8.01(lH,d,J=8.2Hz),7.92(lH,d,J=8.5Hz),7.73(lH,s),7.63(lH,d,J=8.5Hz),7.51(lH,d,J=8.2Hz),7.44(lH,dd,J=1.1Hz,J=7.4Hz),7.15-7.17(2H,m),3.64(2H,s),2.78-3.13(8H,m),2.61(3H,s),2.19(3H,s).
Embodiment 50
Except replacing except 4-bromo-isoquinoline with the bromo-5-of 3-(4-methyl-1 H-imidazole-1-group) pyridine, synthetic method is as embodiment 1.
[M+1]：573； 1HNMR[(400MHz,d-DMSO)]:δ10.73(lH,s),8.63(lH,s),8.41(lH,s),8.25(lH,s),8.13(1H,s),8.01(lH,d,J=8.2Hz),7.92(lH,d,J=8.5Hz),7.73(lH,s),7.63(lH,d,J=8.5Hz),7.51(lH,d,J=8.2Hz),7.43(lH,s),7.19(1H,s),3.63(2H,s),2.77-3.11(8H,m),2.63(3H,s),2.29(3H,s),2.18(3H,s).
Embodiment 51
Except replacing except 4-bromo-isoquinoline with 3-bromo-5-ethoxycarbonyl pyridine, synthetic method is as embodiment 1.
[M+1]：565； 1HNMR[(400MHz,d-DMSO)]:δ10.71(lH,s),8.67(lH,s),8.34(lH,s),8.29(lH,s),8.15(1H,s),8.01(lH,d,J=8.1Hz),7.93(lH,d,J=8.4Hz),7.73(lH,s),7.67(lH,d,J=8.4Hz),7.51(lH,d,J=8.1Hz),4.21(2H,q,J=8.1Hz),3.63(2H,s),2.71-3.13(8H,m),2.63(3H,s),2.15(3H,s),1.32(3H,t,J=8.1Hz).
Embodiment 52
Except replacing except 4-bromo-isoquinoline with the bromo-5-carboxyl pyridine of 3-, synthetic method is as embodiment 1.
[M+1]：537； 1HNMR[(400MHz,d-DMSO)]:δ10.68(lH,s),8.65(lH,s),8.32(lH,s),8.27(lH,s),8.11(1H,s),8.02(lH,d,J=8.2Hz),7.95(lH,d,J=8.6Hz),7.71(lH,s),7.69(lH,d,J=8.6Hz),7.53(lH,d,J=8.2Hz),3.65(2H,s),2.76-3.15(8H,m),2.65(3H,s),2.19(3H,s).
Embodiment 53
Except replacing except 4-bromo-isoquinoline with 3-bromo-5-ethyl aminocarbonyl pyridine, synthetic method is as embodiment 1.
[M+1]：564； 1HNMR[(400MHz,d-DMSO)]:δ10.73(lH,s),9.62(lH,s),8.63(lH,s),8.31(lH,s),8.27(lH,s),8.16(1H,s),8.03(lH,d,J=8.2Hz),7.91(lH,d,J=8.5Hz),7.75(lH,s),7.68(lH,d,J=8.5Hz),7.53(lH,d,J=8.2Hz),3.65(2H,s),2.71-3.17(10H,m),2.61(3H,s),2.17(3H,s),1.05(3H,t,J=8.0Hz).
Embodiment 54
Except replacing except 4-bromo-isoquinoline with dichloro-pyridazine, synthetic method is as embodiment 1.
[M+1]：528； 1HNMR[(400MHz,d-DMSO)]:δ10.75(lH,s),8.32(lH,s),8.16(1H,s),8.03(lH,d,J=8.2Hz),7.86(lH,d,J=8.4Hz),7.75(lH,d,J=7.4Hz),7.58(lH,d,J=8.4Hz),7.39(lH,d,J=7.4Hz),7.19(lH,d,J=8.2Hz),3.61(2H,s),2.70-3.09(8H,m),2.63(3H,s),2.14(3H,s).
Embodiment 55
Except replacing except 4-bromo-isoquinoline with 3-hydroxyl-6-chlorine pyridazine, synthetic method is as embodiment 1.
[M+1]：510； 1HNMR[(400MHz,d-DMSO)]:δ10.76(lH,s),8.33(lH,s),8.17(1H,s),8.11(1H,s),8.01(lH,d,J=8.1Hz),7.85(lH,d,J=8.5Hz),7.73(lH,d,J=7.3Hz),7.57(lH,d,J=8.4Hz),7.36(lH,d,J=7.3Hz),7.18(lH,d,J=8.1Hz),3.62(2H,s),2.73-3.11(8H,m),2.65(3H,s),2.16(3H,s).
Embodiment 56
Except replacing except 4-bromo-isoquinoline with 3-methoxyl group-6-chlorine pyridazine, synthetic method is as embodiment 1.
[M+1]：524； 1HNMR[(400MHz,d-DMSO)]:δ10.77(lH,s),8.31(lH,s),8.13(1H,s),8.01(lH,d,J=8.1Hz),7.85(lH,d,J=8.5Hz),7.73(lH,d,J=7.3Hz),7.56(lH,d,J=8.5Hz),7.38(lH,d,J=7.3Hz),7.17(lH,d,J=8.1Hz),3.95(3H,s),3.63(2H,s),2.72-3.12(8H,m),2.61(3H,s),2.13(3H,s).
Embodiment 57
Except replacing except 4-bromo-isoquinoline with 3-tert.-butoxy-6-chlorine pyridazine, synthetic method is as embodiment 1.
[M+1]：566； 1HNMR[(400MHz,d-DMSO)]:δ10.78(lH,s),8.32(lH,s),8.12(1H,s),8.00(lH,d,J=8.0Hz),7.84(lH,d,J=8.4Hz),7.71(lH,d,J=7.2Hz),7.55(lH,d,J=8.4Hz),7.36(lH,d,J=7.2Hz),7.15(lH,d,J=8.0Hz),3.65(2H,s),2.73-3.15(8H,m),2.64(3H,s),2.16(3H,s),1.51(9H,s).
Embodiment 58
Except replacing except 4-bromo-isoquinoline with 3-amino-6-chlorine pyridazine, synthetic method is as embodiment 1.
[M+1]：509； 1HNMR[(400MHz,d-DMSO)]:δ10.73(lH,s),8.35(lH,s),8.13(1H,s),8.03(lH,d,J=8.1Hz),7.85(lH,d,J=8.4Hz),7.73(lH,d,J=7.3Hz),7.65(2H,s),7.57(lH,d,J=8.4Hz),7.36(lH,d,J=7.3Hz),7.18(lH,d,J=8.1Hz),3.62(2H,s),2.73-3.11(8H,m),2.65(3H,s),2.16(3H,s).
Embodiment 59
Except replacing except 4-bromo-isoquinoline with 3-methylamino-6-chlorine pyridazine, synthetic method is as embodiment 1.
[M+1]：523； 1HNMR[(400MHz,d-DMSO)]:δ10.76(lH,s),8.32(lH,s),8.12(1H,s),8.02(lH,d,J=8.2Hz),7.85(lH,d,J=8.5Hz),7.71(lH,d,J=7.2Hz),7.56(lH,d,J=8.5Hz),7.43(1H,s),7.38(lH,d,J=7.2Hz),7.17(lH,d,J=8.2Hz),3.63(2H,s),2.71-3.10(8H,m),2.61(3H,s),2.55(3H,s),2.12(3H,s).
Embodiment 60
Except replacing except 4-bromo-isoquinoline with 3-cyclopropylamino-6-chlorine pyridazine, synthetic method is as embodiment 1.
[M+1]：549； 1HNMR[(400MHz,d-DMSO)]:δ10.75(lH,s),8.31(lH,s),8.13(1H,s),8.03(lH,d,J=8.1Hz),7.86(lH,d,J=8.4Hz),7.72(lH,d,J=7.3Hz),7.55(lH,d,J=8.4Hz),7.41(1H,s),7.38(lH,d,J=7.3Hz),7.17(lH,d,J=8.1Hz),3.61(2H,s),2.69-3.08(8H,m),2.62(3H,s),2.12(3H,s),1.33(1H,m),0.72-0.95(4H,m).
Embodiment 61
Except replacing except 4-bromo-isoquinoline with 3-tert-butylamino-6-chlorine pyridazine, synthetic method is as embodiment 1.
[M+1]：565； 1HNMR[(400MHz,d-DMSO)]:δ10.71(lH,s),8.30(lH,s),8.11(1H,s),8.01(lH,d,J=8.0Hz),7.83(lH,d,J=8.3Hz),7.71(lH,d,J=7.2Hz),7.56(lH,d,J=8.3Hz),7.43(1H,s),7.37(lH,d,J=7.2Hz),7.18(lH,d,J=8.0Hz),3.63(2H,s),2.72-3.09(8H,m),2.61(3H,s),2.13(3H,s),1.33(9H,s).
Embodiment 62
Except replacing except 4-bromo-isoquinoline with 3-anilino-6-chlorine pyridazine, synthetic method is as embodiment 1.
[M+1]：585； 1HNMR[(400MHz,d-DMSO)]:δ10.67(lH,s),8.31(lH,s),8.13(1H,s),8.03(lH,d,J=8.1Hz),7.85(lH,d,J=8.4Hz),7.70(lH,d,J=7.1Hz),7.55-7.67(3H,m),7.41-7.49(3H,m),7.36(lH,d,J=7.1Hz),7.18(lH,d,J=8.1Hz),6.88(lH,t,J=7.8Hz),3.61(2H,s),2.73-3.11(8H,m),2.62(3H,s),2.18(3H,s).
Embodiment 63
Except replacing beyond 4-bromo-isoquinoline with 3-(2,6-bis-chloro-3,5 dimethoxy benzene amido)-6-chlorine pyridazine, synthetic method is as embodiment 1.
[M+1]：713； 1HNMR[(400MHz,d-DMSO)]:δ10.73(lH,s),8.33(lH,s),8.14(1H,s),8.02(lH,d,J=8.1Hz),7.85(lH,d,J=8.4Hz),7.73(lH,d,J=7.1Hz),7.58(lH,d,J=8.4Hz),7.45(1H,s),7.33(lH,d,J=7.1Hz),7.19(lH,d,J=8.1Hz),6.12(1H,s),3.89(6H,s),3.65(2H,s),2.73-3.11(8H,m),2.62(3H,s),2.19(3H,s).
Embodiment 64
Except replacing except 4-bromo-isoquinoline with 3-(4-trifluoromethylbenzene amido)-6-chlorine pyridazine, synthetic method is as embodiment 1.
[M+1]：653； 1HNMR[(400MHz,d-DMSO)]:δ10.71(lH,s),8.35(lH,s),8.12(1H,s),8.04(lH,d,J=8.2Hz),7.83(lH,d,J=8.5Hz),7.71(lH,d,J=7.2Hz),7.55(lH,d,J=8.5Hz),7.35-7.45(5H,m),7.31(lH,d,J=7.2Hz),7.17(lH,d,J=8.2Hz),3.63(2H,s),2.71-3.09(8H,m),2.60(3H,s),2.17(3H,s).
Embodiment 65
Except replacing except 4-bromo-isoquinoline with 3-acetylaminohydroxyphenylarsonic acid 6-chlorine pyridazine, synthetic method is as embodiment 1.
[M+1]：551； 1HNMR[(400MHz,d-DMSO)]:δ10.77(lH,s),9.63(1H,s),8.33(lH,s),8.13(1H,s),8.03(lH,d,J=8.1Hz),7.83(lH,d,J=8.6Hz),7.73(lH,d,J=7.3Hz),7.55(lH,d,J=8.6Hz),7.37(lH,d,J=7.3Hz),7.15(lH,d,J=8.1Hz),3.61(2H,s),2.75-3.13(8H,m),2.62(3H,s),2.12(3H,s),2.05(3H,s).
Embodiment 66
Except replacing except 4-bromo-isoquinoline with 3-phenyl-6-chlorine pyridazine, synthetic method is as embodiment 1.
[M+1]：570； 1HNMR[(400MHz,d-DMSO)]:δ10.65(lH,s),8.31(lH,s),8.12(1H,s),8.06(2H,t,J=7.8Hz),8.01(lH,d,J=8.2Hz),7.81(lH,d,J=8.5Hz),7.71(lH,d,J=7.2Hz),7.53(lH,d,J=8.5Hz),7.42-7.51(3H,m),7.36(lH,d,J=7.2Hz),7.18(lH,d,J=8.2Hz),3.62(2H,s),2.71-3.10(8H,m),2.63(3H,s),2.15(3H,s).
Embodiment 67
Except replacing except 4-bromo-isoquinoline with 3-(4-p-methoxy-phenyl)-6-chlorine pyridazine, synthetic method is as embodiment 1.
[M+1]：600； 1HNMR[(400MHz,d-DMSO)]:δ10.73(lH,s),8.37(lH,s),8.15(1H,s),8.03(lH,d,J=8.1Hz),7.82(lH,d,J=8.6Hz),7.73(lH,d,J=7.2Hz),7.51-7.56(3H,m),7.31(lH,d,J=7.2Hz),7.22(2H,d,J=7.9Hz),7.13(lH,d,J=8.2Hz),3.88(3H,s),3.65(2H,s),2.70-3.07(8H,m),2.58(3H,s),2.13(3H,s).
Embodiment 68
Except replacing except 4-bromo-isoquinoline with 3-(4-trifluoromethyl)-6-chlorine pyridazine, synthetic method is as embodiment 1.
[M+1]：638； 1HNMR[(400MHz,d-DMSO)]:δ10.71(lH,s),8.35(lH,s),8.12(1H,s),8.04(lH,d,J=8.2Hz),7.83(lH,d,J=8.5Hz),7.71(lH,d,J=7.2Hz),7.61-7.35(4H,m),7.53(lH,d,J=8.5Hz),7.33(lH,d,J=7.2Hz),7.15(lH,d,J=8.2Hz),3.61(2H,s),2.70-3.09(8H,m),2.63(3H,s),2.17(3H,s).
Embodiment 69
Except replacing except 4-bromo-isoquinoline with 3-(3-trifluoromethyl-4-chlorophenyl)-6-chlorine pyridazine, synthetic method is as embodiment 1.
[M+1]：672； 1HNMR[(400MHz,d-DMSO)]:δ10.73(lH,s),8.33(lH,s),8.18(1H,s),8.13(1H,s),8.02(lH,d,J=8.1Hz),7.99(lH,d,J=7.9Hz),7.82(lH,d,J=8.6Hz),7.71(lH,d,J=7.1Hz),7.49-7.53(2H,m),7.33(lH,d,J=7.1Hz),7.16(lH,d,J=8.1Hz),3.63(2H,s),2.75-3.11(8H,m),2.61(3H,s),2.18(3H,s).
Embodiment 70
Except replacing except the iodo-4-tolyl acid of 3-with 3-iodo-benzoic acid, synthetic method is as embodiment 1.
[M+1]：529； 1HNMR[(400MHz,d-DMSO)]:δ10.83(lH,s),9.50(lH,s),8.87(lH,s),8.45(lH,d,J=8.2Hz),8.38(1H,s),8.29-8.36(2H,m),8.17(lH,d,J=8.2Hz),8.03-8.12(2H,m),8.00(lH,d,J=7.9Hz),7.89(2H,d,J=8.2Hz),7.70(lH,d,J=7.8Hz),3.34-3.57(6H,m),3.00-3.24(4H,m),2.78(3H,s).
Embodiment 71
Except replacing except the iodo-4-tolyl acid of 3-with 3-iodo-4-ethyl benzoate, synthetic method is as embodiment 1.
[M+1]：557； 1HNMR[(400MHz,d-DMSO)]:δ10.81(lH,s),9.51(lH,s),8.93(lH,s),8.42(lH,d,J=8.2Hz),8.25-8.35(3H,m),8.16(lH,d,J=7.9Hz),8.07(lH,t,J=7.5Hz),8.02(lH,d,J=8.2Hz),7.79-7.93(2H,m),7.57(lH,d,J=8.3Hz),3.71(2H,s),3.03-3.22(4H,m),2.71-2.83(4H,m),2.62(3H,s),2.57(2H,q,J=7.5Hz),1.23(3H,t,J=7.5Hz).
Embodiment 72
Except replacing except the iodo-4-tolyl acid of 3-with 3-iodo-4-isopropyl acid, synthetic method is as embodiment 1.
[M+1]：557； 1HNMR[(400MHz,d-DMSO)]:δ10.85(lH,s),9.52(lH,s),8.91(lH,s),8.43(lH,d,J=8.1Hz),8.26-8.37(3H,m),8.15(lH,d,J=7.8Hz),8.06(lH,t,J=7.6Hz),8.01(lH,d,J=8.1Hz),7.78-7.91(2H,m),7.55(lH,d,J=8.2Hz),3.72(2H,s),3.01-3.20(4H,m),2.73-2.87(4H,m),2.61-2.63(4H,m),1.27(6H,d,J=6.9Hz).
Embodiment 73
Except replacing except the iodo-4-tolyl acid of 3-with 3-iodo-4-cyclopropyl-phenyl formic acid, synthetic method is as embodiment 1.
[M+1]：569； 1HNMR[(400MHz,d-DMSO)]:δ10.82(lH,s),9.55(lH,s),8.92(lH,s),8.41(lH,d,J=8.2Hz),8.23-8.34(3H,m),8.12(lH,d,J=7.7Hz),8.05(lH,t,J=7.7Hz),8.03(lH,d,J=8.2Hz),7.77-7.90(2H,m),7.54(lH,d,J=8.3Hz),3.69(2H,s),3.00-3.18(4H,m),2.75-2.89(4H,m),2.65(3H,s),1.61(1H,m),1.01-1.25(4H,m).
Embodiment 74
Except replacing except the iodo-4-tolyl acid of 3-with 3-iodo-4-p t butylbenzoic acid, synthetic method is as embodiment 1.
[M+1]：585； 1HNMR[(400MHz,d-DMSO)]:δ10.87(lH,s),9.51(lH,s),8.93(lH,s),8.45(lH,d,J=8.1Hz),8.21-8.33(3H,m),8.09(lH,d,J=7.8Hz),8.01(lH,t,J=7.8Hz),7.99(lH,d,J=8.1Hz),7.79-7.92(2H,m),7.51(lH,d,J=8.2Hz),3.67(2H,s),3.03-3.17(4H,m),2.73-2.87(4H,m),2.62(3H,s),1.37(9H,s).
Embodiment 75
Except replacing except the iodo-4-tolyl acid of 3-with 3-iodo-4-fluorobenzoic acid, synthetic method is as embodiment 1.
[M+1]：547； 1HNMR[(400MHz,d-DMSO)]:δ10.79(lH,s),9.42(lH,s),8.83(lH,s),8.49(lH,dd,J=2.3Hz,J=6.6Hz),8.34(lH,d,J=8.2Hz),8.23-8.30(2H,m),8.13-8.19(1H,m),8.11(lH,dd,J=1.6Hz,J=8.2Hz),8.00(lH,td,J=0.8Hz,J=6.6Hz),7.83(lH,td,J=1.2Hz,J=8.2Hz),7.72(lH,d,J=8.2Hz),7.61(lH,t,J=9.0Hz),3.63(2H,s),2.72-2.95(4H,m),2.49-2.66(7H,m).
Embodiment 76
Except replacing except the iodo-4-tolyl acid of 3-with 3-iodo-4-chloro-benzoic acid, synthetic method is as embodiment 1.
[M+1]：563； 1HNMR[(400MHz,d-DMSO)]:δ10.77(lH,s),9.41(lH,s),8.82(lH,s),8.45(lH,d,J=8.1Hz),8.33(lH,d,J=8.3Hz),8.16-8.29(3H,m),8.11(lH,d,J=8.3Hz),8.00(lH,t,J=8.1Hz),7.81(lH,t,J=8.2Hz),7.73(lH,d,J=8.2Hz),7.60(lH,t,J=8.8Hz),3.65(2H,s),2.76-2.98(4H,m),2.51-2.69(7H,m).
Embodiment 77
Except replacing except the iodo-4-tolyl acid of 3-with 3-iodo-4-bromo-benzoic acid, synthetic method is as embodiment 1.
[M+1]：607； 1HNMR[(400MHz,d-DMSO)]:δ10.75(lH,s),9.45(lH,s),8.81(lH,s),8.49(lH,d,J=8.0Hz),8.32(lH,d,J=8.2Hz),8.15-8.27(3H,m),8.12(lH,d,J=8.2Hz),8.01(lH,t,J=8.0Hz),7.80(lH,t,J=8.2Hz),7.75(lH,d,J=8.2Hz),7.61(lH,t,J=8.5Hz),3.63(2H,s),2.73-2.95(4H,m),2.50-2.70(7H,m).
Embodiment 78
Except replacing except the iodo-4-tolyl acid of 3-with 3-iodo-4-methoxybenzoic acid, synthetic method is as embodiment 1.
[M+1]：607； 1HNMR[(400MHz,d-DMSO)]:δ10.57(lH,s),9.37(lH,s),8.77(lH,s),8.40(lH,d,J=8.3Hz),8.34(lH,d,J=2.3Hz),8.22-8.28(2H,m),8.12(lH,td,J=2.3Hz,J=8.6Hz),8.00(lH,td,J=1.2Hz,J=7.0Hz),7.82(lH,td,J=1.1Hz,J=7.0Hz),7.70(lH,d,J=8.6Hz),7.34(lH,d,J=8.6Hz),4.05(3H,s),3.62(2H,s),2.71-2.92(4H,m),2.38-2.63(7H,m).
Embodiment 79
Except replacing except the iodo-4-tolyl acid of 3-with 3-iodo-4-trifluoromethylbenzoic acid, synthetic method is as embodiment 1.
[M+1]：597； 1HNMR[(400MHz,d-DMSO)]:δ10.81(lH,s),9.43(lH,s),8.82(lH,s),8.43(lH,dd,J=2.1Hz,J=6.8Hz),8.35(lH,d,J=8.3Hz),8.21-8.28(2H,m),8.11-8.18(1H,m),8.13(lH,dd,J=1.7Hz,J=8.3Hz),8.01(lH,td,J=0.9Hz,J=6.8Hz),7.82(lH,td,J=1.1Hz,J=8.1Hz),7.71(lH,d,J=8.1Hz),7.63(lH,t,J=8.8Hz),3.65(2H,s),2.73-2.98(4H,m),2.51-2.68(7H,m).
Embodiment 80
Except replacing except the iodo-4-tolyl acid of 3-with 4-bromopyridine-2-carboxylic acid, synthetic method is as embodiment 1.
[M+1]：530； 1HNMR[(400MHz,CDCl 3)]:δ9.73(lH,s),9.23(lH,s),8.83(lH,s),8.77(lH,s),8.33(lH,d,J=8.3Hz),8.21(1H,s),8.13(lH,d,J=1.9Hz),8.03(lH,dd,J=1.5Hz,J=8.4Hz),7.99(lH,d,J=8.3Hz),7.91(lH,dd,J=1.5Hz,J=5.3Hz),7.79(lH,td,J=1.6Hz,J=7.1Hz),7.62-7.73(2H,m),3.63(2H,s),2.73-2.95(4H,m),2.59-2.73(4H,m),2.53(3H,s).
Embodiment 81
Except replacing except the iodo-4-tolyl acid of 3-with 6-chloropyridine-2-carboxylic acid, synthetic method is as embodiment 1.
[M+1]：530； 1HNMR[(300MHz,CDCl 3)]:δ10.06(lH,s),9.29(lH,s),8.90(lH,s),8.38(lH,d,J=8.4Hz),8.32(lH,d,J=6.7Hz),8.08(1H,s),7.96-8.06(3H,m),7.82-7.92(2H,m),7.78(lH,d,J=8.4Hz),7.73(lH,t,J=7.0Hz),3.66(2H,s),2.43-2.67(8H,m),2.34(3H,s).
Embodiment 82
Except replacing except the iodo-4-tolyl acid of 3-with 5-bromo-nicotinic acid, synthetic method is as embodiment 1.
[M+1]：530； 1HNMR[(300MHz,CDCl 3)]:δ9.36(lH,s),9.29(lH,s),9.03(lH,s),8.81(lH,s),8.45-8.55(2H,m),8.31(lH,d,J=8.4Hz),8.05(lH,d,J=8.7Hz),7.95-8.05(2H,m),7.86(lH,t,J=8.4Hz),7.65-7.76(2H,m),3.72(2H,s),2.68-2.96(8H,m),2.58(3H,s).
Embodiment 83
Except replacing except the iodo-4-tolyl acid of 3-with 2-bromine isonicotinic acid, synthetic method is as embodiment 1.
[M+1]：530； 1HNMR[(400MHz,CDCl 3)]:δ9.75(lH,s),9.21(lH,s),8.81(lH,s),8.78(lH,s),8.31(lH,d,J=8.4Hz),8.24(1H,s),8.11(lH,d,J=2.0Hz),8.06(lH,dd,J=1.7Hz,J=8.6Hz),8.00(lH,d,J=8.4Hz),7.91(lH,dd,J=1.5Hz,J=5.1Hz),7.79(lH,td,J=1.4Hz,J=7.0Hz),7.61-7.71(2H,m),3.65(2H,s),2.75-2.96(4H,m),2.60-2.75(4H,m),2.55(3H,s).
Embodiment 84
Except replacing except the iodo-4-tolyl acid of 3-with 6-bromo-nicotinic acid, synthetic method is as embodiment 1.
[M+1]：530； 1HNMR[(400MHz,CDCl 3)]:δ9.25(lH,s),9.19(lH,d,J=2.4Hz),8.80(lH,s),8.65(lH,s),8.28-8.38(2H,m),8.03(lH,d,J=8.0Hz),7.88-7.97(2H,m),7.73-7.87(3H,m),7.70(lH,t,J=7.0Hz),3.64(2H,s),2.38-2.63(8H,m),2.34(3H,s).
Embodiment 85
Except replacing except the iodo-4-tolyl acid of 3-with 2-chloropyrimide-4-carboxylic acid, synthetic method is as embodiment 1.
[M+1]：531； 1HNMR[(400MHz,d-DMSO)]:δ11.15(lH,s),10.41(lH,s),9.56(lH,s),9.21(lH,d,J=5.0Hz),8.25-8.41(3H,m),8.20(lH,d,J=8.8Hz),8.13(lH,d,J=5.0Hz),8.03(lH,t,J=8.0Hz),7.85(lH,t,J=7.3Hz),7.74(lH,d,J=8.5Hz),3.64(2H,s),3.15-3.49(8H,m),2.61(3H,s).
Embodiment 86
Except replacing except the iodo-4-tolyl acid of 3-with 4-chloropyrimide-2-carboxylic acid, synthetic method is as embodiment 1.
[M+1]：531； 1HNMR[(400MHz,d-DMSO)]:δ11.11(lH,s),10.39(lH,s),9.53(lH,s),9.18(lH,d,J=5.1Hz),8.23-8.40(3H,m),8.18(lH,d,J=8.6Hz),8.11(lH,d,J=5.1Hz),8.02(lH,t,J=7.8Hz),7.84(lH,t,J=7.2Hz),7.73(lH,d,J=8.4Hz),3.62(2H,s),3.12-3.45(8H,m),2.63(3H,s).
Embodiment 87
Except replacing except the iodo-4-tolyl acid of 3-with 6-chloropyrimide-4-carboxylic acid, synthetic method is as embodiment 1.
[M+1]：531； 1HNMR[(400MHz,d-DMSO)]:δ11.07(lH,s),10.32(lH,s),9.51(lH,s),9.43(lH,s),8.61(1H,s),8.21-8.42(3H,m),8.15(lH,d,J=8.4Hz),8.01(lH,t,J=7.8Hz),7.83(lH,t,J=7.5Hz),7.71(lH,d,J=8.4Hz),3.65(2H,s),3.11-3.43(8H,m),2.65(3H,s).
Embodiment 88
Except replacing 4-bromo-isoquinoline with 6-chlorine imidazoles a pair of horses going side by side [1,2-A] pyrimidine, replace beyond the iodo-4-tolyl acid of 3-with 2-chloropyrimide-4-carboxylic acid, synthetic method is as embodiment 1.
[M+1]：521； 1HNMR[(400MHz,d-DMSO)]:δ11.03(lH,s),9.21(lH,d,J=5.2Hz),9.08(2H,s),8.42(lH,d,J=5.2Hz),8.17(lH,s),7.73(lH,d,J=8.1Hz),7.13-7.25(2H,m),7.05(lH,d,J=7.2Hz),3.67(2H,s),3.07-3.41(8H,m),2.62(3H,s).
Embodiment 89
Except replacing 4-bromo-isoquinoline with the bromo-4-hydrogen of 6--imidazoles a pair of horses going side by side [4,5-B] pyridine, replace beyond the iodo-4-tolyl acid of 3-with 2-chloropyrimide-4-carboxylic acid, synthetic method is as embodiment 1.
[M+1]：521； 1HNMR[(400MHz,d-DMSO)]:δ11.33(lH,s),10.97(lH,s),9.23(lH,d,J=5.2Hz),9.01(1H,s),8.55(1H,s),8.41(lH,d,J=5.2Hz),8.16(lH,s),8.06(lH,s),7.75(lH,d,J=8.1Hz),7.15(lH,d,J=8.1Hz),3.65(2H,s),3.02-3.39(8H,m),2.65(3H,s).
Embodiment 90
Except replacing 4-bromo-isoquinoline with 6-bromine [1,2,4] triazole a pair of horses going side by side [1,5-A] pyrimidine, replace beyond the iodo-4-tolyl acid of 3-with 2-chloropyrimide-4-carboxylic acid, synthetic method is as embodiment 1.
[M+1]：522； 1HNMR[(400MHz,d-DMSO)]:δ11.07(lH,s),9.31(lH,d,J=5.1Hz),9.07(2H,s),8.87(lH,s),8.42(lH,d,J=5.2Hz),8.17(lH,s),7.73(lH,d,J=8.1Hz),7.18(lH,d,J=8.2Hz),3.67(2H,s),3.07-3.41(8H,m),2.62(3H,s).
Embodiment 91
Except replacing 4-bromo-isoquinoline with 6-bromine pyrazoles a pair of horses going side by side [1,5-A] pyrimidine, replace beyond the iodo-4-tolyl acid of 3-with 2-chloropyrimide-4-carboxylic acid, synthetic method is as embodiment 1.
[M+1]：521； 1HNMR[(400MHz,d-DMSO)]:δ11.03(lH,s),9.33(lH,d,J=5.1Hz),9.09(2H,s),8.45(lH,d,J=5.2Hz),8.15(lH,s),7.71(lH,d,J=8.2Hz),7.62(lH,d,J=7.8Hz),7.19(lH,d,J=8.2Hz),6.69(lH,d,J=7.8Hz),3.67(2H,s),3.05-3.39(8H,m),2.65(3H,s).
Embodiment 92
Except replacing 4-bromo-isoquinoline with 5-bromo-7-azaindole, replace beyond the iodo-4-tolyl acid of 3-with 2-chloropyrimide-4-carboxylic acid, synthetic method is as embodiment 1.
[M+1]：520； 1HNMR[(400MHz,d-DMSO)]:δ11.31(lH,s),10.96(lH,s),9.23(lH,d,J=5.2Hz),8.89(1H,s),8.41(lH,d,J=5.2Hz),8.16(lH,s),8.06(lH,s),7.75(lH,d,J=8.1Hz),7.55(lH,d,J=3.1Hz),7.15(lH,d,J=8.1Hz),6.63(lH,d,J=3.1Hz),3.62(2H,s),3.03-3.37(8H,m),2.63(3H,s).
Embodiment 93
Except replacing 4-bromo-isoquinoline with 5-bromo-7-aza-titanium oxide indoles, replace beyond the iodo-4-tolyl acid of 3-with 2-chloropyrimide-4-carboxylic acid, synthetic method is as embodiment 1.
[M+1]：536； 1HNMR[(400MHz,d-DMSO)]:δ11.37(lH,s),10.97(lH,s),9.27(lH,d,J=5.2Hz),8.87(1H,s),8.43(lH,d,J=5.2Hz),8.16(lH,s),7.86(lH,s),7.73(lH,d,J=8.3Hz),7.19(lH,d,J=8.3Hz),3.72(2H,s),3.62(2H,s),3.01-3.35(8H,m),2.65(3H,s).
Embodiment 94
Except replacing 4-bromo-isoquinoline with bromo-2,3-dihydro-1H-pyrroles a pair of horses going side by side [2, the 3-B] pyridines of 5-, replace beyond the iodo-4-tolyl acid of 3-with 2-chloropyrimide-4-carboxylic acid, synthetic method is as embodiment 1.
[M+1]：522； 1HNMR[(400MHz,d-DMSO)]:δ11.39(lH,s),10.91(lH,s),9.29(lH,d,J=5.2Hz),8.43(lH,d,J=5.2Hz),8.33(1H,s),8.12(lH,s),7.71(lH,d,J=8.2Hz),7.43(lH,s),7.18(lH,d,J=8.2Hz),3.62(2H,s),3.58(2H,m),3.01-3.35(10H,m),2.61(3H,s).
Embodiment 95
Except replacing except the iodo-4-tolyl acid of 3-with 2-bromine furans-5-carboxylic acid, synthetic method is as embodiment 1.
[M+1]：519； 1HNMR[(400MHz,CD 3OD)]:δ9.24(lH,s),8.66(1H,s),8.28(1H,J=9.1Hz),8.10-8.19(2H,m),7.93(lH,t,J=7.1Hz),7.83(lH,t,J=7.5Hz),7.79(lH,d,J=8.0Hz),7.73(lH,d,J=9.0Hz),7.35(lH,d,J=3.6Hz),7.05(lH,d,J=3.6Hz),3.63(2H,s),2.37-2.67(8H,m),2.29(3H,s).
Embodiment 96
Except replacing except the iodo-4-tolyl acid of 3-with 2-bromo thiazole-5-carboxylic acid, synthetic method is as embodiment 1.
[M+1]：536； 1HNMR[(400MHz,d-DMSO)]:δ10.93(lH,s),9.27(lH,s),8.71(1H,s),8.43(1H,s),8.31(1H,d,J=8.9Hz),8.12-8.21(2H,m),7.91(lH,t,J=7.4Hz),7.82(lH,t,J=7.5Hz),7.76(lH,d,J=8.2Hz),7.71(lH,d,J=8.8Hz),3.65(2H,s),2.71-3.01(8H,m),2.26(3H,s).
Embodiment 97
Except replacing except the iodo-4-tolyl acid of 3-with 2-bromine oxazole-5-carboxylic acid, synthetic method is as embodiment 1.
[M+1]：520； 1HNMR[(400MHz,d-DMSO)]:δ10.99(lH,s),9.33(lH,s),8.81(1H,s),8.49(1H,s),8.33(1H,d,J=8.7Hz),8.13-8.25(2H,m),7.97(lH,t,J=7.6Hz),7.85(lH,t,J=7.6Hz),7.71(lH,d,J=8.1Hz),7.70(lH,d,J=8.7Hz),3.67(2H,s),2.75-3.06(8H,m),2.21(3H,s).
Embodiment 98
Except replacing the iodo-4-tolyl acid of 3-with 3-iodo-benzoic acid, replace beyond 4-bromo-isoquinoline with bromo-1 hydrogen of 4--pyrroles a pair of horses going side by side [2,3-c] pyridine, synthetic method is as embodiment 1.
[M+1]：518； 1HNMR[(400MHz,d-DMSO)]:δ12.38(lH,s),10.71(lH,s),8.82(lH,s),8.49(lH,s),8.21-8.26(2H,m),8.07(lH,dd,J=1.9Hz,J=8.6Hz),7.93(lH,dd,J=1.9Hz,J=8.0Hz),7.76(lH,s),7.65-7.71(2H,m),7.53(lH,d,J=8.3Hz),6.68(lH,d,J=2.8Hz),3.57(2H,s),2.73-3.15(8H,m),2.63(3H,s).
Embodiment 99
Except replacing except N methyl piperazine with morpholino, synthetic method is as embodiment 1.
[M+1]：530； 1HNMR[(400MHz,d-DMSO)]:δ10.77(lH,s),9.51(lH,s),8.95(lH,s),8.43(lH,d,J=8.1Hz),8.23-8.34(3H,m),8.15(lH,d,J=7.6Hz),8.05(lH,t,J=7.3Hz),8.02(lH,d,J=8.1Hz),7.81-7.96(2H,m),7.58(lH,d,J=8.2Hz),3.78(2H,s),3.62-3.72(4H,m),2.63-2.75(4H,m),2.35(3H,s).
Embodiment 100
Except replacing except N methyl piperazine with hexahydropyridine, synthetic method is as embodiment 1.
[M+1]：528； 1HNMR[(400MHz,d-DMSO)]:δ10.73(lH,s),9.49(lH,s),8.89(lH,s),8.41(lH,d,J=8.2Hz),8.22-8.31(3H,m),8.13(lH,d,J=7.5Hz),8.02(lH,t,J=7.5Hz),8.01(lH,d,J=8.2Hz),7.80-7.95(2H,m),7.55(lH,d,J=8.1Hz),3.77(2H,s),2.62-2.72(4H,m),2.31(3H,s),1.63-1.75(6H,m).
Embodiment 101
Except replacing except N methyl piperazine with 1-Boc-piperazine, synthetic method is as embodiment 1, and the product obtained is solvent with methylene dichloride, adds the trifluoracetic acid of 0.3 equivalent, and stirring at room temperature removes Boc protecting group in 3 hours, obtains final product.
[M+1]：529； 1HNMR[(400MHz,d-DMSO)]:δ10.75(lH,s),9.47(lH,s),8.83(lH,s),8.43(lH,d,J=8.2Hz),8.22-8.33(3H,m),8.13(lH,d,J=7.5Hz),8.02(lH,t,J=7.5Hz),8.01(lH,d,J=8.2Hz),7.80-7.95(3H,m),7.55(lH,d,J=8.1Hz),3.77(2H,s),2.81-2.93(4H,m),2.61-2.70(4H,m)2.31(3H,s).
Embodiment 102
Except replacing beyond N methyl piperazine with 1H-1,2,3-triazole, synthetic method is as embodiment 1.
[M+1]：512； 1HNMR[(400MHz,d-DMSO)]:δ10.73(lH,s),9.43(lH,s),8.81(lH,s),8.45(lH,d,J=8.1Hz),8.21-8.30(3H,m),8.13(lH,d,J=7.5Hz),8.02(lH,t,J=7.6Hz),8.01(lH,d,J=8.2Hz),7.80-7.95(2H,m),7.75(lH,d,J=7.4Hz),7.65(lH,d,J=7.4Hz),7.55(lH,d,J=8.1Hz),5.57(2H,s),2.28(3H,s).
Embodiment 103
Except replacing except N methyl piperazine with Pyrrolidine, synthetic method is as embodiment 1.
[M+1]：514； 1HNMR[(400MHz,d-DMSO)]:δ10.75(lH,s),9.42(lH,s),8.80(lH,s),8.47(lH,d,J=8.2Hz),8.22-8.32(3H,m),8.15(lH,d,J=7.4Hz),8.01(lH,t,J=7.4Hz),7.99(lH,d,J=8.2Hz),7.81-7.93(2H,m),7.53(lH,d,J=8.3Hz),3.77(2H,s),2.62-2.76(4H,m),2.28(3H,s),1.71-1.86(4H,m).
Embodiment 104
Except replacing except N methyl piperazine with pyrroles, synthetic method is as embodiment 1.
[M+1]：510； 1HNMR[(400MHz,d-DMSO)]:δ10.77(lH,s),9.45(lH,s),8.80(lH,s),8.41(lH,d,J=8.3Hz),8.23-8.35(3H,m),8.15(lH,d,J=7.7Hz),8.07(lH,t,J=7.5Hz),8.03(lH,d,J=8.4Hz),7.83-7.97(2H,m),7.55(lH,d,J=8.1Hz),7.43(2H,d,J=7.3Hz),6.55(2H,d,J=7.3Hz),5.51(2H,s),2.23(3H,s).
Embodiment 105
Except replacing except N methyl piperazine with imidazoles, synthetic method is as embodiment 1.
[M+1]：511； 1HNMR[(400MHz,d-DMSO)]:δ10.79(lH,s),9.43(lH,s),8.79(lH,s),8.43(lH,d,J=8.4Hz),8.19-8.32(3H,m),8.17(lH,d,J=7.8Hz),8.07(lH,t,J=7.8Hz),8.02(lH,d,J=8.2Hz),7.81-7.95(2H,m),7.71(1H,s),7.52(lH,d,J=8.3Hz),7.11(1H,d,J=7.6Hz),6.95(1H,d,J=7.7Hz),5.53(2H,s),2.19(3H,s).
Embodiment 106
Except replacing except N methyl piperazine with pyrazoles, synthetic method is as embodiment 1.
[M+1]：511； 1HNMR[(400MHz,d-DMSO)]:δ10.81(lH,s),9.45(lH,s),8.81(lH,s),8.45(lH,d,J=8.3Hz),8.21-8.33(3H,m),8.17(lH,d,J=7.5Hz),8.07(lH,t,J=7.6Hz),8.01(lH,d,J=8.3Hz),7.81-7.95(3H,m),7.52(lH,d,J=8.3Hz),7.33(lH,d,J=7.5Hz),6.35(1H,m),5.53(2H,s),2.29(3H,s).
Embodiment 107
Except replacing except N methyl piperazine with 4-methylpyrazole, synthetic method is as embodiment 1.
[M+1]：525； 1HNMR[(400MHz,d-DMSO)]:δ10.83(lH,s),9.43(lH,s),8.80(lH,s),8.43(lH,d,J=8.4Hz),8.22-8.35(3H,m),8.16(lH,d,J=7.6Hz),8.05(lH,t,J=7.6Hz),8.02(lH,d,J=8.4Hz),7.79-7.93(2H,m),7.51(lH,d,J=8.2Hz),7.45(lH,s),7.27(1H,s),5.49(2H,s),2.27(3H,s),2.07(3H,s).
Embodiment 108
Except replacing except N methyl piperazine with high piperidines, synthetic method is as embodiment 1.
[M+1]：542； 1HNMR[(400MHz,d-DMSO)]:δ10.75(lH,s),9.45(lH,s),8.87(lH,s),8.45(lH,d,J=8.3Hz),8.23-8.32(3H,m),8.15(lH,d,J=7.6Hz),8.05(lH,t,J=7.6Hz),8.02(lH,d,J=8.4Hz),7.81-7.93(2H,m),7.53(lH,d,J=8.3Hz),3.78(2H,s),2.92-3.01(4H,m),2.27(3H,s),1.67-1.85(8H,m).
Embodiment 109
Except replacing except N methyl piperazine with 1-Boc-homopiperazine, synthetic method is as embodiment 1, and the product obtained is solvent with methylene dichloride, adds the trifluoracetic acid of 0.3 equivalent, and stirring at room temperature removes Boc protecting group in 3 hours, obtains final product.
[M+1]：543； 1HNMR[(400MHz,d-DMSO)]:δ10.77(lH,s),9.43(lH,s),8.83(lH,s),8.41(lH,d,J=8.2Hz),8.20-8.33(3H,m),8.13(lH,d,J=7.5Hz),8.06(lH,t,J=7.8Hz),8.01(lH,d,J=8.3Hz),7.80-7.91(2H,m),7.53(lH,d,J=8.3Hz),7.37(1H,s),3.75(2H,s),3.11(2H,t,J=7.4Hz),2.42-2.71(6H,m),2.20(3H,s),1.60-1.72(2H,m).
Embodiment 110
Except replacing except N methyl piperazine with azetidine, synthetic method is as embodiment 1.
[M+1]：542；1HNMR[(400MHz,d-DMSO)]:δ10.71(lH,s),9.43(lH,s),8.85(lH,s),8.42(lH,d,J=8.2Hz),8.25-8.37(3H,m),8.17(lH,d,J=7.8Hz),8.07(lH,t,J=7.8Hz),8.03(lH,d,J=8.3Hz),7.73-7.85(2H,m),7.55(lH,d,J=8.2Hz),3.73(2H,s),3.31(4H,t,J=7.0Hz),2.23(5H,m).
Embodiment 111
Except replacing except N methyl piperazine with thiomorpholine, synthetic method is as embodiment 1.
[M+1]：546； 1HNMR[(400MHz,d-DMSO)]:δ10.79(lH,s),9.52(lH,s),8.93(lH,s),8.45(lH,d,J=8.2Hz),8.24-8.37(3H,m),8.17(lH,d,J=7.4Hz),8.07(lH,t,J=7.4Hz),8.01(lH,d,J=8.3Hz),7.83-7.97(2H,m),7.59(lH,d,J=8.4Hz),3.73(2H,s),2.63-2.75(4H,m),2.42-2.55(4H,m),2.32(3H,s).
Embodiment 112
Except replacing beyond N methyl piperazine with thiomorpholine-1,1-dioxide, synthetic method is as embodiment 1.
[M+1]：578； 1HNMR[(400MHz,d-DMSO)]:δ10.77(lH,s),9.53(lH,s),8.91(lH,s),8.43(lH,d,J=8.3Hz),8.25-8.36(3H,m),8.18(lH,d,J=7.5Hz),8.08(lH,t,J=7.6Hz),8.03(lH,d,J=8.4Hz),7.80-7.93(2H,m),7.55(lH,d,J=8.3Hz),3.71(2H,s),3.53-3.67(4H,m),2.92-3.05(4H,m),2.28(3H,s).
Embodiment 113
Except replacing beyond N methyl piperazine with isothiazolidine 1,1-dioxide, synthetic method is as embodiment 1.
[M+1]：564； 1HNMR[(400MHz,d-DMSO)]:δ10.78(lH,s),9.52(lH,s),8.92(lH,s),8.41(lH,d,J=8.4Hz),8.23-8.35(3H,m),8.17(lH,d,J=7.7Hz),8.09(lH,t,J=7.8Hz),8.05(lH,d,J=8.3Hz),7.81-7.94(2H,m),7.53(lH,d,J=8.4Hz),3.71(2H,s),3.51(2H,t,J=7.0Hz),2.62(2H,t,J=7.1Hz),2.28(3H,s),2.01(2H,m).
Embodiment 114
Except replacing except N methyl piperazine with tetrahydroisoquinoline, synthetic method is as embodiment 1.
[M+1]：576； 1HNMR[(400MHz,d-DMSO)]:δ10.75(lH,s),9.53(lH,s),8.91(lH,s),8.43(lH,d,J=8.3Hz),8.21-8.33(3H,m),8.15(lH,d,J=7.6Hz),8.08(lH,t,J=7.5Hz),8.03(lH,d,J=8.0Hz),7.77-7.90(2H,m),7.42-7.55(5H,m),3.79(2H,s),3.67(2H,s),2.82-2.95(4H,m),2.23(3H,s).
Embodiment 115
Except replacing except N methyl piperazine with isoindoline, synthetic method is as embodiment 1.
[M+1]：562； 1HNMR[(400MHz,d-DMSO)]:δ10.73(lH,s),9.57(lH,s),8.93(lH,s),8.45(lH,d,J=8.4Hz),8.22-8.35(3H,m),8.16(lH,d,J=7.8Hz),8.07(lH,t,J=7.8Hz),8.02(lH,d,J=8.1Hz),7.75-7.92(2H,m),7.41-7.53(5H,m),3.79(2H,s),3.67(4H,s),2.26(3H,s).
Embodiment 116
Except replacing except N methyl piperazine with 4-methylimidazole, synthetic method is as embodiment 1.
[M+1]：525； 1HNMR[(400MHz,d-DMSO)]:δ10.85(lH,s),9.40(lH,s),8.81(lH,s),8.41(lH,d,J=8.5Hz),8.23-8.37(3H,m),8.18(lH,d,J=7.8Hz),8.09(lH,t,J=7.7Hz),8.05(lH,d,J=8.2Hz),7.97(lH,s),7.77-7.91(2H,m),7.51(lH,d,J=8.2Hz),7.07(lH,s),5.45(2H,s),2.31(3H,s),2.23(3H,s).
Embodiment 117
Except replacing except N methyl piperazine with N-methylhomopiperazin, synthetic method is as embodiment 1.
[M+1]：557； 1HNMR[(400MHz,d-DMSO)]:δ10.87(lH,s),9.45(lH,s),8.83(lH,s),8.49(lH,d,J=8.4Hz),8.22-8.35(3H,m),8.19(lH,d,J=7.7Hz),8.08(lH,t,J=7.6Hz),8.06(lH,d,J=8.3Hz),7.76-7.93(2H,m),7.53(lH,d,J=8.4Hz),3.77(2H,s),3.08-3.13(4H,m),2.45-2.51(4H,m),2.37(3H,s),2.17(3H,s),1.55(2H,m).
Embodiment 118
Step one:
In round-bottomed flask, add 1g(5mMol) 3-nitro-5-trifluoromethyl-benzyl-alcohol, 2.7g(10mMol) PBr 3with the toluene of 20 milliliters, react 12 hours under room temperature; Reaction terminates rear evaporated under reduced pressure solvent, and column chromatography obtains product 3-nitro-5-trifluoromethyl benzyl bromine 966mg(productive rate: 68%).
Step 2 to eight is with embodiment 1
[M+1]：543； 1HNMR[(400MHz,d-DMSO)]:δ10.73(lH,s),9.52(lH,s),8.91(lH,s),8.45(lH,d,J=8.4Hz),8.26-8.37(3H,m),8.17(lH,d,J=7.6Hz),8.09(lH,t,J=7.3Hz),8.01(lH,s),7.95(lH,t,J=7.4Hz),7.77(lH,s),7.52(lH,s),3.77(2H,s),3.03-3.21(4H,m),2.71-2.84(4H,m),2.66(3H,s),2.43(3H,s).
Embodiment 119
Except replacing except the iodo-4-tolyl acid of 3-with 3-iodo-4-fluorobenzoic acid, synthetic method is as embodiment 118.
[M+1]：547； 1HNMR[(400MHz,d-DMSO)]:δ10.78(lH,s),9.43(lH,s),8.81(lH,s),8.47(lH,dd,J=2.2Hz,J=6.5Hz),8.34(lH,d,J=8.1Hz),8.21-8.29(2H,m),8.15(1H,m),8.10(lH,dd,J=1.6Hz,J=8.2Hz),8.02(lH,td,J=0.8Hz,J=6.6Hz),7.82(lH,s),7.61(lH,t,J=9.0Hz),7.50(lH,s),3.65(2H,s),2.71-2.93(4H,m),2.45-2.63(7H,m).
Embodiment 120
Except replacing beyond 4-bromo-isoquinoline with bromo-1 hydrogen of 4--pyrroles a pair of horses going side by side [2,3-c] pyridine, synthetic method is as embodiment 118.
[M+1]：532； 1HNMR[(400MHz,d-DMSO)]:δ12.37(lH,s),10.72(lH,s),8.81(lH,s),8.43(lH,s),8.23-8.29(2H,m),8.09(lH,dd,J=1.8Hz,J=8.8Hz),7.96(lH,dd,J=1.7Hz,J=8.0Hz),7.93(lH,s),7.77(lH,s),7.52(lH,s),6.69(lH,d,J=2.8Hz),3.59(2H,s),2.71-3.13(8H,m),2.62(3H,s),2.19(3H,s).
Embodiment 121
Except replacing beyond 4-bromo-isoquinoline with the bromo-1-methyl isophthalic acid hydrogen of 4--pyrroles a pair of horses going side by side [2,3-c] pyridine, synthetic method is as embodiment 118.
[M+1]：546； 1HNMR[(400MHz,d-DMSO)]:δ10.70(lH,s),8.85(lH,s),8.52(lH,s),8.26-8.32(2H,m),8.12(lH,dd,J=1.8Hz,J=8.6Hz),7.99(lH,dd,J=1.8Hz,J=8.3Hz),7.91(lH,s),7.79(lH,s),7.53(lH,s),6.65(lH,d,J=2.3Hz),3.63(2H,s),2.73-3.16(8H,m),2.69(3H,s),2.58(3H,s),2.19(3H,s).
Embodiment 122
Except replacing beyond 4-bromo-isoquinoline with the bromo-1-methyl isophthalic acid hydrogen of 4--pyrazoles a pair of horses going side by side [3,4-c] pyridine, synthetic method is as embodiment 118.
[M+1]：547； 1HNMR[(400MHz,d-DMSO)]:δ10.67(lH,s),9.26(lH,s),8.45(lH,s),8.39(lH,s),8.27(lH,d,J=1.7Hz),8.23(lH,d,J=1.7Hz),8.12(lH,dd,J=1.7Hz,J=8.5Hz),7.96(lH,dd,J=1.6Hz,J=8.3Hz),7.87(lH,s),7.55(lH,s),6.61(lH,d,J=2.8Hz),4.22(3H,s),3.67(2H,s),3.23-3.39(4H,m),2.85-3.05(4H,m),2.67(6H,s).
Embodiment 123
Replace beyond 4-bromo-isoquinoline with 1-chlorine phthalazines, synthetic method is as embodiment 118.
[M+1]：544； 1HNMR[(400MHz,d-DMSO)]:δ10.79(lH,s),9.45(lH,s),8.41(lH,d,J=8.2Hz),8.23-8.32(3H,m),8.17(lH,d,J=7.8Hz),8.06(lH,t,J=7.6Hz),8.02(lH,d,J=8.2Hz),7.93(1H,d,J=8.3Hz),7.88(lH,s),7.50(lH,s),3.71(2H,s),3.03-3.27(4H,m),2.71-2.89(4H,m),2.61(3H,s),2.35(3H,s).
Embodiment 124
Except replacing except the iodo-4-tolyl acid of 3-with 5-bromo-nicotinic acid, synthetic method is as embodiment 118.
[M+1]：530； 1HNMR[(400MHz,CDCl 3)]:δ9.39(lH,s),9.27(lH,s),9.09(lH,s),8.88(lH,s),8.42-8.57(2H,m),8.33(lH,d,J=8.4Hz),8.03(lH,d,J=8.5Hz),7.99(lH,d,J=8.5Hz),7.91(lH,s),7.85(lH,t,J=8.4Hz),7.66-7.75(2H,m),3.73(2H,s),2.67-2.93(8H,m),2.61(3H,s).
Embodiment 125
Except replacing except the iodo-4-tolyl acid of 3-with 4-bromopyridine-2-carboxylic acid, synthetic method is as embodiment 118.
[M+1]：530； 1HNMR[(400MHz,CDCl 3)]:δ9.77(lH,s),9.26(lH,s),8.85(lH,s),8.78(lH,s),8.32(lH,d,J=8.4Hz),8.20(1H,s),8.11(lH,d,J=1.7Hz),8.01(lH,dd,J=1.6Hz,J=8.5Hz),7.97(lH,s),7.91(lH,dd,J=1.5Hz,J=5.5Hz),7.79(lH,td,J=1.6Hz,J=7.1Hz),7.61-7.70(2H,m),3.62(2H,s),2.75-2.93(4H,m),2.62-2.72(4H,m),2.59(3H,s).
Embodiment 126
Except replacing except the iodo-4-tolyl acid of 3-with 4-chloropyrimide-2-carboxylic acid, synthetic method is as embodiment 118.
[M+1]：531； 1HNMR[(400MHz,d-DMSO)]:δ11.13(lH,s),10.37(lH,s),9.55(lH,s),9.19(lH,d,J=5.2Hz),8.21-8.37(3H,m),8.16(lH,d,J=8.4Hz),8.07(lH,d,J=5.2Hz),8.03(lH,s),7.89(lH,t,J=7.2Hz),7.73(lH,s),3.62(2H,s),3.12-3.45(8H,m),2.63(3H,s).
Embodiment 127
Except replacing except the iodo-4-tolyl acid of 3-with 2-chloropyrimide-3-carboxylic acid, synthetic method is as embodiment 118.
[M+1]：531； 1HNMR[(400MHz,d-DMSO)]:δ11.18(lH,s),10.43(lH,s),9.58(lH,s),9.22(lH,d,J=5.3Hz),8.22-8.39(3H,m),8.17(lH,d,J=8.8Hz),8.11(lH,d,J=5.0Hz),8.00(lH,s),7.85(lH,t,J=7.3Hz),7.71(lH,s),3.63(2H,s),3.17-3.51(8H,m),2.67(3H,s).
Embodiment 128
Except replacing except the iodo-4-tolyl acid of 3-with 6-chloropyrimide-4-carboxylic acid, synthetic method is as embodiment 118.
[M+1]：531； 1HNMR[(400MHz,d-DMSO)]:δ11.09(lH,s),10.35(lH,s),9.55(lH,s),9.42(lH,s),8.63(1H,s),8.23-8.47(3H,m),8.15(lH,s),8.02(lH,t,J=7.7Hz),7.87(lH,t,J=7.5Hz),7.73(lH,s),3.67(2H,s),3.12-3.45(8H,m),2.67(3H,s).
Embodiment 129
Except replacing except the iodo-4-tolyl acid of 3-with 2-bromo thiazole-5-carboxylic acid, synthetic method is as embodiment 118.
[M+1]：536； 1HNMR[(400MHz,d-DMSO)]:δ10.97(lH,s),9.23(lH,s),8.73(1H,s),8.45(1H,s),8.33(1H,d,J=8.9Hz),8.11-8.17(2H,m),7.91(lH,t,J=7.4Hz),7.82(lH,t,J=7.5Hz),7.79(lH,s),7.71(lH,s),3.67(2H,s),2.72-3.03(8H,m),2.29(3H,s).
Embodiment 130
Step one:
In round-bottomed flask, add 820mg(5mMol) 3-trifluoromethyl-4-tolyl acid, 2.25g(15mMol) NaBrO 3, 1.56g(15mMol) NaHSO 3with the H of the volume ratio 1:1 of 40 milliliters 2o and EtOAc mixing solutions, reacts 12 hours under room temperature; Reaction terminates rear extraction into ethyl acetate, evaporated under reduced pressure solvent, and column chromatography obtains product 2-trifluoromethyl-4-carboxyl benzyl bromine 920mg(productive rate: 65%).
Step 2:
In round-bottomed flask, add 849mg(3mMol) 2-trifluoromethyl-4-carboxyl benzyl bromine, 330mg(3.3mMol) N methyl piperazine, 364mg(3.6mMol) Et 3n and 10 milliliter CH 2cl 2, react 12 hours under room temperature; After reaction terminates, evaporated under reduced pressure solvent, column chromatography obtains product 1-methyl-4-(4-carboxyl-2-(trifluoromethyl) benzyl) piperazine 901mg(productive rate: 99%).
Step 3:
In round-bottomed flask, add 901mg(3mMol) 1-methyl-4-(4-carboxyl-2-(trifluoromethyl) benzyl) piperazine, 15 milliliters of SOCl 2and 18mg(0.25mMol) dry DMF, react 8 hours at heating 100 DEG C with oil bath; After reaction terminates, evaporated under reduced pressure solvent obtains product 4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) Benzoyl chloride, is directly used in next step reaction.
Step 4:
In round-bottomed flask, add 640mg(2mMol) 4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) Benzoyl chloride, 466mg(2mMol) the iodo-4-monomethylaniline of 3-, 223mg(2.2mMol) Et 3n and 15 milliliter DMF, reacts 4 hours under room temperature; After reaction terminates, evaporated under reduced pressure solvent, column chromatography obtains product N-(the iodo-4-aminomethyl phenyl of 3-)-4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) benzamide 706mg(productive rate: 69%).
Step 5:
In round-bottomed flask, add 517mg(1mMol) N-(the iodo-4-aminomethyl phenyl of 3-)-4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) benzamide, 147mg(1.5mMol) trimethyl silicane ethyl-acetylene, 60mg(0.05mMol) Pd (PPh 3) 4, 20mg(0.1mMol) CuI, 390mg(3mMol) DIPEA and 1 milliliter DMF, with power be 150 watts, temperature is the microwave irradiation 20 minutes of 90 DEG C; After reaction terminates, evaporated under reduced pressure solvent, column chromatography obtains product N-(3-((trimethyl silicon based) ethynyl-4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl)-3-((trimethyl silicon based) ethynyl) benzamide 285mg(productive rate: 59%).
Step 6:
285mg(0.59mMol is added in round-bottomed flask) N-(3-((trimethyl silicon based) ethynyl-4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl)-3-((trimethyl silicon based) ethynyl) benzamide, 814mg(5.9mMol) salt of wormwood and 10 ml methanol, react 3 hours under room temperature; After reaction terminates, core filters, evaporated under reduced pressure filtrate, column chromatography obtains product N-(3-ethynyl-4-aminomethyl phenyl)-4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide 220mg(productive rate: 90%).
Step 7
In round-bottomed flask, add 208mg(0.5mMol) N-(3-ethynyl-4-aminomethyl phenyl)-4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide, 70mg(0.33mMol) 4-bromo-isoquinoline, 30mg(0.025mMol) Pd (PPh 3) 4, 10mg(0.05mMol) CuI, 195mg(1.5mMol) DIPEA and 1 milliliter DMF, with power be 150 watts, temperature is the microwave irradiation 20 minutes of 90 DEG C; After reaction terminates, evaporated under reduced pressure solvent, column chromatography obtains end product N-(3-(isoquinoline 99.9-4-ethynyl)-4-aminomethyl phenyl)-4-((4-methylpiperazine-1-yl) methylene radical)-3-(trifluoromethyl) phenyl) benzamide 122mg(productive rate: 45%) [M+1]: 543; 1hNMR [(400MHz, d-DMSO)]: δ 10.79 (lH, s), 9.56 (lH, s), 8.93 (lH, s), 8.42 (lH, d, J=8.5Hz), 8.23-8.37 (3H, m), 8.16 (lH, d, J=7.9Hz), 8.09 (lH, t, J=7.5Hz), 8.03 (lH, d, J=8.4Hz), 7.83-7.96 (2H, m), 7.53 (lH, d, J=8.4Hz), 3.72 (2H, s), 3.06-3.27 (4H, m), 2.76-2.87 (4H, m), 2.68 (3H, s), 2.43 (3H, s).
Embodiment 131
Except replacing except 4-bromo-isoquinoline with 1-chlorine phthalazines, synthetic method is as embodiment 130.
[M+1]：544； 1HNMR[(400MHz,d-DMSO)]:δ10.73(lH,s),9.45(lH,s),8.42(lH,d,J=8.2Hz),8.23-8.32(3H,m),8.17(lH,d,J=7.8Hz),8.07(lH,t,J=7.4Hz),8.03(lH,d,J=8.2Hz),7.75-7.89(2H,m),7.51(lH,d,J=8.3Hz),3.73(2H,s),3.02-3.25(4H,m),2.70-2.87(4H,m),2.63(3H,s),2.37(3H,s).
Embodiment 132
Except replacing beyond 4-bromo-isoquinoline with the bromo-1-methyl isophthalic acid hydrogen of 4--pyrazoles a pair of horses going side by side [3,4-c] pyridine, synthetic method is as embodiment 130.
[M+1]：547； 1HNMR[(400MHz,d-DMSO)]:δ10.63(lH,s),9.27(lH,s),8.45(lH,s),8.33(lH,s),8.25(lH,d,J=1.7Hz),8.21(lH,d,J=1.6Hz),8.07(lH,dd,J=1.6Hz,J=8.4Hz),7.93(lH,dd,J=1.5Hz,J=8.3Hz),7.75(lH,d,J=8.3Hz),7.57(lH,d,J=8.5Hz),6.63(lH,d,J=2.3Hz),4.21(3H,s),3.63(2H,s),3.23-3.37(4H,m),2.86-3.05(4H,m),2.66(6H,s).
Embodiment 133
Except replacing beyond 4-bromo-isoquinoline with the bromo-1-methyl isophthalic acid hydrogen of 4--pyrroles a pair of horses going side by side [2,3-c] pyridine, synthetic method is as embodiment 130.
[M+1]：546； 1HNMR[(400MHz,d-DMSO)]:δ10.68(lH,s),8.85(lH,s),8.53(lH,s),8.23-8.30(2H,m),8.13(lH,dd,J=1.5Hz,J=8.2Hz),7.93(lH,dd,J=1.5Hz,J=8.1Hz),7.77(lH,s),7.71(lH,d,J=8.5Hz),7.52(lH,d,J=8.3Hz),6.66(lH,d,J=2.9Hz),3.62(2H,s),2.73-3.10(8H,m),2.65(3H,s),2.59(3H,s),2.15(3H,s).
Embodiment 134
Except replacing beyond 4-bromo-isoquinoline with chloro-1,2,4-triazole a pair of horses going side by side [4, the 3-B] pyridazine of 6-, synthetic method is as embodiment 130.
[M+1]：534； 1HNMR[(400MHz,d-DMSO)]:δ10.69(lH,s),9.17(lH,s),8.41(lH,d,J=7.5Hz),8.25(1H,s),8.12(1H,s),7.93(lH,d,J=8.4Hz),7.79(lH,d,J=7.4Hz),7.45-7.53(2H,m),7.32(lH,d,J=8.4Hz),3.62(2H,s),2.97-3.18(4H,m),2.75-2.83(4H,m),2.63(3H,s),2.19(3H,s).
Embodiment 135
Except replacing beyond 4-bromo-isoquinoline with 3-chloro-7H-pyrroles a pair of horses going side by side [2,3-C] pyridazine, synthetic method is as embodiment 130.
[M+1]：533； 1HNMR[(400MHz,d-DMSO)]:δ12.31(lH,s),10.75(lH,s),8.47(lH,s),8.22-8.27(2H,m),8.05(lH,dd,J=1.5Hz,J=8.3Hz),7.93(lH,dd,J=1.5Hz,J=8.2Hz),7.73(lH,s),7.71(lH,d,J=8.3Hz),7.50(lH,d,J=8.5Hz),6.63(lH,d,J=2.2Hz),3.64(2H,s),2.75-3.10(8H,m),2.65(3H,s),2.21(3H,s).
Embodiment 136
Except replacing except the iodo-4-monomethylaniline of 3-with 2-bromine 4-amido pyridine, synthetic method is as embodiment 130.
[M+1]：530； 1HNMR[(400MHz,CDCl 3)]:δ9.73(lH,s),9.20(lH,s),8.85(lH,s),8.77(lH,s),8.33(lH,d,J=8.3Hz),8.21(1H,s),8.15(lH,d,J=2.2Hz),8.07(lH,dd,J=1.5Hz,J=8.4Hz),8.02(lH,d,J=8.2Hz),7.93(lH,dd,J=1.3Hz,J=5.0Hz),7.79(lH,td,J=1.4Hz,J=7.2Hz),7.63-7.70(2H,m),3.61(2H,s),2.72-2.93(4H,m),2.61-2.72(4H,m),2.57(3H,s).
Embodiment 137
Except replacing except the iodo-4-monomethylaniline of 3-with 3-bromo-5-amido pyridine, synthetic method is as embodiment 130.
[M+1]：530； 1HNMR[(400MHz,CDCl 3)]:δ9.42(lH,s),9.27(lH,s),9.09(lH,s),8.85(lH,s),8.43-8.51(2H,m),8.35(lH,d,J=8.2Hz),8.08(lH,d,J=8.6Hz),7.93-8.01(2H,m),7.87(lH,t,J=8.5Hz),7.62-7.70(2H,m),3.73(2H,s),2.65-2.93(8H,m),2.59(3H,s).
Embodiment 138
Except replacing except the iodo-4-monomethylaniline of 3-with 2-chloro-4-amine pyrimidine, synthetic method is as embodiment 130.
1HNMR[(400MHz,d-DMSO)]:δ9.27(lH,s),9.21(lH,s),8.93(lH,s),8.15(lH,d,J=4.2Hz),8.07(lH,s),8.01(lH,d,J=8.1Hz),7.45-7.93(4H,m),7.35(lH,d,J=7.6Hz),6.87(lH,d,J=4.2Hz),3.59(2H,s),2.62-3.09(8H,m),2.57(3H,s).
Embodiment 139
Except replacing 4-bromo-isoquinoline with 6-chlorine imidazoles a pair of horses going side by side [1,2-A] pyrimidine, replace beyond the iodo-4-monomethylaniline of 3-with 2-chloro-4-amine pyrimidine, synthetic method is as embodiment 130.
1HNMR[(400MHz,d-DMSO)]:δ9.18(lH,s),8.97(lH,s),8.89(lH,s),8.43(lH,d,J=5.4Hz),8.11(lH,s),7.89(1H,d,J=7.8Hz),7.35(lH,d,J=7.8Hz),7.19(1H,d,J=3.4Hz),7.05(lH,d,J=3.4Hz),6.63(lH,d,J=5.4Hz),3.67(2H,s),2.56-3.01(8H,m),2.60(3H,s).
Embodiment 140
Except replacing 4-bromo-isoquinoline with 6-bromine [1,2,4] triazole a pair of horses going side by side [1,5-A] pyrimidine, replace beyond the iodo-4-monomethylaniline of 3-with 2-chloro-4-amine pyrimidine, synthetic method is as embodiment 130.
1HNMR[(400MHz,d-DMSO)]:δ9.21(lH,s),8.95(lH,s),8.87(lH,s),8.71(lH,s),8.43(lH,d,J=5.4Hz),8.11(lH,s),7.89(1H,d,J=7.8Hz),7.35(lH,d,J=7.8Hz),6.67(lH,d,J=5.4Hz),3.61(2H,s),2.6-3.11(8H,m),2.61(3H,s).
Embodiment 141
Except replacing except the iodo-4-monomethylaniline of 3-with 4-chloro-6-aminopyrimidine, synthetic method is as embodiment 130.
1HNMR[(400MHz,d-DMSO)]:δ9.71(lH,s),9.31(lH,s),8.98(lH,s),8.47(lH,s),8.21(lH,d,J=8.4Hz),7.45-8.03(5H,m),7.55(lH,d,J=7.5Hz),6.87(lH,s),3.65(2H,s),2.6-3.08(8H,m),2.59(3H,s).
Embodiment 142
Except replacing except the iodo-4-monomethylaniline of 3-with 2-amino-5-bromo thiazole, synthetic method is as embodiment 130.
1HNMR[(400MHz,d-DMSO)]:δ9.36(lH,s),8.81(lH,s),8.45(lH,s),8.21(lH,s),8.15(lH,d,J=8.2Hz),7.50-7.95(4H,m),7.78(1H,s),7.55(lH,d,J=7.5Hz),3.69(2H,s),2.6-2.98(8H,m),2.55(3H,s).
Embodiment 143
Except replacing except 4-bromo-isoquinoline with the bromo-5-picoline of 3-, synthetic method is as embodiment 1.
[M+1]：507； 1HNMR[(400MHz,d-DMSO)]:δ10.71(lH,s),8.56(lH,s),8.31(lH,s),8.22(lH,s),8.17(1H,s),8.02(lH,d,J=8.2Hz),7.88(lH,d,J=8.0Hz),7.79(lH,s),7.69(lH,d,J=8.1Hz),7.51(1H,s),3.55(2H,s),2.69-3.12(8H,m),2.61(3H,s),2.42(3H,s),2.15(3H,s).
Embodiment 144
Except replacing except 4-bromo-isoquinoline with the bromo-5-isopropyl pyridine of 3-, synthetic method is as embodiment 1.
[M+1]：535； 1HNMR[(400MHz,d-DMSO)]:δ10.77(lH,s),8.59(lH,s),8.33(lH,s),8.21(lH,s),8.18(1H,s),8.05(lH,d,J=8.2Hz),7.89(lH,d,J=8.0Hz),7.78(lH,s),7.67(lH,d,J=8.1Hz),7.53(1H,s),3.53(2H,s),2.66-3.10(9H,m),2.59(3H,s),2.13(3H,s),1.23(6H,d,J=6.8Hz).
Embodiment 145
Except replacing except 4-bromo-isoquinoline with the bromo-5-cyclopropyl pyridine of 3-, synthetic method is as embodiment 1.
[M+1]：533； 1HNMR[(400MHz,d-DMSO)]:δ10.76(lH,s),8.53(lH,s),8.35(lH,s),8.23(lH,s),8.19(1H,s),8.06(lH,d,J=8.0Hz),7.87(lH,d,J=8.1Hz),7.77(lH,s),7.68(lH,d,J=8.0Hz),7.52(1H,s),3.53(2H,s),2.73-3.15(8H,m),2.65(3H,s),2.18(3H,s)，1.60(1H,m),1.02-1.28(4H,m).
Embodiment 146
Except replacing except N methyl piperazine with dimethylamine, synthetic method is as embodiment 1.
[M+1]：488； 1HNMR[(400MHz,d-DMSO)]:δ10.73(lH,s),9.45(lH,s),8.87(lH,s),8.43(lH,d,J=8.1Hz),8.21-8.33(3H,m),8.15(lH,d,J=7.3Hz),8.03(lH,t,J=7.2Hz),8.01(lH,d,J=8.2Hz),7.81-7.93(2H,m),7.53(lH,d,J=8.1Hz),3.76(2H,s),2.31(3H,s),2.16(6H,s).
Embodiment 147
Except replacing except N methyl piperazine with Isopropylamine, synthetic method is as embodiment 1.
[M+1]：502； 1HNMR[(400MHz,d-DMSO)]:δ10.71(lH,s),9.43(lH,s),8.88(lH,s),8.42(lH,d,J=8.0Hz),8.23-8.30(3H,m),8.12(lH,d,J=7.3Hz),8.05(lH,t,J=7.1Hz),8.03(lH,d,J=8.1Hz),7.80-7.93(3H,m),7.54(lH,d,J=8.0Hz),3.71(2H,s),2.95(1H,m),2.37(3H,s),1.13(6H,d,J=6.3Hz).
Embodiment 148
Except replacing except N methyl piperazine by cyclopentamine, synthetic method is as embodiment 1.
[M+1]：528； 1HNMR[(400MHz,d-DMSO)]:δ10.72(lH,s),9.42(lH,s),8.85(lH,s),8.43(lH,d,J=7.9Hz),8.21-8.30(3H,m),8.11(lH,d,J=7.6Hz),8.03(lH,t,J=7.7Hz),8.00(lH,d,J=8.0Hz),7.81-7.93(3H,m),7.53(lH,d,J=8.0Hz),3.73(2H,s),2.92(1H,m),2.33(3H,s),1.62-1.73(4H,m),1.33-1.45(4H,m).
Embodiment 149
Except replacing except N methyl piperazine with cyclopropylamine, synthetic method is as embodiment 1.
[M+1]：500； 1HNMR[(400MHz,d-DMSO)]:δ10.75(lH,s),9.41(lH,s),8.83(lH,s),8.41(lH,d,J=8.0Hz),8.20-8.31(3H,m),8.11(lH,d,J=7.6Hz),8.04(lH,t,J=7.5Hz),8.02(lH,d,J=8.1Hz),7.79-7.92(2H,m),7.53(lH,d,J=8.0Hz),3.73(2H,s),2.35(3H,s),1.58-1.61(1H,m),1.03-1.07(4H,m).
Biological activity assay embodiment
Test example one: the active Inhibition test of molecular level receptor tyrosine kinase FGFR
1, receptor tyrosine kinase FGFR molecular level enzyme is lived and is suppressed preliminary assessment experiment
(1) the PBS(10mM sodium phosphate buffer of enzyme reaction substrate Poly (Glu, Tyr) 4:1 without potassium ion, 150mM NaCl, pH7.2-7.4) be diluted to 20 μ g/ml, 125 μ l/ hole coated elisa plates, put 37 DEG C of reaction 12-16 hour.Discard liquid in hole.Wash plate, contain the PBS without potassium ion of 0.1%Tween-20 with the T-PBS(in 200 μ l/ holes) wash plate three times, each 5 minutes.Dry enzyme plate 1-2 hour in 37 DEG C of baking ovens.
(2) every hole adds with reaction buffer (50mM HEPES pH7.4,50mM MgCl 2, 0.5mM MnCl 2, 0.2mM Na 3vO 4, 1mM DTT) and the ATP solution 50 μ L that dilutes, final concentration 5 μMs.Add 1 μ l compound (1%DMSO dissolving) in every hole, then add the FGFR protein tyrosine kinase of 50 μ l reaction buffer dilutions.Put 37 DEG C of shaking tables (100rpm) and react 1 hour.Each experiment need be established without ATP control wells holes and corresponding DMSO solvent control hole (negative control hole).Discard liquid in hole, T-PBS washes plate three times.
(3) add antibody PY99100 μ l/ hole (T-PBS of antibody containing BSA5mg/ml dilutes, and concentration is 0.4 μ g/ml), 37 ° of C shaking tables react 0.5 hour.Discard liquid in hole, T-PBS washes plate three times.
(4) add the anti-100 μ l/ holes of sheep anti mouse two (T-PBS of antibody containing BSA5mg/ml dilutes, and concentration is 0.5 μ g/ml) of horseradish peroxidase-labeled, 37 DEG C of shaking tables react 0.5 hour.Discard liquid in hole, T-PBS washes plate three times.
(5) the OPD nitrite ion 100 μ l/ hole of 2mg/ml is added (with containing 0.03%H 2o 20.1M citric acid-sodium citrate damping fluid (pH=5.4) dilution), 25 DEG C of lucifuges reaction 1-10 minute.(need with ultrasonic when OPD dissolves, nitrite ion needs now with the current).
(6) 2M H is added 2sO 450 μ l/ hole stopped reactions, to decline orifice plate microplate reader VERSAmax reading with wavelengthtunable, wavelength is 490nm.
(7) inhibiting rate of sample is tried to achieve by following formula:
Pharmacological experimental example two: cell levels receptor tyrosine kinase FGFR enzyme inhibition test alive
Western blot hybridization (Western Blot) detection compound is on the impact of FGFR2 phosphorylation in KATOIII cell
KATOIII cell is inoculated in (250,000/hole) in 12 orifice plates, cultivates after 18-24 hour and add each compound effects after 2 hours, collecting cell.First contain 1mM vanadic acid sodium with cold PBS() wash once; Then 1 × sds gel sample loading buffer (50mM Tris-HCl (pH6.8), 100mM DTT, 2%SDS, 10% glycerine, 1mM vanadic acid sodium, 0.1% tetrabromophenol sulfonphthalein) lysing cell is added.After cell lysate heats 10 minutes in boiling water bath, in centrifugal 10 minutes of 4 DEG C of 12000rpm.
Get supernatant liquor and carry out SDS-PAGE electrophoresis (Mini-PROTEAN3Cell, Bio-Rad, Hercules, CA, USA), after electrophoresis terminates, by half-dried electrotransfer system by protein delivery to nitrocellulose filter (Amersham Life Sciences, Arlington Heights, IL, USA), nitrocellulose filter is placed in confining liquid (5% skim-milk is diluted in the TBS containing 1mM vanadic acid sodium) room temperature and closes 2 hours, then the antibody 4 DEG C film being placed in anti-p-FGFR (Cell Sinaling Technology) (1:1000) or anti-GAPDH (Kangcheng Bio) (1:6000) spends the night.Three times are washed, each 15min with the TBS containing 1mM vanadic acid sodium.Film is placed in two anti-solution room temperature reaction 1-2 hour; The same wash film 3 times after, with ECL(Picece, Rockford, IL) reagent color development, development.
Pharmacological experimental example three: cell levels receptor tyrosine kinase FGFR enzyme inhibition test alive
Detection compound is on the impact of KATOIII ability of cell proliferation
The growth-inhibiting of tumour cell detects and adopts CCK8 cell viability detection method.Concrete steps are as follows: the KATOIII(3000/ hole being in logarithmic phase) cell is seeded to the 96 micro-culture plates in hole by proper density, every hole 100 μ L, after overnight incubation, add the compound effects 72hr of different concns (1,0.2,0.04,0.008 μM), each concentration establishes three wells, and establishes the physiological saline Vehicle controls of respective concentration and acellular zeroing hole.After effect terminates, every hole adds CCK810 μ L by with the inhibiting rate of following formulae discovery drug on tumor Growth of Cells: inhibiting rate (%)=(OD control wells-OD dosing holes)/OD control wells × 100%.Experiment repetition gets average twice.
Comprehensive organism data are in table 1 and table 2.
Table 1

Claims (10)

1. the alkynyl heterocyclic compound that represents of the following general formula of a class (I),
Wherein, M and Y is CH or N independently of one another;
W is C or N; Wherein, when W is N, R 1do not exist;
L be-C (O) NH-or-NHC (O)-;
R 1be selected from:
1) H, hydroxyl;
2) C 1-C 6alkyl;
3) C 1-C 6alkoxyl group;
4) C 3-C 6cycloalkyl;
5) carboxyl ,-C (=O) O (C 1-C 6alkyl) ,-C (=O) NH (C 1-C 6alkyl);
6) do not replace or be selected from halogen, C by 1-5 1-C 6the C of alkyl, halogen substiuted 1-C 6alkyl, C 1-C 6the C that substituting group in alkoxyl group replaces 6-C 10aryl;
7) do not replace or be selected from halogen, C 1-C 6the C of alkyl, halogen substiuted 1-C 6alkyl, C 1-C 6the heteroatomic 5-8 unit heteroaryl be selected from containing 1-3 in N, O and S that substituting group in alkoxyl group replaces;
8) do not replace or be selected from halogen, C 1-C 6the C of alkyl, halogen substiuted 1-C 6alkyl, C 1-C 6the heteroatomic 4-7 unit heterocyclic radical be selected from containing 1-3 in N, O and S that substituting group in alkoxyl group replaces;
9）(Q 1)(Q 2)N-；
10) R 1phenyl ring, 5-6 unit's hetero-aromatic ring containing 1-2 atom N or the first heterocycle of the 5-6 containing 1-2 atom N can be formed with A ring Y position; Wherein, described phenyl ring, hetero-aromatic ring or heterocycle can be selected from halogen, C 1-C 6the C of alkyl, halogen substiuted 1-C 6alkyl, C 1-C 6alkoxyl group, carboxyl ,-C (=O) O (C 1-C 6alkyl) ,-C (=O) NH (C 1-C 6alkyl) in substituting group replace;
R 2be selected from:
1) H, halogen, hydroxyl;
2) oxo group;
3) C 1-C 6alkyl;
4) C 1-C 6alkoxyl group;
5) C 3-C 6cycloalkyl;
6) do not replace or be selected from halogen, C by 1-5 1-C 6the C of alkyl, halogen substiuted 1-C 6alkyl, C 1-C 6the C that substituting group in alkoxyl group replaces 6-C 10aryl;
7) do not replace or be selected from halogen, C 1-C 6the C of alkyl, halogen substiuted 1-C 6alkyl, C 1-C 6the heteroatomic 5-8 unit heteroaryl be selected from containing 1-3 in N, O and S that substituting group in alkoxyl group replaces;
8) do not replace or be selected from halogen, C 1-C 6the C of alkyl, halogen substiuted 1-C 6alkyl, C 1-C 6the heteroatomic 4-7 unit heterocyclic radical be selected from containing 1-3 in N, O and S that substituting group in alkoxyl group replaces;
9）(Q 1)(Q 2)N-；
10) R 2and R 1and adjacent atom can form the 5-6 unit's hetero-aromatic ring containing 1-2 atom N or contain the 5-6 unit heterocycle of 1-2 atom N; Wherein, described hetero-aromatic ring or heterocycle can be selected from halogen, oxo group, C 1-C 6the C of alkyl, halogen substiuted 1-C 6alkyl, C 1-C 6substituting group in alkoxyl group replaces;
11) R 2the 5-6 unit's hetero-aromatic ring containing 1-2 atom N can be formed with adjacent atom N or contain the 5-6 unit heterocycle of 1-2 atom N; Wherein, described hetero-aromatic ring or heterocycle can be selected from halogen, oxo group, C 1-C 6the C of alkyl, halogen substiuted 1-C 6alkyl, C 1-C 6substituting group in alkoxyl group replaces;
R 3be selected from:
1）H;
2) halogen;
3) not replace or the C of halogen substiuted 1-C 6alkyl;
4) C 1-C 6alkoxyl group;
5) C 3-C 6cycloalkyl;
R 4, R 5and R 6be selected from independently of one another:
1）H；
2) not replace or the C of halogen substiuted 1-C 6alkyl;
3）(CH 2) nNR 7R 8；
Wherein, n is 0 or 1;
R 7and R 8be independently of one another:
1）H；
2) not replace or the C of halogen substiuted 1-C 6alkyl;
3) C 3-C 6cycloalkyl;
4) R 7and R 8ring Het can be formed with the atom N be connected 1, wherein, Het 1for being selected from the heteroatomic 5-8 unit hetero-aromatic ring in N, O and S containing 1-3; The heteroatomic 4-10 unit heterocycle in N, O and S is selected from containing 1-3; Wherein, described hetero-aromatic ring or heterocycle can be selected from halogen, oxo group, C 1-C 6the C of alkyl, halogen substiuted 1-C 6alkyl, C 1-C 6substituting group in alkoxyl group replaces;
Wherein, Q 1and Q 2be hydrogen independently of one another; C 1-C 6alkyl; C 3-C 6cycloalkyl; C 1-C 6alkyloyl; Do not replace or be selected from halogen, C by 1-5 1-C 6the C of alkyl, halogen substiuted 1-C 6alkyl, C 1-C 6the phenyl that substituting group in alkoxyl group replaces;
B ring is phenyl ring; Or the heteroatomic 5-6 unit hetero-aromatic ring be selected from containing 1-3 in N, O and S.
2. alkynyl heterocyclic compound according to claim 1,
Wherein, R 1be selected from:
1) H, hydroxyl;
2) C 1-C 4alkyl;
3) C 1-C 4alkoxyl group;
4) C 3-C 6cycloalkyl;
5) carboxyl ,-C (=O) O (C 1-C 4alkyl) ,-C (=O) NH (C 1-C 4alkyl);
6) do not replace or be selected from halogen, C by 1-5 1-C 4the C of alkyl, halogen substiuted 1-C 4alkyl, C 1-C 4the phenyl that substituting group in alkoxyl group replaces;
7) do not replace or be selected from halogen, C 1-C 4the C of alkyl, halogen substiuted 1-C 4alkyl, C 1-C 4the heteroatomic 5-6 unit heteroaryl be selected from containing 1-3 in N, O and S that substituting group in alkoxyl group replaces;
8) do not replace or be selected from halogen, C 1-C 4the C of alkyl, halogen substiuted 1-C 4alkyl, C 1-C 4the heteroatomic 4-6 unit heterocyclic radical be selected from containing 1-3 in N, O and S that substituting group in alkoxyl group replaces;
9）(Q 1)(Q 2)N-；
10) R 1phenyl ring, 5-6 unit's hetero-aromatic ring containing 1-2 atom N or the first heterocycle of the 5-6 containing 1-2 atom N can be formed with A ring Y position; Wherein, described phenyl ring, hetero-aromatic ring or heterocycle can be selected from halogen, C 1-C 4the C of alkyl, halogen substiuted 1-C 4alkyl, C 1-C 4alkoxyl group, carboxyl ,-C (=O) O (C 1-C 4alkyl) ,-C (=O) NH (C 1-C 4alkyl) in substituting group replace;
R 2be selected from:
1) H, halogen, hydroxyl;
2) oxo group;
3) C 1-C 4alkyl;
4) C 1-C 4alkoxyl group;
5) C 3-C 6cycloalkyl;
6) do not replace or be selected from halogen, C by 1-5 1-C 4the C of alkyl, halogen substiuted 1-C 4alkyl, C 1-C 4the phenyl that substituting group in alkoxyl group replaces;
7) do not replace or be selected from halogen, C 1-C 4the C of alkyl, halogen substiuted 1-C 4alkyl, C 1-C 4the heteroatomic 5-6 unit heteroaryl be selected from containing 1-3 in N, O and S that substituting group in alkoxyl group replaces;
8) do not replace or be selected from halogen, C 1-C 4the C of alkyl, halogen substiuted 1-C 4alkyl, C 1-C 4the heteroatomic 4-6 unit heterocyclic radical be selected from containing 1-3 in N, O and S that substituting group in alkoxyl group replaces;
9）(Q 1)(Q 2)N-；
10) R 2and R 1and adjacent atom can form the 5-6 unit's hetero-aromatic ring containing 1-2 atom N or contain the 5-6 unit heterocycle of 1-2 atom N; Wherein, described hetero-aromatic ring or heterocycle can be selected from halogen, oxo group, C 1-C 4the C of alkyl, halogen substiuted 1-C 4alkyl, C 1-C 4substituting group in alkoxyl group replaces;
11) R 2with adjacent atom N can be formed 5-6 unit's hetero-aromatic ring containing 1-2 atom N or containing 1-2 atom N the first heterocycle of 5-6; Wherein, described fragrant heterocycle or heterocycle can be selected from halogen, oxo group, C 1-C 4the C of alkyl, halogen substiuted 1-C 4alkyl, C 1-C 4substituting group in alkoxyl group replaces;
Wherein, Q 1and Q 2be hydrogen independently of one another; C 1-C 4alkyl; C 3-C 6cycloalkyl; C 1-C 4alkyloyl; Do not replace or be selected from halogen, C by 1-5 1-C 4the C of alkyl, halogen substiuted 1-C 4alkyl, C 1-C 4the phenyl that substituting group in alkoxyl group replaces;
R 3for:
1）H;
2) halogen;
3) not replace or the C of halogen substiuted 1-C 4alkyl;
4) C 1-C 4alkoxyl group;
5) C 3-C 4cycloalkyl;
R 4, R 5and R 6be selected from:
1）H；
2）CF 3；
3）(CH 2) nNR 7R 8；
Wherein, n is 0 or 1;
R 7and R 8be independently of one another:
1）H；
2) not replace or the C of halogen substiuted 1-C 4alkyl;
3) C 3-C 6cycloalkyl;
4) R 7and R 8ring Het can be formed with the atom N be connected 1, wherein, Het 1for being selected from the heteroatomic 5-6 unit hetero-aromatic ring in N, O and S containing 1-3; The heteroatomic 4-10 unit heterocycle in N, O and S is selected from containing 1-3; Wherein, described hetero-aromatic ring or heterocycle can be selected from halogen, oxo group, C 1-C 4the C of alkyl, halogen substiuted 1-C 4alkyl, C 1-C 4substituting group in alkoxyl group replaces.
3. alkynyl heterocyclic compound according to claim 2,
Wherein, R 1be selected from:
1) hydrogen;
2) methyl, ethyl, sec.-propyl, the tertiary butyl;
3) hydroxyl, methoxyl group, oxyethyl group, isopropoxy, tert.-butoxy;
4) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
5) do not replace or to be selected from halogen by 1-4, phenyl that methyl, methoxyl group, trifluoromethyl replace;
6) do not replace or methyl substituted pyrazolyl, not replace or methyl substituted imidazolyl, pyrimidyl;
7) azelidinyl, pyrrolidyl, piperidyl, morpholinyl, do not replace or methyl substituted piperazinyl;
8) carboxyl ,-C (=O) OMe ,-C (=O) OEt ,-C (=O) NHMe ,-C (=O) NHEt;
9) amino; Methylamino-; Dimethylamino; Tert-butylamino; Cyclopropylamino; Kharophen; The phenyl amino not replacing or replaced by halogen, methyl, methoxyl group, trifluoromethyl;
R 2be selected from:
1）H；
2）F、Cl、Br；
3) oxo group;
4) methyl, ethyl, sec.-propyl, the tertiary butyl;
5) hydroxyl, methoxyl group, oxyethyl group, isopropoxy, tert.-butoxy;
6) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
7) do not replace or to be selected from halogen by 1-4, phenyl that methyl, methoxyl group, trifluoromethyl replace;
8) amino; Methylamino-; Dimethylamino; Tert-butylamino; Cyclopropylamino; Kharophen; The phenyl amino not replacing or replaced by halogen, methyl, methoxyl group, trifluoromethyl;
R 3for:
1）H；
2）F、Cl、Br；
3) methyl, ethyl, sec.-propyl, the tertiary butyl;
4) cyclopropyl;
5) trifluoromethyl;
6) methoxyl group, oxyethyl group, tert.-butoxy;
R 4, R 5and R 6be selected from:
1）H；
2）CF 3；
3）
4）(CH 2) n-Het 1；
Wherein, n is 1; Het 1for following structure:
4. the alkynyl heterocyclic compound according to any one of claim 1-3,
Wherein, R 1the fused ring of following structure can be formed with A ring with A ring Y position:
Wherein, R 1', R 1''and R 2be selected from independently of one another:
1）H；
2）F、Cl、Br；
3) methyl, ethyl, sec.-propyl, isobutyl-, trifluoromethyl;
4) cyclopropyl;
5) hydroxyl, methoxyl group, oxyethyl group, isopropoxy, tert.-butoxy;
6) carboxyl ,-C (=O) OMe ,-C (=O) OEt ,-C (=O) NHMe ,-C (=O) NHEt;
7) amino, methylamino-, dimethylamino, tert-butylamino, cyclopropylamino, kharophen;
Or, R 2and R 1and adjacent atom can form the fused ring of following structure with A ring:
Or, R 2the fused ring of following structure can be formed with A ring with adjacent atom N:
5. the alkynyl heterocyclic compound according to any one of claim 1-3,
Wherein, B ring is the divalent group of following structure:
6. the alkynyl heterocyclic compound according to any one of claim 1-3,
Wherein, C ring is following structure:
Wherein, Het 1for following structure:
7. alkynyl heterocyclic compound according to claim 1, wherein, described alkynyl heterocyclic compound is selected from following compound:
。
8. the alkynyl heterocyclic compound according to any one of claim 1-7 is preparing the purposes in anti-tumor drug.
9. purposes according to claim 8, described tumour is any one in nonsmall-cell lung cancer, small cell lung cancer, lung squamous cancer, adenocarcinoma of lung, carcinoma of the pancreas, mammary cancer, prostate cancer, liver cancer, cancer of the stomach, skin carcinoma, cell carcinoma, nasopharyngeal carcinoma, lymphatic cancer, gastrointestinal stromal tumor, leukemia.
10. have a pharmaceutical composition for anti-tumor activity, it comprises one or more and pharmaceutically acceptable auxiliary material in the alkynyl heterocyclic compound being selected from according to any one of claim 1-7 for the treatment of significant quantity.
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CN115947693A (en) * 2022-12-18 2023-04-11 重庆医科大学 FGFR4 inhibitor and preparation and application thereof

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