CN106478621B - Quinoline or quinazoline derivative, preparation method and applications - Google Patents
Quinoline or quinazoline derivative, preparation method and applications Download PDFInfo
- Publication number
- CN106478621B CN106478621B CN201610877470.5A CN201610877470A CN106478621B CN 106478621 B CN106478621 B CN 106478621B CN 201610877470 A CN201610877470 A CN 201610877470A CN 106478621 B CN106478621 B CN 106478621B
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- China
- Prior art keywords
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- methoxy
- oxo
- quinoline
- thiazolin
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- 238000002360 preparation method Methods 0.000 title abstract description 16
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title abstract description 16
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- 150000003839 salts Chemical class 0.000 claims abstract description 20
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- -1 Hydrogen Chemical class 0.000 claims description 99
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 74
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 66
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 50
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of quinoline or quinazoline derivative, preparation method and applications, i.e. quinoline or quinazoline derivative and their pharmaceutically acceptable salts, hydrate or prodrug, structure shown in general formula I is as described below:Wherein A1、A2、R1、R2、R3、R4、R5、R6、X、Y、Z、M、W、Cy1、Cy2, m, n there is the meaning that provides in the description.Have the function of inhibiting MET kinases the invention further relates to the compound of general formula I, and the purposes of such compound and its pharmaceutically acceptable salt, hydrate in the drug that preparation treats due to MET kinases overexpression diseases caused, the especially purposes in the drug that preparation treats and prevents cancer.
Description
Technical Field
The invention relates to quinoline or quinazoline derivatives, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, a preparation method thereof and a pharmaceutical composition containing the compounds. The invention also relates to a quinoline or quinazoline derivative with a strong MET kinase inhibition effect, and also relates to application of the compound and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof in preparing medicines for treating diseases caused by abnormal high expression of MET kinase, in particular to application in preparing medicines for treating and/or preventing cancers.
Background
Malignant tumor is a disease seriously harming human life health, the number of cancer attacks is rising year by year along with the change of external factors such as environmental pollution, 2140 ten thousand new cases and 1320 ten thousand death cases are estimated to occur globally in 2030, and 70 percent of the cases occur in developing countries with low and medium income. According to the statistics of the world health organization, about 1000 ten thousand tumor patients are diagnosed every year in the world at present, 700 thousand people die from related diseases caused by tumors, and therefore, malignant tumors become the second largest killer of people only after cardiovascular diseases.
Protein Kinases (PKs) catalyze the phosphorylation of hydroxyl groups on tyrosine, serine and threonine residues of proteins by the transfer of terminal phosphate esters of ATP, which regulate cell growth, differentiation and proliferation through signal transduction pathways. In addition, abnormal PKs activity is associated with diseases of the host, such as metabolic diseases, skin diseases, tumors, and the like. Protein kinases include two classes: protein Tyrosine Kinases (PTKs) and Serine-threonine kinases (STKs). The former, by binding to growth factor ligands, converts growth factor receptors into an activated form, which interacts with proteins on the inner surface of the cell membrane, phosphorylates tyrosine residues of receptors and other proteins and leads to the formation of complexes with various cytoplasmic signaling molecules within the cell, thereby affecting various cellular responses such as cell proliferation, differentiation, metabolism, and the like.
Growth factor receptors with PTKs activity are called Receptor Tyrosine Kinases (RTKs). MET is one of the members of the large family of tyrosine kinase Growth Factor receptors, and is the only high affinity receptor that binds to Hepatocyte Growth Factor (HGF), and is therefore also referred to as Hepatocyte Growth Factor receptor, the expression product of which is a transmembrane receptor protein with tyrosine kinase activity.
Under normal physiological conditions MET kinase and HGF are expressed in a large number of tissues, but MET RNA is under low level expression and only rises briefly after tissue damage, whereupon normal levels are restored, indicating the ability of normal cells to control their response to HGF by reducing expression of MET kinase. After MET kinase is combined with HGF, epithelial cells can be promoted to disperse, the motility of the cells can be enhanced, multiple processes of growth, proliferation, differentiation, contraction, movement, secretion, mitosis and the like of the cells can be promoted, and the MET kinase has important biological significance for promoting the development of placenta and embryos, and regulating the development and the structural formation of organs such as lung, nervous system, kidney, mammary gland and the like.
However, the abnormal HGF/MET activity is closely related to the occurrence, growth, division, angiogenesis, invasiveness, metastasis, drug resistance and the like of tumors, and it exhibits characteristics such as abnormally high expression, mutation and activity change and the like in various tumor tissues, such as lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, ovarian cancer, head and neck cancer, malignant glioblastoma and the like. In addition, high expression of MET kinase and HGF is also associated with processes such as poor prognosis in tumors. Thus, MET kinase has become one of the important targets for the development of antitumor drugs.
Cabozantinib (FIG.1) belongs to quinoline compounds, is an oral antitumor drug capable of inhibiting MET and other kinase activities, and has IC effect on MET kinase50The values were 1.3nM, respectively, approved by the FDA in the united states for marketing in 2012 for the treatment of malignant locally advanced or metastatic medullary thyroid cancer that cannot be surgically resected.
The inventor designs and synthesizes a series of novel quinoline and quinazoline derivatives on the basis of reference documents; in vitro activity screening shows that the compounds have obvious antitumor activity.
Disclosure of Invention
The invention relates to quinoline or quinazoline derivatives shown in a general formula I, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
wherein,
A1is N;
A2y, Z isN、CH；
X is O, S, NH;
m is an integer between 1 and 3;
n is an integer between 1 and 6;
m is O, S;
w is S (O)0-2；
R1And R2The same or different, are respectively and independently selected from hydrogen and (C)1-C10) Alkyl, (C)3-C7) Cycloalkyl group, (C)2-C10) Alkenyl and (C)2-C10) Alkynyl, which may optionally be interrupted by 0 to 3 identical or different R7Substitution;
or R1And R2Together with the nitrogen atom to which they are attached form a 5-10 membered heterocyclyl or 5-10 membered heteroaryl group, said heterocyclyl and heteroaryl groups other than R1And R2Optionally containing 0 to 4 heteroatoms selected from N, O and S in addition to the attached nitrogen atom, except for R1And R2Said heterocyclyl optionally including, in addition to the nitrogen atom to which it is attached, 0-2 carbon-carbon double or triple bonds, said heterocyclyl and heteroaryl optionally being interrupted by 0-3 identical or different R7Substitution;
R7are each independently selected from (C)6-C10) Aryl, 5-to 10-membered heteroaryl, (C)1-C6) Alkyl, (C)3-C7) Cycloalkyl, said heteroaryl containing 1-3 heteroatoms selected from N, O or S, and R7Optionally 0 to 3 identical or different R6Substitution;
R3is H, NH2、NHS(O)0-2R8、(C1-C6) Alkylamido, optionally 1 to 5 identical or different R4Substituted arylamido, NHCONHR8；
R8Is (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, optionally hydroxy, amino or halo (C)1- C6) Alkyl, (C)6-C10) Aryl, 5-10 membered heteroaryl, wherein said heteroaryl contains 1-3 heteroatoms selected from N, O or S, and optionally 0-5R, which may be the same or different6Substitution;
Cy1is (C)6-C10) Aryl, 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Cy1Optionally 0 to 5 identical or different R6Substitution;
Cy2may be absent or is (C)6-C10) Aryl, 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Cy2Optionally 0 to 5 identical or different R5Substitution;
R4、R5、R6is hydrogen, halogen, haloalkyl, hydroxyl, cyano, amino, nitro, (C)1-C6) Alkoxy (thio) radical, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, optionally hydroxy, amino or halo (C)1-C6) Alkyl or (C)1-C6) Alkoxy radical, 1-2 (C)1-C6) Alkyl-substituted amino group, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkyl acyl, carbamoyl, substituted by 1-2 (C)1-C6) Alkyl-substituted carbamoyl group, (C)1-C3) Alkylenedioxy, allyl.
The invention preferably relates to novel quinoline and quinazoline compounds shown as a general formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
wherein,
A1is N;
A2is CH;
y, Z is N, CH;
x is O, S, NH;
m is an integer between 1 and 3;
n is an integer between 1 and 6;
m is O, S;
w is S (O)0-2；
R1And R2The same or different, are respectively and independently selected from hydrogen and (C)1-C10) Alkyl, (C)3-C7) Cycloalkyl group, (C)2-C10) Alkenyl and (C)2-C10) Alkynyl, which may optionally be interrupted by 0 to 3 identical or different R7Substitution;
or R1And R2Together with the nitrogen atom to which they are attached form a 5-10 membered heterocyclyl or 5-10 membered heteroaryl group, said heterocyclyl and heteroaryl groups other than R1And R2Optionally containing 0 to 4 heteroatoms selected from N, O and S in addition to the attached nitrogen atom, except for R1And R2Said heterocyclyl optionally including, in addition to the nitrogen atom to which it is attached, 0-2 carbon-carbon double or triple bonds, said heterocyclyl and heteroaryl optionally being interrupted by 0-3 identical or different R7Substitution;
R7are each independently selected from (C)6-C10) Aryl, 5-to 10-membered heteroaryl, (C)1-C6) Alkyl, (C)3-C7) Cycloalkyl, said heteroaryl containing 1-3 heteroatoms selected from N, O or S, and R7Optionally 0 to 3 identical or different R6Substitution;
R3is H, NH2、NHS(O)0-2R8、(C1-C6) Alkylamido, optionally 1 to 5 identical or different R4Substituted arylamido, NHCONHR8；
R8Is (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, optionally hydroxy, amino or halo (C)1-C6) Alkyl, (C)6-C10) Aryl, 5-10 membered heteroaryl, wherein said heteroaryl contains 1-3 heteroatoms selected from N, O or S, and optionally 0-5R, which may be the same or different6Substitution;
Cy1is (C)6-C10) Aryl, 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Cy1Optionally 0 to 5 identical or different R6Substitution;
Cy2may be absent or is (C)6-C10) Aryl, 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Cy2Optionally 0 to 5 identical or different R5Substitution;
R4、R5、R6is hydrogen, halogen, haloalkyl, hydroxyl, cyano, amino, nitro, (C)1-C6) Alkoxy (thio) radical, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, optionally hydroxy, amino or halo (C)1-C6) Alkyl or (C)1-C6) Alkoxy radical, 1-2 (C)1-C6) Alkyl-substituted amino group, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkyl acyl, carbamoyl, substituted by 1-2 (C)1-C6) Alkyl-substituted carbamoyl group, (C)1-C3) Alkylenedioxy, allyl.
The invention also preferably relates to quinoline and quinazoline compounds shown as a general formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
wherein,
A1is N;
A2is CH;
y, Z is CH;
x is O;
m is an integer between 1 and 3;
n is an integer between 1 and 6;
m is O, S;
w is S (O)0-2；
R1And R2The same or different, are respectively and independently selected from hydrogen and (C)1-C10) Alkyl, (C)3-C7) Cycloalkyl group, (C)2-C10) Alkenyl and (C)2-C10) Alkynyl, which may optionally be interrupted by 0 to 3 identical or different R7Substitution;
or R1And R2Together with the nitrogen atom to which they are attached form a 5-10 membered heterocyclyl or 5-10 membered heteroaryl group, said heterocyclyl and heteroaryl groups other than R1And R2Optionally containing 0 to 4 heteroatoms selected from N, O and S in addition to the attached nitrogen atom, except for R1And R2Said heterocyclyl optionally including, in addition to the nitrogen atom to which it is attached, 0-2 carbon-carbon double or triple bonds, said heterocyclyl and heteroaryl optionally being interrupted by 0-3 identical or different R7Substitution;
R7are each independently selected from (C)6-C10) Aryl, 5-to 10-membered heteroaryl, (C)1-C6) Alkyl, (C)3-C7) Cycloalkyl, said heteroaryl containing 1-3 heteroatoms selected from N, O or S, and R7Optionally 0 to 3 identical or different R6Substitution;
R3is H, NH2、NHS(O)0-2R8、(C1-C6) Alkylamido, optionally 1 to 5 identical or different R4Substituted arylamido, NHCONHR8；
R8Is (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, optionally hydroxy, amino or halo (C)1-C6) Alkyl, (C)6-C10) Aryl, 5-10 membered heteroaryl, wherein said heteroaryl contains 1-3 heteroatoms selected from N, O or S, and optionally 0-5R, which may be the same or different6Substitution;
Cy1is (C)6-C10) Aryl, 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Cy1Optionally 0 to 5 identical or different R6Substitution;
Cy2may be absent or is (C)6-C10) Aryl, 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Cy2Optionally 0 to 5 identical or different R5Substitution;
R4、R5、R6is hydrogen, halogen, haloalkyl, hydroxyl, cyano, amino, nitro, (C)1-C6) Alkoxy (thio) radical, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, optionally hydroxy, amino or halo (C)1-C6) Alkyl or (C)1-C6) Alkoxy radical, 1-2 (C)1-C6) Alkyl-substituted amino group, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkyl acyl, carbamoyl, substituted by 1-2 (C)1-C6) Alkyl-substituted carbamoyl group, (C)1-C3) Alkylene oxideDioxy group, allyl group.
The invention particularly preferably relates to quinoline and quinazoline compounds shown as a general formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
wherein,
A1is N;
A2is CH;
y, Z is CH;
x is O;
m is an integer between 1 and 3;
n is an integer between 1 and 6;
m is O, S;
w is S;
R1and R2The same or different, are respectively and independently selected from hydrogen and (C)1-C10) Alkyl, (C)3-C7) Cycloalkyl group, (C)2-C10) Alkenyl and (C)2-C10) Alkynyl, which may optionally be interrupted by 0 to 3 identical or different R7Substitution;
or R1And R2Together with the nitrogen atom to which they are attached form a 5-10 membered heterocyclyl or 5-10 membered heteroaryl group, said heterocyclyl and heteroaryl groups other than R1And R2Optionally containing 0 to 4 heteroatoms selected from N, O and S in addition to the attached nitrogen atom, except for R1And R2Said heterocyclyl optionally including, in addition to the nitrogen atom to which it is attached, 0-2 carbon-carbon double or triple bonds, said heterocyclyl and heteroaryl optionally being interrupted by 0-3 identical or different R7Substitution;
R7are each independently selected from (C)6-C10) Aryl, 5-to 10-membered heteroaryl, (C)1-C6) Alkyl, (C)3-C7) Cycloalkyl, said heteroaryl containing 1-3 heteroatoms selected from N, O or S, and R7Optionally 0 to 3 identical or different R6Substitution;
R3is H, NH2、NHS(O)0-2R8、(C1-C6) Alkylamido, optionally 1 to 5 identical or different R4Substituted arylamido, NHCONHR8；
R8Is (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, optionally hydroxy, amino or halo (C)1-C6) Alkyl, (C)6-C10) Aryl, 5-10 membered heteroaryl, wherein said heteroaryl contains 1-3 heteroatoms selected from N, O or S, and optionally 0-5R, which may be the same or different6Substitution;
Cy1is (C)6-C10) Aryl, 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Cy1Optionally 0 to 5 identical or different R6Substitution;
Cy2may be absent or is (C)6-C10) Aryl, 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Cy2Optionally 0 to 5 identical or different R5Substitution;
R4、R5、R6is hydrogen, halogen, haloalkyl, hydroxyl, cyano, amino, nitro, (C)1-C6) Alkoxy (thio) radical, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, optionally hydroxy, amino or halo (C)1-C6) Alkyl or (C)1-C6) Alkoxy radical, 1-2 (C)1-C6) Alkyl-substituted amino group, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkyl acyl, carbamoyl, substituted by 1-2 (C)1-C6) Alkyl-substituted carbamoyl group, (C)1-C3) Alkylenedioxy, allyl.
The invention particularly preferably relates to quinoline or quinazoline derivatives shown in a general formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
wherein,
A1is N;
A2is CH;
y, Z is CH;
x is O;
m is 1;
n is 3;
m is O, S;
w is S;
R1and R2The same or different, are respectively and independently selected from hydrogen and (C)1-C10) Alkyl, (C)3-C7) Cycloalkyl group, (C)2-C10) Alkenyl and (C)2-C10) Alkynyl, which may optionally be interrupted by 0 to 3 identical or different R7Substitution;
or R1And R2Together with the nitrogen atom to which they are attached form a 5-10 membered heterocyclyl or 5-10 membered heteroaryl group, said heterocyclyl and heteroaryl groups other than R1And R2Optionally containing 0 to 4 heteroatoms selected from N, O and S in addition to the attached nitrogen atom, except for R1And R2Said heterocyclyl optionally including, in addition to the nitrogen atom to which it is attached, 0-2 carbon-carbon double or triple bonds, said heterocyclyl and heteroaryl optionally being interrupted by 0-3 identical or different R7Substitution;
R7are each independently selected from (C)6-C10) Aryl, 5-to 10-membered heteroaryl, (C)1-C6) Alkyl, aryl, heteroaryl, and heteroaryl,(C3-C7) Cycloalkyl, said heteroaryl containing 1-3 heteroatoms selected from N, O or S, and R7Optionally 0 to 3 identical or different R6Substitution;
R3is H, NH2、NHS(O)0-2R8、(C1-C6) Alkylamido, optionally 1 to 5 identical or different R4Substituted arylamido, NHCONHR8；
R8Is (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, optionally hydroxy, amino or halo (C)1-C6) Alkyl, (C)6-C10) Aryl, 5-10 membered heteroaryl, wherein said heteroaryl contains 1-3 heteroatoms selected from N, O or S, and optionally 0-5R, which may be the same or different6Substitution;
Cy1is (C)6-C10) Aryl, 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Cy1Optionally 0 to 5 identical or different R6Substitution;
Cy2may be absent or is (C)6-C10) Aryl, 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Cy2Optionally 0 to 5 identical or different R5Substitution;
R4、R5、R6is hydrogen, halogen, haloalkyl, hydroxyl, cyano, amino, nitro, (C)1-C6) Alkoxy (thio) radical, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, optionally hydroxy, amino or halo (C)1-C6) Alkyl or (C)1-C6) Alkoxy radical, 1-2 (C)1-C6) Alkyl-substituted amino group, (C)1-C6) Alkylamido, free, salified, esterified and amidated carboxyl, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkyl acyl, carbamoyl, substituted by 1-2 (C)1-C6) Alkyl-substituted carbamoyl group, (C)1-C3) Alkylenedioxy, allyl.
The invention particularly preferably relates to quinoline and quinazoline compounds shown as a general formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
wherein,
A1is N;
A2is CH;
y, Z is CH;
x is O;
m is 1;
n is 3;
m is O, S;
w is S;
R1and R2The same or different, are respectively and independently selected from hydrogen and (C)1-C10) Alkyl, (C)3-C7) Cycloalkyl group, (C)2-C10) Alkenyl and (C)2-C10) Alkynyl, which may optionally be interrupted by 0 to 3 identical or different R7Substitution;
or R1And R2Together with the nitrogen atom to which they are attached form a 5-10 membered heterocyclyl or 5-10 membered heteroaryl group, said heterocyclyl and heteroaryl groups other than R1And R2Optionally containing 0 to 4 heteroatoms selected from N, O and S in addition to the attached nitrogen atom, except for R1And R2Said heterocyclyl optionally including, in addition to the nitrogen atom to which it is attached, 0-2 carbon-carbon double or triple bonds, said heterocyclyl and heteroaryl optionally being interrupted by 0-3 identical or different R7Substitution;
R3is H,NH2、NHS(O)0-2R8、(C1-C6) Alkylamido, optionally 1 to 5 identical or different R4Substituted arylamido, NHCONHR8；
R8Is (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, optionally hydroxy, amino or halo (C)1-C6) Alkyl, (C)6-C10) Aryl, 5-10 membered heteroaryl, wherein said heteroaryl contains 1-3 heteroatoms selected from N, O or S, and optionally 0-5R, which may be the same or different6Substitution;
Cy1is (C)6-C10) Aryl, 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Cy1Optionally 0 to 5 identical or different R6Substitution;
Cy2may be absent or is (C)6-C10) Aryl, 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Cy2Optionally 0 to 5 identical or different R5Substitution;
R1and R2The same or different, are respectively and independently selected from hydrogen and (C)1-C10) Alkyl, (C)3-C7) Cycloalkyl group, (C)2-C10) Alkenyl and (C)2-C10) Alkynyl, which may optionally be interrupted by 0 to 3 identical or different R7Substitution;
or R1And R2Together with the nitrogen atom to which they are attached form a 5-10 membered heterocyclyl or 5-10 membered heteroaryl group, said heterocyclyl and heteroaryl groups other than R1And R2Optionally containing 0 to 4 heteroatoms selected from N, O and S in addition to the attached nitrogen atom, except for R1And R2Said heterocyclyl optionally including, in addition to the nitrogen atom to which it is attached, 0-2 carbon-carbon double or triple bonds, said heterocyclyl and heteroaryl optionally being interrupted by 0-3 identical or different R7Substitution；
R7Is (C)1-C4) An alkyl group;
Cy1is phenyl, naphthyl, quinolyl, pyridyl, furyl, thienyl or pyrrolyl, and Cy1Optionally 0 to 5 identical or different R6Substitution;
R3is H, NH2、NHS(O)0-2R8、(C1-C6) Alkylamido, optionally 1 to 5 identical or different R4Substituted arylamido, NHCONHR8；
Cy2May be absent or be phenyl, naphthyl, quinolinyl, pyridinyl, furanyl, thienyl and pyrrolyl, and Cy2Optionally 0 to 5 identical or different R5Substitution;
R5、R6is hydrogen or 0 to 5 substituents selected from the group consisting of halogen, (C)1-C4) Alkyl, (C)1-C4) Alkoxy, trifluoromethyl and trifluoromethoxy.
The invention particularly preferably relates to quinoline or quinazoline derivatives shown in a general formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
wherein,
x is O;
A2y, Z are N, CH, respectively;
A1is N;
m is 1;
n is 3;
m is O;
w is S;
R1and R2Together with the nitrogen atom to which they are attached form 1-piperidinyl, 4-morpholinyl, 4-methyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 4-methyl-1-piperidinyl, 4-methylene-1-piperidinyl, 1-pyrrolidinyl, azetidinyl, 4-thiomorpholinyl;
R3is hydrogen, amino, acetamido, trifluoromethanesulfonamido, propylureido, butylureido or substituted phenylureido;
Cy1is phenyl, naphthyl, and Cy1Optionally 0 to 5 identical or different R6Substitution;
Cy2is absent or is phenyl, and Cy2Optionally 0 to 5 identical or different R5Substitution;
R4、R5、R6hydrogen, halogen, trifluoromethyl and methyl.
Furthermore, the quinoline or quinazoline derivatives of the general formula I of the present invention may be combined with an acid to form a pharmaceutically acceptable salt according to methods common in the art to which the present invention pertains. Pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, with the following acids being particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like.
In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the invention are those of formula i which may themselves be less active or even inactive, but which, upon administration, are converted to the corresponding biologically active form under physiological conditions (e.g., by metabolism, solvolysis, or otherwise).
"halogen" in the present invention means fluorine, chlorine, bromine or iodine; "alkyl" refers to straight or branched chain alkyl; "alkylene" refers to straight or branched chain alkylene; "cycloalkyl" refers to a substituted or unsubstituted cycloalkyl; "aryl" means phenyl or naphthyl with no substituents or with substituents; "heteroaryl" means a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, the ring system being aromatic, such as imidazolyl, pyridyl, pyrazolyl, (1,2,3) -and (1,2,4) -triazolyl, furyl, thienyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, and the like; "saturated or partially saturated heterocyclyl" refers to monocyclic or polycyclic ring systems containing one or more heteroatoms selected from N, O, S, such as pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolidinyl, imidazolidinyl, thiazolinyl, and the like.
We have found that the compounds of the present invention have activity in inhibiting the growth of tumor cells in vitro and therefore, it can be used for the preparation of a medicament for the treatment and/or prevention of cancers, such as breast, lung, liver, kidney, colon, rectum, stomach, prostate, bladder, uterus, pancreas, bone marrow, testis, ovary, lymph, soft tissues, head and neck, thyroid, esophageal cancers and leukemias, neuroblastoma and the like.
Through in vitro activity tests of inhibiting colon cancer cells HT-29, human gastric cancer cells MKN-45 and human breast cancer cells MDA-MB-231, the compound has a remarkable inhibiting effect on colon cancer cells, gastric cancer cells, breast cancer liver cancer and the like, and is particularly used for preparing medicines for treating and/or preventing colon cancer, gastric cancer and breast cancer.
The compound disclosed by the invention is found to have obvious MET kinase inhibition activity through MET kinase activity tests, has a strong inhibition effect on MET-highly-expressed colon cancer cells, gastric cancer cells, breast cancer cells and the like, and is particularly used for preparing a medicine for treating and/or preventing gastric cancer.
The active compound or the medicinal salt and the solvate thereof can be used alone as a unique antitumor medicament or can be used together with the antitumor medicaments (such as platinum medicament cisplatin, camptothecin medicament irinotecan, vinca alkali medicament navelbine, deoxycytidine medicament gemcitabine, etoposide, taxol and the like) on the market at present. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and their methods of preparation. It should be understood that the scope of the following examples and preparations are not intended to limit the scope of the invention in any way.
The following synthetic scheme (scheme 1) outlines and describes the preparation of the derivatives of formula I of the present invention, all starting materials are prepared by the means described in these schemes, by methods well known to those of ordinary skill in the art of organic chemistry or are commercially available. All final derivatives of the invention are prepared by the methods described in these schemes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All of the variable factors applied in these flow paths are as defined below or in the claims.
The derivatives of formula I according to the invention can be prepared according to the method of scheme 1 from intermediate Q by addition and dehydration with the corresponding mercapto-substituted acid under the action of silicon tetrachloride. Wherein A in the compound1、A2、R1、R2、R3、R4、R5、R6、X、Y、Z、M、W、Cy1、Cy2M and n are as defined in the claims.
When M is O, R3For H, intermediate Q-1 can be prepared as shown in scheme 2:
when M is S, R3For H, intermediate Q-2 can be prepared as shown in scheme 3:
when M is O, R3Is NH2The preparation of intermediate Q-3 is shown in scheme 4:
substituent A of all intermediates in the above 3 routes1、A2、R1、R2、R3、R4、R5、R6、X、Y、Z、M、W、Cy1、Cy2M and n are as defined in the claims.
Detailed Description
The examples are intended to illustrate, but not to limit, the scope of the invention. The nuclear magnetic resonance hydrogen spectrum of the compound is measured by BrukeraRx-400, and the mass spectrum is measured by Agilent 1100 quadrupole LC-MS; all reagents used were analytically or chemically pure.
Example 1:
step ⑴ 1- [4- (3-chloropropyloxy) -3-methoxy ] acetophenone (III)
500.0g (3.01mol) of 3-methoxy-4-hydroxyacetophenone II and 581.7g (4.22mol) of anhydrous potassium carbonate are added into 2L N, N-Dimethylformamide (DMF) at room temperature, stirred well for 30min, then 311.7mL (3.16mol) of 1, 3-bromochloropropane is added dropwise, and stirring is continued at room temperature for 6 h. The reaction solution was poured into 5L of ice water, filtered with suction, and the filter cake was dried to obtain 692.2g of a white solid.
Step ⑵ 1 [4- (3-chloropropyloxy) -5-methoxy-2-nitro ] acetophenone (IV)
500.0g (2.05mol) of intermediate III are added to 2.5L of dichloromethane. Keeping the temperature of the reaction solution between minus 20 ℃ and minus 10 ℃, slowly dripping 320.0g of fuming nitric acid, and reacting for 2 hours at minus 10 ℃. The reaction solution was poured into ice water, and the organic layer was collected, washed with saturated aqueous sodium bicarbonate solution to neutrality, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain 521.4g of a yellow solid.
Step ⑶ 1- [4- (3-chloropropoxy) -5-methoxy-2-nitrophenyl ] -3- (dimethylamino) propyl-2-en-1-one (V)
500.0g (1.74mol) of intermediate IV was added to 2.5L of xylene, and 1035g (8.69mol) of N, N-dimethylformamide dimethyl acetal (DMF-DMA) was added thereto, followed by reflux reaction for 15 hours. The reaction solution was cooled to-10 ℃, filtered, the filter cake was washed with an appropriate amount of xylene and dried to obtain 442.0g of a yellow solid.
Step ⑷ 7- (3-chloropropoxy) -6-methoxy-4 (1H) -quinolinone (VI)
400.0g (1.17mol) of intermediate V are added to 3L of glacial acetic acid, the temperature is raised to 60 ℃, 328.3g (5.85mol) of reduced iron powder are added in portions, and the reaction is carried out for 2h at 90 ℃. And carrying out suction filtration while the solution is hot, cooling the filtrate, and carrying out suction filtration to obtain a solid in a khaki color. After recrystallization from glacial acetic acid, 216.5g of a yellow solid are obtained.
Step ⑸ 6-methoxy-7- [3- (4-morpholinyl) propoxy ] -4(1H) -quinolinone (VII)
200.0g (0.75mol) of intermediate VI and 650mL (7.5mol) of morpholine were added to 2L of acetonitrile and the reaction was refluxed for 12 h. Most of the solvent is evaporated, the residual liquid is cooled to-10 ℃, solid is precipitated, and the solid 211.9g is obtained after suction filtration and ethyl acetate washing.
Step ⑹ 4-chloro-6-methoxy-7- [3- (4-morpholinyl) propoxy ] quinoline (VIII)
200.0g (0.63mol) of the intermediate VII and 1L of phosphorus oxychloride were added to 1L of dry acetonitrile and reacted under reflux for 6 hours. Evaporating to dryness under reduced pressure, adding the concentrated solution into ice water under vigorous stirring, adjusting pH to 8 with 10% NaOH aqueous solution, and adjusting CH2Cl2Extraction (3X 500mL), combination of organic layers, drying over anhydrous sodium sulfate, evaporation of solvent to dryness, cooling to give 184.2g of an off-white solid.
Step ⑺ 4- (4-Nitrophenoxy) -6-methoxy-7- [3- (4-morpholinyl) propoxy ] quinoline (IX)
150.0g (0.48mol) of intermediate VIII and 77.8g (0.56mol) of 4-nitrophenol are added to 600mL of dry chlorobenzene and refluxed for 20 h. Evaporating the solvent to dryness to obtain grey solid, dissolving in CH2Cl2Then, the mixture was washed with a 10% aqueous solution of sodium hydroxide, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain 125.6g of a solid.
Step ⑻ 4 [ 6-methoxy-7- [3- (4-morpholinyl) propoxy ] quinolin-4-oxy ] phenylamine (X)
120.0g (0.27mol) of intermediate IX, 152.7g (2.72mol) of reduced iron powder and 15mL of concentrated hydrochloric acid were added to 2L 90% EtOH-H2And (4) refluxing for 2h after the addition of the catalyst in O. Suction filtration is carried out while hot, and the filtrate is collected and evaporated to dryness to obtain 111.8g of yellow solid.
Step ⑼ 4 phenyl 4- [4- [7- [3- (4-morpholinyl) propoxy ] -6-methoxyquinoline-4-oxy ] phenyl ] carbamate (XI)
100.0g (0.24mol) of intermediate X and 101.2g (0.73mol) of anhydrous potassium carbonate were added to 1.5L of dry acetone at room temperature, 44.8mL (0.26mol) of phenyl chloroformate was added dropwise at 0 ℃ and, after completion of the addition, the mixture was stirred at room temperature for 5 hours. The solvent was evaporated, 1L of dichloromethane was added, washed with water (3X 100mL), dried over anhydrous sodium sulfate, and evaporated to dryness to give 109.6g of a yellow oily liquid.
Step ⑽ 4 [4- [7- [3- (4-morpholinyl) propoxy ] -6-methoxyquinolin-4-yloxy ] phenyl ] semicarbazide (XII)
100.0g (0.19mol) of intermediate XI was dissolved in 400mL of dioxane, and 500mL of 80% hydrazine hydrate was added thereto and refluxed for about 8 hours. Most of dioxane is evaporated, cooled and filtered to obtain 79.8g of light yellow white solid.
Steps ⑾ (E) -N1- (4- (6-methoxy-7- (3-morpholinopropoxy) quinolin-4-oxy) phenyl) -N4-benzylidene semicarbazone (Q-1)
20.0g (42.8mmol) of intermediate XII and 5.0g (47.1mmol) of benzaldehyde are introduced into 200mL of isopropanol, 1mL of glacial acetic acid are added and the mixture is refluxed for 5 h. Cooling, suction filtering, leaching the filter cake with a little isopropanol to obtain 17.3g of white solid.
Step ⑿ 1- [4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-oxy ] phenyl ] -3- (4-oxo-2-phenylthiazolin-3-yl) urea (example 1)
10.0g (18.0mmol) of intermediate Q-1 was added to 40mL of thioglycolic acid at room temperature, 1mL of silicon tetrachloride was added, and after the addition was completed, stirring was carried out at room temperature for about 6 hours. Adjusting pH to 8 with 10% sodium hydroxide aqueous solution, extracting with dichloromethane (2 × 100mL), drying the organic phase with anhydrous sodium sulfate, evaporating to dryness, and purifying by column chromatography to obtain white solid 5.8 g.
1H-NMR(400MHz,DMSO-d6)δ9.06(s,1H)，8.62(s,1H)，8.46(s,1H)，7.47-7.62(br,5H)，7.42-7.46(br,4H)，7.19(m,2H)，6.42(s,1H)，5.86(s,1H)，4.21(br,2H)，3.95(s,3H)，3.88(br,1H)，3.82(br,1H)，3.61(br,4H)，2.30-2.45(br,6H)，2.00(br,2H)；ESI-MS[M+H](m/z):630.2。
The compounds of examples 2 to 21 were prepared by the method of example 1, using intermediate Q-1 having different substituents as a starting material, and subjecting to addition and dehydration reaction with thioglycolic acid.
Example 21- [4- [ 6-methoxy-7- [3- (4-methylpiperidin-1-yl) propoxy ] quinolin-4-oxy ] phenyl ] -3- (4-oxo-2-phenylthiazolin-3-yl) urea
1H-NMR(400MHz,DMSO-d6)δ8.97-9.03(br,1H)，8.58(s,1H)，8.44(d,J＝5.2Hz,1H)，7.54-7.65(m,6H)，7.37(s,1H)，7.22-7.28(m,2H)，7.19(m,2H)，6.44(d,J＝5.2Hz,1H)，5.85(s,1H)，4.19(t,J＝6.4Hz,2H)，3.96(s,3H)，3.80-3.86(m,2H)，2.87(m,2H)，2.45(m,2H)，1.84-2.01(m,4H)，1.60(m,2H)，1.23-1.40(m,1H)，1.03-1.21(m,2H)，0.90(d,J＝6.4Hz,3H)；ESI-MS[M+H](m/z):642.3。
Example 31- [4- [ 6-methoxy-7- [3- (tetrahydropyrrol-1-yl) propoxy ] quinolin-4-oxy ] phenyl ] -3- (4-oxo-2-phenylthiazolin-3-yl) urea
1H-NMR(400MHz,DMSO-d6)δ9.04(br,1H)，8.66(s,1H)，8.47(d,J＝5.2Hz,1H)，7.91(br,1H)，7.82(d,J＝5.6Hz,1H)，7.73(d,J＝5.6Hz,1H)，7.63-7.67(m,1H)，7.52(d,J＝8.8Hz,2H)，7.51(s,1H)，7.37(s,1H)，7.19(d,J＝8.8Hz,2H)，6.44(d,J＝5.2Hz,1H)，5.94(s,1H)，4.22(t,J＝6.4Hz,2H)，3.96(s,3H)，3.79-3.84(m,2H)，2.65-2.74(m,2H)，2.54-2.61(br,4H)，1.98-2.07(m,2H)，1.65-1.83(br,4H)；ESI-MS[M+H](m/z):614.3。
Example 41- [4- [ 6-methoxy-7- [3- (4-methylpiperazin-1-yl) propoxy ] quinolin-4-oxy ] phenyl ] -3- (4-oxo-2-phenylthiazolin-3-yl) urea
1H-NMR(400MHz,DMSO-d6)δ8.86-8.94(br,1H)，8.45(d,J＝5.2Hz,1H)，8.39(s,1H)，7.54(d,J＝8.8Hz,2H)，7.51(s,1H)，7.39(s,1H)，7.24-7.32(m,2H)，7.19(d,J＝8.8Hz,2H)，6.74(d,J＝8.8Hz,2H)，6.42(d,J＝5.2Hz,1H)，5.71(s,1H)，4.37(d,J＝5.9Hz,2H)，4.07(s,3H)，3.85-3.92(m,2H)，3.44(m,10H)，2.85(s,3H)，2.39(s,2H)；ESI-MS[M+H](m/z):643.3。
Example 51- [4- [ 6-methoxy-7- [3- (4-methylenepiperidin-1-yl) propoxy ] quinolin-4-oxy ] phenyl ] -3- (4-oxo-2-phenylthiazolin-3-yl) urea
1H-NMR(400MHz,DMSO-d6)δ8.92-9.01(br,1H)，8.43(d,J＝5.2Hz,1H)，8.35(s,1H)，7.51(d,J＝8.8Hz,2H)，7.47(s,1H)，7.37(s,1H)，7.21-7.30(m,2H)，7.17(d,J＝8.8Hz,2H)，6.72(d,J＝8.8Hz,2H)，6.40(d,J＝5.2Hz,1H)，5.70(s,1H)，4.94-5.08(m,2H)，4.34(d,J＝6.0Hz,2H)，4.03(s,3H)，3.83-3.90(m,2H)，3.38-3.46(m,8H)，2.04-2.09(m,4H)；ESI-MS[M+H](m/z):640.2。
Example 61- [4- [ 6-methoxy-7- [3- (3, 5-dimethylpiperidin-1-yl) propoxy ] quinolin-4-oxy ] phenyl ] -3- (4-oxo-2-phenylthiazolin-3-yl) urea
1H-NMR(400MHz,DMSO-d6)δ9.06(s,1H)，8.69(s,1H)，8.48(d,J＝5.2Hz,1H)，7.90(br,1H)，7.83(d,J＝5.6Hz,1H)，7.72(d,J＝5.6Hz,1H)，7.61-7.66(m,1H)，7.54(d,J＝8.8Hz,2H)，7.53(s,1H)，7.35(s,1H)，7.16(d,J＝8.8Hz,2H)，6.41(d,J＝5.2Hz,1H)，6.17(s,1H)，4.18(t,J＝6.4Hz,2H)，3.94(s,3H)，3.84(s,2H)，2.81-2.89(m,2H)，2.41-2.48(m,2H)，1.91-2.01(m,2H)，1.52-1.71(m,2H)，1.36-1.48(m,2H)，0.83(d,J＝6.4Hz,6H)，0.45-0.54(m,1H)；ESI-MS[M+H](m/z):655.4。
Example 71- [4- [ 6-methoxy-7- [3- (4-ethylpiperazin-1-yl) propoxy ] quinolin-4-oxy ] phenyl ] -3- (4-oxo-2-phenylthiazolin-3-yl) urea
ESI-MS[M+H](m/z):630.2；1H-NMR(400MHz,DMSO-d6)δ8.97-9.03(br,1H)，8.58(s,1H)，8.44(d,J＝5.2Hz,1H)，7.54-7.65(m,6H)，7.37(s,1H)，7.22-7.28(m,2H)，7.19(m,2H)，6.44(d,J＝5.2Hz,1H)，5.97(s,1H)，4.37(d,J＝6.4Hz,2H)，4.07(s,3H)，3.89(s,2H)，3.44(m,10H)，2.93(q,2H)，2.39(s,2H)，1.04(t,3H)。ESI-MS[M+H](m/z):656.4。
Example 81- [4- [ 6-methoxy-7- [3- (N-heterocyclic-but-1-yl) propoxy ] quinolin-4-oxy ] phenyl ] -3- (4-oxo-2-phenylthiazolin-3-yl) urea
1H-NMR(400MHz,DMSO-d6)δ9.04(s,1H)，8.66(s,1H)，8.46(d,J＝5.2Hz,1H)，7.93(m,1H)，7.81(d,J＝5.6Hz,1H)，7.75(d,J＝5.6Hz,1H)，7.64-7.69(m,1H)，7.54(d,J＝8.8Hz,2H)，7.52(s,1H)，7.39(s,1H)，7.17(d,J＝8.8Hz,2H)，6.47(d,J＝5.2Hz,1H)，5.98(s,1H)，4.21(t,J＝6.4Hz,2H)，3.97(s,3H)，3.77-3.83(m,2H)，2.66-2.72(m,2H)，2.52-2.60(br,4H)，1.98-2.06(m,2H)，1.63-1.74(br,4H)；ESI-MS[M+H](m/z):600.3。
Example 91- [6- [ 6-methoxy-7- [3- (tetrahydropyrrol-1-yl) propoxy ] quinolin-4-oxy ] pyridin-3-yl ] -3- [ 4-oxo-2- (4-fluorophenyl) thiazolin-3-yl) urea
1H-NMR(400MHz,DMSO-d6)δ8.97-9.03(br,1H)，8.53(s,1H)，8.42(d,J＝5.2Hz,1H)，7.50-7.61(m,6H)，7.37(s,1H)，7.21-7.26(m,2H)，7.17(m,2H)，6.41(d,J＝5.2Hz,1H)，5.85(s,1H)，4.21(t,J＝6.4Hz,2H)，3.95(s,3H)，3.79-3.83(m,2H)，2.66-2.72(m,2H)，2.52-2.60(br,4H)，1.98-2.06(m,2H)，1.63-1.74(br,4H)；ESI-MS[M+H](m/z):631.2。
Example 101- [6- [ 6-methoxy-7- [3- (4-methylpiperidin-1-yl) propoxy ] quinolin-4-oxy ] pyridin-3-yl ] -3- [ 4-oxo-2- (4-fluorophenyl) thiazolin-3-yl) urea
1H-NMR(400MHz,DMSO-d6)δ9.03-9.11(br,1H)，8.57(s,1H)，8.46(d,J＝5.2Hz,1H)，7.53-7.64(m,6H)，7.42(s,1H)，7.25-7.30(m,2H)，7.22(m,2H)，6.44(d,J＝5.2Hz,1H)，5.87(s,1H)，4.21(t,J＝6.4Hz,2H)，3.98(s,3H)，3.82-3.89(m,2H)，2.89(m,2H)，2.47(m,2H)，1.85-2.00(m,4H)，1.63(m,2H)，1.25-1.41(m,1H)，1.04-1.19(m,2H)，0.92(d,J＝6.4Hz,3H)；ESI-MS[M+H](m/z):659.3。
Example 111- [6- [ 6-methoxy-7- (3-morpholinylpropoxy) quinolin-4-oxy ] pyridin-3-yl ] -3- [ 4-oxo-2- (4-fluorophenyl) thiazolin-3-yl) urea
1H-NMR(400MHz,DMSO-d6)δ8.98-9.05(br,1H),8.55(s,1H),8.45(d,J＝5.2Hz,1H),7.51-7.63(m,6H),7.39(s,1H),7.23-7.27(m,2H),7.19(m,2H),6.42(d,J＝5.2Hz,1H),5.86(s,1H),4.21(t,J＝6.0Hz,2H),3.94(s,3H),3.80-3.87(m,2H),3.57-3.67(br,4H),2.32-2.47(br,6H),1.95-2.07(br,2H)；ESI-MS[M+H](m/z):647.2。
Example 121- [6- [ 6-methoxy-7- [3- (4-methylpiperazin-1-yl) propoxy ] quinolin-4-oxy ] pyridin-3-yl ] -3- [ 4-oxo-2- (4-fluorophenyl) thiazolin-3-yl) urea
1H-NMR(400MHz,DMSO-d6)δ9.02(s,1H)，8.59(s,1H)，8.48(d,J＝5.2Hz,1H)，7.55-7.65(m,6H)，7.44(s,1H)，7.23-7.31(m,2H)，7.23(m,2H)，6.47(d,J＝5.2Hz,1H)，5.93(s,1H)，4.22(t,J＝6.4Hz,2H)，3.98(s,3H)，3.91(s,2H)，3.32(s,3H)，2.88(m,2H)，2.46(m,2H)，1.82-2.01(m,4H)，1.59(m,2H)，1.12-1.24(m,2H)；ESI-MS[M+H](m/z):660.3。
Example 131- [4- [ 6-methoxy-7- [3- (tetrahydropyrrol-1-yl) propoxy ] quinolin-4-oxy ] phenyl ] -3- [ 4-oxo-2- (3-trifluoromethylphenyl) thiazolin-3-yl ] urea
1H-NMR(400MHz,DMSO-d6)δ9.01-9.09(br,1H)，8.63(s,1H)，8.47(d,J＝5.2Hz,1H)，7.91-7.94(br,1H)，7.84(d,J＝5.6Hz,1H)，7.72(d,J＝5.6Hz,1H)，7.62-7.67(m,1H)，7.54(d,J＝8.8Hz,2H)，7.49(s,1H)，7.39(s,1H)，7.19(d,J＝8.8Hz,2H)，6.43(d,J＝5.2Hz,1H)，5.94(s,1H)，4.23(t,J＝6.4Hz,2H)，3.97(s,3H)，3.78-3.84(m,2H)，2.67-2.73(m,2H)，2.54-2.62(br,4H)，1.98-2.04(m,2H)，1.61-1.72(br,4H)；ESI-MS[M+H](m/z):681.2。
Example 141- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinolin-4-oxy ] phenyl ] -3- [ 4-oxo-2- (3-trifluoromethylphenyl) thiazolin-3-yl ] urea
1H-NMR(400MHz,DMSO-d6)δ9.04(br,1H)，8.65(s,1H)，8.45(d,J＝5.2Hz,1H)，7.92(br,1H)，7.82(d,J＝5.6Hz,1H)，7.73(d,J＝5.6Hz,1H)，7.63-7.67(m,1H)，7.52(d,J＝8.8Hz,2H)，7.50(s,1H)，7.38(s,1H)，7.18(d,J＝8.8Hz,2H)，6.40(d,J＝5.2Hz,1H)，5.96(s,1H)，4.19(t,J＝6.4Hz,2H)，3.93(m,4H)，3.81(s,1H)，3.58-3.60(m,4H)，2.45-2.49(m,2H)，2.34-2.43(br,4H)，1.94-2.07(br,2H)；ESI-MS[M+H](m/z):698.2。
Example 151- [4- [ 6-methoxy-7- [3- (4-methylpiperazin-1-yl) propoxy ] quinolin-4-oxy ] phenyl ] -3- [ 4-oxo-2- (3-trifluoromethylphenyl) thiazolin-3-yl ] urea
1H-NMR(400MHz,DMSO-d6)δ9.06(s,1H)，8.64(s,1H)，8.42(d,J＝5.2Hz,1H)，7.88-7.93(br,1H)，7.83(d,J＝5.6Hz,1H)，7.76(d,J＝5.6Hz,1H)，7.63-7.71(m,1H)，7.59(d,J＝8.8Hz,2H)，7.53(s,1H)，7.45(s,1H)，7.26(d,J＝8.8Hz,2H)，6.48(d,J＝5.2Hz,1H)，6.12(s,1H)，4.21(t,J＝6.4Hz,2H)，3.95(s,3H)，3.90(s,2H)，3.31(s,3H)，2.86(m,2H)，2.45(m,2H)，1.83-2.02(m,4H)，1.62(m,2H)，1.13-1.25(m,2H)；ESI-MS[M+H](m/z):711.3。
Example 161- [6- [ 6-methoxy-7- [3- (4-methylpiperidin-1-yl) propoxy ] quinolin-4-oxy ] pyridin-3-yl ] -3- [ 4-oxo-2- (3-trifluoromethylphenyl) thiazolin-3-yl ] urea
1H-NMR(400MHz,DMSO-d6)δ9.00-9.11(br,1H)，8.66(s,1H)，8.45(d,J＝5.2Hz,1H)，7.94(br,1H)，7.83(d,J＝5.6Hz,1H)，7.75(d,J＝5.6Hz,1H)，7.62-7.67(m,1H)，7.54(d,J＝8.8Hz,2H)，7.53(s,1H)，7.40(s,1H)，7.19(d,J＝8.8Hz,2H)，6.42(d,J＝5.2Hz,1H)，5.97(s,1H)，4.22(t,J＝6.4Hz,2H)，3.96(s,3H)，3.80-3.87(m,2H)，2.87(m,2H)，2.49(m,2H)，1.88-2.01(m,4H)，1.65(m,2H)，1.27-1.40(m,1H)，1.05-1.17(m,2H)，0.91(d,J＝6.4Hz,3H)；ESI-MS[M+H](m/z):710.3。
Example 171- [4- [ 6-methoxy-7- [3- (3, 5-dimethylpiperidin-1-yl) propoxy ] quinolin-4-oxy ] phenyl ] -3- [ 4-oxo-2- (3-trifluoromethylphenyl) thiazolin-3-yl ] urea
1H-NMR(400MHz,DMSO-d6)δ9.01(s,1H)，8.62(s,1H)，8.43(d,J＝5.2Hz,1H)，7.88-7.95(br,1H)，7.81(d,J＝5.6Hz,1H)，7.78(d,J＝5.6Hz,1H)，7.63-7.69(m,1H)，7.56(d,J＝8.8Hz,2H)，7.51(s,1H)，7.46(s,1H)，7.23(d,J＝8.8Hz,2H)，6.46(d,J＝5.2Hz,1H)，6.03(s,1H)，4.21(t,J＝6.4Hz,2H)，3.95(s,3H)，3.84(s,2H)，2.83-2.89(m,2H)，2.42-2.49(m,2H)，1.92-2.04(m,2H)，1.53-1.66(m,2H)，1.34-1.43(m,2H)，0.83(d,J＝6.4Hz,6H)，0.47-0.59(m,1H)；ESI-MS[M+H](m/z):723.4。
Example 181- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinolin-4-oxy ] phenyl ] -3- [ 4-oxo-2- [ (4-dimethylamino) phenyl ] thiazolin-3-yl ] urea
1H-NMR(400MHz,DMSO-d6)δ8.86-8.96(br,1H)，8.43(d,J＝5.2Hz,1H)，8.38(s,1H)，7.51(d,J＝8.8Hz,2H)，7.50(s,1H)，7.38(s,1H)，7.24-7.33(m,2H)，7.18(d,J＝8.8Hz,2H)，6.72(d,J＝8.8Hz,2H)，6.39(d,J＝5.2Hz,1H)，5.72(s,1H)，4.19(t,J＝6.4Hz,2H)，3.93(s,3H)，3.75-3.79(m,1H)，3.58-3.61(m,4H)，2.91(s,6H)，2.45-2.47(m,2H)，2.35-2.43(br,4H)，1.94-2.01(m,2H)；ESI-MS[M+H](m/z):672.3。
Example 191- [4- [ 6-methoxy-7- [3- (4-methylpiperazin-1-yl) propoxy ] quinolin-4-oxy ] phenyl ] -3- [ 4-oxo-2- [ (4-dimethylamino) phenyl ] thiazolin-3-yl ] urea
1H-NMR(400MHz,DMSO-d6)δ8.92-8.98(br,1H)，8.45(d,J＝5.2Hz,1H)，8.42(s,1H)，7.52(d,J＝8.8Hz,2H)，7.48(s,1H)，7.39(s,1H)，7.25-7.35(m,2H)，7.19(d,J＝8.8Hz,2H)，6.71(d,J＝8.8Hz,2H)，6.41(d,J＝5.2Hz,1H)，5.79(s,1H)，4.19(t,J＝6.4Hz,2H)，3.96(s,3H)，3.91(s,2H)，3.30(s,3H)，2.90(s,6H)，2.85(m,2H)，2.47(m,2H)，1.83-2.01(m,4H)，1.64(m,2H)，1.13-1.25(m,2H)；ESI-MS[M+H](m/z):685.3。
EXAMPLE 201- [4- [ 6-methoxy-7- [3- (4-methylenepiperidin-1-yl) propoxy ] quinolin-4-oxy ] phenyl ] -3- [ 4-oxo-2- [ (4-dimethylamino) phenyl ] thiazolin-3-yl ] urea
1H-NMR(400MHz,DMSO-d6)δ8.92(s,1H)，8.47(d,J＝5.2Hz,1H)，8.43(s,1H)，7.54(d,J＝8.8Hz,2H)，7.49(s,1H)，7.37(s,1H)，7.26-7.35(m,2H)，7.21(d,J＝8.8Hz,2H)，6.72(d,J＝8.8Hz,2H)，6.44(d,J＝5.2Hz,1H)，5.88(s,1H)，4.87-5.05(m,2H)，4.21(t,J＝6.4Hz,2H)，3.95(s,3H)，3.78-3.84(m,2H)，2.93(s,6H)，2.67-2.74(m,2H)，2.55-2.65(br,4H)，1.96-2.07(m,2H)，1.63-1.72(br,2H)；ESI-MS[M+H](m/z):682.3。
Example 211- [4- [ 6-methoxy-7- [3- (tetrahydropyrrol-1-yl) propoxy ] quinolin-4-oxy ] phenyl ] -3- [ 4-oxo-2- [ (4-dimethylamino) phenyl ] thiazolin-3-yl ] urea
1H-NMR(400MHz,DMSO-d6)δ8.98(s,1H)，8.49(d,J＝5.2Hz,1H)，8.41(s,1H)，7.55(d,J＝8.8Hz,2H)，7.46(s,1H)，7.39(s,1H)，7.25-7.33(m,2H)，7.17(d,J＝8.8Hz,2H)，6.74(d,J＝8.8Hz,2H)，6.47(d,J＝5.2Hz,1H)，5.96(s,1H)，4.21(t,J＝6.4Hz,2H)，3.95(s,3H)，3.78-3.83(m,2H)，2.93(s,6H)，2.67-2.74(m,2H)，2.54-2.63(br,4H)，1.98-2.06(m,2H)，1.61-1.71(br,4H)；ESI-MS[M+H](m/z):656.3。
Example 22
Step ⑴ 3-methoxy-4-benzyloxyacetophenone (XIV)
400g (2.41mol) of 3-methoxy-4-hydroxyacetophenone II was added to 2L of DMF at room temperature, 997.7g (7.23mol) of anhydrous potassium carbonate was added, and after stirring for 15min, 430.2g (2.53mol) of benzyl bromide was added dropwise, and after completion of the dropwise addition, the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into 10L of ice water, and suction filtration was carried out to obtain 594.5g of a white solid.
Step ⑵ 2-Nitro-4-benzyloxy-5-methoxyacetophenone (XV)
500.0g (1.95mol) of intermediate XIV are added to 2.5L of dichloromethane. Slowly dropping 300.0g of fuming nitric acid between-20 ℃ and-10 ℃, and reacting for 2 hours at-10 ℃. The reaction solution was poured into ice water, and the organic layer was collected, washed with saturated aqueous sodium bicarbonate solution to neutrality, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain 513.6g of a yellow solid.
Step ⑶ 1- [ 2-Nitro-4-benzyloxy-5-methoxyphenyl ] -3- (dimethylamino) propyl-2-en-1-one (XVI)
500.0g (1.66mol) of intermediate XV are added to 2.5L of xylene, followed by 1.05Kg (8.80mol) of DMF-DMA and refluxed for 15 h. The reaction solution was cooled to-10 ℃, filtered, the filter cake was washed with an appropriate amount of xylene and dried to obtain 463.4g of a yellow solid.
Step ⑷ 6-methoxy-7-benzyloxy-4 (1H) -quinolinone (XVII)
400.0g (1.12mol) of intermediate XVI are added to 3L of glacial acetic acid, the temperature is raised to 60 ℃, 313.6g (5.60mol) of reduced iron powder are added in portions, and the reaction is carried out for 2h at 90 ℃. And carrying out suction filtration while the solution is hot, cooling the filtrate, and carrying out suction filtration to obtain a solid in a khaki color. After recrystallization from glacial acetic acid, 229.8g of an off-white solid was obtained.
Step ⑸ 4-chloro-6-methoxy-7-benzyloxyquinoline (XVIII)
200.0g (0.71mol) of intermediate XVII and 1L POCl3Added to 1L of dry acetonitrile and reacted for 6h under reflux. The mixture was evaporated to dryness under reduced pressure, the concentrated solution was added to ice water with vigorous stirring, the pH was adjusted to 8 with 10% NaOH aqueous solution, and the mixture was filtered under suction to give 174.8g of an off-white solid.
Step ⑺ 4- (4-Nitrophenoxy) -6-methoxy-7-benzyloxyquinoline (XIX)
200.0g (0.67mol) of intermediate VXIII and 111.6g (0.80mol) of 4-nitrophenol are added to 800mL of dry chlorobenzene and refluxed for 20 h. Evaporating the solvent to dryness to obtain grey solid, dissolving in CH2Cl2Then, the mixture was washed with a 10% aqueous solution of sodium hydroxide, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain 201.8g of a solid.
Step ⑻ 4- (4-Nitrophenoxy) -6-methoxy-7-benzyloxyquinoline-1-oxide (XX)
200.0g (0.50mol) of intermediate XIX were added to 2L of methylene chloride, 160.9g (0.75mol) of 80% m-chloroperoxybenzoic acid (m-CPBA) were added in portions at 0 ℃ and, after the addition was completed, the mixture was stirred at room temperature for 6 hours. The reaction solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and water, respectively, and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain 157.9g of a brown yellow solid.
Step ⑼ 4- (4-Nitrophenoxy) -6-methoxy-7-hydroxyquinoline-1-oxide (XXI)
150.0g (0.36mol) of intermediate XX is added to a solution of 30% hydrobromic acid in glacial acetic acid and stirred at room temperature for 2 h. Filtering, washing the filter cake to obtain 108.7g of off-white solid.
Step ⑽ 4- (4-Nitrophenoxy) -6-methoxy-7- (3-chloropropoxy) quinoline-1-oxide (XXII)
100.0g (0.30 mol) of intermediate XX was added to 1L of acetone, 126.2g (0.91mol) of anhydrous potassium carbonate was added, and after stirring for 15min, 52.9g (0.35mol) of 1, 3-bromochloropropane was added dropwise, and after completion of the dropwise addition, the mixture was stirred at room temperature for 4 hours. Evaporated to dryness, and about 500mL of methylene chloride was added to the residue, washed with water, dried, and evaporated to dryness to give 89.5g of a yellow solid.
Step ⑾ 4- (4-Nitrophenoxy) -6-methoxy-7- (3-morpholinopropoxy) quinoline-1-oxide (XXIII)
100.0g (0.25mol) of intermediate XXII and 217mL (2.5mol) of morpholine were added to 1L of acetonitrile and the reaction was refluxed for 12 h. Most of the solvent was evaporated, the residue was cooled to-10 deg.C, solids were precipitated, filtered and washed with ethyl acetate to give 91.4g of solids.
Step ⑿ 4- (4-Aminophenoxy) -6-methoxy-7- (3-morpholinopropoxy) quinoline-1-oxide (XXIV)
80.0g (0.18mol) of intermediate XXIII, 49.2g (0.90mol) of reduced iron powder and 5mL of concentrated hydrochloric acid were added to 800mL of 90% EtOH-H2And (4) refluxing for 2h after the addition of the catalyst in O. Suction filtration is carried out while the solution is hot, and the filtrate is collected and evaporated to dryness to obtain 66.4g of light yellow solid.
Step ⒀ 6-methoxy-7- (3-morpholinopropoxy) -4- [ (4-phenoxycarboxamido) phenoxy ] quinoline-1-oxide (XXV)
50.0g (0.12mol) of intermediate X and 50.6g (0.37mol) of anhydrous potassium carbonate were added to 1L of dry acetone at room temperature, 22.4mL (0.13mol) of phenyl chloroformate was added dropwise at 0 ℃ and, after completion of the addition, the mixture was stirred at room temperature for 6 hours. The solvent was evaporated, 500mL of dichloromethane was added, washed with water (2X 100mL), dried over anhydrous sodium sulfate, and evaporated to dryness to give 51.6g of a yellow oily liquid.
Step ⒁ 4- [ (4-hydrazinocarboxamido) phenoxy ] -6-methoxy-7- (3-morpholinylpropoxy) quinoline-1-oxide (XXVI)
50.0g (91.7mmol) of intermediate XXV is dissolved in 300mL of dioxane, 300mL of 80% hydrazine hydrate is added thereto, and the mixture is refluxed for about 5 hours. Most of dioxane was evaporated, cooled and filtered to obtain 32.5g of white solid.
Step ⒂ 4- [4- [2- (2, 4-dichlorobenzylidene) hydrazinocarboxamido ] phenoxy ] -6-methoxy-7- (3-morpholinopropoxy) quinoline-1-oxide (Q-3)
30.0g (62.1mmol) of intermediate XXVI and 12.0g (68.3mmol) of 2, 4-dichlorobenzaldehyde are added to 150mL of isopropanol, 1mL of glacial acetic acid are added and the mixture is refluxed for 4 h. Cooling, filtering, and leaching the filter cake with a small amount of isopropanol to obtain 28.8g of white solid.
Step ⒃ 4- [4- [3- [2- (2, 4-dichlorophenyl) -4-oxothiazolin-3-yl ] ureido ] phenoxy ] -6-methoxy-7- (3-morpholinylpropoxy) quinoline-1-oxide (Q-3-1)
20.0g (31.3mmol) of intermediate Q-3 was added to 80mL of thioglycolic acid at room temperature, 2mL of silicon tetrachloride was added, and stirring was carried out at room temperature for about 6 hours after the addition was completed. Adjusting pH to 8 with 10% sodium hydroxide aqueous solution, extracting with dichloromethane (2 × 150mL), drying the organic phase with anhydrous sodium sulfate, evaporating to dryness, and purifying by column chromatography to obtain white solid 10.9 g.
Step ⒄ 1- [4- [ [ 2-tert-butylamine-6-methoxy-7- (3-morpholinylpropoxy) quinolin-4-yl ] oxy ] phenyl ] -3- [2- (2, 4-dichlorophenyl) -4-oxothiazolin-3-yl ] urea (Q-3-2)
10.0g (14.0mmol) of intermediate Q-3-1 are added to 100mL of dichloromethane at room temperature, 5.2g (70.0mmol) of tert-butylamine are added, and 9.1g (28.0mmol) of p-toluenesulfonic anhydride (Ts) are added at 0 DEG C2O), stirring for 30min at room temperature after the addition is finished. And (4) carrying out suction filtration, washing the filtrate with water, and evaporating to dryness to obtain a yellow solid 10.6 g.
Step ⒅ 1- [4- [ [ 2-amino-6-methoxy-7- (3-morpholinylpropoxy) quinolin-4-yl ] oxy ] phenyl ] -3- [2- (2, 4-dichlorophenyl) -4-oxothiazolin-3-yl ] urea (example 22)
10.0g (13.0mmol) of intermediate Q-3-2 was added to 100mL of trifluoroacetic acid and refluxed for 5 h. The reaction solution was evaporated to dryness, 100mL of dichloromethane and saturated aqueous sodium bicarbonate solution were added thereto and washed twice (2X 50mL), the organic phase was dried and evaporated to dryness to give a brown solid, and 7.3g of a purified white solid was isolated by column chromatography.
The compounds of examples 23-30 were prepared by the method of example 22, using the intermediate Q-3 of different substituents as starting material, and carrying out addition, dehydration, amination, and the like.
Example 231- [4- [ [ 2-amino-6-methoxy-7- [3- (tetrahydropyrrolyl-1-yl) propoxy ] quinolin-4-yl ] oxy ] phenyl ] -3- [2- (2, 4-dichlorophenyl) -4-oxothiazolin-3-yl ] urea
1H-NMR(400MHz,DMSO-d6)δ10.03(s,1H)，9.37(s,1H)，8.42(d,J＝8.4Hz,1H)，8.32(s,1H)，7.87-7.92(dd,J1＝17.6Hz,J2＝2.8Hz,1H)，7.70(d,J＝2.8Hz,1H)，7.61-7.65(m,1H)，7.59(s,1H)，7.52(d,J＝11.2Hz,1H)，7.39-7.45(m,2H)，6.46(s,1H)，6.02(s,1H)，4.24(t,J＝6.4Hz,2H)，3.96(s,3H)，3.78-3.84(m,2H)，2.76-2.98(m,6H)，2.08-2.13(m,2H)，1.78-1.84(m,4H)；ESI-MS[M+H](m/z):696.2,698.2。
Example 241- [4- [ [ 2-amino-6-methoxy-7- [3- (4-methylpiperidin-1-yl) propoxy ] quinolin-4-yl ] oxy ] phenyl ] -3- [2- (2, 4-dichlorophenyl) -4-oxothiazolin-3-yl ] urea
1H-NMR(400MHz,DMSO-d6)δ9.08(s,1H)，8.79(s,1H)，8.41(d,J＝8.4Hz,1H)，8.31(s,1H)，7.87-7.94(dd,J1＝17.6Hz,J2＝2.8Hz,1H)，7.67(d,J＝2.8Hz,1H)，7.61-7.67(m,1H)，7.57(s,1H)，7.53(d,J＝11.2Hz,1H)，7.39-7.46(m,2H)，6.44(s,1H)，5.87(s,1H)，4.19(t,J＝6.4Hz,2H)，3.96(s,3H)，3.82-3.87(m,2H)，2.89(m,2H)，2.47(m,2H)，1.85-2.00(m,4H)，1.63(m,2H)，1.25-1.41(m,1H)，1.04-1.19(m,2H)，0.92(d,J＝6.4Hz,3H)；ESI-MS[M+H](m/z):725.2,727.2。
Example 251- [4- [ [ 2-amino-6-methoxy-7- [3- (4-methylenepiperidin-1-yl) propoxy ] quinolin-4-yl ] oxy ] phenyl ] -3- [2- (2, 4-dichlorophenyl) -4-oxothiazolin-3-yl ] urea
1H-NMR(400MHz,DMSO-d6)δ9.87(s,1H)，9.12(s,1H)，8.45(d,J＝8.4Hz,1H)，8.34(s,1H)，7.87-7.93(dd,J1＝17.6Hz,J2＝2.8Hz,1H)，7.73(d,J＝2.8Hz,1H)，7.62-7.67(m,1H)，7.57(s,1H)，7.53(d,J＝11.2Hz,1H)，7.39-7.46(m,2H)，6.45(s,1H)，5.97(s,1H)，4.87-5.02(m,2H)，4.20(t,J＝6.4Hz,2H)，3.98(s,3H)，3.78-3.85(m,2H)，2.66-2.75(m,2H)，2.58-2.67(br,4H)，1.96-2.05(m,2H)，1.63-1.74(br,2H)；ESI-MS[M+H](m/z):723.2,725.2。
Example 261- [4- [ [ 2-amino-6-methoxy-7- [3- (4-methylpiperazin-1-yl) propoxy ] quinolin-4-yl ] oxy ] phenyl ] -3- [2- (2, 4-dichlorophenyl) -4-oxothiazolin-3-yl ] urea
1H-NMR(400MHz,DMSO-d6)δ9.87(s,1H)，9.04(s,1H)，8.44(d,J＝8.4Hz,1H)，8.34(s,1H)，7.87-7.93(dd,J1＝17.6Hz,J2＝2.8Hz,1H)，7.68(d,J＝2.8Hz,1H)，7.61-7.66(m,1H)，7.57(s,1H)，7.51(d,J＝11.2Hz,1H)，7.39-7.46(m,2H)，6.45(s,1H)，6.11(s,1H)，4.19(t,J＝6.4Hz,2H)，3.95(s,3H)，3.90(s,2H)，3.32(s,3H)，2.91(s,6H)，2.86(m,2H)，2.47(m,2H)，1.83-2.00(m,4H)，1.65(m,2H)，1.12-1.24(m,2H)；ESI-MS[M+H](m/z):726.2,728.2。
Example 271- [4- [ [ 2-amino-6-methoxy-7- (3-morpholinylpropoxy) quinolin-4-yl ] oxy ] phenyl ] -3- (2-naphthyl-4-oxothiazolin-3-yl) urea
1H-NMR(400MHz,DMSO-d6)δ9.02-9.09(br,1H)，8.69(s,1H)，8.00(s,1H)，7.92-7.98(m,2H)，7.64-7.71(m,1H)，7.50-7.58(m,5H)，7.38(s,1H)，7.17(d,J＝9.2Hz,1H)，6.40(s,1H)，6.00(s,1H)，4.19(t,J＝6.4Hz,2H)，3.93(s,3H)，3.81-3.98(m,2H)，3.58-3.60(m,4H)，2.45-2.49(m,2H)，2.33-2.43(br,4H)，1.94-2.01(m,2H)；ESI-MS[M+H](m/z):695.3。
Example 281- [4- [ [ 2-amino-6-methoxy-7- [3- (4-methylpiperidin-1-yl) propoxy ] quinolin-4-yl ] oxy ] phenyl ] -3- (2-naphthalenyl-4-oxothiazolin-3-yl) urea
1H-NMR(400MHz,DMSO-d6)δ9.01-9.07(br,1H)，8.67(s,1H)，7.98(s,1H)，7.91-7.96(m,2H)，7.63-7.70(m,1H)，7.51-7.58(m,5H)，7.37(s,1H)，7.18(d,J＝9.2Hz,1H)，6.41(s,1H)，6.01(s,1H)，4.20(t,J＝6.4Hz,2H)，3.97(s,3H)，3.81-3.87(m,2H)，2.87(m,2H)，2.45(m,2H)，1.83-2.00(m,4H)，1.62(m,2H)，1.24-1.40(m,1H)，1.03-1.15(m,2H)，0.91(d,J＝6.4Hz,3H)；ESI-MS[M+H](m/z):707.3。
Example 291- [4- [ [ 2-amino-6-methoxy-7- [3- (tetrahydropyrrol-1-yl) propoxy ] quinolin-4-yl ] oxy ] phenyl ] -3- (2-naphthalenyl-4-oxothiazolin-3-yl) urea
1H-NMR(400MHz,DMSO-d6)δ9.06-9.13(br,1H)，.69(s,1H)，7.99(s,1H)，7.93-7.97(m,2H)，7.64-7.72(m,1H)，7.52-7.59(m,5H)，7.39(s,1H)，7.21(d,J＝9.2Hz,1H)，6.43(d,J＝5.2Hz,1H)，6.01(s,1H)，4.24(t,J＝6.4Hz,2H)，3.99(s,3H)，3.79-3.86(m,2H)，2.68-2.75(m,2H)，2.55-2.64(br,4H)，1.98-2.06(m,2H)，1.64-1.73(br,4H)；ESI-MS[M+H](m/z):678.2。
Example 301- [4- [ [ 2-amino-6-methoxy-7- [3- (4-methylpiperazin-1-yl) propoxy ] quinolin-4-yl ] oxy ] phenyl ] -3- (2-naphthalenyl-4-oxothiazolin-3-yl) urea
1H-NMR(400MHz,DMSO-d6)δ9.01-9.07(br,1H)，8.67(s,1H)，7.98(s,1H)，7.91-7.96(m,2H)，7.63-7.70(m,1H)，7.51-7.58(m,5H)，7.37(s,1H)，7.18(d,J＝9.2Hz,1H)，6.41(s,1H)，6.01(s,1H)，4.22(t,J＝6.4Hz,2H)，3.98(s,3H)，3.91(s,2H)，3.32(s,3H)，2.88(m,2H)，2.46(m,2H)，1.82-2.01(m,4H)，1.59(m,2H)，1.12-1.24(m,2H)；ESI-MS[M+H](m/z):708.2。
Example 31
Step ⑴ 4- [ 6-methoxy-7- (3-morpholinopropoxy) quinolin-4-yloxy ] phenyl isothiocyanate (X-1)
50g (122.2mmol) of intermediate X are dissolved in 500mL of dichloromethane at room temperature, and 100mL of saturated aqueous sodium bicarbonate solution are added. 11.4mL (28.2mmol) of thiophosgene is dropped at 0 ℃, and after dropping, the mixture is stirred at room temperature for 6 hours, an organic phase is separated, dried by anhydrous sodium sulfate and evaporated to dryness to obtain 38.1g of yellow oily liquid.
Step ⑵ 4- [4- [7- (3-morpholinylpropoxy) -6-methoxyquinoline-4-oxy ] phenyl ] thiosemicarbazide (X-2)
30.0g (66.5mmol) of intermediate X-1 are dissolved in 150mL of dichloromethane at room temperature, 1500mL of 80% hydrazine hydrate are added and the mixture is stirred for 12 h. The organic layer was separated, washed with water (3X 50mL), dried over anhydrous sodium sulfate, evaporated to dryness to give a tan solid, and separated by column chromatography to give 17.9g of a pale yellow solid.
Step ⑶ N1- [4- [7- (3-morpholinylpropoxy) -6-methoxyquinoline-4-oxyl]Phenyl radical]-N4- (2, 6-difluorobenzaldehyde) thiosemicarbazone (Q-2)
10.0g (20.7mmol) of X-2 and 3.2g (22.8mmol) of 2, 6-difluorobenzaldehyde are added to 50mL of isopropanol, 1mL of glacial acetic acid are added and the mixture is refluxed for 4 h. Cooling to room temperature, suction filtering, leaching the filter cake with a little isopropanol to obtain 8.5g of yellow solid.
Step ⑷ 1- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinolin-4-oxy ] phenyl ] -3- [2- (2, 6-difluorophenyl) -4-oxothiazolin-3-yl ] thiourea (example 31)
5.0g (31.3mmol) of intermediate Q-2 was added to 20mL of thioglycolic acid at room temperature, 0.5mL of silicon tetrachloride was added, and stirring was carried out at room temperature for about 6 hours after the addition was completed. Adjusting pH to 8 with 10% sodium hydroxide aqueous solution, extracting with dichloromethane (2 × 50mL), drying the organic phase with anhydrous sodium sulfate, evaporating to dryness, and purifying by column chromatography to obtain 3.1g of white solid.
The compounds of examples 32-39 were prepared by addition and dehydration reactions using the different substituent intermediates Q-2 as starting materials according to the procedure for example 31.
Example 321- [4- [ [ 6-methoxy-7- [3- (4-methylpiperazin-1-yl) propoxy ] quinolin-4-yl ] oxy ] phenyl ] -3- [2- (2, 6-difluorophenyl) -4-oxothiazolin-3-yl ] thiourea
1H-NMR(400MHz,DMSO-d6)δ9.07(s,1H)，8,98(s,1H)，8.45(d,J＝5.2Hz,1H)，7.55(d,J＝8.8Hz,2H)，7.51(s,1H)，7.74-7.49(m,1H)，7.38(s,1H)，7.16-7.21(m,4H)，6.42(d,J＝5.2Hz,1H)，6.17(s,1H)，4.19(t,J＝6.4Hz,2H)，3.95(s,3H)，3.75-3.83(m,2H)，3.31(s,3H)，2.85(m,2H)，2.45(m,2H)，1.82-2.02(m,4H)，1.58(m,2H)，1.07-1.22(m,2H)；ESI-MS[M+H](m/z):695.2。
Example 331- [4- [ [ 6-methoxy-7- [3- (tetrahydropyrrol-1-yl) propoxy ] quinolin-4-yl ] oxy ] phenyl ] -3- [2- (2, 6-difluorophenyl) -4-oxothiazolin-3-yl ] thiourea
1H-NMR(400MHz,DMSO-d6)δ9.04(s,1H)，8,94(s,1H)，8.43(d,J＝5.2Hz,1H)，7.54(d,J＝8.8Hz,2H)，7.50(s,1H)，7.73-7.47(m,1H)，7.36(s,1H)，7.15-7.20(m,4H)，6.41(d,J＝5.2Hz,1H)，6.14(s,1H)，4.20(t,J＝6.4Hz,2H)，3.95(s,3H)，3.75-3.83(m,2H)，2.66-2.72(m,2H)，2.53-2.61(br,4H)，1.97-2.03(m,2H)，1.60-1.71(br,4H)；ESI-MS[M+H](m/z):666.2。
Example 341- [4- [ [ 2-amino-6-methoxy-7- [3- (4-methylpiperidin-1-yl) propoxy ] quinolin-4-yl ] oxy ] phenyl ] -3- [2- (2, 6-difluorophenyl) -4-oxothiazolin-3-yl ] thiourea
1H-NMR(400MHz,DMSO-d6)δ9.08-9.17(br,1H)，8,96-9.03(br,1H)，8.46(d,J＝5.2Hz,1H)，7.57(d,J＝8.8Hz,2H)，7.53(s,1H)，7.54-7.69(m,1H)，7.39(s,1H)，7.17-7.23(m,4H)，6.44(d,J＝5.2Hz,1H)，6.14(s,1H)，4.21(t,J＝6.4Hz,2H)，3.97(s,3H)，3.80-3.87(m,2H)，2.86(m,2H)，2.47(m,2H)，1.86-2.03(m,4H)，1.65(m,2H)，1.26-1.42(m,1H)，1.06-1.18(m,2H)，0.91(d,J＝6.4Hz,3H)；ESI-MS[M+H](m/z):694.2。
Example 351- [4- [ [ 6-methoxy-7- [3- (4-ethylpiperazin-1-yl) propoxy ] quinolin-4-yl ] oxy ] phenyl ] -3- [2- (2, 6-difluorophenyl) -4-oxothiazolin-3-yl ] thiourea
1H-NMR(400MHz,DMSO-d6)δ9.97(s,1H)，8.98(s,1H)，8.43(d,J＝5.2Hz,1H)，7.54(d,J＝8.8Hz,2H)，7.53(s,1H)，7.49-7.67(m,1H)，7.41(s,1H)，7.16-7.23(m,4H)，6.45(d,J＝5.2Hz,1H)，6.12(s,1H)，4.31(d,J＝6.4Hz,2H)，4.06(s,3H)，3.85(s,2H)，3.43(m,10H)，2.92(q,2H)，2.37(s,2H)，1.02(t,3H)；ESI-MS[M+H](m/z):709.2。
Example 361- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinolin-4-oxy ] phenyl ] -3- [2- (2, 4-difluorophenyl) -4-oxothiazolin-3-yl ] thiourea
1H-NMR(400MHz,DMSO-d6)δ9.02-9.09(br,1H)，8.68(s,1H)，8.45(d,J＝5.2Hz,1H)，7.67-7.75(m,1H)，7.55(d,J＝8.8Hz,2H)，7.51(s,1H)，7.38(s,1H)，7.31-7.35(m,1H)，7.20(m,3H)，6.40(d,J＝5.2Hz,1H)，6.04(s,1H)，4.20(t,J＝6.4Hz,2H)，3.87-3.94(m,2H)，3.58-3.61(m,4H)，2.45-2.49(m,2H)，2.35-2.43(br,2H)，1.95-2.01(m,2H)；ESI-MS[M+H](m/z):682.1。
Example 371- [4- [ [ 2-amino-6-methoxy-7- [3- (4-methylpiperidin-1-yl) propoxy ] quinolin-4-yl ] oxy ] phenyl ] -3- [2- (2, 4-difluorophenyl) -4-oxothiazolin-3-yl ] thiourea
1H-NMR(400MHz,DMSO-d6)δ9.14-9.22(br,1H)，8.66(s,1H)，8.46(d,J＝5.2Hz,1H)，7.63-7.72(m,1H)，7.51(d,J＝8.8Hz,2H)，7.48(s,1H)，7.36(s,1H)，7.30-7.35(m,1H)，7.18(m,3H)，6.42(d,J＝5.2Hz,1H)，6.00(s,1H)，4.22(t,J＝6.4Hz,2H)，3.95(s,3H)，3.81-3.87(m,2H)，2.87(m,2H)，2.48(m,2H)，1.83-1.96(m,4H)，1.65(m,2H)，1.23-1.40(m,1H)，1.06-1.17(m,2H)，0.93(d,J＝6.4Hz,3H)；ESI-MS[M+H](m/z):694.2。
Example 381- [4- [ [ 6-methoxy-7- [3- (tetrahydropyrrol-1-yl) propoxy ] quinolin-4-yl ] oxy ] phenyl ] -3- [2- (2, 4-difluorophenyl) -4-oxothiazolin-3-yl ] thiourea
1H-NMR(400MHz,DMSO-d6)δ9.21-9.34(br,1H)，8.66(s,1H)，8.47(d,J＝5.2Hz,1H)，7.68-7.76(m,1H)，7.57(d,J＝8.8Hz,2H)，7.52(s,1H)，7.41(s,1H)，7.33-7.37(m,1H)，7.22(m,3H)，6.43(d,J＝5.2Hz,1H)，6.01(s,1H)，4.22(t,J＝6.4Hz,2H)，3.99(s,3H)，3.76-3.83(m,2H)，2.68-2.75(m,2H)，2.55-2.64(br,4H)，1.99-2.06(m,2H)，1.63-1.74(br,4H)；ESI-MS[M+H](m/z):666.1。
Example 391- [4- [ [ 6-methoxy-7- [3- (4-methylpiperazin-1-yl) propoxy ] quinolin-4-yl ] oxy ] phenyl ] -3- [2- (2, 4-difluorophenyl) -4-oxothiazolin-3-yl ] thiourea
1H-NMR(400MHz,DMSO-d6)δ9.12(s,1H)，8.69(s,1H)，8.49(d,J＝5.2Hz,1H)，7.65-7.73(m,1H)，7.59(d,J＝8.8Hz,2H)，7.55(s,1H)，7.44(s,1H)，7.34-7.39(m,1H)，7.25(m,3H)，6.46(d,J＝5.2Hz,1H)，6.12(s,1H)，4.22(t,J＝6.4Hz,2H)，3.98(s,3H)，3.91(s,2H)，3.32(s,3H)，2.88(m,2H)，2.46(m,2H)，1.82-2.01(m,4H)，1.59(m,2H)，1.12-1.24(m,2H)；ESI-MS[M+H](m/z):695.2。
Research on antitumor activity of product of the invention
MET kinase inhibition assay
The assay used to measure MET kinase activity is based on an enzyme-linked immunosorbent assay (ELISA). The specific operation is as follows:
the example compounds, 50pM MET (His-tagged recombinant human MET (amino acid 974-terminus), expressed by baculovirus) and 5. mu.M ATP in assay buffer (25mM MOPS, pH7.4,5mM MgCl) were added to 0.25mg/mL PGT-coated plates at room temperature2,0.5raM MnCl2100 μ M sodium orthovanadate, 0.01% Triton X-100, 1mM DTT, and finally DMSO concentration 1% (v/v)) for 20 min. The reaction mixture was removed by washing and the phosphorylated polymer substrate was detected with 0.2. mu.g/mL of a phosphotyrosine-specific monoclonal antibody (PY20) conjugated with horseradish peroxidase (HRP). After the color development was stopped by adding 1M phosphoric acid, the color of the developed substrate (TMB) was quantified spectrophotometrically at 450 nm. The inhibition data of the example compounds on MET kinase are shown in table 1.
TABLE 1 inhibitory Activity of the Compounds of the examples on MET kinase
Activity for inhibiting tumor cell proliferation in vitro
The quinoline or quinazoline derivatives of the formula I in the invention are subjected to activity screening for inhibiting colon cancer cells HT-29, human breast cancer cells MDA-MB-231 and human gastric cancer cells MKN-45 in vitro.
1. Recovery, passage and culture of cells
⑴ recovering cells by taking out the frozen tube from refrigerator or liquid nitrogen, thawing rapidly in 37 deg.C water bath, sucking the liquid in the frozen tube, adding 2-3mL culture solution, centrifuging at 800rpm for 8min, collecting cells, culturing in 20% fetal calf serum culture solution, and changing the culture solution after 24 h.
⑵ passage of cells, pouring out old culture solution in culture flask, adding 5-7mL digestive juice, placing at 37 deg.C and CO2In the incubator, the culture bottle is tapped after 2min, the cells are digested, the cells are poured into a centrifuge tube, and about 8mL of culture solution containing 10% fetal calf serum is added to stop the digestion. Centrifuging at 800rpm for 8min, discarding supernatant, adding 4mL culture solution, blowing, mixing, and passaging according to (1/4).
⑶ cultivation of cells, after passage, the cells were placed in CO at 37 deg.C2The cells are cultured in an incubator and can be used for tests after 2 generations.
2. Buried plate
Digesting the cells cultured in a culture bottle until the logarithmic phase of the cells is reached by pancreatin, stopping digestion by using a culture solution containing 10% serum, putting the cells into a centrifuge tube, sealing the centrifuge tube, centrifuging the cells at 800rpm for 8min, removing supernatant, blowing the cells uniformly by using the culture solution containing 10% serum, adjusting the concentration of cell suspension by using the culture solution, adding the cells into a 96-well plate, wherein each well is 100 mu L, and the concentration of the cells is about 1 multiplied by 104Pore, placed at 37 ℃ in 5% CO2The cells are adhered to the wall by incubator for 24h, and the microscopic examination of the cells is about 30 percent of each hole.
3. Dosing
The tested drugs are firstly mixed by 50 mu L DMSO in a vortex mode, then culture solution containing 950 mu L10% serum is added for dilution and mixing, 50 mu L of the diluted drug solution is added into a first row of holes of a 24-hole plate, 950 mu L of culture solution containing 10% serum is added into the holes with the diluted drug solution, a pipette is used for mixing, 200 mu L of the diluted drug solution is added into a second hole, 800 mu L of culture solution containing 10% serum is added into the second hole for 5-fold dilution, and the like, a common 24-hole plate is diluted into 5 drugs with different concentrations for standby, such as 100 mu g/mL, 20 mu g/mL, 4 mu g/mL, 0.8 mu g/mL and 0.16 mu g/mL. Throwing out the culture solution in a 96-well plate embedded with cells with force, averagely dividing the 96-well plate into four areas by using a cross, taking two rows of upper and lower holes of the 96-well plate as blank reference holes, respectively adding the prepared liquid medicine into the 96-well plate according to the sequence of concentration from low to high (the 96-well plate is added from right to left), and adding the liquid medicine into each hole170 mu L of culture medium with 3 holes per concentration, adding the culture medium with 170 mu L per hole, adding the highest concentration of each adjacent drug into the left and right rows of holes without cells, placing at 37 deg.C and 5% CO2Culturing for 72h in an incubator.
4. Adding MTT
Observing the growth of cells in blank holes by microscopic examination, forcibly throwing out liquid in a 96-well plate after the holes with the highest drug concentration have crystallization or other conditions, adding 200 mu L of physiological saline into each hole for cleaning, washing away residual drug, and throwing out liquid. Diluting 5% MTT liquid prepared in advance with culture solution to 0.5% MTT solution, adding diluted MTT into 96-well plate at 100 μ l/well, standing at 37 deg.C and 5% CO2The culture is carried out for 4h in an incubator to promote the reaction to be complete. After 4h, the liquid in the 96-well plate is forcibly thrown out, 100. mu.L DMSO is added into each well, the 96-well plate is placed on a magnetic oscillator to be oscillated for 3min, the crystal is fully dissolved, and the absorbance value of each well is measured on an enzyme linked immunosorbent assay detector by a double wavelength method (490nm and 630 nm).
5. Calculation results
Calculating half inhibitory concentration IC of each drug by Bliss method according to absorbance50Values, activity results are shown in table 2.
TABLE 2 in vitro antitumor Activity of the Compounds of the examples
From the above test results, it is clear that the compound of formula I to be protected by the present invention has good in vitro anti-tumor activity, which is equivalent to or superior to the marketed anti-tumor drug Cabozantinib.
The compounds of general formula I of the present invention can be administered alone, but usually are administered in admixture with a pharmaceutically acceptable carrier selected according to the desired route of administration and standard pharmaceutical practice, and their novel use is illustrated below in the context of methods for the preparation of various pharmaceutical dosage forms, e.g., tablets, capsules, injections, aerosols, suppositories, films, dripping pills, liniments for external use and ointments, respectively, of such compounds.
Example 40: tablet formulation
10g of the compound of claim 1 (in the case of the compound of example 12) is mixed with 20g of excipients according to a general pharmaceutical tableting method, and the mixture is compressed into 100 tablets, wherein each tablet weighs 300 mg.
Example 41: capsule preparation
10g of the compound of claim 1 (taking the compound of example 36 as an example) is mixed with 20g of auxiliary materials according to the requirement of a pharmaceutical capsule, and then the mixture is filled into empty capsules, wherein each capsule weighs 300 mg.
Example 42: injection preparation
The compound of claim 1 (example 1) was used 10g, and the mixture was filtered through a 0.65 μm microporous membrane by activated carbon adsorption, and then filled in a nitrogen tank to prepare a water-in-needle preparation (2 mL each) in a total of 100 bottles.
Example 43: aerosol formulation
The compound of claim 1 (example 22) is dissolved in 10g of propylene glycol, and then 500mL of clear solution is obtained after adding distilled water and other additives.
Example 44: suppository
50 suppositories were prepared by grinding 10g of the compound of claim 1 (example 19) with the appropriate amount of glycerin, mixing well, adding melted glycerin gelatin, grinding well, pouring into lubricant-coated molds
Example 45: film agent
Using 10g of the compound according to claim 1 (in the case of the compound of example 30), polyvinyl alcohol, medicinal glycerin, water and the like were swollen with stirring and then dissolved by heating, and the compound of example 18 was added to the filtrate and dissolved with stirring, and 100 sheets were formed into a film by a film-coating machine.
Example 46: drop pills
10g of the compound of claim 1 (taking the compound in example 17 as an example) and 50g of a matrix such as gelatin are heated, melted and mixed uniformly, and then are dropped into low-temperature liquid paraffin to prepare 1000 pills.
Example 47: external liniment
Prepared by mixing 10g of the compound (taking the compound in the example 29 as the example) in the claim 1 with 2.5g of auxiliary materials such as emulsifier and the like according to a conventional pharmaceutical method, grinding and adding distilled water to 200 mL.
Example 48: ointment formulation
Prepared by grinding 10g of the compound of claim 1 (taking the compound in example 37 as an example), and then uniformly grinding the ground product with 500g of oil-based substance such as vaseline.
While the invention has been described with reference to specific embodiments, modifications and equivalent arrangements will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Claims (13)
1. Compounds of general formula (I) and pharmaceutically acceptable salts thereof,
wherein m is an integer between 1 and 3; n is an integer between 1 and 6; m is O, S;
Cy1is phenyl or naphthyl;
Cy2is a 5-to 10-membered heterocyclic group except Cy2Optionally containing, in addition to the above N atom0-4 heteroatoms selected from N, O and S, said heterocyclyl optionally including 0-2 carbon-carbon double or triple bonds, said heterocyclyl optionally being substituted with 0-3R, which may be the same or different4Is substituted in which R4Is C1-C6An alkyl group;
R1is H, NH2；
R2Hydrogen, halogen;
R3is hydrogen, halogen, cyano, C1-C6Alkyl radical, C1-C6An alkoxy group.
2. A compound of the general formula I in accordance with claim 1, wherein,
Cy1is phenyl;
Cy2is a 5-to 10-membered heterocyclic group except Cy2Optionally containing 0 to 4 heteroatoms selected from N, O and S in addition to the above N atom, said heterocyclyl optionally including 0 to 2 carbon-carbon double or triple bonds, said heterocyclyl optionally being interrupted by 0 to 3 identical or different R4Is substituted in which R4Is C1-C6An alkyl group;
R1is H, NH2；
R2Hydrogen, halogen;
R3is hydrogen, halogen, cyano, C1-C6Alkyl radical, C1-C6An alkoxy group;
m is O, S.
3. A compound of the general formula I in accordance with claim 1, wherein,
R1is H;
R2hydrogen, halogen;
R3is hydrogen, halogen, cyano, C1-C6Alkyl radical, C1-C6An alkoxy group;
m is O, S.
4. A compound of the general formula I in accordance with claim 1, wherein,
R2is H;
m is O, S;
R3is hydrogen, halogen, cyano, C1-C6Alkyl radical, C1-C6An alkoxy group.
5. A compound of the general formula I in accordance with claim 1, wherein,
m is O; r3Is hydrogen, halogen, cyano, C1-C6Alkyl radical, C1-C6An alkoxy group.
6. A compound of the following general formula I:
N1- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- (4-oxo-2-phenylthiazolin-3-yl) urea;
N1- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (4-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (2-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (3-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (4-chlorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (2,4, 6-trifluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (3-trifluoromethylphenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- (3-morpholinyl)Propoxy) quinoline-4-oxyl]Phenyl radical]-N3- [ 4-oxo-2- (2, 4-dichlorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (4-methylphenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- (4-oxo-2-phenylthiazolin-3-yl) urea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (4-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (2-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (3-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (4-chlorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (2,4, 6-trifluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (3-trifluoromethylphenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (2, 4-dichlorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperazinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (4-methylphenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy radical]Phenyl radical]-N3- (4-oxo-2-phenylthiazolin-3-yl) urea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (4-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (2-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (3-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (4-chlorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (2,4, 6-trifluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (3-trifluoromethylphenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (2, 4-dichlorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (4-methylphenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- (4-oxo-2-phenylthiazolin-3-yl) urea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (4-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (2-fluorophenyl) thiazoline-3-yl]Urea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (3-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (4-chlorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (2,4, 6-trifluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (3-trifluoromethylphenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (2, 4-dichlorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (4-methylphenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (4-methylene-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- (4-oxo-2-phenylthiazolin-3-yl) urea;
N1- [4- [ 6-methoxy-7- [3- (4-methylene-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (4-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (4-methylene-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (2-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (4-methylene-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (3-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (4-methylene-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (4-chlorophenyl) thia-zoleAzolin-3-yl]Urea;
N1- [4- [ 6-methoxy-7- [3- (4-methylene-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (2,4, 6-trifluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (4-methylene-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (3-trifluoromethylphenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (4-methylene-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (2, 4-dichlorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (4-methylene-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (4-methylphenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Naphthyl radical]-N3- (4-oxo-2-phenylthiazolin-3-yl) urea;
N1- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Naphthyl radical]-N3- [ 4-oxo-2- (4-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Naphthyl radical]-N3- [ 4-oxo-2- (2-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Naphthyl radical]-N3- [ 4-oxo-2- (3-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Naphthyl radical]-N3- [ 4-oxo-2- (4-chlorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Naphthyl radical]-N3- [ 4-oxo-2- (2,4, 6-trifluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Naphthyl radical]-N3- [ 4-oxo-2- (3-trifluoromethylphenyl) thiazolin-3-yl group]Urea;
N1-[4-[6-methoxy-7- (3-morpholinylpropoxy) quinolin-4-yloxy]Naphthyl radical]-N3- [ 4-oxo-2- (2, 4-dichlorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Naphthyl radical]-N3- [ 4-oxo-2- (4-methylphenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Naphthyl radical]-N3- (4-oxo-2-phenylthiazolin-3-yl) urea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Naphthyl radical]-N3- [ 4-oxo-2- (4-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Naphthyl radical]-N3- [ 4-oxo-2- (2-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Naphthyl radical]-N3- [ 4-oxo-2- (3-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Naphthyl radical]-N3- [ 4-oxo-2- (4-chlorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Naphthyl radical]-N3- [ 4-oxo-2- (2,4, 6-trifluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Naphthyl radical]-N3- [ 4-oxo-2- (3-trifluoromethylphenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Naphthyl radical]-N3- [ 4-oxo-2- (2, 4-dichlorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Naphthyl radical]-N3- [ 4-oxo-2- (4-methylphenyl)
Thiazolin-3-yl urea.
7. A compound of the following general formula I:
N1- [4- [ 2-amino-6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- (4-oxo-2-phenylthiazolin-3-yl) urea;
N1- [4- [ 2-amino-6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (4-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-amino-6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (2-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-amino-6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (3-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-amino-6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (4-chlorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-amino-6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (2,4, 6-trifluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-amino-6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (3-trifluoromethylphenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-amino-6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (2, 4-dichlorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-amino-6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (4-methylphenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-amino-6-methoxy-7- [3- (1-pyrrolidinyl) propoxy ] group]Quinoline-4-oxy]Phenyl radical]-N3- (4-oxo-2-phenylthiazolin-3-yl) urea;
N1- [4- [ 2-amino-6-methoxy-7- [3- (1-pyrrolidinyl) propoxy ] group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (4-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-amino-6-methoxy-7- [3- (1-pyrrolidinyl) propoxy ] group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (2-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-amino-6-methoxy-7- [3- (1-pyrrolidinyl) propoxy ] group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (3-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-amino-6-methoxy-7- [3- (1-pyrrolidinyl) propoxy ] group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (4-chlorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-amino-6-methoxy-7- [3- (1-pyrrolidinyl) propoxy ] group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (2,4, 6-trifluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-amino-6-methoxy-7- [3- (1-pyrrolidinyl) propoxy ] group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (3-trifluoromethylphenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-amino-6-methoxy-7- [3- (1-pyrrolidinyl) propoxy ] group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (2, 4-dichlorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-amino-6-methoxy-7- [3- (1-pyrrolidinyl) propoxy ] group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (4-methylphenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-amino-6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Naphthyl radical]-N3- (4-oxo-2-phenylthiazolin-3-yl) urea;
N1- [4- [ 2-amino-6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Naphthyl radical]-N3- [ 4-oxo-2- (4-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-amino-6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Naphthyl radical]-N3- [ 4-oxo-2- (2-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-amino-6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Naphthyl radical]-N3- [ 4-oxo-2- (3-fluorophenyl) thiazolin-3-yl group]Urea;
N1-4- [ [ 2-amino-6-methoxy-7- (3-morpholinylpropoxy) quinolin-4-yloxy]Naphthyl radical]-N3- [ 4-oxo-2- (4-chlorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-amino-6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Naphthyl radical]-N3- [ 4-oxo-2- (2,4, 6-trifluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-amino-6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Naphthyl radical]-N3- [ 4-oxo-2- (3-trifluoromethylphenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-amino-6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Naphthyl radical]-N3- [ 4-oxo-2- (2, 4-dichlorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-amino-6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Naphthyl radical]-N3- [ 4-oxo-2- (4-methylphenyl) thiazolin-3-yl group]Urea.
8. A compound of the following general formula I:
N1- [4- [ 2-acetylamino-6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- (4-oxo-2-phenylthiazolin-3-yl) urea;
N1- [4- [ 2-acetylamino-6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (4-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-acetylamino-6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (2-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-acetylamino-6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (3-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-acetylamino-6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (4-chlorophenyl) thiazolin-3-yl group]Urea;
N1-[4- [ 2-acetylamino-6-methoxy-7- (3-morpholinylpropoxy) quinolin-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (2,4, 6-trifluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-acetylamino-6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (3-trifluoromethylphenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-acetylamino-6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (2, 4-dichlorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-acetylamino-6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (4-methylphenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-acetylamino-6-methoxy-7- [3- (1-pyrrolidinyl) propoxy ] group]Quinoline-4-oxy]Phenyl radical]-N3- (4-oxo-2-phenylthiazolin-3-yl) urea;
N1- [4- [ 2-acetylamino-6-methoxy-7- [3- (1-pyrrolidinyl) propoxy ] group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (4-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-acetylamino-6-methoxy-7- [3- (1-pyrrolidinyl) propoxy ] group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (2-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-acetylamino-6-methoxy-7- [3- (1-pyrrolidinyl) propoxy ] group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (3-fluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-acetylamino-6-methoxy-7- [3- (1-pyrrolidinyl) propoxy ] group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (4-chlorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-acetylamino-6-methoxy-7- [3- (1-pyrrolidinyl) propoxy ] group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (2,4, 6-trifluorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-acetylamino-6-methoxy-7- [3- (1-pyrrolidinyl) propoxy ] group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (3-trifluoromethyl)Phenyl) thiazolin-3-yl]Urea;
N1- [4- [ 2-acetylamino-6-methoxy-7- [3- (1-pyrrolidinyl) propoxy ] group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (2, 4-dichlorophenyl) thiazolin-3-yl group]Urea;
N1- [4- [ 2-acetylamino-6-methoxy-7- [3- (1-pyrrolidinyl) propoxy ] group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (4-methylphenyl) thiazolin-3-yl group]Urea.
9. A compound of the following general formula I:
N1- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- (4-oxo-2-phenylthiazolin-3-yl) thiourea;
N1- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (4-fluorophenyl) thiazolin-3-yl group]Thiourea;
N1- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (2-fluorophenyl) thiazolin-3-yl group]Thiourea;
N1- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (3-fluorophenyl) thiazolin-3-yl group]Thiourea;
N1- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (4-chlorophenyl) thiazolin-3-yl group]Thiourea;
N1- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (2,4, 6-trifluorophenyl) thiazolin-3-yl group]Thiourea;
N1- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (3-trifluoromethylphenyl) thiazolin-3-yl group]Thiourea;
N1- [4- [ 6-methoxy-7- (3-morpholinylpropoxy) quinoline-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (2, 4-dichlorophenyl) thiazolin-3-yl group]Thiourea;
N1- [4- [ 6-methoxy-7- (3-)Morpholinylpropoxy) quinolin-4-yloxy]Phenyl radical]-N3- [ 4-oxo-2- (4-methylphenyl) thiazolin-3-yl group]Thiourea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- (4-oxo-2-phenylthiazolin-3-yl) thiourea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (4-fluorophenyl) thiazolin-3-yl group]Thiourea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (2-fluorophenyl) thiazolin-3-yl group]Thiourea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (3-fluorophenyl) thiazolin-3-yl group]Thiourea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (4-chlorophenyl) thiazolin-3-yl group]Thiourea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (2,4, 6-trifluorophenyl) thiazolin-3-yl group]Thiourea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (3-trifluoromethylphenyl) thiazolin-3-yl group]Thiourea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (2, 4-dichlorophenyl) thiazolin-3-yl group]Thiourea;
N1- [4- [ 6-methoxy-7- [3- (4-methyl-1-piperidinyl) propoxy group]Quinoline-4-oxy]Phenyl radical]-N3- [ 4-oxo-2- (4-methylphenyl) thiazolin-3-yl group]Thiourea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Naphthyl radical]-N3- (4-oxo-2-phenylthiazolin-3-yl) thiourea;
N1- [4- [ 6-methoxy-7-[3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Naphthyl radical]-N3- [ 4-oxo-2- (4-fluorophenyl) thiazolin-3-yl group]Thiourea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Naphthyl radical]-N3- [ 4-oxo-2- (2-fluorophenyl) thiazolin-3-yl group]Thiourea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Naphthyl radical]-N3- [ 4-oxo-2- (3-fluorophenyl) thiazolin-3-yl group]Thiourea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Naphthyl radical]-N3- [ 4-oxo-2- (4-chlorophenyl) thiazolin-3-yl group]Thiourea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Naphthyl radical]-N3- [ 4-oxo-2- (2,4, 6-trifluorophenyl) thiazolin-3-yl group]Thiourea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Naphthyl radical]-N3- [ 4-oxo-2- (3-trifluoromethylphenyl) thiazolin-3-yl group]Thiourea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Naphthyl radical]-N3- [ 4-oxo-2- (2, 4-dichlorophenyl) thiazolin-3-yl group]Thiourea;
N1- [4- [ 6-methoxy-7- [3- (1-pyrrolidinyl) propoxy group]Quinoline-4-oxy]Naphthyl radical]-N3- [ 4-oxo-2- (4-methylphenyl) thiazolin-3-yl group]And (3) thiourea.
10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and pharmaceutically acceptable salts thereof as an active ingredient together with pharmaceutically acceptable excipients.
11. The use of a compound according to any one of claims 1 to 9, and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment and/or prevention of proliferative diseases.
12. The use of a compound according to any one of claims 1 to 9, and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of cancer.
13. The use of a compound according to any one of claims 1 to 9, and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of lung cancer, liver cancer, stomach cancer, colon cancer, breast cancer.
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| CN114524802B (en) * | 2022-03-07 | 2023-05-23 | 华润三九医药股份有限公司 | Synthesis method of quinoline compound |
| CN114560845B (en) * | 2022-03-07 | 2023-06-20 | 华润三九医药股份有限公司 | Crystal form alpha of quinoline compound, and preparation method and application thereof |
| CN114920703B (en) * | 2022-05-26 | 2024-01-09 | 天津济坤医药科技有限公司 | Quinazoline derivative and preparation method and application thereof |
| CN115433124A (en) * | 2022-10-17 | 2022-12-06 | 常州佳德医药科技有限公司 | Preparation method of 4-chloro-6-methoxy-7-benzyloxy quinoline |
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| US20050245547A1 (en) * | 2004-01-23 | 2005-11-03 | Tae-Seong Kim | Compounds and methods of use |
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| US20050245547A1 (en) * | 2004-01-23 | 2005-11-03 | Tae-Seong Kim | Compounds and methods of use |
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