Quinoline derivatives and their applications
09783499 · 2017-10-10
Assignee
Inventors
Cpc classification
C07D401/12
CHEMISTRY; METALLURGY
C07D215/233
CHEMISTRY; METALLURGY
A61P35/00
HUMAN NECESSITIES
International classification
C07D215/233
CHEMISTRY; METALLURGY
C07D401/12
CHEMISTRY; METALLURGY
Abstract
The invention relates to a series of quinoline derivatives of general formula I, pharmaceutically acceptable salts, hydrates, solvates or prodrugs. Thereof M, R.sub.1, R.sub.2, X, Y and n are defined as claims. And the compounds of general formula I show potent inhibitory activity against c-Met kinase. The present invention further relates to the uses of the compounds, pharmaceutically acceptable salts and hydrates for the preparation of medicaments for the treatment and/or prevention of diseases caused by abnormal expression of c-Met kinase, especially for treatment and/or prevention of cancer. ##STR00001##
Claims
1. Compounds of formula I, or their pharmaceutically acceptable salts, or hydrates ##STR00151## wherein, X is O, S, NH or NCH.sub.3; Y can be 1-4 substituents independently selected from the group consisting of halogen, trihalomethyl, methyl, cyano and nitro groups; M is ##STR00152## Z is O or S; n is an integer between 1 and 6; R.sub.1 and R.sub.2, which are same or different, are independently selected from hydrogen, (C.sub.1-C.sub.10) alkyl, (C.sub.3-C.sub.7) cycloalkyl, (C.sub.2-C.sub.10) alkenyl and (C.sub.2-C.sub.10) alkynyl, wherein R.sub.1 and R.sub.2 are optionally substituted with 1-3 same or different R.sub.3; or R.sub.1 and R.sub.2 together with the nitrogen atom to which they are attached form 5- to 10-membered heterocyclic radical or 5- to 10-membered heteroaryl radical, wherein, besides the nitrogen atom to which R.sub.1 and R.sub.2 are attached, the said heterocyclic and heteroaryl radicals optionally contains 1 to 4 heteroatoms selected from N, O and S, and wherein the said heterocyclic radical optionally contains 1 to 2 carbon-carbon double bonds or triple bonds, and wherein said heterocyclic and heteroaryl radicals can be optionally substituted with 1 to 3 same or different R.sub.3; R.sub.3 and R.sub.4 are independently hydrogen or (C.sub.1-C.sub.6) alkyl; Ar is (C.sub.6-C.sub.10) aryl or 5- to 10-membered heteroaryl radical, wherein said heteroaryl radical optionally contains 1 to 3 heteroatoms selected from N, O and S, and Ar is optionally substituted with 1 to 3 same or different R.sub.5; and R.sub.5 is hydroxyl, halogen, nitro, amino, cyano, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl, or (C.sub.1-C.sub.6) alkoxyl, wherein each of (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl, or (C.sub.1-C.sub.6) alkoxyl is optionally substituted with a substituent selected from the group consisting of hydroxyl, amino, halogen, amino group substituted with 1 or 2 (C.sub.1-C.sub.6) alkyl groups, (C.sub.1-C.sub.6) alkylcarbonylamino, carboxyl group which can be free acids, salts, amidated or form ester group, (C.sub.1-C.sub.6) alkylsulfinyl, (C.sub.1-C.sub.6) alkylsulfonyl, (C.sub.1-C.sub.6) alkylacyl, carbamoyl, carbamoyl substituted with 1 for 2 (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.3) alkylenedioxo, and allyl.
2. The compounds of the formula I, or their pharmaceutically acceptable salts, or hydrates according to claim 1, wherein, Y can be 1-2 substituents independently selected from the group consisting of halogen, trihalomethyl, methyl, cyano and nitro groups; n is an integer between 1 and 4; and R.sub.1 and R.sub.2, which are same or different, are independently selected from hydrogen, (C.sub.1-C.sub.6) alkyl, (C.sub.3-C.sub.5) cycloalkyl, (C.sub.2-C.sub.6) alkenyl and (C.sub.2-C.sub.6) alkynyl, wherein R.sub.1 and R.sub.2 are optionally substituted with 1-3 same or different R.sub.3; or R.sub.1 and R.sub.2 together with the nitrogen atom to which they are attached form 5- to 10-membered heterocyclic radical, wherein besides the nitrogen atom to which R.sub.1 and R.sub.2 are attached, the said heterocyclic radical optionally contains 1 to 4 heteroatoms selected from N, O and S, and wherein said heterocyclic radical optionally contains 1 to 2 carbon-carbon double bonds or triple bonds, said heterocyclic radicals can be optionally substituted with 1 to 3 same or different R.sub.3.
3. The compounds of claim 2, or their pharmaceutically acceptable salts, or hydrates, having Formula II, ##STR00153## wherein, X is O or S; and Y is halogen, trihalomethyl, methyl, cyano or nitro groups.
4. The compounds of claim 3, or their pharmaceutically acceptable salts, or hydrates, wherein, X is O; n is 3 or 4; R.sub.1 and R.sub.2, which are same or different, are independently selected from hydrogen, (C.sub.1-C.sub.4) alkyl, (C.sub.3-C.sub.5) cycloalkyl; or R.sub.1 and R.sub.2 together with the nitrogen atom to which they are attached form 5- or 6-membered heterocyclic radical, wherein besides the nitrogen atom to which R.sub.1 and R.sub.2 are attached, said heterocyclic radicals optionally contains 1 or 2 heteroatoms selected from N, O and S, and wherein said heterocyclic radical optionally contains 1 or 2 carbon-carbon double bonds or triple bonds, and said heterocyclic radical can be optionally substituted with 1 to 3 same or different R.sub.3; R.sub.3 is (C.sub.1-C.sub.4) alkyl; and R.sub.4 is hydrogen, methyl or ethyl.
5. The compounds of claim 4, and or pharmaceutically acceptable salts, or hydrates, wherein, Y is F; n is 3; R.sub.1 and R.sub.2 together with the nitrogen atom to which they are attached form dimethylamino, diethylamino, piperidin-1-yl, morpholin-4-yl, 4-methylpiperazin-1-yl, piperazin1-yl, 4-methylpiperidin-1-yl, pyrrolidin-1-yl, thiomorpholin-4-yl; and R.sub.4 is hydrogen, methyl or ethyl.
6. The compounds of claim 5, or their pharmaceutically acceptable salts or hydrates wherein M is ##STR00154##
7. The compounds of claim 5, or their pharmaceutically acceptable salts, or hydrates, wherein, M is ##STR00155##
8. The compounds of claim 5, or their pharmaceutically acceptable salts, or hydrates, wherein, Ar is phenyl, naphthyl, quinolyl, isoquinolyl, quinazolinyl, indolyl, pyridyl, furanyl, thienyl, pyrrolyl or pyrimidinyl, wherein Ar can be is optionally substituted with 1 to 3 same or different R.sub.5.
9. The compounds of claim 8, or their pharmaceutically acceptable salts, or hydrates, wherein, Ar is phenyl and Ar can be optionally substituted with 1 to 3 same or different R.sub.5; and R.sub.5 is halogen, hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, (C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy, allyl, dimethylamino.
10. The compounds of claim 9, or their pharmaceutically acceptable salts, or hydrates, wherein, R.sub.1 and R.sub.2 together with the nitrogen atom to which they are attached form piperidin-1-yl, morpholin-4-yl, 4-methylpiperazin-1-yl, 4-methylpiperidin-1-yl, or pyrrolidin-1-yl; and R.sub.4 is H.
11. The compounds of the formula I of claim 1, or their pharmaceutically acceptable salts, or hydrates, the compounds being: (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(benzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(benzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(benzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline-4-lyoxy)phenyl)-N.sup.4-(benzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(benzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(3-methoxybenzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinoline-4-yloxy)-phenyl)-N.sup.4-(3-methoxybenzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(3-methoxybenzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(3-methoxy benzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinoline-4-lyoxy)phenyl)-N.sup.4-(4-fluorobenzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(4-fluorobenzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(2-chloro-4-fluorobenzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(2-chloro-4-fluorobenzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(2-chloro-4-fluorobenzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(2-nitrobenzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(2-nitrobenzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(2-nitrobenzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(2-hydroxyl-1-naphthaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(2,4-dichlorobenzaldehyde) semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(2,4-dichlorobenzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(2-hydroxy-1-naphthaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-4-lyoxy)phenyl)-N.sup.4-(3,4-difluorobenzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-oxy)phenyl)-N.sup.4-(3,4-difluorobenzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(3-trifluoromethylbenzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(2, 4-difluorobenzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(3-trifluoromethylbenzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(3,5-dimethyl-4-hydroxybenzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(2-hydroxyl-1-naphthaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(3-allyl-2-hydroxybenzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(3-allyl-2-hydroxybenzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(3,4-difluorobenzaldehyde)thiosemicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-4-yloxy)phenyl])-N.sup.4-(2-nitrobenzaldehyde)thiosemicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(2-nitrobenzaldehyde)thiosemicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(2-nitrobenzaldehyde)thiosemicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(3-allyl-2-hydroxybenzaldehyde)thiosemicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(benzaldehyde)thiosemicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(benzaldehyde)thiosemicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(benzaldehyde)thiosemicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(4-methyl-1-piperazinyl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(benzaldehyde)thiosemicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(4-methyl-1-piperazinyl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(2,4-dichlorobenzaldehyde)thiosemicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(2,4-dichlorobenzaldehyde)thiosemicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(4-methyl-1-piperazinyl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(2-chloro-4-fluorobenzaldehyde)thiosemicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(2-chloro-4-fluorobenzaldehyde)thiosemicarbazone; (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(4-fluorobenzaldehyde)thiosemicarbazone; or (E)-N.sup.1-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)phenyl)-N.sup.4-(4-fluorobenzaldehyde)thiosemicarbazone.
12. The compounds of the formula I of claim 1, or their pharmaceutically acceptable salts, or hydrates, the compounds being: (E)-N.sup.1-(4-chloro-3-(trifluoromethyl)phenyl)-N.sup.4-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinoline-4-yloxy)benzaldehyde)semicarbazone; (E)-N.sup.1-(2-fluorophenyl)-N.sup.4-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy) quinoline-4-yloxy)benzaldehyde)semicarbazone; (E)-N.sup.1-(3,5-dichlorophenyl)-N.sup.4-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy) quinoline-4-yloxy)benzaldehyde)semicarbazone; (E)-N.sup.1-(3,5-dimethoxyphenyl)-N.sup.4-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy) quinoline-4-yloxy)benzaldehyde)semicarbazone; (E)-N.sup.1-(3-fluoro-6-methylphenyl)-N.sup.4-(-3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy) quinoline-4-yloxy)benzaldehyde)semicarbazone; (E)-N.sup.1-(4-chloro-3-(trifluoromethyl)phenyl)-N.sup.4-(3-fluoro-4-(6-methoxy-7-(3-(4-methyl-1-piperazinyl)propoxy)quinoline-4-yloxy)benzaldehyde)semicarbazone; (E)-N.sup.1-phenyl-N.sup.4-(3-fluoro-4-(6-methoxy-7-(3-(4-methyl-1-piperazinyl)propoxy) quinoline-4-yloxy)benzaldehyde)semicarbazone; (E)-N.sup.1-(4-chlorophenyl)-N.sup.4-(3-fluoro-4-(6-methoxy-7-(3-(4-methyl-1-piperazinyl)propoxy)-quinoline-4-yloxy)benzaldehyde)semicarbazone; (E)-N.sup.1-(3-bromophenyl)-N.sup.4-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)benzaldehyde)semicarbazone; (E)-N.sup.1-phenyl-N.sup.4-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)benzaldehyde)semicarbazone; (E)-N.sup.1-(3,5-difluorophenyl)-N.sup.4-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy) quinoline-4-yloxy)benzaldehyde)semicarbazone; (E)-N.sup.1-(3,5-dimethoxyphenyl)-N.sup.4-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy) quinoline-4-oxy)benzaldehyde)semicarbazone; (E)-N.sup.1-phenyl-N.sup.4-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy) quinoline-4-yloxy)benzaldehyde)semicarbazone; (E)-N.sup.1-(3,5-dimethoxyphenyl)-N.sup.4-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinoline-4-yloxy)benzaldehyde)semicarbazone; (E)-N.sup.1-(2-fluorophenyl)-N.sup.4-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinoline-4-yloxy)benzaldehyde)semicarbazone; (E)-N.sup.1-(3,5-dichlorophenyl)-N.sup.4-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinoline-4-yloxy)benzaldehyde)thiosemicarbazone; (E)-N.sup.1-(3,5-dimethoxyphenyl)-N.sup.4-(4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinoline-4-yloxy)-3-fluorobenzaldehyde)thiosemicarbazone; (E)-N.sup.1-phenyl-N.sup.4-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy) quinoline-4-yloxy)benzaldehyde)thiosemicarbazone; (E)-N.sup.1-[4-chloro-3-(trifluoromethyl)phenyl]-N.sup.4-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinoline-4-yloxy)benzaldehyde)thiosemicarbazone; (E)-N.sup.1-(3-bromophenyl)-N.sup.4-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)benzaldehyde)thiosemicarbazone; (E)-N.sup.1-(3,5-difluorophenyl)-N.sup.4-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)benzaldehyde)thiosemicarbazone; (E)-N.sup.1-phenyl-N.sup.4-(3-fluoro-4-(6-methoxy-7-(3-(4-methyl-1-piperazinyl)propoxy)quinoline-4-yloxy)benzaldehyde)thiosemicarbazone; or (E)-N.sup.1-(4-chlorophenyl)-N.sup.4-(3-fluoro-4-(6-methoxy-7-(3-(4-methyl-1-piperazinyl)propoxy)quinoline-4-yloxy)benzaldehyde)thiosemicarbazone.
13. A pharmaceutical composition, comprising the compounds or pharmaceutically acceptable salts or hydrates thereof according to claim 1 as active ingredient and a pharmaceutically acceptable excipient.
14. A method for treating a cancer, the method comprising administering, to a patient in need thereof, a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, or hydrate, wherein the cancer is lung cancer liver cancer, stomach cancer, colon cancer, breast cancer, malignant glioblastoma.
Description
EMBODIMENTS
(1) The following examples aim to illustrate rather than limit the scope of the invention. The nuclear magnetic resonance hydrogen spectrum (.sup.1H-NMR) of compounds in the invention was determined by Bruker ARX-300, and mass spectrum (MS) was determined by Agilent 1100 LC/MSD; all reagents were analytically pure or chemically pure.
(2) ##STR00014##
(3) TABLE-US-00001 Example —NR.sub.1R.sub.2 M Example 1
Example 1
Step A: 1-(4-(3-Chloropropoxy)-3-methoxy)acetophenone (III)
(4) 1-(4-Hydroxy-3-methoxyphenyl)ethanone (600 g, 3.61 mol, Purchased from Zhejiang Dongdong Pharmaceutical Co., Ltd.) and anhydrous potassium carbonate (698 g, 5.055 mol) was added to 2500 mL of dry N,N-dimethylformamide. The mixture was stirred for 30 min at room temperature and then 1-bromo-3-chloropropane (795.9 g, 1.4 mol) was drop-wise added while maintaining the temperature below 25° C. Then the resulted mixture was kept at 25° C. for 10 h. After completion of the reaction, the precipitate was filtered and the filter cake was washed by a small amount of N,N-dimethylformamide. The filtrate was poured into ice-water slowly with vigorous stirring. Then the resulted mixture was stirred for 30 min. The precipitate was filtered, washed with water, and dried to give 827.2 g as white solid. Yield: 93.8%.
Step B: 1-(4-(3-chloropropoxy)-5-methoxy-2-nitrophenyl)ethanone (N)
(5) To a solution of intermediate III (200 g, 0.82 mol) in dichloromethane (1000 mL), fuming nitric acid (130 g, 2.06 mol) was added drop-wise at a rate to maintain the reaction temperature at −10˜-20° C. Upon the completion of addition, the mixture was stirred for 2 h at −10˜-20° C. After completion of the reaction, the reaction mixture was poured slowly into ice water, and the organic layer was separated and washed with saturated sodium bicarbonate solution until the aqueous layer became neutral, then dried with anhydrous sodium sulphate. The solution was evaporated to give 210.0 g yellow solid. Yield: 89.0%.
Step C: (E)-1-(4-(3-chloropropoxy)-5-methoxy-2-nitrophenyl)-3-(dimethylamino)prop-2-en-1-one (V)
(6) To 1000 mL of toluene were added 0.695 mol (200 g) of intermediate N and the mixture was heated to 110° C. to make intermediate N completely dissolved. Then 3.476 mol (414.2 g) of N,N-dimethylformamide dimethyl acetal (DMF-DMA) was added, and the reaction was heated to reflux for 16 h. After completion of the reaction, the resulting precipitate from the cooled reaction (−10° C.) mixture was filtered to obtain the target compound as a yellow powder (180.0 g). Yield: 75.8%.
Step D: 7-(3-chloropropoxy)-6-methoxyquinolin-4(1H)-one (VI)
(7) 0.44 mol (150 g) of intermediate V was dissolved in 1200 mL of glacial acetic acid, and the mixture was heated to 40° C. After intermediate V was completely dissolved, 2.20 mol (123.1 g) ironpowder was added slowly, then the reaction mixture was heated to 80° C. with mechanical stirring for 2 h. After completion of the reaction, the reaction mixture was filtered immediately to remove iron powder. The filtrate was collected and cooled to precipitate solid, and then filtered to give yellow solid, which was dissolved in glacial acetic acid and recrystallized to give solid 79.0 g. Yield: 65.0%.
Step E: 6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4(1H)-one (VII)
(8) To 620 mL of acetonitrile were added 0.232 mol (62 g) of intermediate VI, and 1.16 mol of pyrrolidine (82.46 g), then the reaction mixture was heated to reflux for 8 h. After completion of the reaction, most of the solvent was evaporated, the raffinate was put in cold trap to precipitated solid, then filtered and the filter cake was washed with ethyl acetate to give solid 66.7 g. Yield 95.3%.
Step F: 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolone (VIII)
(9) To 315 mL of acetonitrile were added 0.198 mol (63.0 g) of intermediate VII, 315 ml of phosphorus oxychloride, then the reaction mixture was heated to 85° C. and refluxed for 6 h. After completion of the reaction, the mixture was evaporated to give gray viscous solid, which was poured into plenty of ice water, adjusted to pH 8 with 10% solution of potassium hydroxide, extracted with methylene dichloride (3×200 mL). The organic layer was collected and dried with anhydrous sodium sulfate, and evaporated in vacuo to give solid 58.1 g. Yield: 87.3%.
Step G: 4-(2-fluoro-4-nitrophenoxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolone (IX)
(10) To 250 mL of anhydrous chlorobenzene were added 0.234 mol (36.7 g) of 2-fluoro-4-nitrophenol. The reaction mixture was heated to 140° C. then added 0.2 mol (62.5 g) of intermediate (VIII). The resulted reaction mixture was kept at this temperature for 20 h. After completion of the reaction, the reaction mixture was evaporated in vacuo to give gray solid, which was dissolved with methylene dichloride and washed with saturated potassium carbonate solution. The organic layer was dried with sodium sulfate, evaporated and recrystallized with ethanol to give solid 49.3 g. Yield: 71.4%.
Step H: 3-fluoro-4-((6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yl)oxy)aniline (X)
(11) To 1200 mL of 90% ethanol were added 1.1 mol (61.4 g) of ironpowder, 6 mL of hydrochloric acid, then the reaction mixture was heated to 80° C. with stirring and kept at this temperature for 15 min. After that, the reaction mixture was added portionwise 0.11 mol (48.4 g) intermediate IX, then refluxed for 2 h. After completion of the reaction, the reaction mixture was filtered with cooling. The filtrate was collected and evaporated to give yellow solid 43.2 g. Yield: 95.1%.
Step I: (3-Fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yloxy)phenyl)-4-(benzylidene)semicarbazide (XI)
(12) To the mixture of intermediate X 39.5 g (0.09 mol) and anhydrous K.sub.2CO.sub.3 24.8 g (0.18 mol) in dry acetone (500 mL), phenyl chloroformate 17.5 mL (0.14 mol) was added dropwise. After the addition was completed, the mixture was warmed to room temperature for another 3 h, and the solvent was evaporated under reduced pressure. The residue was dissolved in CH.sub.2Cl.sub.2 (500 mL), and washed with water (3×100 mL), dried over anhydrous Na.sub.2SO.sub.4, concentrated under reduced pressure to afford corresponding phenylcarbamates 45.1 g, Yield: 91.9%.
Step J: 3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yloxy)phenyl)semicarbazide (A-1)
(13) A mixture of intermediate XI 45.1 g (0.08 mol) was dissolved in 1,4-dioxane (200 mL) and 80% hydrazine monohydrate (300 mL) was added and refluxed for 8 h with vigorous agitation. The solvent was evaporated under reduced pressure when white solid appeared. The resulting precipitate was filtered off to afford the title compound (17.8 g) as a yellow solid, yield: 46.1%.
Step K: (E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinolin-4-yloxy)phenyl)-N4-(benzylidene)semicarbazide
Example 1
(14) To a solution of A-1 0.2 g (0.41 mmol) in isopropanol (2 mL), benzaldehydes and acetic acid (1 drop) were added, and the mixture was refluxed for 5 h. After cooling to room temperature, the resultant precipitate was filtered and washed with small amount of isopropanol to afford the title compound (0.16 g) as a white solid, yield: 63.6%.
(15) ESI-MS [M+H] (m/z): 558.5; .sup.1H-NMR (300 MHz, DMSO) δ10.92 (s, 1H), 9.23 (s, 1H), 8.49 (d, J=5.4 Hz, 1H), 7.99 (s, 1H), 7.90-7.97 (dd, J.sub.1=13.5 Hz, J.sub.2=2.4 Hz, 1H), 7.86-7.89 (m, 2H), 7.64-7.69 (m, 1H), 7.55 (s, 1H), 7.38-7.48 (m, 5H), 6.46 (d, J=5.1 Hz, 1H), 4.21 (t, J=6.3 Hz, 2H), 3.96 (s, 3H), 2.58 (t, J=6.9 Hz, 2H), 2.41-2.50 (m, 4H), 1.95-2.04 (m, 2H), 1.63-1.74 (m, 4H).
(16) According to the methods in example 1, example 2-30 can be obtained by condensation reaction from varies substituted intermediates A-1 reacted with corresponding aldehydes.
Example 2
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(benzaldehyde)semicarbazone
(17) ESI-MS [M+H] (m/z): 586.8; .sup.1H-NMR (300 MHz, DMSO) δ10.91 (s, 1H), 9.22 (s, 1H), 8.47 (d, J=5.4 Hz, 1H), 7.97 (s, 1H), 7.90-7.95 (dd, J.sub.1=13.5 Hz, J.sub.2=2.1 Hz, 1H), 7.84-7.88 (m, 2H), 7.64-7.70 (m, 1H), 7.53 (s, 1H), 7.38-7.48 (m, 5H), 6.46 (d, J=5.1 Hz, 1H), 4.21 (t, J=6.3 Hz, 2H), 3.96 (s, 3H), 2.97 (br s, 2H), 2.53-2.67 (m, 2H), 1.92-2.14 (m, 4H), 1.58-1.69 (m, 2H), 1.39 (br s, 1H), 1.11-1.27 (m, 2H), 0.91 (d, J=6.6 Hz, 3H).
Example 3
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(benzaldehyde)semicarbazone
(18) ESI-MS [M+H] (m/z): 574.7; .sup.1H-NMR (300 MHz, DMSO) δ10.93 (s, 1H), 9.23 (s, 1H), 8.48 (d, J=5.1 Hz, 1H), 8.00 (s, 1H), 7.91-7.96 (dd, J.sub.1=16.5 Hz, J.sub.2=2.4 Hz, 1H), 7.86-7.89 (m, 2H), 7.65-7.68 (m, 1H), 7.59 (s, 1H), 7.39-7.48 (m, 5H), 6.46 (d, J=5.1 Hz, 1H), 4.21 (t, J=6.3 Hz, 2H), 3.93 (s, 3H), 3.68 (m, 4H), 2.44-2.49 (m, 2H), 2.35-2.43 (br s, 4H), 1.94-2.03 (m, 2H).
Example 4
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline-4-lyoxy)phenyl)-N4-(benzaldehyde)semicarbazone
(19) ESI-MS [M+H] (m/z): 587.6; .sup.1H-NMR (300 MHz, DMSO) δ10.98 (s, 1H), 9.29 (s, 1H), 8.45 (d, J=5.1 Hz, 1H), 8.05 (s, 1H), 7.92-7.98 (dd, J.sub.1=16.5 Hz, J.sub.2=2.4 Hz, 1H), 7.86-7.89 (m, 2H), 7.64-7.70 (m, 1H), 7.62 (s, 1H), 7.41-7.49 (m, 5H), 6.47 (d, J=5.1 Hz, 1H), 4.29 (d, J=5.9 Hz, 2H), 3.98 (s, 3H), 3.38-3.47 (m, 10H), 2.85 (s, 3H), 2.39 (s, 2H).
Example 5
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(benzaldehyde)semicarbazone
(20) ESI-MS [M+H] (m/z): 571.6; .sup.1H-NMR (300 MHz, DMSO) δ10.93 (s, 1H), 9.24 (s, 1H), 8.47 (d, J=5.1 Hz, 1H), 7.99 (s, 1H), 7.90-7.95 (dd, J.sub.1=13.6 Hz, J.sub.2=2.4 Hz, 1H), 7.86-7.88 (m, 2H), 7.65-7.68 (m, 1H), 7.55 (s, 1H), 7.38-7.48 (m, 5H), 6.45 (d, J=5.6 Hz, 1H), 4.19 (t, J=6.9 Hz, 2H), 3.96 (s, 3H), 2.43 (t, J=6.9 Hz, 2H), 2.29-2.39 (m, 4H), 1.92-2.01 (m, 2H), 1.45-1.55 (m, 4H), 1.34-1.44 (m, 2H).
Example 6
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(3-methoxybenzaldehyde)semicarbazone
(21) ESI-MS [M+H] (m/z): 587.7; .sup.1H-NMR (300 MHz, DMSO) δ10.94 (s, 1H), 9.27 (s, 1H), 8.48 (d, J=5.4 Hz, 1H), 7.96 (s, 1H), 7.90-7.94 (dd, J.sub.1=13.5 Hz, J.sub.2=2.4 Hz, 1H), 7.62-7.67 (m, 1H), 7.59 (s, 1H), 7.46-7.50 (m, 1H), 7.32-7.44 (m, 4H), 6.96-7.00 (m, 1H), 6.45 (d, J=5.4 Hz, 1H), 4.21 (t, J=6.3 Hz, 2H), 3.96 (s, 3H), 3.83 (s, 3H), 2.67 (t, J=7.2 Hz, 2H), 2.53-2.62 (m, 4H), 1.97-2.06 (m, 2H), 1.69-1.76 (m, 4H).
Example 7
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy quinoline-4-yloxy)phenyl)-N4-(3-methoxybenzaldehyde)semicarbazone
(22) ESI-MS [M+H] (m/z): 616.6; .sup.1H-NMR (300 MHz, DMSO) δ11.03 (s, 1H), 9.31 (s, 1H), 8.48 (d, J=5.1 Hz, 1H), 7.99 (s, 1H), 7.89-7.94 (dd, J.sub.1=13.5 Hz, J.sub.2=2.1 Hz, 1H), 7.63-7.71 (m, 1H), 7.59 (s, 1H), 7.47-7.54 (m, 1H), 7.34-7.44 (m, 4H), 6.97-7.04 (m, 1H), 6.45 (d, J=5.1 Hz, 1H), 4.22 (t, J=6.3 Hz, 2H), 3.95 (s, 3H), 3.85 (s, 3H), 2.95-2.99 (br s, 2H), 2.53-2.69 (m, 2H), 1.93-2.12 (m, 4H), 1.61-1.69 (m, 2H), 1.36-1.41 (br s, 1H), 1.14-1.25 (m, 2H), 0.94 (d, J=6.6 Hz, 3H).
Example 8
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(3-methoxybenzaldehyde)semicarbazone
(23) ESI-MS [M+H] (m/z): 604.7; .sup.1H-NMR (300 MHz, DMSO) δ10.94 (s, 1H), 9.28 (s, 1H), 8.48 (d, J=5.1 Hz, 1H), 7.96 (s, 1H), 7.91-7.95 (dd, J.sub.1=13.5 Hz, J.sub.2=2.1 Hz, 1H), 7.62-7.69 (m, 1H), 7.58 (s, 1H), 7.46-7.51 (m, 1H), 7.33-7.45 (m, 4H), 6.96-7.01 (m, 1H), 6.44 (d, J=5.1 Hz, 1H), 4.21 (t, J=6.3 Hz, 2H), 3.96 (s, 3H), 3.83 (s, 3H), 3.55-3.63 (m, 4H), 2.43-2.49 (m, 2H), 2.33-2.43 (m, 4H), 1.93-2.04 (m, 2H).
Example 9
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(3-methoxybenzaldehyde)semicarbazone
(24) ESI-MS [M+H] (m/z): 602.6; .sup.1H-NMR (300 MHz, DMSO) δ10.93 (s, 1H), 9.26 (s, 1H), 8.48 (d, J=5.1 Hz, 1H), 7.96 (s, 1H), 7.91-7.95 (dd, J.sub.1=13.5 Hz, J.sub.2=2.4 Hz, 1H), 7.62-7.68 (m, 1H), 7.54 (s, 1H), 7.46-7.50 (m, 1H), 7.32-7.44 (m, 4H), 6.96-7.00 (m, 1H), 6.44 (d, J=5.1 Hz, 1H), 4.19 (t, J=6.6 Hz, 2H), 3.96 (s, 3H), 3.83 (s, 3H), 2.41-2.47 (m, 2H), 2.30-2.39 (m, 4H), 1.90-2.01 (m, 2H), 1.45-1.55 (m, 4H), 1.34-1.44 (m, 2H).
Example 10
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinoline-4-lyoxy)phenyl)-N4-(4-fluorobenzaldehyde)semicarbazone
(25) ESI-MS [M+H] (m/z): 604.8; .sup.1H-NMR (300 MHz, DMSO) δ11.11 (s, 1H), 9.34 (s, 1H), 8.48 (d, J=5.1 Hz, 1H), 7.97 (s, 1H), 7.87-7.95 (m, 3H), 7.61-7.68 (m, 1H), 7.56 (s, 1H), 7.36-7.45 (m, 2H), 7.28 (m, 2H), 6.46 (d, J=5.1 Hz, 1H), 4.22 (t, J=6.3 Hz, 2H), 3.96 (s, 3H), 2.95-2.99 (br s, 2H), 2.52-2.64 (m, 2H), 1.95-2.13 (m, 4H), 1.61-1.67 (m, 2H), 1.36-1.44 (br s, 1H), 1.14-1.22 (m, 2H), 0.97 (d, J=6.6 Hz, 3H).
Example 11
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(4-fluorobenzaldehyde)semicarbazone
(26) ESI-MS [M+H] (m/z): 590.7; .sup.1H-NMR (300 MHz, DMSO) δ10.74-11.11 (br s, 1H), 9.14-9.45 (br s, 1H), 8.48 (d, J=5.4 Hz, 1H), 7.99 (s, 1H), 7.86-7.97 (m, 3H), 7.61-7.68 (m, 1H), 7.54 (s, 1H), 7.36-7.45 (m, 2H), 7.28 (m, 2H), 6.46 (d, J=5.4 Hz, 1H), 4.19 (t, J=6.6 Hz, 2H), 3.96 (s, 3H), 2.43 (t, J=7.2 Hz, 2H), 2.27-2.39 (br s, 4H), 1.89-2.02 (m, 2H), 1.44-1.56 (m, 4H), 1.32-1.44 (m, 2H).
Example 12
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(2-chloro-4-fluorobenzaldehyde)semicarbazone
(27) ESI-MS [M+H] (m/z): 611.0.
Example 13
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(2-chloro-4-fluorobenzaldehyde)semicarbazone
(28) ESI-MS [M+H] (m/z): 639.3; .sup.1H-NMR (300 MHz, DMSO) δ11.08 (s, 1H), 9.28 (s, 1H), 8.47 (d, J=5.1 Hz, 1H), 8.40-8.44 (m, 1H), 8.35 (s, 1H), 7.88-7.93 (dd, J.sub.1=13.5 Hz, J.sub.2=2.4 Hz, 1H), 7.59-7.65 (m, 1H), 7.48-7.56 (m, 2H), 7.32-7.43 (m, 3H), 6.44 (d, J=5.1 Hz, 1H), 4.20 (t, J=6.3 Hz, 2H), 3.96 (s, 3H), 2.93-2.98 (br s, 2H), 2.52-2.61 (m, 2H), 1.94-2.15 (m, 4H), 1.63-1.68 (m, 2H), 1.36-1.43 (br s, 1H), 1.17-1.24 (m, 2H), 0.95 (d, J=6.3 Hz, 3H).
Example 14
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(2-chloro-4-fluorobenzaldehyde)semicarbazone
(29) ESI-MS [M+H] (m/z): 627.1; .sup.1H-NMR (300 MHz, DMSO) δ11.14 (s, 1H), 9.31 (s, 1H), 8.48 (d, J=5.4 Hz, 1H), 8.43-8.47 (m, 1H), 8.34 (s, 1H), 7.88-7.93 (dd, J.sub.1=13.5 Hz, J.sub.2=2.7 Hz, 1H), 7.59-7.67 (m, 1H), 7.50-7.56 (m, 2H), 7.32-7.45 (m, 3H), 6.46 (d, J=5.4 Hz, 1H), 4.21 (t, J=6.3 Hz, 2H), 3.98 (s, 3H), 3.58-3.63 (m, 4H), 2.43-2.49 (m, 2H), 2.35-2.43 (br s, 4H), 1.94-2.03 (m, 2H).
Example 15
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(2-nitrobenzaldehyde)semicarbazone
(30) ESI-MS [M+H] (m/z): 603.8.
Example 16
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(2-nitrobenzaldehyde)semicarbazone
(31) ESI-MS [M+H] (m/z): 631.8.
Example 17
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(acetophenone)semicarbazone
(32) ESI-MS [M+H] (m/z): 586.3.
Example 18
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(2-hydroxyl-1-naphthaldehyde)semicarbazone
(33) ESI-MS [M+H] (m/z): 623.8; .sup.1H-NMR (300 MHz, DMSO) δ9.84 (br s, 1H), 9.05 (s, 1H), 8.48 (d, J=5.1 Hz, 1H), 8.40 (d, J=8.4 Hz, 1H), 7.81-7.92 (m, 3H), 7.52-7.63 (m, 2H), 7.34-7.50 (m, 4H), 7.24 (d, J=8.4 Hz, 1H), 6.47 (d, J=5.1 Hz, 1H), 4.22 (t, J=5.7 Hz, 2H), 3.97 (s, 3H), 2.56-2.75 (m, 6H), 2.03-2.12 (m, 2H), 1.54-1.66 (m, 4H), 1.38-1.50 (m, 2H).
Example 19
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propox)quinoline-4-yloxy)phenyl)-N4-(2,4-dichlorobenzaldehyde)semicarbozone
(34) ESI-MS [M+H] (m/z): 627.4; .sup.1H-NMR (300 MHz, DMSO) δ11.22 (s, 1H), 9.37 (s, 1H), 8.49 (d, J=5.1 Hz, 1H), 8.42 (d, J=8.4 Hz, 1H), 8.34 (s, 1H), 7.87-7.92 (dd, J.sub.1=13.2 Hz, J.sub.2=2.1 Hz, 1H), 7.70 (d, J=2.1 Hz, 1H), 7.61-7.65 (m, 1H), 7.59 (s, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.39-7.45 (m, 2H), 6.46 (d, J=5.1 Hz, 1H), 4.24 (t, J=4.0 Hz, 2H), 3.96 (s, 3H), 2.76-2.98 (m, 6H), 2.08-2.13 (m, 2H), 1.78-1.84 (m, 4H).
Example 20
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(2,4-dichlorobenzaldehyde)semicarbazone
(35) ESI-MS [M+H] (m/z): 643.7; .sup.1H-NMR (300 MHz, DMSO) δ11.20 (s, 1H), 9.34 (s, 1H), 8.49 (d, J=5.1 Hz, 1H), 8.43 (d, J=8.7 Hz, 1H), 8.34 (s, 1H), 7.86-7.93 (dd, J.sub.1=13.5 Hz, J.sub.2=2.4 Hz, 1H), 7.70 (d, J=2.4 Hz, 1H), 761-7.67 (m, 1H), 7.56 (s, 1H), 7.50-7.54 (dd, J.sub.1=8.7 Hz, J.sub.2=2.4 Hz, 1H), 7.40-7.46 (m, 2H), 6.47 (d, J=5.1 Hz, 1H), 4.24 (t, J=6.0 Hz, 2H), 3.97 (s, 3H), 3.64-3.74 (m, 4H), 2.63-2.93 (br s, 6H), 2.05-2.18 (m, 2H).
Example 21
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(2-hydroxy-1-naphthaldehyde)semicarbazone
(36) ESI-MS [M+H] (m/z): 652.8; .sup.1H-NMR (300 MHz, DMSO) δ11.01 (s, 1H), 9.84 (s, 1H), 9.05 (s, 1H), 8.48 (d, J=5.1 Hz, 1H), 8.40 (d, J=8.7 Hz, 1H), 7.81-7.92 (m, 3H), 7.52-7.63 (m, 2H), 7.34-7.50 (m, 4H), 7.24 (d, J=8.7 Hz, 1H), 6.47 (d, J=5.1 Hz, 1H), 4.22 (t, J=5.7 Hz, 2H), 3.97 (s, 3H), 2.93-2.99 (br s, 2H), 2.52-2.59 (m, 2H), 1.92-2.10 (m, 4H), 1.65-1.69 (m, 2H), 1.36-1.44 (br s, 1H), 1.17-1.23 (m, 2H), 0.97 (d, J=6.3 Hz, 3H).
Example 22
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-4-lyoxy)phenyl)-N4-(3,4-difluorobenzaldehyde)semicarbazone
(37) ESI-MS [M+H] (m/z): 594.8; .sup.1H-NMR (300 MHz, DMSO) δ11.18 (s, 1H), 9.41 (s, 1H), 8.48 (d, J=5.1 Hz, 1H), 8.11-8.18 (m, 1H), 7.97 (s, 1H), 7.89-7.94 (dd, J.sub.1=13.5 Hz, J.sub.2=2.4 Hz, 1H), 7.73-7.85 (m, 1H), 7.61-7.67 (m, 2H), 7.55 (s, 1H), 7.38-7.52 (m, 2H), 6.46 (d, J=5.1 Hz, 1H), 4.24 (t, J=6.3 Hz, 2H), 3.95 (s, 3H), 2.73-2.91 (m, 6H), 2.06-2.15 (m, 2H), 1.70-1.86 (m, 4H).
Example 23
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-oxy)phenyl)-N4-(3,4-difluorobenzaldehyde)semicarbazone
(38) ESI-MS [M+H] (m/z): 619.6; .sup.1H-NMR (300 MHz, DMSO) δ11.05 (s, 1H), 9.27 (s, 1H), 8.49 (d, J=5.1 Hz, 1H), 8.14-8.22 (m, 1H), 7.96 (s, 1H), 7.89-7.94 (dd, J.sub.1=13.5 Hz, J.sub.2=2.4 Hz, 1H), 7.60-7.68 (m, 2H), 7.55 (s, 1H), 7.40-7.52 (m, 3H), 6.46 (d, J=5.4 Hz, 1H), 4.21 (t, J=6.3 Hz, 2H), 3.96 (s, 3H), 3.58-3.62 (m, 4H), 2.45-2.48 (m, 2H), 2.35-2.43 (br s, 4H), 1.95-2.04 (m, 2H).
Example 24
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(3-trifluoromethylbenzaldehyde)semicarbazone
(39) ESI-MS [M+H] (m/z): 626.8.
Example 25
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(2,4-difluorobenzaldehyde) semicarbazone
(40) ESI-MS [M+H] (m/z): 622.7.
Example 26
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(3-trifluoromethylbenzaldehyde)semicarbazone
(41) ESI-MS [M+H] (m/z): 642.8; .sup.1H-NMR (300 MHz, DMSO) δ11.10 (s, 1H), 9.38 (s, 1H), 8.49 (d, J=5.4 Hz, 1H), 8.26 (s, 1H), 8.18 (d, J=8.1 Hz, 1H), 8.08 (s, 1H), 7.90-7.95 (dd, J.sub.1=13.5 Hz, J.sub.2=2.1 Hz, 1H), 7.63-7.78 (m, 3H), 7.55 (s, 1H), 7.40-7.46 (m, 2H), 6.46 (d, J=5.1 Hz, 1H), 4.21 (t, J=6.3 Hz, 2H), 3.97 (s, 3H), 3.58-3.62 (m, 4H), 2.44-2.48 (m, 2H), 2.33-2.42 (br s, 4H), 1.96-2.05 (m, 2H).
Example 27
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(3,5-dimethyl-4-hydroxybenzaldehyde)semicarbazone
(42) ESI-MS [M+H] (m/z): 617.9; .sup.1H-NMR (300 MHz, DMSO) δ10.66 (s, 1H), 9.11 (s, 1H), 8.64 (s, 1H), 8.48 (d, J=5.1 Hz, 1H), 7.91-7.97 (dd, J.sub.1=13.5 Hz, J.sub.2=2.4 Hz, 1H), 7.83 (s, 1H), 7.64-7.68 (m, 1H), 7.55 (s, 1H), 7.37-7.42 (m, 4H), 6.45 (d, J=5.1 Hz, 1H), 4.21 (t, J=6.3 Hz, 2H), 3.96 (s, 3H), 3.58-3.61 (m, 4H), 2.40-2.47 (m, 2H), 2.34-2.44 (br s, 4H), 2.21 (s, 6H), 1.94-2.04 (m, 2H).
Example 28
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(2-hydroxyl-1-naphthaldehyde)semicarbazone
(43) ESI-MS [M+H] (m/z): 640.7.
Example 29
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(3-allyl-2-hydroxybenzaldehyde)semicarbazone
(44) ESI-MS [M+H] (m/z): 614.9; .sup.1H-NMR (300 MHz, DMSO) δ11.09 (s, 1H), 9.84 (s, 1H), 8.51 (d, J=5.4 Hz, 1H), 8.28 (s, 1H), 7.89 (d, J=12.3 Hz, 1H), 7.58 (s, 1H), 7.45-7.39 (m, 4H), 7.14 (d, J=7.2 Hz, 1H), 6.88 (t, J=7.2 Hz, 1H), 6.51 (d, J=4.8 Hz, 1H), 5.93-6.07 (m, 1H), 5.02-5.10 (m, 2H), 4.28 (t, J=5.7 Hz, 2H), 3.98 (s, 3H), 3.25 (m, 2H), 2.63 (t, J=6.9 Hz, 2H), 2.45-2.54 (m, 4H), 1.99-2.07 (m, 2H), 1.65-1.77 (m, 4H).
Example 30
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(propiophenone)thiosemicarbazone
(45) ESI-MS [M+H] (m/z): 600.3.
Step L: 4-(2-fluoro-4-isothiocyanatophenoxy)-6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinolone (XII)
(46) Intermediate X 10 g (23.5 mmol) was dissolved in CH.sub.2Cl.sub.2 (100 mL) and sat. aq. NaHCO.sub.3 (20 mL) was added. The resulting biphasic solution was cooled to 0° C. and thiophosgene 2.2 mL (28.2 mmol) was then carefully added via syringe. After the addition was completed, the reaction was allowed to warm to room temperature and stirred for 6 h. The organic layer was separated and the aqueous layer was extracted with CH.sub.2Cl.sub.2. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford intermediate XII (8.14 g) as a yellow oil, yield: 74.1%.
Step L: 4-(4-(7-(3-(piperidin-1-yl)propoxy)-6-methoxyquinolin-4-yloxy)-3-fluorophenyl)thiosemicarbazide (A-2)
(47) To a solution of intermediate XII 6 g (12.8 mmol) in CH.sub.2Cl.sub.2 (40 mL) was added 80% hydrazine monohydrate 30 mL), and the biphasic solution was vigorously stirred for 12 h at room temperature. The organic layer was separated and washed with water (3×20 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to afford A-2 (4.5 g) as a yellow solid, yield: 69.5%.
Step N: (E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-yloxy)phenyl)-N4-(3,4-difluorobenzylidene)thiosemicarbazide
Example 31
(48) To a solution of A-7 0.2 g (0.40 mmol) in isopropanol (2 mL), 2,4-difluorobenzylidene 0.07 g (0.50 mmol) and acetic acid (1 drop) were added, and the mixture was refluxed for 6 h. The resultant precipitate was filtered and washed with a little amount of isopropanol to afford the target compound 0.13 g as a yellow solid, yield: 52.2%.
(49) ESI-MS [M+H] (m/z): 607.7; .sup.1H-NMR (300 MHz, DMSO) δ11.08 (s, 1H), 9.34 (s, 1H), 8.47 (d, J=5.1 Hz, 1H), 8.09-8.17 (m, 1H), 7.96 (s, 1H), 7.86-7.92 (dd, J.sub.1=13.5 Hz, J.sub.2=2.4 Hz, 1H), 7.73-7.84 (m, 1H), 7.60-7.66 (m, 2H), 7.52 (s, 1H), 7.38-7.50 (m, 2H), 6.46 (d, J=5.1 Hz, 1H), 4.22 (t, J=6.3 Hz, 2H), 3.94 (s, 3H), 2.41-2.45 (m, 2H), 2.33-2.39 (m, 4H), 1.90-1.98 (m, 2H), 1.45-1.54 (m, 4H), 1.34-1.42 (m, 2H).
(50) According to the methods in example 31, examples 32-45 can be obtained by condensation reaction between varies substituted intermediates A-1 and corresponding aldehydes.
Example 32
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-4-yloxy)phenyl))-N4-(2-nitrobenzaldehyde)thiosemicarbazone
(51) ESI-MS [M+H] (m/z): 620.0.
Example 33
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(2-nitrobenzaldehyde)thiosemicarbazone
(52) ESI-MS [M+H] (m/z): 635.8; .sup.1H-NMR (300 MHz, DMSO) δ11.25 (s, 1H), 9.28 (s, 1H), 8.47-8.51 (m, 2H), 8.40 (m, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.87-7.93 (dd, J.sub.1=13.5 Hz, J.sub.2=2.1 Hz, 1H), 7.78-7.84 (m, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.61-7.63 (m, 1H), 7.54 (s, 1H), 7.42-7.46 (m, 1H), 7.40 (s, 1H), 6.47 (d, J=5.1 Hz, 1H), 4.22 (t, J=6.0 Hz, 2H), 3.96 (s, 3H), 3.55-3.61 (m, 4H), 2.42-2.47 (m, 2H), 2.32-2.41 (br s, 4H), 1.95-2.05 (m, 2H).
Example 34
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(2-nitrobenzaldehyde)thiosemicarbazone
(53) ESI-MS [M+H] (m/z): 635.6.
Example 35
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(3-allyl-2-hydroxybenzaldehyde)thiosemicarbazone
(54) ESI-MS [M+H] (m/z): 630.6.
Example 36
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(benzaldehyde)thiosemicarbazone
(55) ESI-MS [M+H] (m/z): 574.5; .sup.1H-NMR (300 MHz, DMSO) δ10.89 (s, 1H), 9.21 (s, 1H), 8.47 (d, J=5.1 Hz, 1H), 7.97 (s, 1H), 7.88-7.95 (dd, J.sub.1=13.5 Hz, J.sub.2=2.4 Hz, 1H), 7.81-7.85 (m, 2H), 7.64-7.68 (m, 1H), 7.57 (s, 1H), 7.39-7.48 (m, 5H), 6.46 (d, J=5.1 Hz, 1H), 4.20 (t, J=6.3 Hz, 2H), 3.95 (s, 3H), 2.55 (t, J=6.9 Hz, 2H), 2.41-2.52 (m, 4H), 1.93-2.04 (m, 2H), 1.61-1.70 (m, 4H).
Example 37
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(benzaldehyde)thiosemicarbazone
(56) ESI-MS [M+H] (m/z): 602.8.
Example 38
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(benzaldehyde)thiosemicarbazone
(57) ESI-MS [M+H] (m/z): 590.8; .sup.1H-NMR (300 MHz, DMSO) δ10.88 (s, 1H), 9.26 (s, 1H), 8.45 (d, J=5.1 Hz, 1H), 8.05 (s, 1H), 7.92-7.98 (dd, J.sub.1=13.5 Hz, J.sub.2=2.1 Hz, 1H), 7.84-7.88 (m, 2H), 7.65-7.68 (m, 1H), 7.57 (s, 1H), 7.36-7.49 (m, 5H), 6.46 (d, J=5.4 Hz, 1H), 4.20 (t, J=6.3 Hz, 2H), 3.95 (s, 3H), 3.59-3.62 (m, 4H), 2.44-2.49 (m, 2H), 2.33-2.42 (br s, 4H), 1.94-2.02 (m, 2H).
Example 39
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(4-methyl-1-piperazinyl)propoxy)quinoline-4-yloxy)phenyl)-N4-(benzaldehyde)thiosemicarbazone
(58) ESI-MS [M+H] (m/z): 603.6; .sup.1H-NMR (300 MHz, DMSO) δ10.93 (s, 1H), 9.26 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.02 (s, 1H), 7.88-7.95 (dd, J.sub.1=13.5 Hz, J.sub.2=2.1 Hz, 1H), 7.79-7.84 (m, 2H), 7.63-7.71 (m, 1H), 7.60 (s, 1H), 7.41-7.47 (m, 5H), 6.45 (d, J=5.1 Hz, 1H), 4.23 (d, J=6.3 Hz, 2H), 3.96 (s, 3H), 3.37-3.49 (m, 10H), 2.88 (s, 3H), 2.35 (s, 2H).
Example 40
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(4-methyl-1-piperazinyl)propoxy)quinoline-4-yloxy)phenyl)-N4-(2,4-dichlorobenzaldehyde)thiosemicarbazone
(59) ESI-MS [M+H] (m/z): 672.6; .sup.1H-NMR (300 MHz, DMSO) δ10.96 (s, 1H), 9.40 (s, 1H), 8.48 (d, J=5.1 Hz, 1H), 8.35-8.42 (d, J=8.7 Hz, 1H), 8.26 (s, 1H), 7.83-7.91 (dd, J.sub.1=13.5 Hz, J.sub.2=2.1 Hz, 1H), 7.66 (d, J=2.1 Hz, 1H), 7.58-7.63 (m, 1H), 7.52 (s, 1H), 7.45-7.51 (dd, J.sub.1=8.7 Hz, J.sub.2=2.1 Hz, 1H), 7.36-7.42 (m, 2H), 6.46 (d, J=5.1 Hz, 1H), 4.22 (t, J=6.0 Hz, 2H), 3.94 (s, 3H), 3.35-3.44 (m, 10H), 2.87 (s, 3H), 2.33 (s, 2H).
Example 41
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(2,4-dichlorobenzaldehyde)thiosemicarbazone
(60) ESI-MS [M+H] (m/z): 641.6; .sup.1H-NMR (300 MHz, DMSO) δ11.05 (s, 1H), 9.45 (s, 1H), 8.47 (d, J=5.1 Hz, 1H), 8.39-8.43 (d, J=8.7 Hz, 1H), 8.32 (s, 1H), 7.86-7.93 (dd, J.sub.1=13.5 Hz, J.sub.2=2.4 Hz, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.61-7.65 (m, 1H), 7.54 (s, 1H), 7.47-7.52 (dd, J.sub.1=8.7 Hz, J.sub.2=2.4 Hz, 1H), 7.38-7.44 (m, 2H), 6.45 (d, J=5.1 Hz, 1H), 4.19 (t, J=6.0 Hz, 2H), 3.95 (s, 3H), 2.38-2.45 (m, 2H), 2.29-2.35 (m, 4H), 1.90-1.99 (m, 2H), 1.43-1.52 (m, 4H), 1.32-1.41 (m, 2H).
Example 42
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(4-methyl-1-piperazinyl)propoxy)quinoline-4-yloxy)phenyl)-N4-(2-chloro-4-fluorobenzaldehyde)thiosemicarbazone
(61) ESI-MS [M+H] (m/z): 655.9; .sup.1H-NMR (300 MHz, DMSO) δ11.01 (s, 1H), 9.29 (s, 1H), 8.49 (d, J=5.1 Hz, 1H), 8.39-8.44 (m, 1H), 8.36 (s, 1H), 7.89-7.95 (dd, J.sub.1=13.5 Hz, J.sub.2=2.7 Hz, 1H), 7.58-7.70 (m, 1H), 7.47-7.54 (m, 2H), 7.35-7.43 (m, 3H), 6.46 (d, J=5.1 Hz, 1H), 4.20 (t, J=6.3 Hz, 2H), 3.97 (s, 3H), 3.37-3.47 (m, 10H), 2.89 (s, 3H), 2.36 (s, 2H).
Example 43
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(2-chloro-4-fluorobenzaldehyde)thiosemicarbazone
(62) ESI-MS [M+H] (m/z): 625.1; .sup.1H-NMR (300 MHz, DMSO) δ10.97 (s, 1H), 9.26 (s, 1H), 8.46 (d, J=5.4 Hz, 1H), 8.39-8.44 (m, 1H), 8.32 (s, 1H), 7.88-7.93 (dd, J.sub.1=13.5 Hz, J.sub.2=2.7 Hz, 1H), 7.57-7.68 (m, 1H), 7.47-7.54 (m, 2H), 7.32-7.41 (m, 3H), 6.46 (d, J=5.4 Hz, 1H), 4.18 (t, J=6.3 Hz, 2H), 3.94 (s, 3H), 2.38-2.46 (m, 2H), 2.30-2.37 (m, 4H), 1.92-1.99 (m, 2H), 1.43-1.55 (m, 4H), 1.31-1.39 (m, 2H).
Example 44
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(4-fluorobenzaldehyde)thiosemicarbazone
(63) ESI-MS [M+H] (m/z): 592.7; .sup.1H-NMR (300 MHz, DMSO) δ10.91 (s, 1H), 9.20 (s, 1H), 8.48 (d, J=5.1 Hz, 1H), 7.99 (s, 1H), 7.89-7.98 (m, 3H), 7.63-7.66 (m, 1H), 7.55 (s, 1H), 7.41 (d, J=9.0 Hz, 2H), 7.28 (d, J=9.0 Hz, 2H), 6.46 (d, J=5.1 Hz, 1H), 4.23 (t, J=6.0 Hz, 2H), 3.97 (s, 3H), 2.60-2.85 (m, 6H), 2.01-2.10 (m, 2H), 1.70-1.85 (m, 4H).
Example 45
(E)-N1-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)phenyl)-N4-(4-fluorobenzaldehyde)thiosemicarbazone
(64) ESI-MS [M+H] (m/z): 608.8.
Step O: 3-Fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)-quinolin-4-yloxy)benzaldehyde (B)
(65) To dry chlorobenzene (240 mL) was added 3-fluoro-4-hydroxybenzaldehyde 37.6 g (0.27 mol), then intermediate VII was added at 140° C. and reacted for 23 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to yield a pale brown solid. The solid was dissolved in CH.sub.2Cl.sub.2, and washed with saturated K.sub.2CO.sub.3 aqueous solution, and dried over anhydrous Na.sub.2SO.sub.4, concentrated under reduced pressure and recrystallization from ethanol to afford corresponding benzaldehyde (54.6 g), yield: 69.6%.
Step P: phenyl(4-chloro-3-(trifluoromethyl)phenyl)carbamate (W-1)
(66) To the mixture of 4-chloro-3-(trifluoromethyl)aniline 10 g (0.05 mol) and K.sub.2CO.sub.3 14.1 g (0.10 mol) in dry acetone (100 mL), phenyl chloroformate 7.5 mL (0.06 mol) was added dropwise while maintaining the temperature between 0 and 5° C. After the addition was completed, the mixture was warmed to room temperature for another 1.5 h, and the solvent was evaporated under reduced pressure. The residue was washed with water, filtered, and dried under vacuum to afford corresponding compound 14.8 g as a white solid, yield: 93.7%.
Step Q: N-(4-chloro-3-(trifluoromethyl)phenyl)hydrazinecarboxamide (W-2)
(67) A mixture of an intermediate W-1 4 g (13.6 mmol) and 80% hydrazine hydrate (20 mL) in 1,4-dioxane (30 mL) was refluxed for 4 h with vigorous agitation. After cooling to room temperature, the solvent was evaporated under reduced pressure. And the resulting precipitate was filtered-off to afford corresponding semicarbazides 3.0 g, 86.4%.
Step R: (E)-N1-(4-chloro-3-(trifluoromethyl)phenyl)-N4-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-yloxy)benzylidene)-semicarbazide
Example 46
(68) To a solution of W-2 0.12 g (0.48 mmol) in isopropanol (2 mL), 0.2 g (0.46 mmol) B and acetic acid (1 drop) were added, and the mixture was refluxed for 7 h. The resultant precipitate was filtered and washed with a little amount of isopropanol to afford the target compound 0.24 g as a white solid, yield: 74.8%.
(69) ESI-MS [M+H] (m/z): 675.1; .sup.1H-NMR (300 MHz, DMSO) δ11.17 (s, 1H), 9.45 (s, 1H), 8.50 (d, J=5.4 Hz, 1H), 8.27 (d, J=2.7 Hz, 1H), 8.19 (dd, J.sub.1=12.0 Hz, J.sub.2=1.6 Hz, 1H), 8.02-8.06 (m, 2H), 7.72-7.77 (m, 1H), 7.66 (d, J=9.0 Hz, 1H), 7.49-7.54 (m, 2H), 7.42 (s, 1H), 6.52 (d, J=5.4 Hz, 1H), 4.21 (t, J=6.3 Hz, 2H), 3.96 (s, 3H), 2.53-2.60 (m, 2H), 2.39-2.48 (br s, 4H), 1.97-2.06 (m, 2H), 1.52-1.59 (m, 4H), 1.36-1.46 (m, 2H).
(70) According to the methods in example 46, example 47-60 can be obtained by condensation reaction between varies substituted intermediate B and corresponding semicarbazides.
Example 47
(E)-N1-(2-fluorophenyl)-N4-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinoline-4-yloxy)benzaldehyde)semicarbazone
(71) ESI-MS [M+H] (m/z): 590.7; .sup.1H-NMR (300 MHz, DMSO) δ11.08 (s, 1H), 8.87 (s, 1H), 8.50 (d, J=5.1 Hz, 1H), 8.08 (d, J=12.0 Hz, 1H), 8.02 (s, 1H), 7.72-7.76 (m, 1H), 7.68 (d, J=12.0 Hz, 1H), 7.48-7.53 (m, 2H), 7.42 (s, 1H), 7.22-7.30 (m, 1H), 7.13-7.20 (m, 2H), 6.53 (d, J=5.1 Hz, 1H), 4.21 (t, J=6.3 Hz, 2H), 3.96 (s, 3H), 2.53-2.71 (m, 6H), 2.00-2.09 (m, 2H), 1.52-1.65 (m, 4H), 1.36-1.50 (m, 2H).
Example 48
(E)-N1-(3,5-dichlorophenyl)-N4-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinoline-4-yloxy)benzaldehyde)semicarbazone
(72) ESI-MS [M+H] (m/z): 641.7; .sup.1H-NMR (300 MHz, DMSO) δ11.18 (s, 1H), 9.31 (s, 1H), 8.52 (d, J=5.1 Hz, 1H), 8.21 (dd, J.sub.1=12.0 Hz, J.sub.2=1.8 Hz, 1H), 8.03 (s, 1H), 7.87 (s, 1H), 7.86 (s, 1H), 7.49-7.60 (m, 3H), 7.30 (m, 1H), 7.22 (t, J=1.8 Hz, 1H), 6.54 (d, J=5.1 Hz, 1H), 4.28 (t, J=6.0 Hz, 2H), 3.97 (s, 3H), 3.42-3.56 (m, 2H), 3.16-3.25 (m, 2H), 2.77-3.00 (br s, 2H), 2.25-2.36 (m, 2H), 1.74-1.86 (m, 4H), 1.30-1.55 (br s, 2H).
Example 49
(E)-N1-(3,5-dimethoxyphenyl)-N4-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinoline-4-yloxy)benzaldehyde)semicarbazone
(73) ESI-MS [M+H] (m/z): 632.6; .sup.1H-NMR (300 MHz, DMSO) δ10.96 (s, 1H), 8.98 (s, 1H), 8.61 (d, J=5.4 Hz, 1H), 8.22 (dd, J.sub.1=12.0 Hz, J.sub.2=1.8 Hz, 1H), 8.03 (s, 1H), 7.52-7.57 (m, 2H), 7.45 (d, J=8.7 Hz, 1H), 7.42 (s, 1H), 6.99 (s, 1H), 6.98 (s, 1H), 6.67 (d, J=5.4 Hz, 1H), 6.19 (t, J=1.8 Hz, 1H), 4.30 (t, J=6.3 Hz, 2H), 3.99 (s, 3H), 3.73 (s, 6H), 3.47-3.51 (m, 2H), 3.18-3.22 (m, 2H), 2.85-2.93 (m, 2H), 2.29-2.39 (m, 2H), 1.68-1.91 (m, 6H).
Example 50
(E)-N1-(3-fluoro-6-methylphenyl)-N4-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinoline-4-yloxy)benzaldehyde)semicarbazone
(74) ESI-MS [M+H] (m/z): 604.6.
Example 51
(E)-N1-(4-chloro-3-(trifluoromethyl)phenyl)-N4-(3-fluoro-4-(6-methoxy-7-(3-(4-methyl-1-piperazinyl)propoxy)quinoline-4-yloxy)benzaldehyde)semicarbazone
(75) ESI-MS [M+H] (m/z): 690.1; .sup.1H-NMR (300 MHz, DMSO) δ11.05 (s, 1H), 9.40 (s, 1H), 8.39 (d, J=5.1 Hz, 1H), 8.24 (d, J=2.7 Hz, 1H), 8.15 (dd, J.sub.1=12.0 Hz, J.sub.2=1.6 Hz, 1H), 8.00-8.05 (m, 2H), 7.71-7.75 (m, 1H), 7.62 (d, J=9.0 Hz, 1H), 7.46-7.51 (m, 2H), 7.40 (s, 1H), 6.46 (d, J=5.1 Hz, 1H), 4.22 (t, J=6.0 Hz, 2H), 3.94 (s, 3H), 3.35-3.44 (m, 10H), 2.87 (s, 3H), 2.33 (s, 2H).
Example 52
(E)-N1-phenyl-N4-(3-fluoro-4-(6-methoxy-7-(3-(4-methyl-1-piperazin yl)propoxy)quinoline-4-yloxy)benzaldehyde)semicarbazone
(76) ESI-MS [M+H] (m/z): 587.6.
Example 53
(E)-N1-(4-chlorophenyl)-N4-(3-fluoro-4-(6-methoxy-7-(3-(4-methyl-1-piperazinyl)propoxy)quinoline-4-yloxy)benzaldehyde)semicarbazone
(77) ESI-MS [M+H] (m/z): 622.2.
Example 54
(E)-N1-(3-bromophenyl)-N4-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)benzaldehyde)semicarbazone
(78) ESI-MS [M+H] (m/z): 653.6.
Example 55
(E)-N1-phenyl-N4-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)prop oxy)quinoline-4-yloxy)benzaldehyde)semicarbazone
(79) ESI-MS [M+H] (m/z): 574.7.
Example 56
(E)-N1-(3,5-difluorophenyl)-N4-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)benzaldehyde)semicarbazone
(80) ESI-MS [M+H] (m/z): 610.5.
Example 57
(E)-N1-(3,5-dimethoxyphenyl)-N4-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-oxy)benzaldehyde)semicarbazone
(81) ESI-MS [M+H] (m/z): 634.8; .sup.1H-NMR (300 MHz, DMSO) δ11.13 (s, 1H), 9.18 (s, 1H), 8.81 (d, J=5.4 Hz, 1H), 8.42 (dd, J.sub.1=12.0 Hz, J.sub.2=1.8 Hz, 1H), 8.18 (s, 1H), 7.65 (d, J=8.7 Hz, 1H), 7.59 (s, 1H), 7.53-7.57 (m, 2H), 7.05 (s, 1H), 7.03 (s, 1H), 6.77 (d, J=5.4 Hz, 1H), 6.39 (t, J=1.8 Hz, 1H), 4.21 (t, J=6.3 Hz, 2H), 3.93 (s, 3H), 3.76 (s, 6H), 3.68 (m, 4H), 2.41-2.47 (m, 2H), 2.35-2.46 (br s, 4H), 1.96-2.04 (m, 2H).
Example 58
(E)-N1-phenyl-N4-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinoline-4-yloxy)benzaldehyde)semicarbazone
(82) ESI-MS [M+H] (m/z): 586.6.
Example 59
(E)-N1-(3,5-dimethoxyphenyl)-N4-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinoline-4-yloxy)benzaldehyde)semicarbazone
(83) ESI-MS [M+H] (m/z): 660.9.
Example 60
(E)-N1-(2-fluorophenyl)-N4-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinoline-4-yloxy)benzaldehyde)semicarbazone
(84) ESI-MS [M+H] (m/z): 604.9; .sup.1H-NMR (300 MHz, DMSO) δ11.09 (s, 1H), 8.87 (s, 1H), 8.51 (d, J=5.1 Hz, 1H), 8.08 (dd, J.sub.1=12.3 Hz, J.sub.2=1.2 Hz, 1H), 8.03 (s, 1H), 7.73-7.79 (m, 1H), 7.69 (d, J=5.1 Hz, 1H), 7.48-7.54 (m, 2H), 7.43 (s, 1H), 7.23-7.31 (m, 1H), 7.15-7.22 (m, 2H), 6.54 (d, J=5.1 Hz, 1H), 4.22 (t, J=6.3 Hz, 2H), 3.96 (s, 3H), 3.05-3.10 (m, 2H), 2.63-2.80 (br s, 2H), 2.17-2.38 (br s, 2H), 2.01-2.15 (m, 2H), 1.60-1.71 (m, 2H), 1.21-1.47 (m, 4H).
Step S: 3,5-dichloroisothiocyanatobenzene (W-3)
(85) 3,5-dichloroaniline 20 g (0.32 mol) was dissolved in CH.sub.2Cl.sub.2 (150 mL) and sat. aq. NaHCO.sub.3 (50 mL) was added. The resulting biphasic solution was cooled to 0° C. and thiophosgene (0.38 mol) was then carefully added via syringe. After the addition was completed, the reaction was allowed to warm to room temperature and stirred for 2 h. The organic layer was separated and dried over Na.sub.2SO.sub.4. The filtrate was concentrated under reduced pressure to afford title compound 47.1 g as a yellow oil, yield: 72.1%.
Step T: 3,5-dichlorophenyl isothiocyanate (W-4)
(86) To a solution of intermediate W-3 10 g (49.0 mmol) in CH.sub.2Cl.sub.2 (100 mL) was added 80% hydrazine monohydrate (50 mL), and the biphasic solution was vigorously stirred for 10 h at room temperature. The organic layer was separated and washed with water (3×20 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure and washed with anhydrous diethyl ether, dry to constant weight to afford a paw yellow solid 8.2 g, yield: 71.0%.
Step U: (E)-N1-(3,5-dichlorophenyl)-N4-(3-fluoro-4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinolin-4-yloxy)benzylidene)thiosemicarbazide
Example 61
(87) To a solution of W-4 0.11 g (0.48 mmol) in isopropanol (2 mL), 0.2 g (0.46 mmol) B and acetic acid (1 drop) were added, and the mixture was refluxed for 8 h. The resultant precipitate was filtered and washed with a little amount of isopropanol to afford the target compound 0.22 g as a white solid, yield: 73.1%.
(88) ESI-MS [M+H] (m/z): 641.7; .sup.1H-NMR (300 MHz, DMSO) δ11.12 (s, 1H), 9.18 (s, 1H), 8.48 (d, J=5.1 Hz, 1H), 8.18 (dd, J.sub.1=12.0 Hz, J.sub.2=1.5 Hz, 1H), 8.00 (s, 1H), 7.83 (s, 1H), 7.81 (s, 1H), 7.49-7.57 (m, 3H), 7.32 (m, 1H), 7.24 (t, J=1.5 Hz, 1H), 6.47 (d, J=5.1 Hz, 1H), 4.25 (t, J=6.0 Hz, 2H), 3.95 (s, 3H), 3.41-3.54 (m, 2H), 3.16-3.27 (m, 2H), 2.77-2.95 (br s, 2H), 2.25-2.37 (m, 2H), 1.74-1.84 (m, 4H), 1.33-1.51 (br s, 2H).
(89) According to the methods in example 61, example 62-68 can be obtained by condensation reaction between varies substituted intermediate B and corresponding thiosemicarbazides.
Example 62
(E)-N1-(3,5-dimethoxyphenyl)-N4-(4-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinoline-4-yloxy)-3-fluorobenzaldehyde)thiosemicarbazone
(90) ESI-MS [M+H] (m/z): 648.8.
Example 63
(E)-N1-phenyl-N4-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinoline-4-yloxy)benzaldehyde)thiosemicarbazone
(91) ESI-MS [M+H] (m/z): 586.8; .sup.1H-NMR (300 MHz, DMSO) δ11.21 (s, 1H), 9.52 (s, 1H), 8.57 (d, J=5.4 Hz, 1H), 8.04 (s, 1H), 7.92-7.99 (dd, J.sub.1=13.5 Hz, J.sub.2=2.1 Hz, 1H), 7.84-7.89 (m, 2H), 7.66-7.73 (m, 1H), 7.59 (s, 1H), 7.38-7.48 (m, 5H), 6.46 (d, J=5.4 Hz, 1H), 4.21 (t, J=6.3 Hz, 2H), 3.95 (s, 3H), 2.92-2.99 (br s, 2H), 2.56-2.68 (m, 2H), 1.92-2.14 (m, 4H), 1.58-1.69 (m, 2H), 1.39 (br s, 1H), 1.11-1.27 (m, 2H), 0.95 (d, J=6.6 Hz, 3H).
Example 64
(E)-N1-[4-chloro-3-(trifluoromethyl)phenyl]-N4-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinoline-4-yloxy)benzaldehyde)thiosemicarbazone
(92) ESI-MS [M+H] (m/z): 705.4.
Example 65
(E)-N1-(3-bromophenyl)-N4-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)benzaldehyde)thiosemicarbazone
(93) ESI-MS [M+H] (m/z): 669.7.
Example 66
(E)-N1-(3,5-difluorophenyl)-N4-(3-fluoro-4-(6-methoxy-7-(3-(morpholin-4-yl)propoxy)quinoline-4-yloxy)benzaldehyde)thiosemicarbazone
(94) ESI-MS [M+H] (m/z): 625.8.
Example 67
(E)-N1-phenyl-N4-(3-fluoro-4-(6-methoxy-7-(3-(4-methyl-1-piperazinyl)propoxy)quinoline-4-yloxy)benzaldehyde)thiosemicarbazone
(95) ESI-MS [M+H] (m/z): 602.9.
Example 68
(E)-N1-(4-chlorophenyl)-N4-(3-fluoro-4-(6-methoxy-7-(3-(4-methyl-1-piperazinyl)propoxy)quinoline-4-yloxy)benzaldehyde)thiosemicarbazone
(96) ESI-MS [M+H] (m/z): 637.3.
(97) Anti-Tumor Activity of the Compounds of the Invention
(98) In Vitro Anti-Tumor Cellular Activity
(99) The in vitro inhibitory activity of the quinoline derivatives of formula I in the invention was evaluated against the cancer cell lines H460 (human lung cancer cell), HT-29 (colon cancer cell), MKN-45 (human gastric carcinoma cell), SMMC-7721 (hepatoma cell), MDA-MB-231 (human beast cancer cell), U87MG (Human malignant glioblastoma cell).
(100) (1) After recovery and passaged 2-3 times stable, the cells were digested with trypsin solution (0.25%) from the bottom of culture bottle. After pouring the cell dissociation buffer to the centrifugetube, nutrient solution was added to stop digestion. The centrifugetube were centrifuged for 10 min under 800 r/min, the liquid supernatant was removed, 5 mL culture solution was added, after mixing by pipetting the cell, took 10 μL cell suspension to the cell counting plat, and adjusted the cell concentration to 10.sup.4/well. Among the 96 wells, A1 is empty, 100 μL of cell suspension were added to the other wells. The 96 well plates were incubated in the incubator for 24 h.
(101) (2) 50 μL dimethyl sulfoxide was used to dissolve the test samples, and then a suitable amount of culture media was added so as to reach a final concentration of 2 mg/mL. Then the samples were diluted to 20, 4, 0.8, 0.16, 0.032 mg/mL in a 24-well plate, respectively.
(102) There were three wells for each concentration, wherein the cell growth in the surrounding two rows and columns was significantly influenced by environments and thus only taken as blank cell wells. The 96-well plates were placed in an incubator and cultivated for 72 hours.
(103) (3) The culture media containing the compounds in the 96-well plates was discarded, and the cells were washed with phosphate buffered solution (PBS) twice. Each well was added with 100 μL MTT (tetrazole) (0.5 mg/mL), and then placed in an incubator to incubate for 4 hours, after which MTT solution was discarded and 100 μL dimethyl sulfoxide was added thereto. The reaction product of survival cells with MTT, i.e. formazan, was dissolved completely by oscillation on a magnetic oscillator, then placed into a microplate reader to measure the results, and the IC.sub.50 values of compounds could be deduced by Bliss method.
(104) As illustrated in Table 1, all the target compounds showed moderate to excellent antitumour activity against H460, HT-29, MKN-45, SMMC-7721, MDA-MB-231 and U87MG.
(105) TABLE-US-00002 TABLE 1 H460 HT-29 MKN-45 SMMC-7721 MDA-MB-231 U87MG Example IC.sub.50(μg/mL) IC.sub.50(μg/mL) IC.sub.50(μg/mL) IC.sub.50(μg/mL) IC.sub.50(μg/mL) IC.sub.50(μg/mL) Example 1 0.093 0.18 0.26 0.29 0.088 0.17 Example 2 0.15 0.17 0.18 0.43 0.12 0.31 Example 3 0.11 0.42 0.12 2.1 0.13 0.33 Example 4 0.084 0.093 0.11 0.23 0.066 0.25 Example 5 0.012 0.0088 0.012 0.16 0.010 0.19 Example 6 0.99 1.2 1.3 1.7 0.85 0.91 Example 7 0.0012 0.00060 0.0021 0.13 0.011 0.10 Example 8 1.4 6.1 3.7 4.9 0.90 2.7 Example 9 0.12 0.20 0.14 0.50 0.11 0.42 Example 10 0.0092 0.0015 0.038 0.16 0.011 0.019 Example 11 0.17 0.069 0.13 0.42 0.15 0.13 Example 12 0.33 0.15 0.62 1.0 0.40 0.95 Example 13 0.097 0.16 0.27 0.29 0.16 0.33 Example 14 1.2 0.81 0.65 1.5 0.90 1.4 Example 15 1.5 0.93 1.1 2.7 1.1 3.2 Example 16 0.019 0.0015 0.0092 0.10 0.0070 0.091 Example 17 0.069 0.0057 0.072 0.13 0.071 0.24 Example 18 0.19 0.10 0.13 0.47 0.21 0.49 Example 19 0.96 1.4 0.71 0.97 1.2 1.9 Example 20 1.1 0.84 1.5 6.7 1.7 4.2 Example 21 0.16 0.065 0.10 0.98 0.087 0.89 Example 22 0.29 0.19 0.37 1.2 0.31 0.66 Example 23 3.6 — 5.7 5.9 2.9 5.6 Example 24 0.14 0.11 0.23 1.2 0.21 0.63 Example 25 0.0066 0.0013 0.025 0.095 0.019 0.12 Example 26 5.7 21 9.8 13 4.9 — Example 27 1.3 0.59 0.20 0.53 0.96 1.4 Example 28 0.27 0.18 0.25 0.95 0.31 0.88 Example 29 0.011 0.0019 0.021 0.056 0.011 0.090 Example 30 0.0012 0 0.0020 0.44 0.0021 0.051 Example 31 0.041 0.013 0.11 0.39 0.059 0.22 Example 32 0.19 0.24 0.33 0.77 0.13 1.2 Example 33 0.19 0.11 0.23 0.31 0.12 0.30 Example 34 0.089 0.076 0.12 0.24 0.077 0.19 Example 35 0 0.045 0.029 0.17 0.0030 0.091 Example 36 0.034 0.012 0.11 0.35 0.048 0.29 Example 37 0.089 0.13 0.56 0.43 0.13 0.50 Example 38 0.16 0.28 0.11 1.4 0.18 0.90 Example 39 1.1 0.94 0.59 1.7 0.97 1.6 Example 40 2.8 1.9 1.5 3.1 1.9 — Example 41 0.097 0.13 0.10 0.66 0.088 0.54 Example 42 0.38 0.55 0.34 0.96 0.29 1.0 Example 43 0.0067 0.0031 0 0.069 0.0029 0.092 Example 44 0.0065 0.019 0.0007 0.098 0.0042 0.17 Example 45 0.11 0.19 0.37 1.0 0.17 0.90 Example 46 0.33 0.45 0.23 0.69 0.25 1.2 Example 47 0.019 0.0078 0.024 0.099 0.082 0.11 Example 48 0.077 0.16 0.082 0.20 0.13 0.33 Example 49 0.0075 0.010 0.0039 0.034 0.00050 0.094 Example 50 0.088 0.11 0.027 0.34 0.043 0.10 Example 51 0.23 0.31 0.98 1.4 0.19 0.69 Example 52 0.19 0.44 0.39 1.2 0.23 0.77 Example 53 0.32 0.19 0.48 0.53 0.25 0.54 Example 54 1.5 1.3 2.0 2.7 0.96 1.8 Example 55 0.97 0.65 0.43 1.1 0.65 0.90 Example 56 0.66 0.47 0.51 1.9 0.71 0.99 Example 57 0.091 0.12 0.15 0.33 0.10 0.28 Example 58 0.019 0.18 0.038 0.33 0.0089 0.21 Example 59 0.60 1.4 0.80 3.5 0.45 1.9 Example 60 0.22 0.11 0.13 0.73 0.17 0.88 Example 61 0.054 0.076 0.15 0.22 0.092 0.21 Example 62 0.079 0.11 0.17 0.16 0.11 0.76 Example 63 0.33 0.50 0.73 0.64 0.14 1.0 Example 64 0.56 0.34 0.65 1.0 0.98 1.7 Example 65 2.4 1.9 4.8 2.8 2.1 3.4 Example 66 1.0 0.58 0.94 1.5 0.92 1.7 Example 67 1.1 0.90 1.6 1.1 0.87 1.4 Example 68 1.9 1.7 2.2 2.1 1.3 3.0 Cisplatin 0.23 1.0 0.68 0.90 0.46 0.19
c-Met Kinase Assay:
c-Met Kinase Activity was Measured with an ELISA Reader. The Specific Operation as Follows:
(106) To the plate filled with 0.25 mg/mL PGT, the compounds, 50 pM c-Met (His-tagged recombinant human Met (Amino acids 974-ends), by baculovirus expression) and 5 μM ATP in buffer solution (25 mM MOPS, pH 7.4, 5 mM MgCl2, 0.5 raM MnCl.sub.2, 100 μM sodium orthovanadate, 0.01% Triton X-100, 1 mM DTT, 1% of DMSO1% (v/v)) was added, the solution was incubated for 20 min. The reaction mixture was removed by washing with 0.2 μg/mL conjugated horseradish peroxidase (HRP) monoclonal antibody specific for phosphotyrosine (PY20) detecting phosphorylation of the substrate polymer. 1M phosphoric acid was added to terminate the color, the chromogenic substrate (TMB) was tested by spectrophotometry at 450 nm. The c-Met kinase inhibition data was illustrated in Table 2.
(107) TABLE-US-00003 TABLE 2 c-Met IC.sub.50 Example (μg/mL) Example 1 0.017 Example 2 0.20 Example 5 0.030 Example 6 0.55 Example 9 0.15 Example 10 0.0070 Example 12 0.30 Example 15 0.67 Example 24 0.35 Example 25 0.0071 Example 28 0.71 Example 29 0.020 Example 30 0.00020 Example 32 0.39 Example 33 0.20 Example 35 0.012 Example 47 0.021 Example 48 0.11 Example 51 0.69 Example 52 0.66 Example 53 0.58 Example 55 0.50 Example 56 0.47 Example 59 0.51
(108) It can be clearly seen from the results of the above test, the protected compounds in formula I in this invention have good anti-tumor activity in vitro, and are better than the anticancer drug cisplatin.
(109) Compounds of Formula I in the invention may be used alone, but usually given with a pharmaceutically acceptable carrier, which is selected according to the desired route of administration and standard pharmaceutical practice, the following preparation methods of such various pharmaceutical dosages (tablets, capsules, injections, aerosols, suppositories, films, pills, liniment, topical ointments) were used to describe new application in the pharmaceutical field.
Example 69: Tablet
(110) 10 g compound (e.g., the compound of Example 12) containing the compound of claim 1 was mixed homogeneously with 20 g adjuvants and tableted into 100 tablets by general compression method, 300 mg each tablet.
Example 70: Capsule
(111) 10 g compound (e.g., the compound of Example 36) containing the compound of claim 1 was mixed homogeneously with 20 g adjuvants according to the requirements of pharmaceutical capsules, and filled into empty capsules, 300 mg each capsule.
Example 71: Injection
(112) 10 g compound (e.g., the compound of Example 1) containing the compound of claim 1 was absorbed by activate charcoal by conventional pharmaceutical method, filtered through 0.65 μm microporous membrane and filled into nitrogen bottle to prepare water injection preparation, 2 mL each bottle, and 100 bottles in total.
Example 72: Aerosol
(113) 10 g compound (e.g., the compound of Example 22) containing the compound of claim 1 was dissolved with a suitable amount of propylene glycol, and added with distilled water and other adjuvants to get 500 mL clear solution.
Example 73: Suppository
(114) 10 g compound (e.g., the compound of Example 19) containing the compound of claim 1 was grinded and a suitable amount of glycerol was added and mixed homogeneously. Then melt glycerol gelatin was added and grinded homogeneously, and the mixture was poured into a mold coated with lubricant to produce 50 suppository particles.
Example 74: Film
(115) 10 g compound (e.g., the compound of Example 13) containing the compound of claim 1 was mixed and expanded with polyvinyl alcohol, pharmaceutically acceptable glycerol, water etc., and dissolved by heating. After filtration on an 80 mesh screen, the compound of Example 18 was added to the filtrate and dissolved therein by agitation. 100 films were produced by coater machine.
Example 75: Dripping Pill
(116) 10 g compound (e.g., the compound of Example 17) containing the compound of claim 1 was mixed homogeneously with 50 g substrate such as gelatin by heating and melting, then the mixture was dropped into a liquid paraffin at low temperature. 1000 pills of dripping pill were produced.
Example 76: Liniment for External Use
(117) 10 g compound (e.g., the compound of Example 31) containing the compound of claim 1 was mixed and ground with 2.5 g adjuvants such as emulsifier by conventional formulation methods, then 200 mL water was added to prepare the liniment for external use.
Example 77: Ointment
(118) 10 g compound (e.g., the compound of Example 47) containing the compound of claim 1 was ground and then mixed homogeneously with 500 g oleaginous base such as Vaseline.
(119) Although the present invention has been described through specific embodiments, but modifications and equivalent changes to those skilled person in this field are apparent, and they are included within the scope of the invention.