CN106543145B - C-Met kinases presses down agent 3- (4- fluorophenyl) pyrimidone -5- benzoic acid amides derivative, preparation method and application - Google Patents
C-Met kinases presses down agent 3- (4- fluorophenyl) pyrimidone -5- benzoic acid amides derivative, preparation method and application Download PDFInfo
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- CN106543145B CN106543145B CN201610966753.7A CN201610966753A CN106543145B CN 106543145 B CN106543145 B CN 106543145B CN 201610966753 A CN201610966753 A CN 201610966753A CN 106543145 B CN106543145 B CN 106543145B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
(such as the cancer) for being used to treat abnormal cell with it the present invention relates to a series of novel poyrimidine derivatives as c-Met tyrosine kinase inhibitor and preparation method thereof increases.It is tested through pharmacological activity, formula (I) compound provided by the invention, its pharmaceutically acceptable salt have good anti-tumor activity, can be used to treat or prevent with c-Met inhibitor in relation to various cancers.
Description
Technical field
The novel poyrimidine derivatives and preparation method thereof that the present invention relates to a series of as c-Met tyrosine kinase inhibitor
The growth of (such as cancer) for being used to treat abnormal cell with it.
Background technique
C-Met, also referred to as hepatocyte growth factor receptor are a kind of protein products encoded by c-Met proto-oncogene,
With tyrosine kinase activity.Hepatocyte growth factor (the Hepatocyte growth that it can be generated with interstitial cell
Factor receptor, HGF) combination forms homodimer, to activate a plurality of downstream signaling pathway, adjusts a variety of
Cell effect, comprising: promote the growth, migration and invasion of cell, angiogenesis, wound healing and regeneration.
Normal HGF/c-Met signal is especially right in different cells, in different differential periods participate in various physiological processes
Placenta development, wound healing and liver regeneration play a key effect.Abnormal HGF/c-Met signal by autocrine, paracrine and
The signal cascade of the generations such as endocrine reacts, and causes cell that a series of vicious transformation occurs.Research shows that: c-Met matches with it
Body HGF almost participates in all stages of malignant development, plays vital work in a plurality of types of tumours are generated and shifted
With.It is related to the highly expressed various malignant tumours of c-Met and includes, but are not limited to sdenocarcinoma of stomach, kidney, Small Cell Lung Cancer, colorectum
Cancer, prostate cancer, the cancer of the brain, liver cancer, cancer of pancreas and breast cancer.
By using c-Met as drug target, may compare easy to accomplish while interfering a variety of accesses, so that interference is swollen
The formation and transfer of tumor.Therefore c-Met, which has become, becomes one of most promising drug target, researches and develops c-Met protein kinase
There is an urgent need for the compound of acceptor inhibitor.
Summary of the invention
The present invention is intended to provide it is a kind of can be used as c-Met inhibitor and for treat c-Met mediation abnormal cell (such as
Cancer) growth, specifically a kind of -4 (3H)-pyrimidone -5- first of 3- (4- fluoro-phenyl) with c-Met kinase inhibiting activity
Acid amide derivatives and the preparation method and application thereof.
The present invention is achieved by the following technical solutions: a kind of compound, its pharmaceutically acceptable salt of formula (I),
Wherein:
R1Selected from hydrogen, hydroxyl, amino ,-O (CH2)nCH3,-NH (CH2)nCH3,-(CH2)nCH3,-NH (CH2)nR3,-O
(CH2)nR3,-(CH2)nR3,-CN ,-SH ,-the O replaced by 0-3 halogen (CH2)nCH3、-NH(CH2)nCH3、-(CH2)nCH3、-
NH(CH2)nR3、-O(CH2)nR3、-(CH2)nR3；Wherein n is the integer of 0-6；
Each R3Selected from group shown in formula (II), (III), (IV), (V) (VI):
R2The group shown in formula (VII), (VIII), (IX), (X), (XI):
Wherein, R5Selected from-CH3And (XII), (XIII), (XIV), (XV), group shown in (XVI):
In above content ,-O (CH2)nCH3、-NH(CH2)nCH3、-(CH2)nCH3、-NH(CH2)nR3、-O(CH2)nR3、-
(CH2)nR3It can be replaced by 0-3 halogen.
Preferably, the pharmaceutically acceptable salt includes the compound of formula (I) and the acid-addition salts that following acid is formed: salt
Acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzene sulfonic acid, hydrobromic acid, p-methyl benzenesulfonic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, salicylic acid,
Naphthalene sulfonic acids, citric acid, fumaric acid, succinic acid, maleic acid, phenylacetic acid, tussol；It further include the acid salt of inorganic base.
Further, the inorganic basic ion of the acid salt of the inorganic base is ammonium cation, alkali metal cations, alkaline earth gold
Belong to cation.
In addition the present invention provides a kind of compounds, are selected from following compounds:
2- hydroxyl -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid [3- fluorophenyl -4- (6,7- dimethoxy
Base quinoline -4- oxygroup)] amide；
2- methoxyl group -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid [3- fluorophenyl -4- (6,7- diformazan
Phenoxyl quinoline -4- oxygroup)] amide；
2- ethyoxyl -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid [3- fluorophenyl -4- (6,7- diformazan
Phenoxyl quinoline -4- oxygroup)] amide；
2- benzyloxy -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid [3- fluorophenyl -4- (6,7- diformazan
Phenoxyl quinoline -4- oxygroup)] amide；
2- amino -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid [3- fluorophenyl -4- (6,7- dimethoxy
Base quinoline -4- oxygroup)] amide；
2- methylamino -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid [3- fluorophenyl -4- (6,7- diformazan
Phenoxyl quinoline -4- oxygroup)] amide；
2- ethylamino -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid [3- fluorophenyl -4- (6,7- diformazan
Phenoxyl quinoline -4- oxygroup)] amide；
2- [(3- morpholine propyl) amino] -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid [3- fluorobenzene
Base -4- (6,7- dimethoxy-quinoline -4- oxygroup)] amide；
2- [(3- (1 (1H)-imidazoles) propyl) amino] -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid
[3- fluorophenyl -4- (6,7- dimethoxy-quinoline -4- oxygroup)] amide；
2- [(3- (1- pyrrolidinyl) propyl) amino] -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid
[3- fluorophenyl -4- (6,7- dimethoxy-quinoline -4- oxygroup)] amide；
2- [(3- (1- piperidines alkyl) propyl) amino] -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid
[3- fluorophenyl -4- (6,7- dimethoxy-quinoline -4- oxygroup)] amide；
2- benzyloxy -3- (4- fluorophenyl) -4- oxygen -3,4- dihydro-pyrimidin -5- formic acid [3- fluorophenyl -4- (7- pyrrolo-
[2,3-d] pyrimidine -4- oxygroup)] amide；
2- [(3- morpholine propyl) amino] -3- (4- fluorophenyl) -4- oxygen -3,4- dihydro-pyrimidin -5- formic acid [3- fluorophenyl -
4- (7- pyrrolo- [2,3-d] pyrimidine -4- oxygroup)] amide；
2- [(3- (1- pyrrolidinyl) propyl) amino] -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid
[3- fluorophenyl -4- (7- pyrrolo- [2,3-d] pyrimidine -4- oxygroup)] amide；
2- [(3- (1- piperidines alkyl) propyl) amino] -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid
[3- fluorophenyl -4- (7- pyrrolo- [2,3-d] pyrimidine -4- oxygroup)] amide；
2- hydroxyl -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid { 3- fluorophenyl -4- [6- methoxyl group -
7- (3- morpholine propoxyl group) quinoline -4- oxygroup] } amide；
2- amino -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid { 3- fluorophenyl -4- [6- methoxyl group -
7- (3- morpholine propoxyl group) quinoline -4- oxygroup] } amide；
2- methylamino -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid { 3- fluorophenyl -4- [6- methoxy
Base -7- (3- morpholine propoxyl group) quinoline -4- oxygroup] } amide；
2- ethylamino -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid { 3- fluorophenyl -4- [6- methoxy
Base -7- (3- morpholine propoxyl group) quinoline -4- oxygroup] } amide；
2- [(3- morpholine propyl) amino] -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid { 3- fluorobenzene
Base -4- [6- methoxyl group -7- (3- morpholine propoxyl group) quinoline -4- oxygroup] } amide；
2- [(3- (1 (1H)-imidazoles) propyl) amino] -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid
{ 3- fluorophenyl -4- [6- methoxyl group -7- (3- morpholine propoxyl group) quinoline -4- oxygroup] } amide；
2- [(3- (1- pyrrolidinyl) propyl) amino] -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid
{ 3- fluorophenyl -4- [6- methoxyl group -7- (3- morpholine propoxyl group) quinoline -4- oxygroup] } amide；
2- [(3- (1- piperidines alkyl) propyl) amino] -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid
{ 3- fluorophenyl -4- [6- methoxyl group -7- (3- morpholine propoxyl group) quinoline -4- oxygroup] } amide；
2- methylamino -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid { 3- fluorophenyl -4- [6- methoxy
Base-7- (3- (4- methyl-1-piperidines) propoxyl group) quinoline-4- oxygroup] } amide；
2- ethylamino -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid { 3- fluorophenyl -4- [6- methoxy
Base-7- (3- (4- methyl-1-piperidines) propoxyl group) quinoline-4- oxygroup] } amide；
The third amino of 2- -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid { 3- fluorophenyl -4- [6- methoxy
Base-7- (3- (4- methyl-1-piperidines) propoxyl group) quinoline-4- oxygroup] } amide；
2- [(3- morpholine propyl) amino] -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid { 3- fluorobenzene
Base-4- [6- methoxyl group-7- (3- (4- methyl-1-piperidines) propoxyl group) quinoline-4- oxygroup] } amide；
2- [(3- (1 (1H)-imidazoles) propyl) amino] -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid
{ 3- fluorophenyl-4- [6- methoxyl group-7- (3- (4- methyl-1-piperidines) propoxyl group) quinoline-4- oxygroup] } amide；
2- [(3- (1- pyrrolidinyl) propyl) amino] -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid
{ 3- fluorophenyl-4- [6- methoxyl group-7- (3- (4- methyl-1-piperidines) propoxyl group) quinoline-4- oxygroup] } amide；
2- [(3- (1- piperidines alkyl) propyl) amino] -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid
{ 3- fluorophenyl-4- [6- methoxyl group-7- (3- (4- methyl-1-piperidines) propoxyl group) quinoline-4- oxygroup] } amide；
2- hydroxyl -3- (4- fluorophenyl) -4- oxygen -3,4- dihydro-pyrimidin -5- formic acid [3- fluorophenyl -4- (7- pyrrolo- [2,
3-d] pyrimidine -4- oxygroup)] amide；
2- propoxyl group -3- (4- fluorophenyl) -4- oxygen -3,4- dihydro-pyrimidin -5- formic acid [3- fluorophenyl -4- (7- pyrrolo-
[2,3-d] pyrimidine -4- oxygroup)] amide；
2- [(3- morpholine propyl) amino] -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid { 3- fluorobenzene
Base -4- [6- methoxyl group -7- (3- (4- methyl piperazine) propoxyl group) quinoline -4- oxygroup] } amide；
2- [(3- (1 (1H)-imidazoles) propyl) amino] -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid
{ 3- fluorophenyl -4- [6- methoxyl group -7- (3- (4- methyl piperazine) propoxyl group) quinoline -4- oxygroup] } amide；
2- [(3- (1- pyrrolidinyl) propyl) amino] -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid
{ 3- fluorophenyl -4- [6- methoxyl group -7- (3- (4- methyl piperazine) propoxyl group) quinoline -4- oxygroup] } amide；
2- [(3- (1- piperidines alkyl) propyl) amino] -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid
{ 3- fluorophenyl -4- [6- methoxyl group -7- (3- (4- methyl piperazine) propoxyl group) quinoline -4- oxygroup] } amide；
2- [(3- morpholine propyl) amino] -3- (4- fluorophenyl) -4- oxygen -3,4- dihydro-pyrimidin -5- formic acid [3- fluorophenyl -
4- (7- pyrrolo- [2,3-d] pyrimidine -4- oxygroup)] amide；
2- [(3- (1 (1H)-imidazoles) propyl) amino] -3- (4- fluorophenyl) -4- oxygen -3,4- dihydro-pyrimidin -5- formic acid [3-
Fluorophenyl -4- (7- pyrrolo- [2,3-d] pyrimidine -4- oxygroup)] amide；
2- [(3- (1- pyrrolidinyl) propyl) amino] -3- (4- fluorophenyl) -4- oxygen -3,4- dihydro-pyrimidin -5- formic acid [3-
Fluorophenyl -4- (7- pyrrolo- [2,3-d] pyrimidine -4- oxygroup)] amide.
Further, the present invention provides above-mentioned compound, its pharmaceutically acceptable salts in the preparation of antitumor drugs
Application.
Another of the invention purpose is to provide a kind of pharmaceutical composition, the pharmaceutical composition include 1., and 2., 3.,
4. at least one of substance；
1. described is any of the above-described compound, its pharmaceutically acceptable salt；
2. described is pharmaceutically acceptable carrier；
3. described is adjuvant；
4. described is medium.
Compound of the present invention, its pharmaceutically acceptable salt can with 2., 3., at least one of 4. substance is made
Suitable for clinical pharmaceutical preparation.The carrier can for any of the above-described compound, its pharmaceutically acceptable salt diluent or
Excipient.When carrier is as diluent or excipient, solid, semisolid or liquid substance can be.Medicine group of the invention
Closing object can be by the way that active component and carrier to be blended, or is diluted in carrier, or encapsulated or packing in the carrier
(can be the forms such as capsule, pouch, paper container) is made.
The various forms for being suitble to required administration mode can be made in pharmaceutical composition of the present invention.For example, pharmaceutical composition
Tablet, pill, pulvis, pouch, cachet, suspending agent, elixir, emulsion, solution, syrup, aerosol can be made (as solid in object
Calmly or in fluid matrix), soft gel capsule, hard gelatin capsules, suppository, aseptic parenteral solution, powder of aseptic packaging etc..
Further, the present invention provides the pharmaceutical composition application in preparations of anti-tumor drugs.
For more detailed description technical solution of the present invention, the present invention provides a kind of preparations of the compound of formula (I)
Method, the compound of formula (a) and the compound of formula (b) in dehydrating agent (such as HATU, HBTU, TBTU or EDC/HOBt) and have
In the presence of machine alkali (such as N-methylmorpholine, trimethylamine (TEA) or n,N-diisopropylethylamine (DIPEA)), organic solvent (such as
Anhydrous acetonitrile, DCM, NMP, DMF) in reaction acquisition formula (I) compound；Certainly, catalyst (such as DMAP) can also be added to add
Fast response.Dehydrating agent (such as HATU, HBTU, TBTU or EDC/HOBt) is used as amidation in the preparation method of the compound of formula (I)
Reagent, organic base (such as N-methylmorpholine, trimethylamine (TEA) or n,N-diisopropylethylamine (DIPEA)) are used as acid binding agent.Work as acyl
Amination reagent is existed simultaneously with acid binding agent can guarantee that reacts goes on smoothly.Wherein:
The structural formula of formula (a) is
The structural formula of formula (b) is
Wherein R1With R2Ibid.
" Met " " c-Met ", " cMet " or " c-Met receptor " that the present invention uses refer to hepatocyte growth factor (HGF) by
Body and its form.
Anti-tumor drug of the present invention refers to includes for treating the highly expressed various malignant tumours of c-Met, but unlimited
In sdenocarcinoma of stomach, kidney, Small Cell Lung Cancer, colorectal cancer, prostate cancer, the cancer of the brain, liver cancer, cancer of pancreas and breast cancer medicines
Purposes.
The compound of formula (I) of the present invention can be such as synthesis, wherein R as shown in following reaction route I1And R2Such as the above institute
Definition.
Reaction route I:
The compound of formula (a) can be prepared as shown in reaction route II, wherein R1As defined above.With 4-
Fluorophenyl thiocarbamide and ethoxy methylene diethyl (DEMM) are starting material, pass through cyclization, alkylation, oxidation, water
The series reactions such as solution, addition, the inferior ether synthesis of William, ester hydrolysis synthesize the pyrimidone acid compound accordingly replaced.
Reaction route II:
The present invention provides a series of novel poyrimidine derivatives as c-Met tyrosine kinase inhibitor, through pharmacology
Active testing, compound, its pharmaceutically acceptable salt of formula (I) provided by the invention have good anti-tumor activity, can
For treating or preventing with c-Met inhibitor in relation to various cancers.
Specific embodiment
Preparation example 1
2- benzyloxy -3- (4- fluorophenyl) -4- oxygen -3,4- dihydro-pyrimidin -5- formic acid [3- fluorophenyl -4- (7- pyrrolo-
[2,3-d] pyridine -4- oxygen)] amide
In the single-necked flask of 25ml, it is separately added into compound 2- benzyloxy -3- (4- fluoro-phenyl) -4 (3H)-pyrimidone -
After 4ml anhydrous acetonitrile, 10min is stirred at room temperature in 5- formic acid (0.033mol), HATU (0.036mol), DIEPA (0.98mol), to
Reaction solution color turns yellow, and compound 4- (7-H pyrrolo- [2,3-d] pyridine -4- oxygroup) -3- fluoroaniline (0.03mol) is added,
TLC monitoring reaction, to which after the reaction was completed, revolving removes solvent, respectively with 10% citric acid (50ml × 3) and saturated sodium bicarbonate
Solution (50ml × 3) extraction, merges organic phase, solvent removed by evaporation at reduced pressure, column chromatographic purifying.Obtain 2- benzyloxy -3- (4- fluorobenzene
Base -4- oxygen -3,4- dihydro-pyrimidin -5- formic acid [the fluoro- 4- of 3- (7- pyrrolo- [2,3-d] pyridine -4- oxygen) phenyl] amide, yield are
34%.1H-NMR(CDCl3,600MHz),δ:5.22(s,2H,ArCH 2O)；6.70(d,1H,ArH)；7.30-7.45(m,12H,
ArH)；7.92 (dd, 1H, J=10.8,3.0Hz, ArH)；8.29(s,1H,ArH)；8.98(s,1H,pyrimidine-6'-H)；
10.99(s,1H,NH)；12.30(s,1H,pyrrole-NH).13C-NMRδ:163.5,161.3,160.7,154.0,151.3,
150.8,150.4,136.3,130.1,129.1,128.4,125.0,116.4,105.2,104.4,98.2,52.8。MS m/z
(%): 567.2 (MH+, 100%).
Following compound is prepared by the method for preparation example 1:
Preparation example 2 is to 38 nuclear magnetic data information of preparation example:
Preparation example 2:1H-NMR(CDCl3,600MHz),δ:4.04(s,3H,-OCH 3,)；4.08(s,3H,-OCH 3,)；
6.75(d,1H,ArH)；7.15-7.28(m,8H,ArH)；7.90 (dd, 1H, J=10.8,3.0Hz, ArH)；8.47(d,1H,J
=1.3Hz, ArH)；8.61(s,1H,pyrimidine-6'-H)；10.23(d,1H,ArOH)；11.09(s,1H,NH).13C-
NMRδ:163.7,161.4,159.9,153.5,152.5,150.6,149.3,149.3,146.8,131.7,130.8,130.7,
124.6,117.0,116.5,116.0,115.7,108.3,104.3,102.6,99.4,56. 2.MS m/z (%): 547.1 (MH+, 100%) and
Preparation example 3:1H-NMR(CDCl3,600MHz),δ:3.60(s,3H,OCH 3)；4.04(s,3H,-OCH 3,)；4.08
(s,3H,-OCH 3,)；6.47(d,1H,ArH)；7.33-7.45(m,8H,ArH)；7.90 (dd, 1H, J=10.8,3.0Hz,
ArH)；8.47 (d, 1H, J=1.3Hz, ArH)；8.61(s,1H,pyrimidine-6'-H)；11.09(s,1H,NH).13C-NMR
δ:163.7,161.0,159.7,153.1,152.6,150.9,149.9,149.3,146.8,131.3,131.2,130.1,
124.6,117.0,116.5,116.3,115.0,108.3,104.0,102.5,99.4,56. 2,37.9.MS m/z (%):
561.1(MH+, 100%) and
Preparation example 4:1H-NMR(CDCl3, 600MHz), δ: 1.49 (t, 3H, J=10.8Hz, OCH2CH 3)；4.02(m,2H,
J=10.8Hz, OCH 2CH3)；4.10(s,3H,-OCH 3,)；4.14(s,3H,-OCH 3,)；6.75(d,1H,ArH)；7.35-
7.57(m,8H,ArH)；8.00 (dd, 1H, J=10.8,3.0Hz, ArH)；8.15 (d, 1H, J=1.3Hz, ArH)；8.68(s,
1H,pyrimidine-6'-H)；11.09(s,1H,NH).13C-NMRδ:163.7,161.0,159.7,153.1,152.6,
150.9,149.9,149.3,146.8,131.3,131.2,130.1,124.6,117.0,116.5,116.3,115.0,
108.3,104.0,102.5,99.4,63.2,56.2,15.4.MS m/z (%): 575.3 (MH+, 100%) and
Preparation example 5:1H-NMR(CDCl3,600MHz),δ:4.04(s,3H,-OCH 3,)；δ4.08(s,3H,-OCH 3,)；
5.13(s,2H,ArCH 2O)；6.45(d,1H,ArH)；7.35-7.57(m,13H,ArH)；8.12 (dd, 1H, J=10.8,
3.0Hz,ArH)；8.48 (d, 1H, J=1.3Hz, ArH)；8.66(s,1H,pyrimidine-6'-H)；11.23(s,1H,NH)
.13C-NMRδ:163.5,160.8,159.6,153.1,151.3,150.8,149.9,149.3,146.8,137.3,136.3,
130.1,129.2,128.5,128.4,124.6,117.1,116.5,116.3,115.0,108.3,105.2,102.6,99.4,
56.2,52.8.MS m/z (%): 637.2 (MH+, 100%) and
Preparation example 6:1H-NMR (DMSO, 600MHz), δ: 3.94 (sd, 6H, J=2.4Hz, OCH 3,OCH 3,),6.45(d,
1H, ArH), 7.37-7.54 (m, 8H, ArH), 8.12 (dd, 1H, J=10.8,3.0Hz, ArH), 8.48 (d, 1H, J=1.3Hz,
ArH),8.66(s,1H,pyrimidine-6’-H),11.23(s,1H,NH).13C-NMRδ:162.8,162.3,161.3,
156.2,152.4,150.2,149.1,146.5,130.9,130.0,129.3,123.4,118.8,118.5,116.5,
109.2,106.5,102.5,99.4,56.9,56.7.MS m/z (%): 546.2 (MH+, 100%) and
Preparation example 7:1H-NMR(DMSO,600MHz),δ:2.0(s,3H,CH3),2.20(s,1H,pyrimidine-2’-
), NH 4.06 (sd, 6H, J=2.4Hz, OCH 3,OCH 3,),6.43(d,1H,ArH),7.15-7.41(m,8H,ArH),8.12
(dd, 1H, J=10.8,3.0Hz, ArH), 8.48 (d, 1H, J=1.3Hz, ArH), 8.66 (s, 1H, pyrimidine-6 '-H),
11.23(s,1H,NH).13C-NMRδ:162.8,162.3,161.53,156.02,130.39,130.30,129.93,123.44,
118.68,118.45,116.25,109.42,106.45,102.15,99.64,56.59,56.37,31.93,27.23.MS m/
Z (%): 560.3 (MH+, 100%) and
Preparation example 8:1H-NMR (400MHz, DMSO-d) δ 10.31 (s, 1H, NH), 8.47 (d, 1H, J=8.8Hz, ArH),
7.87 (dd, 1H, J=18,3Hz, ArH), 7.53 (s, 1H, ArH), 7.42 (m, 8H, ArH), 6.43 (d, 1H, J=7.8Hz,
NH),3.95(s,6H,CH3-H),2.09(s,2H,CH3- H), 1.21 (t, 3H, J=10.8Hz, CH3-H)；13C-NMRδ:
174.80,171.96,163.74,161.49,161.00,159.70,154.88–154.12,153.11,152.60,150.97,
149.94,149.31,146.88,137.46,136.47(s),131.81,131.27,130.11,124.68,117.07,
116.48,116.39,115.00,108.31,102.59,99.40,56.20,34.2,15.8；MS m/z:575.04[M+H]+.
Preparation example 9:1H NMR(600MHz,CDCl3) δ 11.04 (s, 1H), 8.95 (s, 1H), 8.48 (d, J=5.3Hz,
1H), 7.91 (dd, J=12.3,2.3Hz, 1H), 7.58 (s, 1H), 7.41 (s, 1H), 7.40-7.32 (m, 4H), 7.30 (d, J
=8.8Hz, 1H), 7.16 (t, J=8.7Hz, 1H), 6.41 (d, J=5.2Hz, 1H), 5.59 (t, J=5.2Hz, 1H), 4.05
(s, 3H), 4.04 (s, 3H), 3.61 (dd, J=12.0,6.3Hz, 2H), 3.49 (d, J=4.3Hz, 4H), 2.35 (t, J=
6.3Hz,2H),2.31–2.28(m,4H),1.77–1.72(m,2H).13C NMR(151MHz,CDCl3)δ164.30,162.87,
162.27,161.40,160.14,155.50,153.48,152.76,149.47,148.80,146.78,137.39,136.51,
130.40,130.34,129.18,123.51,118.40,118.25,116.07,115.51,109.47,107.76,106.23,
102.23,99.47,66.33(2C),56.62,56.11,56.05,53.68(2C),41.61,24.55.ESI-MS m/z:
671.56[M-H]+.
Preparation example 10:1H NMR(600MHz,CDCl3) δ 11.02 (s, 1H), 8.94 (s, 1H), 8.48 (d, J=5.3Hz,
1H), 7.91 (dd, J=12.2,2.3Hz, 1H), 7.58 (s, 1H), 7.41 (s, 1H), 7.41-7.29 (m, 4H), 7.29-7.27
(m, 2H), 7.17 (t, J=8.7Hz, 1H), 7.01 (s, 1H), 6.88 (s, 1H), 6.42 (d, J=5.2Hz, 1H), 4.99 (t, J
=5.3Hz, 1H), 4.05 (s, 3H), 4.04 (s, 3H), 4.02 (t, J=6.6Hz, 2H), 3.50 (dd, J=13.5,6.5Hz,
2H), 2.11 (dt, J=13.7,6.8Hz, 2H)13C NMR(151MHz,CDCl3)δ162.79,162.65,162.22,
161.14,160.34,156.35,155.71,153.47,152.96,149.64,148.49,146.44,137.38,136.59,
130.46,130.29,130.23,128.71,123.54,118.42,118.27,118.05,116.14,115.51,109.51,
107.45,106.64,102.24,99.50,56.14,56.12,53.77,39.61,30.25.ESI-MS m/z:652.60[M-
H]+.
Preparation example 11:1H NMR(600MHz,CDCl3) δ 11.08 (s, 1H), 8.95 (s, 1H), 8.47 (d, J=5.3Hz,
1H), 7.91 (dd, J=12.4,2.3Hz, 1H), 7.58 (s, 1H), 7.41 (s, 1H), 7.36-7.30 (m, 5H), 7.29 (d, J
=1.2Hz, 1H), 7.15 (t, J=8.7Hz, 1H), 6.41 (d, J=5.2Hz, 1H), 4.05 (s, 3H), 4.04 (s, 3H),
3.63 (t, J=5.8Hz, 2H), 2.53-2.48 (m, 2H), 2.26 (s, 4H), 1.73-1.67 (m, 2H), 1.48 (s, 4H)13C
NMR(151MHz,CDCl3)δ164.10,163.05,162.50,16 1.44,160.16,155.64,155.10,152.75,
149.45,148.80,146.75,137.49,136.48,130.27,129.46,123.46,118.04,117.88,116.03,
115.51,109.42,109.27,107.75,105.70,102.2 3,99.47,56.18,56.10,56.04,54.04(2C),
43.32,25.49,23.18(2C).ESI-MS m/z:655.53[M-H]+.
Preparation example 12:1H NMR(600MHz,CDCl3) δ 11.06 (s, 1H), 8.95 (s, 1H), 8.48 (d, J=5.3Hz,
1H), 7.91 (dd, J=12.4,2.3Hz, 1H), 7.58 (s, 1H), 7.41 (s, 1H), 7.38-7.32 (m, 4H), 7.30 (d, J
=9.9Hz, 1H), 7.15 (t, J=8.7Hz, 1H), 6.42 (d, J=5.2Hz, 1H), 4.05 (s, 3H), 4.04 (s, 3H),
3.61 (t, J=6.0Hz, 2H), 2.33 (t, J=6.0Hz, 2H), 2.19 (s, 3H), 1.78 (s, 2H), 1.71 (dt, J=
12.2,6.1Hz, 2H), 1.34 (d, J=5.1Hz, 2H), 1.27 (d, J=5.0Hz, 4H)13C NMR(151MHz,CDCl3)δ
164.31,163.01,162.42,161.39,160.16,155.63,153.48,152.76,149.47,148.81,146.78,
137.46,136.54,130.37,129.22,123.48,118.34,118.18,116.07,115.52,109.45,109.30,
107.77,105.94,102.24,99.48,56.30,56.11,56.05,54.18,41.78(2C),24.45,24.16(2C),
23.61.ESI-MS m/z:669.66[M-H]+.
Preparation example 13:1H NMR(600MHz,CDCl3) δ 11.04 (s, 1H), 8.95 (s, 1H), 8.46 (d, J=5.2Hz,
1H), 7.91 (dd, J=12.3,2.3Hz, 1H), 7.56 (s, 1H), 7.43 (s, 1H), 7.41-7.31 (m, 4H), 7.30 (d, J
=7.4Hz, 1H), 7.16 (t, J=8.7Hz, 1H), 6.41 (d, J=5.2Hz, 1H), 5.61 (t, J=5.2Hz, 1H), 4.26
(t, J=6.5Hz, 2H), 4.02 (s, 3H), 3.61 (dd, J=12.0,6.2Hz, 2H), 3.55-3.42 (m, 4H), 2.78 (s,
8H), 2.68 (t, J=6.7Hz, 3H), 2.52 (s, 3H), 2.36 (t, J=6.3Hz, 2H), 2.33-2.24 (m, 4H), 2.14
(p,2H),1.75(p,2H).13C NMR(151MHz,CDCl3)δ164.33,162.89,162.29,161.43,160.23,
155.51,153.48,152.12,149.78,148.65,146.57,137.44,136.56,130.41,130.35,129.17,
123.50,118.44,118.29,116.10,115.50,109.34,108.54,106.26,102.21,99.63,66.81,
66.29(2C),56.60,56.10,54.26,53.67(2C),51.40(2C),44.82(2C),41.58,29.65,26.00,
24.51.ESI-MS m/z:797.60[M-H]+.
Preparation example 14:1H NMR(600MHz,CDCl3) δ 11.01 (s, 1H), 8.94 (s, 1H), 8.46 (d, J=5.2Hz,
1H), 7.90 (dd, J=12.3,2.2Hz, 1H), 7.56 (s, 1H), 7.40 (s, 1H), 7.38-7.29 (m, 4H), 7.29-7.27
(m, 2H), 7.16 (t, J=8.7Hz, 1H), 6.99 (s, 1H), 6.86 (s, 1H), 6.40 (d, J=5.2Hz, 1H), 4.25 (t, J
=6.7Hz, 2H), 4.02 (s, 3H), 4.01 (d, J=6.5Hz, 2H), 3.49 (dd, J=12.7,6.3Hz, 2H), 2.58 (t, J
=7.2Hz, 3H), 2.47 (s, 5H), 2.29 (s, 3H), 2.11 (dt, J=14.2,7.1Hz, 4H), 1.84 (s, 3H)13C NMR
(151MHz,CDCl3)δ164.28,162.74,162.12,161.14,160.10,155.64,155.11,153.46,
152.16,149.73,148.66,146.70,137.27,136.67,130.25,130.19,129.49,128.79,123.53,
118.67,118.38,118.23,116.07,115.42,109.48,108.59,106.69,102.14,99.55,67.14,
56.08(2C),54.77(2C),54.70,52.54,45.56,44.52,39.65,30.38,26.18.ESI-MS m/z:
778.78[M-H]+.
Preparation example 15:1H NMR(600MHz,CDCl3) δ 11.07 (s, 1H), 8.95 (s, 1H), 8.46 (d, J=5.3Hz,
1H), 7.91 (dd, J=12.4,2.3Hz, 1H), 7.55 (s, 1H), 7.41 (s, 1H), 7.36-7.30 (m, 5H), 7.29 (d, J
=1.2Hz, 1H), 7.14 (t, J=8.7Hz, 1H), 6.40 (d, J=5.2Hz, 1H), 4.25 (t, J=6.7Hz, 2H), 4.02
(s, 3H), 3.63 (t, J=5.8Hz, 2H), 2.57 (t, J=7.2Hz, 3H), 2.52-2.48 (m, 3H), 2.45-2.17 (m,
11H),2.15–2.10(m,2H),1.73–1.68(m,2H),1.48(s,4H).13C NMR(151MHz,CDCl3)δ164.14,
163.06,162.48,161.44,160.11,155.65,155.11,152.15,149.72,148.74,146.76,137.46,
136.53,130.26,129.43,123.46,118.09,117.93,116.04,115.41,109.42,109.27,108.67,
105.75,102.15,99.55,67.25,56.08,55.93,54.98(2C),54.81,54.00(2C),52.89(2C),
45.82,43.06,26.26,25.43,23.19(2C).ESI-MS m/z:781.72[M-H]+.
Preparation example 16:1H NMR(600MHz,CDCl3) δ 11.06 (s, 1H), 8.95 (s, 1H), 8.46 (d, J=5.2Hz,
1H), 7.91 (dd, J=12.3,2.2Hz, 1H), 7.56 (s, 1H), 7.41 (s, 1H), 7.38-7.32 (m, 4H), 7.30 (d, J
=9.6Hz, 1H), 7.15 (t, J=8.7Hz, 1H), 6.40 (d, J=5.2Hz, 1H), 4.25 (t, J=6.7Hz, 2H), 4.02
(s, 3H), 3.61 (t, J=6.0Hz, 2H), 2.58 (t, J=7.2Hz, 3H), 2.48 (s, 3H), 2.33 (t, J=5.9Hz,
2H), 2.29 (s, 3H), 2.19 (s, 5H), 2.12 (dt, J=13.8,6.9Hz, 2H), 1.76 (s, 2H), 1.71 (dt, J=
11.8,6.0Hz, 2H), 1.34 (d, J=5.0Hz, 2H), 1.30-1.24 (m, 6H)13C NMR(151MHz,CDCl3)δ
164.30,163.01,162.41,161.40,160.11,155.62,153.47,152.16,149.72,148.73,146.76,
137.43,136.57,130.37,129.22,123.48,118.33,118.18,116.04,115.41,109.45,109.29,
108.66,105.93,102.15,99.55,67.25,56.33,56.08(2C),54.97(2C),54.82,54.19,52.90
(2C),45.82,41.85,26.26,24.48(2C),24.16,23.63.ESI-MS m/z:795.85[M-H]+.
Preparation example 17:1H-NMR(600MHz,DMSO),δ11.52(s,1H,NH),11.02(s,1H,OH),8.69(s,
1H, ArH), 8.37 (d, 1H, J=1.3Hz, ArH), 8.11 (dd, 1H, J=10.8,3.0Hz, ArH), 7.57-7.34 (m, 8H,
), ArH 7.07 (d, 1H, J=4.5Hz, ArH), 6.25 (d, 1H, J=3.2Hz, ArH), 4.18 (t, 2H, J=9.6Hz, CH2-
H),3.92(s,3H,CH3- H), 3.59 (t, 4H, J=4.4Hz, ArH), 2.46 (t, 2H, J=10.2Hz, CH2-H),2.36(s,
4H,CH2-H),2.0(m,2H,CH2-H)；13C-NMRδ:164.18,163.82,162.86,162.41,162.32,161.06,
159.74,156.86,152.40,150.02,149.32,146.84,131.76,130.35,130.12,124.58,117.86,
117.71,116.67,116.56,114.94,108.99,108.89,108.75,104.76,102.52,99.50,67.14,
66.69,56.23,55.29,53.85,35.59；MS m/z:660.22[M+H]+.
Preparation example 18:1H-NMR(DMSO,600MHz),δ:2.0(m,5H,NH2,CH2CH 2CH2),2.39(s,4H,
NCH 2CH2O,NCH 2CH2), O 2.47 (t, 2H, J=10.8Hz, NCH 2CH2CH2O),3.94(s,3H,CH3), 4.20 (t, 2H, J=
9.6Hz,NCH2CH2CH 2), O 6.45 (d, 1H, ArH), 7.37-7.54 (m, 8H, ArH), 8.09 (dd, 1H, J=10.8,
3.0Hz, ArH), 8.47 (d, 1H, J=1.3Hz, ArH), 8.66 (s, 1H, pyrimidine-6 '-H), 11.23 (s, 1H, NH)
.13C-NMRδ:174.7,163.0,162.9,161.7,159.7,158.6,152.3,150.0,149.3,146.8,131.3,
131.3,130.1,124.5,117.7,117.5,108.9,104.2,99.5,67.1,66.6,56.2,55.2,53.8,
35.6.MS m/z (%): 657.3 (MH-, 100%) and
Preparation example 19:1H-NMR(400MHz,DMSO)δ11.24(s,1H,NH),8.73(s,1H,ArH),8.47(d,1H,
J=5.2Hz, ArH), 8.02 (dd, 1H, J=13.1,2.2Hz, ArH), 7.62-7.35 (m, 8H, ArH), 7.07 (d, 1H, J=
4.5Hz, ArH), 6.45 (d, 1H, J=5.1Hz, NH), 4.20 (t, 2H, J=6.4Hz, CH2-H),3.94(s,3H,CH3-H),
3.59 (t, 4H, J=4.4Hz, ArH), 2.84 (d, 3H, J=4.4Hz), 2.46 (t, 2H, J=10.8, CH2-H),2.39(s,
4H,CH2-H),1.98(m,2H,CH2-H)；13C-NMRδ:164.18,163.82,163.05,162.93,162.86,162.41,
162.32,161.06,159.74,156.86,152.40,150.02,149.32,146.84,131.76,130.35,130.12,
124.58,117.86,117.71,116.67,114.94,108.99,108.89,108.70,104.76,102.52,99.50,
67.14,66.69,56.23,31.76,26.16；MS m/z:673.25[M+H]+.
Preparation example 20:1H-NMR (DMSO, 600MHz), δ: 1.21 (t, 3H, J=10.8Hz, NHCH2CH 3)；1.69(s,
1H,NH)；3.52 (m, 2H, J=10.8Hz, NHCH 2CH3)；2.39(s,4H,NCH 2CH2O,NCH 2CH2O)；2.47 (t, 2H, J=
10.8Hz,NCH 2CH2CH2O)；3.94(s,3H,CH3)；4.20 (t, 2H, J=9.6Hz, NCH2CH2CH 2O)；6.45(d,1H,
ArH)；7.37-7.54(m,8H,ArH)；8.09 (dd, 1H, J=10.8,3.0Hz, ArH)；8.47 (d, 1H, J=1.3Hz,
ArH)；8.66(s,1H,pyrimidine-6'-H)；11.23(s,1H,NH).13C-NMRδ:174.8,163.2,162.9,
1618,159.7,158.6,152.3,150.0,149.3,146.8,131.3,131.3,130.1,124.5,117.7,117.6,
108.8,104.3,99.5,67.1,66.6,56.2,55.2,53.8,36.4,14.6.MS m/z (%): 687.1 (MH+,
100%)
Preparation example 21:1H NMR(600MHz,CDCl3) δ 11.04 (s, 1H), 8.95 (s, 1H), 8.46 (d, J=5.3Hz,
1H), 7.91 (dd, J=12.3,2.3Hz, 1H), 7.56 (s, 1H), 7.43 (s, 1H), 7.41-7.31 (m, 4H), 7.30 (d, J
=10.2Hz, 1H), 7.16 (t, J=8.7Hz, 1H), 6.41 (d, J=5.2Hz, 1H), 5.63 (t, J=4.9Hz, 1H), 4.27
(t, J=6.6Hz, 2H), 4.03 (s, 3H), 3.74 (t, J=4.1Hz, 4H), 3.61 (dd, J=12.0,6.2Hz, 2H), 3.51
(s, 5H), 2.60 (t, J=7.0Hz, 2H), 2.52 (s, 4H), 2.38 (t, J=6.3Hz, 2H), 2.33 (s, 5H), 2.15 (dt,
J=13.4,6.6Hz, 3H), 1.76 (p, 2H)13CNMR(151MHz,CDCl3)δ164.32,162.87,162.27,161.40,
160.25,155.51,153.46,152.22,149.77,148.53,146.50,137.42,136.56,130.39,130.33,
129.15,123.49,118.42,118.27,116.08,115.45,109.48,108.47,106.25,102.17,99.58,
67.13,66.80(2C),66.21(2C),56.51,56.10,55.35,53.59(4C),41.47,25.83,24.47.ESI-
MS m/z:784.46[M-H]+.
Preparation example 22:1H NMR(600MHz,CDCl3)δ11.01(s,1H),8.95(s,1H),8.48–8.45(m,1H),
7.90 (d, J=12.3Hz, 1H), 7.56 (s, 1H), 7.42 (d, J=2.1Hz, 1H), 7.41-7.30 (m, 4H), 7.28 (dd, J
=5.2,2.7Hz, 2H), 7.17 (t, J=8.8Hz, 1H), 7.05-6.90 (m, 2H), 6.87 (d, J=7.8Hz, 1H), 6.41
(d, J=5.2Hz, 1H), 4.27 (t, J=6.1Hz, 2H), 4.03 (s, 3H), 4.02-3.94 (m, 2H), 3.72 (s, 4H),
3.53-3.47 (m, 2H), 2.57 (t, J=7.1Hz, 2H), 2.48 (s, 4H), 2.16-2.08 (m, 4H)13C NMR(151MHz,
CDCl3)δ164.27,162.75,16 2.15,161.15,160.22,155.68,155.08,153.43,152.22,
149.77,148.48,146.46,137.32,136.69,130.27,130.21,129.20,128.82,123.52,118.71,
118.35,118.20,116.11,115.4 3,109.48,108.41,106.62,102.14,99.57,67.10,66.75
(2C),56.08,55.32,53.55(2C),44.56,39.62,30.34,25.80.ESI-MS m/z:765.73[M-H]+.
Preparation example 23:1H NMR(600MHz,CDCl3) δ 11.08 (s, 1H), 8.95 (s, 1H), 8.47 (d, J=5.3Hz,
1H), 7.91 (dd, J=12.4,2.3Hz, 1H), 7.56 (s, 1H), 7.42 (s, 1H), 7.36-7.30 (m, 5H), 7.30 (d, J
=4.4Hz, 1H), 7.24-7.22 (m, 1H), 7.15 (t, J=8.7Hz, 1H), 6.40 (d, J=5.2Hz, 1H), 4.26 (t, J
=6.7Hz, 2H), 4.03 (s, 3H), 3.72 (t, J=4.5Hz, 5H), 3.63 (t, J=5.9Hz, 2H), 2.57 (t, J=
7.1Hz, 2H), 2.50 (dd, J=12.6,6.7Hz, 7H), 2.26 (s, 5H), 2.15-2.10 (m, 2H), 1.89-1.60 (m,
7H).13C NMR(151MHz,CDCl3)δ163.05,162.49,161.44,160.11,156.92,155.64,155.12,
152.12,149.69,148.73,146.72,137.46,136.50,130.40,130.27,123.45,118.03,117.88,
117.49,116.04,115.41,109.41,108.63,105.67,102.15,99.55,67.14,66.93(2C),56.07,
55.32,54.03(2C),53.99,53.64(2C),53.37,25.94,25.49,23.18(2C).ESI-MS m/z:768.66
[M-H]+.
Preparation example 24:1H NMR(600MHz,CDCl3) δ 11.11 (s, 1H), 8.92 (s, 1H), 8.48 (d, J=5.4Hz,
1H), 7.92 (dd, J=12.3,2.1Hz, 1H), 7.56 (s, 1H), 7.49 (s, 1H), 7.36-7.30 (m, 4H), 7.29 (d, J
=3.1Hz, 1H), 7.23-7.21 (m, 1H), 7.15 (t, J=8.7Hz, 1H), 6.43 (d, J=5.3Hz, 1H), 4.26 (t, J
=6.5Hz, 2H), 4.03 (s, 3H), 3.75 (t, J=4.5Hz, 4H), 3.57 (t, J=6.2Hz, 2H), 3.46 (t, J=
6.2Hz, 2H), 2.75 (dd, J=13.3,5.9Hz, 4H), 2.65-2.61 (m, 2H), 2.55 (s, 4H), 2.18-2.12 (m,
2H), 2.02-1.98 (m, 2H), 1.54 (d, J=1.7Hz, 4H), 1.25 (s, 2H)13C NMR(151MHz,CDCl3)δ
166.78,163.03,162.48,161.29,160.56,159.04,156.84,155.95,152.38,149.87,148.07,
137.56,136.41,130.40,123.48,118.27,118.12,117.91,117.76,116.14,109.51,109.35,
107.83,106.05,102.17,99.60,67.10,66.48(2C),56.10,55.25,54.16,53.29(2C),53.07,
53.04,39.42,25.48,23.58,22.80(2C),22.41.ESI-MS m/z:782.68[M-H]+.
Preparation example 25:1H-NMR (DMSO, 600MHz), δ: 1.15 (td, 3H, J=13.2,5.4Hz, Piperidine-
4’-CH3)；1.24(s,4H,Piperidine-2'-H,Piperidine-4'-H)；1.58 (dd, 2H, J=15.0,1.2Hz,
Piperidine-4'-H)；1.87 (t, 2H, J=16.8Hz, CH2CH 2CH2)；1.98(m,3H,NH2,CH2CH 2CH2)；2.44
(t, 2H, J=10.2Hz, NCH 2CH2CH2O)；2.84(s,3H,NHCH 3),3.95(s,3H,OCH3)；4.18(t,2H,
NCH2CH2CH 2O)；6.45(d,1H,ArH),7.38-7.54(m,8H,ArH)；8.02 (dd, 1H, J=10.8,3.0Hz, ArH)；
8.47 (d, 1H, J=1.3Hz, ArH)；8.74(s,1H,pyrimidine-6'-H)；11.25(s,1H,NH).13C-NMRδ:
163.0,162.8,161.0,159.7,156.8,152.4,150.0,149.3,146.8,131.7,131.6,130.3,
130.1,124.5,117.8,117.7,116.6,114.9,108.9,104.7,102.5,99.5,67.2,56.2,55.2,
53.9,34.5,30.9.MS m/z (%): 685.4 (MH+, 100%) and
Preparation example 26:1H-NMR (DMSO, 600MHz), δ: 1.07 (t, 3H, J=10.8Hz, NHCH2CH 3)；1.15 (t,
3H, J=13.2Hz, Piperidine-4 '-CH3)；1.24(s,4H,Piperidine-2'-H,Piperidine-4'-H)；
1.58 (dd, 2H, J=15.0,1.2Hz, Piperidine-4 '-H), 1.87 (t, 2H, J=16.8Hz, CH2CH 2CH2)；1.98
(m,3H,NH2,CH2CH 2CH2)；2.44 (t, 2H, J=10.2Hz, NCH 2CH2CH2O)；2.85(s,2H,NHCH 2CH3)；3.95
(s,3H,OCH3)；4.18(t,2H,NCH2CH2CH 2O)；6.45(d,1H,ArH)；7.38-7.54(m,8H,ArH)；8.02(dd,
1H, J=10.8,3.0Hz, ArH)；8.47 (d, 1H, J=1.3Hz, ArH)；8.74(s,1H,pyrimidine-6'-H)；
11.25(s,1H,NH).13C-NMRδ:162.7,161.2,159.9,156.7,152.4,150.0,149.3,146.9,131.4,
130.2,124.5,117.8,117.7,116.6,115.7,108.9,104.7,102.8,99.6,67.3,56.3,55.2,
53.9,37.3,14.7.MS m/z (%): 699.5 (MH+, 100%) and
Preparation example 27:1H-NMR (DMSO, 600MHz), δ: 1.07 (t, 3H, J=10.8Hz, NHCH2CH2CH 3)；1.15
(t, 3H, J=13.2Hz, Piperidine-4 '-CH3)；1.24(s,4H,Piperidine-2'-H,Piperidine-4'-
H)；1.58 (dd, 2H, J=15.0,1.2Hz, Piperidine-4 '-H)；1.60 (m, 2H, J=10.8Hz, NHCH2CH 2CH3)；
1.87 (t, 2H, J=16.8Hz, CH2CH 2CH2)；1.98(m,3H,NH2,CH2CH 2CH2)；2.44 (t, 2H, J=10.2Hz,
NCH 2CH2CH2O)；2.85(s,2H,NHCH 2CH2CH3)；3.95(s,3H,OCH3)；4.18(t,2H,NCH2CH2CH 2O)；6.45
(d,1H,ArH)；7.38-7.54(m,8H,ArH)；8.02 (dd, 1H, J=10.8,3.0Hz, ArH)；8.47 (d, 1H, J=
1.3Hz,ArH)；8.74(s,1H,pyrimidine-6'-H)；11.25(s,1H,NH).13C-NMRδ:163.0,162.8,
161.0,159.7,156.8,152.4,150.0,149.3,146.8,131.7,131.6,130.3,130.1,124.5,
117.8,117.7,116.6,114.9,108.9,104.7,102.5,99.5,67.2,56.2,55.2,53.9,42.7,23.2,
11.9.MS m/z (%): 711.6 (MH-, 100%) and
Preparation example 28:1H NMR(400MHz,CDCl3) δ 11.04 (s, 1H), 8.95 (s, 1H), 8.46 (d, J=5.3Hz,
1H), 7.91 (dd, J=12.4,2.2Hz, 1H), 7.55 (s, 1H), 7.35 (ddd, J=15.2,13.3,6.9Hz, 6H), 7.16
(t, J=8.7Hz, 1H), 6.40 (d, J=5.2Hz, 1H), 5.59 (t, J=5.2Hz, 1H), 4.24 (t, J=6.7Hz, 2H),
4.02 (s, 3H), 3.66-3.58 (m, 3H), 3.51-3.45 (m, 4H), 2.92 (d, J=11.3Hz, 2H), 2.54 (t, J=
7.3Hz, 2H), 2.35 (t, J=6.3Hz, 2H), 2.32-2.26 (m, 4H), 2.13 (p, 2H), 1.95 (t, J=11.2Hz,
2H), 1.74 (p, J=12.6,6.3Hz, 3H), 1.62 (d, J=12.6Hz, 2H), 1.41-1.31 (m, 1H), 1.30-1.21
(m, 3H), 0.92 (d, J=6.3Hz, 3H)13C NMR(151MHz,CDCl3)δ164.32,162.88,162.27,161.41,
160.11,15 5.51,153.49,152.04,149.70,148.74,146.71,137.37,136.63,130.40,
130.35,129.18,123.51,118.42,118.27,116.07,115.49,109.48,108.74,106.25,102.20,
99.60,67.24,66.33(2C),56.62,56.08,55.27,53.69(4C),41.61,33.46(2C),30.40,
25.88,24.55,21.60.ESI-MS m/z:798.47[M+H]+.
Preparation example 29:1H NMR(600MHz,CDCl3) δ 11.00 (s, 1H), 8.95 (d, J=4.6Hz, 1H), 8.46 (dd,
J=6.8,3.5Hz, 1H), 7.90 (d, J=12.2Hz, 1H), 7.56 (s, 1H), 7.41 (d, J=5.2Hz, 1H), 7.40-
7.29 (m, 4H), 7.29-7.27 (m, 2H), 7.17 (t, J=8.6Hz, 1H), 7.06-6.91 (m, 2H), 6.88 (s, 1H),
6.40 (d, J=5.2Hz, 1H), 4.24 (t, J=6.6Hz, 2H), 4.02 (s, 3H), 4.00 (dd, J=15.1,4.1Hz, 2H),
3.53-3.47 (m, 2H), 2.92 (d, J=13.2Hz, 2H), 2.55 (d, J=7.2Hz, 2H), 2.12 (ddd, J=20.1,
13.4,6.8Hz, 4H), 1.95 (d, J=12.3Hz, 2H), 1.63-1.60 (m, 4H), 1.37-1.33 (m, 1H), 0.92 (d, J
=6.3Hz, 3H) .ESI-MS m/z:777.79 [M-H]+.
Preparation example 30:1H NMR(600MHz,CDCl3) δ 11.07 (s, 1H), 8.96 (s, 1H), 8.46 (d, J=5.2Hz,
1H), 7.91 (dd, J=12.4,2.3Hz, 1H), 7.55 (s, 1H), 7.40 (s, 1H), 7.33 (dt, J=9.1,6.6Hz, 4H),
7.29 (d, J=1.2Hz, 1H), 7.23 (d, J=5.1Hz, 1H), 7.15 (t, J=8.7Hz, 1H), 6.40 (d, J=5.2Hz,
1H), 4.24 (t, J=6.7Hz, 2H), 4.02 (s, 3H), 3.66-3.60 (m, 2H), 2.92 (d, J=11.1Hz, 2H), 2.54
(t, J=7.3Hz, 2H), 2.52-2.48 (m, 2H), 2.26 (s, 6H), 2.17-2.10 (m, 2H), 1.95 (t, J=11.1Hz,
2H), 1.84-1.64 (m, 6H), 1.62 (d, J=12.4Hz, 2H), 1.38-1.32 (m, 1H), 1.24 (d, J=8.4Hz, 3H)
.13C NMR(151MHz,CDCl3)δ163.07,162.50,161.47,160.11,156.98,155.64,152.14,
149.71,148.72,146.74,137.47,136.53,130.42,130.28,130.23,123.46,118.02,117.87,
117.62,116.04,115.43,109.42,108.68,105.68,102.15,99.56,67.41,56.07,55.33,
54.07(2C),54.05,53.86(2C),43.54,33.98(2C),30.61,26.27,25.51,23.19(2C),
21.74.ESI-MSm/z:780.71[M-H]+.
Preparation example 31:1H NMR(600MHz,CDCl3) δ 11.06 (s, 1H), 8.95 (s, 1H), 8.46 (d, J=5.3Hz,
1H), 7.91 (dd, J=12.4,2.3Hz, 1H), 7.56 (s, 1H), 7.41 (s, 1H), 7.39-7.32 (m, 4H), 7.30 (d, J
=8.8Hz, 1H), 7.15 (t, J=8.7Hz, 1H), 6.40 (d, J=5.2Hz, 1H), 4.24 (t, J=6.7Hz, 2H), 4.02
(s, 3H), 3.61 (t, J=6.0Hz, 2H), 2.92 (d, J=10.8Hz, 2H), 2.55 (t, J=7.2Hz, 2H), 2.33 (t, J
=6.0Hz, 2H), 2.19 (s, 3H), 2.14 (dt, J=13.7,6.8Hz, 2H), 1.95 (t, J=10.9Hz, 2H), 1.71
(dt, J=11.7,5.8Hz, 4H), 1.62 (d, J=12.8Hz, 2H), 1.35 (dd, J=16.2,11.0Hz, 3H), 1.27
(dd, J=9.9,6.0Hz, 6H), 0.92 (d, J=6.4Hz, 3H)13C NMR(151MHz,CDCl3)δ164.35,163.03,
162.45,161.43,160.12,155.61,153.49,152.07,149.71,148.77,146.76,137.50,136.58,
130.39,129.28,123.48,118.34,118.19,116.06,115.47,109.46,109.31,108.76,105.93,
102.19,99.59,67.31,56.50,56.11(2C),55.23,54.26(2C),53.79,42.06,33.71(2C),
30.52,26.03,24.56(2C),24.20,23.71,21.66.ESI-MS m/z:794.83[M-H]+.
Preparation example 32:1H-NMR(CDCl3,600MHz)；δ:6.69(d,1H,ArH)；7.19-7.34(m,8H,ArH)；
8.02 (dd, 1H, J=10.8,3.0Hz, ArH)；8.40 (d, 1H, J=4.8Hz, ArH)；8.60(s,1H,ArH)；9.47(s,
1H,ArOH)；10.85(s,1H,NH)；11.01(s,1H,pyrrole-NH).13C-NMRδ:163.6,162.0,161.5,
157.9,156.6,151.0,144.5,131.3,130.8,130.1,125.1,124.6,117.8,116.8,109.4,
108.7,104.4,98.8.MS m/z (%): 477.1 (MH+, 100%) and
Preparation example 33:1H-NMR(CDCl3,600MHz),δ:5.22(s,2H,ArCH 2O)；6.70(d,1H,ArH)；7.30-
7.45(m,12H,ArH)；7.92 (dd, 1H, J=10.8,3.0Hz, ArH)；8.29(s,1H,ArH)；8.98(s,1H,
pyrimidine-6'-H)；10.99(s,1H,NH)；12.30(s,1H,pyrrole-NH).13C-NMRδ:163.5,161.3,
160.7,154.0,151.3,150.8,150.4,136.3,130.1,129.1,128.4,125.0,116.4,105.2,
104.4,98.2,52.8.MS m/z (%): 567.2 (MH+, 100%) and
Preparation example 34:1H-NMR(600MHz,DMSO)δ11.80(s,1H,NH),11.01(s,1H,ArH),8.98(s,
1H, ArH), 8.07 (d, 1H, J=5.3Hz, ArH), 7.97 (d, 1H, J=12.7Hz, ArH), 7.55-7.22 (m, 12H,
), ArH 6.37 (d, 1H, J=5.3Hz, ArH), 6.26 (s, 1H, NH), 3.35 (s, 2H, CH2-H)；13C-NMRδ:163.54,
163.13,161.50,160.80,157.54,154.87,153.24,151.56,151.35,150.84,144.70,137.33,
136.98,136.33,131.80,131.35,130.61,130.11,129.77,129.19,128.49,127.84,127.34,
(126.69,126.63,125.37,124.33,116.92,116.42,109.85,109.10 d, J=23.1Hz), 105.21,
101.19,97.21.MS m/z:566.46[M+H]+.
Preparation example 35:1H NMR(600MHz,CDCl3) δ 11.00 (s, 1H), 8.95 (s, 1H), 8.12 (d, J=5.5Hz,
1H), 7.88 (dd, J=12.4,2.3Hz, 1H), 7.40-7.33 (m, 4H), 7.19 (s, 1H), 7.14 (t, J=8.7Hz, 1H),
6.45 (s, 1H), 6.41 (d, J=5.4Hz, 1H), 5.57-5.54 (m, 1H), 4.30 (t, J=6.7Hz, 1H), 4.08 (d, J=
6.7Hz, 1H), 3.61 (dd, J=12.0,6.3Hz, 2H), 3.49 (s, 4H), 2.36 (t, J=6.3Hz, 2H), 2.30 (s,
4H),1.76–1.72(m,2H).13C NMR(151MHz,D2O)δ164.36,162.89,162.25,161.29,158.45,
155.63,155.20,154.31,153.57,150.77,144.23,137.33,137.00,130.89,130.35,128.81,
123.41,123.33,118.45,118.29,115.92,109.37,106.41,98.43,65.55(2C),55.88,53.15
(2C),40.63,30.54.ESI-MSm/z:600.48[M-H]+.
Preparation example 36:1H NMR (600MHz, DMSO) δ 11.19 (s, 1H), 8.71 (s, 1H), 8.06 (d, J=5.4Hz,
1H), 7.97 (dd, J=13.1,2.2Hz, 1H), 7.49 (ddd, J=35.7,18.0,11.6Hz, 5H), 7.41 (s, 1H),
7.40 (s, 1H), 7.38-7.35 (m, 1H), 7.32 (t, J=9.0Hz, 1H), 7.16 (s, 1H), 7.14 (s, 1H), 6.87 (d, J
=10.4Hz, 1H), 6.36 (d, J=5.4Hz, 1H), 6.24 (dd, J=3.3,2.0Hz, 1H), 3.94 (dd, J=12.0,
4.9Hz, 2H), 3.24 (dd, J=12.7,6.5Hz, 2H), 1.90 (dd, J=13.9,7.0Hz, 2H) .ESI-MS m/z:
581.54[M-H]+.
Preparation example 37:1H NMR(600MHz,CDCl3) δ 11.04 (s, 1H), 8.95 (s, 1H), 8.13 (d, J=5.5Hz,
1H), 7.88 (dd, J=12.4,2.3Hz, 1H), 7.36-7.30 (m, 4H), 7.28 (d, J=7.9Hz, 1H), 7.20 (d, J=
1.5Hz, 1H), 7.14 (dd, J=18.2,9.4Hz, 2H), 6.44 (d, J=2.4Hz, 1H), 6.42 (d, J=5.5Hz, 1H),
3.65–3.61(m,2H),2.52–2.49(m,2H),2.27(s,4H),1.72–1.69(m,3H),1.49(s,4H).13C NMR
(151MHz,CDCl3)δ164.16,163.05,162.47,161.37,158.38,155.70,155.21,153.56,
151.10,144.31,137.30,137.06,130.26,123.45,123.30,118.12,117.96,115.88,110.37,
109.32,109.17,105.91,101.45,98.27,53.96(2C),31.89,29.66,25.48,23.20(2C).ESI-
MS m/z:584.60[M-H]+.
Preparation example 38:1H NMR(600MHz,CDCl3) δ 11.03 (s, 1H), 8.95 (s, 1H), 8.12 (d, J=5.5Hz,
1H), 7.88 (dd, J=12.4,2.1Hz, 1H), 7.37-7.31 (m, 4H), 7.20 (d, J=1.9Hz, 1H), 7.14 (t, J=
8.7Hz, 1H), 6.43 (d, J=2.8Hz, 1H), 6.42 (d, J=5.5Hz, 1H), 6.23 (s, 1H), 3.60 (t, J=6.0Hz,
2H), 2.32 (t, J=6.0Hz, 2H), 2.19 (s, 4H), 1.81 (s, 2H), 1.71 (dt, J=12.0,6.0Hz, 2H), 1.34
(d, J=5.2Hz, 2H), 1.28 (d, J=4.9Hz, 4H)13C NMR(151MHz,CDCl3)δ164.25,163.00,
162.38,161.33,158.35,155.63,153.56,151.11,144.14,137.30,137.01,130.38,129.25,
123.54,123.28,118.27,118.11,115.87,110.39,109.31,109.15,105.95,101.37,98.15,
56.41,54.22(2C),41.89,24.56,24.30(2C),23.68.ESI-MS m/z:598.60[M-H]+.
Preparation example 39
Thio -2,4 (1H, 3H)-hybar X -5- Ethyl formate of 3- (4- fluoro-phenyl) -2-:
It is dense that the DEMM of the 4- fluorophenyl thiocarbamide of 2.54g (15.0mol) and 3.2mL (13.8mol) is added sequentially to 3.2mL
In the mixed solution of hydrochloric acid and 9.6mL ethyl alcohol, the back flow reaction 4h at 105 DEG C.TLC tracing detection to reaction terminates.After cooling
Filtering collects solid and uses ethanol washing.Obtain 4.12g white solid 3- (4- fluoro-phenyl) -2- thio -2,4 (1H, 3H) -
Hybar X -5- Ethyl formate (compound 2 corresponds to (d) in reaction route), yield 94%.
Preparation example 40
- 4 (3H)-pyrimidone -5- Ethyl formate of 2- methyl mercapto -3- (4- fluoro-phenyl):
In 50mL single-necked flask, the compound 2 of 5.0g (17.1mol), methanol, the 5.6ml of 15.0ml are sequentially added
The CH of (17.4mol)3I, the saturated sodium bicarbonate solution of 10mL, is stirred overnight at room temperature.It is extracted with dichloromethane after cooling
(1000mL × 3) merge organic phase.Solvent removed by evaporation at reduced pressure.Residue chromatographs [eluant, eluent: A=V (petroleum ether): V with column
(ethyl acetate)=1: 1] after obtain pulverulent solids 2- methyl mercapto -3- (4- fluoro-phenyl) -4 (3H)-pyrimidine of 5.1g white
Ketone -5- Ethyl formate (compound 3 corresponds to (e) in reaction route), yield 98%.
Preparation example 41
- 4 (3H)-pyrimidone -5- Ethyl formate of 2- hydroxyl -3- (4- fluoro-phenyl):
In the single-necked flask of 50mL, the compound 3 of 3.0g (9.7mol), potassium hydrogen persulfate, the 4mL of 0.3g are sequentially added
Methanol, 1.0mL water, are stirred at room temperature 2h, after reaction, use CH2Cl2It extracts (1000mL × 3), merges organic phase.It is evaporated under reduced pressure
Remove solvent.[eluant, eluent: A=V (petroleum ether): V (ethyl acetate)=1: 1] 2.5g white powder is obtained after residue column chromatography
(compound 4 corresponds in reaction route shape solid 2- hydroxyl -3- (4- fluoro-phenyl) -4 (3H)-pyrimidone -5- Ethyl formate
(f)), yield 93%.
Preparation example 42
- 4 (3H)-pyrimidone -5- Ethyl formate of 2- methoxyl group -3- (4- fluoro-phenyl):
In the single-necked flask of 25mL, compound 4, the 30.0mg (21.7mmol) of 60.0mg (21.5mmol) are sequentially added
Anhydrous potassium carbonate, the anhydrous propanone of 4.0mL, 13.4 μ L (21.5mmol) iodomethane, 2h is stirred at room temperature, after reaction,
It is extracted with ethyl acetate (50.0mL × 3), merges organic phase.Solvent removed by evaporation at reduced pressure rear pillar chromatographs [eluant, eluent: A=V (stone
Oily ether): V (ethyl acetate)=3: 1] dry the white powdery solids 2- methoxyl group -3- (4- fluoro-phenyl) -4 (3H)-of purifying
Pyrimidone -5- Ethyl formate (compound 5 corresponds to (g) in reaction route), yield 91%.
Following compound is prepared basically by the method for preparation example 42:
Preparation example 46
2- amino -3- (4- fluoro-phenyl) -4- oxo -3,4- dilzydro-pyrimidine -5- Ethyl formate:
In the single-necked flask of 25mL, the compound 3 of 60.0mg (0.20mol), the acetic acid of 0.20g (2.5mol) is added
Ammonium, 150 DEG C of back flow reaction 2h are cooled to room temperature after reaction, are extracted with ethyl acetate (50.0mL × 3), merge organic
Phase.Solvent removed by evaporation at reduced pressure.Residue column, which chromatographs, [eluant, eluent: to be obtained after A=V (petroleum ether): V (ethyl acetate)=1: 1]
(change to 49.0mg white powdery solids 2- amino -3- (4- fluoro-phenyl) -4- oxo -3,4- dilzydro-pyrimidine -5- Ethyl formate
Close object 6, (h) in corresponding reaction route), yield 91%.
Preparation example 47
- 4 (3H)-pyrimidone -5- Ethyl formate of 2- methylamino -3- (4- fluoro-phenyl)
At 0 DEG C, in the single-necked flask of 25mL, 4.2mL glacial acetic acid is added, after the methylamine of 4.6mL, is added 0.060g's
3,150 DEG C of back flow reaction 2h of compound are extracted with ethyl acetate (50.0mL × 3) after reaction, merge organic phase.Decompression
After evaporation of solvent, residue is chromatographed with column and [eluant, eluent: A=V (petroleum ether): V (ethyl acetate)=1: 1] obtains white powder
(compound 7 corresponds in reaction route last -4 (3H)-pyrimidone -5- Ethyl formate of shape solid 2- methylamino -3- (4- fluoro-phenyl)
(h)), yield 89%.
Following compound is prepared by the method for preparation example 47:
Preparation example 54
2- methoxyl group -3- (4- fluoro-phenyl) -4- oxo -3,4- dilzydro-pyrimidine -5- formic acid:
In the single-necked flask of 25ml, the compound 5 of 1.0g (3.42mol) is added, after the methanol dissolution of 20ml, is added
NaOH (1mol/mL, 6.84mol) solution of 6.8ml, is stirred at room temperature, and TCL monitors reaction process to after reaction, with dilute salt
Sour (1mol/L) is adjusted to acidity, is extracted with ethyl acetate (50.0mL × 3), merges organic phase, and solvent removed by evaporation at reduced pressure is remaining
Object is chromatographed with column and [eluant, eluent: A=V (petroleum ether): V (ethyl acetate): V (glacial acetic acid)=4: 1: 0.06] obtains 2- methoxyl group-
3- (4- fluoro-phenyl) -4- oxo -3,4- dilzydro-pyrimidine -5- formic acid (compound 8 corresponds to (a) in reaction route), yield
46%.
Following compound is prepared basically by the method for preparation example 54:
The measurement of target compound anti tumor activity in vitro:
GTL16 cell line derives from patients with gastric cancer.Due to gene magnification, GTL16 expresses high-caliber c-Met receptor junket ammonia
Acid kinase.The growing height of GTL16 depends on c-Met kinase activity；Therefore its cell for being used as monitoring c-Met kinase inhibitor
Activity test.
By culture medium (Gibco of the GTL-16 gastric carcinoma cells of logarithmic growth phase containing 0.5% fetal calf serum (Gibco)
1640) cell suspension is made, is inoculated into 96 orifice plates, 100 μ L are added in every hole, set 37 DEG C, 5%CO2Culture in incubator
For 24 hours, adherent to its.After untested compound is dissolved with DMSO, it is diluted to respective concentration with complete medium, compound is arranged
Concentration gradient: after 1000nmol/L, 200nmol/L, 40nmol/L, 8nmol/L, 1.6nmol/L, for use.Old culture medium is discarded,
Culture medium (containing fetal calf serum 0.5%) 100 μ L of every group of addition drug containing various concentration, blank control add same not drug containing
Culture medium (contains serum 0.5%), and 4 multiple holes are arranged in each concentration, sets 37 DEG C, 5%CO272h is cultivated in incubator.Discard old training
After supporting base, the MTT solution of 100 μ L serum free mediums and the 5mg/mL of 10 μ L is added in every hole, continues to set 37 DEG C, 5%CO2Culture
4h is cultivated in case.It inhales and abandons culture medium in hole, every 100 μ LDMSO of Kong Junjia, concussion dissolves crystallization.Each hole is measured with microplate reader
Absorbance (wavelength) calculates IC using Spotfire software50。
Prepared its active determination in vitro result of the compound (IC obtained of preparation example 1-3850, nM) and it is shown in Table 1:
The external GTL-16 gastric carcinoma cells active testing result of 1 part of compounds of table
Pharmacological activity test result shows that above compound provided by the invention has good anti-tumor activity, can
For treating or preventing with c-Met inhibitor in relation to various cancers.Obviously, the present invention is included compound can pharmaceutically connect
The salt received is far above to be referred in above-mentioned preparation example, but those skilled in the art will appreciate that preparation example of the present invention is unmentioned
The compound of formula (I), its pharmaceutically acceptable salt have good anti-tumor activity, can be used to treat or prevent and c-Met
Inhibitor is in relation to various cancers.Compound, pharmaceutically acceptable salt only make change or replacement to compound in preparation example, no
Can obviously there be detrimental effect to their effects in pharmaceutical composition.Therefore, the present invention is not intended to be limited to aforementioned system
Standby example describes, but determined by technical solution.
Claims (4)
1. a kind of compound is selected from following compounds:
2- ethyoxyl -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid [3- fluorophenyl -4- (6,7- dimethoxy
Quinoline -4- oxygroup)] amide；
2- amino -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid [3- fluorophenyl -4- (6,7- dimethoxy quinoline
Quinoline -4- oxygroup)] amide；
2- methylamino -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid [3- fluorophenyl -4- (6,7- dimethoxy
Quinoline -4- oxygroup)] amide；
2- ethylamino -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid [3- fluorophenyl -4- (6,7- dimethoxy
Quinoline -4- oxygroup)] amide；
2- [(3- morpholine propyl) amino] -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid [3- fluorophenyl -4-
(6,7- dimethoxy-quinoline -4- oxygroup)] amide；
2- [(3- (1 (1H)-imidazoles) propyl) amino] -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid [3- fluorine
Phenyl -4- (6,7- dimethoxy-quinoline -4- oxygroup)] amide；
2- [(3- (1- piperidines alkyl) propyl) amino] -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid [3- fluorine
Phenyl -4- (6,7- dimethoxy-quinoline -4- oxygroup)] amide；
2- amino -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid { 3- fluorophenyl -4- [6- methoxyl group -7- (3-
Morpholine propoxyl group) quinoline -4- oxygroup] amide；
2- [(3- (1- pyrrolidinyl) propyl) amino] -3- (4- fluorophenyl) -4- oxygroup -3,4- dihydro-pyrimidin -5- formic acid { 3- fluorine
Phenyl -4- [6- methoxyl group -7- (3- morpholine propoxyl group) quinoline -4- oxygroup] } amide.
2. compound described in claim 1, its pharmaceutically acceptable salt application in preparation of anti-tumor drugs.
3. a kind of pharmaceutical composition, comprising 1., and 2., 3., at least one of 4. substance；
1. described is compound described in claim 1, its pharmaceutically acceptable salt；
2. described is pharmaceutically acceptable carrier；
3. described is adjuvant；
4. described is medium.
4. claim 3 described pharmaceutical composition application in preparation of anti-tumor drugs.
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| US11623923B2 (en) | 2017-11-24 | 2023-04-11 | Medshine Discovery, Inc. | Uracil compound as c-MET/AXL inhibitor |
| KR20220011705A (en) * | 2019-05-24 | 2022-01-28 | 메드샤인 디스커버리 아이엔씨. | Crystalline form as c-MET/AXL inhibitor |
| WO2020238802A1 (en) * | 2019-05-24 | 2020-12-03 | 南京明德新药研发有限公司 | Crystal form of c-met/axl inhibitor |
| CN112625026B (en) * | 2019-09-24 | 2022-09-09 | 药捷安康(南京)科技股份有限公司 | Quinoline derivatives of TAM family kinase inhibitors |
| CN113372267A (en) * | 2020-03-10 | 2021-09-10 | 鲁南制药集团股份有限公司 | C-Met kinase inhibitor |
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| EP1827434B1 (en) * | 2004-11-30 | 2014-01-15 | Amgen Inc. | Quinolines and quinazoline analogs and their use as medicaments for treating cancer |
| AU2006265835B2 (en) * | 2005-06-30 | 2012-05-03 | Amgen Inc. | Bis-aryl kinase inhibitors and their use in the treatment of inflammation, angiogenesis and cancer |
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| CN103958497A (en) * | 2011-11-14 | 2014-07-30 | 赛福伦公司 | Uracil derivatives as AXL and c-MET kinase inhibitors |
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