CN109180642A - Phthalazines ketone BTK inhibitor and its application - Google Patents
Phthalazines ketone BTK inhibitor and its application Download PDFInfo
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- CN109180642A CN109180642A CN201811164076.2A CN201811164076A CN109180642A CN 109180642 A CN109180642 A CN 109180642A CN 201811164076 A CN201811164076 A CN 201811164076A CN 109180642 A CN109180642 A CN 109180642A
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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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- A61P35/00—Antineoplastic agents
Abstract
The invention belongs to medicinal chemistry arts, it is related to phthalazines ketone BTK inhibitor and its application, more particularly to phthalazines ketone BTK inhibitor, preparation method shown in formula (I), the pharmaceutical composition containing such compound and its purposes in treatment bruton's tyrosine kinase related disease
Description
Technical field
The invention belongs to medicinal chemistry arts, are related to phthalazines ketone BTK inhibitor and its application, and in particular to phthalazines ketone
BTK inhibitor, preparation method, the pharmaceutical composition containing such compound and its treatment bruton's tyrosine kinase
Purposes in related disease.
Background technique
Bu Ludun histidine kinase (Bruton's tyrosine kinase, BTK) belongs to the member of Tec family.It is by only
N- terminal domains, that is, PH (pleckstrin homology) structural domain, TH (Tec homology) homologous region, SH3 (Src of spy
Homology3) structural domain, SH2 (Src homology2) structural domain and catalyst structure domain, also referred to as SH1/TK (Src
Homologyl/Tyrosine kinase) structural domain or kinase domain form (Akinleye et al:Ibrutinib
and novel BTK inhibitors in clinical development.Journal of Hematology&
Oncology2013,6:59).In bone-marrow-derived lymphocyte development process, the correct expression of BTK gene difference protein domain is in B
There is key effect in the function of cell and a variety of transduction pathway.
It is B cell class tumour such as leukaemia, hair property myeloma based on BTK signal transduction pathway exploitation small molecule targeted drug
And the treatment of B cell para-immunity disease provides a completely new approach.The evidence of effect of the BTK in autoimmune disease is
(Kil LP, et al:Bruton's tyrosine is provided by BTK- deletion form mouse and BTK- abundance type mouse model experiment
kinase mediated signaling enhances leukemogenesis in a mouse model for
Chronic lymphocytic leukemia.Am J Blood Res2013,3 (1): 71-83.).It is white in chronic lymphocytic
In blood disease (CLL) mouse model, BTK- deletion form mouse abrogates chronic lymphocytic leukemia completely, and BTK overexpression can add
Fast leukaemia morbidity, increases the death rate.
The selectivity for being currently known BTK inhibitor is undesirable, in addition to inhibiting BTK, also inhibit other a variety of kinases (such as ETK,
EGF, BLK, FGR, HCK, YES, BRK and JAK3 etc.), to generate more side effect；Meanwhile BTK binding site occurs to dash forward
It frequently can lead to the generation of drug resistance after change.Therefore more BTK inhibitor are clinically needed, for treating the diseases such as tumour,
Such adverse events can be overcome simultaneously.
Summary of the invention
It is an object of the present invention to provide the phthalazines ketone BTK inhibitor of logical formula (I) or its pharmaceutically acceptable salt, different
Structure body, solvate, crystallization or prodrug,
It is a further object to provide the compound for preparing logical formula (I) of the invention or its is pharmaceutically acceptable
The method of salt, isomers, solvate, crystallization or prodrug.
It is also another object of the present invention to provide the compound comprising logical formula (I) of the invention or its is pharmaceutically acceptable
The composition of salt, isomers, solvate, crystallization or prodrug and pharmaceutically acceptable carrier.
The of the invention compound that logical formula (I) of the invention is provided or its pharmaceutically acceptable salt, different of a further object is
Structure body, solvate, crystallization or prodrug are in preparation for treating and/or preventing the application in tumour medicine.
For above-mentioned purpose, the present invention the following technical schemes are provided:
In a first aspect, the present invention provides compounds of formula I or its pharmaceutically acceptable salt, isomers, solvate, knot
Brilliant or prodrug,
Wherein:
R1Selected from hydrogen, halogen, nitro, alkyl；
R2Selected from halogen, hydroxyl, amino, carboxyl, cyano, nitro, alkoxy, halogenated alkyl, hydroxy alkyl, carboxyl alkane
Base, alkyl monosubstituted amino, double alkyl aminos, alkyl acyl, alkoxyacyl, alkyl acyl oxygroup.
In some preferred embodiments, the compound of the present invention is compounds of formula I and its pharmaceutically acceptable
Salt, isomers, solvate, crystallization or prodrug, in which: R1Selected from hydrogen, halogen, nitro, C1-6Alkyl；Preferably, R1Selected from hydrogen,
Fluorine, chlorine, nitro, C1-3Alkyl；It is further preferred that R1Selected from hydrogen, chlorine, nitro, methyl and ethyl.
In some preferred embodiments, the compound of the present invention is compounds of formula I and its pharmaceutically acceptable
Salt, isomers, solvate, crystallization or prodrug, in which: R2Selected from halogen, nitro, alkoxy；Preferably, R2Selected from halogen, nitre
Base, C1-3Alkoxy；It is further preferred that R2Selected from halogen, nitro, methoxyl group.
The present invention provides compounds in detail below:
Second aspect, the present invention provide the preparation method of general formula compound of the invention, the preparation side of compounds of formula I
Method includes the following steps:
Step A: the compound of formula (1) and the compound condensation of formula (2) obtain the compound of formula (3)；
Step B: the compound of formula (3) reacts to obtain the compound of formula (5) with the compound of formula (4)；
Step C: the compound of formula (5) sloughs protecting group and obtains the compound of formula (6)；
Step D: the compound of formula (6) and substituted alkene acyl chloride reaction obtain compounds of formula I, and reaction route is as follows:
In formula, R1And R2Definition such as general formula I；X indicates halogen, it is preferable that X indicates chlorine, bromine.
The third aspect, the present invention provide pharmaceutical composition, and it includes the compounds of the logical formula (I) of the present invention or its pharmacy to connect
Salt, isomers, solvate, crystallization or the prodrug received.
In some embodiments, the present invention provides the compound or its pharmaceutically acceptable salt, different of the logical formula (I) of the present invention
Structure body, solvate, crystallization or prodrug and compound comprising the logical formula (I) of the present invention or its pharmaceutically acceptable salt, isomers,
The pharmaceutical composition of solvate, crystallization or prodrug, the compound or pharmaceutical composition are for treating and/or preventing and cloth Shandong
The relevant disease of tyrosine kinase.
In some embodiments, the present invention provides pharmaceutical composition, it includes the compound of the logical formula (I) of the present invention or its
Pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, also comprising one or more selected from following composition: HDAC
Inhibitor, PD-1 inhibitor, EGFR inhibitor etc..
Can by the compound of the logical formula (I) of the present invention or its pharmaceutically acceptable salt, isomers, solvate, crystallization or
Prodrug and pharmaceutically acceptable carrier, diluent or excipient are prepared by mixing into pharmaceutical preparation, to be suitable for oral or stomach and intestine
External administration.Medication includes, but are not limited in intradermal, intramuscular, peritonaeum, intravenous, subcutaneous, intranasal and peroral route.It is described
Preparation can be applied by any approach, such as by being transfused or injecting, and pass through transepithelial or mucocutaneous (such as oral mucosa
Or rectum etc.) absorb approach application.Administration can be whole body or local.The example of oral administration preparation include solid or
Liquid dosage form, specifically, including tablet, pill, granula, pulvis, capsule, syrup, emulsion, suspension etc..The preparation
It can be prepared by methods known in the art, and include the conventional use of carrier of field of pharmaceutical preparations, diluent or excipient.
Fourth aspect, the present invention provide the compound or its pharmaceutically acceptable salt, isomers, molten of the logical formula (I) of the present invention
Agent is closed object, crystallization or prodrug or pharmaceutical composition of the invention in preparation prevention and/or is treated and bruton's tyrosine kinase phase
Application in the disease medicament of pass, it is logical that the tumor disease patient including over-expressing to bruton's tyrosine kinase applies the present invention
The compound of formula (I) or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug include general formula of the present invention
(I) pharmaceutical composition of compound or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, effectively to press down
Bruton's tyrosine kinase overexpression processed, prevents disease progression.
Specific embodiment
The preparation of embodiment 1 (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid neighbour's benzyl chloride ester
Weigh -2 (1H)-t-butyl formate (50mmol) of 5- amino -3,4- dihydro-isoquinoline and DIPEA (100mmol) in
In reaction flask, methylene chloride 300ml is added, is stirred at room temperature down and chloro-carbonic acid neighbour's benzyl chloride ester (51mmol) is slowly added dropwise, drop finishes, room temperature
Under continue stir 1h, stop reaction, concentrated reaction mixture, be added ethyl acetate 70ml, diluted hydrochloric acid aqueous solution (0.2-0.3N)
With saturated common salt water washing, anhydrous sodium sulfate is dried, filtered, and is concentrated to give title compound, is directly used in next step.
ESI–MS:[M+H]+m/z 417。
Embodiment 2 (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base) preparation of-carbamic acid to benzyl chloride ester
Triphosgene (5mmol) is weighed in reaction flask, toluene 100ml is added, is added dropwise at 0 DEG C and is dissolved with parachlorophenol
The tetrahydrofuran solution 20ml of (5mmol) and pyridine (10ml), drop finish, the reaction was continued at room temperature 8h, concentration of reaction solution, addition two
Chloromethanes 40ml is hanged and is done, and chloro-carbonic acid is made to benzyl chloride ester, is directly used in next step.
With -2 (1H)-t-butyl formate of 5- amino -3,4- dihydro-isoquinoline and chloro-carbonic acid to benzyl chloride ester for raw material, with implementation
Title compound is made in the method for example 1.
ESI–MS:[M+H]+m/z 417。
The preparation of 3 2H- phthalazines -1- ketone of embodiment
Step 1: dimethoxy-methyl benzene (500mmol) is weighed in reaction flask, and tetrahydrofuran (800ml) dissolution is added,
60 DEG C, under nitrogen protection, be added s-BuLi (565mmol), reaction solution stirred into 1h at -60 DEG C.
Step 2: dry ice (50mmol) is weighed in reaction flask, is added tetrahydrofuran (200ml), is added n-BuLi (5ml),
After stirred under nitrogen atmosphere 2h, the mixture of step 1 is added, continues to stir 30min, stops reaction, water 1000ml is added, use is dense
Salt acid for adjusting pH separates organic phase, water phase is extracted with ethyl acetate, and merges organic phase, saturated common salt water washing, anhydrous sulphur to 2
Sour sodium is dry, is recrystallized to give 2- dimethoxy-methyl benzoic acid.
Step 3: weighing step 2 gains (400mmol), acetic acid (93mmol), hydrazine (600mmol) in reaction flask, add
Entering isopropanol 300ml, under nitrogen protection, 100 DEG C of back flow reaction 2h stop reaction, ethyl acetate 300ml, water 500ml is added,
Extraction merges organic phase, and anhydrous sodium sulfate is dry, hangs and does, column chromatographic purifying obtains title compound.
ESI–MS:[M+H]+m/z 147。
The preparation of the fluoro- 2H- phthalazines -1- ketone of embodiment 48-
Using the fluoro- 1- dimethoxy-methyl benzene of 3- and hydrazine as raw material, title compound is made in the method with embodiment 3.
ESI–MS:[M+H]+m/z 165。
The preparation of embodiment 58- methoxyl group -2H- phthalazines -1- ketone
Using 3- methoxyl group -1- dimethoxy-methyl benzene and hydrazine as raw material, title compound is made in the method with embodiment 3.
ESI–MS:[M+H]+m/z 177。
The preparation of 6 8- nitro -2H- phthalazines -1- ketone of embodiment
Using 3- methoxyl group -1- dimethoxy-methyl benzene and hydrazine as raw material, title compound is made in the method with embodiment 3.
ESI–MS:[M+H]+m/z 192。
Embodiment 7 (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid -2- (2H)-phthalazines -1-
The preparation of ketone group benzyl ester
Weigh 2H- phthalazines -1- ketone (150mmol), (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-amino
Formic acid neighbour's benzyl chloride ester (195mmol) is added DMF100ml, is reacted overnight at 55 DEG C, stop reaction, water is added in reaction flask
100ml, methylene chloride 200ml, extraction separate organic phase, and water phase continues to be extracted with dichloromethane (3*50ml), merge organic
Phase, anhydrous sodium sulfate is dry, and column chromatographic purifying obtains title compound.
ESI–MS:[M+H]+m/z 527。
(3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid -2- of embodiment 8 [8- fluoro- (2H) -
Phthalazines -1- ketone group] benzyl ester preparation
With the fluoro- 2H- phthalazines -1- ketone of 8- and (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid
Adjacent benzyl chloride ester is raw material, and title compound is made in the method with embodiment 7.
ESI–MS:[M+H]+m/z 545。
Embodiment 9 (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid -2- [8- nitro -
(2H)-phthalazines -1- ketone group] benzyl ester preparation
With 8- nitro -2H- phthalazines -1- ketone and (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-amino first
Sour neighbour's benzyl chloride ester is raw material, and title compound is made in the method with embodiment 7.
ESI–MS:[M+H]+m/z 572。
Embodiment 10 (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid -2- [8- methoxyl group -
(2H)-phthalazines -1- ketone group] benzyl ester preparation
With 8- methoxyl group -2H- phthalazines -1- ketone and (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-amino
Formic acid neighbour's benzyl chloride ester is raw material, and title compound is made in the method with embodiment 7.
ESI–MS:[M+H]+m/z 557。
Embodiment 11 (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid -4- (2H)-phthalazines -
The preparation of 1- ketone group benzyl ester
With 2H- phthalazines -1- ketone and (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid to benzyl chloride
Ester is raw material, and title compound is made in the method with embodiment 7.
ESI–MS:[M+H]+m/z 527。
(3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid -4- of embodiment 12 [8- fluoro- (2H) -
Phthalazines -1- ketone group] benzyl ester preparation
With the fluoro- 2H- phthalazines -1- ketone of 8- and (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid
It is raw material to benzyl chloride ester, title compound is made in the method with embodiment 7.
ESI–MS:[M+H]+m/z 545。
Embodiment 13 (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid -4- [8- nitro -
(2H)-phthalazines -1- ketone group] benzyl ester preparation
With 8- nitro -2H- phthalazines -1- ketone and (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-amino first
Acid is raw material to benzyl chloride ester, and title compound is made in the method with embodiment 7.
ESI–MS:[M+H]+m/z 572。
Embodiment 14 (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid -4- [8- methoxyl group -
(2H)-phthalazines -1- ketone group] benzyl ester preparation
With 8- methoxyl group -2H- phthalazines -1- ketone and (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-amino
Formic acid is raw material to benzyl chloride ester, and title compound is made in the method with embodiment 7.
ESI–MS:[M+H]+m/z 557。
Embodiment 15 [2 (1H)-acryloyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -2- [(2H)-phthalazines -1-
Ketone group] benzyl ester preparation
Weigh (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid -2- (2H)-phthalazines -1- ketone
Base benzyl ester (50mmol) is added trifluoroacetic acid 20ml, stirs 1h at room temperature, be concentrated to dryness in reaction flask, and acetic acid is added
Ethyl ester 80ml is successively dried, filtered with 1.5M disodium hydrogen phosphate aqueous solution and saturated common salt water washing, anhydrous sodium sulfate, is depressurized
It is concentrated to give intermediate (1,2,3,4- tetrahydroisoquinoline -5- base) carbamic acid -2- (2H)-phthalazines -1- ketone group benzyl ester, is directly cast
One step.
Weigh intermediate (1,2,3,4- tetrahydroisoquinoline -5- base) carbamic acid -2- (2H)-phthalazines -1- ketone group benzyl ester
(20mmol) is added methylene chloride 100ml dissolution, DIEA (40mmol) is added at 0 DEG C in reaction flask, after stirring 30min, after
Continue dropwise addition acryloyl chloride (20mmol) at 0 DEG C, drop finishes, and 3h is stirred at room temperature, and stops reaction, adds water 100ml, methylene chloride extraction
(3*50ml) merges organic phase, and anhydrous sodium sulfate is dry, and column chromatographic purifying obtains title compound.
1H NMR(600MHz,CDCl3) (δ, ppm): 9.51 (s, 1H), 8.23~8.20 (m, 1H), 8.15 (s, 1H),
8.05~8.00 (m, 1H), 7.79~7.74 (m, 3H), 7.37~7.36 (m, 2H), 7.20~7.12 (m, 4H), 6.65~
6.63 (m, 1H), 5.98~5.95 (m, 1H), 5.37~5.34 (m, 1H), 5.12 (s, 2H), 4.25 (s, 2H), 3.64~3.60
(m, 2H), 3.14~3.11 (m, 2H)
ESI–MS:[M+H]+m/z 481。
Embodiment 16 [2 (1H)-acryloyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -2- [fluoro- (2H)-phthalein of 8-
Piperazine -1- ketone group] benzyl ester preparation
With (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid-[the fluoro- 2- of 8- (2H)-phthalazines -
1- ketone group] benzyl ester and acryloyl chloride be raw material, title compound is made in the method with embodiment 15.
1H NMR(600MHz,CDCl3) (δ, ppm): 9.50 (s, 1H), 8.15 (s, 1H), 7.88~7.85 (m, 1H),
7.78~7.74 (m, 2H), 7.67~7.65 (m, 1H), 7.36~7.34 (m, 2H), 7.25~7.23 (m, 2H), 7.14~
7.13 (m, 2H), 6.65~6.64 (m, 1H), 5.97~5.95 (m, 1H), 5.38~5.37 (m, 1H), 5.09 (s, 2H), 4.22
(s, 2H), 3.61~3.59 (m, 2H), 3.12~3.10 (m, 2H)
ESI–MS:[M+H]+m/z 499。
Embodiment 17 [2 (1H)-acryloyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -2- [8- nitro-(2H) -
Phthalazines -1- ketone group] benzyl ester preparation
With (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid-[8- nitro -2- (2H)-phthalein
Piperazine -1- ketone group] benzyl ester and acryloyl chloride be raw material, title compound is made in the method with embodiment 15.
1H NMR(600MHz,CDCl3) (δ, ppm): 9.49 (s, 1H), 8.41~8.40 (m, 1H), 8.19~8.18 (m,
2H), 8.06~8.05 (m, 1H), 7.76~7.75 (m, 1H), 7.36~7.34 (m, 2H), 7.21~7.18 (m, 2H), 7.13
~7.11 (m, 2H), 6.66~6.64 (m, 1H), 5.96~5.94 (m, 1H), 5.34~5.33 (m, 1H), 5.09 (s, 2H),
4.22 (s, 2H), 3.61~3.59 (m, 2H), 3.12~3.10 (m, 2H)
ESI–MS:[M+H]+m/z 526。
Embodiment 18 [2 (1H)-acryloyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -2- [8- methoxyl group -
(2H)-phthalazines -1- ketone group] benzyl ester preparation
With (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid-[8- methoxyl group -2- (2H)-phthalein
Piperazine -1- ketone group] benzyl ester and acryloyl chloride be raw material, title compound is made in the method with embodiment 15.
1H NMR(600MHz,CDCl3) (δ, ppm): 9.50 (s, 1H), 8.10 (s, 1H), 7.79~7.77 (m, 1H),
7.66~7.65 (m, 2H), 7.47~7.45 (m, 1H), 7.37~7.35 (m, 2H), 7.21~7.18 (m, 4H), 6.62~
6.60 (m, 1H), 5.96~5.94 (m, 1H), 5.34~5.33 (m, 1H), 5.10 (s, 2H), 4.23 (s, 2H), 3.84 (s,
3H), 3.61~3.59 (m, 2H), 3.12~3.10 (m, 2H)
ESI–MS:[M+H]+m/z 411。
Embodiment 19 [2 (1H)-acryloyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [(2H)-phthalazines -1-
Ketone group] benzyl ester preparation
With (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid -4- [(2H)-phthalazines -1- ketone
Base] benzyl ester and acryloyl chloride be raw material, title compound is made in the method with embodiment 15.
1H NMR(600MHz,CDCl3) (δ, ppm): 9.50 (s, 1H), 8.18~8.16 (m, 1H), 8.10 (s, 1H),
8.01~7.99 (m, 1H), 7.77~7.70 (m, 2H), 7.54~7.53 (m, 2H), 7.34~7.33 (m, 2H), 7.21~
7.18 (m, 2H), 7.15~7.13 (m, 1H), 6.62~6.60 (m, 1H), 5.96~5.94 (m, 1H), 5.36~5.34 (m,
1H), 4.65 (s, 2H), 4.22 (s, 2H), 3.61~3.59 (m, 2H), 3.13~3.11 (m, 2H) .ESI-MS:[M+H]+m/z
481。
[8- is fluoro- by carbamic acid -4- for embodiment 20 [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base] -
(2H)-phthalazines -1- ketone group] benzyl ester preparation
With (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid -4- [fluoro- (the 2H)-phthalazines-of 8-
1- ketone group] benzyl ester and but-2-ene acyl chlorides be raw material, title compound is made in the method with embodiment 15.
1H NMR(600MHz,CDCl3) (δ, ppm): 9.50 (s, 1H), 8.10 (s, 1H), 7.88~7.85 (m, 1H),
7.77~7.75 (m, 1H), 7.54~7.52 (m, 3H), 7.34~7.32 (m, 2H), 7.21~7.18 (m, 3H), 6.57~
6.55 (m, 1H), 6.41~6.39 (m, 1H), 4.65 (s, 2H), 4.22 (s, 2H), 3.61~3.59 (m, 2H), 3.13~3.11
(m, 2H), 2.05~2.03 (m, 3H)
ESI–MS:[M+H]+m/z 513。
Embodiment 21 [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [8- nitro -
(2H)-phthalazines -1- ketone group] benzyl ester preparation
With (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid -4- [8- nitro-(2H)-phthalein
Piperazine -1- ketone group] benzyl ester and but-2-ene acyl chlorides be raw material, title compound is made in the method with embodiment 15.
1H NMR(600MHz,CDCl3) (δ, ppm): 9.50 (s, 1H), 8.40~8.39 (m, 1H), 8.16~8.15 (m,
1H), 8.10 (s, 1H), 8.03~8.01 (m, 1H), 7.54~7.53 (m, 2H), 7.34~7.33 (m, 2H), 7.21~7.18
(m, 3H), 6.57~6.55 (m, 1H), 6.40~6.38 (m, 1H), 4.65 (s, 2H), 4.22 (s, 2H), 3.61~3.59 (m,
2H), 3.13~3.11 (m, 2H), 2.05~2.03 (m, 3H)
ESI–MS:[M+H]+m/z 540。
Embodiment 22 [2 (1H)-amyl- 2- enoyl- -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [8- nitro -
(2H)-phthalazines -1- ketone group] benzyl ester preparation
With (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base)-carbamic acid -4- [8- nitro-(2H)-phthalein
Piperazine -1- ketone group] benzyl ester and amyl- 2- alkene acyl chlorides be raw material, title compound is made in the method with embodiment 15.
1H NMR(600MHz,CDCl3) (δ, ppm): 9.50 (s, 1H), 8.10 (s, 1H), 7.56~7.54 (m, 4H),
7.44~7.43 (m, 1H), 7.34~7.32 (m, 2H), 7.21~7.18 (m, 2H), 7.17~7.15 (m, 1H), 6.57~
6.55 (m, 1H), 6.43~6.41 (m, 1H), 4.65 (s, 2H), 4.22 (s, 2H), 3.61~3.59 (m, 2H), 3.13~3.11
(m, 2H), 2.01~1.99 (m, 2H), 1.05~1.03 (m, 3H)
ESI–MS:[M+H]+m/z 539。
The evaluation of 1 the compound of the present invention vitro kinase activity of experimental example
The compound of the present invention of above embodiments preparation successively dilutes after each compound is diluted to 10mM with DMSO
To 1uM, 100nM, 10nM, 1nM, 0.1nM, 0.01nM.
Take the 10 μ l of compound solution of each concentration into 96 orifice plates, addition 90 μ l1 × kinase buffer liquid (50mMHEPES,
PH7.5,0.0015%Brij-35,10mMMgCl2,2mM DTT, prepared before use)；Set up DMSO control group and without enzyme simultaneously
Control group living, contains only 10 μ lDMSO and 90 μ l1 × kinase buffer liquid.Each group mixes 10min at room temperature, then shifts respectively
5 μ l are into 384 orifice plates；Kinase b TK is dissolved in 1 × kinase buffer liquid, is configured to 2.5 × kinase solution, then shifts 10 μ l2.5
× kinase solution is into above-mentioned 384 orifice plates containing each concentration compound；10 μ l2.5 × kinase solution is added in DMSO control group；Nothing
1 × kinase buffer liquid that 10 μ l are free of kinases is added in enzyme activity control group.It is incubated for 10min at room temperature；By FAM label polypeptide and
ATP is dissolved in 1 × kinase buffer liquid, is configured to 2.5 × substrate solution, then shifts 10 μ l2.5 × substrate solution to above-mentioned 384 hole
In plate, 28 DEG C of incubation 1hr；25 μ l (100mMHEPES, pH7.5,0.015%Brij-35,0.2% are added in each hole
CoatingReagent#3,50mMEDTA prepared before use), terminate liquid terminates reaction；It is placed on LabChipEZReader and reads
Conversion data, and inhibiting rate I% is calculated, calculation formula is I%=(Max-Conversion)/(Max-Min) × 100,
Middle Max is the conversion ratio of DMSO control group, and Min is the conversion ratio of no enzyme activity control group, and Conversion is compound processing group
Conversion ratio, data handle through XLfit, are fitted to obtain IC50。IC50Value indicates that compound presses down with not plus compared with compound processing group
Make corresponding compound concentration when 50% enzyme activity.IC50 the results are shown in Table 1.
Table 1
| Test-compound | IC50(nM) | Test-compound | IC50(nM) |
| Embodiment 15 | 10.2 | Embodiment 16 | 8.3 |
| Embodiment 17 | 15.0 | Embodiment 18 | 7.8 |
| Embodiment 19 | 1.2 | Embodiment 20 | 1.0 |
| Embodiment 21 | 4.2 | Embodiment 22 | 1.5 |
The external Romas cell activity evaluation of 2 the compound of the present invention of experimental example
It takes in exponential phase of growth in good condition one bottle of Raji cell, collects cell, low speed desk centrifuge, 1500
Turn/min, is centrifuged 3min.Supernatant is abandoned, 5mL complete medium is added with pipettor and carries out cell resuspension.Use cell count instrument meter
Number, complete medium are diluted, adjustment cell density to 5 × 104A/mL.It is inoculated on 96 orifice plates using the volley of rifle fire, 100 μ L/
Constant temperature CO is set in hole2It is cultivated 24 hours in incubator.Compound sample-adding, which is carried out, using nanoliter sample adding instrument adds CCK-8 after 72 hours,
Its light absorption value is detected in 10 holes μ L/ at Envision microplate reader 450nm after 2 hours, calculate inhibiting rate, and calculate IC50, as a result see
Table 2.
Table 2
Claims (7)
1. compounds of formula I or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug,
Wherein:
R1Selected from hydrogen, halogen, nitro, alkyl；
R2Selected from halogen, hydroxyl, amino, carboxyl, cyano, nitro, alkoxy, halogenated alkyl, hydroxy alkyl, carboxyalkyl, single alkane
Base amino, double alkyl aminos, alkyl acyl, alkoxyacyl, alkyl acyl oxygroup.
2. compound as described in claim 1 or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug,
It is characterized in that: R1Selected from hydrogen, halogen, nitro, C1-6Alkyl；Preferably, R1Selected from hydrogen, fluorine, chlorine, nitro, C1-3Alkyl；Further
Preferably, R1Selected from hydrogen, chlorine, nitro, methyl and ethyl.
3. compound as described in claim 1 or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug,
It is characterized in that: R2Selected from halogen, nitro, alkoxy；Preferably, R2Selected from halogen, nitro, C1-3Alkoxy；It is further preferred that
R2Selected from halogen, nitro, methoxyl group.
4. compound as described in claim 1 or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, tool
Body compound is as follows:
5. compound described in claim 1-4 or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug
Preparation method includes the following steps:
Step A: the compound of formula (1) and the compound condensation of formula (2) obtain the compound of formula (3)；
Step B: the compound of formula (3) reacts to obtain the compound of formula (5) with the compound of formula (4)；
Step C: the compound of formula (5) sloughs protecting group and obtains the compound of formula (6)；
Step D: the compound of formula (6) and substituted alkene acyl chloride reaction obtain compounds of formula I, and reaction route is as follows:
In formula, R1And R2Definition such as general formula I；X indicates halogen, it is preferable that X indicates chlorine, bromine.
6. including compound or its pharmaceutically acceptable salt, isomers, solvate, crystallization or preceding described in claim 1-4
The pharmaceutical composition of medicine.
7. compound described in claim 1-4 or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug or
The pharmaceutical composition of claim 6 is in preparation prevention and/or treatment disease medicament relevant to bruton's tyrosine kinase
Using.
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