CN105461720B - Morpholine class tyrosine kinase inhibitor - Google Patents
Morpholine class tyrosine kinase inhibitor Download PDFInfo
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- CN105461720B CN105461720B CN201410389941.9A CN201410389941A CN105461720B CN 105461720 B CN105461720 B CN 105461720B CN 201410389941 A CN201410389941 A CN 201410389941A CN 105461720 B CN105461720 B CN 105461720B
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Abstract
The invention belongs to medicinal chemistry arts, it is related to a kind of morpholine class tyrosine kinase inhibitor, more particularly to a kind of compound or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug with Bruton ' s tyrosine kinase (BTK) inhibitory activity, and the pharmaceutical composition containing these compounds and application of these compound or compositions in medicine preparation, compound provided by the invention show the BTK inhibitory activity better than Ibrutinib.
Description
Technical field
The invention belongs to chemical medicines, and in particular to one kind has Bruton ' s tyrosine kinase (BTK)
The compound of inhibitory activity or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug, and contain these changes
Close the pharmaceutical composition and application of these compound or compositions in medicine preparation of object.
Background of invention
The signal path that B-cell receptor (BCR) mediates has the existence of a variety of lymthomas including CLL important
Effect, and Bruton ' s tyrosine kinase (BTK) is one of the key enzyme in BCR approach.BTK belongs to non-receptor junket ammonia
Acid kinase Tec family, other than T lymphocyte and natural killer cells, in bone-marrow-derived lymphocyte, basophilic granulocyte, monocyte
There is expression in equal myeloid cells, participates in many A signal pathways in organism, all have for the proliferation of cell, differentiation and apoptosis
Highly important effect.
BTK takes part in the signal path of B cell mediation, by the way that the site Tyr551 occurs under the effect of Src family molecule
After Tyr223 site phosphorylation, activate phospholipase C (PLC- γ), and then the diphosphonic acid phosphatidylinositols on activated cell film
(PIP2) hydrolysis generation second messenger's InsP3 (IP3) and diacylglycerol (DAG), activate downstream signaling pathway.Study table
Bright BTK also takes part in the signal path of Toll-like receptor mediation, mast cell degranulation, and Fas, g protein coupled receptor mediate
Signal path etc..In addition, having had been reported that BTK plays a role in Apoptosis.Therefore, BTK inhibitor is developed, for lymph
Tumor, leukaemia will be all very effective.
Summary of the invention
It is an object of the present invention to provide the pyrazoles that there is one kind of general formula I the 1- morpholinyl of BTK inhibitory activity to replace
And [3,4-d] pyrimidines or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug,
Wherein,
X is selected from key, CH2、O、S、S(O)2,NH,-NH-C(O)-,-C(O)-NH-；
Y is selected from hydrogen, halogen, alkyl, halogenated alkyl；
R1Selected from aryl, C1-6Alkylaryl, heteroaryl, C1-6Miscellaneous alkyl aryl, C2-4Alkynyl, the aryl, heteroaryl
Or alkynyl can be by one or more halogens, hydroxyl, carboxyl, amino, alkyl, alkoxy, alkoxyalkyl, alkoxy alcoxyl
Base, acylamino-, alkyl acylamino, aminoacyl, alkyl monosubstituted amino acyl group, double alkylaminoacyls, acyl group, alkyl acyl,
Hydroxyalkyl, alkyl monosubstituted amino, double alkyl aminos, Mono-alkylaminoalkyl, double alkylaminoalkyl groups, nitro, cyano replace；
R2Selected from aryl, heteroaryl, the aryl, heteroaryl can be by one or more halogens, hydroxyl, carboxyl, ammonia
Base, alkyl, alkoxy, alkoxyalkyl, alkyloxy-alkoxy, acylamino-, alkyl acylamino, aminoacyl, monoalkyl ammonia
Base acyl group, double alkylaminoacyls, acyl group, alkyl acyl, hydroxyalkyl, alkyl monosubstituted amino, double alkyl aminos, alkyl monosubstituted amino alkane
Base, double alkylaminoalkyl groups, nitro, cyano replace；
R3Selected from-C (O)-R4、-S(O)2-R4, wherein R4Selected from C2-4Alkenyl, C2-4Alkynyl, the alkenyl or alkynyl can be with
By one or more cyano, alkyl, naphthenic base, halogenated alkyl, halogenated cycloalkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkane
Oxyalkyl, amino, alkyl monosubstituted amino, double alkyl aminos, cycloalkyl amino, aminoalkyl, Mono-alkylaminoalkyl, double alkyl ammonia
Base alkyl, cycloalkyl amino alkyl, saturated heterocyclyl, saturated heterocyclyl alkyl, heteroaryl, heteroaryl alkyl replace.
It is a further object to provide prepare compounds of formula I or its pharmaceutically acceptable salt of the invention,
The method of isomers, solvate, crystallization or prodrug.
It is also another object of the present invention to provide comprising compounds of formula I of the invention or its pharmaceutically acceptable salt,
The composition of isomers, solvate, crystallization or prodrug and pharmaceutically acceptable carrier, and include general formula I's of the invention
Compound or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug and one or more BTK inhibitor
Composition.
Of the invention a further object is provides compounds of formula I or its pharmaceutically acceptable salt, isomery of the invention
Body, solvate, crystallization or prodrug treatment and/or the prevention extremely caused disease of BTK, such as B cell lymphoma, leukaemia
Deng and compounds of formula I of the invention or its pharmaceutically acceptable salt, isomers, solvate, crystallization or prodrug making
The application being ready for use in the drug for the treatment of and/or the prevention extremely caused disease of BTK.
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,
X is selected from key, CH2、O、S、S(O)2,NH,-NH-C(O)-,-C(O)-NH-；
Y is selected from hydrogen, halogen, alkyl, halogenated alkyl；
R1Selected from aryl, C1-6Alkylaryl, heteroaryl, C1-6Miscellaneous alkyl aryl, C2-4Alkynyl, the aryl, heteroaryl
Or alkynyl can be by one or more halogens, hydroxyl, carboxyl, amino, alkyl, alkoxy, alkoxyalkyl, alkoxy alcoxyl
Base, acylamino-, alkyl acylamino, aminoacyl, alkyl monosubstituted amino acyl group, double alkylaminoacyls, acyl group, alkyl acyl,
Hydroxyalkyl, alkyl monosubstituted amino, double alkyl aminos, Mono-alkylaminoalkyl, double alkylaminoalkyl groups, nitro, cyano replace；
R2Selected from aryl, heteroaryl, the aryl, heteroaryl can be by one or more halogens, hydroxyl, carboxyl, ammonia
Base, alkyl, alkoxy, alkoxyalkyl, alkyloxy-alkoxy, acylamino-, alkyl acylamino, aminoacyl, monoalkyl ammonia
Base acyl group, double alkylaminoacyls, acyl group, alkyl acyl, hydroxyalkyl, alkyl monosubstituted amino, double alkyl aminos, alkyl monosubstituted amino alkane
Base, double alkylaminoalkyl groups, nitro, cyano replace；
R3Selected from-C (O)-R4、-S(O)2-R4, wherein R4Selected from C2-4Alkenyl, C2-4Alkynyl, the alkenyl or alkynyl can be with
By one or more cyano, alkyl, naphthenic base, halogenated alkyl, halogenated cycloalkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, alkane
Oxyalkyl, amino, alkyl monosubstituted amino, double alkyl aminos, cycloalkyl amino, aminoalkyl, Mono-alkylaminoalkyl, double alkyl ammonia
Base alkyl, cycloalkyl amino alkyl, saturated heterocyclyl, saturated heterocyclyl alkyl, heteroaryl, heteroaryl alkyl replace.
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:
X is selected from key, CH2,O,S；
It is further preferred that
X is selected from key, O.
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:
Y is selected from hydrogen, fluorine, chlorine, C1-6Alkyl；
It is further preferred that
Y is selected from hydrogen, fluorine, methyl, 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:
R1Selected from aryl, C1-3Alkylaryl, heteroaryl, C1-3Miscellaneous alkyl aryl, C2-4Alkynyl, the aryl, heteroaryl
Or alkynyl can be by one or more halogens, hydroxyl, carboxyl, amino, C1-6Alkyl, C1-6Alkoxy, C1-6Alkoxy -C1-6Alkane
Base, C1-6Alkoxy -C1-6Alkoxy, acylamino-, C1-6Alkyl acylamino, aminoacyl, list C1-6It is alkylaminoacyl, double
C1-6Alkylaminoacyl, acyl group, C1-6Alkyl acyl, hydroxyl C1-6Alkyl, list C1-6Alkyl amino, double C1-6Alkyl amino, list C1-6
Alkyl amino-C1-6Alkyl, double C1-6Alkyl amino-C1-6Alkyl, nitro, cyano replace；
It is further preferred that
R1Selected from phenyl, naphthalene, pyridyl group, oxazolyl, isoxazolyl, oxadiazoles base, thiazolyl, isothiazolyl, thiophene two
Oxazolyl, furyl, thienyl, indyl, isoindolyl, quinolyl, isoquinolyl, C1-3Alkyl phenyl, C1-3Alkyl naphthalene,
C1-3Alkylpyridyl, C1-3Alkylated oxazoline base, C1-3Alkyl isoxazolyl, C1-3Alkyl oxadiazoles base, C1-3Alkyl thiazolyl, C1-3
Alkyl isothiazole base, C1-3Alkyl thiadiazoles base, C1-3Alkyl furan base, C1-3Alkylthrophene base, C1-3Alkyl-indol base, C1-3Alkane
Base isoindolyl, C1-3Alkyl quinoline base, C1-3Alkylisoquinolinium base, acetenyl, the phenyl, naphthalene, pyridyl group, oxazole
Base, isoxazolyl, oxadiazoles base, thiazolyl, isothiazolyl, thiadiazolyl group, furyl, thienyl, indyl, isoindolyl,
Quinolyl, isoquinolyl or alkynyl can be by one or more halogens, hydroxyl, carboxyl, amino, C1-6Alkyl, C1-6Alkoxy,
C1-6Alkoxy -C1-6Alkyl, C1-6Alkoxy -C1-6Alkoxy, acylamino-, C1-6Alkyl acylamino, aminoacyl, list C1-6Alkane
Base aminoacyl, double C1-6Alkylaminoacyl, acyl group, C1-6Alkyl acyl, hydroxyl-C1-6Alkyl, list C1-6Alkyl amino, double C1-6
Alkyl amino, list C1-6Alkyl amino-C1-6Alkyl, double C1-6Alkyl amino-C1-6Alkyl, nitro, cyano replace；
It is further preferred that
R1Selected from phenyl, naphthalene, pyridyl group, oxazolyl, isoxazolyl, oxadiazoles base, thiazolyl, isothiazolyl, thiophene two
Oxazolyl, furyl, thienyl, indyl, isoindolyl, quinolyl, isoquinolyl, acetenyl, the phenyl, naphthalene, pyrrole
Piperidinyl, oxazolyl, isoxazolyl, oxadiazoles base, thiazolyl, isothiazolyl, thiadiazolyl group, furyl, thienyl, indyl,
Isoindolyl, quinolyl, isoquinolyl or alkynyl can be by one or more halogens, hydroxyl, carboxyl, amino, C1-3Alkyl, C1-3
Alkoxy, C1-3Alkoxy -C1-3Alkyl, C1-3Alkoxy -C1-3Alkoxy, acylamino-, C1-3Alkyl acylamino, aminoacyl,
Single C1-3Alkylaminoacyl, double C1-3Alkylaminoacyl, acyl group, C1-3Alkyl acyl, hydroxyl-C1-3Alkyl, list C1-3Alkyl ammonia
Base, double C1-3Alkyl amino, list C1-3Alkyl amino-C1-3Alkyl, double C1-3Alkyl amino-C1-3Alkyl, nitro, cyano replace.
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 aryl, heteroaryl, the aryl, heteroaryl can be by one or more halogens, hydroxyl, carboxyl, ammonia
Base, C1-6Alkyl, C1-6Alkoxy, C1-6Alkoxy -C1-6Alkyl, C1-6Alkoxy -C1-6Alkoxy, acylamino-, C1-6Alkyl acyl
Amino, aminoacyl, list C1-6Alkylaminoacyl, double C1-6Alkylaminoacyl, acyl group, C1-6Alkyl acyl, hydroxyl C1-6Alkyl,
Single C1-6Alkyl amino, double C1-6Alkyl amino, list C1-6Alkyl amino-C1-6Alkyl, double C1-6Alkyl amino-C1-6Alkyl, nitro,
Cyano replaces；
It is further preferred that
R2Selected from phenyl, naphthalene, pyridyl group, oxazolyl, isoxazolyl, oxadiazoles base, thiazolyl, isothiazolyl, thiophene two
Oxazolyl, furyl, thienyl, indyl, isoindolyl, quinolyl, isoquinolyl, the phenyl, naphthalene, pyridyl group, evil
Oxazolyl, isoxazolyl, oxadiazoles base, thiazolyl, isothiazolyl, thiadiazolyl group, furyl, thienyl, indyl, iso-indoles
Base, quinolyl, isoquinolyl can be by one or more halogens, hydroxyl, carboxyl, amino, C1-3Alkyl, C1-3Alkoxy, C1-3Alkane
Oxygroup-C1-3Alkyl, C1-3Alkoxy -C1-3Alkoxy, acylamino-, C1-3Alkyl acylamino, aminoacyl, list C1-3Alkyl ammonia
Base acyl group, double C1-3Alkylaminoacyl, acyl group, C1-3Alkyl acyl, hydroxyl C1-3Alkyl, list C1-3Alkyl amino, double C1-3Alkyl ammonia
Base, list C1-3Alkyl amino-C1-3Alkyl, double C1-3Alkyl amino-C1-3Alkyl, nitro, cyano replace.
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:
R3Selected from-C (O)-R4、-S(O)2-R4, wherein R4Selected from C2-4Alkenyl, C2-4Alkynyl, the alkenyl or alkynyl can
By one or more cyano, C1-6Alkyl, C3-8Naphthenic base, halogenated-C1-6Alkyl, halogenated C3-8Naphthenic base, hydroxyl-C1-6Alkyl,
C1-6Alkoxy, halogenated-C1-6Alkoxy, C1-6Alkoxy -C1-6Alkyl, amino, list C1-6Alkyl amino, double C1-6Alkyl amino,
C3-8Cycloalkyl amino, amino-C1-6Alkyl, list C1-6Alkyl amino-C1-6Alkyl, double C1-6Alkyl amino-C1-6Alkyl, C3-8Ring
Alkyl amino-C1-6Alkyl, saturation C4-8Heterocycle, saturation C4-8Heterocycle-C1-6Alkyl, heteroaryl, heteroaryl-C1-6Alkyl takes
Generation；
It is further preferred that
R3Selected from-C (O)-R4、-S(O)2-R4, wherein R4Selected from C2-4Alkenyl, C2-4Alkynyl, the alkenyl or alkynyl can
By one or more cyano, C1-3Alkyl, C3-6Naphthenic base, halogenated-C1-3Alkyl, halogenated C3-6Naphthenic base, hydroxyl-C1-3Alkyl,
C1-3Alkoxy, halogenated-C1-3Alkoxy, C1-3Alkoxy -C1-3Alkyl, amino, list C1-3Alkyl amino, double C1-3Alkyl amino,
C3-6Cycloalkyl amino, amino-C1-3Alkyl, list C1-3Alkyl amino-C1-3Alkyl, double C1-3Alkyl amino-C1-3Alkyl, C3-6Ring
Alkyl amino-C1-3Alkyl, saturation C4-8Heterocycle, saturation C4-8Heterocycle-C1-3Alkyl, heteroaryl, heteroaryl-C1-3Alkyl takes
Generation.
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:
X is selected from key, CH2,O,S；
Y is selected from hydrogen, fluorine, C1-3Alkyl；
R1Selected from phenyl, naphthalene, pyridyl group, acetenyl, the phenyl, naphthalene, pyridyl group, acetenyl can be by one
Or multiple halogens, hydroxyl, amino, C1-6Alkyl, C1-6Alkoxy, hydroxyl-C1-6Alkyl, nitro, cyano replace；
R2Selected from phenyl, naphthalene, pyridyl group, the phenyl, naphthalene, pyridyl group can be by one or more halogens, hydroxyl
Base, C1-6Alkyl, C1-6Alkoxy, hydroxyl-C1-6Alkyl, nitro, cyano replace；
R3Selected from-C (O)-R4、-S(O)2-R4, wherein R4Selected from vinyl, acetenyl, the vinyl, acetenyl can
By one or more cyano, C1-6Alkyl, C3-8Naphthenic base, halogenated-C1-6Alkyl, halogenated C3-8Naphthenic base, hydroxyl-C1-6Alkyl,
C1-6Alkoxy, halogenated-C1-6Alkoxy, C1-6Alkoxy -C1-6Alkyl, amino, list C1-6Alkyl amino, double C1-6Alkyl amino,
C3-6Cycloalkyl amino, amino-C1-6Alkyl, list C1-6Alkyl amino C1-6Alkyl, double C1-6Alkyl amino-C1-6Alkyl, C3-6Cycloalkanes
Base amino-C1-6Alkyl, saturation C3-8Heterocycle, saturation C3-8Heterocycle-C1-6Alkyl, heteroaryl, heteroaryl-C1-6Alkyl replaces.
The present invention provides compounds in detail below:
On the other hand, the present invention provides the preparation method of general formula compound of the invention, the preparation side of compounds of formula I
Method includes the following steps:
A) compound of formula (1) reacts to obtain the compound of formula (3) with the compound of formula (2)；
B) compound of formula (3) and the compound condensation of formula (4) obtain the compound of formula (5)；
C) compound of formula (5) sloughs protecting group and obtains the compound of formula (6)；
D) compound of formula (6) obtains the general formula compound of formula (I) by condensation reaction.
Wherein, X, Y, R1、R2、R3With the definition in general formula, Pro indicates amino protecting group, is preferably selected from tertiary butyloxycarbonyl
Base, benzyl, benzyloxycarbonyl group, p-toluenesulfonyl, trifluoroacetyl group, M indicate halogen, are preferably selected from bromine, iodine.
The third aspect, the present invention provide pharmaceutical composition, it includes the compound of the present invention or its pharmaceutically acceptable salt,
Isomers, solvate, crystallization or prodrug.
In some embodiments, the present invention provides pharmaceutical composition, and it includes the compound of the present invention, isomers, molten
Object, crystallization or prodrug are closed in agent, also comprising one or more selected from following composition: Ibrutinib, Abexinostat, PCI-
27483, Motexafin, gadolinium, CC-292 etc..
Can by the compound of the present invention, 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 parenteral.Medication includes, but unlimited
In in intradermal, intramuscular, peritonaeum, intravenous, subcutaneous, intranasal and peroral route.The preparation can be applied by any approach, example
Such as by being transfused or injecting, the approach for passing through transepithelial or mucocutaneous (such as oral mucosa or rectum etc.) absorption is applied.It gives
Medicine can be whole body or local.The example of oral administration preparation includes solid or liquid dosage form, specifically, including piece
Agent, pill, granula, pulvis, capsule, syrup, emulsion, suspension etc..The preparation can be by methods known in the art system
It is standby, and include the conventional use of carrier of field of pharmaceutical preparations, diluent or excipient.
Fourth aspect, the present invention provide the compound of the present invention, isomers, solvate, crystallization or prodrug or the present invention
Medicine composite for curing or prevention by the extremely caused disease of BTK method and preparation prevent or treatment BTK cause extremely
Disease medicament in application, including apply the compound of the present invention, isomers, solvent to leukaemic, Lymphoma
Object, crystallization or prodrug or the pharmaceutical composition comprising the compound of the present invention, isomers, solvate, crystallization or prodrug are closed,
With the signal path for effectively inhibiting BTK to excite extremely, disease progression is prevented.
Term explanation
" alkyl " of the invention refers to linear or branched saturated hydrocarbon base.
" naphthenic base " of the invention refers to cricoid saturated hydrocarbyl.
" alkoxy " of the invention refers to-O- alkyl.
" halogen " of the invention refers to fluorine, chlorine, bromine, iodine.
" halogenated alkyl " of the invention refers to the alkyl at least replaced by a halogen.
" halogenated alkoxy " of the invention refers to the alkoxy at least replaced by a halogen.
" aryl " of the invention, which refers to, may include monocycle or the multi-fused rings such as aromatic series of two rings or the aromatic rings of tricyclic,
A part of wherein at least condensed ring forms the aromatic series of conjugation, contains 5 to 50 carbon atoms, and preferably from about 6 to about 14
Carbon atom.Suitable aryl includes but is not limited to phenyl, naphthalene, xenyl, anthryl, tetralyl, fluorenyl, indanyl, sub- connection
Phenyl and acenaphthenyl.
" heteroaryl " of the invention refers at least one carbon atom quilt of aromatic monocyclic or multi-fused rings such as two rings or tricyclic
The aromatic radical of hetero atom substitution, the hetero atom are O, S, N.Suitable heteroaryl includes but is not limited to imidazole radicals, benzene
And imidazole radicals, imidazopyridyl, quinazoline ketone group, pyrrole radicals, imidazoles ketone group, furyl, thienyl, pyrazolyl, oxazolyl,
Thiazolyl, isoxazolyl, isothiazolyl, oxadiazoles base, triazolyl, pyridyl group etc..
" solvate " of the invention refer in a conventional sense solute (such as salt of reactive compound, reactive compound) and
The compound that solvent (such as water) combination is formed.Solvent refers to the solvent of known to those of skill in the art or easy determination.Such as
Fruit is water, then solvate is commonly referred to as hydrate, such as monohydrate, dihydrate, trihydrate etc..
" crystallization " of the invention refers to that the various solid forms that compound of the present invention is formed, including crystal form, nothing are determined
Shape.
" isomers " of the invention refers in molecule atom spatially stereoisomer caused by arrangement mode difference,
Including enantiomter and diastereoisomer.
" prodrug " of the invention refer under the physiological condition of organism, due to reacting and conversion cost with enzyme, gastric acid etc.
The compound of invention is converted to the compound of the present invention by the oxidation of enzyme, reduction, hydrolysis etc. and/or by gastric acid etc.
Hydrolysis etc. is converted to the compound of the present invention.
" pharmaceutically acceptable salt " of the invention refers to the compound of the present invention and the pharmaceutically acceptable salt that acid is formed,
The acid include but is not limited to phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid,
Fumaric acid, acetic acid, lactic acid, nitric acid etc..
" pharmaceutical composition " of the invention refer to comprising any compound as described herein, including isomers, prodrug,
Solvate, the protection form of pharmaceutically acceptable salt or its chemistry and one or more pharmaceutically acceptable carriers it is mixed
Close object.
" pharmaceutically acceptable carrier " of the invention refer to obvious irritation is not caused to organism and do not interfere to
Give the bioactivity of compound and the carrier of property, comprising solvent, diluent or other excipient, dispersing agent, surfactant,
Isotonic agent, thickener or emulsifier, preservative, solid binder, lubricant etc..Unless any conventional carrier medium and the present invention
Compound is incompatible.The some examples that can be used as pharmaceutically acceptable carrier include, but are not limited to carbohydrate, such as lactose, Portugal
Grape sugar and sucrose；Starch, such as cornstarch and potato starch；Cellulose and its derivates, such as sodium carboxymethylcellulose and
Cellulose and cellulose acetate；Malt, gelatin etc..
" excipient " of the invention, which refers to, to be added in Pharmaceutical composition with the further inert substance for promoting to give compound.
Excipient may include calcium carbonate, calcium phosphate, various saccharides and a plurality of types of starch, cellulose derivative, gelatin, plant
Oil, polyethylene glycol.
Specific embodiment
Representative embodiment is protection model and is not intended to limit the present invention in order to better illustrate the present invention below
It encloses.
1 1- of embodiment (2- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base) morpholine
Base) propyl- 2- alkene -1- ketone
Step 1 2- (iodo- 1H- pyrazolo [3,4-d] pyrimidine -1- base of 4- amino -3-) morpholinyl -4- t-butyl formate
Iodo- 4- amino -1H- pyrazolo [3, the 4-d] pyrimidine of 0.1g3- is weighed in reaction flask, after 5ml DMF dissolution is added,
78mg2- hydroxyl -4- tertbutyloxycarbonyl morpholine, 157mg tributylphosphine ((n-Bu) is added3P), 191mg azodicarbonyldipiperidine
(ADDP), it is stirred at room temperature to after reaction, water quenching is added to go out, ethyl acetate extraction is dried, filtered, is concentrated, and column chromatography must be marked
Inscribe compound.
Step 2 2- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base) morpholinyl -4-
T-butyl formate
Weigh the compound 2- (iodo- 1H- pyrazolo [3,4-d] pyrimidine -1- base of 4- amino -3-) of 220mg step 1 preparation
After 10ml DMF dissolution is added, 296mg4- phenoxy group phenyl boric acid pinacol is added in reaction flask in quinoline base -4- t-butyl formate
Ester, 17mg bi triphenyl phosphorus dichloro palladium, 326mg cesium carbonate (Cs2CO3), 90 DEG C of stirrings add water quenching to go out, acetic acid to after reaction
Ethyl ester extraction, dries, filters, and is concentrated, and column chromatography obtains title compound.
Step 3 1- (morpholinyl -2- base) -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -4- amine
Weigh compound 2- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] of 100mg step 2 preparation
Pyrimidine -1- base) morpholinyl -4- t-butyl formate is in reaction flask, and the ethyl acetate solution of addition 5ml HCl saturation, stirring is extremely
Reaction terminates, and concentration obtains title compound, directly progress next step reaction.
Step 4 1- (2- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base) morpholinyl)
Propyl- 2- alkene -1- ketone
Weigh compound 1- (morpholinyl -2- base) -3- (4- Phenoxyphenyl) -1H- pyrazolo of 100mg step 3 preparation
2ml bis- is added in reaction flask in [3,4-d] pyrimidine -4- amine, 19mg acrylic acid, 39mg n,N-diisopropylethylamine (DIPEA)
After chloromethanes dissolution, 99mg HBTU is added, stirring is to after reaction, and methylene chloride extraction is dried, filtered, is concentrated, purifying,
Obtain title compound.
1H-NMR(500MHz,CDCl3) δ (ppm): 8.42 (s, 1H, ArH)；7.67~7.07 (m, 9H, 9 × ArH)；6.60
~6.33 (m, 3H, COCHCH 2)；5.70(s,1H,NCHO)；4.82~3.35 (m, 6H, 3 × CH 2)。
ESI-MS m/z:443.2 [M+H]+。
2 1- of embodiment (2- (4- amino -3- (6- (pyridyl group -2- base oxygroup) naphthalene -2- base) -1H- pyrazolo [3,4-d]
Pyrimidine -1- base) morpholinyl) propyl- 2- alkene -1- ketone
Step 1 6- (pyridine -2- base oxygroup) naphthalene -2- ylboronic acid pinacol ester
Weigh the bromo- beta naphthal of 5g6-, 4.63g K2CO3, 0.1g CuI is in reaction flask, addition 30mL DMF dissolution, argon gas
After protecting lower 110 DEG C of reactions 1h, 4.25g2- bromopyridine is added, reacts 4h, after reaction, 150mL water and 150ml second is added
Organic phase, saturated common salt water washing are collected in acetoacetic ester extraction, and anhydrous sodium sulfate dries, filters, and is concentrated, and column chromatographic purifying obtains 2-
((6- bromonaphthalene -2- base) oxygroup) pyridine.
Weigh 2.38g2- ((6- bromonaphthalene -2- base) oxygroup) pyridine, bis- (pinacol combined) two boron of 1.57g KOAc, 2.40g,
0.30g Pd(dppf)2Cl2In reaction flask, 30ml is added to enter Isosorbide-5-Nitrae-dioxane dissolution, argon gas protects lower 110 DEG C of 3h, reaction knot
It is filtered after beam, solvent is removed under reduced pressure, column chromatographic purifying obtains title compound.
((4- amino -3- (6- (pyridyl group -2- base oxygroup) naphthalene -2- base) -1H- pyrazolo [3,4-d] is phonetic by 2- by step 2 1-
Pyridine -1- base) morpholinyl) propyl- 2- alkene -1- ketone
Obtained by iodo- 4- amino -1H- pyrazolo [3,4-d] pyrimidine of 3-, 2- hydroxyl -4- tertbutyloxycarbonyl morpholine, step 1
Object 6- (pyridine -2- base oxygroup) naphthalene -2- ylboronic acid pinacol ester and acrylic acid are raw material, and title is made in the method with embodiment 1
Compound.
1H-NMR(500MHz,CDCl3) δ (ppm): 8.52~7.07 (m, 11H, 11 × ArH)；6.63~6.08 (m, 3H,
COCHCH 2)；5.76(s,1H,NCHO)；4.17~3.67 (m, 6H, 3 × CH 2)。
ESI-MS m/z:494.2 [M+H]+。
3 1- of embodiment (2- (4- amino -3- (6- phenoxypyridines base -3- base) -1H- pyrazolo [3,4-d] pyrimidine -1-
Base) morpholinyl) propyl- 2- alkene -1- ketone
Step 1 6- phenoxypyridines -3- base -3- pinacol borate
With the bromo- 2 hydroxy pyrimidine of 5-, bromobenzene, bis- (pinacol combined) two boron and Pd (dppf)2Cl2For raw material, with embodiment 2
Title compound is made in the method for step 1.
Step 2 1- (2- (4- amino -3- (6- phenoxypyridines base -3- base) -1H- pyrazolo [3,4-d] pyrimidine -1- base)
Morpholinyl) propyl- 2- alkene -1- ketone
Obtained by iodo- 4- amino -1H- pyrazolo [3,4-d] pyrimidine of 3-, 2- hydroxyl -4- tertbutyloxycarbonyl morpholine, step 1
Object 6- phenoxypyridines -3- base -3- pinacol borate and acrylic acid are raw material, and title compound is made in the method with embodiment 1
Object.
1H-NMR(500MHz,CDCl3) δ (ppm): 8.52~7.07 (m, 9H, 9 × ArH)；6.63~6.08 (m, 3H,
COCHCH 2)；5.76(s,1H,NCHO)；4.82~3.35 (m, 6H, 3 × CH 2)。
ESI-MS m/z:444.2 [M+H]+。
4 1- of embodiment (2- (4- amino -3- (6- phenoxypyridines base -3- base) -1H- pyrazolo [3,4-d] pyrimidine -1-
Base) morpholinyl) -2- methyl propyl- 2- alkene -1- ketone
With iodo- 4- amino -1H- pyrazolo [3,4-d] pyrimidine of 3-, 2- hydroxyl -4- tertbutyloxycarbonyl morpholine, 3 step of embodiment
Rapid 1 gains 6- phenoxypyridines -3- base -3- pinacol borate and 2- methacrylic acid are raw material, with the method for embodiment 1
Title compound is made.
1H-NMR(500MHz,CDCl3) δ (ppm): 7.62~7.08 (m, 9H, 9 × ArH)；6.09(m,1H,NCHO)；
5.27~5.13 (d, 2H, COCCH 2)；4.13~3.86 (m, 6H, 3 × CH 2)；1.98(s,3H,CH 3)。
ESI-MS m/z:458.2 [M+H]+。
5 1- of embodiment (2- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base) morpholine
Base) Propargyl -1- ketone
With iodo- 4- amino -1H- pyrazolo [3,4-d] pyrimidine of 3-, 2- hydroxyl -4- tertbutyloxycarbonyl morpholine, 4- phenoxy group benzene
Pinacol borate and propiolic acid are raw material, and title compound is made in the method with embodiment 1.
1H-NMR(500MHz,CDCl3) δ (ppm): 8.42 (d, 1H, ArH)；7.68~7.08 (m, 9H, 9 × ArH)；6.13
~6.05 (m, 1H, NCHO)；4.67~3.32 (m, 6H, 3 × CH 2)；3.21~3.11 (d, 1H, CCH)。
ESI-MS m/z:441.3 [M+H]+。
6 1- of embodiment (2- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base) morpholine
Base) -2- methyl propyl- 2- alkene -1- ketone
With iodo- 4- amino -1H- pyrazolo [3,4-d] pyrimidine of 3-, 2- hydroxyl -4- tertbutyloxycarbonyl morpholine, 4- phenoxy group benzene
Pinacol borate and 2- methacrylic acid are raw material, and title compound is made in the method with embodiment 1.
1H-NMR(500MHz,CDCl3) δ (ppm): 8.32 (s, 1H, ArH)；7.62~7.08 (m, 9H, 9 × ArH)；6.06
(m,1H,NCHO)；5.27~5.13 (d, 2H, COCCH 2)；4.14~3.49 (m, 6H, 3 × CH 2)；1.97(s,3H,CH 3)。
ESI-MS m/z:457.2 [M+H]+。
7 1- of embodiment (2- (4- amino -3- (6- phenoxypyridines base -3- base) -1H- pyrazolo [3,4-d] pyrimidine -1-
Base) morpholinyl) Propargyl -1- ketone
With iodo- 4- amino -1H- pyrazolo [3,4-d] pyrimidine of 3-, 2- hydroxyl -4- tertbutyloxycarbonyl morpholine, 3 step of embodiment
Rapid 1 gains 6- phenoxypyridines -3- base -3- pinacol borate and propiolic acid are raw material, and mark is made in the method with embodiment 1
Inscribe compound.
1H-NMR(500MHz,CDCl3) δ (ppm): 8.52~7.07 (m, 9H, 9 × ArH)；6.13~6.05 (m, 1H,
NCHO)；4.82~3.35 (m, 6H, 3 × CH 2)；3.21~3.11 (d, 1H, CCH)。
ESI-MS m/z:442.1 [M+H]+。
The evaluation of 1 the compound of the present invention vitro kinase activity of experimental example
1 experimental material
1.1 compound
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.
1.2 reagent
BTK (Bruton ' s tyrosine kinase, Bruton tyrosine protein kinase) is purchased from Japan Carna
Biosciences company；
Dimethyl sulfoxide (Dimethyl sulfoxide, DMSO) is purchased from Sigma Co., USA；
EDTA is purchased from Sigma Co., USA；
96 orifice plates (96well plate) are purchased from U.S. Corning company；
384 orifice plates (384well plate) are purchased from U.S. Corning company.
1 × kinase buffer liquid (50mM HEPES, pH7.5,0.0015%Brij-35,10mM MgCl2, 2mM DTT), face
With preceding preparation；
Terminate liquid (100mM HEPES, pH7.5,0.015%Brij-35,0.2%Coating Reagent#3,50mM
EDTA), prepared before use.
1.3 instrument
LabChip EZ Reader is purchased from U.S. Caliper company.
2 experimental methods
1) it takes the 10 μ l of compound solution of each concentration into 96 orifice plates, 90 μ l1 × kinase buffer liquid is added；It sets up simultaneously
DMSO control group and without enzyme activity control group, contains only 10 μ l DMSO and 90 μ l1 × kinase buffer liquid.Each group mixes at room temperature
Then 10min shifts 5 μ l into 384 orifice plates respectively；
2) kinase b TK is dissolved in 1 × kinase buffer liquid, is configured to 2.5 × kinase solution, then shift 10 μ l2.5 × swash
Enzyme solutions are into above-mentioned 384 orifice plates containing each concentration compound；10 μ l2.5 × kinase solution is added in DMSO control group；Without enzyme activity
1 × kinase buffer liquid that 10 μ l are free of kinases is added in control group.It is incubated for 10min at room temperature；
3) polypeptide of FAM label and ATP are dissolved in 1 × kinase buffer liquid, are configured to 2.5 × substrate solution, then shift
10 μ l2.5 × substrate solution is into above-mentioned 384 orifice plate, 28 DEG C of incubation 1hr；
4) 25 μ l terminate liquids are added in each hole and terminate reaction；
5) reading and converting rate data on LabChip EZ Reader are placed in, and calculate inhibiting rate I%, calculation formula I%
=(Max-Conversion)/(Max-Min) × 100, wherein Max is the conversion ratio of DMSO control group, and Min compares for no enzyme activity
The conversion ratio of group, Conversion are the conversion ratio of compound processing group.Data are handled through XLfit, are fitted to obtain IC50。IC50Value
It indicates with not plus compared with compound processing group, corresponding compound concentration when compound inhibits 50% enzyme activity.IC50It the results are shown in Table
1。
Table 1
| Test-compound | IC50(nM) | Test-compound | IC50(nM) |
| Embodiment 1 | 1.0 | Embodiment 2 | 0.9 |
| Embodiment 3 | 0.6 | Embodiment 4 | 0.5 |
| Embodiment 5 | 0.8 | Embodiment 6 | 1.2 |
| Embodiment 7 | 1.4 |
The IC of the compound of the present invention inhibition BTK kinases50It is living to embody good BTK kinase inhibition in nM rank for range
Property.
2 the compound of the present invention cell in vitro activity rating of experimental example
1 experimental material
1.1 compound
The compound of the present invention of above embodiments preparation, each compound are diluted to 10mM with DMSO, are successively diluted to
20uM、10uM、1uM、100nM、10nM、1nM、0.1nM。
1.2 reagent
RPMI-1640 is purchased from U.S. Invitrogen company；
FBS is purchased from U.S. Invitrogen company；
Culture medium: 4:1 is prepared RPMI1640 and FBS by volume.
EDTA is purchased from Sigma Co., USA；
96 orifice plates (96well plate) are purchased from U.S. Corning company；
Luminescent Cell Viability Assay Kit, it is public purchased from U.S. Progema
Department；
Backseal film is purchased from U.S. Perkin Elmer company.
2 experimental methods
1) Mino (ATCC:CRL3000) cell culture:
Cell recovery: Mino cell being placed in 37 degree of water-baths and is dissolved, and is then transferred into the warmed-up culture medium of 15ml,
1000rpm is centrifuged 5 minutes, discards culture medium, and cell is resuspended with 15ml fresh culture, is transferred in T75 culture bottle, is placed in 37
DEG C, 5%CO2Incubator in cultivate, after 24 hours cell replace fresh culture.
Cell passage: the cell of above-mentioned recovery is transferred in 50ml sterile centrifugation tube, and 1000rpm is centrifuged 5 minutes, is discarded
Culture medium takes finely dispersed cell count, adjusts suitable cell concentration to 15ml fresh culture, is added to T75 culture
In bottle, 37 degree are placed in, 5%CO2Incubator in cultivate.
2) experimental procedure:
Cell is long to 1x10 in T75 Tissue Culture Flask5-1x106After cells/ml, fresh culture (RPMI1640+ is used
It 20%FBS) is resuspended, and counts.The cell of resuspension is adjusted into cell concentration to 10,000cells/ml, 20,000cells/ml,
30,000cells/ml, 50,000cells/ml, 80,000cells/ml, 100,000cells/ml, 150,000cells/ml
And200,000cells/ml8 concentration gradient.Cell suspension is added in 96 porocyte culture plates, 100 μ l of every hole addition (1,
000cells/well,2,000cells/well,3,000cells/well,5,000cells/well,8,000cells/
well,10,000cells/well,15,000cells/well and20,000cells/well).Every kind of two multiple holes of concentration, paving
Three blocks of plates.100 μ l are added to gaging hole backward in 72hLuminescent Cell Viability Assay
buffer.Gently shake up.After ten minutes, Backseal film is sticked in Assay board bottom portion, is placed on Envison and reads fluorescence reading
Number, and cell survival rate (cell survive (%)) is calculated, calculation formula is cell survive (%)=(drug hole reading
Number-Min)/(Max-Min), wherein Max is the reading of vehicle control group, and Min is the reading of cell-free control group, and medicine group is
The reading of compound processing group, data are handled through XLfit, are fitted to obtain IC50, experimental result is shown in Table 2.
Table 2
| Test-compound | IC50(μM) | Test-compound | IC50(μM) |
| Embodiment 1 | 0.037 | Embodiment 2 | 0.659 |
| Embodiment 3 | 0.754 | Embodiment 4 | 0.093 |
| Embodiment 5 | 0.018 | Embodiment 6 | 0.065 |
| Embodiment 7 | 0.784 |
The external Mino cell of the compound of the present invention also shows good inhibitory activity.
The BTK occupation rate of 3 the compound of the present invention of experimental example is evaluated
1 experimental material
1.1 compound
The compound of the present invention of above embodiments preparation, each compound are dissolved to 6mg/ml with CMC-Na, give medicament
Amount is 30mg/kg.
1.2 reagent
RBC solution buffer is purchased from U.S.'s Boston biological products company；
Culture medium: RPMI complete medium；
The anti-BTK antibody of mouse, purchased from Bake Charles Dixon BectonDickinson company；
Secondary goat anti-mouse HRP antibody is purchased from Ze Mude Zymed company；
It is coated with the elisa plate of streptavidin, is purchased from U.S.'s Pierce Corporation；
The auspicious moral of Bayer dissolves buffer, is purchased from U.S. Biorad company；
BTK is recombinated, U.S. hero company is purchased from；
B220+ antibody-magnetic bead grain conjugate.Purchased from German Mei Tian Ni company；
2 experimental methods
Orally administration rat 30mg/kg compound, and spleen is collected after 2 hours or 24 hours after compound processing.?
It is covered with the spleen that rat is destroyed between 2 microscopes of frosted glass, to recycle single cell suspension.By at room temperature with RBC
Dissolution buffer is cultivated 2 minutes together carrys out lysed erythrocyte, and then these cells are resuspended in RMPI complete medium, and
Keep its coalescence agglomerating by centrifugation.Rat B cell is separated by carrying out positive selection with B220+ antibody-magnetic bead grain conjugate,
It is purified by MACS column, and with 106The concentration of a cell/100ul is dissolved in the auspicious moral dissolution buffer of Bayer and being dissolved,
Probe compound is added and reaches final concentration 1uM, at room temperature, oscillation is cultivated 1 hour in mixed plate, so that probe combines
In free BTK.After cultivating together, sample is added on the elisa plate for being coated with streptavidin by washing, and
Oscillation is cultivated 1 hour at room temperature.Automatic washer is then used, washs plate with the PBS containing 0.05%Tween-20.Containing
Anti- BTK antibody is prepared with the dilution of 1:1000 in the PBS (containing 0.05%Tween-20) of 0.5%BSA, and is added to ELISA
In plate.At room temperature, oscillation is cultivated 1 hour.As described above, plate is washed, and (contains 0.05% in the PBS containing 0.5%BSA
Tween-20 secondary HRP antibody is resisted with the dilution preparation of 1:5000 in).Breezing plate is washed as described above.By TMB
It is added in plate, and monitors OD650, go directly to 1 OD unit.Then pass through addition H2SO4Make reaction terminating.Use Gen5 software
Plate is analyzed, and quantifies sample using this base of a fruit (4Parameter Logistic curve) curve of 4 parameter logistics.For
Standard curve uses recombination BTK.Experimental result is shown in Table 3.
Table 3
| Handle group | 2 hours BTK occupation rates | 24 hours BTK occupation rates |
| Solvent | 0 | 0 |
| Embodiment 1 | 96 | 81 |
| Embodiment 2 | 87 | 70 |
| Embodiment 3 | 81 | 64 |
| Embodiment 4 | 95 | 73 |
| Embodiment 5 | 93 | 84 |
| Embodiment 6 | 94 | 51 |
| Embodiment 7 | 90 | 49 |
The above results show that the compound of the present invention maintains the time of drug effect longer, and experience 24 as a child still kept higher
BTK occupation rate.
Although being described in detail above to the present invention, however it is understood by skilled practitioners that without departing from this hair
The present invention can be carry out various modifications and be changed under the premise of bright spirit and scope.Interest field of the invention is not limited to
Detailed description made by above, and claims should be belonged to.
Claims (4)
1. logical formula (I) compound represented or its pharmaceutically acceptable salt,
Wherein,
X is-O-；
Y is hydrogen；
R1Selected from naphthalene and pyridyl group；
R2Selected from phenyl and pyridyl group；With
R3Selected from-C (O)-R4, wherein R4Selected from C2-4Alkenyl and C2-4Alkynyl, the alkenyl or alkynyl can be one or more
C1-6Alkyl replaces.
2. compound according to claim 1 or its pharmaceutically acceptable salt, wherein the compound is selected from the following
Compound:
3. a kind of pharmaceutical composition, it includes compound of any of claims 1 or 2 or its pharmaceutically acceptable salt and pharmacy
Upper acceptable carrier.
4. compound of any of claims 1 or 2 or its pharmaceutically acceptable salt or pharmaceutical composition as claimed in claim 3
Preparing the application in the drug for treating or preventing tumour.
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| CN106146511A (en) * | 2015-04-03 | 2016-11-23 | 安润医药科技（苏州）有限公司 | Pyrazolopyrimidine derivative, preparation method, pharmaceutical composition and purposes |
| CN106146518A (en) * | 2016-06-30 | 2016-11-23 | 苏州爱玛特生物科技有限公司 | A kind of bruton's tyrosine kinase inhibitor intermediate and preparation method thereof |
| CN108069974B (en) * | 2016-11-15 | 2019-12-10 | 杭州和正医药有限公司 | Selective Bruton tyrosine kinase inhibitor and application thereof |
| CN112574191B (en) * | 2019-09-29 | 2024-01-23 | 南京圣和药业股份有限公司 | Isoxazole heterocyclic compound and application thereof |
| TWI797711B (en) * | 2020-08-13 | 2023-04-01 | 大陸商上海和譽生物醫藥科技有限公司 | A kind of FGFR and mutation inhibitor thereof, its preparation method and application |
| CN115073469B (en) * | 2021-03-15 | 2023-12-22 | 药雅科技(上海)有限公司 | Preparation and application of pyrrolopyrimidine compound as kinase inhibitor |
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