CN105461720A - Morpholine tyrosine kinase inhibitors - Google Patents
Morpholine tyrosine kinase inhibitors Download PDFInfo
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- CN105461720A CN105461720A CN201410389941.9A CN201410389941A CN105461720A CN 105461720 A CN105461720 A CN 105461720A CN 201410389941 A CN201410389941 A CN 201410389941A CN 105461720 A CN105461720 A CN 105461720A
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Abstract
The present invention belongs to the field of pharmaceutical chemistry, and relates to a class of morpholine tyrosine kinase inhibitors, particularly to a class of compounds having Bruton's tyrosine kinase (BTK) inhibition activity, or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof, and applications of pharmaceutical compositions containing the compounds and the compounds or compositions in drug preparation. The compounds of the present invention provide good BTK inhibition activity compared to Ibrutinib.
Description
Technical field
The invention belongs to chemical medicine, be specifically related to compound or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug that a class has Bruton ' styrosinekinase (BTK) inhibit activities, and the application in medicine preparation with these compounds or composition of the pharmaceutical composition containing these compounds.
Background of invention
The signal path that B-cell receptor (BCR) mediates has vital role for the multiple lymphadenomatous existence comprising CLL, and Bruton ' styrosinekinase (BTK) is one of key enzyme in BCR approach.BTK belongs to nonreceptor tyrosine kinase Tec family, except T lymphocyte and natural killer cell, expression is all had in the myeloid cells such as bone-marrow-derived lymphocyte, basophilic granulocyte, monocyte, participate in many A signal pathways in organism, the propagation of cell, differentiation and apoptosis are all had a very important role.
BTK take part in the signal path of B cell mediation, after it passes through, under the effect of Src family molecule, Tyr551 site and Tyr223 site phosphorylation occur, activate Phospholipase C (PLC-γ), and then the bisphosphate phosphatidylinositols (PIP on activated cell film
2) hydrolysis generation second messenger InsP3 (IP
3) and DG (DAG), activate downstream signaling pathway.Research shows that BTK also take part in the signal path of Toll-like receptor mediation, mast cell degranulation, the signal path etc. of Fas, g protein coupled receptor mediation.In addition, report BTK has been had to play a role in apoptosis.Therefore, exploitation BTK inhibitor will be all very effective for lymphoma, leukemia.
Summary of the invention
Pyrazolo [3, the 4-d] pyrimidines that the 1-morpholinyl that the class that an object of the present invention is to provide general formula I has BTK inhibit activities replaces or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug,
Wherein,
X is selected from key, CH
2, O, S, S (O)
2, NH ,-NH-C (O)-,-C (O)-NH-;
Y is selected from hydrogen, halogen, alkyl, haloalkyl;
R
1be selected from aryl, C
1-6alkylaryl, heteroaryl, C
1-6miscellaneous alkyl aryl, C
2-4alkynyl, described aryl, heteroaryl or alkynyl can be replaced by one or more halogen, hydroxyl, carboxyl, amino, alkyl, alkoxyl group, alkoxyalkyl, alkyloxy-alkoxy, amido, alkyl acylamino, aminoacyl, alkyl monosubstituted amino acyl group, two alkylaminoacyl, acyl group, alkyl acyl, hydroxyalkyl, alkyl monosubstituted amino, two alkylamino, Mono-alkylaminoalkyl, two alkylaminoalkyl group, nitro, cyano group;
R
2be selected from aryl, heteroaryl, described aryl, heteroaryl can be replaced by one or more halogen, hydroxyl, carboxyl, amino, alkyl, alkoxyl group, alkoxyalkyl, alkyloxy-alkoxy, amido, alkyl acylamino, aminoacyl, alkyl monosubstituted amino acyl group, two alkylaminoacyl, acyl group, alkyl acyl, hydroxyalkyl, alkyl monosubstituted amino, two alkylamino, Mono-alkylaminoalkyl, two alkylaminoalkyl group, nitro, cyano group;
R
3be selected from-C (O)-R
4,-S (O)
2-R
4, wherein R
4be selected from C
2-4thiazolinyl, C
2-4alkynyl, described alkenyl or alkynyl can be replaced by one or more cyano group, alkyl, cycloalkyl, haloalkyl, halogenated cycloalkyl, hydroxyalkyl, alkoxyl group, halogenated alkoxy, alkoxyalkyl, amino, alkyl monosubstituted amino, two alkylamino, cycloalkyl amino, aminoalkyl group, Mono-alkylaminoalkyl, two alkylaminoalkyl group, cycloalkyl amino alkyl, saturated heterocyclyl, saturated heterocyclyl alkyl, heteroaryl, heteroarylalkyl.
Another object of the present invention is to provide the method for the compound of preparing general formula I of the present invention or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug.
Another object of the present invention is to provide the composition of compound or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug and the pharmaceutically acceptable carrier comprising general formula I of the present invention, and comprises the compound of general formula I of the present invention or the composition of its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug and another kind or multiple BTK inhibitor.
Also object of the present invention is to provide the compound of general formula I of the present invention or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug treat and/or prevent the abnormal disease caused of BTK, such as B cell lymphoma, leukemia etc., and the compound of general formula I of the present invention or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug are for the preparation of the application treated and/or prevented in the medicine of the abnormal disease caused of BTK.
For above-mentioned purpose, the invention provides following technical scheme:
First aspect, the invention provides compound or its pharmacologically acceptable salts, isomer, solvate, crystallization or the prodrug of general formula I,
Wherein,
X is selected from key, CH
2, O, S, S (O)
2, NH ,-NH-C (O)-,-C (O)-NH-;
Y is selected from hydrogen, halogen, alkyl, haloalkyl;
R
1be selected from aryl, C
1-6alkylaryl, heteroaryl, C
1-6miscellaneous alkyl aryl, C
2-4alkynyl, described aryl, heteroaryl or alkynyl can be replaced by one or more halogen, hydroxyl, carboxyl, amino, alkyl, alkoxyl group, alkoxyalkyl, alkyloxy-alkoxy, amido, alkyl acylamino, aminoacyl, alkyl monosubstituted amino acyl group, two alkylaminoacyl, acyl group, alkyl acyl, hydroxyalkyl, alkyl monosubstituted amino, two alkylamino, Mono-alkylaminoalkyl, two alkylaminoalkyl group, nitro, cyano group;
R
2be selected from aryl, heteroaryl, described aryl, heteroaryl can be replaced by one or more halogen, hydroxyl, carboxyl, amino, alkyl, alkoxyl group, alkoxyalkyl, alkyloxy-alkoxy, amido, alkyl acylamino, aminoacyl, alkyl monosubstituted amino acyl group, two alkylaminoacyl, acyl group, alkyl acyl, hydroxyalkyl, alkyl monosubstituted amino, two alkylamino, Mono-alkylaminoalkyl, two alkylaminoalkyl group, nitro, cyano group;
R
3be selected from-C (O)-R
4,-S (O)
2-R
4, wherein R
4be selected from C
2-4thiazolinyl, C
2-4alkynyl, described alkenyl or alkynyl can be replaced by one or more cyano group, alkyl, cycloalkyl, haloalkyl, halogenated cycloalkyl, hydroxyalkyl, alkoxyl group, halogenated alkoxy, alkoxyalkyl, amino, alkyl monosubstituted amino, two alkylamino, cycloalkyl amino, aminoalkyl group, Mono-alkylaminoalkyl, two alkylaminoalkyl group, cycloalkyl amino alkyl, saturated heterocyclyl, saturated heterocyclyl alkyl, heteroaryl, heteroarylalkyl.
In some preferred embodiments, compound of the present invention is compound and pharmacologically acceptable salts, isomer, solvate, crystallization or the prodrug of general formula I, wherein:
X is selected from key, CH
2, O, S;
Further preferably,
X is selected from key, O.
In some preferred embodiments, compound of the present invention is compound and pharmacologically acceptable salts, isomer, solvate, crystallization or the prodrug of general formula I, wherein:
Y is selected from hydrogen, fluorine, chlorine, C
1-6alkyl;
Further preferably,
Y is selected from hydrogen, fluorine, methyl, ethyl.
In some preferred embodiments, compound of the present invention is compound and pharmacologically acceptable salts, isomer, solvate, crystallization or the prodrug of general formula I, wherein:
R
1be selected from aryl, C
1-3alkylaryl, heteroaryl, C
1-3miscellaneous alkyl aryl, C
2-4alkynyl, described aryl, heteroaryl or alkynyl can by one or more halogen, hydroxyl, carboxyl, amino, C
1-6alkyl, C
1-6alkoxyl group, C
1-6alkoxy-C
1-6alkyl, C
1-6alkoxy-C
1-6alkoxyl group, amido, C
1-6alkyl acylamino, aminoacyl, single C
1-6alkylaminoacyl, two C
1-6alkylaminoacyl, acyl group, C
1-6alkyl acyl, hydroxyl C
1-6alkyl, single C
1-6alkylamino, two C
1-6alkylamino, single C
1-6alkylamino-C
1-6alkyl, two C
1-6alkylamino-C
1-6alkyl, nitro, cyano group replace;
Further preferably,
R
1be selected from phenyl, naphthyl, pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl group, furyl, thienyl, indyl, pseudoindoyl, quinolyl, isoquinolyl, C
1-3alkyl phenyl, C
1-3alkyl naphthyl, C
1-3alkylpyridyl, C
1-3wan Ji oxazolyl, C
1-3wan isoxazole base, C
1-3wan oxadiazole base, C
1-3alkyl thiazolyl, C
1-3alkyl isothiazole base, C
1-3alkyl thiadiazolyl group, C
1-3alkyl furan base, C
1-3alkylthrophene base, C
1-3alkyl-indol base, C
1-3alkyl pseudoindoyl, C
1-3alkyl quinoline base, C
1-3alkylisoquinolinium base, ethynyl, described phenyl, naphthyl, pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl group, furyl, thienyl, indyl, pseudoindoyl, quinolyl, isoquinolyl or alkynyl can by one or more halogen, hydroxyl, carboxyl, amino, C
1-6alkyl, C
1-6alkoxyl group, C
1-6alkoxy-C
1-6alkyl, C
1-6alkoxy-C
1-6alkoxyl group, amido, C
1-6alkyl acylamino, aminoacyl, single C
1-6alkylaminoacyl, two C
1-6alkylaminoacyl, acyl group, C
1-6alkyl acyl, hydroxyl-C
1-6alkyl, single C
1-6alkylamino, two C
1-6alkylamino, single C
1-6alkylamino-C
1-6alkyl, two C
1-6alkylamino-C
1-6alkyl, nitro, cyano group replace;
Still more preferably,
R
1be selected from phenyl, naphthyl, pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl group, furyl, thienyl, indyl, pseudoindoyl, quinolyl, isoquinolyl, ethynyl, described phenyl, naphthyl, pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl group, furyl, thienyl, indyl, pseudoindoyl, quinolyl, isoquinolyl or alkynyl can by one or more halogen, hydroxyl, carboxyl, amino, C
1-3alkyl, C
1-3alkoxyl group, C
1-3alkoxy-C
1-3alkyl, C
1-3alkoxy-C
1-3alkoxyl group, amido, C
1-3alkyl acylamino, aminoacyl, single C
1-3alkylaminoacyl, two C
1-3alkylaminoacyl, acyl group, C
1-3alkyl acyl, hydroxyl-C
1-3alkyl, single C
1-3alkylamino, two C
1-3alkylamino, single C
1-3alkylamino-C
1-3alkyl, two C
1-3alkylamino-C
1-3alkyl, nitro, cyano group replace.
In some preferred embodiments, compound of the present invention is compound and pharmacologically acceptable salts, isomer, solvate, crystallization or the prodrug of general formula I, wherein:
R
2be selected from aryl, heteroaryl, described aryl, heteroaryl can by one or more halogen, hydroxyl, carboxyl, amino, C
1-6alkyl, C
1-6alkoxyl group, C
1-6alkoxy-C
1-6alkyl, C
1-6alkoxy-C
1-6alkoxyl group, amido, C
1-6alkyl acylamino, aminoacyl, single C
1-6alkylaminoacyl, two C
1-6alkylaminoacyl, acyl group, C
1-6alkyl acyl, hydroxyl C
1-6alkyl, single C
1-6alkylamino, two C
1-6alkylamino, single C
1-6alkylamino-C
1-6alkyl, two C
1-6alkylamino-C
1-6alkyl, nitro, cyano group replace;
Further preferably,
R
2be selected from phenyl, naphthyl, pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl group, furyl, thienyl, indyl, pseudoindoyl, quinolyl, isoquinolyl, described phenyl, naphthyl, pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl group, furyl, thienyl, indyl, pseudoindoyl, quinolyl, isoquinolyl can by one or more halogen, hydroxyl, carboxyl, amino, C
1-3alkyl, C
1-3alkoxyl group, C
1-3alkoxy-C
1-3alkyl, C
1-3alkoxy-C
1-3alkoxyl group, amido, C
1-3alkyl acylamino, aminoacyl, single C
1-3alkylaminoacyl, two C
1-3alkylaminoacyl, acyl group, C
1-3alkyl acyl, hydroxyl C
1-3alkyl, single C
1-3alkylamino, two C
1-3alkylamino, single C
1-3alkylamino-C
1-3alkyl, two C
1-3alkylamino-C
1-3alkyl, nitro, cyano group replace.
In some preferred embodiments, compound of the present invention is compound and pharmacologically acceptable salts, isomer, solvate, crystallization or the prodrug of general formula I, wherein:
R
3be selected from-C (O)-R
4,-S (O)
2-R
4, wherein, R
4be selected from C
2-4thiazolinyl, C
2-4alkynyl, described alkenyl or alkynyl can by one or more cyano group, C
1-6alkyl, C
3-8cycloalkyl, halo-C
1-6alkyl, halo C
3-8cycloalkyl, hydroxyl-C
1-6alkyl, C
1-6alkoxyl group, halo-C
1-6alkoxyl group, C
1-6alkoxy-C
1-6alkyl, amino, single C
1-6alkylamino, two C
1-6alkylamino, C
3-8cycloalkyl amino, amino-C
1-6alkyl, single C
1-6alkylamino-C
1-6alkyl, two C
1-6alkylamino-C
1-6alkyl, C
3-8cycloalkyl amino-C
1-6alkyl, saturated C
4-8heterocyclic radical, saturated C
4-8heterocyclic radical-C
1-6alkyl, heteroaryl, heteroaryl-C
1-6alkyl replaces;
Further preferably,
R
3be selected from-C (O)-R
4,-S (O)
2-R
4, wherein, R
4be selected from C
2-4thiazolinyl, C
2-4alkynyl, described alkenyl or alkynyl can by one or more cyano group, C
1-3alkyl, C
3-6cycloalkyl, halo-C
1-3alkyl, halo C
3-6cycloalkyl, hydroxyl-C
1-3alkyl, C
1-3alkoxyl group, halo-C
1-3alkoxyl group, C
1-3alkoxy-C
1-3alkyl, amino, single C
1-3alkylamino, two C
1-3alkylamino, C
3-6cycloalkyl amino, amino-C
1-3alkyl, single C
1-3alkylamino-C
1-3alkyl, two C
1-3alkylamino-C
1-3alkyl, C
3-6cycloalkyl amino-C
1-3alkyl, saturated C
4-8heterocyclic radical, saturated C
4-8heterocyclic radical-C
1-3alkyl, heteroaryl, heteroaryl-C
1-3alkyl replaces.
In some preferred embodiments, compound of the present invention is compound and pharmacologically acceptable salts, isomer, solvate, crystallization or the prodrug of general formula I, wherein:
X is selected from key, CH
2, O, S;
Y is selected from hydrogen, fluorine, C
1-3alkyl;
R
1be selected from phenyl, naphthyl, pyridyl, ethynyl, described phenyl, naphthyl, pyridyl, ethynyl can by one or more halogen, hydroxyl, amino, C
1-6alkyl, C
1-6alkoxyl group, hydroxyl-C
1-6alkyl, nitro, cyano group replace;
R
2be selected from phenyl, naphthyl, pyridyl, described phenyl, naphthyl, pyridyl can by one or more halogen, hydroxyl, C
1-6alkyl, C
1-6alkoxyl group, hydroxyl-C
1-6alkyl, nitro, cyano group replace;
R
3be selected from-C (O)-R
4,-S (O)
2-R
4, wherein, R
4be selected from vinyl, ethynyl, described vinyl, ethynyl can by one or more cyano group, C
1-6alkyl, C
3-8cycloalkyl, halo-C
1-6alkyl, halo C
3-8cycloalkyl, hydroxyl-C
1-6alkyl, C
1-6alkoxyl group, halo-C
1-6alkoxyl group, C
1-6alkoxy-C
1-6alkyl, amino, single C
1-6alkylamino, two C
1-6alkylamino, C
3-6cycloalkyl amino, amino-C
1-6alkyl, single C
1-6alkylamino C
1-6alkyl, two C
1-6alkylamino-C
1-6alkyl, C
3-6cycloalkyl amino-C
1-6alkyl, saturated C
3-8heterocyclic radical, saturated C
3-8heterocyclic radical-C
1-6alkyl, heteroaryl, heteroaryl-C
1-6alkyl replaces.
The invention provides following particular compound:
On the other hand, the invention provides the preparation method of general formula compound of the present invention, the preparation method of the compound of general formula I comprises the steps:
A) compound of formula (1) and the compound of formula (2) are obtained by reacting the compound of formula (3);
B) compound of formula (3) and the compound condensation of formula (4) obtain the compound of formula (5);
C) compound of formula (5) sloughs the compound that protecting group obtains formula (6);
D) compound of formula (6) obtains the general formula compound of formula (I) by condensation reaction.
Wherein, X, Y, R
1, R
2, R
3have the definition in general formula, Pro represents amino protecting group, and be preferably selected from tertbutyloxycarbonyl, benzyl, carbobenzoxy-(Cbz), p-toluenesulfonyl, trifluoroacetyl group, M represents halogen, is preferably selected from bromine, iodine.
The third aspect, the invention provides pharmaceutical composition, and it comprises compound of the present invention or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug.
In some embodiments, the invention provides pharmaceutical composition, it comprises compound of the present invention, isomer, solvate, crystallization or prodrug, also comprises one or more that be selected from following composition: Ibrutinib, Abexinostat, PCI-27483, Motexafin, gadolinium, CC-292 etc.
Compound of the present invention, isomer, solvate, crystallization or prodrug and pharmaceutically acceptable carrier, thinner or mixed with excipients can be prepared into pharmaceutical preparation, to be suitable for per os or parenteral admin.Medication includes, but are not limited to intracutaneous, intramuscular, intraperitoneal, intravenously, subcutaneous, nose interior and peroral route.Described preparation can be used by any approach, such as, by infusion or inject, is used by the approach absorbed through epithelium or mucocutaneous (such as oral mucosa or rectum etc.).Administration can be whole body or local.The example of oral administration preparation comprises solid or liquid dosage form, specifically, comprises tablet, pill, granula, pulvis, capsule, syrup, emulsion, suspensoid etc.Described preparation is prepared by methods known in the art, and comprises conventional carrier, thinner or the vehicle used of field of pharmaceutical preparations.
Fourth aspect, the invention provides compound of the present invention, isomer, solvate, crystallization or prodrug or medicine composite for curing of the present invention or prevention are by the method for the abnormal disease caused of BTK and the application in preparation prevention or the abnormal disease medicament caused for the treatment of BTK, comprise to leukaemic, Lymphoma uses compound of the present invention, isomer, solvate, crystallization or prodrug or comprise compound of the present invention, isomer, solvate, the pharmaceutical composition of crystallization or prodrug, effectively to suppress the abnormal signal path excited of BTK, stop course advancement.
Term explanation
" alkyl " of the present invention refers to the saturated hydrocarbyl of straight or branched.
" cycloalkyl " of the present invention refers to the saturated hydrocarbyl of ring-type.
" alkoxyl group " of the present invention refers to-O-alkyl.
" halogen " of the present invention refers to fluorine, chlorine, bromine, iodine.
" haloalkyl " of the present invention refers at least by the alkyl of a halogen substiuted.
" halogenated alkoxy " of the present invention refers at least by the alkoxyl group of a halogen substiuted.
" aryl " of the present invention refers to the aromatic series that can comprise monocycle or many condensed ring such as aromatic nucleus of two rings or three rings, and a part for the ring wherein at least condensed forms the aromatic series of conjugation, and it contains 5 to 50 carbon atoms, preferably about 6 to about 14 carbon atoms.Suitable aryl includes but not limited to phenyl, naphthyl, xenyl, anthryl, tetralyl, fluorenyl, indanyl, biphenylene and acenaphthenyl.
" heteroaryl " of the present invention refers to aromatic monocyclic or the many condensed ring aromatic radical having at least a carbon atom to be substituted by heteroatoms as two rings or three rings, and described heteroatoms is O, S, N.Suitable heteroaryl includes but not limited to imidazolyl, benzimidazolyl-, imidazopyridyl, quinazoline ketone group, pyrryl, imidazoles ketone group, furyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, pyridyl etc.
" solvate " of the present invention refers to the mixture that solute (salt as active compound, active compound) and solvent (as water) are combined to form in a conventional sense.Solvent refers to solvent that is known to those of skill in the art or that easily determine.If water, then solvate is commonly referred to as hydrate, such as monohydrate, dihydrate, trihydrate etc.
" crystallization " of the present invention refers to the various solid form of compound formation of the present invention, comprises crystal formation, amorphous.
" isomer " of the present invention refers to the molecule Atom spatially different steric isomer produced of arrangement mode, comprises enantiomer and diastereomer.
" prodrug " of the present invention refers under the physiological condition of organism, change into compound of the present invention owing to reacting with enzyme, hydrochloric acid in gastric juice etc., namely change into compound of the present invention by the oxidation, reduction, hydrolysis etc. of enzyme and/or change into compound of the present invention by the hydrolysis reaction etc. of hydrochloric acid in gastric juice etc.
" pharmacologically acceptable salts " of the present invention refers to the pharmacy acceptable salt that compound of the present invention is formed with acid, and described acid includes but not limited to phosphoric acid, sulfuric acid, hydrochloric acid, Hydrogen bromide, citric acid, toxilic acid, propanedioic acid, amygdalic acid, succsinic acid, fumaric acid, acetic acid, lactic acid, nitric acid etc.
" pharmaceutical composition " of the present invention refers to and comprises any one compound as herein described, comprises the protection form of isomer, prodrug, solvate, pharmacy acceptable salt or its chemistry, and the mixture of one or more pharmaceutically acceptable carriers.
" pharmaceutically acceptable carrier " of the present invention refers to and does not cause obvious irritation to organism and do not disturb the biological activity of given compound and the carrier of character, comprises solvent, thinner or other vehicle, dispersion agent, tensio-active agent, isotonic agent, thickening material or emulsifying agent, sanitas, solid binder, lubricant etc.Unless any conventional carrier medium is incompatible with the compounds of this invention.Carbohydrate can be included, but are not limited to, as lactose, dextrose plus saccharose as some examples of pharmaceutically acceptable carrier; Starch, as W-Gum and yam starch; Cellulose and its derivates, as Xylo-Mucine and Mierocrystalline cellulose and rhodia; Fructus Hordei Germinatus, gelatin etc.
" vehicle " of the present invention refers to join in medicinal compositions to promote to give the inert substance of compound further.Vehicle can comprise calcium carbonate, calcium phosphate, various saccharides and polytype starch, derivatived cellulose, gelatin, vegetables oil, polyoxyethylene glycol.
Embodiment
Representational embodiment is to better the present invention is described below, but not for limiting the scope of the invention.
Embodiment 11-(2-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) morpholinyl) the third-2-alkene-1-ketone
Step 12-(4-amino-3-iodo-1H-pyrazolo [3,4-d] pyrimidine-1-base) morpholinyl-4-t-butyl formate
Take the iodo-4-amino of 0.1g3--1H-pyrazolo [3,4-d] pyrimidine in reaction flask, after adding 5mlDMF dissolving, add 78mg2-hydroxyl-4-tertbutyloxycarbonyl morpholine, 157mg tributylphosphine ((n-Bu)
3p), 191mg azodicarbonyldipiperidine (ADDP), after stirring at room temperature to reaction terminates, add water cancellation, extraction into ethyl acetate, dry, filters, and concentrated, column chromatography, obtains title compound.
Step 22-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) morpholinyl-4-t-butyl formate
Take compound 2-(the iodo-1H-pyrazolo [3 of 4-amino-3-of 220mg step 1 preparation, 4-d] pyrimidine-1-base) morpholinyl-4-t-butyl formate is in reaction flask, after adding 10mlDMF dissolving, add 296mg4-phenoxy group phenylo boric acid pinacol ester, 17mg bi triphenyl phosphorus dichloro palladium, 326mg cesium carbonate (Cs
2cO
3), 90 DEG C are stirred to after reaction terminates, and add water cancellation, extraction into ethyl acetate, dry, filters, and concentrated, column chromatography, obtains title compound.
Step 31-(morpholinyl-2-base)-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine
Take compound 2-(4-amino-3-(4-the Phenoxyphenyl)-1H-pyrazolo [3 of 100mg step 2 preparation, 4-d] pyrimidine-1-base) morpholinyl-4-t-butyl formate is in reaction flask, add the ethyl acetate solution that 5mlHCl is saturated, be stirred to reaction to terminate, concentrated, obtain title compound, directly carry out next step reaction.
Step 41-(2-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) morpholinyl) the third-2-alkene-1-ketone
Take compound 1-(morpholinyl-2-base)-3-(4-Phenoxyphenyl)-1H-pyrazolo [3, the 4-d] pyrimidine-4-amine of 100mg step 3 preparation, 19mg vinylformic acid, 39mgN, N-diisopropylethylamine (DIPEA) in reaction flask, add 2ml methylene dichloride dissolve after, add 99mgHBTU, be stirred to after reaction terminates, dichloromethane extraction, dry, filter, concentrated, purifying, obtains title compound.
1H-NMR(500MHz,CDCl
3)δ(ppm)：8.42(s,1H,Ar
H)；7.67～7.07(m,9H,9×Ar
H)；6.60～6.33(m,3H,COC
HC
H 2)；5.70(s,1H,NC
HO)；4.82～3.35(m,6H,3×C
H 2)。
ESI-MSm/z：443.2[M+H]
+。
Embodiment 21-(2-(4-amino-3-(6-(pyridyl-2-base oxygen base) naphthalene-2-base)-1H-pyrazolo [3,4-d] pyrimidine-1-base) morpholinyl) the third-2-alkene-1-ketone
Step 16-(pyridine-2-base oxygen base) naphthalene-2-ylboronic acid pinacol ester
Take the bromo-beta naphthal of 5g6-, 4.63gK
2cO
3, 0.1gCuI, in reaction flask, adds 30mLDMF and dissolves; after the lower 110 DEG C of reaction 1h of argon shield, add 4.25g2-bromopyridine, reaction 4h; after reaction terminates; add 150mL water and 150ml extraction into ethyl acetate, collect organic phase, saturated common salt water washing; anhydrous sodium sulfate drying; filter, concentrated, column chromatography purification obtains 2-((6-bromonaphthalene-2-base) oxygen base) pyridine.
Take 2.38g2-((6-bromonaphthalene-2-base) oxygen base) pyridine, two (tetramethyl ethylene ketone conjunction) two boron of 1.57gKOAc, 2.40g, 0.30gPd (dppf)
2cl
2in reaction flask, add 30ml and enter Isosorbide-5-Nitrae-dioxane dissolving, the lower 110 DEG C of 3h of argon shield, reaction terminates rear filtration, removal of solvent under reduced pressure, and column chromatography purification obtains title compound.
Step 21-(2-(4-amino-3-(6-(pyridyl-2-base oxygen base) naphthalene-2-base)-1H-pyrazolo [3,4-d] pyrimidine-1-base) morpholinyl) the third-2-alkene-1-ketone
With the iodo-4-amino of 3--1H-pyrazolo [3,4-d] pyrimidine, 2-hydroxyl-4-tertbutyloxycarbonyl morpholine, step 1 gains 6-(pyridine-2-base oxygen base) naphthalene-2-ylboronic acid pinacol ester and vinylformic acid is raw material, the method with embodiment 1 obtains title compound.
1H-NMR(500MHz,CDCl
3)δ(ppm)：8.52～7.07(m,11H,11×Ar
H)；6.63～6.08(m,3H,COC
HC
H 2)；5.76(s,1H,NC
HO)；4.17～3.67(m,6H,3×C
H 2)。
ESI-MSm/z：494.2[M+H]
+。
Embodiment 31-(2-(4-amino-3-(6-phenoxypyridines base-3-base)-1H-pyrazolo [3,4-d] pyrimidine-1-base) morpholinyl) the third-2-alkene-1-ketone
Step 16-phenoxypyridines-3-base-3-pinacol borate
With the bromo-2 hydroxy pyrimidine of 5-, bromobenzene, two (tetramethyl ethylene ketone conjunction) two boron and Pd (dppf)
2cl
2for raw material, the method with embodiment 2 step 1 obtains title compound.
Step 21-(2-(4-amino-3-(6-phenoxypyridines base-3-base)-1H-pyrazolo [3,4-d] pyrimidine-1-base) morpholinyl) the third-2-alkene-1-ketone
With the iodo-4-amino of 3--1H-pyrazolo [3,4-d] pyrimidine, 2-hydroxyl-4-tertbutyloxycarbonyl morpholine, step 1 gains 6-phenoxypyridines-3-base-3-pinacol borate and vinylformic acid for raw material, the method with embodiment 1 obtains title compound.
1H-NMR(500MHz,CDCl
3)δ(ppm)：8.52～7.07(m,9H,9×Ar
H)；6.63～6.08(m,3H,COC
HC
H 2)；5.76(s,1H,NC
HO)；4.82～3.35(m,6H,3×C
H 2)。
ESI-MSm/z：444.2[M+H]
+。
Embodiment 41-(2-(4-amino-3-(6-phenoxypyridines base-3-base)-1H-pyrazolo [3,4-d] pyrimidine-1-base) morpholinyl)-2-methyl-prop-2-alkene-1-ketone
With the iodo-4-amino of 3--1H-pyrazolo [3,4-d] pyrimidine, 2-hydroxyl-4-tertbutyloxycarbonyl morpholine, embodiment 3 step 1 gains 6-phenoxypyridines-3-base-3-pinacol borate and 2-methacrylic acid be raw material, the method with embodiment 1 obtains title compound.
1H-NMR(500MHz,CDCl
3)δ(ppm)：7.62～7.08(m,9H,9×Ar
H)；6.09(m,1H,NC
HO)；5.27～5.13(d,2H,COCC
H 2)；4.13～3.86(m,6H,3×C
H 2)；1.98(s,3H,C
H 3)。
ESI-MSm/z：458.2[M+H]
+。
Embodiment 51-(2-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) morpholinyl) Propargyl-1-ketone
With the iodo-4-amino of 3--1H-pyrazolo [3,4-d] pyrimidine, 2-hydroxyl-4-tertbutyloxycarbonyl morpholine, 4-phenoxy group phenylo boric acid pinacol ester and propynoic acid for raw material, the method with embodiment 1 obtains title compound.
1H-NMR(500MHz,CDCl
3)δ(ppm)：8.42(d,1H,Ar
H)；7.68～7.08(m,9H,9×Ar
H)；6.13～6.05(m,1H,NC
HO)；4.67～3.32(m,6H,3×C
H 2)；3.21～3.11(d,1H,CC
H)。
ESI-MSm/z：441.3[M+H]
+。
Embodiment 61-(2-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base) morpholinyl)-2-methyl-prop-2-alkene-1-ketone
With the iodo-4-amino of 3--1H-pyrazolo [3,4-d] pyrimidine, 2-hydroxyl-4-tertbutyloxycarbonyl morpholine, 4-phenoxy group phenylo boric acid pinacol ester and 2-methacrylic acid for raw material, the method with embodiment 1 obtains title compound.
1H-NMR(500MHz,CDCl
3)δ(ppm)：8.32(s,1H,Ar
H)；7.62～7.08(m,9H,9×Ar
H)；6.06(m,1H,NC
HO)；5.27～5.13(d,2H,COCC
H 2)；4.14～3.49(m,6H,3×C
H 2)；1.97(s,3H,C
H 3)。
ESI-MSm/z：457.2[M+H]
+。
Embodiment 71-(2-(4-amino-3-(6-phenoxypyridines base-3-base)-1H-pyrazolo [3,4-d] pyrimidine-1-base) morpholinyl) Propargyl-1-ketone
With the iodo-4-amino of 3--1H-pyrazolo [3,4-d] pyrimidine, 2-hydroxyl-4-tertbutyloxycarbonyl morpholine, embodiment 3 step 1 gains 6-phenoxypyridines-3-base-3-pinacol borate and propynoic acid be raw material, the method with embodiment 1 obtains title compound.
1H-NMR(500MHz,CDCl
3)δ(ppm)：8.52～7.07(m,9H,9×Ar
H)；6.13～6.05(m,1H,NC
HO)；4.82～3.35(m,6H,3×C
H 2)；3.21～3.11(d,1H,CC
H)。
ESI-MSm/z：442.1[M+H]
+。
Experimental example 1 Compound ira vitro kinase activity of the present invention is evaluated
1 experiment material
1.1 compound
Compound of the present invention prepared by above embodiment, after each compound DMSO is diluted to 10mM, is diluted to 1uM, 100nM, 10nM, 1nM, 0.1nM, 0.01nM successively.
1.2 reagent
BTK (Bruton ' styrosinekinase, Bruton tyrosine protein kinase), purchased from Japanese CarnaBiosciences company;
Dimethyl sulfoxide (DMSO) (Dimethylsulfoxide, DMSO), purchased from Sigma Co., USA;
EDTA, purchased from Sigma Co., USA;
96 orifice plates (96wellplate), purchased from Corning company of the U.S.;
384 orifice plates (384wellplate), purchased from Corning company of the U.S..
1 × kinase buffer liquid (50mMHEPES, pH7.5,0.0015%Brij-35,10mMMgCl
2, 2mMDTT), prepared before use;
Stop buffer (100mMHEPES, pH7.5,0.015%Brij-35,0.2%CoatingReagent#3,50mMEDTA), prepared before use.
1.3 instrument
LabChipEZReader, purchased from Caliper company of the U.S..
2 experimental techniques
1) get in compound solution 10 μ l to 96 orifice plate of each concentration, add 90 μ l1 × kinase buffer liquid; Set up DMSO control group simultaneously and without enzyme control group alive, all only contain 10 μ lDMSO and 90 μ l1 × kinase buffer liquid.Each group at room temperature mixes 10min, then distinguishes in transferase 45 μ l to 384 orifice plate;
2) kinase b TK is dissolved in 1 × kinase buffer liquid, is mixed with 2.5 × kinase solution, then shift 10 μ l2.5 × kinase solution to above-mentioned containing in 384 orifice plates of each concentration compound; DMSO control group adds 10 μ l2.5 × kinase solution; 10 μ l are added not containing kinase whose 1 × kinase buffer liquid without enzyme control group alive.Incubated at room temperature 10min;
3) polypeptide marked by FAM and ATP are dissolved in 1 × kinase buffer liquid, are mixed with 2.5 × substrate solution, then shift in 10 μ l2.5 × substrate solutions to above-mentioned 384 orifice plates, hatch 1hr for 28 DEG C;
4) 25 μ l stop buffer termination reactions are added in each hole;
5) reading and converting rate data on LabChipEZReader are placed in, and calculate inhibiting rate I%, calculation formula is I%=(Max-Conversion)/(Max-Min) × 100, wherein Max is the transformation efficiency of DMSO control group, Min is the transformation efficiency without enzyme control group alive, and Conversion is the transformation efficiency of compound treatment group.Data are through XLfit process, and matching obtains IC
50.IC
50value represents and does not add compared with compound treatment group, compound concentration corresponding when compound suppresses 50% enzyme activity.IC
50the results are shown in Table 1.
Table 1
| Test-compound | IC 50(nM) | Test-compound | IC 50(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 |
Compound of the present invention suppresses the kinase whose IC of BTK
50scope, in nM rank, embodies good BTK kinase inhibiting activity.
Experimental example 2 Compound ira vitro cytoactive of the present invention is evaluated
1 experiment material
1.1 compound
Compound of the present invention prepared by above embodiment, each compound DMSO is diluted to 10mM, and dilution is 20uM, 10uM, 1uM, 100nM, 10nM, 1nM, 0.1nM successively.
1.2 reagent
RPMI-1640, purchased from American I nvitrogen company;
FBS, purchased from American I nvitrogen company;
Substratum: RPMI1640 and FBS 4:1 preparation by volume.
EDTA, purchased from Sigma Co., USA;
96 orifice plates (96wellplate), purchased from Corning company of the U.S.;
luminescentCellViabilityAssayKit, purchased from Progema company of the U.S.;
Backseal film, purchased from PerkinElmer company of the U.S..
2 experimental techniques
1) Mino (ATCC:CRL3000) cell cultures:
Cell recovery: Mino cell is placed in 37 degree of water-baths and dissolves, then transfer in the substratum of 15ml preheating, centrifugal 5 minutes of 1000rpm, discards substratum, with 15ml fresh culture re-suspended cell, is transferred in T75 culturing bottle, is placed in 37 DEG C, 5%CO
2incubator in cultivate, 24 hours later cell change fresh cultures.
Passage: the cell of above-mentioned recovery is transferred in 50ml sterile centrifugation tube, centrifugal 5 minutes of 1000rpm, discards substratum, get finely dispersed cell counting, adjust suitable cell concn to 15ml fresh culture, join in T75 culturing bottle, be placed in 37 degree, 5%CO
2incubator in cultivate.
2) experimental procedure:
In T75 Tissue Culture Flask, cell grows to 1x10
5-1x10
6after cells/ml, use fresh culture (RPMI1640+20%FBS) resuspended, and count.By resuspended cell adjustment cell concn to 10,000cells/ml, 20,000cells/ml, 30,000cells/ml, 50,000cells/ml, 80,000cells/ml, 100,000cells/ml, 150,000cells/mland200,000cells/ml8 concentration gradient.Added by cell suspension in 96 porocyte culture plates, every hole adds 100 μ l (1,000cells/well, 2,000cells/well, 3,000cells/well, 5,000cells/well, 8,000cells/well, 10,000cells/well, 15,000cells/welland20,000cells/well).Often kind of multiple hole of concentration two, spreads three blocks of plates.72h is backward treats that gaging hole adds 100 μ l
luminescentCellViabilityAssaybuffer.Shake up gently.After 10 minutes, Backseal film is sticked bottom Assay plate, be placed on Envison and read fluorescence reading, and calculating cell survival rate (cellsurvive (%)), calculation formula is cellsurvive (%)=(medicine hole reading-Min)/(Max-Min), and wherein Max is the reading of Vehicle controls group, Min is the reading of acellular control group, medicine group is the reading of compound treatment group, and data are through XLfit process, and matching obtains IC
50, experimental result is in table 2.
Table 2
| Test-compound | IC 50(μM) | Test-compound | IC 50(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 |
Compound ira vitro Mino cell of the present invention also shows good inhibit activities.
The BTK occupation rate of experimental example 3 compound of the present invention is evaluated
1 experiment material
1.1 compound
Compound of the present invention prepared by above embodiment, each compound CMC-Na is dissolved to 6mg/ml, and dosage is 30mg/kg.
1.2 reagent
RBC solution damping fluid, purchased from Boston biological products company of the U.S.;
Substratum: RPMI perfect medium;
Little mouse-anti BTK antibody, purchased from Charles Dixon BectonDickinson company of pausing in Bake;
Secondary goat anti-mouse HRP antibody, purchased from Ze Mude Zymed company;
Scribble the elisa plate of streptavidin, purchased from Pierre Si company of the U.S.;
The auspicious moral of Bayer dissolves damping fluid, purchased from American Biorad company;
Restructuring BTK, purchased from American hero company;
B220+ antibody-magnetic bead burl compound.Purchased from German Mei Tian Ni company;
2 experimental techniques
Per os gives rat 30mg/kg compound, and after compound treatment 2 hours or 24 h before harvest spleens.The spleen of rat is destroyed, to reclaim single-cell suspension liquid between 2 microscopes being covered with obscure glass.Within 2 minutes, carry out lysed erythrocyte by room temperature dissolving with RBC to cultivate together with damping fluid, subsequently by these cell settling flux in RMPI perfect medium, and make it coalescent agglomerating by centrifugal.Select to be separated rat B cell by carrying out the positive with B220+ antibody-magnetic bead burl compound, carry out purifying by MACS post, and with 10
6the concentration of individual cell/100ul is dissolved in Bayer auspicious moral dissolving damping fluid dissolves, and add probe compound and make it reach final concentration 1uM, at room temperature, cultivation 1 hour of vibrating in mixed plate, is incorporated into free BTK to make probe.After cultivating together, sample is added to scribbling on the elisa plate of streptavidin through washing, and cultivation 1 hour of at room temperature vibrating.Use automatic washer subsequently, by the PBS wash plate containing 0.05%Tween-20.In containing the PBS (containing 0.05%Tween-20) of 0.5%BSA, prepare anti-BTK antibody with the extent of dilution of 1:1000, and add in elisa plate.At room temperature, vibration cultivation 1 hour.As described above, wash plate, and anti-secondary HRP antibody is prepared with the extent of dilution of 1:5000 in containing the PBS (containing 0.05%Tween-20) of 0.5%BSA.Breezing plate, washs as described above.TMB is added in plate, and monitors OD
650, go directly 1 OD unit.Subsequently by adding H
2sO
4make reaction terminating.Use Gen5 software to analyze plate, and use the quantitative sample of this base of a fruit of 4 parameter logistics (4ParameterLogisticcurve) curve.For typical curve, use restructuring BTK.Experimental result is in table 3.
Table 3
| Process 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 shows that the time of compound of the present invention maintenance drug effect is longer, and experience 24 as a child still kept higher BTK occupation rate.
Although be below described in detail the present invention, it will be appreciated by those skilled in the art that and can carry out various amendment and change to the present invention under prerequisite without departing from the spirit and scope of the present invention.Interest field of the present invention is not limited to done detailed description above, and should belong to claims.
Claims (10)
1. the compound shown in general formula (I) or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug,
Wherein,
X is selected from key, CH
2, O, S, S (O)
2, NH ,-NH-C (O)-,-C (O)-NH-;
Y is selected from hydrogen, halogen, alkyl, haloalkyl;
R
1be selected from aryl, C
1-6alkylaryl, heteroaryl, C
1-6miscellaneous alkyl aryl, C
2-4alkynyl, described aryl, heteroaryl or alkynyl can be replaced by one or more halogen, hydroxyl, carboxyl, amino, alkyl, alkoxyl group, alkoxyalkyl, alkyloxy-alkoxy, amido, alkyl acylamino, aminoacyl, alkyl monosubstituted amino acyl group, two alkylaminoacyl, acyl group, alkyl acyl, hydroxyalkyl, alkyl monosubstituted amino, two alkylamino, Mono-alkylaminoalkyl, two alkylaminoalkyl group, nitro, cyano group;
R
2be selected from aryl, heteroaryl, described aryl, heteroaryl can be replaced by one or more halogen, hydroxyl, carboxyl, amino, alkyl, alkoxyl group, alkoxyalkyl, alkyloxy-alkoxy, amido, alkyl acylamino, aminoacyl, alkyl monosubstituted amino acyl group, two alkylaminoacyl, acyl group, alkyl acyl, hydroxyalkyl, alkyl monosubstituted amino, two alkylamino, Mono-alkylaminoalkyl, two alkylaminoalkyl group, nitro, cyano group;
R
3be selected from-C (O)-R
4,-S (O)
2-R
4, wherein R
4be selected from C
2-4thiazolinyl, C
2-4alkynyl, described alkenyl or alkynyl can be replaced by one or more cyano group, alkyl, cycloalkyl, haloalkyl, halogenated cycloalkyl, hydroxyalkyl, alkoxyl group, halogenated alkoxy, alkoxyalkyl, amino, alkyl monosubstituted amino, two alkylamino, cycloalkyl amino, aminoalkyl group, Mono-alkylaminoalkyl, two alkylaminoalkyl group, cycloalkyl amino alkyl, saturated heterocyclyl, saturated heterocyclyl alkyl, heteroaryl, heteroarylalkyl.
2. compound according to claim 1 or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug, wherein Y is selected from hydrogen, fluorine, chlorine, C
1-6alkyl, is preferably hydrogen, fluorine, methyl, ethyl.
3. compound according to claim 1 and 2 or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug, wherein X is selected from key, CH
2, O, S, be preferably key or O.
4. compound according to claim 1 and 2 or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug, wherein:
R
1be selected from aryl, C
1-3alkylaryl, heteroaryl, C
1-3miscellaneous alkyl aryl, C
2-4alkynyl, described aryl, heteroaryl or alkynyl can by one or more halogen, hydroxyl, carboxyl, amino, C
1-6alkyl, C
1-6alkoxyl group, C
1-6alkoxy-C
1-6alkyl, C
1-6alkoxy-C
1-6alkoxyl group, amido, C
1-6alkyl acylamino, aminoacyl, single C
1-6alkylaminoacyl, two C
1-6alkylaminoacyl, acyl group, C
1-6alkyl acyl, hydroxyl C
1-6alkyl, single C
1-6alkylamino, two C
1-6alkylamino, single C
1-6alkylamino-C
1-6alkyl, two C
1-6alkylamino-C
1-6alkyl, nitro, cyano group replace,
Preferably, R
1be selected from phenyl, naphthyl, pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl group, furyl, thienyl, indyl, pseudoindoyl, quinolyl, isoquinolyl, C
1-3alkyl phenyl, C
1-3alkyl naphthyl, C
1-3alkylpyridyl, C
1-3wan Ji oxazolyl, C
1-3wan isoxazole base, C
1-3wan oxadiazole base, C
1-3alkyl thiazolyl, C
1-3alkyl isothiazole base, C
1-3alkyl thiadiazolyl group, C
1-3alkyl furan base, C
1-3alkylthrophene base, C
1-3alkyl-indol base, C
1-3alkyl pseudoindoyl, C
1-3alkyl quinoline base, C
1-3alkylisoquinolinium base, ethynyl, described phenyl, naphthyl, pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl group, furyl, thienyl, indyl, pseudoindoyl, quinolyl, isoquinolyl or alkynyl can by one or more halogen, hydroxyl, carboxyl, amino, C
1-6alkyl, C
1-6alkoxyl group, C
1-6alkoxy-C
1-6alkyl, C
1-6alkoxy-C
1-6alkoxyl group, amido, C
1-6alkyl acylamino, aminoacyl, single C
1-6alkylaminoacyl, two C
1-6alkylaminoacyl, acyl group, C
1-6alkyl acyl, hydroxyl-C
1-6alkyl, single C
1-6alkylamino, two C
1-6alkylamino, single C
1-6alkylamino-C
1-6alkyl, two C
1-6alkylamino-C
1-6alkyl, nitro, cyano group replace;
Further preferably, R
1be selected from phenyl, naphthyl, pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl group, furyl, thienyl, indyl, pseudoindoyl, quinolyl, isoquinolyl, ethynyl, described phenyl, naphthyl, pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl group, furyl, thienyl, indyl, pseudoindoyl, quinolyl, isoquinolyl or alkynyl can by one or more halogen, hydroxyl, carboxyl, amino, C
1-3alkyl, C
1-3alkoxyl group, C
1-3alkoxy-C
1-3alkyl, C
1-3alkoxy-C
1-3alkoxyl group, amido, C
1-3alkyl acylamino, aminoacyl, single C
1-3alkylaminoacyl, two C
1-3alkylaminoacyl, acyl group, C
1-3alkyl acyl, hydroxyl-C
1-3alkyl, single C
1-3alkylamino, two C
1-3alkylamino, single C
1-3alkylamino-C
1-3alkyl, two C
1-3alkylamino-C
1-3alkyl, nitro, cyano group replace.
5. compound according to claim 1 and 2 or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug, wherein:
R
2be selected from aryl, heteroaryl, described aryl, heteroaryl can by one or more halogen, hydroxyl, carboxyl, amino, C
1-6alkyl, C
1-6alkoxyl group, C
1-6alkoxy-C
1-6alkyl, C
1-6alkoxy-C
1-6alkoxyl group, amido, C
1-6alkyl acylamino, aminoacyl, single C
1-6alkylaminoacyl, two C
1-6alkylaminoacyl, acyl group, C
1-6alkyl acyl, hydroxyl C
1-6alkyl, single C
1-6alkylamino, two C
1-6alkylamino, single C
1-6alkylamino-C
1-6alkyl, two C
1-6alkylamino-C
1-6alkyl, nitro, cyano group replace,
Preferably, R
2be selected from phenyl, naphthyl, pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl group, furyl, thienyl, indyl, pseudoindoyl, quinolyl, isoquinolyl, described phenyl, naphthyl, pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl group, furyl, thienyl, indyl, pseudoindoyl, quinolyl, isoquinolyl can by one or more halogen, hydroxyl, carboxyl, amino, C
1-3alkyl, C
1-3alkoxyl group, C
1-3alkoxy-C
1-3alkyl, C
1-3alkoxy-C
1-3alkoxyl group, amido, C
1-3alkyl acylamino, aminoacyl, single C
1-3alkylaminoacyl, two C
1-3alkylaminoacyl, acyl group, C
1-3alkyl acyl, hydroxyl C
1-3alkyl, single C
1-3alkylamino, two C
1-3alkylamino, single C
1-3alkylamino-C
1-3alkyl, two C
1-3alkylamino-C
1-3alkyl, nitro, cyano group replace.
6. compound according to claim 1 and 2 or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug, wherein:
R
3be selected from-C (O)-R
4,-S (O)
2-R
4, wherein, R
4be selected from C
2-4thiazolinyl, C
2-4alkynyl, described alkenyl or alkynyl can by one or more cyano group, C
1-6alkyl, C
3-8cycloalkyl, halo-C
1-6alkyl, halo C
3-8cycloalkyl, hydroxyl-C
1-6alkyl, C
1-6alkoxyl group, halo-C
1-6alkoxyl group, C
1-6alkoxy-C
1-6alkyl, amino, single C
1-6alkylamino, two C
1-6alkylamino, C
3-8cycloalkyl amino, amino-C
1-6alkyl, single C
1-6alkylamino-C
1-6alkyl, two C
1-6alkylamino-C
1-6alkyl, C
3-8cycloalkyl amino-C
1-6alkyl, saturated C
4-8heterocyclic radical, saturated C
4-8heterocyclic radical-C
1-6alkyl, heteroaryl, heteroaryl-C
1-6alkyl replaces;
Preferably, R
3be selected from-C (O)-R
4,-S (O)
2-R
4, wherein, R
4be selected from C
2-4thiazolinyl, C
2-4alkynyl, described alkenyl or alkynyl can by one or more cyano group, C
1-3alkyl, C
3-6cycloalkyl, halo-C
1-3alkyl, halo C
3-6cycloalkyl, hydroxyl-C
1-3alkyl, C
1-3alkoxyl group, halo-C
1-3alkoxyl group, C
1-3alkoxy-C
1-3alkyl, amino, single C
1-3alkylamino, two C
1-3alkylamino, C
3-6cycloalkyl amino, amino-C
1-3alkyl, single C
1-3alkylamino-C
1-3alkyl, two C
1-3alkylamino-C
1-3alkyl, C
3-6cycloalkyl amino-C
1-3alkyl, saturated C
4-8heterocyclic radical, saturated C
4-8heterocyclic radical-C
1-3alkyl, heteroaryl, heteroaryl-C
1-3alkyl replaces.
7. compound according to claim 1 or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug, wherein:
X is selected from key, CH
2, O, S;
Y is selected from hydrogen, fluorine, C
1-3alkyl;
R
1be selected from phenyl, naphthyl, pyridyl, ethynyl, described phenyl, naphthyl, pyridyl, ethynyl can by one or more halogen, hydroxyl, amino, C
1-6alkyl, C
1-6alkoxyl group, hydroxyl-C
1-6alkyl, nitro, cyano group replace;
R
2be selected from phenyl, naphthyl, pyridyl, described phenyl, naphthyl, pyridyl can by one or more halogen, hydroxyl, C
1-6alkyl, C
1-6alkoxyl group, hydroxyl-C
1-6alkyl, nitro, cyano group replace;
R
3be selected from-C (O)-R
4,-S (O)
2-R
4, wherein, R
4be selected from vinyl, ethynyl, described vinyl, ethynyl can by one or more cyano group, C
1-6alkyl, C
3-8cycloalkyl, halo-C
1-6alkyl, halo C
3-8cycloalkyl, hydroxyl-C
1-6alkyl, C
1-6alkoxyl group, halo-C
1-6alkoxyl group, C
1-6alkoxy-C
1-6alkyl, amino, single C
1-6alkylamino, two C
1-6alkylamino, C
3-6cycloalkyl amino, amino-C
1-6alkyl, single C
1-6alkylamino C
1-6alkyl, two C
1-6alkylamino-C
1-6alkyl, C
3-6cycloalkyl amino-C
1-6alkyl, saturated C
3-8heterocyclic radical, saturated C
3-8heterocyclic radical-C
1-6alkyl, heteroaryl, heteroaryl-C
1-6alkyl replaces.
8. compound according to claim 1 or its pharmacologically acceptable salts, isomer, solvate, crystallization or prodrug, wherein said compound is be selected from following compound:
9. a pharmaceutical composition, it comprises compound described in any one of claim 1-8 or its pharmacy acceptable salt, isomer, solvate, crystallization or prodrug and pharmaceutically acceptable carrier.
10. the compound described in any one of claim 1-8 or its pharmacy acceptable salt, isomer, solvate, crystallization or prodrug or the application of pharmaceutical composition according to claim 9 in the medicine for the preparation for the treatment of or prophylaxis of tumours.
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| 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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