CN108948082A - A kind of diaminopyrimidine compounds and the composition comprising the compound - Google Patents

A kind of diaminopyrimidine compounds and the composition comprising the compound Download PDF

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CN108948082A
CN108948082A CN201810922557.9A CN201810922557A CN108948082A CN 108948082 A CN108948082 A CN 108948082A CN 201810922557 A CN201810922557 A CN 201810922557A CN 108948082 A CN108948082 A CN 108948082A
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compound
deuterium
diaminopyrimidine compounds
pharmaceutically acceptable
compounds
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王义汉
李焕银
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Shenzhen Rui Rui Rui Biological Medicine Co Ltd
Shenzhen Targetrx Inc
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Abstract

The present invention provides a kind of diaminopyrimidine compounds and comprising the composition of the compound, the invention discloses the diaminopyrimidine compounds as shown in formula (I) and the pharmaceutical compositions containing the compound or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, stereoisomer, prodrug or isotopic variations.Diaminopyrimidine compounds disclosed by the invention and composition comprising the compound have excellent inhibition to protein kinase, there is better pharmacokinetic parameter characteristic simultaneously, it can be improved the drug concentration of compound in animal body, to improve curative effect of medication and safety.

Description

A kind of diaminopyrimidine compounds and the composition comprising the compound
The application be the applying date be on July 22nd, 2016, application No. is 201610587472.0, it is entitled " a kind of The divisional application of the application for a patent for invention of diaminopyrimidine compounds and composition comprising the compound ".
Technical field
The invention belongs to pharmaceutical technology field more particularly to a kind of diaminopyrimidine compounds and include the group of the compound Close object.
Background technique
In Past 30 Years, lung cancer mortality rises 465%, and disease incidence increases by 26.9% every year, it has also become China is first Position Death Cause for Malignant Tumors.Wherein non-small cell lung cancer (non-small cell lung cancer, NSCLC) accounts for all lungs 80% or more of cancer, only the NSCLC patient of one third there are the chance of operative treatment, about 70% patient when medical Belong to Locally Advanced or DISTANT METASTASES IN occur, loses the chance of operation, in this case, drug therapy is particularly important. Anaplastic lymphoma kinase (anaplasticlymphoma kinase, ALK) Gene Fusion in the recent period have become one it is important Biomarker, provide help for patient's selection of specific NSCLC subgroup, to carry out treatment using corresponding inhibitor.Lung Cancer research international association (IASLC) recommends to merge detection using ALK to instruct patient screening, and late selection can in adenocarcinoma patients The patient of ALK inhibitor for treating is adopted, no matter its sex, race, smoking history or other clinical risk factors.Using double labels point For selecting the patient of acceptable ALK-TKI treatment, this diagnostic method is obtained for fluorescence in situ hybridization (FISH) detection from probe U.S. FDA approval is obtained, treats in the research that ALK resets tumour and is used for Buddhist nun in gram azoles.Gram azoles is three phosphorus of oral type for Buddhist nun Adenosine monophosphate (ATP) competitive inhibitor, can inhibit ALK and MET tyrosine kinase, additionally it is possible to inhibit the work of ROS1 and RON kinases Property.
But gram azoles will appear following side effect: dysopia, gastrointestinal side effect for Buddhist nun, 3-4 occurs for 16% case Grade liver transaminase levels increase.In addition, ALK positive patient is inevitable after gram azoles of incipient stage treats sensitive periods for Buddhist nun There is acquired resistance in ground.Therefore, for need develop to it is with ALK kinase inhibiting activity and/or have more preferable pharmacodynamics/ The compound of pharmacokinetics performance.
Summary of the invention
Against the above technical problems, the invention discloses a kind of diaminopyrimidine compounds and include the combination of the compound Object with better ALK kinase inhibiting activity and/or has more preferable pharmacodynamics/pharmacokinetics performance.
In this regard, the technical solution adopted by the present invention are as follows:
The object of the present invention is to provide it is a kind of novel with ALK kinase inhibiting activity and/or with more preferable pharmacodynamics/ The compound of pharmacokinetics performance.
In the first aspect of the present invention, diaminopyrimidine compounds or its crystal form, medicine shown in a kind of formula (I) are provided Acceptable salt, hydrate or solvated compounds on.
In formula:
Wherein: R1a、R1b、R1c、R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R6、R7a、R7b、R8a、R8b、R9a、R9b、R10a、 R10b、R11、R12、R13、R14a、R14b、R14c、R15、R16、R17a、R17b、R17c、R18a、R18b、R18c、R19、R20、R21And R22Respectively solely It is on the spot hydrogen, deuterium, halogen or trifluoromethyl；
R16For hydrogen, deuterium, halogen, cyano, not deuterated C1-C6Alkyl or C1-C6Alkoxy, it is one or many deuterated or Complete deuterated C1-C6Alkyl or C1-C6Alkoxy, or C that one or more halogens replace or that perhalogeno element replaces1-C6Alkyl Or C1-C6Alkoxy；
Additional conditions are R1a、R1b、R1c、R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R6、R7a、R7b、R8a、R8b、R9a、R9b、 R10a、R10b、R11、R12、R13、R14a、R14b、R14c、R15、R16、R17a、R17b、R17c、R18a、R18b、R18c、R19、R20、R21And R22In At least one is deuterated or deuterium.
Shape and volume of the deuterium in drug molecule are substantially the same with hydrogen, if hydrogen is selectively replaced in drug molecule For deuterium, deuterated drug generally can also retain original bioactivity and selectivity.Inventor passes through it is experimentally confirmed that carbon deuterium key simultaneously Combination it is more more stable than the combination of C-H bond, the attributes such as absorption, distribution, metabolism and the excretion of some drugs can be directly affected, from And improve curative effect, safety and the tolerance of drug.
In another preferred example, deuterium isotopic content of the deuterium in each deuterated position is at least greater than natural deuterium isotopic content (0.015%), it is preferably greater than 30%, even more preferably greater than 50%, even more preferably greater than 75%, even more preferably greater than 95%, more preferably Greater than 99%.
Specifically, R in the present invention1a、R1b、R1c、R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R6、R7a、R7b、R8a、 R8b、R9a、R9b、R10a、R10b、R11、R12、R13、R14a、R14b、R14c、R15、R16、R17a、R17b、R17c、R18a、R18b、R18c、R19、R20、 R21And R22Deuterium isotopic content is at least 5% in each deuterated position, is preferably greater than 10%, even more preferably greater than 15%, more preferably Greater than 20%, even more preferably greater than 25%, even more preferably greater than 30%, even more preferably greater than 35%, even more preferably greater than 40%, more preferably greatly In 45%, even more preferably greater than 50%, even more preferably greater than 55%, even more preferably greater than 60%, even more preferably greater than 65%, even more preferably greater than 70%, even more preferably greater than 75%, even more preferably greater than 80%, even more preferably greater than 85%, even more preferably greater than 90%, even more preferably greater than 95%, even more preferably greater than 99%.
In another preferred example, compound at least contains a D-atom in formula (I), and the number containing D-atom can be Any one in 1 to 38.
In another preferred example, compound at least contains a D-atom in formula (I), and the number containing D-atom can be Any one in 1 to 38.
In another preferred example, in formula (I) compound R1a、R1b、R1c、R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R6、 R7a、R7b、R8a、R8b、R9a、R9b、R10a、R10b、R11、R12、R13、R14a、R14b、R14c、R15、R16、R17a、R17b、R17c、R18a、R18b、 R18c、R19、R20、R21And R22, at least one of which R contains deuterium, and more preferably two R contain deuterium, and more preferably three R contain deuterium, and more preferably four A R contains deuterium, and more preferably five R contain deuterium, and more preferably six R contain deuterium, and more preferably seven R contain deuterium, and more preferably eight R contain deuterium, more preferably Nine, ground R contains deuterium, and more preferably ten R contain deuterium, and more preferably 11 R contain deuterium, and more preferably 12 R contain deuterium, more preferably 13 R Containing deuterium, more preferably 14 R contain deuterium, and more preferably 15 R contain deuterium, and more preferably 16 R contain deuterium, and more preferably 17 R contain deuterium, More preferably 18 R contain deuterium, and more preferably 19 R contain deuterium, and more preferably 20 R contain deuterium, and more preferably 21 R contain deuterium, more Good 22 R in ground contain deuterium, and more preferably 23 R contain deuterium, and more preferably 24 R contain deuterium, and more preferably 25 R contain Deuterium, more preferably 26 R contain deuterium, and more preferably 27 R contain deuterium, and more preferably 28 R contain deuterium, and more preferably 29 R contains deuterium, and more preferably 30 R contain deuterium, and more preferably 31 R contain deuterium, and more preferably 32 R contain deuterium, and more preferably 33 A R contains deuterium, and more preferably 34 R contain deuterium, and more preferably 35 R contain deuterium, and more preferably 36 R contain deuterium, and more preferably three 17 R contain deuterium, and more preferably 38 R contain deuterium.
In another preferred example, R1a、R1bAnd R1cIt is each independently deuterium or hydrogen.
In another preferred example, R2a、R2b、R3a、R3b、R4a、R4b、R5aAnd R5bIt is each independently deuterium or hydrogen.
In another preferred example, R6For deuterium or hydrogen.
In another preferred example, R7a、R7b、R8a、R8b、R9a、R9b、R10aAnd R10bIt is each independently deuterium or hydrogen.
In another preferred example, R11、R12And R13It is each independently deuterium or hydrogen.
In another preferred example, R14a、R14bAnd R14cIt is each independently deuterium or hydrogen.
In another preferred example, R17a、R17bAnd R17cIt is each independently deuterium or hydrogen.
In another preferred example, R18a、R18bAnd R18cIt is each independently deuterium or hydrogen.
In another preferred example, R19、R20、R21And R22It is each independently deuterium or hydrogen.
In another preferred example, R16Separately select halogen, trifluoromethyl, cyano, one or many deuterated alkane Base and alkoxy.
In another preferred example, which is characterized in that R16It is chlorine.
In another preferred example, which is characterized in that R1a、R1b、R1cIt is deuterium.
In another preferred example, which is characterized in that R2a、R2b、R5a、R5bIt is deuterium.
In another preferred example, which is characterized in that R3a、R3b、R4a、R4bIt is deuterium.
In another preferred example, R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5bIt is deuterium.
In another preferred example, R6It is deuterium.
In another preferred example, R7a、R7b、R10a、R10bIt is deuterium.
In another preferred example, R8a、R8b、R9a、R9bIt is deuterium.
In another preferred example, R7a、R7b、R8a、R8b、R9a、R9b、R10a、R10bIt is deuterium.
In another preferred example, R11、R13It is deuterium.
In another preferred example, R11、R12、R13It is deuterium.
In another preferred example, R14a、R14b、R14cIt is deuterium.
In another preferred example, R17a、R17b、R17c、R18a、R18b、R18cIt is deuterium.
In another preferred example, R20、R22It is deuterium.
In another preferred example, R19、R20、R21、R22It is deuterium.
In another preferred example, the compound is selected from the group compound or its pharmaceutically acceptable salt:
The chloro- N of 5-4[2- (solutions of dimethyl phosphoryl base) phenyl]-N2{ 2-d3- methoxyl group -4- [4- (4- methylpiperazine-1-yl) Piperidin-1-yl] phenyl } pyrimidine -2,4- diamines, shown in structural formula such as formula (2)；
The chloro- N of 5-4[2- (solutions of dimethyl phosphoryl base) phenyl]-N2{ 2- methoxyl group -4- [4- (4-d3- methylpiperazine-1-yl) Piperidin-1-yl] phenyl } pyrimidine -2,4- diamines, shown in structural formula such as formula (3)；
The chloro- N of 5-4[2- (solutions of dimethyl phosphoryl base) phenyl]-N2{ 2- methoxyl group -4- [4- (4- thyl-piperazin -1- base) -4- D- piperidin-1-yl] phenyl } pyrimidine -2,4- diamines, shown in structural formula such as formula (4)；
The chloro- N of 5-4[2- (solutions of dimethyl phosphoryl base) phenyl]-N2{ 2- methoxyl group -4- [4- (4- methyl -3,3,5,5-d4- piperazine Piperazine -1- base) piperidin-1-yl] phenyl } pyrimidine -2,4- diamines, shown in structural formula such as formula (5)；
In another preferred example, the compound is selected from the group compound or its pharmaceutically acceptable salt:
In another preferred example, the compound does not include non-deuterated compound.
In another preferred example, the non-deuterated compound is the chloro- N4- of 5- (2- (dimethyl oxygen phosphino-) phenyl)-N2- (2- methoxyl group -4- (4- (4- methylpiperazine-1-yl)-piperidin-1-yl) phenyl) pyrimidine -2,4- diamines.
In the second aspect of the present invention, a kind of method for preparing pharmaceutical composition is provided, comprising steps of will pharmaceutically Compound described in acceptable carrier and first aspect present invention or its crystal form, pharmaceutically acceptable salt, hydrate or Solvate is mixed, to form pharmaceutical composition.
In the third aspect of the invention, provide a kind of pharmaceutical composition, it contain pharmaceutically acceptable carrier and Compound described in first aspect present invention or its crystal form, pharmaceutically acceptable salt, hydrate or solvate.
In another preferred example, the pharmaceutical composition is injection, wafer, tablet, pill, powder or granule.
In another preferred example, the pharmaceutical composition also contains other therapeutic agent, the other treatment Drug is cancer, cardiovascular disease, inflammation, infection, immunity disease, cell proliferation disorders, viral disease, metabolic disease Disease or the drug of organ transplant.
In the fourth aspect of the invention, compound described in first aspect present invention or its crystal form, pharmacy are provided Upper acceptable salt, prodrug, stereoisomer, isotopic variations, the purposes of hydrate or solvate, they be used to prepare The pharmaceutical composition of protease inhibition.
In another preferred example, the pharmaceutical composition is for treating and preventing following disease: cancer, cell proliferative Disease, inflammation, infection, immunity disease, organ transplant, viral disease, cardiovascular disease or metabolic disease.
In another preferred example, the cancer includes but is not limited to: lung cancer, head and neck cancer, breast cancer, prostate cancer, Cancer of the esophagus, the carcinoma of the rectum, colon cancer, nasopharyngeal carcinoma, uterine cancer, cancer of pancreas, lymthoma, leukemia, osteosarcoma, melanoma, kidney, stomach Cancer, liver cancer, bladder cancer, thyroid cancer or colorectal cancer.
In another preferred example, the immunity disease or inflammation include but is not limited to: rheumatoid arthritis, bone close Save inflammation, poker back, gout, asthma, bronchitis, rhinitis, chronic obstructive pulmonary disease, cystic fibrosis.
In another preferred example, the cell proliferation disorders refer to lung cancer, head and neck cancer, breast cancer, prostate cancer, food Road cancer, the carcinoma of the rectum, colon cancer, nasopharyngeal carcinoma, uterine cancer, cancer of pancreas, lymthoma, leukemia, osteosarcoma, melanoma, kidney, stomach Cancer, liver cancer, bladder cancer, thyroid cancer or colorectal cancer.
In another preferred example, the cancer is non-small cell lung cancer.
In in the fifth aspect of the invention, a kind of method or a kind of disease for inhibiting protein kinase (such as ALK kinases) is provided Sick (such as cancer, cell proliferation disorders, inflammation, infection, immunity disease, organ transplant, viral disease, cardiovascular disease Or metabolic disease) treatment method, it comprising steps of to object in need for the treatment of application first aspect present invention described in Compound or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, or described in application third aspect present invention Pharmaceutical composition.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist This no longer tires out one by one states.
The invention also includes the compounds of isotope labelling, are equal to original chemical and are disclosed.This hair can be classified as The example of bright compound isotope includes hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine isotope, respectively such as2H,3H,13C,14C,15N,17O,18O,31P,32P,35S,18F and36Cl.Compound or enantiomer in the present invention, diastereomer, isomers or medicine Acceptable salt or solvate on, wherein containing the isotope of above compound or other other isotope atoms all at this Within the scope of invention.Certain compound isotopically labelleds in the present invention, such as3H and14The radioactive isotope of C also wherein, It is useful in the experiment of the Tissue distribution of drug and substrate.Tritium, i.e.,3H and carbon-14, i.e.,14C, their preparation and detection are compared It is easy, is the first choice in isotope.In addition, higher isotope replaces such as deuterium, i.e.,2H, since its good metabolic stability is at certain It is advantageous in a little therapies, such as in vivo therefore increase half-life period or reduction dosage can be paid the utmost attention in some cases. The compound of isotope labelling can use general method, non isotopic by being replaced with the isotope labeling reagent being easy to get Reagent can be prepared with the scheme in example.
Herein, unless otherwise instructed, " halogen " refers to F, Cl, Br and I.More preferably, halogen atom is selected from F, Cl and Br.
Herein, unless otherwise instructed, " C1-C6Alkyl " refers to the alkyl of the linear chain or branched chain including 1-6 carbon atom, Such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl or similar group.
Herein, unless otherwise instructed, " deuterated " refers to one or more hydrogen in compound or group replaced deuterium；Deuterium In generation, can be a substitution, two replace, polysubstituted or full substitution.Term " one or more deuterated " and " one or many deuterated " It is used interchangeably.
Herein, unless otherwise instructed, " non-deuterated compound " refers to ratio containing D-atom not higher than the same position of natural deuterium The compound of cellulose content (0.015%).
In the present invention, pharmaceutically acceptable salt includes inorganic salts and organic salt.A kind of preferred salt is chemical combination of the present invention The salt that object and acid are formed.The acid for suitably forming salt includes but is not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid Equal inorganic acids；Formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, apple Acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, naphthalene sulfonic acids etc. are organic Acid；And the amino acid such as proline, phenylalanine, aspartic acid, glutamic acid.Another kind of preferred salt be the compounds of this invention with The salt that alkali is formed, such as alkali metal salt (such as sodium salt or sylvite), alkali salt (such as magnesium salts or calcium salt), ammonium salt are (such as low Grade alkanol ammonium salt and other pharmaceutically acceptable amine salt), such as methylamine salt, ethylamine salt, propylamine salt, dimethyl amine salt, Trismethylamine salt, diethyl amine salt, triethyl amine salt, tert-butylamine salt, ethylenediamine salt, oxyethylamine salt, dihydroxy ethylamine salt, three hydroxyls Ethylamine salt, and the amine salt formed respectively by morpholine, piperazine, lysine.
Term " solvate " refers to that the compounds of this invention and solvent molecule are coordinated the complex to form special ratios." hydration Object " refers to that the compounds of this invention and water carry out the complex of coordination formation.
Compared with prior art, the invention has the benefit that
(1) the compounds of this invention has excellent inhibition to protein kinase (kinase) (such as ALK kinases).
(2) metabolism of the compound in organism is changed by this technology of deuterate, makes compound that there is better medicine generation Kinetic parameter characteristic.In such a case, it is possible to change dosage and form durative action preparation, improve applicability.
(3) compound can be improved in animal body due to its deuterium isotope effect with the hydrogen atom in deuterium substituted compound Interior drug concentration, to improve curative effect of medication.
(4) peace of compound may be improved since certain metabolites are suppressed with the hydrogen atom in deuterium substituted compound Quan Xing.
Specific embodiment
The preparation method of formula (I) structural compounds of the present invention is described more particularly below, but these specific methods are not to this Invention constitutes any restrictions.The compounds of this invention can also optionally will be describing or known in the art various in the present specification Synthetic method combines and is easily made, such combination can by those skilled in the art in the invention easily into Row.
The preparation method of the salt for the not deuterated diaminopyrimidine compounds and its physical compatibility that the present invention uses is Know.The preparation of corresponding deuterated diaminopyrimidine compounds can be raw material with corresponding deuterated initial compounds, with same Route synthesis.For example, formula (I) compound of the present invention can be prepared by the preparation method described in WO2012061299, difference It is to replace non-deuterated raw material with deuterated raw material in the reaction.
In general, each reaction is usually in atent solvent, in room temperature to reflux temperature (such as 0 DEG C~100 in preparation flow DEG C, preferably 0 DEG C~80 DEG C) under carry out.Reaction time is usually -60 hours 0.1 hour, preferably 0.5-24 hours.
Following general preparation route can be used for synthesizing the compound of formula (I) structure of the present invention.The following institute of synthetic route Show:
The synthesis of piperazine substituted piperidine amine is as follows:
It is described in detail below with reference to embodiment.
Embodiment 1
The chloro- N of 5- is prepared according to following synthetic route4[2- (solutions of dimethyl phosphoryl base) phenyl]-N2{ 2-d3- methoxyl group -4- [4- (4- methylpiperazine-1-yl)-piperidin-1-yl] phenyl } pyrimidine -2,4- diamines (compound 9 in following synthetic routes):
It is prepared using following steps:
(1) prepare compound 2:
In 100mL single port bottle be added 30mL acetone, sequentially added under stirring the fluoro- 2- nitrophenol of 5- (2.0g, 12.7mmol), Anhydrous potassium carbonate (3.5g, 25.4mmol), deuterated iodomethane (2.4g, 16.5mmol), are warming up to 60 DEG C and protect Temperature stirring 2h.It is cooled to room temperature, rotary evaporation falls acetone, and water 20mL is added in residue, and ethyl acetate extracts (30mL x 3), closes And organic layer, anhydrous sodium sulfate dry, filter, filtrate is concentrated to give white solid 2.0g, yield 90%.
1H NMR(300MHz,CDCl3) (δ/ppm) 8.00-7.95 (m, 1H), 6.83-6.71 (m, 2H), LC-MS (APCI): m/z=175.2 (M+1)+, 95%.
(2) prepare compound 4:
N,N-Dimethylformamide (4mL) is added in 25mL single-necked flask, the fluoro- 2-d3- first of 4- is sequentially added under stirring Oxygroup nitrobenzene (0.4g, 2.3mmol), 1- methyl -4- (piperidin-4-yl) piperazine hydrochloride (0.7g, 3.2mmol), anhydrous carbon Sour potassium (0.95g, 6.9mmol), reaction mixture are warming up to 80 DEG C, N2It is reacted overnight under atmosphere.It is cooled to room temperature, pours into ice water In (80mL), a large amount of yellow solids are precipitated, filter, and be dissolved in DCM (40mL), anhydrous sodium sulfate dries, filters, filtrate concentration Obtain yellow solid 0.55g, yield 70.9%.
LC-MS (APCI): m/z=338.2 (M+1)+；1H NMR(300MHz,CDCl3) (δ/ppm) 8.01 (d, J= 9.3Hz, 1H), 6.43 (dd, J=9.6Hz, J=2.7Hz, 1H), 6.31 (d, J=2.4Hz, 1H), 3.98-3.94 (m, 2H), 3.03-2.94(m,2H),2.65-2.62(m,4H),2.54-2.46(m,5H),2.32(s,3H),2.01-1.96(m,2H), 1.65-1.60(m,2H)。
(3) prepare compound 5:
Ethyl alcohol 6mL and water 2mL is added in 25mL single port bottle, 1- (1- (3-d3- methoxyl group -4- nitre is sequentially added under stirring Base phenyl) piperidin-4-yl) -4- methyl piperazine (0.2g, 0.59mmol), reduced iron powder (0.20g, 3.55mmol), ammonium chloride (16mg, 0.30mmol), reaction mixture N285 DEG C are warming up under atmosphere, and insulated and stirred reacts 1h.It is cooled to room temperature, is filtered solid Body substance, filtrate are concentrated, and saturated sodium bicarbonate (5mL) is added in residue, and methylene chloride extracts (15mL x 2), merge organic Phase, anhydrous sodium sulfate dry, filter, and are concentrated to give off-white powder 0.15g, and yield 79.6% is directly thrown in next step.
(4) prepare compound 8:
In 25mL single port bottle be added DMF (3mL), sequentially added under stirring 2,5,6- trichloropyrimidines (0.72g, 3.9mmol), 2- (dimethyl phosphino-) aniline (0.5g, 3mmol), Anhydrous potassium carbonate (0.62g, 4.5mmol), are warming up to 60 DEG C and keep the temperature Stir 4h.It is cooled to room temperature, sequentially adds ethyl acetate (30mL), water (30mL), concussion layering, aqueous layer with ethyl acetate extraction (30mL x 2) merges organic phase, washes (60mL x 2), and organic layer anhydrous sodium sulfate dries, filters, concentration, residue mistake Silicagel column obtains faint yellow solid 0.8g, yield 84.6%.
LC-MS (APCI): m/z=175.2 (M+1)+；1H NMR(CDCl3,300MHz)(δ/ppm)8.00-7.95(m, 1H),6.83-6.71(m,2H)。
(5) prepare compound 9:
Glycol monoethyl ether 2mL is added in 25mL single port bottle, 2,5-, bis- chloro- N- (2- (dimethyl is sequentially added under stirring Phosphoroso-) phenyl) pyrimidine -4- amine (60mg, 0.19mmol), 1- (1- (3-d3- methoxyl group -4- aminocarbonyl phenyl) piperidin-4-yl) - 4- methyl piperazine (60mg, 0.2mmol), concentrated hydrochloric acid (two drops), reaction mixture N2100 DEG C, and insulated and stirred are warming up under atmosphere Reaction is overnight.It is cooled to room temperature, is added saturated sodium bicarbonate water liquid (10mL), methylene chloride extracts (15mL x 3), is associated with Machine phase, anhydrous sodium sulfate dry, filter, concentration, cross silicagel column and obtain white solid 60mg, yield 50.1%；
LC-MS (APCI): m/z=587.2 (M+1)+；1H NMR(300MHz,DMSO-d6)(δ/ppm)11.18(s,1H), 8.51-8.47(m,1H),0.08-8.07(m,2H),7.57-7.50(m,1H),7.40-7.32(m,2H),7.12-7.07(m, 1H), 6.62 (d, J=2.4Hz, 1H), 6.47 (dd, J=9.0Hz, 2.4Hz, 1H), 3.77-3.72 (m, 2H), 2.82-2.61 (m,11H),2.48-2.34(m,3H),1.91-1.85(m,2H),1.79(s,3H),1.74(s,3H),1.59-1.52(m, 2H)。
Embodiment 2
The chloro- N of 5- is prepared according to following synthetic route4[2- (solutions of dimethyl phosphoryl base) phenyl]-N2{ 2- methoxyl group -4- [4- (4-d3- methylpiperazine-1-yl)-piperidin-1-yl] phenyl } pyrimidine -2,4- diamines (compound 15 in following synthetic routes):
The following steps are included:
(1) prepare compound 10:
N,N-Dimethylformamide (10mL) is added in 100mL single-necked flask, the fluoro- 2- methoxyl group of 4- is sequentially added under stirring Nitrobenzene (2g, 11.8mmol), piperidin-4-one hydrochloride (2.23g, 16.5mmol), Anhydrous potassium carbonate (4.88g, 35.4mmol), reaction mixture is warming up to 80 DEG C, N2It is reacted overnight under atmosphere.It is cooled to room temperature, is poured into ice water (80mL), is analysed A large amount of yellow solids out, filtering, and be dissolved in DCM (100mL), anhydrous sodium sulfate dries, filters, and filtrate is concentrated to give yellow solid 2.2g, yield 74.6%.
LC-MS (APCI): m/z=251.2 (M+1)+；1H NMR (300MHz, DMSO-d6) (δ/ppm) 7.93 (d, J= 9.6Hz, 1H), 6.62 (dd, J=9.6Hz, 2.4Hz, 1H), 6.53 (d, J=2.4Hz, 1H), 3.94 (s, 3H), 3.84 (t, J =6.3Hz, 4H), 2.50 (t, J=6.3Hz, 4H).
(2) prepare compound 11:
Toluene 20mL is added in 100mL single-necked flask, 1- (3- methoxyl group -4- nitrobenzophenone) piperazine is sequentially added under stirring Pyridine -4- ketone (0.53g, 2.1mmol), triethylamine (0.8mL), N-Boc piperazine (0.85g, 4.5mmol), N2It is stirred to react under atmosphere 30min is added at one time acetic acid sodium borohydride (0.4g, 1.92mmol), is stirred 30min, is added acetic acid boron hydrogen again in three times Change sodium 1.2g, fully reacting.It is added saturated sodium bicarbonate water liquid (30mL), separates organic layer, water layer ethyl acetate extracts (30mL X 2), merge organic phase, anhydrous sodium sulfate dries, filters, and is concentrated, and residue crosses silicagel column and obtains faint yellow solid 0.58g, yield 65.7%.
LC-MS (APCI): m/z=421.2 (M+1)+；1H NMR(300MHz,CDCl3) (δ/ppm) 8.01 (d, J= 9.3Hz, 1H), 6.43 (dd, J=9.6Hz, 2.7Hz, 1H), 6.31 (d, J=2.4Hz, 1H), 3.94 (s, 3H), 3.03-2.94 (m,2H),2.65-2.62(m,4H),2.54-2.46(m,5H),2.32(s,3H),2.01-1.96(m,2H),1.65-1.60 (m, 2H), 1.51 (s, 9H).
(3) prepare compound 12:
Methylene chloride 20mL is added in 100mL single-necked flask, 4- (1- (3- methoxyl group -4- nitro is sequentially added under stirring Phenyl) piperidin-4-yl) piperazinyl -1- tert-butyl ester (0.58g, 1.4mmol), trifluoracetic acid (2mL), N2Stirring at normal temperature is anti-under atmosphere 1h is answered, reaction solution is concentrated to dryness, and is added saturated sodium bicarbonate water liquid (10mL), and mixture methylene chloride extracts (20mL x 3), Anhydrous sodium sulfate dries, filters, and is concentrated to give yellow solid 0.45g, yield 100%, and LC-MS (APCI): m/z=321.2 (M+1 )+。
(4) prepare compound 13:
Acetonitrile 5mL is added in 25mL single-necked flask, 4- (1- (3- methoxyl group -4- nitrobenzophenone) is sequentially added under stirring Piperidin-4-yl) piperazine (0.32g, 1mmol), addition triethylamine (0.12g, 1.2mmol), ice-water bath is cooling, is slowly added dropwise into deuterium For iodomethane (0.16g, 1.1mmol), be stirred to react 30min under ice-water bath, be concentrated to dryness, residue cross silicagel column obtain it is yellow Color solid 0.15g, yield 44.5%.
LC-MS (APCI): m/z=338.2 (M+1)+；1H NMR(300MHz,CDCl3) (δ/ppm) 8.01 (d, J= 9.3Hz, 1H), 6.43 (dd, J=9.6Hz, 2.7Hz, 1H), 6.31 (d, J=2.4Hz, 1H), 3.98-3.94 (m, 2H), 3.92 (s,3H),3.03-2.94(m,2H),2.65-2.62(m,4H),2.54-2.46(m,5H),2.01-1.96(m,2H),1.65- 1.60(m,2H)。
(5) prepare compound 14, preparation method is consistent with the preparation method of compound 5, the difference is that with 1- (1- (3- methoxyl group -4- nitrobenzophenone) piperidin-4-yl) -4-d3- methyl piperazine substitution 1- (1- (3-d3- methoxyl group -4- nitrobenzene Base) piperidin-4-yl) -4- methyl piperazine.
(6) the chloro- N of 5- is prepared4[2- (dimethyl oxygen phosphino-) phenyl]-N2{ 2- methoxyl group -4- [4- (4-d3- methyl piperazine Piperazine -1- base)-piperidin-1-yl] phenyl } pyrimidine -2,4- diamines (compound 14), the preparation method of preparation method and compound 9 Unanimously, the difference is that substituting 1- using 1- (1- (3- methoxyl group -4- aminocarbonyl phenyl) piperidin-4-yl) -4-d3- methyl piperazine (1- (3-d3- methoxyl group -4- aminocarbonyl phenyl) piperidin-4-yl) -4- methyl piperazine.
LC-MS (APCI): m/z=587.2 (M+1)+；1H NMR(300MHz,DMSO-d6)(δ/ppm)11.18(s,1H), 8.51-8.47(m,1H),0.08-8.07(m,2H),7.57-7.50(m,1H),7.40-7.32(m,2H),7.12-7.07(m, 1H), 6.62 (d, J=2.4Hz, 1H), 6.47 (dd, J=9.0Hz, 2.4Hz, 1H), 3.76-3.71 (m, 6H), 2.82-2.61 (m,11H),2.48-2.34(m,3H),1.91-1.85(m,2H),1.79(s,3H),1.74(s,3H),1.59-1.52(m, 2H)。
Embodiment 3
The chloro- N of 5- is prepared according to following synthetic route4[2- (solutions of dimethyl phosphoryl base) phenyl]-N2{ 2- methoxyl group -4- [4- (4- methylpiperazine-1-yl) -4-d- piperidin-1-yl] phenyl } pyrimidine -2,4- diamines (compound 20 in following synthetic routes):
The following steps are included:
(1) prepare compound 16:
Deuterated methanol 10mL is added in 50mL single-necked flask, ice-water bath is added with stirring 1- (3- methoxyl group -4- nitrobenzene Base) piperidin-4-one (0.25g, 1mmol), deuterated sodium borohydride (42mg, 1mmol), ice-water bath N are slowly added to after complete dissolved clarification2 It is stirred to react 5min under atmosphere, heavy water (2mL) quenching reaction, and stirring at normal temperature 30min is added, sequentially adds water (30mL) and acetic acid Ethyl ester (30mL) separates organic layer, and water layer ethyl acetate extracts (30mL x 2), and concentration, residue is again dissolved in ethyl acetate (50mL), saturated common salt water washing (20mL x 1), organic phase anhydrous sodium sulfate dries, filters, and is concentrated to give yellow solid 0.25g, yield 96%.
LC-MS (ESI): m/z=254.2 (M+1)+；1H NMR(300MHz,DMSO-d6) (δ/ppm) 7.88 (d, J= 9.3Hz, 1H), 6.58 (dd, J=9.3Hz, 2.4Hz, 1H), 6.49 (d, J=2.4Hz, 1H), 4.75 (s, 1H), 3.90 (s, 3H),3.83-3.77(m,2H),3.23-3.14(s,2H),1.84-1.76(m,2H),1.45-1.37(m,2H)。
(2) prepare compound 17:
Methylene chloride (15mL) is added in 50mL single-necked flask, 1- (3- methyl -4- nitrobenzophenone)-is added under ice-water bath 4-d- piperidines -4- alcohol (0.25g, 1mmol) is added with stirring triethylamine (0.18g, 1.8mmol), is slowly added dropwise into sulfonyloxy methyl Chlorine (0.17g, 1.5mmol), room temperature N21h is stirred to react under atmosphere.It is added water (20mL), concussion separates organic layer, water layer dichloromethane Alkane extracts (20mL x 2), merges organic layer, successively uses 0.5M HCl/water liquid (20mL x 1), saturated sodium bicarbonate water liquid (15mL x 1), saturated salt solution (15mL x 1), anhydrous sodium sulfate dries, filters, and is concentrated to dryness to obtain yellow solid 0.3g, receives Rate 90.9% is directly used in next step.
(3) prepare compound 18:
DMF (3mL) is added in 25mL single-necked flask, 1- (3- methyl -4- nitrobenzophenone) -4-d- is sequentially added under stirring Piperidines -4- methanesulfonate ester (0.3g, 0.9mmol), 1- methyl piperazine (0.36g, 3.6mmol), Anhydrous potassium carbonate (0.62g, 4.5mmol), mixture is warming up to 100 DEG C, N2Insulated and stirred reaction is stayed overnight under atmosphere.It is cooled to room temperature, water (30mL) and second is added Acetoacetic ester (30mL) separates organic layer, and water layer ethyl acetate extracts (20mL x 2), merges organic phase, washes (40mL x3), Organic layer anhydrous sodium sulfate dries, filters, and concentration, residue crosses silicagel column and obtains yellow solid 100mg, yield 33.1%.
LC-MS (APCI): m/z=339.2 (M+1)+；1H NMR(300MHz,CDCl3) (δ/ppm) 8.01 (d, J= 9.3Hz, 1H), 6.43 (dd, J=9.6Hz, 2.7Hz, 1H), 6.31 (d, J=2.4Hz, 1H), 3.98-3.94 (m, 2H), 3.03-2.94(m,2H),2.65-2.62(m,4H),2.54-2.46(m,5H),2.32(s,3H),2.01-1.96(m,2H), 1.65-1.60(m,2H)。
(4) 1- [1- (3- methoxyl group -4- aminocarbonyl phenyl) -4-d- piperidin-4-yl] -4- methyl piperazine (compound is prepared 19), preparation method is consistent with the preparation method of compound 5, the difference is that with 1- [1- (3- methoxyl group -4- nitrobenzene Base) -4-d- piperidin-4-yl] -4- methyl piperazine substitution 1- [1- (3-d3- methoxyl group -4- nitrobenzophenone) piperidin-4-yl] -4- first Base piperazine.
(5) the chloro- N of 5- is prepared4[2- (solutions of dimethyl phosphoryl base) phenyl]-N2{ 2- methoxyl group -4- [4- (4- methyl piperazine -1- Base) -4-d- piperidin-1-yl] phenyl } pyrimidine -2,4- diamines (compound 20), the preparation method of preparation method and compound 9 Unanimously, the difference is that being substituted using 1- [1- (3- methoxyl group -4- aminocarbonyl phenyl) -4-d- piperidin-4-yl] -4- methyl piperazine 1- [1- (3-d3- methoxyl group -4- aminocarbonyl phenyl) piperidin-4-yl] -4- methyl piperazine.
LC-MS (APCI): m/z=587.2 (M+1)+；1H NMR(300MHz,DMSO-d6)δ(ppm):11.18(s,1H), 8.51-8.47(m,1H),0.08-8.07(m,2H),7.57-7.50(m,1H),7.40-7.32(m,2H),7.12-7.07(m, 1H), 6.62 (d, J=2.4Hz, 1H), 6.47 (dd, J=9.0Hz, 2.4Hz, 1H), 3.76-3.71 (m, 6H), 2.82-2.61 (m,10H),2.48-2.34(m,3H),1.91-1.85(m,2H),1.79(s,3H),1.74(s,3H),1.59-1.52(m, 2H)。
Embodiment 4
Prepare the chloro- N of 5-4[2- (solutions of dimethyl phosphoryl base) phenyl]-N2{ 2- methoxyl group -4- [4- (4- methyl -3,3,5,5- D4- piperazine -1- base)-piperidin-1-yl] phenyl } pyrimidine -2,4- diamines (compound 21), structural formula is as follows:
With similar method described in embodiment 2, difference is that, using 4- methyl -3,3,5,5-d4- piperazines replace N- methyl Piperazine, so that target compound be made.
Embodiment 5
Prepare the chloro- N of 5-4[2- (solutions of dimethyl phosphoryl base) phenyl]-N22- methoxyl group -4- [4- (4- methyl 2,2,3,3,5, 5,6,6-d8- piperazine -1- bases) piperidin-1-yl] phenyl } pyrimidine -2,4- diamines (compound 22), structural formula is as follows:
With similar method described in embodiment 2, difference was using 4- methyl -2,2,3,3,5,5,6,6-d8- piperazine generations For N methyl piperazine, so that target compound be made.
LC-MS (APCI): m/z=592.4 (M+1)+；1H NMR(400MHz,CD3OD) (δ/ppm) 8.35 (dd, J= 8.4Hz, 4.4Hz, 1H), 8.04 (s, 1H), 7.69 (d, J=8.8Hz, 1H), 7.65-7.59 (m, 1H), 7.53 (t, J=8Hz, 1H), 7.29-7.25 (m, 1H), 6.67 (d, J=2.4Hz, 1H), 6.46 (dd, J=8.8Hz, 2.4Hz, 1H), 3.86 (s, 3H), 3.71 (d, J=12.8Hz, 2H), 2.76-2.70 (m, 2H), 2.61-2.56 (m, 4H), 2.04 (d, J=12.8Hz, 2H),1.87(s,3H),1.83(s,3H),1.76-1.65(m,2H)。
Embodiment 6
The chloro- N of 5- is prepared according to following synthetic route4[2- (solutions of dimethyl phosphoryl base) phenyl]-N2{ 2-d3- methoxyl group -4- [4- (4-d3- methylpiperazine-1-yl) piperidin-1-yl] phenyl } pyrimidine -2,4- diamines (compound in following synthetic routes 25):
(1) prepare compound 23:
Acetonitrile 5mL is added in 25mL single-necked flask, 4- (1- (3- methoxyl group -4- nitrobenzophenone) is sequentially added under stirring Piperidin-4-yl) piperazine (0.32g, 1mmol), addition triethylamine (0.12g, 1.2mmol), ice-water bath is cooling, is slowly added dropwise into deuterium For iodomethane (0.16g, 1.1mmol), be stirred to react 30min under ice-water bath, be concentrated to dryness, residue cross silicagel column obtain it is yellow Color solid 0.15g, yield 44.5%.
LC-MS (APCI): m/z=340.2 (M+1)+。
(2) prepare compound 24, preparation method is consistent with the preparation method of compound 5, the difference is that with 1- [1- (3-d3- methoxyl group -4- nitrobenzophenone) piperidin-4-yl] -4-d3- methyl piperazine substitution 1- [1- (3-d3- methoxyl group -4- nitro Phenyl) piperidin-4-yl] -4- methyl piperazine.
(3) prepare compound 25, preparation method is consistent with the preparation method of compound 9, the difference is that using 1- [1- (3-d3- methoxyl group -4- aminocarbonyl phenyl) piperidin-4-yl] -4-d3- methyl piperazine substitutes 1- [1- (3-d3- methoxyl group -4- amine Base phenyl) piperidin-4-yl] -4- methyl piperazine.
LC-MS (APCI): m/z=587.2 (M+1)+；1H NMR(300MHz,DMSO-d6)(δ/ppm)11.18(s,1H), 8.51-8.47(m,1H),0.08-8.07(m,2H),7.57-7.50(m,1H),7.40-7.32(m,2H),7.12-7.07(m, 1H), 6.62 (d, J=2.4Hz, 1H), 6.47 (dd, J=9.0Hz, 2.4Hz, 1H), 3.76-3.71 (m, 6H), 2.82-2.61 (m,11H),2.48-2.34(m,3H),1.91-1.85(m,2H),1.79(s,3H),1.74(s,3H),1.59-1.52(m, 2H)。
Embodiment 7
The chloro- N of 5- is prepared according to following synthetic route4[2- (solutions of dimethyl phosphoryl base) phenyl]-N2{ 2- methoxyl group -4- [4- (4-d3- methyl -2,2,3,3,5,5,6,6-d8- piperazine -1- base) piperidin-1-yl] phenyl } pyrimidine -2,4- diamines (following synthesis Compound 29 in route):
(1) prepare compound 27:
By compound 26 (214mg, 652 μm of ol), deuterated formaldehyde heavy aqueous solution (313mg, 1.95mmol, 20%/ D2) and CH O3COOD (1 drop) is stirred at room temperature 10 minutes, and deuterated sodium cyanoborohydride (129mg, 1.95mmol) is added, after After continuous stirring 30 minutes, triethylamine is added and neutralizes, yellow solid 175mg, yield are obtained by column chromatography separating purification after concentration It is 77.8%.
LC-MS (APCI): m/z=346.4 (M+1)+。
(2) prepare compound 28, preparation method is consistent with the preparation method of compound 5, the difference is that with 1- [1- (3- methoxyl group -4- nitrobenzophenone) piperidin-4-yl] -4-d3- methyl -2,2,3,3,5,5,6,6-d8- piperazine substitution 1- [1- (3- D3- methoxyl group -4- nitrobenzophenone) piperidin-4-yl] -4- methyl piperazine.
(3) prepare compound 29, preparation method is consistent with the preparation method of compound 9, the difference is that using 1- [1- (methoxyl group -4- aminocarbonyl phenyl) piperidin-4-yl] -4-d3- methyl -2,2,3,3,5,5,6,6-d8- piperazine substitutes 1- [1- (3-d3- methoxyl group -4- aminocarbonyl phenyl) piperidin-4-yl] -4- methyl piperazine.
LC-MS (APCI): m/z=595.4 (M+1)+；1H NMR(300MHz,CDCl3)(δ/ppm)10.80(s,1H), 8.63 (dd, J=4.8Hz, 2.4Hz, 1H), 8.09-8.07 (m, 2H), 7.50 (t, J=4.5Hz, 1H), 7.30-7.25 (m, 2H), 7.14-7.10 (m, 1H), 6.55 (d, J=1.5Hz, 1H), 6.49 (dd, J=5.4Hz, 1.5Hz, 1H), 3.87 (s, 3H), 3.66 (d, J=7.5Hz, 2H), 2.73-2.68 (m, 2H), 2.40-2.36 (m, 1H), 1.95 (d, J=7.5Hz, 2H), 1.85(s,3H),1.82(s,3H),1.76-1.68(m,2H)。
Embodiment 8
The chloro- N of 5- is prepared according to following synthetic route4[2- (solutions of dimethyl phosphoryl base) phenyl]-N2{ 2-d3- methoxyl group -4- [4- (4- methyl -2,2,3,3,5,5,6,6-d8- piperazine -1- base) piperidin-1-yl] phenyl } pyrimidine -2,4- diamines (following synthesis Compound 32 in route):
(1) prepare compound 30, preparation method is consistent with the preparation method of compound 10, the difference is that using d3- The fluoro- 2- Nitroanisole of 5- substitutes the fluoro- 2- Nitroanisole of 5-.
LC-MS (APCI): m/z=254.5 (M+1)+。
(2) prepare compound 31:
By tetraisopropyl titanate (Ti (Oi-Pr)4, 5mL) and it is added to compound 30 (900mg, 3.6mmol) and 2,2,3,3, It in the solution of 5,5,6,6-d8- piperazines (474mg, 5.03mmol), is stirred overnight at room temperature, 10mL ethyl alcohol is added, continuously adds Itrile group sodium borohydride (678mg, 10.79mmol) after this mixed liquor is stirred at room temperature 3 hours, is poured into dissolved with 5g celite (celite) water (10mL) continues stirring 30 minutes, obtains yellow solid by column chromatography separating purification after removal solvent and produce Object 300mg, yield 25.4%.
LC-MS (APCI): m/z=332.5 (M+1)+。
(3) prepare compound 32, preparation method is consistent with the preparation method of compound 29, the difference is that using chemical combination 31 alternative compounds 26 of object, formaldehyde substitute deuterated formaldehyde, and itrile group sodium borohydride substitutes deuterated sodium borohydride.Finally obtain target production Object is white solid, total 40mg, yield 53.0%.
LC-MS (APCI): m/z=595.5 (M+1)+；1H NMR(300MHz,CDCl3)(δ/ppm)10.80(s,1H), 8.62 (dd, J=8.1Hz, 4.5Hz, 1H), 8.11-8.08 (m, 2H), 7.50 (t, J=7.8Hz, 1H), 7.32-7.25 (m, 2H), 7.16-7.11 (m, 1H), 6.54 (d, J=1.6Hz, 1H), 6.48 (dd, J=8.4Hz, 2.4Hz, 1H), 3.66 (d, J= 12Hz, 2H), 2.74-2.67 (m, 2H), 2.61-2.55 (m, 1H), 2.48 (s, 3H), 2.02 (d, J=12.3Hz, 2H), 1.84 (s,3H),1.81(s,3H),1.79-1.73(m,2H)。
Embodiment 9
Prepare the chloro- N of 5-4[2- (solutions of dimethyl phosphoryl base) phenyl]-N22-d3- methoxyl group -4- [4- (methyl -2 4-d2-, 2,3,3,5,5,6,6-d8- piperazine -1- bases) piperidin-1-yl] phenyl } pyrimidine -2,4- diamines (compound 33), structural formula is as follows It is shown:
It is similar to 7 the method for embodiment, the difference is that with 31 alternative compounds 26 of compound, itrile group sodium borohydride Substitute deuterated sodium borohydride.Finally obtaining target product is yellow solid, total 70mg, yield 27.2%.
LC-MS (APCI): m/z=597.4 (M+1)+；1H NMR(300MHz,CDCl3)(δ/ppm)10.82(s,1H), 8.62 (dd, J=8.4Hz, 4.5Hz, 1H), 8.13-8.09 (m, 2H), 7.50 (t, J=7.5Hz, 1H), 7.33-7.26 (m, 2H), 7.16-7.10 (m, 1H), 6.54 (d, J=2.1Hz, 1H), 6.48 (dd, J=9.0Hz, 2.4Hz, 1H), 3.66 (d, J= 12.6Hz,2H),2.76-2.59(m,3H),2.56(s,1H),2.08-2.00(m,2H),1.86(s,3H),1.81(s,3H), 1.79-1.72(m,2H)。
Embodiment 10
Prepare the chloro- N of 5-4[2- (solutions of dimethyl phosphoryl base) phenyl]-N22-d3- methoxyl group -4- [4- (methyl -2 4-d3-, 2,3,3,5,5,6,6-d8- piperazine -1- bases) piperidin-1-yl] phenyl } pyrimidine -2,4- diamines (compound 34), structural formula is as follows It is shown:
It is similar to 7 the method for embodiment, the difference is that with 31 alternative compounds 26 of compound.Finally obtain target Product is white solid, total 110mg, yield 36.7%.
LC-MS (APCI): m/z=598.4 (M+1)+；1H NMR(300MHz,CDCl3) (δ/ppm) 8.35 (dd, J= 8.4Hz, 4.4Hz, 1H), 8.04 (s, 1H), 7.68 (d, J=8.4Hz, 1H), 7.65-7.59 (m, 1H), 7.52 (t, J=8Hz, 1H), 7.29-7.25 (m, 1H), 6.67 (d, J=6.8Hz, 1H), 6.46 (dd, J=8.8Hz, 2.4Hz, 1H), 3.71 (d, J= 12.4Hz, 2H), 2.76-2.70 (m, 2H), 2.64-2.58 (m, 1H), 2.04 (d, J=12.4Hz, 2H), 1.87 (s, 3H), 1.83(s,3H),1.76-1.66(m,2H)。
Embodiment 11
The biological assessment of compound
Biological activity to determine they is evaluated the compound of the present invention in multiple tests.For example, can survey Examination the compounds of this invention inhibits the ability of a variety of concern of albumen kinases.The compound of some tests shows by force ALK kinases The inhibitory activity of effect.
(1) kinase inhibitory activity is evaluated
Compound is prepared: test-compound is dissolved in DMSO and is made into 20mM mother liquor.Compound is diluted in DMSO using preceding At 0.1mM (dilution of 100 times of final concentrations), and 3 times of gradient dilutions are done, 11 concentration.4 times are diluted to buffer when dosing The dilution of final concentration.
Kinase assay: after preparing buffer, enzyme is mixed with the various concentration compound that beforehand dilution is prepared, is placed at room temperature for 30 minutes, each concentration duplicate hole.Corresponding substrate and ATP is added, reacts at room temperature 60 minutes (being provided with yin and yang attribute control).Instead Addition antibody test should be finished, Evnvision is detected after sixty minutes for incubation at room temperature, acquires data.It is carried out according to XLfit5 software Data analysis and quasi- figure.And replace Buddhist nun as reference substance using gram azoles.
IC50=[(ABS test-ABS starts)/(ABS control-ABS starts)] x 100
The results are shown in Table 1 for kinase inhibitory activity in embodiment.
1 Examples 1 to 10 of table and reference substance gram azoles replace the kinase inhibitory activity contrast table of Buddhist nun
Embodiment number ALK WT IC50(nM) ALK L1196M IC50(nM)
Embodiment 1 <20 <20
Embodiment 2 <20 <20
Embodiment 3 <20 <20
Embodiment 4 <20 <20
Embodiment 5 <20 <20
Embodiment 6 <20 <20
Embodiment 7 <20 <20
Embodiment 8 <20 <20
Embodiment 9 <20 <20
Embodiment 10 <20 <20
Reference substance gram azoles replaces Buddhist nun <20 >75
As shown in table 1, compared with ALK inhibitor gram azoles compare for Buddhist nun, the compounds of this invention to ALK L1196M be mutated Body surface reveals excellent inhibitory activity (IC50Less than 20), illustrate the compounds of this invention can pair between modification lymphom kinase (ALK) With very strong rejection ability.
(2) cytotoxicity experiment
Inhibiting effect to the compound on tumor cell of Examples 1 to 10 is had detected using tetrazolium salts (MTS) method, and with Gram azoles is reference substance for Buddhist nun.Experimental result is as shown in table 2.
2 Examples 1 to 10 of table and reference substance gram azoles replace the cytotoxicity experiment contrast table of Buddhist nun
Embodiment number ALK WT IC50(nM) ALK L1196M IC50(nM)
Embodiment 1 <20 <50
Embodiment 2 <20 <50
Embodiment 3 <20 <50
Embodiment 4 <20 <50
Embodiment 5 <20 <20
Embodiment 6 <20 <20
Embodiment 7 <20 <20
Embodiment 8 <20 <20
Embodiment 9 <20 <20
Embodiment 10 <20 <20
Reference substance gram azoles replaces Buddhist nun >70 >600
As shown in table 2, compared with ALK inhibitor gram azoles compare for Buddhist nun, the compounds of this invention all show inhibit expression The excellent antitumor activity of ALK mutant L1196M growth of cancer cells.
(3) metabolic stability is evaluated
Microsomal assay: people's hepatomicrosome: 0.5mg/mL, Xenotech；Rat liver microsomes: 0.5mg/mL, Xenotech；Coenzyme (NADPH/NADH): 1mM, Sigma Life Science；Magnesium chloride: 5mM, 100mM phosphate buffer (pH 7.4).
The preparation of stock solution: precision weighs a certain amount of embodiment compound, and is dissolved to 5mM respectively with DMSO.
The preparation of phosphate buffer (100mM, pH7.4): take the 0.5M potassium dihydrogen phosphate 150mL for preparing in advance and The 0.5M dipotassium hydrogen phosphate solution of 700mL mixes, then adjusts mixed liquor pH value to 7.4 with 0.5M dipotassium hydrogen phosphate solution, uses It is preceding to dilute 5 times with ultrapure water, magnesium chloride is added, phosphate buffer (100mM) is obtained, wherein potassium phosphate containing 100mM, 3.3mM Magnesium chloride, pH 7.4.
It prepares NADPH regenerative system solution and (contains 6.5mM NADP, 16.5mM G-6-P, 3U/mL G-6-P D, 3.3mM Magnesium chloride), using it is preposition in it is wet on ice.
Prepare terminate liquid: the acetonitrile containing 50ng/mL Propranolol Hydrochloride and 200ng/mL orinase (internal standard) is molten Liquid.It takes 25057.5 μ L phosphate buffers (pH7.4) into 50mL centrifuge tube, is separately added into 812.5 μ L people's hepatomicrosomes, mix It is even, obtain the hepatomicrosome dilution that protein concentration is 0.625mg/mL.Take 25057.5 μ L phosphate buffers (pH7.4) extremely In 50mL centrifuge tube, 812.5 μ L SD rat liver microsomes are separately added into, are mixed, the liver that protein concentration is 0.625mg/mL is obtained Microsome dilution.
The incubation of sample: being diluted to 0.25mM for the stock solution of respective compound with the aqueous solution containing 70% acetonitrile respectively, It is spare as working solution.It takes people's hepatomicrosome of 398 μ L or rat liver microsomes dilution that 96 holes are added respectively to be incubated in plate (N=2), it is separately added into the working solution of 2 μ L 0.25mM, mixes.
The measurement of metabolic stability: the terminate liquid of 300 μ L pre-cooling is added in every hole of 96 hole deep-well plates, is placed in ice On, as termination plate.96 holes are incubated for plate and NADPH regenerative system is placed in 37 DEG C of water baths, 100 revs/min of concussions are incubated in advance 5min.80 μ L Incubating Solutions addition termination plate is taken out from the every hole of plate is incubated for, mixes, supplements 20 μ L NADPH regenerative system solution, make For 0min sample.Again to the NADPH regenerative system solution for being incubated for 80 μ L of the every hole addition of plate, starting reaction starts timing.Correspondingization The reaction density for closing object is 1 μM, protein concentration 0.5mg/mL.When reacting 10,30,90min, 100 μ L is respectively taken to react Liquid is added in termination plate, and vortex 3min terminates reaction.Termination plate is centrifuged 10min under the conditions of 5000 × g, 4 DEG C.Take 100 μ L Supernatant is mixed to being previously added in 96 orifice plates of 100 μ L distilled water, carries out sample analysis using LC-MS/MS.
Data analysis: by LC-MS/MS system detection respective compound and interior target peak area, calculate compound with it is interior Mark peak area ratio.Slope is measured by the natural logrithm of the percentage of compound surplus and time mapping, and according to following Formula calculates t1/2And CLint, wherein V/M is equal to 1/ protein concentration.
To the compounds of this invention and its not deuterated compound is test compare simultaneously, and it is micro- with rat liver in people to evaluate it The metabolic stability of plastochondria.The half-life period of index as metabolic stability and liver clearance rate (Clint) are as shown in table 3. It uses without deuterated compound AP26113 in table 3 as control sample；The AP26113 is the third generation for being the prior art ALK inhibitor is tried for treating the metastatic ALK positive non-small cell lung cancer for replacing Buddhist nun's tolerance to gram azoles in I/II phase clinic In testing, to the Patients with Non-small-cell Lung of the ALK positive, including brain metastes patient, AP26113 has duration anti-tumor activity.
As shown in table 3, by compareing with without deuterated compound AP26113, the compounds of this invention can be significantly improved Metabolic stability, and then it is more suitable for preparation for treating the metastatic ALK positive non-small cell lung cancer for replacing Buddhist nun to be resistant to gram azoles Drug.
The metabolic stability contrast table of 3 Examples 1 to 10 of table and AP26113 control sample
(4) Pharmacokinetic Evaluation in rat
6 male Sprague-Dawley rats, 7-8 week old, weight about 210g are divided into 2 groups, every group 3, through vein or The compound (through vein 3mg/kg, taking orally 10mg/kg) of oral single dosage, compares its pharmacokinetic difference.
Rat is raised using standard feed, gives water.Test is fasted for first 16 hours.Drug is sub- with PEG400 and diformazan Sulfone dissolution.Eye socket blood sampling, the time point of blood sampling are 0.25 hour, 0.5 hour, 1 hour, 2 hours, 4 0.083 hour after administration Hour, 6 hours, 8 hours, 12 hours and 24 hours.
Rat sucks of short duration anesthesia after ether, and eye socket acquires 300 μ L sample of blood in test tube.There are 30 μ L1% heparinates in test tube Solution.Before use, test tube is stayed overnight in 60 DEG C of drying.After being completed with the latter time point blood specimen collection, rat etherization After put to death.
It after blood specimen collection, leniently overturns test tube at least 5 times, is placed on ice after guaranteeing mixing sufficiently immediately.Blood sample is 4 DEG C 5000rpm is centrifuged 5 minutes, and blood plasma is separated with red blood cell.100 μ L blood plasma are sucked out to clean plastic centrifuge tube with pipettor In, show title and the time point of compound.Blood plasma is stored in -80 DEG C before being analyzed.With in LC-MS/MS measurement blood plasma The concentration of the compounds of this invention.Pharmacokinetic parameter is based on every animal blood concentration in different time points into calculating.
Experimental result is as shown in table 4 below, relative to control compound AP26113, the compound 15 of embodiment 2 in the present invention Oral availability (F) it is suitable with control compound AP26113, but its Increased Plasma Half-life, metabolic stability are obviously improved；Implement The Oral availability of the compound 9 of example 1 increases substantially and (improves 20%), and illustrating it in animal body has better drug dynamic Mechanics.
The experiment of 4 pharmacokinetics in rats of table
It should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention, in embodiment not The experimental method of actual conditions is indicated, usually according to normal condition, or according to the normal condition proposed by manufacturer.Unless in addition saying Bright, otherwise parts and percentages are parts by weight and weight percent.
The above content is a further detailed description of the present invention in conjunction with specific preferred embodiments, and it cannot be said that Specific implementation of the invention is only limited to these instructions.For those of ordinary skill in the art to which the present invention belongs, exist Under the premise of not departing from present inventive concept, a number of simple deductions or replacements can also be made, all shall be regarded as belonging to of the invention Protection scope.

Claims (9)

1. a kind of diaminopyrimidine compounds, it is characterised in that: the diaminopyrimidine compounds as shown in formula (I) or its crystal form, Pharmaceutically acceptable salt, hydrate or solvated compounds,
Wherein, R1a、R1b、R1c、R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R6、R7a、R7b、R8a、R8b、R9a、R9b、R10a、R10b、 R11、R12、R13、R14a、R14b、R14c、R15、R16、R17a、R17b、R17c、R18a、R18b、R18c、R19、R20、R21And R22Each independently For hydrogen, deuterium, halogen or trifluoromethyl；
R16For hydrogen, deuterium, halogen, cyano, not deuterated C1-C6Alkyl or C1-C6Alkoxy, one or many deuterated or full deuterium The C in generation1-C6Alkyl or C1-C6Alkoxy, or C that one or more halogens replace or that perhalogeno element replaces1-C6Alkyl or C1- C6Alkoxy；
Additional conditions are R1a、R1b、R1c、R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R6、R7a、R7b、R8a、R8b、R9a、R9b、R10a、 R10b、R11、R12、R13、R14a、R14b、R14c、R15、R16、R17a、R17b、R17c、R18a、R18b、R18c、R19、R20、R21And R22In at least One is deuterated or deuterium.
2. diaminopyrimidine compounds according to claim 1, it is characterised in that: R1a、R1bAnd R1cIt is deuterium.
3. diaminopyrimidine compounds according to claim 1, it is characterised in that: R7a、R7b、R8a、R8b、R9a、R9b、R10a And R10bIt is each independently deuterium or hydrogen.
4. diaminopyrimidine compounds according to claim 1, it is characterised in that: R14a、R14bAnd R14cIt is deuterium.
5. diaminopyrimidine compounds according to claim 1, it is characterised in that: the compound is selected from the group compound Or its pharmaceutically acceptable salt:
6. a kind of pharmaceutical composition preparation method of diaminopyrimidine compounds as claimed in any one of claims 1 to 5, wherein, It is characterized in that: by compound or its crystal form described in pharmaceutically acceptable carrier and first aspect present invention, pharmaceutically may be used Salt, the prodrug of receiving, stereoisomer, isotopic variations hydrate or solvate are mixed, to form pharmaceutical composition Object.
7. a kind of pharmaceutical composition, it is characterised in that: it contains pharmaceutically acceptable carrier and as Claims 1 to 5 is any It is diaminopyrimidine compounds described in one or its crystal form, pharmaceutically acceptable salt, hydrate or solvate, three-dimensional different The pharmaceutical composition of structure body, prodrug or isotopic variations.
8. pharmaceutical composition according to claim 7, it is characterised in that: it also includes other treatment drug, the treatment Drug is cancer, cardiovascular disease, inflammation, infection, immunity disease, cell proliferation disorders, viral disease, metabolic disease Disease or the drug of organ transplant.
9. a kind of diaminopyrimidine compounds as claimed in any one of claims 1 to 5, wherein or its crystal form, pharmaceutically acceptable Salt, hydrate or solvated compounds purposes, it is characterised in that: be used to prepare inhibit anaplastic lymphoma kinase medicine group Close object.
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Application publication date: 20181207