CN106188138A - A kind of diaminopyrimidine compounds and comprise the compositions of this compound - Google Patents

A kind of diaminopyrimidine compounds and comprise the compositions of this compound Download PDF

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CN106188138A
CN106188138A CN201610587472.0A CN201610587472A CN106188138A CN 106188138 A CN106188138 A CN 106188138A CN 201610587472 A CN201610587472 A CN 201610587472A CN 106188138 A CN106188138 A CN 106188138A
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compound
deuterium
compounds
diaminopyrimidine compounds
pharmaceutically acceptable
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CN106188138B (en
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王义汉
李焕银
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Shenzhen Rui Rui Rui Biological Medicine Co Ltd
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Shenzhen Rui Rui Rui Biological Medicine Co Ltd
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Priority to CN202111097366.1A priority patent/CN113912648A/en
Priority to PCT/CN2016/096320 priority patent/WO2017092413A1/en
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract

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

Description

A kind of diaminopyrimidine compounds and comprise the compositions of this compound
Technical field
The invention belongs to pharmaceutical technology field, particularly relate to a kind of diaminopyrimidine compounds and the group comprising this compound Compound.
Background technology
In Past 30 Years, lung cancer mortality rises 465%, and sickness rate increases by 26.9% every year, it has also become China is first Position Death Cause for Malignant Tumors.Wherein nonsmall-cell lung cancer (non-small cell lung cancer, NSCLC) accounts for all lungs More than the 80% of cancer, only there is the chance of operative treatment in the NSCLC patient of 1/3rd, the patient of about 70% when medical Belonging to Locally Advanced or metastasis occur, losing the chance of operation, in this case, Drug therapy is particularly important. Anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (anaplasticlymphoma kinase, ALK) gene fusion have become as in the recent period one important Biomarker, the patient for specific NSCLC subgroup selects thus uses corresponding inhibitor to carry out treatment and provide help.Lung Cancer research international association (IASLC) recommends to use ALK fusion detection to instruct patient screening, and selecting in adenocarcinoma patients late can Adopt the patient of ALK inhibitor for treating, no matter its sex, race, smoking history or other clinical risk factors.Double label is used to divide Fluorescence in situ hybridization (FISH) from probe detects the patient for selecting acceptable ALK-TKI treatment, and this diagnostic method obtains Obtain U.S. FDA approval, replace Buddhist nun to treat in the research of ALK rearrangement tumor at gram azoles and be used.Gram azoles is oral type three phosphorus for Buddhist nun Adenosine monophosphate (ATP) competitive inhibitor, can suppress ALK and MET tyrosine kinase, additionally it is possible to the suppression kinase whose work of ROS1 and RON Property.
But, gram azoles there will be following side effect for Buddhist nun: visual disorder, gastrointestinal side effect, the case of 16% occurs 3-4 Level liver transaminase levels raises.Additionally, gram azoles that ALK positive patient is through the incipient stage is inevitable after treating sensitive period for Buddhist nun There is acquired drug-resistance in ground.Therefore, for need exploitation to that there is ALK kinase inhibiting activity and/or have more preferable pharmacodynamics/ The compound of pharmacokinetics performance.
Summary of the invention
For above technical problem, the invention discloses a kind of diaminopyrimidine compounds and the combination comprising this compound Thing, it has more preferable ALK kinase inhibiting activity and/or has more preferable pharmacodynamics/pharmacokinetics performance.
To this, the technical solution used in the present invention is:
It is an object of the invention to provide a class novel there is ALK kinase inhibiting activity and/or have more preferable pharmacodynamics/ The compound of pharmacokinetics performance.
In a first aspect of the present invention, it is provided that the diaminopyrimidine compounds shown in a kind of formula (I), or its crystal formation, medicine 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 R22The most solely It is on the spot hydrogen, deuterium, halogen or trifluoromethyl；
R16For hydrogen, deuterium, halogen, cyano group, the most deuterated C1-C6Alkyl or C1-C6Alkoxyl, one or many deuterated or The most deuterated C1-C6Alkyl or C1-C6Alkoxyl, or one or more halogen substiuted or perhalogeno element substituted C1-C6Alkyl Or C1-C6Alkoxyl；
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.
Deuterium shape in drug molecule is substantially the same with hydrogen with volume, if hydrogen is replaced by selectivity in drug molecule For deuterium, deuterated medicine the most also can retain original biological activity and selectivity.Inventor is through it is experimentally confirmed that carbon deuterium bond simultaneously Combination more more stable than the combination of C-H bond, the attributes such as the absorption of some medicines, distribution, metabolism and excretion can be directly affected, from And improve the curative effect of medicine, safety and toleration.
In another preference, the deuterium deuterium isotopic content in each deuterated position is at least more 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 More 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 R22In each deuterated position, deuterium isotopic content is at least 5%, is preferably greater than 10%, and even more preferably greater than 15%, more preferably More 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%, the most 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 preference, in formula (I), compound at least contains a D-atom, and its number containing D-atom can be Any one in 1 to 38.
In another preference, in formula (I), compound at least contains a D-atom, and its number containing D-atom can be Any one in 1 to 38.
In another preference, the R of compound in formula (I)1a、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, more preferably two R containing deuterium, more preferably three R containing deuterium, more preferably four Individual R contains deuterium, and more preferably five R are containing deuterium, and more preferably six R are containing deuterium, and more preferably seven R are containing deuterium, and more preferably eight R are containing deuterium, more preferably Nine, ground R is containing deuterium, and more preferably ten R are containing deuterium, and more preferably 11 R are containing deuterium, and more preferably 12 R are containing deuterium, more preferably 13 R Containing deuterium, more preferably 14 R contain deuterium containing deuterium, more preferably 16 R containing deuterium, more preferably 17 R containing deuterium, more preferably 15 R, More preferably 18 R contain deuterium, more containing deuterium, more preferably 20 R containing deuterium, more preferably 21 R containing deuterium, more preferably nineteen R Good 22 R in ground are containing deuterium, and more preferably 23 R are containing deuterium, and more preferably 24 R are containing deuterium, and more preferably 25 R contain Deuterium, more preferably 26 R are containing deuterium, and more preferably 27 R are containing deuterium, and more preferably 28 R are containing deuterium, more preferably two nineteens R contains deuterium, more preferably 30 R containing deuterium, more preferably 31 R containing deuterium, more preferably 32 R containing deuterium, more preferably 33 Individual R contains deuterium, more preferably 34 R containing deuterium, more preferably 35 R containing deuterium, more preferably 36 R containing deuterium, more preferably three 17 R are containing deuterium, and more preferably 38 R are containing deuterium.
In another preference, R1a、R1bAnd R1cIt is each independently deuterium or hydrogen.
In another preference, R2a、R2b、R3a、R3b、R4a、R4b、R5aAnd R5bIt is each independently deuterium or hydrogen.
In another preference, R6For deuterium or hydrogen.
In another preference, R7a、R7b、R8a、R8b、R9a、R9b、R10aAnd R10bIt is each independently deuterium or hydrogen.
In another preference, R11、R12And R13It is each independently deuterium or hydrogen.
In another preference, R14a、R14bAnd R14cIt is each independently deuterium or hydrogen.
In another preference, R17a、R17bAnd R17cIt is each independently deuterium or hydrogen.
In another preference, R18a、R18bAnd R18cIt is each independently deuterium or hydrogen.
In another preference, R19、R20、R21And R22It is each independently deuterium or hydrogen.
In another preference, R16Separately select the alkane that halogen, trifluoromethyl, cyano group, one or many are deuterated Base and alkoxyl.
In another preference, it is characterised in that R16It is chlorine.
In another preference, it is characterised in that R1a、R1b、R1cIt it is deuterium.
In another preference, it is characterised in that R2a、R2b、R5a、R5bIt it is deuterium.
In another preference, it is characterised in that R3a、R3b、R4a、R4bIt it is deuterium.
In another preference, R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5bIt it is deuterium.
In another preference, R6It it is deuterium.
In another preference, R7a、R7b、R10a、R10bIt it is deuterium.
In another preference, R8a、R8b、R9a、R9bIt it is deuterium.
In another preference, R7a、R7b、R8a、R8b、R9a、R9b、R10a、R10bIt it is deuterium.
In another preference, R11、R13It it is deuterium.
In another preference, R11、R12、R13It it is deuterium.
In another preference, R14a、R14b、R14cIt it is deuterium.
In another preference, R17a、R17b、R17c、R18a、R18b、R18cIt it is deuterium.
In another preference, R20、R22It it is deuterium.
In another preference, R19、R20、R21、R22It it is deuterium.
In another preference, described compound is selected from lower group of 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-diamidogen, 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-diamidogen, 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-diamidogen, 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-diamidogen, shown in structural formula such as formula (5)；
In another preference, described compound is selected from lower group of compound or its pharmaceutically acceptable salt:
In another preference, described compound does not include non-deuterated compound.
In another preference, described 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-diamidogen.
In a second aspect of the present invention, it is provided that a kind of method preparing pharmaceutical composition, including step: will pharmaceutically Compound described in acceptable carrier and first aspect present invention, or its crystal formation, pharmaceutically acceptable salt, hydrate or Solvate mixes, thus forms pharmaceutical composition.
In a third aspect of the present invention, it is provided that a kind of pharmaceutical composition, it contain pharmaceutically acceptable carrier and Compound described in first aspect present invention, or its crystal formation, pharmaceutically acceptable salt, hydrate or solvate.
In another preference, described pharmaceutical composition is injection, wafer, tablet, pill, powder or granule.
In another preference, described pharmaceutical composition is possibly together with other medicine, described other treatment Medicine is cancer, cardiovascular disease, inflammation, infection, immune disease, cell proliferation disorders, viral disease, metabolic disease Disease or the medicine of organ transplantation.
In a fourth aspect of the present invention, it is provided that the compound described in first aspect present invention, or its crystal formation, pharmacy Upper acceptable salt, prodrug, stereoisomer, isotopic variations, hydrate or the purposes of solvate, they are used for preparation The pharmaceutical composition of protease inhibition.
In another preference, described pharmaceutical composition is used for treating and preventing following disease: cancer, cell proliferative Disease, inflammation, infection, immune disease, organ transplantation, viral disease, cardiovascular disease or metabolic disease.
In another preference, described cancer includes, but are not limited to: pulmonary carcinoma, head and neck cancer, breast carcinoma, carcinoma of prostate, Esophageal carcinoma, rectal cancer, colon cancer, nasopharyngeal carcinoma, uterus carcinoma, cancer of pancreas, lymphoma, leukemia, osteosarcoma, melanoma, renal carcinoma, stomach Cancer, hepatocarcinoma, bladder cancer, thyroid carcinoma or colorectal cancer.
In another preference, described immune disease or inflammation include, but are not limited to: rheumatoid arthritis, bone close Joint inflammation, poker back, gout, asthma, bronchitis, rhinitis, chronic obstructive pulmonary disease, cystic fibrosis.
In another preference, described cell proliferation disorders refers to pulmonary carcinoma, head and neck cancer, breast carcinoma, carcinoma of prostate, food Road cancer, rectal cancer, colon cancer, nasopharyngeal carcinoma, uterus carcinoma, cancer of pancreas, lymphoma, leukemia, osteosarcoma, melanoma, renal carcinoma, stomach Cancer, hepatocarcinoma, bladder cancer, thyroid carcinoma or colorectal cancer.
In another preference, described cancer is nonsmall-cell lung cancer.
In a fifth aspect of the present invention, it is provided that a kind of method of suppression protein kinase (such as ALK kinases) or a kind of disease Sick (such as cancer, cell proliferation disorders, inflammation, infection, immune disease, organ transplantation, viral disease, cardiovascular disease Or metabolic disease) Therapeutic Method, it includes step: the object treated to needs is used described in first aspect present invention Compound, or its crystal formation, pharmaceutically acceptable salt, hydrate or solvate, or use described in third aspect present invention Pharmaceutical composition.
In should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and having in below (eg embodiment) Can be combined with each other between each technical characteristic that body describes, thus constitute new or preferred technical scheme.As space is limited, exist This tires out the most one by one states.
Present invention additionally comprises isotope-labeled compound, be equal to original chemical and be disclosed.Can be classified as this The isotopic example of bright compound includes hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotope, the most such as2H,3H,13C,14C,15N,17O,18O,31P,32P,35S,18F and36Cl.Compound in the present invention, or enantiomer, diastereomer, isomer, or medicine Acceptable salt or solvate on, wherein contain the isotope of above-claimed cpd or other other isotope atoms all at this Within the scope of invention.Some compound isotopically labelled in the present invention, such as3H and14The radiosiotope of C the most wherein, It is useful in the tissue distribution of medicine and substrate is tested.Tritium, i.e.3H and carbon-14, i.e.14C, their preparation and detection are compared Easily, it is the first-selection in isotope.Additionally, higher isotope replaces such as deuterium, i.e.2H, owing to its good metabolic stability is at certain A little therapies have superiority, increases the half-life the most in vivo or reduce consumption, therefore, can pay the utmost attention in some cases. Isotope-labeled compound can be non isotopic by replacing with the isotope labeling reagent being easy to get by general method Reagent, can prepare by the scheme in example.
Herein, if no special instructions, " halogen " refers to F, Cl, Br and I.More preferably, halogen atom is selected from F, Cl and Br.
Herein, if no special instructions, " C1-C6Alkyl " refer to the alkyl of the straight or branched of 1-6 carbon atom, Such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group or similar group.
Herein, if no special instructions, the one or more hydrogen during " deuterated " refers to compound or group are replaced by deuterium；Deuterium Generation can be a replacement, two replacements, polysubstituted or entirely replace.Term " one or more deuterated " and " one or many is deuterated " It is used interchangeably.
Herein, if no special instructions, " non-deuterated compound " refers to that the ratio containing D-atom is not higher than natural deuterium coordination The compound of cellulose content (0.015%).
In the present invention, pharmaceutically acceptable salt includes inorganic salt and organic salt.The one preferred salt of class is chemical combination of the present invention The salt that thing is formed with acid.The acid suitably forming salt includes, but are not limited to: hydrochloric acid, hydrobromic acid, Fluohydric acid., sulphuric acid, nitric acid, phosphoric acid Deng mineral acid；Formic acid, acetic acid, trifluoroacetic acid, propanoic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, Fructus Mali pumilae Acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, benzenesulfonic acid, LOMAR PWA EINECS 246-676-2 etc. are organic Acid；And the aminoacid 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 potassium salt), alkali salt (such as magnesium salt or calcium salt), ammonium salt are (as low Level 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 by morpholine, piperazine, lysine respectively.
Term " solvate " refers to that the compounds of this invention forms the coordination compound of special ratios with solvent molecule coordination." hydration Thing " refer to that the compounds of this invention and water carry out the coordination compound that coordination is formed.
Compared with prior art, the invention have the benefit that
(1) the compounds of this invention has the inhibition of excellence to protein kinase (kinase) (such as ALK kinases).
(2) change compound metabolism in organism by this technology of deuterate, make compound have more preferable medicine generation Kinetic parameter characteristic.In such a case, it is possible to change dosage and form durative action preparation, improve the suitability.
(3) with the hydrogen atom in deuterium substituted compound, due to its deuterium isotope effect, it is possible to increase compound is at animal body Interior drug level, to improve curative effect of medication.
(4) with the hydrogen atom in deuterium substituted compound, owing to some metabolite is suppressed, the peace of compound may be improved Quan Xing.
Detailed description of the invention
The preparation method of of the present invention formula (I) structural compounds is described more particularly below, but these concrete grammars are not to this Invention constitutes any restriction.The compounds of this invention can also be optionally by that describe or known in the art various in this manual Synthetic method combines and prepares easily, and such combination easily can be entered by those skilled in the art in the invention OK.
The most deuterated diaminopyrimidine compounds and the preparation method of the salt of physical compatibility thereof that the present invention uses are Know.The preparation of corresponding deuterated diaminopyrimidine compounds can be raw material with corresponding deuterated initial compounds, with same Route synthesis.Such as, 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.
Generally, in preparation flow, each reaction is generally in atent solvent, in room temperature to reflux temperature (such as 0 DEG C～100 DEG C, preferably 0 DEG C～80 DEG C) under carry out.Response time is usually 0.1 hour-60 hours, preferably 0.5-24 hour.
Following general syntheti c route may 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 in conjunction with 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-diamidogen (compound 9 in following synthetic route):
Prepared by employing following steps:
(1) compound 2 is prepared:
In 100mL single port bottle add 30mL acetone, be sequentially added under stirring 5-fluoro-2-nitrophenol (2.0g, 12.7mmol), Anhydrous potassium carbonate (3.5g, 25.4mmol), deuterated iodomethane (2.4g, 16.5mmol), be warmed up to 60 DEG C and protect Temperature stirring 2h.Being cooled to room temperature, rotary evaporation falls acetone, and residue adds water 20mL, ethyl acetate extraction (30mLx3), merges Organic layer, anhydrous sodium sulfate is dried, and filters, and 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) compound 4 is prepared:
In 25mL single port flask, add DMF (4mL), under stirring, be sequentially added into 4-fluoro-2-d3-first Epoxide Nitrobenzol (0.4g, 2.3mmol), 1-methyl-4-(piperidin-4-yl) piperazine hydrochloride (0.7g, 3.2mmol), anhydrous carbon Acid potassium (0.95g, 6.9mmol), reactant mixture is warmed up to 80 DEG C, N2React overnight under atmosphere.It is cooled to room temperature, pours frozen water into (80mL) in, separating out a large amount of yellow solid, filter, and be dissolved in DCM (40mL), anhydrous sodium sulfate is dried, and filters, and filtrate concentrates 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) compound 5 is prepared:
25mL single port bottle adds under ethanol 6mL and water 2mL, stirring and be sequentially added into 1-(1-(3-d3-methoxyl group-4-nitre Base phenyl) piperidin-4-yl)-4-methyl piperazine (0.2g, 0.59mmol), reduced iron powder (0.20g, 3.55mmol), ammonium chloride (16mg, 0.30mmol), reactant mixture N285 DEG C it are warmed up under atmosphere, and insulated and stirred reaction 1h.It is cooled to room temperature, filters solid Body material, filtrate concentrates, and adds saturated sodium bicarbonate (5mL), dichloromethane extraction (15mLx2), merge organic in residue Phase, anhydrous sodium sulfate is dried, and filters, is concentrated to give off-white color solid 0.15g, yield 79.6%, directly throws in next step.
(4) compound 8 is prepared:
25mL single port bottle adds DMF (3mL), under stirring, is sequentially added into 2,5,6-trichloropyrimidines (0.72g, 3.9mmol), 2-(dimethyl phosphino-) aniline (0.5g, 3mmol), Anhydrous potassium carbonate (0.62g, 4.5mmol), be warmed up to 60 DEG C and be incubated Stirring 4h.Being cooled to room temperature, be sequentially added into ethyl acetate (30mL), water (30mL), concussion layering, aqueous layer with ethyl acetate extracts (30mLx2), merging organic facies, wash (60mLx2), organic layer anhydrous sodium sulfate is dried, and filters, and concentrates, and residue crosses silica gel Post 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) compound 9 is prepared:
In 25mL single port bottle, add glycol monoethyl ether 2mL, be sequentially added into 2 under stirring, 5-bis-chloro-N-(2-(dimethyl 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), reactant mixture N2100 DEG C, and insulated and stirred it is warmed up under atmosphere Reaction is overnight.It is cooled to room temperature, adds saturated sodium bicarbonate water liquid (10mL), dichloromethane extraction (15mLx3), merge organic Phase, anhydrous sodium sulfate is dried, and filters, and concentrates, and crosses silicagel column and obtains 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-diamidogen (compound 15 in following synthetic route):
Comprise the following steps:
(1) compound 10 is prepared:
Add DMF (10mL) at 100mL single port flask, under stirring, be sequentially added into 4-fluoro-2-methoxyl group Nitrobenzol (2g, 11.8mmol), piperidin-4-one hydrochlorate (2.23g, 16.5mmol), Anhydrous potassium carbonate (4.88g, 35.4mmol), reactant mixture is warmed up to 80 DEG C, N2React overnight under atmosphere.It is cooled to room temperature, pours in frozen water (80mL), analysis Going out a large amount of yellow solid, filter, and be dissolved in DCM (100mL), anhydrous sodium sulfate is dried, and 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) compound 11 is prepared:
In 100mL single port flask, add toluene 20mL, under stirring, be sequentially added into 1-(3-methoxyl group-4-nitrobenzophenone) piperazine Pyridine-4-ketone (0.53g, 2.1mmol), triethylamine (0.8mL), N-Boc piperazine (0.85g, 4.5mmol), N2Stirring reaction under atmosphere 30min, the disposable acetic acid sodium borohydride (0.4g, 1.92mmol) that adds, stirring 30min, adds acetic acid boron hydrogen the most again Changing sodium 1.2g, reaction is completely.Adding saturated sodium bicarbonate water liquid (30mL), separate organic layer, water layer ethyl acetate extracts (30mLx2), merging organic facies, anhydrous sodium sulfate is dried, and filters, and concentrates, and residue is crossed silicagel column and obtained 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) compound 12 is prepared:
In 100mL single port flask, add dichloromethane 20mL, under stirring, be sequentially added into 4-(1-(3-methoxyl group-4-nitro Phenyl) piperidin-4-yl) piperazinyl-1-tert-butyl ester (0.58g, 1.4mmol), trifluoracetic acid (2mL), N2Under atmosphere, stirring at normal temperature is anti- Answer 1h, reactant liquor to be concentrated to dryness, add saturated sodium bicarbonate water liquid (10mL), mixture dichloromethane extraction (20mLx3), nothing Aqueous sodium persulfate is dried, and filters, is concentrated to give yellow solid 0.45g, yield 100%, LC-MS (APCI): m/z=321.2 (M+1)+。
(4) compound 13 is prepared:
In 25mL single port flask, add acetonitrile 5mL, under stirring, be sequentially added into 4-(1-(3-methoxyl group-4-nitrobenzophenone) Piperidin-4-yl) piperazine (0.32g, 1mmol), add triethylamine (0.12g, 1.2mmol), ice-water bath cool down, be slowly added dropwise into deuterium For iodomethane (0.16g, 1.1mmol), under ice-water bath, stirring reaction 30min, is evaporated to do, and residue is crossed silicagel column and obtained 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) preparing compound 14, its preparation method is consistent with the preparation method of compound 5, and difference is with 1-(1- (3-methoxyl group-4-nitrobenzophenone) piperidin-4-yl)-4-d3-methyl piperazine replacement 1-(1-(3-d3-methoxyl group-4-Nitrobenzol 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-diamidogen (compound 14), its preparation method and the preparation method of compound 9 Unanimously, difference is to use 1-(1-(3-methoxyl group-4-aminocarbonyl phenyl) piperidin-4-yl)-4-d3-methyl piperazine to substitute 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,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-diamidogen (compound 20 in following synthetic route):
Comprise the following steps:
(1) compound 16 is prepared:
In 50mL single port flask, add deuterated methanol 10mL, under ice-water bath stirring, add 1-(3-methoxyl group-4-Nitrobenzol Base) piperidin-4-one (0.25g, 1mmol), complete molten clear after be slowly added to deuterated sodium borohydride (42mg, 1mmol), ice-water bath N2 Stirring reaction 5min under atmosphere, adds heavy water (2mL) cancellation reaction, and stirring at normal temperature 30min, is sequentially added into water (30mL) and acetic acid Ethyl ester (30mL), separates organic layer, water layer ethyl acetate extraction (30mLx2), concentrates, and residue is again dissolved in ethyl acetate (50mL), saturated aqueous common salt washing (20mLx1), organic facies anhydrous sodium sulfate is dried, and filters, 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) compound 17 is prepared:
Dichloromethane (15mL) is added in 50mL single port flask, addition 1-(3-methyl-4-nitrobenzophenone) under ice-water bath- 4-d-piperidines-4-alcohol (0.25g, 1mmol), adds triethylamine (0.18g, 1.8mmol), is slowly added dropwise into sulfonyloxy methyl under stirring Chlorine (0.17g, 1.5mmol), room temperature N2Stirring reaction 1h under atmosphere.Adding water (20mL), concussion separates organic layer, water layer dichloromethane Alkane extraction (20mLx2), merges organic layer, successively with 0.5M HCl/water liquid (20mLx1), saturated sodium bicarbonate water liquid (15mLx1), saturated aqueous common salt (15mLx1), anhydrous sodium sulfate is dried, filter, be concentrated to dryness to obtain yellow solid 0.3g, yield 90.9%, it is directly used in next step.
(3) compound 18 is prepared:
In 25mL single port flask, add DMF (3mL), under stirring, be sequentially added into 1-(3-methyl-4-nitrobenzophenone)-4-d- Piperidines-4-methanesulfonate ester (0.3g, 0.9mmol), 1-methyl piperazine (0.36g, 3.6mmol), Anhydrous potassium carbonate (0.62g, 4.5mmol), mixture is warmed up to 100 DEG C, N2Under atmosphere, insulated and stirred is reacted overnight.It is cooled to room temperature, adds water (30mL) and second Acetoacetic ester (30mL), separates organic layer, water layer ethyl acetate extraction (20mLx2), merges organic facies, wash (40mLx3), organic Layer anhydrous sodium sulfate is dried, and filters, and concentrates, and residue is crossed silicagel column and obtained 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), its preparation method is consistent with the preparation method of compound 5, and difference is with 1-[1-(3-methoxyl group-4-Nitrobenzol Base)-4-d-piperidin-4-yl]-4-methyl piperazine replacement 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-diamidogen (compound 20), its preparation method and the preparation method of compound 9 Unanimously, difference is to use 1-[1-(3-methoxyl group-4-aminocarbonyl phenyl)-4-d-piperidin-4-yl]-4-methyl piperazine to substitute 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
The preparation 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-diamidogen (compound 21), structural formula is as follows:
With similarity method described in embodiment 2, difference is to use 4-methyl-3,3,5,5-d4-piperazines to replace N-methyl Piperazine, thus prepare target compound.
Embodiment 5
The preparation chloro-N of 5-4-[2-(solutions of dimethyl phosphoryl base) phenyl]-N2-2-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-diamidogen (compound 22), structural formula is as follows:
With similarity method described in embodiment 2, difference is to use 4-methyl-2,2,3,3,5,5,6,6-d8-piperazine generations For N methyl piperazine, thus prepare target compound.
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-diamidogen (compound in following synthetic route 25):
(1) compound 23 is prepared:
In 25mL single port flask, add acetonitrile 5mL, under stirring, be sequentially added into 4-(1-(3-methoxyl group-4-nitrobenzophenone) Piperidin-4-yl) piperazine (0.32g, 1mmol), add triethylamine (0.12g, 1.2mmol), ice-water bath cool down, be slowly added dropwise into deuterium For iodomethane (0.16g, 1.1mmol), under ice-water bath, stirring reaction 30min, is evaporated to do, and residue is crossed silicagel column and obtained yellow Color solid 0.15g, yield 44.5%.
LC-MS (APCI): m/z=340.2 (M+1)+。
(2) preparing compound 24, its preparation method is consistent with the preparation method of compound 5, and difference is with 1-[1- (3-d3-methoxyl group-4-nitrobenzophenone) piperidin-4-yl]-4-d3-methyl piperazine replacement 1-[1-(3-d3-methoxyl group-4-nitro Phenyl) piperidin-4-yl]-4-methyl piperazine.
(3) preparing compound 25, its preparation method is consistent with the preparation method of compound 9, and difference is to use 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-diamidogen (following synthesis Compound 29 in route):
(1) compound 27 is prepared:
By compound 26 (214mg, 652 μm ol), deuterated formaldehyde heavy aqueous solution (313mg, 1.95mmol, 20%/ D2And CH O)3COOD (1) is stirred at room temperature 10 minutes, adds deuterated sodium cyanoborohydride (129mg, 1.95mmol), continues After continuous stirring 30 minutes, add triethylamine and neutralize, after concentration, obtain yellow solid 175mg, yield by column chromatography separating purification It is 77.8%.
LC-MS (APCI): m/z=346.4 (M+1)+。
(2) preparing compound 28, its preparation method is consistent with the preparation method of compound 5, and difference is with 1-[1- (3-methoxyl group-4-nitrobenzophenone) piperidin-4-yl]-4-d3-methyl-2,2,3,3,5,5,6,6-d8-piperazine replacement 1-[1-(3- D3-methoxyl group-4-nitrobenzophenone) piperidin-4-yl]-4-methyl piperazine.
(3) preparing compound 29, its preparation method is consistent with the preparation method of compound 9, and difference is to use 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-diamidogen (following synthesis Compound 32 in route):
(1) preparing compound 30, its preparation method is consistent with the preparation method of compound 10, and difference is to use d3- 5-fluoro-2-Nitroanisole substitutes 5-fluoro-2-Nitroanisole.
LC-MS (APCI): m/z=254.5 (M+1)+。
(2) compound 31 is prepared:
By tetraisopropyl titanate (Ti (Oi-Pr)4, 5mL) add to compound 30 (900mg, 3.6mmol) and 2,2,3,3, In the solution of 5,5,6,6-d8-piperazines (474mg, 5.03mmol), it is stirred overnight under room temperature, adds 10mL ethanol, continuously add Itrile group sodium borohydride (678mg, 10.79mmol), after this mixed liquor is stirred at room temperature 3 hours, pours into dissolved with 5g celite (celite) water (10mL), continues stirring 30 minutes, obtains yellow solid by column chromatography separating purification and produce after removing solvent Thing 300mg, yield is 25.4%.
LC-MS (APCI): m/z=332.5 (M+1)+。
(3) preparing compound 32, its preparation method is consistent with the preparation method of compound 29, and difference is to use chemical combination Thing 31 alternative compounds 26, formaldehyde substitutes deuterated formaldehyde, and itrile group sodium borohydride substitutes deuterated sodium borohydride.Finally give target to produce Thing is white solid, altogether 40mg, and yield is 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
The preparation chloro-N of 5-4-[2-(solutions of dimethyl phosphoryl base) phenyl]-N2-2-d3-methoxyl group-4-[4-(4-d2-methyl-2, 2,3,3,5,5,6,6-d8-piperazine-1-bases) piperidin-1-yl] phenyl } pyrimidine-2,4-diamidogen (compound 33), structural formula is as follows Shown in:
Similar to method described in embodiment 7, difference is with compound 31 alternative compounds 26, itrile group sodium borohydride Substitute deuterated sodium borohydride.Finally giving target product is yellow solid, altogether 70mg, and yield is 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
The preparation chloro-N of 5-4-[2-(solutions of dimethyl phosphoryl base) phenyl]-N2-2-d3-methoxyl group-4-[4-(4-d3-methyl-2, 2,3,3,5,5,6,6-d8-piperazine-1-bases) piperidin-1-yl] phenyl } pyrimidine-2,4-diamidogen (compound 34), structural formula is as follows Shown in:
Similar to method described in embodiment 7, difference is by compound 31 alternative compounds 26.Finally give target Product is white solid, altogether 110mg, and yield is 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
The compound of the present invention is evaluated determining their biologic activity in multiple tests.Such as, can survey Examination the compounds of this invention suppresses the ability of the protein kinase of multiple concern.ALK kinases is demonstrated by force by the compound of some tests The inhibitory activity of effect.
(1) kinase inhibitory activity evaluation
Compound is prepared: test-compound is dissolved in DMSO and is made into 20mM mother solution.Before using, compound is diluted in DMSO Become 0.1mM (diluents of 100 times of final concentrations), and do 3 times of gradient dilutions, 11 concentration.It is diluted to 4 times with buffer during dosing The diluent of final concentration.
Kinase assay: after preparation buffer, being mixed by the variable concentrations compound that enzyme is prepared with beforehand dilution, room temperature is placed 30 minutes, each concentration duplicate hole.Add corresponding substrate and ATP, room temperature reaction 60 minutes (being provided with yin and yang attribute comparison).Instead Answering complete addition antibody test, incubated at room is Evnvision detection after 60 minutes, gathers data.Carry out according to XLfit5 software Data analysis and plan figure.And use gram azoles for Buddhist nun as reference substance.
IC50=[(ABS test-ABS starts)/(ABS comparison-ABS starts)] x100
Kinase inhibitory activity result in embodiment is as shown in table 1.
Table 1 embodiment 1～10 and reference substance gram azoles replace the kinase inhibitory activity contrast table of Buddhist nun
Embodiment is numbered 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, ALK L1196M is suddenlyd change by the compounds of this invention Body surface reveals excellent inhibitory activity (IC50Less than 20), illustrate the compounds of this invention can pair between modification lymphom kinase (ALK) There is the strongest rejection ability.
(2) cytotoxicity experiment
Tetrazolium salts (MTS) method is used to have detected the inhibitory action of the compound on tumor cell to embodiment 1～10, and with Gram azoles is reference substance for Buddhist nun.Experimental result is as shown in table 2.
Table 2 embodiment 1～10 and reference substance gram azoles replace the cytotoxicity experiment contrast table of Buddhist nun
Embodiment is numbered 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 shows suppression and expresses The excellent antitumor activity of ALK mutant L1196M growth of cancer cells.
(3) metabolic stability evaluation
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 is 7.4).
The preparation of storing 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 mixing of 700mL, then with 0.5M dipotassium hydrogen phosphate solution regulation mixed liquor pH value to 7.4, use Front ultra-pure water dilutes 5 times, adds magnesium chloride, obtains phosphate buffer (100mM), the wherein potassium phosphate Han 100mM, 3.3mM Magnesium chloride, pH is 7.4.
Preparation NADPH regenerative system solution is (containing 6.5mM NADP, 16.5mM G-6-P, 3U/mL G-6-P D, 3.3mM Magnesium chloride), use preposition in wet on ice.
Preparation stop buffer: the acetonitrile containing 50ng/mL propranolol hydrochloride and 200ng/mL tolbutamide (internal standard) is molten Liquid.Take 25057.5 μ L phosphate buffer (pH7.4) in 50mL centrifuge tube, be separately added into 812.5 μ L people's hepatomicrosomes, mixed Even, obtain the hepatomicrosome diluent that protein concentration is 0.625mg/mL.Take 25057.5 μ L phosphate buffer (pH7.4) extremely In 50mL centrifuge tube, it is separately added into 812.5 μ L SD rat liver microsomes, mixing, obtain the liver that protein concentration is 0.625mg/mL Microsome diluent.
Hatching of sample: the storing solution of respective compound is diluted to 0.25mM respectively with the aqueous solution containing 70% acetonitrile, As working solution, standby.The people's hepatomicrosome or the rat liver microsomes diluent that take 398 μ L respectively add 96 holes and hatch in plate (N=2), be separately added into 2 μ L 0.25mM working solution in, mixing.
The mensuration of metabolic stability: add the stop buffer of 300 μ L pre-coolings in every hole of 96 hole depth orifice plates, be placed in ice On, as termination plate.96 holes are hatched plate and NADPH regenerative system is placed in 37 DEG C of water baths, 100 revs/min of concussions, incubate in advance 5min.Take out 80 μ L Incubating Solutions addition termination plates, mixing from hatching the every hole of plate, supplement 20 μ LNADPH regenerative system solution, as 0min sample.Again to hatching the every hole of plate and add the NADPH regenerative system solution of 80 μ L, start reaction, start timing.Corresponding chemical combination The reaction density of thing is 1 μM, and protein concentration is 0.5mg/mL.Respectively at react 10,30,90min time, respectively take 100 μ L reactant liquors, Adding in termination plate, vortex 3min terminates reaction.By termination plate in 5000 × g, centrifugal 10min under the conditions of 4 DEG C.Take on 100 μ L Clear liquid in 96 orifice plates being previously added 100 μ L distilled water, mixing, use LC-MS/MS to carry out sample analysis.
Data analysis: by LC-MS/MS system detection respective compound and interior target peak area, computerized compound is with interior Mark peak area ratio.Slope is recorded with time mapping by the natural logrithm of the percentage rate of compound surplus, and according to following Formula calculates t1/2And CLint, wherein V/M is i.e. equal to 1/ protein concentration.
To the compounds of this invention and do not have deuterated compound to test to compare, evaluate it micro-with rat liver people simultaneously The metabolic stability of plastochondria.Half-life of index and CLint (Clint) as metabolic stability are as shown in table 3. Table 3 uses without deuterated compound AP26113 as control sample；Described AP26113 is to be the third generation of prior art ALK inhibitor, the transitivity ALK positive nonsmall-cell lung cancer tolerated gram azoles for Buddhist nun for treatment, it tries in I/II phase clinic In testing, the Patients with Non-small-cell Lung positive to ALK, including brain metastes patient, AP26113 all has persistence anti-tumor activity.
As shown in table 3, by compareing with without deuterated compound AP26113, the compounds of this invention can significantly improve Metabolic stability, and then be more suitable for preparing for treatment the transitivity ALK positive nonsmall-cell lung cancer that gram azoles tolerates for Buddhist nun Medicine.
Table 3 embodiment 1～10 contrasts table with the metabolic stability of AP26113 control sample
(4) Pharmacokinetic Evaluation in rat
6 male Sprague-Dawley rats, 7-8 week old, body weight about 210g, be divided into 2 groups, often group 3, through vein or The compound (through vein 3mg/kg, oral 10mg/kg) of oral single dosage, compares its pharmacokinetic difference.
Rat uses standard feed to raise, and gives water.Test first 16 hours and start fasting.Medicine PEG400 and diformazan are sub- Sulfone dissolves.Eye socket take a blood sample, the time point of blood sampling for be administered latter 0.083 hour, 0.25 hour, 0.5 hour, 1 hour, 2 hours, 4 Hour, 6 hours, 8 hours, 12 hours and 24 hours.
Rat sucks of short duration anesthesia after ether, and eye socket gathers 300 μ L sample of blood in test tube.30 μ L1% heparinates are had in test tube Solution.Before using, test tube is dried overnight in 60 DEG C.After completing with later time point blood specimen collection, rat etherization Rear execution.
After blood specimen collection, the most leniently overturn test tube at least 5 times, it is ensured that be positioned on ice after mixing fully.Blood sample is 4 DEG C 5000rpm is centrifuged 5 minutes, is separated with erythrocyte by blood plasma.With pipettor sucking-off 100 μ L blood plasma to clean plastic centrifuge tube In, show title and the time point of compound.Blood plasma is saved in-80 DEG C before being analyzed.Measure in blood plasma with LC-MS/MS The concentration of the compounds of this invention.Pharmacokinetic parameter enters to calculate at the blood drug level of different time points based on every animal.
Experimental result is as shown in table 4 below, relative to control compound AP26113, and the compound 15 of embodiment 2 in the present invention Oral availability (F) and control compound AP26113 suitable, but its Increased Plasma Half-life, metabolic stability is obviously improved；Implement The Oral availability of the compound 9 of example 1 increases substantially (improving 20%), illustrates that it has more preferable medicine in animal body and moves Mechanics.
Table 4 pharmacokinetics in rats is tested
Should be understood that these embodiments are merely to illustrate the present invention rather than limit the scope of the present invention, in embodiment not Indicate the experimental technique of actual conditions, generally according to normal condition, or according to the condition proposed by manufacturer.Unless additionally said Bright, otherwise parts and percentages are weight portion and percentage by weight.
Above content is to combine concrete preferred implementation further description made for the present invention, it is impossible to assert Being embodied as of the present invention is confined to these explanations.For general technical staff of the technical field of the invention, On the premise of present inventive concept, it is also possible to make some simple deduction or replace, all should be considered as belonging to the present invention's Protection domain.

Claims (9)

1. a diaminopyrimidine compounds, it is characterised in that: the diaminopyrimidine compounds as shown in formula (I), or its crystal formation, 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 R22Independently of one another For hydrogen, deuterium, halogen or trifluoromethyl；
R16For hydrogen, deuterium, halogen, cyano group, the most deuterated C1-C6Alkyl or C1-C6Alkoxyl, one or many be deuterated or full deuterium The C in generation1-C6Alkyl or C1-C6Alkoxyl, or one or more halogen substiuted or perhalogeno element substituted C1-C6Alkyl or C1- C6Alkoxyl；
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.
Diaminopyrimidine compounds the most according to claim 1, it is characterised in that: R1a、R1bAnd R1cIt it is deuterium.
Diaminopyrimidine compounds the most according to claim 1, it is characterised in that: R7a、R7b、R8a、R8b、R9a、R9b、R10a And R10bIt is each independently deuterium or hydrogen.
Diaminopyrimidine compounds the most according to claim 1, it is characterised in that: R14a、R14bAnd R14cIt it is deuterium.
Diaminopyrimidine compounds the most according to claim 1, it is characterised in that: described compound is selected from lower group of compound Or its pharmaceutically acceptable salt:
6. a pharmaceutical composition preparation method for diaminopyrimidine compounds as claimed in any one of claims 1 to 5, wherein, its It is characterised by: by the compound described in pharmaceutically acceptable carrier and first aspect present invention, or its crystal formation, pharmaceutically may be used The salt of acceptance, prodrug, stereoisomer, isotopic variations hydrate or solvate mix, thus form drug regimen Thing.
7. a pharmaceutical composition, it is characterised in that: it contains pharmaceutically acceptable carrier and as Claims 1 to 5 is any One described diaminopyrimidine compounds, or its crystal formation, pharmaceutically acceptable salt, hydrate or solvate, three-dimensional different The pharmaceutical composition of structure body, prodrug or isotopic variations.
Pharmaceutical composition the most according to claim 7, it is characterised in that: it also comprises other treatment medicine, described treatment Medicine is cancer, cardiovascular disease, inflammation, infection, immune disease, cell proliferation disorders, viral disease, metabolic disease Disease or the medicine of organ transplantation.
9. a diaminopyrimidine compounds as claimed in any one of claims 1 to 5, wherein, or its crystal formation, pharmaceutically acceptable The purposes of salt, hydrate or solvated compounds, it is characterised in that: for preparing the medicine group of suppression anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase Compound.
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106220608A (en) * 2016-07-25 2016-12-14 张柏 Diphenylamino pyrimidine and triaizine compounds, its Pharmaceutical composition and purposes
WO2017088784A1 (en) * 2015-11-27 2017-06-01 正大天晴药业集团股份有限公司 Deuterium-modified brigatinib derivatives, pharmaceutical compositions comprising same, and use thereof
CN108689994A (en) * 2017-07-01 2018-10-23 浙江同源康医药股份有限公司 Compound as ALK kinase inhibitors and its application
CN109593102A (en) * 2018-01-04 2019-04-09 深圳市塔吉瑞生物医药有限公司 A kind of preparation method and its crystal form of deuterated diphenylamino pyrimidines
CN109851638A (en) * 2018-02-07 2019-06-07 深圳市塔吉瑞生物医药有限公司 Substituted diaminopyrimidine compounds
CN112824420A (en) * 2019-11-21 2021-05-21 浙江同源康医药股份有限公司 Compounds useful as EGFR kinase inhibitors and uses thereof

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021150613A1 (en) 2020-01-20 2021-07-29 Incyte Corporation Spiro compounds as inhibitors of kras
US11739102B2 (en) 2020-05-13 2023-08-29 Incyte Corporation Fused pyrimidine compounds as KRAS inhibitors
WO2022072783A1 (en) 2020-10-02 2022-04-07 Incyte Corporation Bicyclic dione compounds as inhibitors of kras
CA3235146A1 (en) 2021-10-14 2023-04-20 Incyte Corporation Quinoline compounds as inhibitors of kras

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102105150A (en) * 2008-05-21 2011-06-22 阿里亚德医药股份有限公司 Phosphorous derivatives as kinase inhibitors
CN104327053A (en) * 2014-08-06 2015-02-04 北京凯悦宁医药科技有限公司 Deuterated crizotinib and derivative thereof, preparation method and application
CN105061506A (en) * 2015-07-27 2015-11-18 苏州明锐医药科技有限公司 Preparation method for anti-tumor drug AP26113
CN105085489A (en) * 2014-11-05 2015-11-25 上海页岩科技有限公司 Pyrimidine or pyridine compound, and preparation method and pharmaceutical application thereof

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009045476A1 (en) * 2007-10-02 2009-04-09 Concert Pharmaceuticals, Inc. Pyrimidinedione derivatives
US20150299166A1 (en) * 2012-12-20 2015-10-22 Concert Pharmaceuticals, Inc. Deuterated alk inhibitors
CN103965114B (en) * 2013-01-28 2016-01-06 苏州泽璟生物制药有限公司 Deuterated phenyl amino pyrimidine compounds and comprise the pharmaceutical composition of this compound
CN104109149B (en) * 2013-04-22 2018-09-28 苏州泽璟生物制药有限公司 Deuterated diaminopyrimidine compounds and the pharmaceutical composition comprising the compound
EP3381925B1 (en) * 2015-11-27 2020-12-16 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Deuterium-modified brigatinib derivatives, pharmaceutical compositions comprising same, and use thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102105150A (en) * 2008-05-21 2011-06-22 阿里亚德医药股份有限公司 Phosphorous derivatives as kinase inhibitors
CN104327053A (en) * 2014-08-06 2015-02-04 北京凯悦宁医药科技有限公司 Deuterated crizotinib and derivative thereof, preparation method and application
CN105085489A (en) * 2014-11-05 2015-11-25 上海页岩科技有限公司 Pyrimidine or pyridine compound, and preparation method and pharmaceutical application thereof
CN105061506A (en) * 2015-07-27 2015-11-18 苏州明锐医药科技有限公司 Preparation method for anti-tumor drug AP26113

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SOLOMON, B. ET AL: "Current Status of Targeted Therapy for Anaplastic Lymphoma Kinase-Rearranged Non-Small Cell Lung Cancer", 《CLINICAL PHARMACOLOGY & THERAPEUTICS (NEW YORK, NY, UNITED STATES)》 *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108350006B (en) * 2015-11-27 2020-01-03 正大天晴药业集团股份有限公司 Deuterium-modified Brigatinib derivative, pharmaceutical composition containing compound and application of deuterium-modified Brigatinib derivative
WO2017088784A1 (en) * 2015-11-27 2017-06-01 正大天晴药业集团股份有限公司 Deuterium-modified brigatinib derivatives, pharmaceutical compositions comprising same, and use thereof
CN108350006A (en) * 2015-11-27 2018-07-31 正大天晴药业集团股份有限公司 Brigatinib derivatives, the medical composition and its use containing the compound of deuterium modification
US10717753B2 (en) 2015-11-27 2020-07-21 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Deuterium-modified brigatinib derivatives, pharmaceutical compositions comprising same, and use thereof
WO2018018986A1 (en) * 2016-07-25 2018-02-01 安润医药科技（苏州）有限公司 Diphenylaminopyrimidine and triazine compound, and pharmaceutical composition and use thereof
CN106220608B (en) * 2016-07-25 2018-11-27 安润医药科技（苏州）有限公司 Diphenylamino pyrimidine and triaizine compounds, its Pharmaceutical composition and purposes
CN106220608A (en) * 2016-07-25 2016-12-14 张柏 Diphenylamino pyrimidine and triaizine compounds, its Pharmaceutical composition and purposes
US10647694B2 (en) 2016-07-25 2020-05-12 Arromax Pharmatech Co., Ltd. Diphenylaminopyrimidine and triazine compound, and pharmaceutical composition and use thereof
WO2019007293A1 (en) * 2017-07-01 2019-01-10 浙江同源康医药股份有限公司 Compound used as alk kinase inhibitor and use thereof
CN108689994A (en) * 2017-07-01 2018-10-23 浙江同源康医药股份有限公司 Compound as ALK kinase inhibitors and its application
WO2019134573A1 (en) * 2018-01-04 2019-07-11 深圳市塔吉瑞生物医药有限公司 Method for preparing deuterated diphenylaminopyrimidine compound and crystal form thereof
CN109593102A (en) * 2018-01-04 2019-04-09 深圳市塔吉瑞生物医药有限公司 A kind of preparation method and its crystal form of deuterated diphenylamino pyrimidines
CN109593102B (en) * 2018-01-04 2022-02-08 深圳市塔吉瑞生物医药有限公司 Preparation method and crystal form of deuterated diphenylaminopyrimidine compound
CN109851638A (en) * 2018-02-07 2019-06-07 深圳市塔吉瑞生物医药有限公司 Substituted diaminopyrimidine compounds
CN112824420A (en) * 2019-11-21 2021-05-21 浙江同源康医药股份有限公司 Compounds useful as EGFR kinase inhibitors and uses thereof

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