CN105111201A - 5-methyl-2-(pyridinyl-2-amino)-8H-pyrido[2,3-d]pyrimidin-7-ketone compounds - Google Patents

5-methyl-2-(pyridinyl-2-amino)-8H-pyrido[2,3-d]pyrimidin-7-ketone compounds Download PDF

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CN105111201A
CN105111201A CN201410548970.5A CN201410548970A CN105111201A CN 105111201 A CN105111201 A CN 105111201A CN 201410548970 A CN201410548970 A CN 201410548970A CN 105111201 A CN105111201 A CN 105111201A
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compound
diastereomer
enantiomer
acceptable salt
prodrugs
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CN105111201B (en
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江岳恒
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Yifang Biotechnology (Shanghai) Co.,Ltd.
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Shanghai Yeyan Technology Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The invention provides a series of 5-methyl-2-(pyridinyl-2-amino)-8H-pyrido[2,3-d]pyrimidin-7-ketone compounds shown in formula (I), as well as pharmaceutically acceptable salts, enantiomers, diastereomers or racemic mixtures, prodrug molecules and solvates of the compounds, which can be used as selective inhibitors of cyclin-dependent kinase CDK4 and/or CDK6, and are used for treating diseases related to cyclin-dependent kinase signal pathway. More particularly, the compounds can effectively inhibit growth of a plurality of tumor cells, and are used for preparing antitumor drugs, which are used for treatment combination, therapy or prevention of different cancers.

Description

5-methyl-2-(pyridine-2-base is amino)-8H-pyrido [2,3-d] pyrimidin-7-one compounds
Technical field
The present invention relates to medical art, be specifically related to 5-methyl-2-(pyridine-2-base is amino)-8H-pyrido [2,3-d] pyrimidin-7-ones compounds or its pharmacy acceptable salt, enantiomer, diastereomer, racemic modification or their mixture, prodrug, solvated compounds and preparation method thereof, the pharmaceutical composition comprising these materials with and uses thereof.
Background technology
An item key of cancer be exactly cell cycle imbalance cause immoderate growth.Under normal circumstances, the cell cycle that cell has to pass through four-stage grows, and divides and copies: the G1 phase (vegetative period), S phase (DNA synthesis phase), G2 and M phase (m period).In the cell cycle, each stage is by the regulation and control being called as cell cycle protein dependent kinase (cyclin-dependentkinase, CDK).The key regulatory proteins kinases of decision G1-S phase transition is exactly CDK4, and it and Cyclin D1 (cyclinD) form a complex body, by the protein phosphorylation of retinoblastoma (Rb).Once there is phosphorylation in tumor suppressor protein Rb, the transcription factor E2F that it combines closely under the state be not phosphorylated can be discharged, and E2F activate transcribe further and promote the cell cycle by restriction check point (restrictioncheckpoint, R point).Cell enters the S phase once by R point is just irreversible.In later stage and the G2 phase of S phase, CDK1 and CDK2 and their affiliate's cyclin A and B together cooperates to play an important role, and promotes cell and enters the M phase, complete division and the growth cycle of cell.In cancer cells, cell cycle regulating is damaged, cancer cells becomes to be had no to grow temperately, divide and copy, and therefore for regulating the path of cell cycle to find and find selectivity and potent CDK inhibitor, becomes the major objective of oncologic research for many years.
Selectivity target therapeutic agent for CDK4 and/or CDK6 can play a role in following several mechanism: the high expression level of (1) CDK4 gene amplification or albumen, the liposarcoma that this change often appears at differentiated and dedifferentes, and also at some other solid tumor and hematologic malignancies; (2) amplification of cyclin D1 or high expression level, this is at lymphoma mantle cell, also observes in multiple solid tumor; (3) loss of p16INK4A gene (CDKN2A), this is also event common in many cancers.In cell, p16INK4A albumen is the natural inhibitor of CDK4, and having p16 to lose cancer generally may be responsive to the suppression of CDK4.Such as in ovarian cancer, these cancerous cell lines have the expression of low p16 protein level and high Rb, can be more responsive to the inhibitor of CDK4.Because the high similarity of the albumen of CDK6 and CDK4, current CDK4 inhibitor also has similar restraining effect to CDK6 protein kinase simultaneously.Three CDK4/CDK6 inhibitor are had to enter clinical trial at present: palbociclib (PD0332991), LEE011 and LY2835219, these inhibitor make CDK4/6 cannot form mixture with CyclinD, effectively block the cell cycle from the G1 phase to the process of S phase, thus reach the object of inhibition tumor cell propagation, and in mammary cancer, neuroblastoma, pernicious rhabdomyoma, lymphoma, the anti-tumor activity showing single dose or combine with other target therapeutic agents in sarcoma and other tumour.
Summary of the invention
The invention provides a series of 5-methyl-2-(pyridine-2-base is amino)-8H-pyrido [2,3-d] pyrimidin-7-ones compounds, its pharmacy acceptable salt, enantiomer, diastereomer, racemic modification, prodrugs or solvate, can be used for the medicine preparing the treatment disease relevant with cell cycle protein dependent kinase signal path.
The invention provides with the compound shown in following formula I, its pharmacy acceptable salt, enantiomer, diastereomer, racemic modification, prodrugs or solvate,
Wherein,
R 1be selected from following group:
Wherein, R 2and R 2' be selected from H independently of one another, deuterium (D), C1-C4 alkyl, fluorine and cyano group, and, R 2and R 2' can on same or different carbon atom;
N=1 or 2
R 3be selected from following group:
Wherein, R 4be selected from H, deuterium (D) and C1-C4 alkyl,
W is selected from CH 2, CH 2cH 2, O and NH
X is selected from CH and N
Y is selected from CH 2, NH and O
M=0,1 or 2
N=0,1 or 2;
Preferably,
R 1be selected from following group:
R 3be selected from following group:
More preferably,
R 1be selected from following group:
R 3be selected from following group:
More preferably,
R 1be selected from following group:
R 3be selected from following group:
Preferably, 5-methyl-2-of the present invention (pyridine-2-base is amino)-8H-pyrido [2,3-d] pyrimidin-7-ones compounds, its pharmacy acceptable salt, enantiomer, diastereomer, racemic modification, prodrugs or solvate comprise following compound:
Wherein, above compound comprises its enantiomer, diastereomer, racemic modification and its mixture, prodrugs or solvate, such as compound 1 has enantiomer 1A and 1B, compound 5 has enantiomer 5A and 5B, compound 7 has enantiomer 7A and 7B, compound 24 has diastereomer 24A and 24B, and compound 25 has diastereomer 25A and 25B, and compound 26 has diastereomer 26A and 26B and diastereomer 27A and 27B.
Most preferably, described compound is selected from following compound:
Wherein, cis represents cis, and trans represents trans.
Also namely, above-mentioned particular compound is following compound:
Another aspect of the present invention additionally provides the application in preparation CDK4 and/or CDK6 selective depressant of described 5-methyl-2-(pyridine-2-base is amino)-8H-pyrido [2,3-d] pyrimidin-7-ones compounds, its pharmacy acceptable salt, enantiomer, diastereomer, racemic modification, prodrugs or solvate.
Another aspect of the present invention additionally provides described 5-methyl-2-(pyridine-2-base is amino)-8H-pyrido [2,3-d] pyrimidin-7-one compounds, its pharmacy acceptable salt, enantiomer, diastereomer, racemic modification, prodrugs or solvate, especially as CDK4 and/or CDK6 selective depressant for the preparation of the purposes in the medicine of the treatment disease relevant with cell cycle protein dependent kinase signal path.
The described disease relevant with cell cycle protein dependent kinase signal path comprises tumour, such as mammary cancer, glioma, glioblastoma multiforme, lung cancer, colorectal carcinoma, cancer of the stomach, gastrointestinal stromal knurl (GIST), hepatocellular carcinoma, prostate tumor, sarcoma, ovarian cancer, cervical cancer, carcinoma of the pancreas, melanoma, thyroid carcinoma, cholangiocarcinoma, carcinoma of endometrium, kidney, mesothelioma, lymphoma, leukemia, non-Hodgkin lymphoma, primary cutaneous type, acute myelocytic leukemia (AML), multiple myeloma.
Another aspect of the present invention provides a kind of pharmaceutical composition, described pharmaceutical composition contains: being selected from for the treatment of significant quantity is above-mentioned according to one or more in 5-methyl-2-of the present invention (pyridine-2-base is amino)-8H-pyrido [2,3-d] pyrimidin-7-ones compounds, its pharmacy acceptable salt, enantiomer, diastereomer, racemic modification and their mixture, prodrugs and solvate; Optionally pharmaceutically acceptable carrier.Described pharmaceutical composition can be used for interior therapeutic and has biocompatibility.
Another object of the present invention is to provide a kind of compound of the present invention, its pharmacy acceptable salt, enantiomer, diastereomer, racemic modification, prodrugs or solvate and other antitumor drug (comprise chemotherapy, tumour immunotherapy) method of combination therapy cancer, comprise simultaneously, respectively or successively co-administered described compound, its pharmacy acceptable salt, enantiomer, diastereomer, racemic modification, prodrugs or solvate and other antitumor drug.In this conjoint therapy, other antitumor drugs and the compounds of this invention and salt thereof or prodrug can be arranged side by side, side by side, sequentially, or administration respectively, and can including but not limited to one or more of the antineoplastic agent of Types Below: alkylating agent (such as card molybdenum, Ao Shali molybdenum, along molybdenum, endoxan, nitrosoureas, mustargen, melphalan), antimetabolite (such as gemcitabine), and antifol (such as 5 FU 5 fluorouracil and Tegafur, Raltitrexed, Rheumatrex, cytosine arabinoside, hydroxyurea), topoisomerase enzyme inhibitor (such as Etoposide, Hycamtin, camptothecine), antimitotic agent (such as vincristine(VCR), vinealeucoblastine(VLB), vinorelbine, taxol, taxotere), antitumor antibiotics (such as Zorubicin, bleomycin, Dx, daunomycin, ametycin, actinomycin), antiestrogen (such as tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene), antiandrogen (such as bicalutamide, flutamide, Nilutamide), lhrh antagonist or LHRH agonist (such as goserelin, Leuprolide, and buserelin), aromatase inhibitor (such as Anastrozole, letrozole), CYP17 lyase inhibitors (such as Abiraterone), anti-erbB 2 antibody trastuzumab [Trastuzumab], anti-egfr antibodies Cetuximab [Erbitux], Tyrosylprotein kinase, inhibitor (the such as imatinib of serine/threonine kinase, AMN107, Xarelto, Sibutramine Hydrochloride is for Buddhist nun (trametinib), Da Lafeini (dabrafenib), lapatinibditosylate (lapatinib)), anti-human vascular endothelial growth factor antibody Avastin (Avastin) and vegf receptor tyrosine kinase inhibitor (such as Ah handkerchief is for Buddhist nun), immunity tumor therapeuticing method, such as anti-PD-1 antibody (pembrolizumab, nivolumab), anti-PD-L1 antibody, anti-lag-3 antibody, anti-CTLA-4 antibody, anti-4-1BB antibody, anti-GITR antibody, anti-ICOS antibody, anti-OX40 antibody, interleukin II.
According to the present invention, described pharmacy acceptable salt is conventional pharmacy acceptable salt, comprise hydrochloride, hydrobromate, hydriodate, vitriol, phosphoric acid salt, nitrate, acetate, trifluoroacetate, tosilate, salicylate, mesylate, oxalate, succinate, Citrate trianion, malate, lactic acid salt, fumarate etc.
Compound of the present invention or its pharmacy acceptable salt, enantiomer, diastereomer, racemic modification, prodrugs or solvate, also comprise its polymorphic, the crystal that namely structure that crystallizes under different physical and chemical conditions of chemicals molecule is different.
According to 5-methyl-2-of the present invention (pyridine-2-base is amino)-8H-pyrido [2,3-d] pyrimidin-7-ones compounds, its pharmacy acceptable salt, enantiomer, diastereomer, racemic modification, prodrugs or solvate, specifically prepare according to following route:
Step 1: under nitrogen protection, in there-necked flask, adds A, bromo-2, the 4-dichloro pyrimidines of 5-, salt of wormwood and Isosorbide-5-Nitrae-dioxane, and stirring at room temperature reaction is spent the night.Add ethyl acetate, salt is washed.Organic phase anhydrous sodium sulfate drying, silica gel column chromatography, collects product and obtains compd B.
Step 2: nitrogen protection, in there-necked flask, adds B, β-crotonic acid, DIPEA, insulated and stirred 10 minutes, and add three (2-tolyl) phosphine, two (cyanophenyl) palladium chloride, finishes, and nitrogen replacement three times, reacting by heating is spent the night.Be down to room temperature, add diluted ethyl acetate, saturated aqueous common salt backwash.Organic phase anhydrous sodium sulfate drying, is spin-dried for, and obtains Compound C and reacts for next step.
Step 3: in there-necked flask, under nitrogen protection, be dissolved in by C and heavily steam in tetrahydrofuran (THF), add acetic anhydride, reacting by heating is spent the night.Be down to room temperature, add diluted ethyl acetate, saturated aqueous common salt backwash.Organic phase anhydrous sodium sulfate drying, after being spin-dried for solvent, directly silicagel column is separated, and obtains solid D.
Step 4: in there-necked flask, under nitrogen protection, is dissolved in acetic acid by solid D, adds sodium-acetate, is cooled to 0 DEG C and drips bromine, finish, reacting by heating.Be down to room temperature, add saturated sodium bisulfite cancellation reaction.Dichloromethane extraction, collects organic phase.Saturated aqueous common salt backwash, anhydrous sodium sulfate drying, after being spin-dried for solvent, direct silicagel column is separated to obtain solid E.
Step 5: in there-necked flask, under nitrogen protection, by H 2the toluene solution of N-R is cooled to 0 DEG C, adds LHMDS, and stirring at room temperature 30 minutes, is cooled to 0 DEG C, and drip the toluene solution of E, finish, room temperature reaction spends the night.Add dchloromethane, saturated aqueous common salt backwash.Organic phase anhydrous sodium sulfate drying, after being spin-dried for solvent, direct silicagel column is separated to obtain solid F.
Step 6: in there-necked flask; under nitrogen protection; F is dissolved in propyl carbinol, adds vinyl n-butyl ether, add N; N-diisopropylethylamine; add catalytic amount 1,1'-bis-(diphenyl phosphine) ferrocene palladium chloride (II), finish; displaced air three times, reacting by heating is spent the night.Be down to room temperature, add diluted ethyl acetate, saturated aqueous common salt backwash.Collect organic phase, anhydrous sodium sulfate drying, after being spin-dried for solvent, direct silicagel column is separated to obtain solid G.
Step 7: in there-necked flask, adds G, tetrahydrofuran (THF).Add 6N hydrochloric acid under ice bath, room temperature reaction spends the night.Regulate reaction solution PH=8 ~ 9 under ice bath, extraction into ethyl acetate, collect organic phase.Organic phase anhydrous sodium sulfate drying, is spin-dried for obtain target product H.If target product H is the mixture of steric isomer, optically pure enantiomer can be obtained by chiral separation.If target product H reversed-phase column is purified, trifluoroacetate can be obtained.Target product H also can use HCl treatment, obtains hydrochloride,
Wherein, R is r 1and R 3definition the same.
Technique effect
5-methyl-2-of the present invention (pyridine-2-base is amino)-8H-pyrido [2,3-d] pyrimidin-7-ones compounds, its pharmacy acceptable salt, enantiomer, diastereomer, racemic modification, prodrugs or solvate, as novel C DK4 and/or CDK6 selective depressant, can be used for the medicine preparing the treatment disease relevant with cell cycle protein dependent kinase signal path or the obstacle caused by abnormal cell proliferation or illness.Compound of the present invention, its pharmacy acceptable salt, enantiomer, diastereomer or racemic modification, prodrugs or solvate for CDK4 and/or CDK6 inhibit activities not only with the biological activity of the inhibitor of prior art quite or better, and than the inhibitor of prior art, there is better internal metabolism character, higher Plasma Concentration, the metabolite of less toxic side effect.
Embodiment
The present invention will be illustrated further below in an example.These embodiments only for illustration of the present invention, but do not limit the present invention in any way.
The analytical data of sample is by following Instrument measuring:
LC-MS: shimadzuLCMS-2020 chromatographic column: shimadzushim-packXR-ODS3.0*50mm, 2.2um
Nucleus magnetic resonance: BrukerAV-III300MHz; Varian400MHz
Deuterated DMSO and MeOH: Sigma-Aldrich (Shanghai) trade Co., Ltd.Deuterochloroform: Beijing Yi Nuokai Science and Technology Ltd..Heavy water: Beijing lark prestige Science and Technology Ltd..
Chiral separation HPLC
Instrument: shimadzuLC20AD
Chiral column: CHIRALPAKAD-H, CHIRALPAKIA, CHIRALPAKIB, CHIRALPAKIC, Lux3umCellulose-4.
Preparation high pressure liquid chromatography (Prep-HPLC) instrument
Instrument: Waters2545
Chromatographic column: 1) WatersX-bridgeRP18,19*150mm, 5um.2) sunfireprepC18/OBD, 19*150mm, 5um.
Supercritical fluid chromatograph device (SFC)
Instrument: SFC350
Chromatographic column: 1) ChiralpakAS-H5*25cm, 5um.2) CHIRALPAKAD-HSFC5*25cm, 5um
Unless otherwise indicated, in following examples conventional reagent used, medicine all purchased from:
Nanjing remedies medicament research and development company limited; Ladder is uncommon likes that (Shanghai) changes into industrial development company limited; Shanghai Shu Ya Pharmaceutical Technology Co., Ltd; Zhangjiagang Ai Mate Chemical Co., Ltd.; (Jiangsu) Yancheng City Jing Hua Chemical Co., Ltd.; The special trade Co., Ltd of Chengdu Ace; Tianjin method Moses Pharmaceutical Technology Co., Ltd; Tianjin recovery development in science and technology company limited; Sichuan Xilong Chemical Co., Ltd.; Tianjin good fortune chemical reagent factory in morning; Traditional Chinese medicines group chemical reagent Shaanxi company limited; Shaanxi Xin Tong Chemical Co., Ltd.; Tianjin Concord Technology Co., Ltd.; Sigma-Aldrich (Shanghai) trade Co., Ltd; Upper starfish can biochemical company limited; Xi'an Dong Guan distilled water company limited, waits company.
Concrete preparation example is as follows:
The synthesis of intermediate 1-6
Step 1: in 2000mL there-necked flask, adds 1-1 (80g) under nitrogen protection, ammonia soln (665g, 25%).Be warming up to 60 DEG C of reactions to spend the night.Cooling, leads to nitrogen 1 hour to system.System pH hydrochloric acid (6N) is adjusted to 4-5, obtains 1-2 after being spin-dried for rear solvent, directly throw next step.
Step 2: in 2000mL there-necked flask, adds 1-2 (60g) under nitrogen protection, anhydrous methanol (1000mL), triethylamine (132g).Add di-tert-butyl dicarbonic acid ester, room temperature reaction spends the night in batches.Be spin-dried for methyl alcohol (1000mL), add 1500mL diluted ethyl acetate, water 3x500mL backwash, merge organic phase, anhydrous sodium sulfate drying, crude product silica column purification (pentane: ethyl acetate=50:1-20:1) obtains 1-3.
Step 3: in 1000mL there-necked flask, adds under nitrogen protection in 1-3 (40g) and 800mL methylene dichloride.Cool to 0 DEG C, add Dai Si-Martin (Dess-Martin) oxygenant reagent (101g) in batches, get back to room temperature reaction and spend the night.Add 1000mL diluted ethyl acetate, water 3x500mL backwash, merge organic phase, anhydrous sodium sulfate drying.Crude product silica column purification (pentane: ethyl acetate=30:1-10:1) obtains 1-4.
Step 4: in 1000mL there-necked flask, adds under nitrogen protection in 1-4 (30g) and 600mL methylene dichloride.Cool to 0 DEG C, drip diethylaminosulfurtrifluoride (DAST, 121g), get back to room temperature reaction and spend the night.System poured in frozen water, methylene dichloride (600mL) extracts 3x500mL.Anhydrous sodium sulfate drying, filters, and after filtrate is concentrated, silicagel column is separated (pentane: ethyl acetate=30:1-10:1) and obtains 1-5.
Step 5: in 250mL there-necked flask, adds 1-5 (15g) and methylene dichloride (200mL).After passing into hydrogen chloride gas, room temperature reaction 2 hours.Product 1-6 is obtained after being spin-dried for solvent.
The synthesis of intermediate 2-4:
Step 1: nitrogen protection, toward in 250mL there-necked flask, adds 2-1 (10g), TMSA and toluene (120mL).Be chilled to 20-30 DEG C, drip boron trifluoride diethyl etherate (17g) room temperature reaction 24 hours.Stratification, 1x50mL10% sodium bicarbonate aqueous solution washes organic phase, anhydrous sodium sulfate drying, for next step reaction.
Step 2: under nitrogen protection, in 500mL there-necked flask, adds the toluene solution of 2-2, ether (100mL).Then triethoxy phosphorus (16.3g) is slowly added, complete, room temperature reaction 2 days.Be spin-dried for obtain water white transparency oily thing, for next step reaction.
Step 3: nitrogen protection, in 100mL there-necked flask, adds 2-3 (23g), p-methyl benzenesulfonic acid (9.51g), and ethanol (60mL) and water (0.8g), 80 DEG C of reactions are spent the night.Be spin-dried for, resistates adds 100mL ether, suction filtration, collects filter cake.Filter cake 3x30mL ether is washed, and dries to obtain target product 2-4.
The synthesis of intermediate 3-4
Step 1: in 2000mL four-hole bottle, adds 500mLN under nitrogen protection, N-dimethyl sulfoxide (DMSO).Be cooled to 20-25 DEG C, add sodium hydride (19g) in batches, then add Trimethylsulfoxonium Iodide (118g) at this temperature in batches, and stir 1 hour at such a temperature, the N of 3-1 (40g) is dripped, N-dimethyl sulfoxide (DMSO) (100mL) solution at 20 DEG C.This system is warming up to 50 DEG C after stirring 30 minutes at 20-25 DEG C and reacts 2 hours.After reaction terminates, cooling, pours cancellation in frozen water into.With the extraction of 3x1000mL anhydrous diethyl ether, merge organic phase, anhydrous sodium sulfate drying, filter.Filtrate is spin-dried at lower than 30 DEG C, obtains 3-2 (crude product).
Step 2: in 2000mL there-necked flask, adds 3-2 (90g) under nitrogen protection, water (900mL), oxammonium hydrochloride (82.8g), sodium acetate (153g).Be warming up to 80 DEG C of reactions 2 hours.Be extracted with ethyl acetate 4x500mL after cooling, merge organic phase, anhydrous sodium sulfate drying, filter.After filtrate is concentrated, silicagel column is separated (ethyl acetate/pentane=1:30-1:10) and obtains 3-3.
Step 3: in 2000mL four-hole bottle, adds under nitrogen protection in lithium aluminum hydride (34g) and 600mL tetrahydrofuran (THF).Cool to 0 DEG C, 3-3 is dissolved in 400mL tetrahydrofuran (THF), be added drop-wise in above-mentioned system, get back to room temperature reaction and spend the night.0 DEG C slowly adds 34mL shrend and goes out.And then add 102mL sodium hydroxide (15%) aqueous solution and 34mL water.Suction filtration, filter cake tetrahydrofuran (THF) 5x100mL washes.Gained filtrate is spin-dried for, and obtains 3-4.
The synthesis of intermediate 4-6
Step 1: under nitrogen protection, adds potassium hydroxide (46g) in 1L there-necked flask, water (12mL), ethanol (225mL).4-1 (130g) is dripped under ice bath.Finish room temperature reaction 10 minutes, reaction terminates.Filter, collect filter cake.Ether 500mL drip washing filter cake, dries, obtains 4-2.
Step 2: under nitrogen protection, adds 4-2 (140g) in 2L there-necked flask, N, N-dimethyl sulfoxide (DMSO) (1000mL), glycol dibromide (174g).Room temperature reaction spends the night.Pour cancellation reaction in 1L water into, extracted with diethyl ether (300mLx3), salt is washed.Organic phase anhydrous sodium sulfate drying, concentrated, obtain 4-3.
Step 3: under nitrogen protection, adds 4-3 (210g) in 2L there-necked flask, HMPA (1000mL), lithium chloride (19g).Be warming up to 140 DEG C of reactions to spend the night.Underpressure distillation, collects product for 100 DEG C and obtains 4-4.
Step 4: under nitrogen protection, adds 4-4 (16g) in 500mL there-necked flask, ethanol (150mL), water (150mL), oxammonium hydrochloride (20g), sodium carbonate (30g).Room temperature reaction spends the night.Add 50mL water, extraction into ethyl acetate (100mLx3), collect organic phase.Salt washing (200mLx2).Organic phase anhydrous sodium sulfate drying, concentrates to obtain 4-5.
Step 5: under nitrogen protection, adds 4-5 (6g) in 500mL there-necked flask, tetrahydrofuran (THF) (200mL).Be cooled to 0 DEG C, add lithium aluminum hydride (5.5g) in batches.Finish, be warming up to 55 DEG C of reactions 5 hours.Be cooled to 0 DEG C, add 5.5mL water.PH=7 is adjusted with the aqueous sodium hydroxide solution of 1N.Add the water of 5.5mL and the ethyl acetate of 200mL again.Organic phase anhydrous sodium sulfate drying, filters, and collects filtrate.In filtrate, add 5.5g oxalic acid after filtrate drying, stir 30 minutes, filter, collect the oxalate that filter cake obtains 4-6.
The synthesis of intermediate 5-3
Step 1: under nitrogen protection, adds 5-1 (20g) in 500mL there-necked flask, ethanol (250mL), oxammonium hydrochloride (16g), pyridine (18.6g).Be warming up to 80 DEG C of reactions to spend the night.Be down to room temperature, add 200mL water, extraction into ethyl acetate (200mLx3), salt washing (500mLx5).Organic phase anhydrous sodium sulfate drying, concentrates to obtain 5-2.
Step 2: under nitrogen protection, adds 5-2 (18g) in 500mL there-necked flask, tetrahydrofuran (THF) (500mL).Be cooled to 0 DEG C, add lithium aluminum hydride (16g) in batches.Finish, room temperature reaction spends the night.Be cooled to 0 DEG C, add 16mL water.Reaction solution pH=7 is adjusted with sodium hydroxide solution (1N).Add water 16mL, the methylene dichloride layering of 200mL.Separate organic phase anhydrous sodium sulfate drying, concentrate to obtain 5-3.
The synthesis of intermediate 6-4
Step 1: under nitrogen protection, in 2000mL there-necked flask, adds 6-1 (60g), toluene (600mL), triethylamine (81g), diphenyl phosphoryl azide (DPPA, 191g).Reaction system was 100 DEG C of reactions 1 hour.Then phenylcarbinol is dripped at being cooled to 40-50 DEG C.Be warming up to 100 DEG C after dripping off, reaction is spent the night.Be down to room temperature, add 500mL diluted ethyl acetate, salt washing 500mLx3.Organic phase anhydrous sodium sulfate drying, after being spin-dried for solvent, silicagel column is separated to obtain 6-2.
Step 2: in 2000mL there-necked flask, adds 6-2 (50g) under nitrogen protection, methylene dichloride (1000mL).Be cooled to 0 DEG C, drip zinc ethyl (276mL, 1M).Then be added dropwise to methylene iodide (73g), and in this thermotonus after 1 hour, room temperature reaction spends the night.Reaction solution 3x500mL water backwash, organic phase anhydrous sodium sulfate drying, after concentrated, silicagel column is separated (eluent pentane: ethyl acetate=50:1-20:1) and obtains 6-3.
Step 3: in 1000mL single port bottle, adds anhydrous methanol (600mL) under nitrogen protection, 6-3 (45g) and have water palladium carbon (10g, 10%).Room temperature hydrogenation reaction is spent the night.After suction filtration, collect filtrate, be spin-dried for solvent and obtain 6-4.
The synthesis of intermediate 7-6
Step 1: in 2000mL there-necked flask, adds 7-1 (80g) under nitrogen protection, triethylamine (107g), diphenyl phosphoryl azide (DPPA, 255g), dry toluene (800mL).100 DEG C are reacted 1 hour, are then cooled to 40-50 DEG C, drip phenylcarbinol (114g) at such a temperature, be warming up to 100 DEG C of reactions and spend the night after dripping off.Cooling, adds 500mL diluted ethyl acetate, and salt washing 500mL washes 3 times, organic phase dried over sodium sulfate, filters, and is spin-dried for rear silicagel column separation (ethyl acetate/pentane=1:100-1:50) and obtains 7-2.
Step 2: in 2000mL there-necked flask, adds 7-2 (50g) under nitrogen protection, tetrahydrofuran (THF) (500mL).Be cooled to 0 DEG C, drip borine tetrahydrofuran solution (450mL, 1M), and in this thermotonus after 1 hour, room temperature reaction spend the night.Be down to 0 DEG C, add 100mL water, drip sodium hydroxide (350mL, 10%), drip hydrogen peroxide (250mL, 30%) at 0 DEG C, room temperature reaction 5 hours.After cooling, extraction into ethyl acetate 500mL extracts 3 times, merging organic phase, and anhydrous sodium sulfate drying, filters, and after concentrated, silicagel column is separated (ethyl acetate/pentane=1:50-1:30) and obtains 7-3.
Step 3: in 3L four-hole bottle, under nitrogen protection, adds 7-3 (40g) and methylene dichloride (1600mL).Cool to 0 DEG C, add pyridinium chlorochromate (PCC, 54g) in batches, get back to room temperature reaction 4 hours.Add water, dchloromethane.Be separated, aqueous phase dichloromethane extraction 3 times.Anhydrous sodium sulfate drying, filters, and after concentrated, silicagel column is separated (ethyl acetate/pentane=1:20-1:10) and obtains 7-4.
Step 4: in 2000mL four-hole bottle, adds under nitrogen protection in 7-4 (33.8g) and trichloromethane (1500mL), cools to 0 DEG C, drips diethylin borontrifluoride (DAST, 116g).Get back to room temperature reaction to spend the night.System is poured into cancellation in 1000mL frozen water, ethyl acetate 1000mL extracts 3 times, 500mL water backwash 4 times, anhydrous sodium sulfate drying, filters, and after concentrated, silicagel column is separated (ethyl acetate/pentane=1:50-1:20) and obtains 7-5.
Step 5: in 1000mL single port bottle, adds 7-5 (30g, 0.12mol) and methyl alcohol (500mL), has water palladium carbon (6g, 10%) under nitrogen protection.After passing into hydrogen, room temperature reaction spends the night.Suction filtration, filtrate adds 10mL concentrated hydrochloric acid, obtains the hydrochloride of product 7-6 after being spin-dried for.
The synthesis of intermediate 8-5
Under step 1:0 DEG C of condition, in 250mL round-bottomed flask, add ether (150mL) successively, deuterated lithium aluminum hydride-d4 (2.15g), 8-1 (15g).40 DEG C of stirrings are spent the night.Add water (2.15mL) successively, 15% sodium hydroxide (2.15mL), water (6.45mL), filter, filtrate anhydrous sodium sulfate drying, concentrated, underpressure distillation obtains 8-2.H-NMR(400MHz,CDCl 3,ppm):δ1.77-1.75(m,4H),1.55(d,J＝2.8Hz,4H)。
Under step 2:0 DEG C of condition, in 500mL round-bottomed flask, add 8-2 (6g) successively, methylene dichloride (200mL), triethylamine (14g).Drip Methanesulfonyl chloride (11.8g), stir 1 hour.Use 1N hydrochloric acid (100mL) and saturated sodium bicarbonate (150mL) washing successively, organic phase anhydrous sodium sulfate drying, concentrates and obtains 8-3.H-NMR(400MHz,CDCl 3,ppm):δ2.97(s,3H),1.90-1.83(m,4H),1.82-1.77(m,2H),1.74-1.65(m,2H)。
Step 3: add 8-3 (10g) in 250mL round-bottomed flask successively, DMF (150mL), sodiumazide (7.4g).65 DEG C of stirrings are spent the night.Add water 100mL, extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, concentrates and obtain 8-4.H-NMR(400MHz,CDCl 3,ppm):δ1.83-1.78(m,2H),1.74-1.66(m,4H),1.62-1.59(m,2H)。
Step 4: add 8-4 (5g) in 250mL round-bottomed flask successively, methyl alcohol (100mL), palladium carbon (300mg).Pass into hydrogen, 25 DEG C of stirrings are spent the night.Filter, filtrate adds concentrated hydrochloric acid 5 milliliters, the concentrated hydrochloride obtaining 8-5.
H-NMR(400MHz,d6-DMSO,ppm):δ8.10(brs,2H),1.87-1.80(m,2H),1.68-1.64(m,2H),1.63-1.46(m,4H)。
The synthesis of intermediate 10-8
In step 1:500mL single port bottle, by water-soluble for sodiumazide (32g) (300mL), then drip ether (100mL) solution of Vinyl chloroformate (45g) under ice bath, system stirred overnight at room temperature.Ether (300mL) is added, organic phase anhydrous sodium sulfate drying in reaction solution, concentrated, obtain 10-2.
In step 2:500mL there-necked flask, in Skellysolve A (200mL) solution of 10-2 (24g), add norbornylene (20g), 20 DEG C are stirred 4 days.Reaction solution is concentrated obtains 10-3.
In step 3:500mL single port bottle, be dissolved in by 10-3 (55g) in methyl alcohol (300mL), system was 40 degree of reactions 2 hours.Reaction solution concentrates, and underpressure distillation (70 degree, 10mmHg vacuum tightness) obtains 10-4.
Step 4: slowly drip bromine (28g) under 40 degree in tetraline (20g), within 2 hours, drip off, the bromize hydrogen gas simultaneously produced passes in Skellysolve A (200mL) solution of 10-4 (16g), room temperature reaction 4 hours.Reaction solution concentrates, and add ether (300mL), saturated sodium bicarbonate (100mL), extraction is washed.Organic phase anhydrous sodium sulfate drying, filters, and concentrates and obtains 10-5.
In step 5:250mL there-necked flask, Na (5g) is slowly joined in methyl alcohol (100mL), stir 1 hour, then add 10-5 (10g).Heating systems to 60 is spent, reaction 16h.Reaction solution concentrates, and add ether (300mL), water (200mL), extraction is washed.Organic phase anhydrous sodium sulfate drying, filters, and concentrated, underpressure distillation (100 degree, 5mmHg vacuum tightness) obtains 10-6.
In step 6:100mL single port bottle, be dissolved in ethanol (40mL) by 10-6 (4.5g), add 10% palladium carbon (400mg), after hydrogen exchange, system room temperature reaction under hydrogen balloon spends the night.Reaction system is filtered, and filtrate concentrates to obtain 10-7.
In step 7:100mL single port bottle, by water-soluble for sodium hydroxide (9g) (40mL), then add ethylene glycol (20mL) and 10-7 (7g), heating systems to 110 spends reaction 3 days.Cool to room temperature, adds salt solution (60mL) in reaction solution, extracts with Skellysolve A (300mL).Organic phase anhydrous sodium sulfate drying, filters, concentrated, obtains 10-8.
The synthesis of intermediate 11-3 and 15-1
In step 1:1000mL single port bottle, be dissolved in tetrahydrofuran (THF) (700mL) by sodium hydride (15.4g, 60%), then add adiponitrile (37.9g), heating systems spends the night to back flow reaction.In reaction solution, add water (300mL), extract with ether (3x100mL).Organic phase is dry, filters, concentrated, obtains 11-1.
In step 2:250mL there-necked flask, in the methanol solution of 11-1 (6.0g), add hydrochloric acid to pH=3.Keep pH=3 ~ 4, add sodium cyanoborohydride (10.5g) in batches, stirring at room temperature 2h.Reaction solution concentrates, and adds methylene dichloride (100mL), uses saturated sodium bicarbonate aqueous solution (100mL) and saturated aqueous common salt (100mL) extraction to wash respectively.Organic phase is dry, filters, concentrated, obtains 11-2.
In step 3:250mL single port bottle, by 11-2 (3.0g), DIPEA (6.86g), bromo-2, the 4-dichloro pyrimidines (3.0g) of 5-are dissolved in acetonitrile (100mL), and heating systems to 70 is spent reaction and spent the night.In reaction solution, add water (100mL), extract by ethyl acetate (3x100m).Organic phase is dry, filters, and concentrated, silica gel column chromatography (ethyl acetate/petroleum ether/methylene dichloride=1:15:1-1:7:1) purifying, obtains yellow solid product 11-3 (1g) and 15-1 (2g) respectively.
The synthesis of intermediate 12-3:
Step 1: under nitrogen protection, adds 12-1 (2.3g) successively in 100mL there-necked flask, bromo-2 nitropyridines (1.99g) of 5-, 25mLN, N-dimethyl sulfoxide (DMSO), and triethylamine (996mg), oil bath is warming up to 80 DEG C of reactions and spends the night.Be cooled to room temperature.The 50mL cancellation that adds water is reacted.75mL extraction into ethyl acetate 3 times.100mL saturated aqueous common salt backwash 3 times.Anhydrous sodium sulfate drying, is spin-dried for.Crude product silica gel column chromatography (eluant ethyl acetate: pentane=1:5-2:1), obtains 12-2 after being spin-dried for.
Step 2: add 12-2 (2.0g) successively, 15mL methyl alcohol, methylene dichloride 15mL in 100mL single port bottle, have water palladium charcoal (60%) 2.0g, ammonium formiate 2.0g.Finish room temperature reaction to spend the night.Filter, collect filtrate.Filter cake 75mL methylene dichloride washes 3 times.Collect organic phase 100mL saturated aqueous common salt backwash 3 times.Anhydrous sodium sulfate drying, obtains 12-3 after organic phase is spin-dried for.
The synthesis of intermediate 13-3
Step 1: under nitrogen protection, adds 13-1 (2.0g) successively in 100mL there-necked flask, bromo-2 nitropyridines (1.73g) of 5-; N; N-dimethyl sulfoxide (DMSO) (20mL), triethylamine (865mg), oil bath is warming up to 80 DEG C of reactions and spends the night.Be cooled to room temperature.The 50mL cancellation that adds water is reacted.75mL extraction into ethyl acetate 3 times.100mL saturated aqueous common salt backwash 3 times.Anhydrous sodium sulfate drying, is spin-dried for.Crude product silica gel column chromatography (eluant ethyl acetate: pentane=1:5-2:1).Be spin-dried for obtain 13-2.
Step 2: add 13-2 (1.5g) successively, methyl alcohol 15mL, methylene dichloride 15mL in 100mL single port bottle, have water palladium charcoal (60%) 1.5g, ammonium formiate 1.5g.Finish room temperature reaction to spend the night.Filter, collect filtrate.Filter cake 75mL methylene dichloride washes 3 times.Collect organic phase 100mL saturated aqueous common salt backwash 3 times.Anhydrous sodium sulfate drying, is spin-dried for obtain 13-3.
The synthesis of intermediate 14-3
Step 1: under nitrogen protection, adds 14-1 (2.0g) successively in 100mL there-necked flask, bromo-2 nitropyridines (1.85g) of 5-, N, N-dimethyl sulfoxide (DMSO) 20mL, and triethylamine (925mg), oil bath is warming up to 80 DEG C of reactions and spends the night.Be cooled to room temperature.The 50mL cancellation that adds water is reacted.75mL extraction into ethyl acetate 3 times.100mL saturated aqueous common salt backwash 3 times.Anhydrous sodium sulfate drying, is spin-dried for.Crude product silica gel column chromatography (eluant ethyl acetate: pentane=1:5-2:1).14-2 is obtained after being spin-dried for.
Step 2: add 14-2 (1.1g) successively, methyl alcohol 15mL, methylene dichloride 15mL in 100mL single port bottle, have water palladium charcoal (60%) 1.1g, ammonium formiate 1.1g.Finish room temperature reaction to spend the night.Filter, collect filtrate.Filter cake 75mL methylene dichloride washes 3 times.Collect organic phase 100mL saturated aqueous common salt backwash 3 times.Organic phase anhydrous sodium sulfate drying, is spin-dried for obtain 14-3.
The synthesis of intermediate 16-2
Step 1: under nitrogen protection; 8-oxa--3-azabicyclo [3.2.1] octane hydrochloride (3.29g) is added successively in 100mL there-necked flask; the bromo-2-nitropyridine (4.06g) of 5-; N; N-dimethyl sulfoxide (DMSO) (45mL); triethylamine (4.06g), oil bath is warming up to 80 DEG C of reactions and spends the night.Be cooled to room temperature.The 50mL cancellation that adds water is reacted.Ethyl acetate 75mL extracts 3 times.Saturated aqueous common salt 100mL backwash 3 times.Anhydrous sodium sulfate drying, is spin-dried for.Crude product silica gel column chromatography (eluant ethyl acetate: pentane=1:5-2:1).Be spin-dried for obtain 16-1.
Step 2: add 16-1 (600mg) successively, methyl alcohol 15mL, methylene dichloride 15mL in 100mL single port bottle, have water palladium charcoal (60%) 600mg, ammonium formiate (804mg).Finish room temperature reaction to spend the night.Filter, collect filtrate.Methylene dichloride 75mL drip washing filter cake 3 times.Saturated aqueous common salt 100mL backwash 3 times.Anhydrous sodium sulfate drying, is spin-dried for obtain 16-2.
The synthesis of intermediate 17-5
Step 1: under nitrogen protection, 250mL there-necked flask, is dissolved in 17-1a (3.0g) in tetrahydrofuran (THF) 30mL and adds reaction flask, and-78 DEG C drip two trimethyl silicon based potassium amide (16mL, 1M) ,-78 DEG C of insulation reaction 3h.The tetrahydrofuran (THF) 10mL solution of-78 DEG C of droppings 17-1b (5.3g), drips and finishes back room temperature reaction 2h.Saturated ammonium chloride 50mL cancellation is reacted.Ethyl acetate 100mL extracts 2 times, merges organic phase.Saturated aqueous common salt 100mL backwash 1 time.Anhydrous sodium sulfate drying, is spin-dried for.Crude product silica gel column chromatography (ethyl acetate: pentane=1:20).Be spin-dried for obtain 17-2.
Step 2: under nitrogen protection; 17-2 (2.6g) is added successively in 100mL there-necked flask; 1; 4 dioxane 26mL; 17-2b (2.0g), 1,1'-bis-(diphenyl phosphine) ferrocene palladium chloride (II) (0.21g); Potassium ethanoate (2.08g), finishes oil bath and is warming up to 80 DEG C of reactions and spends the night.Be down to room temperature, suction filtration, collect filtrate.100mL shrend is gone out reaction.Ethyl acetate 100mL extracts 3 times.Saturated aqueous common salt 100mL backwash 3 times.Anhydrous sodium sulfate drying, is spin-dried for.Crude product silica gel column chromatography (ethyl acetate: pentane=1:30).Be spin-dried for obtain 17-3.
Step 3: under nitrogen protection; 17-3 (0.96g) is added successively in 100mL there-necked flask; the bromo-2-nitropyridine (1.6g) of 5-, Isosorbide-5-Nitrae dioxane 40mL; water 1.5mL; 1,1'-bis-(diphenyl phosphine) ferrocene palladium chloride (II) (0.33g), cesium carbonate (3.0g); finish oil bath to be warming up to 85 DEG C of reactions and to spend the night, be down to room temperature.System is poured in frozen water (100mL).Ethyl acetate 100mL extracts 3 times.Saturated aqueous common salt 100mL backwash 3 times.Anhydrous sodium sulfate drying, is spin-dried for.Crude product silica gel column chromatography (ethyl acetate: pentane=1:10-1:3).Be spin-dried for obtain 17-4.
Step 4:100mL there-necked flask, 17-4 (900mg) is dissolved in ethanol 45mL and acetic acid 4mL, is warming up to 70 DEG C, and batch adds iron powder (696mg), and 70 DEG C are reacted 30 minutes.Filter, collect filtrate.Be spin-dried for.Add 1M sodium hydroxide and adjust pH=8.Extract 3 times with ethyl acetate 100mL, merge organic phase.Saturated aqueous common salt 100mL backwash 1 time.Anhydrous sodium sulfate drying, is spin-dried for.50mL ether washes 1 time, obtains 17-5.
The synthesis of intermediate 18-6 and 19-2
Step 1: under nitrogen protection, adds 18-1 (8g) in the round-bottomed flask of 100mL, ethanol (50mL), oxammonium hydrochloride (5.15g), sodium-acetate (2.92g).Reaction mixture stirs 5 hours at 80 DEG C.Reaction mixture cool to room temperature.Filter, collect filtrate.Be spin-dried for.Add 100mL water in mixture, extract 3 times with ethyl acetate 100mL, merge organic phase.Saturated aqueous common salt 100mL backwash 1 time.Anhydrous sodium sulfate drying, is spin-dried for obtain 18-2.
Step 2: under nitrogen protection, in 250mL there-necked flask, adds 18-2 (8.2g), acetone (50mL), water (50mL) and sodium carbonate (10.86g).At 10-20 DEG C, in 5 minutes, add 4-methylbenzene-1-SULPHURYL CHLORIDE (9.79g) in batches.Gained reaction mixture at room temperature stirs and spends the night.Go out with 50mL shrend.Extract 3 times with ethyl acetate 100mL, merge organic phase.Saturated aqueous common salt 100mL backwash 1 time.Anhydrous sodium sulfate drying, is spin-dried for.Gained mixture adds hexanol (100mL).Collecting by filtration products obtained therefrom 18-3.
Step 3: under nitrogen protection; in 100ml there-necked flask; add 18-3 (6.2g); the bromo-2-nitropyridine (5.24g) of 5-; two diphenylphosphine-9,9-dimethyl xanthene (Xantphos) (2.24g) of 4,5-; palladium (579mg), cesium carbonate (12.6g). stir 3 hours at 105 DEG C.Go out with 50mL shrend.Extract 3 times with ethyl acetate 100mL, merge organic phase.Saturated aqueous common salt 75ml backwash 2 times.Anhydrous sodium sulfate drying, is spin-dried for.Gained mixture crosses post, with ethyl acetate/dichloromethane drip washing (1:10-1:1)..Obtain product 18-4.
Step 4: split 18-4
Splitting condition: chiral column, CHIRALPAKIC size 20mm*250mm; Moving phase is ethanol/normal hexane=50%/50%, and obtaining 18-5 (3.34g, peak one) is white solid, and 19-1 (3.66g, peak two) is white solid.
Step 5: under nitrogen protection; in 500ml round-bottomed bottle, add 18-5 (500mg), methyl alcohol (100mL); methylene dichloride (100mL), palladium carbon (10%) (0.5g) and ammonium formiate (500mg).At room temperature stir and spend the night.Filter, be spin-dried for.Obtaining product 18-6 is white solid.
According to the method that step 5 is similar, obtain compound 19-2 from compound 19-1.
The synthesis of intermediate 20-5
Step 1: under nitrogen protection, adds 20-1 (2.7g) successively, acetonitrile 60mL in 100mL there-necked flask, triethylamine (3.86g), and 0 DEG C drips bromobenzyl (2.61g), drips complete room temperature anti-3 hours.After reaction terminates, the 50mL cancellation that adds water is reacted.Methylene dichloride 75mL extracts 3 times.Saturated aqueous common salt 100mL backwash 4 times.With anhydrous sodium sulfate drying, be spin-dried for obtain 20-2.
Step 2: under nitrogen protection, adds 20-2 (2.9g) successively, methylene dichloride 30mL in 100mL single port bottle, and 0 DEG C drips trifluoroacetic acid 2mL, drips complete room temperature reaction 3 hours.Add water after reaction terminates 50mL cancellation reaction, and saturated solution of sodium bicarbonate adjusts pH=8.Methylene dichloride 50mL extracts 3 times, saturated aqueous common salt 75mL backwash 2 times, and anhydrous sodium sulfate drying, is spin-dried for obtain 20-3.
Step 3: under nitrogen protection, adds 20-3 (2.0g) successively in 100mL there-necked flask, the bromo-2-nitropyridine (1.82g) of 5-; N, N-dimethyl sulfoxide (DMSO) 20mL, triethylamine (910mg); oil bath is warming up to 80 DEG C of reactions and spends the night, and is cooled to room temperature.The 50mL cancellation that adds water is reacted, and ethyl acetate 75mL extracts 3 times, and saturated aqueous common salt 100mL backwash 3 times, anhydrous sodium sulfate drying, is spin-dried for.Crude product silica gel column chromatography (eluant ethyl acetate: pentane=1:5-2:1).20-4 is obtained after being spin-dried for.
Step 4: add 20-4 (1.1g) successively in 100mL there-necked flask, ethanol 50mL, acetic acid 5mL, be warming up to 70 DEG C, batch adds iron powder (951mg), and 70 DEG C are reacted 2 hours, are cooled to room temperature.Filter, collect filtrate, filtrate is spin-dried for.1N sodium hydroxide solution regulates pH=8-9, ethyl acetate 75mL to extract 3 times, saturated aqueous common salt 100mL backwash 2 times, and anhydrous sodium sulfate drying, is spin-dried for obtain 20-5.
The synthesis of intermediate 21-3
Step 1: under nitrogen protection, adds 18-5 (2.62g) successively in 250mL there-necked flask, methylene dichloride (102mL).0 DEG C drips trifluoroacetic acid (10.2mL), within 3 minutes, drips off.Room temperature reaction 4h.Be spin-dried for and obtain 21-1.
Step 2: under nitrogen protection, adds 21-1 (2.25g) successively in 250mL there-necked flask, methyl alcohol (160mL), formaldehyde (695mg).0 DEG C adds acetic acid (899mg) successively, sodium cyanoborohydride (566mg).0 DEG C of reaction 5min.React with frozen water 160mL cancellation.Saturated sodium carbonate solution adjusts pH to be 9,160mL extraction into ethyl acetate 3 times.500mL saturated aqueous common salt backwash 3 times.Anhydrous sodium sulfate drying, is spin-dried for obtain 21-2.
Step 3: under nitrogen protection, in 250mL single port bottle, add 21-2 (970mg) successively, methyl alcohol 50mL, methylene dichloride (50mL), Pd/C (10%, 0.97g), ammonium formiate (970mg), room temperature reaction spends the night.Filter, concentrated, use C18 column purification, be spin-dried for obtain 21-3.
The synthesis of intermediate 22-3
Step 1: under nitrogen protection, adds 19-1 (2.21g) successively, methylene dichloride 121mL in 250mL there-necked flask.0 DEG C adds trifluoroacetic acid 12.1mL.Room temperature reaction 4h.Be spin-dried for, obtain 22-1.
Step 2: under nitrogen protection, adds 22-1 (2.08g) successively, methyl alcohol 150mL in 250mL there-necked flask, formaldehyde (642mg).0 DEG C adds acetic acid (830mg) successively, sodium cyanoborohydride (523mg).0 DEG C is reacted 5 minutes, reacts with frozen water 150mL cancellation.Saturated sodium carbonate solution adjusts pH to be 9,150mL extraction into ethyl acetate 3 times.500mL saturated aqueous common salt backwash 3 times, anhydrous sodium sulfate drying, is spin-dried for obtain 22-2.
Step 3: under nitrogen protection, in 100mL single port bottle, add 22-2 (720mg) successively, methyl alcohol 50mL, methylene dichloride (50mL), palladium carbon 0.72g, ammonium formiate (720mg), room temperature reaction spends the night.Filter, dense dry, use C18 column purification, be spin-dried for obtain 22-3.
The synthesis of intermediate 23-5
In step 1:250mL there-necked flask, at 5 DEG C, metachloroperbenzoic acid (m-CPBA, 12g) is added in batches in methylene dichloride (100mL) solution of 1-methyl cyclopentene (3.8g), room temperature reaction 16 hours.Reacting liquid filtering, filtrate water (100mL), sodium bicarbonate aqueous solution (150mL) and sodium thiosulfate solution (150mL) extraction are washed.Organic phase is dry, filters, and concentrates and obtains 23-2.
Step 2: be added to by ammoniacal liquor (8mL) in ethanol (8mL) solution of 23-3 (2.4g), reacts 6 hours at 85 DEG C in the vexed tank of glass.Reaction solution cool to room temperature, concentrates and obtains 23-3.
In step 3:100mL single port bottle, bromo-for 5-2,4-dichloro pyrimidines (1.26g) be dissolved in ethanol (20mL), then add 23-3 (0.9g), DIPEA (2.1g), room temperature reaction spends the night.Add water (50mL) after reaction solution is concentrated, extract by ethyl acetate (100mL).Organic phase is dry, filters, and concentrated, sherwood oil recrystallization obtains 23-4.
Step 4: under nitrogen protection, is added in methylene dichloride (40mL) solution of 23-4 (1.3g) by borontrifluoride for diethylin (DAST, 1.5g) at-78 DEG C, react 1 hour at-78 DEG C.Add Virahol cancellation at-78 DEG C, be raised to room temperature, reaction solution use water (30mL), sodium bicarbonate aqueous solution (30mL) extraction is washed.Organic phase is dry, filters, and concentrated, silica gel column chromatography (ethyl acetate/petroleum ether=1:10) purifying, obtains 23-5.
The synthesis of intermediate 26-1 (cis) and 27-1 (trans)
Step 1: under nitrogen protection, in 1L four-hole bottle, by bromo-for 5-2; 4-dichloro pyrimidine (70g) is dissolved in 600mL dioxane, is cooled to 11 DEG C, drips triethylamine (62.5g); the dioxane solution of 3-4 (30g), finish, room temperature reaction spends the night.System is poured into 1L mixture of ice and water cancellation reaction.With 1L extraction into ethyl acetate 3 times, with 0.5L saturated aqueous common salt backwash 3 times after organic phase merges, organic phase anhydrous Na SO 4concentrated dry after dry.Crude product silica gel column chromatography (eluent petroleum ether/ethyl acetate=100:1 – 30:1), collects product and concentrates to obtain 3-5.
Step 2: in 1L single port bottle, by 3-5 (23g), (E)-2-butylene acid (17.3g), N, N-diisopropylethylamine (104g) is dissolved in 500mL tetrahydrofuran (THF), with nitrogen replacement air 3 times, then adds three (o-tolyl) phosphine (2.42g) and two (cyano group benzene) palladium chloride (1.5g), use nitrogen replacement air again 3 times, the 80 DEG C of reactions that heat up are spent the night.Concentrated dry after reaction system being down to room temperature.Crude product silica gel column chromatography (eluent petroleum ether: ethyl acetate=5:1 – 1:1), collects product and concentrates to obtain 3-6.
Step 3: in 1L there-necked flask, is dissolved in 3-6 (40g) in diacetyl oxide (200mL), is warming up to 130 DEG C, reaction 2h.Diacetyl oxide is spin-dried for after being down to room temperature by reaction system.Crude product silica gel column chromatography (eluent oil ether: ethyl acetate=10:1 – 4:1) obtains mixture.Mixture positive rapid column chromatography separation and purification, collection product peak is concentrated respectively obtains first peak 26-1 (cis) 3.6g yellow solid and second peak 27-1 (trans) 1.7g yellow solid.
embodiment
Embodiment 1A and 1B
The synthesis of step 1:1-7
In 250mL there-necked flask, add 2,2-difluoro cyclopentamine hydrochloride (6.0g) under nitrogen protection, 70mL dioxane, triethylamine (33g).Cool to less than 10 DEG C, add bromo-2, the 4-dichloro pyrimidines (7.5g) of 5-, room temperature reaction spends the night in batches.Add 100mL diluted ethyl acetate, with the backwash of 3x100mL water, anhydrous sodium sulfate drying, after filtering, silica gel column chromatography (eluant ethyl acetate: sherwood oil=1:50-1:30) obtains 1-7.
The synthesis of step 2:1-8
In 250mL there-necked flask, under nitrogen protection, add 1-7 (5g), propyl carbinol (70mL), (E)-2-butylene acid (6.86g), DIPEA (20.5g).Displaced air three times, adds three (o-tolyl) phosphine (2.42g) and two (cyano group benzene) palladium chloride (1.5g), is warming up to 95 DEG C of reactions and spends the night.Be down to room temperature, after being spin-dried for solvent, directly silicagel column is separated (eluant ethyl acetate: sherwood oil=1:10-1:2) and obtains 1-8.
The synthesis of step 3:1-9
In 50mL single port bottle, add 1-8 (2.8g) and diacetyl oxide (15mL), rise to 130 DEG C of reactions 2 hours.Be down to room temperature, after being spin-dried for solvent, direct silicagel column is separated (eluant ethyl acetate: sherwood oil=1:20-1:10) and obtains 1-9.
The synthesis of step 4:1-10
In 50mL single port bottle, add 1-9 (1.5g), 20mL acetonitrile/methanol (3:1), N-bromo-succinimide (NBS, 1.2g).Rise to 80 DEG C of reactions 2 hours.Add 50mL diluted ethyl acetate, with the backwash of 3x50mL water, anhydrous sodium sulfate drying, after filtering, filtrate is spin-dried for.Silica gel column chromatography (eluant ethyl acetate: sherwood oil=1:50-1:20) obtains 1-10.
The synthesis of step 5:1-11
In 100mL there-necked flask, under nitrogen protection, add J (1.29g) and 20mL toluene.Be cooled to 10 DEG C, add LHMDS (1.29g), and stir 1 hour at such a temperature.At 10 DEG C, add 1-10 (0.8g) in batches, get back to room temperature reaction and spend the night.Filter, collect filter cake, and with the water of 3x10mL and the n-hexane of 2x20mL, obtain 1-11.
The synthesis of step 6:1-12
In 100mL there-necked flask, under nitrogen protection, add 1-11 (0.23g), propyl carbinol (20mL), vinyl n-butyl ether (0.18g), DIPEA (0.14g).Displaced air three times, adds 1,1'-bis-(diphenyl phosphine) ferrocene palladium chloride (II) (0.03g), is warming up to 95 DEG C of reactions and spends the night.Be down to room temperature, after being spin-dried for solvent, direct silicagel column is separated (eluant ethyl acetate: sherwood oil=1:20-1:3) and obtains 1-12.
The synthesis of step 7:1-13
In the there-necked flask of 50mL, add 1-12 (0.13g) under nitrogen protection, hydrochloric acid (15mL, 6N).Room temperature reaction 2h.Be down to room temperature, be spin-dried for solvent and obtain 1-13.
Step 8: chirality preparative separation
Preparative column: CHIRALPAKAD-HSFC5*25cm, 5um, moving phase: A phase: CO 2: 50, B phase: EtOH (0.2%DEA)-HPLC:50; Cycling time: 12 minutes, determined wavelength: 220nm.
Chiral HPLC (PhenomenexLuxCellulose-4 post): first peak in embodiment 1A (retention time=28.6 minute) corresponding chiral separation.Second peak in embodiment 1B (retention time=23.9 minute) corresponding chiral separation.
Embodiment 1A:LC-MS (ES, m/z): 484 [M+H] +; H-NMR (300MHz, CDCl 3, ppm): δ 8.86 (s, 1H), 8.34 (s, 1H), 8.17 (d, J=9Hz, 1H), 8.07 (d, J=3Hz, 1H), 7.35-7.27 (m, 1H), 6.27-6.11 (m, 1H), 3.50-3.09 (m, 8H), 2.89-2.63 (m, 2H), 2.56 (s, 3H), 2.41 (s, 3H), 2.31-2.10 (m, 4H).
Embodiment 1B:LC-MS (ES, m/z): 484 [M+H] +; H-NMR (300MHz, CDCl 3, ppm): δ 8.84 (s, 1H), 8.33 (s, 1H), 8.16 (d, J=9Hz, 1H), 8.06 (d, J=3Hz, 1H), 7.35-7.26 (m, 1H), 6.25-6.11 (m, 1H), 3.49-3.10 (m, 8H), 2.86-2.61 (m, 2H), 2.54 (s, 3H), 2.40 (s, 3H), 2.30-2.11 (m, 4H).
Embodiment 2
Except replacing except 1-6, according to the compound of the similarity method synthetic example 2 in embodiment 1 with 2-4 in step 1.LC-MS(ES,m/z):462[M+H] +；H-NMR(300MHz,DMSO,ppm):δ10.02(1H,s),8.87(1H,s),8.04-8.03(1H,d,J＝3Hz),7.86-7.83(1H,d,J＝8.7Hz),7.46-7.42(1H,dd,J＝9.2Hz,J＝3.0Hz),3.32-3.07(4H,m),2.94-2.87(4H,m),2.38(3H,s),2.28(3H,s),1.73-1.56(11H,m)。
Embodiment 3
Except replacing except 1-6, according to the compound of the similarity method synthetic example 3 in embodiment 1 with 3-4 in step 1.LC-MS(ES,m/z):460[M+H] +；H-NMR(300MHz,CDCl 3,ppm):δ10.12(s,1H),8.94(s,1H),8.03(s,1H),7.87(d,J＝7.5Hz,1H),7.42(d,J＝6.9Hz,1H),6.09-6.00(m,1H),3.06(s,4H),2.86(s,4H),2.42(s,3H),2.30(s,3H),1.84(m,2H),1.49(s,1H),1.32-1.24(m,4H),0.46(s,1H)。
Embodiment 4
Except replacing, except 1-6, according to the similarity method synthetic compound 4 in embodiment 1, purifying with reversed-phase column, obtaining the trifluoroacetate of the compound 4 of embodiment 4 with 4-6 in step 1.LC-MS(ES,m/z):474[M+H] +；H-NMR(300MHz,CD 3OD,ppm):δ0.10-0.70(4H,m),1.32-2.22(4H,m),2.43(3H,s),2.51-2.56(5H,m),3.46-3.50(8H,m),5.95-6.02(1H,m),7.78(1H,brs),7.93-7.96(1H,d,J＝6.6Hz),8.05(1H,s),9.02(1H,s)。
Embodiment 5A and 5B
Except replacing except 1-6 with 5-3 in step 1, according to the similarity method synthesis in embodiment 1.Chiral separation, obtains the compound of embodiment 5A and embodiment 5B.
Chirality preparative separation, preparative column: CHIRALPAKAD-HSFC5*25cm, 5um, moving phase: A phase: CO2:50, B phase: EtOH (0.2%DEA)-HPLC:50; Cycling time: 6 minutes, determined wavelength: 220nm.
Chiral HPLC (CHIRALPAKIC post): first peak in embodiment 5A (retention time=44.8 minute) corresponding chiral separation.Second peak in embodiment 5B (retention time=53.5 minute) corresponding chiral separation.
Embodiment 5A:LC-MS (ES, m/z): 474 [M+H] +; H-NMR (300MHz, CF 3cOOD, ppm): δ 1.15-1.82 (7H, m), 2.39 (3H, s), 2.40-2.76 (6H, m), 3.64-3.72 (8H, m), 4.96-5.24 (1H, m), 7.89-8.16 (3H, m), (9.07-9.08 1H, d, J=3.6Hz).
Embodiment 5B:LC-MS (ES, m/z): 474 [M+H] +; H-NMR (300MHz, CF 3cOOD, ppm): δ 1.32-1.74 (7H, m), 2.40 (3H, s), 2.47-2.75 (6H, m), 3.66-3.71 (8H, m), 5.19-5.23 (1H, m), 7.89-7.92 (1H, d, J=9.3Hz), 8.06 (1H, s), 8.13-8.16 (1H, d, J=9.6Hz), 9.08 (1H, s).
Embodiment 6
Except replacing, except 1-6, according to the similarity method synthetic compound 6 in embodiment 1, purifying with reversed-phase column, obtaining the trifluoroacetate of the compound 6 of embodiment 6 with 6-4 in step 1.LC-MS(ES,m/z):460[M+H] +；H-NMR(300MHz,D 2O,ppm):δ8.99(1H,s),8.06-8.02(1H,dd,J＝9.3Hz,J＝2.7Hz),7.81(1H,s),7.48-7.45(1H,m),6.16-6.07(1H,m),3.70-3.64(8H,m),2.45(3H,s),2.32(3H,s),2.17-1.90(4H,m),1.36(2H,m),0.85(1H,m),0.54(1H,m)。
Embodiment 7A and 7B
Except replacing except 1-6 with 7-6 in step 1, according to the similarity method synthesis in embodiment 1.Chiral separation, obtains the compound of embodiment 7A and embodiment 7B.
Chirality preparative separation, preparative column: CHIRALPAKAD-HSFC5*25cm, 5um, moving phase: A phase: CO2:50, B phase: EtOH (0.2%DEA)-HPLC:50; Cycling time: 12 minutes, determined wavelength: 220nm.
Chiral HPLC (CHIRALPAKAD-H post): first peak in embodiment 7A (retention time=30.7 minute) corresponding chiral separation.Second peak in embodiment 7B (retention time=38.6 minute) corresponding chiral separation.
Embodiment 7A:LC-MS (ES, m/z): 484 [M+H] +; H-NMR (300MHz, CDCl 3, ppm): δ 8.83 (s, 1H), 8.13-8.04 (m, 2H), 7.98 (s, 1H), 7.37-7.33 (m, 1H), 6.19-6.12 (m, 1H), 3.18-3.11 (m, 8H), 2.64 (m, 2H), 2.57 (s, 3H), 2.40 (s, 3H), 2.39-2.15 (s, 3H).
Embodiment 7B:LC-MS (ES, m/z): 484 [M+H] +; H-NMR (300MHz, CDCl 3, ppm): δ 8.83 (s, 1H), 8.13-8.05 (m, 2H), 7.97 (s, 1H), 7.6 (d, J=3Hz, 1H), 6.21-6.13 (m, 1H), 3.18-3.11 (m, 8H), 2.65 (s, 2H), 2.57 (s, 3H), 2.40 (s, 3H), 2.39-2.15 (s, 3H).
Embodiment 8
Except replacing except 1-6, according to the compound of the similarity method synthetic example 8 in embodiment 1 with 8-5 in step 1.LC-MS(ES,m/z):449[M+H] +；H-NMR(400MHz,CD 3OD,ppm):δ9.14(s,1H),8.20-8.17(m,1H),8.01(d,J＝2.8Hz,1H),7.62(d,J＝9.2Hz,1H),3.57-3.54(m,4H),3.45-3.43(m,4H),2.50(s,3H),2.43(s,3H)，2.31-2.26(m,2H),2.10-2.08(m,2H),2.07-1.90(m,2H)，1.90-1.67(m,2H)。
Embodiment 9
Except replacing, beyond 1-6, according to the similarity method synthetic compound 9 in embodiment 1, being used HCl treatment, obtaining the hydrochloride of the compound 9 of embodiment 9 with 3,3-difluoro ring butylamine in step 1.LC-MS(ES,m/z):470[M+H] +；H-NMR(400MHz,CD 3OD,ppm):δ9.16(s,1H),8.21(dd,J＝2.4Hz,9.6Hz,1H),8.01(d,J＝2.4Hz,1H),7.61(d,J＝9.6Hz,1H),5.72-5.67(m,1H),3.57-3.55(m,6H),3.35-3.25(m,4H),3.06-2.98(m,2H),2.52(s,3H),2.45(s,3H)。
Embodiment 10
Except replacing except 1-6, according to the compound of the similarity method synthetic example 10 in embodiment 1 with 10-8 in step 1.LC-MS(ES,m/z):474[M+H] +；H-NMR(400MHz,CD 3OD,ppm):δ9.06(s,1H),8.15(dd,J＝2.8Hz,9.6Hz,1H),7.96(d,J＝2.8Hz,1H),7.61(d,J＝9.6Hz,1H),4.29(s,1H),3.42-3.54(m,8H),3.25(s,2H),2.46(s,3H),2.38(s,3H),1.84(m,2H),1.54(m,2H),1.34(m,4H)。
Embodiment 11
Except replacing except 1-7, according to the compound of the similarity method synthetic example 11 in embodiment 1 with 11-3 in step 2.LC-MS(ES,m/z):473[M+H] +；H-NMR(400MHz,CD 3OD,ppm):δ9.07(s,1H),8.02(d,J＝2.8Hz,1H),7.94(dd,J＝2.4Hz,9.6Hz,1H),7.82(d,J＝9.6Hz,1H),6.38-6.30(m,1H),3.49-3.40(m,9H),2.61-2.56(m,2H),2.49(s,3H),2.43(s,3H),2.22-2.15(m,2H),2.06-2.03(m,1H),1.70-1.65(m,1H)。
Embodiment 12
Except replacing 1-6 with cyclopentamine in step 1, replace beyond J, according to the compound of the similarity method synthetic example 12 in embodiment 1 with 12-3 in steps of 5.LC-MS(ES,m/z):474[M+H] +；H-NMR(300MHz,CDCl 3,ppm):δ1.69-2.07(10H,m),2.24-384(5H,m),2.56(3H,s),2.98-3.01(2H,d,J＝10.5Hz),3.42-3.46(2H,d,J＝10.5Hz),3.72(2H,m),2.83-5.95(1H,m),7.19-7.23(1H,dd,J 1＝2.4Hz,J 2＝9.3Hz),7.94-7.95(1H,m),8.03(1H,m),8.10-8.13(1H,d,J＝9.3Hz),8.81(1H,s)。
Embodiment 13
Except replacing 1-6 with cyclopentamine in step 1, replace, beyond J, according to the similarity method synthetic compound 13 in embodiment 1, purifying with reversed-phase column, obtaining the trifluoroacetate of the compound 13 of embodiment 13 with 13-3 in steps of 5.LC-MS(ES,m/z):474[M+H] +；H-NMR(300MHz,d 6-DMSO,ppm):δ0.96-0.98(2H,m),1.00-1.09(2H,m),1.58-1.90(6H,m),2.21-2.27(2H,m),2.32(3H,s),2.43(3H,s),3.32(2H,s),3.41-3.43(4H,m),5.80-5.86(1H,m),7.56-7.60(1H,dd,J 1＝2.7Hz,J 2＝9.3Hz),7.88-7.91(1H,d,J＝9Hz),8.10-8.11(1H,d,J＝2.7Hz),8.97(1H,s),9.21(1H,brs),10.31(1H,s)。
Embodiment 14
Except replacing 1-6 with cyclopentamine in step 1, replace, beyond J, according to the similarity method synthetic compound 14 in embodiment 1, purifying with reversed-phase column, obtaining the trifluoroacetate of the compound 14 of embodiment 14 with 14-3 in steps of 5.LC-MS(ES,m/z):460[M+H] +；H-NMR(300MHz,d 6-DMSO,ppm):δ1.59-1.96(m,6H),2.14-2.25(m,3H),2.31(s,3H),2.43(s,3H),3.21-3.29(m,3H),3.64-3.67(m,1H),4.49(s,1H),4.70(s,1H),5.81-5.86(m,1H),7.27-7.30(d,1H,J＝8.7Hz),7.81-7.84(m,2H),8.54-8.57(m,1H),8.95(brs,1H),9.02(s,1H),10.21(s,1H)。
Embodiment 15
Except replacing except 1-7, according to the compound of the similarity method synthetic example 15 in embodiment 1 with 15-1 in step 2.LC-MS(ES,m/z):473[M+H] +；H-NMR(400MHz,CDCl 3,ppm):δ9.07(s,1H),8.02(d,J＝2.8Hz,1H),7.94(dd,J＝2.4Hz,9.6Hz,1H),7.82(d,J＝9.6Hz,1H),6.38-6.30(m,1H),3.49-3.40(m,9H),2.61-2.56(m,2H),2.49(s,3H),2.43(s,3H),2.22-2.15(m,2H),2.06-2.03(m,1H),1.70-1.65(m,1H)。
Embodiment 16
Except replacing 1-6 with cyclopentamine in step 1, replace beyond J, according to the compound of the similarity method synthetic example 16 in embodiment 1 with 16-2 in steps of 5.LC-MS(ES,m/z):475[M+H] +；H-NMR(300MHz,CDCl 3,ppm):δ1.40-1.87(9H,m),2.21-2.32(3H,m),2.33(3H,s),2.44(3H,s),2.86-2.89(2H,d,J＝9.9Hz),3.42-3.46(2H,d,J＝10.8Hz),4.39-4.47(2H,m),5.72-5.87(1H,m),7.69-7.92(3H,m),8.98(1H,s),10.74(1H,brs)。
Embodiment 17
Except replacing 1-6 with cyclopentamine in step 1, replace beyond J, according to the compound of the similarity method synthetic example 17 in embodiment 1 with 17-5 in steps of 5.LC-MS(ES,m/z):475[M+H] +；H-NMR(300MHz,CDCl 3,ppm):δδ1.75-1.91(2H,m),1.93-2.04(2H,m),2.08-2.11(3H,m),2.26-2.41(6H,m),2.44(3H,s),2.51(3H,s),2.67-2.78(1H,m),3.17-3.32(1H,m)4.38-4.48(2H,m),6.00-6.06(1H,m),6.63-6.65(1H,d,J＝5.7Hz),7.86-7.89(1H,d,J＝9.0Hz),8.28-8.32(1H,dd,J＝2.1Hz,J＝9.0Hz),8.44(1H,s),9.10(1H,s)。
Embodiment 18
Except replacing 1-6 with cyclopentamine in step 1, replace beyond J, according to the compound of the similarity method synthetic example 18 in embodiment 1 with 18-6 in steps of 5.LC-MS(ES,m/z):503[M+H] +；H-NMR(300MHz,CDCl 3,ppm):δ1.60-1.94(m,10H),2.23-2.29(m,2H),2.33(s,3H),2.43(s,3H),2.60-2.67(m,1H,J＝21.9Hz),2.81-2.86(d,1H,J＝15.9Hz),3.48-3.60(m,3H),3.99-4.04(d,1H,J＝14.1Hz),5.81-5.92(m,1H),7.64-7.68(m,1H),8.07-8.10(d,1H,J＝9Hz),8.18-8.18(d,1H,J＝2.4Hz),9.02(s,1H),10.43(s,1H)。Chiral HPLC (LuxCellulose-4 post): embodiment 18 (retention time=21.5 minute).
Embodiment 19
Except replacing 1-6 with cyclopentamine in step 1, replace beyond J, according to the compound of the similarity method synthetic example 19 in embodiment 1 with 19-2 in steps of 5.LC-MS(ES,m/z):503[M+H] +；H-NMR(DMSO,300MHz,ppm):δ1.59-1.93(m,10H),2.23-2.33(m,2H),2.34(s,3H),2.47(s,3H),2.59-2.67(m,1H),2.81-2.86(d,1H,J＝15.3Hz)，3.48-3.58(m,3H),3.99-4.04(d,1H,J＝14.4Hz),5.81-5.92(m,1H),7.64-7.68(m,1H),8.07-8.09(d,1H,J＝8.7Hz),8.17-8.18(d,1H,J＝2.4Hz),9.01(s,1H),10.43(s,1H)。Chiral HPLC (LuxCellulose-4 post): embodiment 19 (retention time=15.2 minute).
Embodiment 20
Except replacing 1-6 with cyclopentamine in step 1, replace beyond J, according to the compound of the similarity method synthetic example 20 in embodiment 1 with 20-5 in steps of 5.LC-MS(ES,m/z):503[M+H] +；H-NMR(300MHz,d 6-DMSO,ppm):δ1.48-2.32(14H,m),2.43(3H,s),3.04-3.14(4H,m),4.40-4.49(2H,m),5.78-5.87(1H,m),7.48-7.50(1H,d,J＝5.7Hz),7.86-7.92(1H,m),8.08(1H,s),8.74(1H,broads),8.90-8.96(2H,m),10.19(1H,s)。
Embodiment 21
Except replacing 1-6 with cyclopentamine in step 1, replace, beyond J, according to the similarity method synthetic compound 21 in embodiment 1, purifying with reversed-phase column, obtaining the trifluoroacetate of the compound 21 of embodiment 21 with 21-3 in steps of 5.LC-MS(ES,m/z):516[M+H] +；H-NMR(300MHz,d 6-DMSO,ppm):δ1.60-1.67(m,2H),1.81-1.83(m,6H),1.96-2.30(m,4H,),2.33(S,1H),2.50-2.51(m,3H),2.83-2.90(d,4H),3.19-3.25(d,1H),3.83-3.90(m,1H),4.02-4.12(m,2H),4.33-4.37(d,1H),5.84-5.90(m,1H),7.77-7.81(m,1H),8.11-8.29(d,1H),8.03(s,1H),9.02(s,1H),10.09(s,1H),10.52(s,1H)。Chiral HPLC (LuxCellulose-4 post): embodiment 21 (retention time=34.7 minute).
Embodiment 22
Except replacing 1-6 with cyclopentamine in step 1, replace, beyond J, according to the similarity method synthetic compound 22 in embodiment 1, purifying with reversed-phase column, obtaining the trifluoroacetate of the compound 22 of embodiment 22 with 22-3 in steps of 5.LC-MS(ES,m/z):516[M+H] +；H-NMR(300MHz,d 6-DMSO,ppm):1.95-2.01(m,2H),2.14-2.16(m,6H),2.23-2.30(m,4H),2.38(s,1H),2.51(s,3H),2.83-2.90(m,4H),3.21-3.26(d,1H,J＝17.1Hz),3.83-3.90(m,1H,J＝23.1Hz),4.00-4.13(m,2H),4.33-4.39(d,1H,J＝17.1Hz),5.85-5.91(m,1H),7.78-7.82(m,1H),8.11-8.14(d,1H,J＝8.7Hz),8.30-8.31(d,1H,J＝2.4Hz),9.03(s,1H),10.14(s,1H),10.53(s,1H)。Chiral HPLC (LuxCellulose-4 post): embodiment 22 (retention time=24.2 minute).
Embodiment 23
Except replacing except 1-6, according to the compound of the similarity method synthetic example 23 in embodiment 1 with 23-5 in step 1.LC-MS(ES,m/z):480[M+H] +；H-NMR(400MHz,d 6-DMSO,ppm):δ10.15(s,1H),8.92(s,1H),8.07(d,J＝2.4Hz,1H),7.90(d,J＝8.4Hz,1H),7.52(dd,J＝2.4,8.8Hz,1H),5.79(m,1H),3.17-3.18(m,8H),3.04(m,1H),2.38(s,3H),2.29(s,3H),2.22(m,1H),2.00(m,1H),1.80(m,2H),1.55(m,1H),1.32(d,J＝22Hz,3H)。
Embodiment 24A and 24B
Except replacing except J with 18-6 in steps of 5, according to the similarity method synthesis in embodiment 1.Chiral separation intermediate 24-11 obtains 24-11A and 24-11B, and the step 6 and 7 that then can refer in embodiment 1 synthetic line obtains the compound of embodiment 24A and embodiment 24B.
Gained racemate intermediate compound 24-11 Pre-SFC chirality preparative separation, preparative column: DAICELCHIRALPAKAD-H19*250mm, 5um; Moving phase: A phase: HEX (0.1%DEA), B phase: ETOH; Gradient: PhaseA/PhaseB=70/30; Determined wavelength: 220nm.Collect two peaks, first peak 24-11A (appearance time: 8.1 minutes) and second peak 24-11B (appearance time: 11.2 minutes) respectively
Chiral HPLC (CHIRALPAKIC post): first peak in embodiment 24A (retention time=8.53 minute) corresponding chiral separation.Second peak in embodiment 24B (retention time=8.73 minute) corresponding chiral separation.
Embodiment 24A:LC-MS (ES, m/z): 538 [M+H] +; H-NMR (300MHz, CDCl 3, ppm): δ 1.75-2.34 (6H), 2.42 (s, 3H), 2.50 (3H), 2.54-2.99 (m, 4H), 3.57-3.65 (m, 1H), 3.72-3.84 (m, 2H), 4.19-4.24 (m, 1H), 6.16-6.21 (m, 1H), 7.57-7.61 (m, 1H), 8.24-8.25 (d, 1H, J=2.7Hz), 8.34-8.37 (d, 1H, J=9.0Hz), 8.56 (brs, 1H), 8.89 (s, 1H).
Embodiment 24B:LC-MS (ES, m/z): 538 [M+H] +; H-NMR (300MHz, CDCl 3, ppm): δ 1.76-1.88 (m, 2H), 2.03-2.04 (m, 2H), 2.08-2.33 (m, 4H), 2.42 (s, 3H), 2.54 (s, 3H), 2.68-2.83 (m2H), 2.96-2.99 (m, 2H), 3.58-3.66 (m, 1H), 3.76-3.81 (m, 2H), (4.17-4.22 d, 1H, J=14.7Hz), 6.14-6.22 (m, 1H), 7.59-7.63 (m, 1H), 8.24-8.25 (d, 1H, J=2.4Hz), 8.36-8.39 (d, 1H, J=9.0Hz), 8.86 (brs, 1H), 8.92 (s, 1H)
Embodiment 25A and 25B
Except replacing except J with 19-2 in steps of 5, according to the similarity method synthesis in embodiment 1.Chiral separation intermediate 25-12 obtains 25-12A and 25-12B, and the step 7 that then can refer in embodiment 1 synthetic line obtains the compound of embodiment 25A and embodiment 25B.
Gained racemate intermediate compound 25-12 Pre-SFC chirality preparative separation, preparative column: ChiralpakAS-H5*25cm, 5um, moving phase: A phase: CO2:50, B phase: MEOH (0.2%DEA): 50; Cycling time: 3.4 minutes, determined wavelength: 220nm.Collect two peaks, first peak 25-12A (appearance time: 5.51 minutes) and second peak 25-12B (appearance time: 6.76 minutes) respectively.
Embodiment 25A:LC-MS:(ES, m/z): 538 [M+H] +; H-NMR (300MHz, CDCl 3, ppm): δ 1.78-2.33 (m, 6H), 2.42 (s, 3H), 2.53 (s, 3H), 2.73-2.83 (m, 2H), 2.95-2.96 (m, 2H), 3.58-3.65 (m, 1H), 3.76-3.81 (m, 2H), 4.15-4.20 (d, 1H, J=14.7Hz), 6.14-6.22 (m, 1H), 7.59-7.63 (m, 1H), 8.23-8.24 (d, 1H, J=2.4Hz), 8.35-8.38 (d, 1H, J=9.0Hz), 8.66 (brs, 1H), 8.90 (s, 1H).
Embodiment 25B:LC-MS:(ES, m/z): 538 [M+H] +; H-NMR:(300MHz, CDCl 3, ppm): δ 1.74-2.27 (m, 6H), 2.42 (s, 3H), 2.54 (s, 3H), 2.73-2.82 (m, 2H), 2.95-2.96 (m, 2H), 3.57-3.64 (m, 1H), 3.77-3.79 (m, 2H), 4.13-4.18 (d, 1H, J=14.7Hz), 6.13-6.21 (m, 1H), 7.57-7.61 (m, 1H), 8.25-8.26 (d, 1H, J=2.4Hz), 8.34-8.37 (d, 1H, J=9.0Hz), 8.62 (brs, 1H), 8.90 (s, 1H).
Embodiment 26A and 26B
From 26-1 to 26-4 and the synthesis of 26-5 can refer to step 4 in embodiment 1 synthetic line, 5 and step 6.Chiral separation method obtains 26-4 and 26-5.Preparative column: CHIRALPAKAD-HSFC5*25cm, 5um, moving phase: A phase: CO2:50, B phase: EtOH (0.2%DEA)-HPLC:50; Cycling time: 6 minutes, determined wavelength: 220nm.First peak (retention time=8.69 minute) in the corresponding chiral separation of 26-4.Second peak (retention time=10.98 minute) in the corresponding chiral separation of 26-5.The step 7 in embodiment 1 synthetic line is can refer to the synthesis of final product from 26-4 to 26-5.
Embodiment 26A:LC-MS:(ES, m/z): 513 [M+H] +; H-NMR:(300MHz, CDCl 3, ppm): δ 0.63-0.66 (m, 1H), 1.34-2.34 (m, 7H), 2.38 (s, 3H), 2.44-2.50 (m, 1H), 2.55 (s, 3H), 3.01-3.09 (m, 1H), 3.38-3.44 (m, 1H), 3.67-3.74 (m, 2H), 4.12-4.19 (m, 2H), 4.61-4.65 (m, 1H), 6.01-6.08 (m, 1H), 7.57-7.61 (m, 1H), 8.14-8.21 (m, 2H), 8.42-8.45 (d, 1H, J=8.7Hz), 8.82 (s, 1H).
Embodiment 26B:LC-MS:(ES, m/z): 513 [M+H] +; H-NMR:(300MHz, CDCl3, ppm): δ 0.72-0.74 (m, 1H), 1.35-2.37 (m, 7H), 2.42 (s, 3H), 2.43-2.52 (m, 1H), 2.54 (s, 3H), 2.97-3.14 (m, 2H), 3.58-3.65 (m, 1H), 3.79-3.83 (m, 2H), 4.19-4.24 (m, 1H), 5.89-5.90 (m, 1H), 7.57-7.61 (m, 1H), 8.20-8.21 (m, 2H), 8.45-8.46 (m, 1H), 8.83 (s, 1H).
Embodiment 27A and 27B
From 27-1 to 27-4 and the synthesis of 27-5 can refer to step 4 in embodiment 1 synthetic line, 5 and step 6.Chiral separation method obtains 27-4 and 27-5.Preparative column: CHIRALPAKAD-HSFC5*25cm, 5um, moving phase: A phase: CO2:50, B phase: EtOH (0.2%DEA)-HPLC:50; Cycling time: 6 minutes, determined wavelength: 220nm.First peak (retention time=20.2 minute) in the corresponding chiral separation of 27-4.Second peak (retention time=26.5 minute) in the corresponding chiral separation of 27-5.The step 7 in embodiment 1 synthetic line is can refer to the synthesis of final product from 27-4 to 27-5.
Embodiment 27A:LC-MS:(ES, m/z): 513 [M+H] +; H-NMR:(300MHz, CDCl 3, ppm): δ 0.72-0.75 (m, 1H), 1.35-2.07 (m, 5H), 2.38 (s, 3H), 2.55-2.98 (m, 4H), 2.97-2.98 (m, 2H), 3.58-3.65 (m, 1H), 3.78-3.83 (m, 2H), 4.18-4.23 (m, 2H), 5.88-5.89 (m, 1H), 7.57-7.61 (m, 1H), 8.18-8.20 (m, 2H), 8.42-8.47 (d, 1H, J=9.0Hz), 8.82 (s, 1H).
Embodiment 27B:LC-MS:(ES, m/z): 513 [M+H] +; H-NMR:(300MHz, CDCl 3, ppm): δ 0.72-0.74 (m, 1H), 1.35-2.10 (m, 5H), 2.42 (s, 3H), 2.54-2.58 (m, 4H), 2.97-2.98 (m, 2H), 3.58-3.65 (m, 1H), 3.79-3.83 (m, 2H), 4.19-4.24 (m, 2H), 5.89-5.90 (m, 1H), 7.57-7.61 (m, 1H), 8.20-8.21 (m, 2H), 8.45-8.46 (m, 1H), 8.83 (s, 1H).
EXPERIMENTAL EXAMPLE
cDK4 and CDK6 kinases external activity experimental technique
CDK4 and CDK6 kinases external activity screening experiment employing method is CaliperMobilityShiftAssay, the detection platform that the method is is core with the mobility detection technique of microfluidic chip technology.Experimental configuration: 1xCDK4 kinase reaction damping fluid (20mMHEPES, pH7.5,0.01%TritonX-100,10mMMgCl 2, 2mMDTT); 1xCDK6 kinase reaction damping fluid (50mMHEPES, pH7.5,0.0015%Brij-35,10mMMgCl 2, 2mMDTT); Kinase reaction stop buffer (100mMHEPES, pH7.5,0.015%Brij-35,0.2%CoatingReagent#3,50mMEDTA); 2.5xCDK4 kinase solution [25nMCDK4 kinases/cyclinD3 (Carna, Cat#04-105) is in 1xCDK4 kinase solution]; 2.5xCDK6 kinase solution [50nMCDK6 kinases/cyclinD3 (Carna, Cat#04-107) is in 1xCDK6 kinase solution]; 2.5x peptide substrate solution [7.5 μMs of peptide substrate FAM-P8 (GLBiochem, Cat.#112396) and 552.5 μMs of ATP in 1xCDK4 kinase solution, or 7.5uMFAM-P8 and 2mMATP is in 1xCDK6 kinase solution].CDK4 kinase reaction solution ultimate density: 10nMCDK4/CyclinD3,3 μMs of peptide substrate FAM-P8,221 μMs of ATP, 10mMMgCl 2, 2mMDTT; CDK6 kinase reaction solution ultimate density: 20nMCDK6/CyclinD3,3 μMs of peptide substrate FAM-P8,800 μMs of ATP, 10mMMgCl 2, 2mMDTT.
Experimental procedure: first prepare the compound solution that 5x reacts final concentration in 96 orifice plates: prepare the compound solution that 50x reacts final concentration with 100%DMSO, is diluted to 5x with 1x kinase reaction damping fluid and reacts final concentration compound solution; Earthquake device shakes 10 minutes; Then in 384 hole test panels, following solution is added: (in final 384 hole test panels, 1x compound of reaction final concentration is CDK4 or the CDK6 kinase solution of the 2.5x of 0.1nM – 1000nM and 10 μ L to the compound solution of the 5x reaction final concentration of 5uL, incubated at room adds the 2.5x peptide substrate solution of 10 μ L again after 10 minutes, place at 28 DEG C after one hour and add 25 μ L kinase reaction stop buffers, centrifugal one minute of 1200RPM.Finally 384 hole test panels are put on CaliperEZReader and collect test data (transformation efficiency), kinase whose suppression curve is gone out by GraphPadPrismV5.0 computed in software, and calculate the compound concentration needed for acquisition 50% inhibition based on these data, i.e. the IC of compound 50.

Claims (10)

1. the compound shown in following formula I, its pharmacy acceptable salt, enantiomer, diastereomer, racemic modification, prodrugs or solvate:
Wherein,
R 1be selected from following group:
R 2and R 2 'be selected from H independently of one another, deuterium (D), C1-C4 alkyl, fluorine and cyano group, and, R 2and R 2 'can on same or different carbon atom;
N=1 or 2
R 3be selected from following group:
R 4be selected from H, deuterium (D) and C1-C4 alkyl,
W is selected from CH 2, CH 2cH 2, O and NH
X is selected from CH and N
Y is selected from CH 2, NH and O
M=0,1 or 2
N=0,1 or 2.
2. compound according to claim 1, its pharmacy acceptable salt, enantiomer, diastereomer, racemic modification, prodrugs or solvate, wherein,
R 1be selected from following group:
R 3be selected from following group:
3. the compound according to claim 1 Chinese style I, its pharmacy acceptable salt, enantiomer, diastereomer, racemic modification, prodrugs or solvate, wherein,
R 1be selected from following group:
R 3be selected from following group:
4. the compound according to claim 1 Chinese style I, its pharmacy acceptable salt, enantiomer, diastereomer, racemic modification, prodrugs or solvate, wherein,
R 1be selected from following group:
R 3be selected from following group:
5. compound shown in formula I according to claim 1, its pharmacy acceptable salt, enantiomer, diastereomer, racemic modification, prodrugs or solvate, wherein, described compound is selected from following compound:
6. the compound according to any one of claim 1-5, its pharmacy acceptable salt, enantiomer, diastereomer, racemic modification, prodrugs or solvate, wherein, described pharmacy acceptable salt comprise hydrochloride, hydrobromate, hydriodate, vitriol, phosphoric acid salt, nitrate, acetate, trifluoroacetate, tosilate, salicylate, mesylate, oxalate, succinate, Citrate trianion, malate, lactic acid salt, fumarate.
7. the compound according to any one of claim 1-6, its pharmacy acceptable salt, enantiomer, diastereomer, racemic modification, prodrugs or solvate are for the preparation of the purposes for the treatment of in the medicine of the disease relevant with cell cycle protein dependent kinase signal path.
8. purposes according to claim 7, wherein, described compound, its pharmacy acceptable salt, enantiomer, diastereomer, racemic modification, prodrugs or solvate are as cell cycle protein dependent kinase CDK4 and/or CDK6 selective depressant.
9. the purposes according to claim 7 or 8, wherein, the described disease relevant with cell cycle protein dependent kinase signal path comprises mammary cancer, neuroblastoma, pernicious rhabdomyoma, glioma, lung cancer, colorectal carcinoma, cancer of the stomach, gastrointestinal stromal knurl (GIST), hepatocellular carcinoma, prostate tumor, sarcoma, ovarian cancer, cervical cancer, carcinoma of the pancreas, melanoma, thyroid carcinoma, cholangiocarcinoma, carcinoma of endometrium, kidney, mesothelioma, lymphoma, leukemia, non-Hodgkin lymphoma, primary cutaneous type, acute myelocytic leukemia (AML), multiple myeloma.
10. a pharmaceutical composition, described pharmaceutical composition contains: the one in the compound, its pharmacy acceptable salt, enantiomer, diastereomer, racemic modification prodrugs, solvate and their mixture that are selected from according to any one of claim 1-6 for the treatment of significant quantity; Optionally pharmaceutically acceptable carrier.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105622638A (en) * 2014-10-29 2016-06-01 广州康盛贝特医药技术有限公司 Pyrimido or pyridopyridone compound and its preparation method and use
CN106967064A (en) * 2017-03-29 2017-07-21 郑州泰基鸿诺医药股份有限公司 Deuterated Palbociclib derivative, preparation method and applications
WO2020239051A1 (en) * 2019-05-30 2020-12-03 江苏恒瑞医药股份有限公司 Uses of cdk4/6 inhibitor jointly with vegfr inhibitor in preparing tumor-treating medicament
CN115551856A (en) * 2020-02-28 2022-12-30 重庆复尚源创医药技术有限公司 Compounds as CDK2/4/6 inhibitors

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SG11202002610TA (en) * 2017-09-22 2020-04-29 Hoffmann La Roche Process for the prepration of 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one derivatives
TW202237585A (en) 2020-11-27 2022-10-01 瑞士商瑞森製藥公司 Cdk inhibitors
WO2022149057A1 (en) 2021-01-05 2022-07-14 Rhizen Pharmaceuticals Ag Cdk inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003062236A1 (en) * 2002-01-22 2003-07-31 Warner-Lambert Company Llc 2-(PYRIDIN-2-YLAMINO)-PYRIDO[2,3d]PYRIMIDIN-7-ONES
WO2011101409A1 (en) * 2010-02-19 2011-08-25 Novartis Ag Pyrrolopyrimidine compounds as inhibitors of cdk4/6
WO2014150925A2 (en) * 2013-03-15 2014-09-25 Concert Pharmaceuticals, Inc. Deuterated palbociclib

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2007297286A1 (en) * 2006-09-08 2008-03-20 Pfizer Products Inc. Synthesis of 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones
CN104447739B (en) * 2014-11-07 2016-02-17 郑州泰基鸿诺药物科技有限公司 A kind of deuterated Palbociclib derivative, preparation method and application

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003062236A1 (en) * 2002-01-22 2003-07-31 Warner-Lambert Company Llc 2-(PYRIDIN-2-YLAMINO)-PYRIDO[2,3d]PYRIMIDIN-7-ONES
WO2011101409A1 (en) * 2010-02-19 2011-08-25 Novartis Ag Pyrrolopyrimidine compounds as inhibitors of cdk4/6
WO2014150925A2 (en) * 2013-03-15 2014-09-25 Concert Pharmaceuticals, Inc. Deuterated palbociclib

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PETER L. TOOGOOD ET AL.: ""Discovery of a Potent and Selective Inhibitor of Cyclin-Dependent Kinase 4/6"", 《JOURNAL OF MEDICINAL CHEMISTRY》 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105622638A (en) * 2014-10-29 2016-06-01 广州康盛贝特医药技术有限公司 Pyrimido or pyridopyridone compound and its preparation method and use
CN105622638B (en) * 2014-10-29 2018-10-02 广州必贝特医药技术有限公司 Pyrimidine or pyridopyridine ketone compounds and its preparation method and application
CN106967064A (en) * 2017-03-29 2017-07-21 郑州泰基鸿诺医药股份有限公司 Deuterated Palbociclib derivative, preparation method and applications
CN106967064B (en) * 2017-03-29 2018-03-23 郑州泰基鸿诺医药股份有限公司 Deuterated Palbociclib derivative, preparation method and applications
WO2020239051A1 (en) * 2019-05-30 2020-12-03 江苏恒瑞医药股份有限公司 Uses of cdk4/6 inhibitor jointly with vegfr inhibitor in preparing tumor-treating medicament
CN113840608A (en) * 2019-05-30 2021-12-24 江苏恒瑞医药股份有限公司 Application of CDK4/6 inhibitor and VEGFR inhibitor in preparation of drugs for treating tumors
CN113840608B (en) * 2019-05-30 2023-11-14 江苏恒瑞医药股份有限公司 Use of CDK4/6 inhibitors in combination with VEGFR inhibitors for the preparation of a medicament for the treatment of tumors
CN115551856A (en) * 2020-02-28 2022-12-30 重庆复尚源创医药技术有限公司 Compounds as CDK2/4/6 inhibitors

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