CN110330484A - Replace class phenyl pyrimidine derivative as jak kinase inhibitor or its pharmaceutical salt, Preparation method and use - Google Patents

Replace class phenyl pyrimidine derivative as jak kinase inhibitor or its pharmaceutical salt, Preparation method and use Download PDF

Info

Publication number
CN110330484A
CN110330484A CN201910653403.9A CN201910653403A CN110330484A CN 110330484 A CN110330484 A CN 110330484A CN 201910653403 A CN201910653403 A CN 201910653403A CN 110330484 A CN110330484 A CN 110330484A
Authority
CN
China
Prior art keywords
pyrimidine
phenyl
amino
base
pyrazoles
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201910653403.9A
Other languages
Chinese (zh)
Other versions
CN110330484B (en
Inventor
张大永
张天泰
舒蕾
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
China Pharmaceutical University
Original Assignee
China Pharmaceutical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by China Pharmaceutical University filed Critical China Pharmaceutical University
Priority to CN201910653403.9A priority Critical patent/CN110330484B/en
Publication of CN110330484A publication Critical patent/CN110330484A/en
Application granted granted Critical
Publication of CN110330484B publication Critical patent/CN110330484B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Immunology (AREA)
  • Dermatology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Ophthalmology & Optometry (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses have the substitution class phenyl pyrimidine derivative of logical formula (I) as jak kinase inhibitor or its pharmaceutical salt, Preparation method and use.The compound has excellent JAK inhibiting effect, is used as the drug for preventing, treating or improving autoimmune disease, siogren's syndrome, Behcet's disease, multiple sclerosis, systemic loupus erythematosus etc..The compounds of this invention shows the JAK-3 inhibiting effect IC of high activity50It can reach 1.7nM, synthetic route of the present invention is simple, and implementation is strong.

Description

Replace class phenyl pyrimidine derivative as jak kinase inhibitor or its pharmaceutical salt, Preparation method and use
Technical field
The present invention relates to kinase inhibitor, preparation method and application, in particular to substitution class phenyl pyrimidine derivative conducts Jak kinase inhibitor or its pharmaceutical salt, Preparation method and use.
Background technique
There are four types of hypotypes for jak kinase (janus kinase): JAK-1, JAK-2, JAK-3 and TYK-2, the effect with downstream Answer device, signal transduction and transcription activating protein (signal transducers and activators oftranscription Proteins, STATs) form important cytokine signaling pathway --- JAK-STAT access (Science, 1994, 264:1415-1421).The discovery of the access substantially increases researcher to the understanding of gene regulation, and research finds JAK-STAT Access can by cytokine profiles, growth factor and receptor activation, participate in cell Proliferation, differentiation, apoptosis, angiogenesis and The processes such as immunological regulation (World J Gastroenterol, 2007,13:6478-6491).In jak kinase mediated cell mostly The signal transduction of number cell factor, such as interleukin (IL) class, interferon (IFN) class, hematopoietin (EPO), granulocyte With macrophage colony stimulating factor (GMCSF), somatotropin (GH), prolactin (PRL), thrombopoietin (TPO), blood Platelet derivative factor (PDGF) and epithelical cell growth factor (EGF) etc., and isoacceptor can not activate the JAK of different subtype Kinases.
Wherein, JAK-3 by with the I cytokines such as IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 by bluk recombination γ chain (γ c) in object combines, and adjusts cellular signal transduction.When JAK-3 defect or γ c are mutated, severe joint can lead to Immune deficiency (severe combined immunodeficiency, SCID), shows as T cell and natural killer cells The symptom of the immune limitations such as (natural killer cell, NK) Leukopenia, the forfeiture of B cell function.When there are suitable quantities These cytokines when, these cytokines play an important role in immune response.However, it is believed that their excessive generation It is related with many autoimmune diseases, for example, psoriasis, rheumatoid arthritis, inflammatory bowel disease, siogren's syndrome, Behcet's disease, multiple sclerosis, systemic loupus erythematosus etc. (Journal of Allergy andClinical Tmmurmlogy 127,3,701-721.e70 (2011), Cytokine&Growth Factor Reviews19,41-52 (2008), Invest Ophthalmol Vis Sci.2008Jul；49 (7): 3058-3064, Ann Rheum Dis.2010Jul；69 (7): 1325-1328).Furthermore JAK-1, JAK-2 and TYK-2 be widely present in vivo it is various tissue and In cell, JAK3 is primarily present in bone marrow cell, thymocyte, in NK cell and the bone-marrow-derived lymphocyte of activation, T lymphocyte, JAK-3 is safer effective anti-autoimmunity target spot in generally acknowledged JAK-STAT access.
The combination for how inhibiting ATP-binding site on ATP and JAK blocks the hydrolysis of ATP, interferes JAKs phosphorylation, thus Prevent JAKs activation, cut off its to STATs transmit signal, cause its can not the intragentic expression of regulating cell core, thus hinder Disconnected JAK-STAT signal path is the emphasis of research.
Summary of the invention
Goal of the invention: it is an object of the present invention to provide replace class phenyl pyrimidine derivative as jak kinase inhibitor or its can Medicinal salt.
It is a further object of the present invention to provide the substitution class phenyl pyrimidine derivative as jak kinase inhibitor or its can The preparation method of medicinal salt.
Final object of the present invention be to provide the substitution class phenyl pyrimidine derivative as jak kinase inhibitor or The purposes of its pharmaceutical salt.
Technical solution: the present invention provides a kind of substitution class phenyl pyrimidine derivative with logical formula (I) and presses down as jak kinase Preparation or its pharmaceutical salt,
Wherein,
X is nitrogen-atoms or-CH-；
Y is nitrogen-atoms or-CH-；
Z isSubstituted or unsubstituted C3-8Heterocyclic hydrocarbyl；
W is substituted 5 unit's heteroaryl；
R1It is
Wherein,
V is hydrogen atom, halogen or cyano；
R4、R5、R6And R7Respectively hydrogen atom, substituted or unsubstituted C1-6It is alkyl, substituted or do not taken The C in generation1-6Miscellaneous alkyl；
R2It is hydrogen atom, halogen atom, substituted or unsubstituted 4,5,6,7- or 8- circle heterocyclic ring；
R3It is substituted C1-6Alkyl, substituted or unsubstituted C1-6Miscellaneous alkyl.
Further, described
Z is
Further, the R2It is hydrogen atom, fluorine atom, substitution or unsubstituted 4,5 or 6- member heterocyclic ring containing nitrogen.It is described W is nitrogenous five yuan of hetero-aromatic rings.The R3It is methyl or substituted C1-6Alkyl, the C1-6The substituent group of alkyl is that halogen is former Son, hydroxyl, C1-6Alkoxy, fat amido, amide groups.
Further, there is the substitution class phenyl pyrimidine derivative of logical formula (I) as jak kinase inhibitor or its is pharmaceutically acceptable Salt,
N- (3- (6- ((1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) acrylamide,
N- (3- (6- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) acrylamide,
N- (4- (6- ((1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) acrylamide,
N- (3- (2- ((1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) acrylamide,
N- (4- (2- ((1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) acrylamide,
N- (3- (6- (4- morpholine phenylamino) pyrimidine-4-yl) phenyl) acrylamide,
N- (4- (6- (4- morpholine phenylamino) pyrimidine-4-yl) phenyl) acrylamide,
N- (3- (2- (4- morpholine phenylamino) pyrimidine-4-yl) phenyl) acrylamide,
N- (4- (2- (4- morpholine phenylamino) pyrimidine-4-yl) phenyl) acrylamide,
N- (3- (6- ((1- (2-N, N- dimethyl ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) propylene Amide,
N- (3- (6- ((1- (N- methylacetamide) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) acrylamide,
N- (3- (6- ((1- (2- hydroxyethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) acrylamide,
N- (3- (6- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) -2- crotonamide,
N- (3- (6- ((1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) -2- crotonoyl Amine,
N- (4- (6- ((1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) -2- crotonoyl Amine,
N- (4- (2- ((1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) -2- crotonoyl Amine,
N- (3- (6- (4- morpholine phenylamino) pyrimidine-4-yl) phenyl) -2- crotonamide,
N- (3- (2- (4- morpholine phenylamino) pyrimidine-4-yl) phenyl) -2- crotonamide,
N- (4- (6- (4- morpholine phenylamino) pyrimidine-4-yl) phenyl) -2- crotonamide,
N- (4- (2- (4- morpholine phenylamino) pyrimidine-4-yl) phenyl) -2- crotonamide,
N- (3- (6- ((1- (2-N, N- dimethyl ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) -2- fourth Acrylamide,
N- (3- (6- ((1- (N- methylacetamide) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) -2- crotonoyl Amine,
N- (3- (6- ((1-1- (2- hydroxyethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) -2- crotonoyl Amine,
2- cyano-N- (3- (6- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) acetamide,
2- cyano-N- (3- (6- ((1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) second Amide,
2- cyano-N- (4- (6- ((1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) second Amide,
2- cyano-N- (4- (2- ((1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) second Amide,
2- cyano-N- (3- (((6- (4- morpholine phenylamino) pyrimidine-4-yl) amino) methyl) phenyl) acetamide,
2- cyano-N- (3- (((2- (4- morpholine phenylamino) pyrimidine-4-yl) amino) methyl) phenyl) acetamide,
2- cyano-N- (4- (((6- (4- morpholine phenylamino) pyrimidine-4-yl) amino) methyl) phenyl) acetamide,
2- cyano-N- (4- (((2- (4- morpholine phenylamino) pyrimidine-4-yl) amino) methyl) phenyl) acetamide,
N- [2- oxo -2- ((3- (6- (1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl)-benzene Base-amino) ethyl] acrylamide,
N- [2- oxo -2- ((3- (6- (1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl)-benzene Base-amino) ethyl] crotonamide,
N- [2- oxo -2- ((3- (6- (4- morpholine phenylamino) amino) pyrimidine-4-yl)-phenyl-amino) ethyl] propylene Amide,
N- [2- oxo -2- ((3- (6- (4- morpholine phenylamino) amino) pyrimidine-4-yl)-phenyl-amino) ethyl] butylene Amide, 2- cyano-N- [2- oxo -2- ((3- (6- (1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl)-phenyl-ammonia Base) ethyl] acetamide,
2- cyano-N- [2- oxo -2- ((3- (6- (4- morpholine phenylamino) amino) pyrimidine-4-yl)-phenyl-amino) second Base] acetamide,
2- cyano-N- [2- oxo -2- ((3- (6- (1- (N- methylacetamide) -1H- pyrazoles -4- base) amino) pyrimidine -4- Base)-phenyl-amino) ethyl] acetamide,
2- cyano-N- (4- (6- ((1-1- (2- hydroxyethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) second Amide.
A kind of pharmaceutical composition, it is one or more as described in any one of claim 1-6 containing therapeutically effective amount Have the substitution class phenyl pyrimidine derivative of logical formula (I) as jak kinase inhibitor or its pharmaceutical salt, and pharmaceutically Acceptable carrier or auxiliary material.
The described substitution class phenyl pyrimidine derivative with logical formula (I) is as jak kinase inhibitor or its is pharmaceutical The preparation method of salt, includes the following steps:
Wherein,
Step 1: compound III makes under conditions of tetra-triphenylphosphine palladium and alkaline potassium acetate with duplex pinacol borate Compound III is converted into compound IV；
Step 2: the chloro- pyrimidine of 2,4- or 4, the chloro- pyrimidine of 6-, tetra-triphenylphosphine palladium and carbon being added into the reaction solution of step 1 Sour aqueous solutions of potassium carries out suziki reaction, obtains compound V；
Step 3: compound V is reacted with amine is replaced, and obtains compound VI；
Step 4: the reduction reaction of compound VI is converted into compound VII；
Step 5: compound VII and R1Replace reagent progress to react at amide, obtains the compounds of this invention.
The described substitution class phenyl pyrimidine derivative with logical formula (I) is as jak kinase inhibitor or its is pharmaceutical Salt treats autoimmune disease, siogren's syndrome, Behcet's disease, multiple sclerosis, systemic loupus erythematosus in preparation Drug in purposes.
Further, the autoimmune disease is psoriasis, rheumatoid arthritis or inflammatory bowel disease.
The JAK inhibitor or its pharmaceutical salt of high activity that the present invention develops and selectivity, Reverse transcriptase ATP with The combination of the upper ATP-binding site of JAK, blocks the hydrolysis of ATP, and interference JAKs Phosphorylation events are cut to prevent the activation of JAKs Broken its to STATs transmit signal, cause its can not the intragentic expression of regulating cell core, thus reach block JAK-STAT letter The purpose of number access.
The utility model has the advantages that the compounds of this invention has excellent JAK-1 and/or JAK-3 inhibiting effect, it is used as prevention, controls It treats or improves autoimmune disease (for example, psoriasis, rheumatoid arthritis, inflammatory bowel disease are (for example, Crohn disease, ulcer Property colitis etc.), siogren's syndrome, Behcet's disease, multiple sclerosis, systemic loupus erythematosus etc.) drug, Etc., 5 compound of embodiment shows the JAK-3 inhibiting effect (IC of high activity50=1.7nm), the selection activity of moderate strength (JAK-1/JAK-3=586, JAK-2/JAK-3=60), synthetic route of the present invention is simple, and implementation is strong.
Specific embodiment
In following embodiment, " room temperature " refers to about 10 DEG C to about 35 DEG C.The ratio that mixed solvent indicates is that volume is mixed Composition and division in a proportion example, unless otherwise mentioned.Unless otherwise noted, % refers to wt%.
In silica gel column chromatography, alkaline silica gel refers to the silica gel combined using aminopropyl silane.In high performance liquid chromatography (HP1C) in, C18 refers to the silica gel combined using octadecyl.The ratio of eluting solvent is volume mixture ratio, unless separately making Explanation.
In embodiment and EXPERIMENTAL EXAMPLE below, following abbreviations are used.
THF: tetrahydrofuran,
HATU:2- (7- aoxidizes benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester,
DIEA:N, N- diisopropylethylamine
M: molar concentration.
Utilize Fourier alternative types NMR, measurement1H-NMR (proton nuclear magnetic resonance spectroscopy).For analysis, ACD/ is used SpecManager etc..The peak of very light proton (such as hydroxyl, amino etc.) is not described.
MS (mass spectrum) is measured using 1C/MS (liquid chromatography mass instrument).As ionization method, ESI (electrojet ion is used Change) method etc..Data indicate those measured values.In general, observation molecular ion peak.In the case where salt, it is generally observed free The molecular ion peak or fragment ion peak of form.
The following are the structural formulas and preparation method of part Z substituent group:
(1) N- methyl -4- aminooimidazole
By 4- nitroimidazole (1.41g), potassium carbonate (2.5g), iodomethane (1.9g) and 20mL acetonitrile, back flow reaction 12h. Decompression is spin-dried for, and 50mL water is added, and is extracted 3 times with 50mL ethyl acetate respectively, and organic layer is merged, and saturated common salt water washing is organic It is added to anhydrous Na2SO4It is dry, it is dried under reduced pressure, obtains 1- methyl-4-nitro iminazole (1.5g).
By 1- methyl-4-nitro iminazole (1g), Pd/C (0.1g) and 20ml ethyl alcohol, in hydrogen balloon displaced air, room temperature is anti- It should about for 24 hours.Diatomite decompression filters, and filtrate decompression is dry, obtains title product (0.75g).
MS(ESI+): [M+H]+98.0.
(2) 1- (2- methoxy ethyl) -1H- pyrazoles -4- amine
Using the method as reference implementation example 1, title is obtained by 4- nitropyrazole, 2- bromo-ethyl-methyl ether, Pd/C Compound.
MS(ESI+): [M+H]+142.0。
(3) 2- (4- amino -1H- pyrazol-1-yl) ethyl alcohol
Using the method as reference implementation example 1, title compound is obtained by 4- nitropyrazole, ethylene bromohyrin, Pd/C.
MS(ESI+): [M+H]+128.0。
(4) N, N- dimethyl -2- (4- amino -1H- pyrazol-1-yl) second ammonia
Using the method as reference implementation example 1, by 4- nitropyrazole, N, the bromo- second ammonia of N- dimethyl -2-, Pd/C are obtained Obtain title compound.
MS(ESI+): [M+H]+154.1。
(5) N- methyl -2- (4- amino -1H- pyrazol-1-yl) acetamide
Using the method as reference implementation example 1, obtained by 4- nitropyrazole, the bromo- acetamide of N- methyl -2-, Pd/C Title compound.
MS(ESI+): [M+H]+154.0。
(6) 4- (4- morpholinyl) aniline
By 4- fluoronitrobenzene (1g), K2CO3(1.1g) and 5ml DMSO is stirred at room temperature reaction 30min, is added dropwise to morphine Quinoline (0.6g), 120 DEG C of heating are stirred to react 2h mixture and pour into pure and mild water mixed liquid (1: 1) 20mL, and yellow mercury oxide filters 4- (4- nitrobenzophenone) morpholine 1.4g.By 4- (4- nitrobenzophenone) morpholine (1g), Pd/C (0.1g) and 20ml ethyl alcohol, in hydrogen balloon Displaced air, room temperature reaction is about for 24 hours.Diatomite decompression filters, and filtrate decompression is dry, obtains title product (0.85g).MS(ESI+): [M+H]+179.1。
The following are the preparation methods of the application part of compounds:
Embodiment 1
N- (3- (6- ((1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) acrylamide
A) the chloro- 6- of 4- (3- nitrobenzene) pyrimidine
At room temperature, into 3- bromo nitrobenzene (1g) and the anhydrous Isosorbide-5-Nitrae dioxane of 50mL, duplex pinacol borate is added (1.34g) and KOAc (1.48g) are in catalyst Pd (PPh3)4(3%) and the lower 100 DEG C of reactions 12h of oxygen free condition.It is cooled to room temperature, 4,6- dichloro pyrimidine (1.07g), 2M K are added into mixed liquor2CO3Aqueous solution and Pd (PPh3)4(3%) 100 DEG C of guarantors are warming up to Demonstrate,prove oxygen free condition the reaction was continued 12h.It is cooled to room temperature, diatomite filtering is dried under reduced pressure, through silica gel chromatography, obtains title Compound (0.93g).
1H NMR (300MHz, CDCl3) δ 9.11 (s, 1H), 8.95 (s, 1H), 8.45 (d, J=8.0Hz, 1H), 8.41 (d, J=9.3Hz, 1H), 7.85 (s, 1H), 7.74 (t, J=8.0Hz, 1H)
B) 6- (3- nitrobenzene)-N4(1- (2- methoxy ethyl) -1H- pyrazoles -4- base) -4- aminopyrimidine
At room temperature, into the chloro- 6- of 4- (3- nitrobenzene) pyrimidine (0.3g) and isopropanol 10mL, 1- (2- methoxyl group is added Ethyl) -1H- pyrazoles -4- amine (0.24g) and DIEA (0.41g), react 6h under counterflow condition, are cooled to room temperature, it is heavy to be precipitated It forms sediment, filters, washing obtains title compound.
1H NMR (300MHz, CDCl3) δ 8.74 (s, 1H), 8.70 (s, 1H), 8.34-8.22 (m, 2H), 7.78 (s, 1H), 7.61 (t, J=8.0Hz, 1H), 7.56 (s, 1H), 7.50 (s, 1H), 6.93 (s, 1H), 4.31 (t, J=5.1Hz, 2H), 3.77 (t, J=5.1Hz, 2H), 3.35 (s, 3H)
C) 6- (3- aminobenzene)-N4(1- (2- methoxy ethyl) -1H- pyrazoles -4- base) -4- aminopyrimidine
The chloro- 6- of 4- (3- nitrobenzene)-N is added in reaction flask4(1- (2- methoxy ethyl) -1H- pyrazoles -4- base) -4- Aminopyrimidine (0.2g), 0.02g Pd/C and 20mL EtOH, N2Under protection, it is heated to flowing back, is slowly added dropwise in 30min Reaction is added dropwise in 85% hydrazine hydrate (0.32g), filter, filtrate decompression it is dry title compound.
MS(ESI+): [M+H]+311.2
D) N- (3- (6- ((1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) acryloyl Amine
6- (3- aminobenzene)-N is added in reaction flask4(1- (2- methoxy ethyl) -1H- pyrazoles -4- base) -4- amino Pyrimidine (0.04g), the dry diluted acryloyl chloride of DCM of 10mL dry DCM, 0 DEG C of dropwise addition 1mL, stirs 30min, filters available Title compound.
1H NMR (300MHz, DMSO) δ 8.69 (s, 1H), 8.48 (s, 1H), 8.06 (s, 1H), 7.81 (d, J=7.7Hz, 1H), 7.73 (d, J=7.5Hz, 1H), 7.59 (s, 1H), 7.47 (t, J=7.8Hz, 1H), 7.10 (s, 1H), 6.49 (dd, J= 16.9,10.0Hz, 1H), 6.31 (d, J=16.7Hz, 1H), 5.78 (d, J=10.6Hz, 1H), 4.25 (t, J=4.9Hz, 2H), 3.68 (t, J=4.9Hz, 2H), 3.23 (s, 3H)
MS(ESI)m/z 365.2[M+H]+.
Embodiment 2 to 23
In embodiment 2 to 23, method in the same manner as in Example 1 is utilized.
Wherein 3- bromo nitrobenzene (1g) correspondence in step A) of embodiment 3,5,7,9,15,16,19 and 20 changes 4- bromine nitre into Base benzene (1g) other conditions are constant.
According to example structure formula, step B) different aminoalkylated substituent groups is corresponded to, it is specifically Z substituent group (above-mentioned to be described).
Wherein embodiment 13-23, corresponding step D) in 0 DEG C of dropwises addition 1mL dry the diluted acryloyl chloride of DCM and change 0 DEG C of drop into Add the dry diluted crotonyl chloride of DCM of 1mL, other conditions are constant.
The above molar equivalent ratio is identical as the corresponding reaction equivalent of embodiment 1.
Then it can get following title compound, be shown in Table 2.MS in the table refers to measured value.
2 part of compounds structure of table and nuclear magnetic data
Embodiment 24
2- cyano-N- (3- (6- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) acetamide
Experimental procedure A), B), C) using method in the same manner as in Example 1, can get 6- (3- aminobenzene)-N4(1- first Base -1H- pyrazoles -4- base) -4- aminopyrimidine.
E) 2- cyano-N- (3- (6- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) acetamide
By 6- (3- aminobenzene)-N4(1- methyl-1 H- pyrazoles -4- base) -4- aminopyrimidine (0.12g), cyanoacetic acid (0.04g), DIEA (0.13g) and 15mL dry THF, 0 DEG C is added with stirring HATU (0.37g) and is stirred to react 30min, after go to It is stirred to react at room temperature.Reaction terminates, and ethyl acetate 20mL is added, and 10% aqueous citric acid solution is added and is saturated NaHCO3Aqueous solution Wash it is each organic phase mixes sample twice, through silica gel column chromatogram separating purification, can get title compound.
1H NMR (300MHz, DMSO) δ 8.66 (s, 1H), 8.33 (s, 1H), 8.02 (s, 1H), 7.73 (d, J=7.5Hz, 1H), 7.64 (d, J=7.1Hz, 1H), 7.53 (s, 1H), 7.47 (t, J=7.9Hz, 1H), 7.07 (s, 1H), 3.94 (s, 2H), 3.83 (s, 2H)
MS(ESI+): [M+H]+334.2。
Embodiment 25 to 32
In embodiment 25 to 32, the method as embodiment 24 is utilized.
Wherein 3- bromo nitrobenzene (1g) correspondence changes 4- bromo nitrobenzene into step A) in 26,27 and 30-32 of embodiment (1g) other conditions are constant.
According to example structure formula, step B) different aminoalkylated substituent groups is corresponded to, it is specifically Z substituent group (above-mentioned to be described).
The above molar equivalent ratio is identical as the corresponding reaction equivalent of embodiment 1.
Then it can get following title compound, be shown in Table 2.MS in the table refers to measured value.
2 part of compounds structure of table and nuclear magnetic data
Embodiment 33
N- [2- oxo -2- ((3- (6- (1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl)-benzene Base-amino) ethyl] acrylamide
Experimental procedure A), B), C) using method in the same manner as in Example 1, can get 6- (3- aminobenzene)-N4-(1-(2- Methoxy ethyl) -1H- pyrazoles -4- base) -4- aminopyrimidine.
F) 6- [3- (carbamic acid, N- (2- oxo -2- (phenyl amino) ethyl) -, 1,1- dimethyl ethyl ester)]-N4- (1- methyl-1 H- pyrazoles -4- base) -4- aminopyrimidine
At room temperature, 6- (3- aminobenzene)-N4(1- methyl-1 H- pyrazoles -4- base) -4- aminopyrimidine (0.2g) is dissolved in In 10mLDCM, EDCI (0.36g), HOBt (0.25g), DIEA (0.34g) is added, 0 DEG C is stirred to react 30min, and 6- (3- is added Aminobenzene)-N4(1- (2- methoxy ethyl) -1H- pyrazoles -4- base) -4- aminopyrimidine, after go to and be stirred to react 6h at room temperature. Reaction terminates, and DCM 20mL is added, and NaHCO is added3Aqueous solution is washed twice, and organic phase mixes sample, through silica gel column chromatogram separating purification, It can get title compound.
1H NMR (300MHz, CDCl3) δ 9.05 (s, 1H), 8.53 (s, 2H), 7.91 (s, 1H), 7.78 (s, 1H), 7.71- 7.58 (m, 1H), 7.55 (s, 1H), 7.50-7.40 (m, 1H), 7.30-7.15 (m, 1H), 6.74 (s, 1H), 6.04 (s, 1H), 4.24 (t, J=5.0Hz, 2H), 3.95 (s, 2H), 3.71 (t, J=4.9Hz, 2H), 3.29 (s, 3H), 1.40 (s, 9H)
G) 6- [3- (2- (amino) antifebrin)]-N4(1- (2- methoxy ethyl) -1H- pyrazoles -4- base) -4- pyrimidine Amine
6- [3- (carbamic acid, N- (2- oxo -2- (phenyl amino) ethyl) -, 1,1- dimethyl ethyl ester)]-N4-(1- Methyl-1 H- pyrazoles -4- base) -4- aminopyrimidine (0.5g) is dissolved in 2mLDCM, is cooled to 0 DEG C and is slowly added to TFA (2mL), room Temperature is stirred to react 5h.After reaction, it is dried under reduced pressure, ether mashing filters to obtain title compound.
MS(ESI+): [M+H]+368.2。
H) using with D in embodiment 1) or E) method equally for title compound.Molar equivalent is anti-with other Answer condition constant.
1H NMR (300MHz, DMSO) δ 8.83 (s, 1H), 8.57 (s, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 7.74 (d, J=15.0Hz, 2H), 7.63-7.53 (m, 2H), 7.49 (s, 1H), 6.33 (dd, J=15.2,8.2Hz, 1H), 6.12 (d, J=16.8Hz, 1H), 5.63 (d, J=8.9Hz, 1H), 4.28 (s, 2H), 4.04 (s, 2H), 3.68 (s, 2H), 3.23 (s, 3H).
MS(ESI+): [M+H]+422.2。
Embodiment 34 to 39
In embodiment 34 to 39, using the method as embodiment 33, it can get title compound, be shown in Table 3.The table In MS refer to measured value.
3 part of compounds structure of table and nuclear magnetic data
Embodiment 40: EXPERIMENTAL EXAMPLE (JAK-1 and JAK-3 enzyme inhibits test)
Experiment purpose:
Compound is evaluated to the inhibiting effect of JAK-1 and JAK-3 kinases.
Experimental principle:
It is more to specific phosphorylation and non-phosphorylating based on fluorescence resonance energy transfer technology (FRET) coupling protein hydrolase The different proteolysis of peptide substrates.Peptide substrate both ends are respectively labeled as FRET energy donor cumarin and energy acceptor is glimmering Light element, supplies, receptor is closer excited donor that energy transfer can occur at this time.
In kinase reaction (Kinase Reaction), γ-phosphoric acid in ATP can be transferred to more by JAK-1 or JAK-3 On the single tyrosine residue of peptide substrates, if γ-phosphate there are JAK-1 or JAK-3 inhibitor in system, on ATP Group will not be transferred in substrate polypeptide, and phosphorylation reaction cannot occur.The evaluation of kinase inhibitor is devised based on this principle Experiment, substrate polypeptide design have kinase phosphorylation sites, while being also protease cutting site, and both ends connect 2 kinds of fluorophors respectively, Respectively donor and receptor, if kinase activity is kept in reaction system, γ-phosphate group if, is transferred to the digestion position of substrate Point, to will not be cut by protease and be separated into two sections, under specific wavelength laser excitation, the energy of one section of fluorescence can be turned Move on to the fluorophor of the other end and emitted energy.Otherwise and enzymatic activity be suppressed after, phosphate group cannot be transferred, substrate Restriction enzyme site can be cut by the digestion in system, and substrate is separated into two sections, then the energy transfer of fluorescence will not occur.Based on this evaluation The activity of kinases.
Experimental procedure:
10 μ l kinase reaction system of this experimental selection, in JAK1 inhibitor screening, system kinase concentration containing JAK1 is 1ng/ μ 3.92 μM of l, ATP；In JAK2 inhibitor screening, 3.96 μM of l, ATP of JAK2 kinases 0.004ng/ μ；In JAK3 inhibitor screening, 1.43 μM of l, ATP of every system kinases containing JAK3 0.012ng/ μ.TK Substrate-biotin substrate is 1 μM, compound primary dcreening operation 10 μM of concentration.
(1) preparation of kinase reaction buffer
5 × Kinase of 1ml Buffer is added in 4ml distilled water and is diluted to 1 ×, 5 μ l 1M DTT and 25 μ l are added 1M MgCl2 is named as Kinase Buffer room temperature storage.
(2) compound configuration to be screened
Sample compound presses quality, is dissolved in DMSO, is made into the mother liquor that concentration is 100mM, is diluted with kinase reaction buffer With configuration compound, final concentration of 10 μM of the reaction of compound.
(3) reaction system
This experiment support plate is 384 hole micro plate of black, and reaction system is 10 μ l.
Fluorescence detection
Under 330nm excitation, the emissive porwer of 665nm and 620nm is detected.
Microplate reader calculates Ratio=665/620*10000 automatically
(5) data are analyzed
The inhibiting rate of each sample is calculated as follows
Inhibiting rate=(Ratio MAX-Ratio sample)/(Ratio MAX-Ratio NEG) * 100
4 experimental result of table
As the result is shown: multiple compounds show certain inhibiting effect to jak kinase
IC50Evaluation
To evaluating its IC after showing preferable active compound concentration doubling dilution50Value, as a result, it has been found that 5 chemical combination of embodiment Object shows the JAK-3 inhibiting effect (IC of high activity50=1.7nm), the selection activity (JAK-1/JAK-3=of moderate strength 586, JAK-2/JAK-3=60).

Claims (10)

1. a kind of substitution class phenyl pyrimidine derivative with logical formula (I) is as jak kinase inhibitor or its pharmaceutical salt:
Wherein,
X is nitrogen-atoms or-CH-；
Y is nitrogen-atoms or-CH-；
Z isSubstituted or unsubstituted C3-8Heterocyclic hydrocarbyl；
W is substituted 5 unit's heteroaryl；
R1It is
Wherein,
V is hydrogen atom, halogen or cyano；
R4、R5、R6And R7Respectively hydrogen atom, substituted or unsubstituted C1-6It is alkyl, substituted or unsubstituted C1-6Miscellaneous alkyl；
R2It is hydrogen atom, halogen atom, substituted or unsubstituted 4,5,6,7- or 8- circle heterocyclic ring；
R3It is substituted C1-6Alkyl, substituted or unsubstituted C1-6Miscellaneous alkyl.
2. the substitution class phenyl pyrimidine derivative with logical formula (I) according to claim 1 as jak kinase inhibitor or Its pharmaceutical salt, which is characterized in that
Z is
3. the substitution class phenyl pyrimidine derivative with logical formula (I) according to claim 2 as jak kinase inhibitor or Its pharmaceutical salt, which is characterized in that the R2It is hydrogen atom, fluorine atom, substitution or unsubstituted 4,5 or 6- member nitrogen-containing hetero Ring.
4. the substitution class phenyl pyrimidine derivative with logical formula (I) according to claim 2 as jak kinase inhibitor or Its pharmaceutical salt, which is characterized in that the W is nitrogenous five yuan of hetero-aromatic rings.
5. the substitution class phenyl pyrimidine derivative with logical formula (I) according to claim 2 as jak kinase inhibitor or Its pharmaceutical salt, which is characterized in that the R3It is methyl or substituted C1-6Alkyl, the C1-6The substituent group of alkyl is halogen Plain atom, hydroxyl, C1-6Alkoxy, fat amido, amide groups.
6. have according to claim 1 the substitution class phenyl pyrimidine derivative of logical formula (I) as jak kinase inhibitor or its Pharmaceutical salt is following any:
N- (3- (6- ((1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) acrylamide,
N- (3- (6- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) acrylamide,
N- (4- (6- ((1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) acrylamide,
N- (3- (2- ((1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) acrylamide,
N- (4- (2- ((1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) acrylamide,
N- (3- (6- (4- morpholine phenylamino) pyrimidine-4-yl) phenyl) acrylamide,
N- (4- (6- (4- morpholine phenylamino) pyrimidine-4-yl) phenyl) acrylamide,
N- (3- (2- (4- morpholine phenylamino) pyrimidine-4-yl) phenyl) acrylamide,
N- (4- (2- (4- morpholine phenylamino) pyrimidine-4-yl) phenyl) acrylamide,
N- (3- (6- ((1- (2-N, N- dimethyl ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) acrylamide,
N- (3- (6- ((1- (N- methylacetamide) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) acrylamide,
N- (3- (6- ((1- (2- hydroxyethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) acrylamide,
N- (3- (6- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) -2- crotonamide,
N- (3- (6- ((1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) -2- crotonamide,
N- (4- (6- ((1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) -2- crotonamide,
N- (4- (2- ((1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) -2- crotonamide,
N- (3- (6- (4- morpholine phenylamino) pyrimidine-4-yl) phenyl) -2- crotonamide,
N- (3- (2- (4- morpholine phenylamino) pyrimidine-4-yl) phenyl) -2- crotonamide,
N- (4- (6- (4- morpholine phenylamino) pyrimidine-4-yl) phenyl) -2- crotonamide,
N- (4- (2- (4- morpholine phenylamino) pyrimidine-4-yl) phenyl) -2- crotonamide,
N- (3- (6- ((1- (2-N, N- dimethyl ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) -2- crotonoyl Amine,
N- (3- (6- ((1- (N- methylacetamide) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) -2- crotonamide,
N- (3- (6- ((1-1- (2- hydroxyethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) -2- crotonamide,
N- (3- (6- ((1-1- (2- hydroxyethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) -2- crotonamide,
2- cyano-N- (3- (6- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) acetamide,
2- cyano-N- (3- (6- ((1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) acetyl Amine,
2- cyano-N- (4- (6- ((1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) acetyl Amine,
2- cyano-N- (4- (2- ((1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) acetyl Amine,
2- cyano-N- (3- (((6- (4- morpholine phenylamino) pyrimidine-4-yl) amino) methyl) phenyl) acetamide,
2- cyano-N- (3- (((2- (4- morpholine phenylamino) pyrimidine-4-yl) amino) methyl) phenyl) acetamide,
2- cyano-N- (4- (((6- (4- morpholine phenylamino) pyrimidine-4-yl) amino) methyl) phenyl) acetamide,
2- cyano-N- (4- (((2- (4- morpholine phenylamino) pyrimidine-4-yl) amino) methyl) phenyl) acetamide,
N- [2- oxo -2- ((3- (6- (1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl)-phenyl-ammonia Base) ethyl] acrylamide,
N- [2- oxo -2- ((3- (6- (1- (2- methoxy ethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl)-phenyl-ammonia Base) ethyl] crotonamide,
N- [2- oxo -2- ((3- (6- (4- morpholine phenylamino) amino) pyrimidine-4-yl)-phenyl-amino) ethyl] acrylamide,
N- [2- oxo -2- ((3- (6- (4- morpholine phenylamino) amino) pyrimidine-4-yl)-phenyl-amino) ethyl] crotonamide, 2- cyano-N- [2- oxo -2- ((3- (6- (1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl)-phenyl-amino) second Base] acetamide,
2- cyano-N- [2- oxo -2- ((3- (6- (4- morpholine phenylamino) amino) pyrimidine-4-yl)-phenyl-amino) ethyl] second Amide,
2- cyano-N- [2- oxo -2- ((3- (6- (1- (N- methylacetamide) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) - Phenyl-amino) ethyl] acetamide,
2- cyano-N- (4- (6- ((1-1- (2- hydroxyethyl) -1H- pyrazoles -4- base) amino) pyrimidine-4-yl) phenyl) acetyl Amine.
7. a kind of pharmaceutical composition, one or more as of any of claims 1-6 containing therapeutically effective amount Substitution class phenyl pyrimidine derivative with logical formula (I) is as jak kinase inhibitor or its pharmaceutical salt, and pharmaceutically may be used The carrier or auxiliary material of receiving.
8. the substitution class phenyl pyrimidine derivative with logical formula (I) described in claim 1 as jak kinase inhibitor or its can The preparation method of medicinal salt, includes the following steps:
Wherein,
Step 1: compound III and duplex pinacol borate make chemical combination under conditions of tetra-triphenylphosphine palladium and alkaline potassium acetate Object III is converted into compound IV；
Step 2: the chloro- pyrimidine of 2,4- or 4, the chloro- pyrimidine of 6-, tetra-triphenylphosphine palladium and potassium carbonate being added into the reaction solution of step 1 Aqueous solution carries out suziki reaction, obtains compound V；
Step 3: compound V is reacted with amine is replaced, and obtains compound VI；
Step 4: the reduction reaction of compound VI is converted into compound VII；
Step 5: compound VII and R1Replace reagent progress to react at amide, obtains the compounds of this invention.
9. the substitution class phenyl pyrimidine derivative with logical formula (I) described in any one of claims 1-6 inhibits as jak kinase Agent or its pharmaceutical salt preparation treatment autoimmune disease, siogren's syndrome, Behcet's disease, multiple sclerosis, Purposes in the drug of systemic loupus erythematosus.
10. purposes according to claim 9, the autoimmune disease is psoriasis, rheumatoid arthritis or inflammatory Intestinal disease.
CN201910653403.9A 2019-07-18 2019-07-18 Substituted phenyl pyrimidine derivative as JAK kinase inhibitor or pharmaceutically acceptable salt thereof, preparation method and application Active CN110330484B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201910653403.9A CN110330484B (en) 2019-07-18 2019-07-18 Substituted phenyl pyrimidine derivative as JAK kinase inhibitor or pharmaceutically acceptable salt thereof, preparation method and application

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910653403.9A CN110330484B (en) 2019-07-18 2019-07-18 Substituted phenyl pyrimidine derivative as JAK kinase inhibitor or pharmaceutically acceptable salt thereof, preparation method and application

Publications (2)

Publication Number Publication Date
CN110330484A true CN110330484A (en) 2019-10-15
CN110330484B CN110330484B (en) 2022-08-26

Family

ID=68145173

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910653403.9A Active CN110330484B (en) 2019-07-18 2019-07-18 Substituted phenyl pyrimidine derivative as JAK kinase inhibitor or pharmaceutically acceptable salt thereof, preparation method and application

Country Status (1)

Country Link
CN (1) CN110330484B (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110627775A (en) * 2019-10-24 2019-12-31 嘉兴特科罗生物科技有限公司 Small molecule compound
CN110862380A (en) * 2019-10-24 2020-03-06 嘉兴特科罗生物科技有限公司 Small molecule compound
WO2020119819A1 (en) * 2018-12-14 2020-06-18 Lynk Pharmaceuticals Co. Ltd. Benzamides of pyrazolyl-amino-pyrimidinyl derivatives, and compositions and methods thereof
CN115124471A (en) * 2021-03-24 2022-09-30 中国工程物理研究院化工材料研究所 Pyrazole ring explosive with high-energy and low-melting-point characteristics and synthesis method thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004041789A1 (en) * 2002-11-01 2004-05-21 Vertex Pharmaceuticals Incorporated Compositions useful as inhibitors of jak and other protein kinases
WO2008124085A2 (en) * 2007-04-03 2008-10-16 Exelixis, Inc. Methods of using combinations of mek and jak-2 inhibitors
CN102791697A (en) * 2009-10-12 2012-11-21 瑞科西有限公司 Amino-pyrimidine compounds as inhibitors of TBKL and/or IKK epsilon
CN103298794A (en) * 2010-11-09 2013-09-11 塞尔卓姆有限公司 Pyridine compounds and aza analogues thereof as TYK2 inhibitors
CN104030990A (en) * 2007-03-12 2014-09-10 Ym生物科学澳大利亚私人有限公司 Phenyl amino pyrimidine compounds and uses thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004041789A1 (en) * 2002-11-01 2004-05-21 Vertex Pharmaceuticals Incorporated Compositions useful as inhibitors of jak and other protein kinases
CN104030990A (en) * 2007-03-12 2014-09-10 Ym生物科学澳大利亚私人有限公司 Phenyl amino pyrimidine compounds and uses thereof
WO2008124085A2 (en) * 2007-04-03 2008-10-16 Exelixis, Inc. Methods of using combinations of mek and jak-2 inhibitors
CN102791697A (en) * 2009-10-12 2012-11-21 瑞科西有限公司 Amino-pyrimidine compounds as inhibitors of TBKL and/or IKK epsilon
CN103298794A (en) * 2010-11-09 2013-09-11 塞尔卓姆有限公司 Pyridine compounds and aza analogues thereof as TYK2 inhibitors

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DENNIS BENSINGER等: "Virtual Screening Identifies Irreversible FMS-like Tyrosine Kinase 3 Inhibitors with Activity toward Resistance-Conferring Mutations", 《JOURNAL OF MEDICINAL CHEMISTRY》 *
LI TAN等: "Development of Selective Covalent Janus Kinase 3 Inhibitors", 《JOURNAL OF MEDICINAL CHEMISTRY》 *
TIMOTHY FORSYTH等: "SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
YU-YI CHU-FARSEEVA等: "Design and synthesis of potent dual inhibitors of JAK2 and HDAC based on fusing the pharmacophores of XL019 and vorinostat", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020119819A1 (en) * 2018-12-14 2020-06-18 Lynk Pharmaceuticals Co. Ltd. Benzamides of pyrazolyl-amino-pyrimidinyl derivatives, and compositions and methods thereof
US20240025882A1 (en) * 2018-12-14 2024-01-25 Lynk Pharmaceuticals Co. Ltd. Benzamides of pyrazolylamino- pyrimidinyl derivatives, and compositions and methods thereof
CN110627775A (en) * 2019-10-24 2019-12-31 嘉兴特科罗生物科技有限公司 Small molecule compound
CN110862380A (en) * 2019-10-24 2020-03-06 嘉兴特科罗生物科技有限公司 Small molecule compound
WO2021078023A1 (en) * 2019-10-24 2021-04-29 嘉兴特科罗生物科技有限公司 Small molecule compound
WO2021078022A1 (en) * 2019-10-24 2021-04-29 嘉兴特科罗生物科技有限公司 Small molecule compound
JP2022553765A (en) * 2019-10-24 2022-12-26 嘉興特科羅生物科技有限公司 small molecule compound
JP7397187B2 (en) 2019-10-24 2023-12-12 特科▲羅▼生物科技（成都）有限公司 small molecule compound
CN115124471A (en) * 2021-03-24 2022-09-30 中国工程物理研究院化工材料研究所 Pyrazole ring explosive with high-energy and low-melting-point characteristics and synthesis method thereof
CN115124471B (en) * 2021-03-24 2024-02-13 中国工程物理研究院化工材料研究所 Pyrazole ring explosive with high energy and low melting point characteristics and synthesis method thereof

Also Published As

Publication number Publication date
CN110330484B (en) 2022-08-26

Similar Documents

Publication Publication Date Title
CN110330484A (en) Replace class phenyl pyrimidine derivative as jak kinase inhibitor or its pharmaceutical salt, Preparation method and use
KR101826015B1 (en) Pyrimidine fgfr4 inhibitors
Breitenlechner et al. Structure-based optimization of novel azepane derivatives as PKB inhibitors
CN106573001B (en) Amino pyridazine ketone compound as kinases inhibitor
AU2004279427B2 (en) Compounds and compositions as protein kinase inhibitors
CN103965120A (en) Quinoline and quinazoline derivative, preparation method, intermediate, composition and application
JP2019520330A (en) Benzazepine dicarboxamide compounds having a secondary amide group
EP2663553B1 (en) Quinoline and isoquinoline derivatives for use as jak modulators
CN100354271C (en) Piperazine derivatives and process for the preparation thereof
EP4050009A1 (en) Small molecule compound
JP2009502843A (en) Azabenzimidazole derivatives, their production and use as anticancer agents
CN102250022B (en) Substituted quinoxalinamine compounds, and preparation method and application thereof
KR20200056652A (en) Novel compound as a protein kinase inhibitor, and the pharmaceutical composition comprising thereof
CN114105976B (en) Selective ROCK2 kinase inhibitors
WO2023040537A1 (en) Aminopyrimidine derivative, preparation method therefor and use thereof
Kalesh et al. Rapid synthesis of Abelson tyrosine kinase inhibitors using click chemistry
EP2870139B1 (en) Novel adamantyl derivatives as cannabinoid receptor 2 agonists
CN117024445A (en) Compounds for preparing HPK1 kinase inhibitor and synthesis method thereof
Im et al. Rational design and synthesis of 2-(1 H-indazol-6-yl)-1 H-benzo [d] imidazole derivatives as inhibitors targeting FMS-like tyrosine kinase 3 (FLT3) and its mutants
CN102260266B (en) Pyrazolo[3,4-d]pyrimidone compounds and application thereof in preparation of phosphodiesterase IX inhibitor
Li et al. Design, synthesis and antitumor evaluation of a new series of N‐substituted‐thiourea derivatives 1
CN102558172B (en) 5,8-bis-replaces-1,6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof, Preparation Method And The Use
CN105646371B (en) The 2,4- diaryl-amine yl pyrimidines analog derivative of the segment containing hydroxamic acid and preparation and application
Mazurov Solid phase synthesis of 5, 6, 7, 8-tetrahydro-1H-imidazo [4, 5-g] quinoxalin-6-ones
CN113956233B (en) Amide compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant