CN110330484B - Substituted phenyl pyrimidine derivative as JAK kinase inhibitor or pharmaceutically acceptable salt thereof, preparation method and application - Google Patents
Substituted phenyl pyrimidine derivative as JAK kinase inhibitor or pharmaceutically acceptable salt thereof, preparation method and application Download PDFInfo
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- CN110330484B CN110330484B CN201910653403.9A CN201910653403A CN110330484B CN 110330484 B CN110330484 B CN 110330484B CN 201910653403 A CN201910653403 A CN 201910653403A CN 110330484 B CN110330484 B CN 110330484B
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- Prior art keywords
- jak
- phenyl
- pyrimidin
- amino
- pyrazol
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- 108091082332 JAK family Proteins 0.000 title abstract description 21
- 229940043355 kinase inhibitor Drugs 0.000 title abstract description 14
- 239000003757 phosphotransferase inhibitor Substances 0.000 title abstract description 14
- 150000003839 salts Chemical class 0.000 title abstract description 14
- OXPDQFOKSZYEMJ-UHFFFAOYSA-N 2-phenylpyrimidine Chemical class C1=CC=CC=C1C1=NC=CC=N1 OXPDQFOKSZYEMJ-UHFFFAOYSA-N 0.000 title abstract description 12
- 238000002360 preparation method Methods 0.000 title abstract description 11
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- -1 N- (3- (2- (4-morpholinophenylamino) pyrimidin-4-yl) phenyl) -2-butenamide Chemical compound 0.000 claims description 27
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- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
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- HSCOLDQJZRZQMV-UHFFFAOYSA-N 1-Methyl-4-nitroimidazole Chemical compound CN1C=NC([N+]([O-])=O)=C1 HSCOLDQJZRZQMV-UHFFFAOYSA-N 0.000 description 2
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- IAJDSUYFELYZCS-UHFFFAOYSA-N 4-(4-nitrophenyl)morpholine Chemical compound C1=CC([N+](=O)[O-])=CC=C1N1CCOCC1 IAJDSUYFELYZCS-UHFFFAOYSA-N 0.000 description 2
- XOSNCCCAIJCCFS-UHFFFAOYSA-N 4-chloro-6-(3-nitrophenyl)pyrimidine Chemical compound [O-][N+](=O)C1=CC=CC(C=2N=CN=C(Cl)C=2)=C1 XOSNCCCAIJCCFS-UHFFFAOYSA-N 0.000 description 2
- DBPKMSBWOKAKLA-UHFFFAOYSA-N 4-chloropyrimidine Chemical compound ClC1=CC=NC=N1 DBPKMSBWOKAKLA-UHFFFAOYSA-N 0.000 description 2
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- BCSRMXDDIRDZEP-UHFFFAOYSA-N N-[3-[6-[[1-(2-hydroxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]phenyl]prop-2-enamide Chemical compound C(C=C)(=O)NC1=CC(=CC=C1)C1=NC=NC(=C1)NC=1C=NN(C=1)CCO BCSRMXDDIRDZEP-UHFFFAOYSA-N 0.000 description 1
- UXJWKEBWYYWGQW-UHFFFAOYSA-N N-[4-[2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]phenyl]prop-2-enamide Chemical compound O1CCN(CC1)C1=CC=C(C=C1)NC1=NC=CC(=N1)C1=CC=C(C=C1)NC(C=C)=O UXJWKEBWYYWGQW-UHFFFAOYSA-N 0.000 description 1
- CKHJIDHRSXTJER-UHFFFAOYSA-N N-[4-[2-[[1-(2-methoxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]phenyl]prop-2-enamide Chemical compound C(C=C)(=O)NC1=CC=C(C=C1)C1=NC(=NC=C1)NC=1C=NN(C=1)CCOC CKHJIDHRSXTJER-UHFFFAOYSA-N 0.000 description 1
- GDLPWJVKIULAIP-UHFFFAOYSA-N N-[4-[6-(4-morpholin-4-ylanilino)pyrimidin-4-yl]phenyl]prop-2-enamide Chemical compound O1CCN(CC1)C1=CC=C(C=C1)NC1=CC(=NC=N1)C1=CC=C(C=C1)NC(C=C)=O GDLPWJVKIULAIP-UHFFFAOYSA-N 0.000 description 1
- MVKOIQROLYNKGI-UHFFFAOYSA-N N-[4-[6-[[1-(2-methoxyethyl)pyrazol-4-yl]amino]pyrimidin-4-yl]phenyl]prop-2-enamide Chemical compound C(C=C)(=O)NC1=CC=C(C=C1)C1=NC=NC(=C1)NC=1C=NN(C=1)CCOC MVKOIQROLYNKGI-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 241000219061 Rheum Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 102100038803 Somatotropin Human genes 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
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- 230000006907 apoptotic process Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- SGCLBIRCSTXTIU-UHFFFAOYSA-N boric acid;2,3-dimethylbutane-2,3-diol Chemical compound OB(O)O.CC(C)(O)C(C)(C)O.CC(C)(O)C(C)(C)O SGCLBIRCSTXTIU-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960000956 coumarin Drugs 0.000 description 1
- 235000001671 coumarin Nutrition 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000010250 cytokine signaling pathway Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 238000001917 fluorescence detection Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000007365 immunoregulation Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 108010074108 interleukin-21 Proteins 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000000752 ionisation method Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
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- 239000010452 phosphate Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 102000042286 type I cytokine receptor family Human genes 0.000 description 1
- 108091052247 type I cytokine receptor family Proteins 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- WCJYTPVNMWIZCG-UHFFFAOYSA-N xylylcarb Chemical compound CNC(=O)OC1=CC=C(C)C(C)=C1 WCJYTPVNMWIZCG-UHFFFAOYSA-N 0.000 description 1
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- 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
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- 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
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Abstract
The invention discloses a substituted phenyl pyrimidine derivative with a general formula (I) as a JAK kinase inhibitor or a pharmaceutically acceptable salt thereof, a preparation method and application thereof. The compound has an excellent JAK inhibitory action and is useful as a medicament for preventing, treating or ameliorating autoimmune diseases, Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus or the like. The compounds of the invention exhibit highly active JAK-3 inhibitory IC 50 Can reach 1.7nM, the invention has simple synthetic route and strong practicability.
Description
Technical Field
The invention relates to a kinase inhibitor, a preparation method and application thereof, in particular to a substituted phenyl pyrimidine derivative serving as a JAK kinase inhibitor or pharmaceutically acceptable salt thereof, a preparation method and application thereof.
Background
There are four subtypes of JAK kinases (janus kinases): JAK-1, JAK-2, JAK-3 and TYK-2, which form an important cytokine signaling pathway with downstream effector, signal transducers and activators of transcription proteins (STATs), JAK-STAT pathway (Science, 1994, 264: 1415-. The discovery of the pathway greatly improves the knowledge of researchers on gene regulation, and the researches discover that the JAK-STAT pathway can be activated by various cytokines, growth factors and receptors and participates in the processes of cell proliferation, differentiation, apoptosis, angiogenesis, immunoregulation and the like (World J Gastroenterol, 2007, 13: 6478-. JAK kinases mediate the signaling of most cytokines within cells, such as Interleukins (ILs), Interferons (IFNs), Erythropoietin (EPO), Granulocyte and Macrophage Colony Stimulating Factor (GMCSF), somatotropin (GH), Prolactin (PRL), Thrombopoietin (TPO), platelet derived factor (PDGF), and Epidermal Growth Factor (EGF), among others, and different receptors activate different subtypes of JAK kinases.
Among them, JAK-3 regulates cell signaling by binding to the gamma chain (yc) in the type I cytokine receptor complex such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. When JAK-3 is deficient or gammac mutated, Severe Combined Immunodeficiency (SCID) can result, manifested by immune-restricted symptoms such as T-cell and Natural Killer (NK) cell depletion, B-cell loss of function, and the like. When present in suitable amounts, these cytokines play an important role in the immune response. However, their overproduction is thought to be associated with a number of autoimmune diseases, such as psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus and the like (Journal of Allergy and clinical Tmmurmogy 127, 3, 701-721.e70(2011), Cytoki ne & Growth Factor Reviews19, 41-52(2008), Invest Ophthalmol Vis Sci.2008Jul; 49 (7): 3058 3064, Ann Rheum Dis.2010Jul; 69 (7): 1325) 1328). In addition, JAK-1, JAK-2 and TYK-2 are widely present in various tissues and cells in vivo, JAK3 is mainly present in bone marrow cells, thymocytes, NK cells, activated B lymphocytes and T lymphocytes, and JAK-3 is a well-known, safe and effective anti-autoimmune target in a JAK-STAT pathway.
How to inhibit the combination of ATP and ATP binding sites on JAK, block the hydrolysis of ATP, interfere the phosphorylation of JAKs, thereby preventing the activation of JAKs, cutting off signals transmitted to STATs, and leading the expression of genes in nuclei to be incapable of being regulated, thereby blocking a JAK-STAT signal passage is the key point of research.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a substituted phenyl pyrimidine derivative as a JAK kinase inhibitor or a pharmaceutically acceptable salt thereof.
The invention also aims to provide a preparation method of the substituted phenyl pyrimidine derivative as a JAK kinase inhibitor or a pharmaceutically acceptable salt thereof.
A final object of the invention is to provide the use of said substituted phenylpyrimidine derivatives as JAK kinase inhibitors or pharmaceutically acceptable salts thereof.
The technical scheme is as follows: the invention provides a substituted phenyl pyrimidine derivative with a general formula (I) as a JAK kinase inhibitor or a pharmaceutically acceptable salt thereof,
wherein,
x is a nitrogen atom or-CH-;
y is a nitrogen atom or-CH-;
z is
Substituted or unsubstituted C 3-8 A heterocyclic hydrocarbon group;
w is substituted 5-membered heteroaryl;
R 1 is that
Wherein,
v is a hydrogen atom, a halogen atom or a cyano group;
R 4 、R 5 、R 6 and R 7 Each is a hydrogen atom, substituted or unsubstituted C 1-6 Hydrocarbyl, substituted or unsubstituted C 1-6 A heterohydrocarbyl group;
R 2 is a hydrogen atom, a halogen atom, a substituted or unsubstituted 4, 5, 6, 7-or 8-membered heterocyclic ring;
R 3 is substituted C 1-6 Hydrocarbyl, substituted or unsubstituted C 1-6 A heterohydrocarbyl group.
Further, the
Z is
Further, said R 2 Is a hydrogen atom, a fluorine atom, a substituted or unsubstituted 4-, 5-or 6-membered nitrogen-containing heterocyclic ring. W is a nitrogen-containing five-membered heteroaromatic ring. Said R is 3 Is methyl or substituted C 1-6 Alkyl radical, said C 1-6 Alkyl radicalThe substituent is halogen atom, hydroxyl, C 1-6 Alkoxy, fatty amino, amide.
Further, the substituted phenyl pyrimidine derivatives with the general formula (I) are used as JAK kinase inhibitors or pharmaceutically acceptable salts thereof,
n- (3- (6- ((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acrylamide,
N- (3- (6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acrylamide,
N- (4- (6- ((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acrylamide,
N- (3- (2- ((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acrylamide,
N- (4- (2- ((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acrylamide,
N- (3- (6- (4-morpholinylphenylamino) pyrimidin-4-yl) phenyl) acrylamide,
N- (4- (6- (4-morpholinylphenylamino) pyrimidin-4-yl) phenyl) acrylamide,
N- (3- (2- (4-morpholinylphenylamino) pyrimidin-4-yl) phenyl) acrylamide,
N- (4- (2- (4-morpholinylphenylamino) pyrimidin-4-yl) phenyl) acrylamide,
N- (3- (6- ((1- (2-N, N-dimethylethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acrylamide,
N- (3- (6- ((1- (N-methylacetamide) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acrylamide,
N- (3- (6- ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acrylamide,
N- (3- (6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) -2-butenamide,
N- (3- (6- ((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) -2-butenamide,
N- (4- (6- ((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) -2-butenamide,
N- (4- (2- ((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) -2-butenamide,
N- (3- (6- (4-morpholinylphenylamino) pyrimidin-4-yl) phenyl) -2-butenamide,
N- (3- (2- (4-morpholinylphenylamino) pyrimidin-4-yl) phenyl) -2-butenamide,
N- (4- (6- (4-morpholinylphenylamino) pyrimidin-4-yl) phenyl) -2-butenamide,
N- (4- (2- (4-morpholinylphenylamino) pyrimidin-4-yl) phenyl) -2-butenamide,
N- (3- (6- ((1- (2-N, N-dimethylethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) -2-butenamide,
N- (3- (6- ((1- (N-methylacetamide) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) -2-butenamide,
N- (3- (6- ((1-1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) -2-butenamide,
2-cyano-N- (3- (6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acetamide,
2-cyano-N- (3- (6- ((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acetamide,
2-cyano-N- (4- (6- ((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acetamide,
2-cyano-N- (4- (2- ((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acetamide,
2-cyano-N- (3- (((6- (4-morpholinylphenylamino) pyrimidin-4-yl) amino) methyl) phenyl) acetamide,
2-cyano-N- (3- (((2- (4-morpholinylphenylamino) pyrimidin-4-yl) amino) methyl) phenyl) acetamide,
2-cyano-N- (4- (((6- (4-morpholinylphenylamino) pyrimidin-4-yl) amino) methyl) phenyl) acetamide,
2-cyano-N- (4- (((2- (4-morpholinylphenylamino) pyrimidin-4-yl) amino) methyl) phenyl) acetamide,
N- [ 2-oxo-2- ((3- (6- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -phenyl-amino) ethyl ] acrylamide,
N- [ 2-oxo-2- ((3- (6- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -phenyl-amino) ethyl ] butenamide,
N- [ 2-oxo-2- ((3- (6- (4-morpholinylphenylamino) amino) pyrimidin-4-yl) -phenyl-amino) ethyl ] acrylamide,
N- [ 2-oxo-2- ((3- (6- (4-morpholinylphenylamino) amino) pyrimidin-4-yl) -phenyl-amino) ethyl ] butenamide,
2-cyano-N- [ 2-oxo-2- ((3- (6- (1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -phenyl-amino) ethyl ] acetamide,
2-cyano-N- [ 2-oxo-2- ((3- (6- (4-morpholinylphenylamino) amino) pyrimidin-4-yl) -phenyl-amino) ethyl ] acetamide,
2-cyano-N- [ 2-oxo-2- ((3- (6- (1- (N-methylacetamide) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -phenyl-amino) ethyl ] acetamide,
2-cyano-N- (4- (6- ((1-1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acetamide.
A pharmaceutical composition comprising a therapeutically effective amount of one or more substituted phenylpyrimidine derivatives of general formula (I) according to any one of claims 1 to 6 as a JAK kinase inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or adjuvant.
The preparation method of the substituted phenyl pyrimidine derivative with the general formula (I) as a JAK kinase inhibitor or a pharmaceutically acceptable salt thereof comprises the following steps:
wherein,
step 1: converting the compound III into a compound IV with the compound III and the bis-pinacol borate under the conditions of palladium tetratriphenylphosphine and alkaline potassium acetate;
step 2: adding 2, 4-chloro-pyrimidine or 4, 6-chloro-pyrimidine, palladium tetratriphenylphosphine and potassium carbonate aqueous solution into the reaction solution obtained in the step (1) to carry out suziki reaction to obtain a compound V;
and step 3: reacting the compound v with substituted amine to obtain a compound VI;
and 4, step 4: the compound VI is subjected to reduction reaction and converted into a compound VII;
and 5: compounds VII and R 1 The substitution reagent is subjected to amide-forming reaction to obtain the compound of the invention.
The substituted phenyl pyrimidine derivative with the general formula (I) is used as a JAK kinase inhibitor or a medicinal salt thereof in preparation of medicines for treating autoimmune diseases, Sjogren's syndrome, Behcet's disease, multiple sclerosis and systemic lupus erythematosus.
Further, the autoimmune disease is psoriasis, rheumatoid arthritis or inflammatory bowel disease.
The JAK inhibitor with high activity and selectivity developed by the invention or the pharmaceutically acceptable salt thereof competitively inhibits the combination of ATP and ATP binding sites on JAK, blocks the hydrolysis of ATP and interferes the phosphorylation process of JAKs, thereby preventing the activation of JAKs and cutting off the signal transmission to STATs, so that the JAKs inhibitor can not regulate the expression of genes in nuclei, and the aim of blocking a JAK-STAT signal channel is fulfilled.
Has the beneficial effects that: the compound of the present invention has an excellent JAK-1 and/or JAK-3 inhibitory action and is useful as a medicament for preventing, treating or ameliorating autoimmune diseases (e.g., psoriasis, rheumatoid arthritis, inflammatory bowel diseases (e.g., Crohn's disease, ulcerative colitis, etc.), Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, etc.), etc., and the compound of example 5 exhibits a JAK-3 inhibitory action (IC) of high activity 50 1.7nm), medium-strength selective activity (JAK-1/JAK-3 586, JAK-2/JAK-3 60), the synthetic route of the invention is simple and the implementation is strong.
Detailed Description
In the following examples, "room temperature" means about 10 ℃ to about 35 ℃. The proportions indicated by the mixed solvents are volume mixing proportions unless otherwise specified. Unless otherwise specified,% means wt%.
In silica gel column chromatography, basic silica gel refers to silica gel bound using aminopropylsilane. In high performance liquid chromatography (HP1C), C18 refers to the use of octadecyl coupled silica gel. The ratio of elution solvents is a volume mixing ratio unless otherwise specified.
In the following examples and experimental examples, the following abbreviations are used.
THF: the reaction mixture of tetrahydrofuran and tetrahydrofuran is prepared by reacting tetrahydrofuran,
HATU: 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate,
DIEA: n, N-diisopropylethylamine
M: molar concentration.
Determination by Fourier transform type NMR 1 H-NMR (proton nuclear magnetic resonance spectrum). For the analysis, ACD/SpecMarager, etc. were used. The peaks of very light protons (e.g. hydroxyl, amino, etc.) are not described.
MS (Mass Spectrometry) was determined by 1C/MS (liquid chromatography Mass Spectrometry). As the ionization method, ESI (electrospray ionization) method or the like is used. The data represent those measured values. Typically, molecular ion peaks are observed. In the case of salts, a molecular ion peak or fragment ion peak is usually observed in free form.
The following structural formula of partial Z substituent and preparation method are as follows:
(1) n-methyl-4-aminoimidazole
4-nitroimidazole (1.41g), potassium carbonate (2.5g), methyl iodide (1.9g) and 20mL of acetonitrile were reacted under reflux for 12 h. Spin-drying under reduced pressure, adding 50mL water, extracting with 50mL ethyl acetate for 3 times, mixing organic layers, washing with saturated saline, adding anhydrous Na into organic phase 2 SO 4 Drying, drying under reduced pressure to obtain 1-methyl-4-nitroimidazole (1.5 g).
1-methyl-4-nitroimidazole (1g), Pd/C (0.1g) and 20ml ethanol were reacted at room temperature for about 24 hours while replacing the air with a hydrogen balloon. Suction filtration over celite was carried out under reduced pressure and the filtrate was dried under reduced pressure to give the title product (0.75 g).
MS(ESI + )：[M+H] + 98.0。
(2)1- (2-methoxyethyl) -1H-pyrazol-4-amine
The title compound was obtained from 4-nitropyrazole, 2-bromomethylethyl ether, Pd/C using the same method as in reference example 1.
MS(ESI + )：[M+H] + 142.0。
(3)2- (4-amino-1H-pyrazol-1-yl) ethanol
The title compound was obtained from 4-nitropyrazole, 2-bromoethanol, Pd/C using the same method as in reference example 1.
MS(ESI + )：[M+H] + 128.0。
(4) N, N-dimethyl-2- (4-amino-1H-pyrazol-1-yl) ethylamin
The title compound was obtained from 4-nitropyrazole, N-dimethyl-2-bromo-ethylammonium, Pd/C using the same method as in reference example 1.
MS(ESI + )：[M+H] + 154.1。
(5) N-methyl-2- (4-amino-1H-pyrazol-1-yl) acetamide
The title compound was obtained from 4-nitropyrazole, N-methyl-2-bromo-acetamide, Pd/C using the same method as in reference example 1.
MS(ESI + )：[M+H] + 154.0。
(6)4- (4-morpholinyl) aniline
4-Fluoronitrobenzene (1g), K 2 CO 3 (1.1g) and 5mL DMSO are stirred and reacted for 30min at room temperature, morpholine (0.6g) is added dropwise, the mixture is heated to 120 ℃ and stirred and reacted for 2h, the mixture is poured into 20mL of mixed solution of alcohol and water (1: 1), and yellow precipitate is filtered to obtain 1.4g of 4- (4-nitrophenyl) morpholine. 4- (4-Nitrophenyl) morpholine (1g), Pd/C (0.1g) and 20ml ethanol were reacted at room temperature for about 24 hours under a hydrogen balloon with air replaced. Suction filtration over celite under reduced pressure and drying of the filtrate under reduced pressure gave the title product (0.85 g). MS (ESI) + )：[M+H] + 179.1。
The following are some of the compounds of the present application:
example 1
N- (3- (6- ((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acrylamide
A) 4-chloro-6- (3-nitrophenyl) pyrimidine
To 3-bromonitrobenzene (1g) and 50mL of anhydrous 1, 4 dioxane, at room temperature, were added bis-pinacolato borate (1.34g) and KOAc (1.48g) over Pd (PPh) catalyst 3 ) 4 (3%) and reacting for 12h at 100 ℃ under the anaerobic condition. Cooled to room temperature, and 4, 6-dichloropyrimidine (1.07g), 2M K were added to the mixture 2 CO 3 Aqueous solution and Pd (PPh) 3 ) 4 (3%) heating to 100 deg.C to ensure anaerobic condition to continue reaction for 12 h. Cooled to room temperature, filtered through celite, dried under reduced pressure, and purified by silica gel column chromatography to give the title compound (0.93 g).
1 H NMR(300MHz，CDCl 3 )δ9.11(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) -N 4 - (1- (2-methoxyethyl) -1H-pyrazol-4-yl) -4-aminopyrimidine
To 4-chloro-6- (3-nitrophenyl) pyrimidine (0.3g) and 10mL of isopropanol were added 1- (2-methoxyethyl) -1H-pyrazol-4-amine (0.24g) and DIEA (0.41g) at room temperature, and the mixture was reacted under reflux for 6 hours, cooled to room temperature, and a precipitate was precipitated, which was filtered with suction and washed to give the title compound.
1 H NMR(300MHz，CDCl3)δ8.74(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-aminophenyl) -N 4 - (1- (2-methoxyethyl) -1H-pyrazol-4-yl) -4-aminopyrimidine
Adding 4-chloro-6- (3-nitrobenzene) -N into a reaction bottle 4 - (1- (2-methoxyethyl) -1H-pyrazol-4-yl) -4-aminopyrimidine (0.2g), 0.02g Pd/C, and 20mL EtOH, N 2 Heating to reflux under protection, slowly dropwise adding 85% hydrazine hydrate (0.32g) within 30min, reacting after dropwise adding, filtering, and drying the filtrate under reduced pressure to obtain the title compound.
MS(ESI + )：[M+H] + 311.2
D) N- (3- (6- ((1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acrylamide
Adding 6- (3-aminobenzene) -N into a reaction bottle 4 - (1- (2-methoxyethyl) -1H-pyrazol-4-yl) -4-aminopyrimidine (0.04g), 10mL of dry DCM, 1mL of acryloyl chloride diluted with dry DCM was added dropwise at 0 deg.C, stirred for 30min, and filtered with suction to give the title compound.
1 H NMR(300MHz，DMSO)δ8.69(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]+.
Examples 2 to 23
In examples 2 to 23, the same method as in example 1 was used.
In which the other conditions in examples 3, 5, 7, 9, 15, 16, 19 and 20 were unchanged, with the 3-bromonitrobenzene (1g) being exchanged for 4-bromonitrobenzene (1g) in step A).
According to the formula of the examples, step B) corresponds to different aminoalkylated substituents, in particular the Z substituent (described above).
In examples 13 to 23, acryloyl chloride diluted with 1mL of dry DCM was added dropwise at 0 ℃ instead of 0 ℃ in step D), and crotonyl chloride diluted with 1mL of dry DCM was added dropwise without changing other conditions.
The molar equivalent ratio is the same as the reaction equivalent corresponding to example 1.
The following title compounds were then obtained, see table 1. The MS in the table is an observed value.
Table 1 partial compound structure and nuclear magnetic data
Example 24
2-cyano-N- (3- (6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acetamide
Experimental Steps A), B) and C) Using the same procedure as in example 1, 6- (3-aminophenyl) -N) was obtained 4 - (1-methyl-1H-pyrazol-4-yl) -4-aminopyrimidine.
E) 2-cyano-N- (3- (6- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) phenyl) acetamide
Reacting 6- (3-aminobenzene) -N 4 - (1-methyl-1H-pyrazol-4-yl) -4-aminopyrimidine (0.12 g), cyanoacetic acid (0.04g), DIEA (0.13g) and 15mL of dry THF were added to HATU (0.37g) with stirring at 0 ℃ and reacted for 30min, and then the mixture was stirred at room temperature. After the reaction, 20mL of ethyl acetate was added, and then saturated NaHCO was added, 10% aqueous citric acid solution 3 The title compound was obtained by washing twice each with aqueous solution, mixing the samples with organic phase, and separating and purifying by silica gel column chromatography.
1 H NMR(300MHz，DMSO)δ8.66(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。
Examples 25 to 32
In examples 25 to 32, the same method as in example 24 was used.
In examples 26, 27 and 30 to 32, the other conditions were unchanged, with the 3-bromonitrobenzene (1g) being exchanged for 4-bromonitrobenzene (1g) in step A).
According to the formula of the examples, step B) corresponds to different aminoalkylated substituents, in particular the Z substituent (described above).
The molar equivalent ratio is the same as the reaction equivalent corresponding to example 1.
The following title compounds were then obtained, see table 2. The MS in the table is an observed value.
Table 2 partial compound structure and nuclear magnetic data
Example 33
N- [ 2-oxo-2- ((3- (6- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -phenyl-amino) ethyl ] acrylamide
Experimental Steps A), B) and C) Using the same procedure as in example 1, 6- (3-aminophenyl) -N) was obtained 4 - (1- (2-methoxyethyl) -1H-pyrazol-4-yl) -4-aminopyrimidine.
F)6- [3- (carbamic acid, N- (2-oxo-2- (phenylamino) ethyl) -, 1, 1-dimethylethyl ester)]-N 4 - (1-methyl-1H-pyrazol-4-yl) -4-aminopyrimidines
At room temperature, 6- (3-aminophenyl) -N 4 - (1-methyl-1H-pyrazol-4-yl) -4-aminopyrimidine (0.2g) was dissolved in 10ml of EDCM, EDCI (0.36g), HOBt (0.25g) and DIEA (0.34g) were added thereto, the mixture was stirred at 0 ℃ for reaction for 30min, and 6- (3-aminobenzene) -N was added thereto 4 - (1- (2-methoxyethyl) -1H-pyri-dineAnd (3) transferring the mixture to room temperature, and stirring for reaction for 6 hours. After the reaction is finished, 20mL of DCM is added, and NaHCO is added 3 The title compound can be obtained by washing twice with aqueous solution, mixing the organic phase with the sample, and separating and purifying by silica gel column chromatography.
1 H NMR(300MHz，CDCl 3 )δ9.05(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) acetanilide)]-N 4 - (1- (2-methoxyethyl) -1H-pyrazol-4-yl) -4-pyrimidinamine
6- [3- (carbamic acid, N- (2-oxo-2- (phenylamino) ethyl) -, 1, 1-dimethylethyl ester)]-N 4 - (1-methyl-1H-pyrazol-4-yl) -4-aminopyrimidine (0.5g) was dissolved in 2mL of EDC, cooled to 0 ℃ and TFA (2mL) was added slowly, and the reaction was stirred at room temperature for 5 hours. After the reaction, the reaction mixture was dried under reduced pressure, slurried with diethyl ether and filtered under suction to give the title compound.
MS(ESI + )：[M+H] + 368.2。
H) The title compound was obtained using the same method as D) or E) in example 1. The molar equivalents and other reaction conditions were unchanged.
1 H NMR(300MHz，DMSO)δ8.83(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。
Examples 34 to 39
In examples 34 to 39, the title compound was obtained in the same manner as in example 33, see Table 3. The MS in the table is an observed value.
Table 3 partial compound structure and nuclear magnetic data
Example 40: experimental example (JAK-1 and JAK-3 enzyme inhibition assay)
Purpose of the experiment:
compounds were evaluated for inhibition of JAK-1 and JAK-3 kinases.
The experimental principle is as follows:
proteolytic effects of fluorescence resonance energy transfer technology (FRET) -based coupled proteolytic enzymes on specific phosphorylated versus non-phosphorylated polypeptide substrates. Two ends of the polypeptide substrate are respectively marked as FRET energy donor coumarin and energy acceptor fluorescein, and then the donor and the acceptor can be excited to transfer energy when being close to each other.
In the Kinase Reaction (Kinase Reaction), JAK-1 or JAK-3 can transfer gamma-phosphate in ATP to single tyrosine residue of polypeptide substrate, if JAK-1 or JAK-3 inhibitor exists in the system, the gamma-phosphate group on ATP can not be transferred to the substrate polypeptide, and phosphorylation Reaction can not occur. An evaluation experiment of a kinase inhibitor is designed based on the principle, a substrate polypeptide is designed with a kinase phosphorylation site and is also a protein enzyme cutting site, two ends of the substrate polypeptide are respectively connected with 2 fluorescent groups which are respectively a donor and an acceptor, if the activity of the kinase is maintained in a reaction system, the gamma-phosphate group is transferred to the enzyme cutting site of a substrate, so that the substrate polypeptide cannot be cut by protease and is separated into two sections, and under the excitation of laser with specific wavelength, the energy of one section of fluorescence can be transferred to the fluorescent group at the other end to emit energy. Otherwise, after the enzyme activity is inhibited, the phosphate group can not be transferred, the enzyme cutting site of the substrate can be cut by enzyme in the system, and the substrate is separated into two sections, so that the energy transfer of fluorescence can not occur. Based on this, the activity of the kinase was evaluated.
The experimental steps are as follows:
in the experiment, a 10-mul kinase reaction system is selected, and in the JAK1 inhibitor screening, the JAK1 kinase concentration of the system is 1 ng/mul, and ATP is 3.92 mul; in JAK2 inhibitor screening, JAK2 kinase is 0.004 ng/mu l, and ATP is 3.96 mu M; in the JAK3 inhibitor screening, each system contains 0.012 ng/mu l of JAK3 kinase and 1.43 mu M of ATP. TK Substrate-biotin Substrate was 1. mu.M, and the primary screening concentration of the compound was 10. mu.M.
(1) Preparation of kinase reaction buffer
1ml of 5 XKinase Buffer was diluted to 1X in 4ml of double distilled water, 5. mu.l of 1M DTT and 25. mu.l of 1M MgCl2 were added and the mixture was named Kinase Buffer and stored at room temperature.
(2) Preparation of Compounds to be screened
The sample compounds were dissolved in DMSO by mass to prepare a mother solution at a concentration of 100mM, and the compound was diluted and prepared with a kinase reaction buffer solution at a final reaction concentration of 10. mu.M.
(3) Reaction system
The experimental carrier is a black 384-well microplate, and the reaction system is 10 μ l.
Fluorescence detection
Emission intensities at 665nm and 620nm were detected under 330nm excitation.
Automatic calculation Ratio 665/620 10000 of microplate reader
(5) Data analysis
The inhibition ratio of each sample was calculated as follows
Suppression Ratio (Ratio MAX-Ratio sample)/(Ratio MAX-Ratio NEG) 100
TABLE 4 results of the experiment
The results show that: a plurality of compounds show certain inhibition effect on JAK kinase
IC 50 Evaluation of
Evaluation of IC of the concentration of the Compounds showing better Activity 50 As a result, it was found that the compound of example 5 exhibited a JAK-3 inhibitory effect (IC) of high activity 50 1.7nm), medium-strength selective activity (JAK-1/JAK-3 586, JAK-2)/JAK-3＝60)。
Claims (5)
- N- (3- (2- (4-morpholinophenylamino) pyrimidin-4-yl) phenyl) -2-butenamide having the following structural formula:
- 2. a pharmaceutical composition comprising a therapeutically effective amount of N- (3- (2- (4-morpholinophenylamino) pyrimidin-4-yl) phenyl) -2-butenamide, and a pharmaceutically acceptable carrier or adjuvant.
- Use of N- (3- (2- (4-morpholinophenylamino) pyrimidin-4-yl) phenyl) -2-butenamide in the manufacture of a medicament for the treatment of autoimmune disease, sjogren's syndrome, behcet's disease.
- 4. The use according to claim 3, wherein the autoimmune disease is psoriasis, rheumatoid arthritis or inflammatory bowel disease.
- 5. Use according to claim 3, wherein the autoimmune disease is multiple sclerosis, systemic lupus erythematosus.
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