CN109535132A

CN109535132A - 2- substituted pyrazolecarboxylic amino -4- substituted-amino -5- pyrimidinecarboxamides compound, composition and its application

Info

Publication number: CN109535132A
Application number: CN201811099717.0A
Authority: CN
Inventors: 张强; 刘彦生; 李兴福; 胡晨明
Original assignee: Beijing Saite Mingqiang Medicine Technology Co Ltd
Current assignee: Beijing Saite Mingqiang Medicine Technology Co Ltd
Priority date: 2017-09-21
Filing date: 2018-09-20
Publication date: 2019-03-29
Anticipated expiration: 2038-09-20
Also published as: CN109535132B; CN113214230B; CN113214230A

Abstract

The present invention relates to a kind of noval chemical compound, composition and its applications as JAK inhibitor.Specifically, the present invention provides a kind of compounds (as shown in formula (1)) or its stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, metabolite, isotope derivatives and solvate with strength JAK inhibitory, and it includes the pharmaceutical compositions of the compound.The invention also discloses the application of the compounds of this invention or pharmaceutical composition in medicine preparation, the drug is for treating autoimmune disease or cancer.

Description

2- substituted pyrazolecarboxylic amino -4- substituted-amino -5- pyrimidinecarboxamides compound, combination Object and its application

Technical field

The invention belongs to chemical medicines, and in particular to one kind has the compound or its medicine of jak kinase inhibitory activity Acceptable salt, isomers, solvate, crystallization or prodrug are learned, and contains the pharmaceutical composition of these compounds and these Application of the compound or composition in medicine preparation.

Background technique

Jak kinase (Janus kinase) and effector, signal transduction and transcription activating protein downstream form weight The cytokine signaling pathway wanted --- JAK-STAT access.Research find JAK-STAT access can by various kinds of cell because Son, growth factor and receptor activation participate in the processes such as cell Proliferation, differentiation, apoptosis, angiogenesis and immunological regulation.JAK Kinases is the Key kinases in JAK-STAT signal path, after which is found more than 20 years, the first jak kinase inhibitor (tofacitinib) treatment [Norman P., the Selective JAK of rheumatoid arthritis was just approved in 2012 Inhibitors in development for rheumatoid arthritis, Expert Opin Investig Drugs,2014,23:1067-1077]。

In the mammalian body, three members in jak kinase family: JAK1, JAK2, JAK3 and TYK2 are by more than 1100 Amino acid composition, for relative molecular mass up to 120000-140000, homology reaches 40%-70%, these jak kinase families at Member can successively be divided into 7 homeodomains (JH) from C-terminal to N-terminal: JH1 is kinases area, highly conserved in JAK family；JH2 is Kinases sample area or "false" kinases area, the vacation kinase domain are the particular features that JAK albumen is different from other tyrosine proteins, should Though kinases area does not have catalytic activity, the activity of JH1 is played regulatory role, the mutation in the structural domain often can lead to JAK and swash The enhancing or decrease of enzymatic activity, and lead to the generation of certain diseases in turn；JH3-JH4 is SH2 structural domain (Src homology 2domain), which contains about 100 amino acid residues, can specifically identify and in conjunction with phosphorylation on aglucon Tyrosine residue；JH5-JH7 is FERM structural domain, the conservative domain, the main combination for adjusting JAK and receptor.JAK3 conduct One of jak kinase family member equally contains above-mentioned kinases area in structure, specific amino acids in different structure territory Mutation will also result in the change of its kinase activity.

JAK-STAT signal path is various kinds of cell growth, activation, breaks up, is important during apoptosis and its Function One intracellular signal transduction approach.STAT is that one kind can be under JAK with the cytoplasmic protein in conjunction with target gene control region DNA Swim substrate.In STAT family including STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6 etc. 7 members. Interaction between JAKs and STATs plays an important role [O'Sullivan LA in cytokine receptor signal path Et al., Cytokine receptor signaling through the JAK-Stat-Socs pathway in Disease, Mol Immunol, 2007,44:2497-2506].When the cytokine receptor and its respective cell of cell surface Factor ligand causes the dimerization of acceptor molecule after combining so that close to each other with the jak kinase of coupled receptors and pass through interaction Tyrosine phosphorylation effect and activate.JAK-STAT signal path is that a signal by cytokine profiles receptor for stimulating turns Guiding path, the signal transduction of most cytokines in jak kinase mediated cell, such as interleukin (IL) class, interferon (IFN) Class, hematopoietin (EPO), granulocyte and macrophage colony stimulating factor (GMCSF), somatotropin (GH), stimulating milk secretion Element (PRL), thrombopoietin (TPO), platelet derived growth factor (PDGF) and epithelical cell growth factor (EGF) etc., And isoacceptor can not activate the jak kinase of different subtype, thus show differentiation biological function [Pesu M.et al., Therapeutic targeting of Janus kinases,Immunol Rev,2008,223:132-142]。

JAK1 and JAK2 has expression in each histocyte of human body, and JAK3 is mainly expressed in each hematopoietic tissue cell, It is primarily present in bone marrow cell, thymocyte, in NK cell and the bone-marrow-derived lymphocyte of activation, T lymphocyte.JAK1 and JAK2 etc. Missing will cause human body fatal injury, and JAK3 missing then can avoid damaging other histiocytic toxicity adverse reactions [Yamaoka K.,et al.,JAK3negatively regulates dendritic-cell cytokine production and survival,Blood,2005,106:3227-3233].Function based on each hypotype in jak kinase family Energy feature and special Tissue distribution, JAK3 have become the popular target for the treatment of autoimmune disease, and more and more clinics are ground Study carefully also to focus on the treatment of rheumatoid arthritis and block on JAK3 signal transduction pathway.2012, selective JAK 3 inhibited Agent Tofacitinib has passed through clinical test, is approved for the treatment of rheumatoid arthritis.

Tofacitinib (CP690550) is a kind of Pyrrolopyrimidine selective JAK 3 kinases of Pfizer company research and development Inhibitor, to the inhibitory activity (IC of JAK3₅₀=1nmol/L) it is JAK2 (IC₅₀=20nmol/L) 20 times and JAK1 (IC₅₀= 112nmol/L) 100 times.The stereochemical structure of research Tofacitinib finds that its chiral structure determines that it being capable of specificity Ground is integrated on JAK3 molecule, to inhibit JAK3 phosphorylation, is further resulted in STAT phosphorylation and is obstructed, cause downstream inflammatory thin Intracellular cytokine synthesis is suppressed.Tofacitinib shows good clinical efficacy in clinical studies, in rheumatoid joint In scorching clinical experimental study, 5mg or 10mg Tofacitinib metering group and the comparison of equivalent placebo show significant system Meter learns difference, but finds to increase related, long-term safety to severe infections risk using Tofacitinib in clinical experimental study Property needs further to be studied.

JAK-STAT signal path plays an important role in cell differentiation and breeding, the active change of JAK The change of path signal transmitting is also led to, and then influences cell function.Based on jak kinase in the transmitting of JAK-STAT signal Key effect, and JAK3 kinases specific histocyte distribution so that it is good that JAK3 becomes the diseases such as rheumatoid arthritis Good therapy target.

JAK3 inhibitor is mainly used for the treatment of middle severe rheumatoid arthritis patient at present, such drug is in the treatment Good therapeutic effect and preferable safety are shown, but its long-term safety still needs to be further increased.Tofacitinib It finds during clinical research, using will lead to certain adverse reaction, including infection, tuberculosis, tumour and liver damage after the drug Wound etc., so improving the drug effect of JAK3 inhibitor, reducing toxic side effect is research field critical issue urgently to be resolved.

The ATP-binding site homology of the several hypotypes of jak kinase is higher, and structural difference is smaller, this is that JAK is caused to inhibit The not high major reason of agent selectivity.A series of current published jak kinase inhibitor are in curative effect, selectivity and safety side There is room for improvement in face, it is still necessary to develop drug effect more preferably with the better JAK inhibitor of safety.Although highly selective JAK Inhibitor is the research emphasis of current this field, but is transmitted in view of each member of jak kinase family and JAK-STAT signal Closely related, general JAK inhibitor will significantly improve drug effect, substantially reduce dosage, to reach control toxic side effect Purpose.In addition, significantly improving for drug effect will be helpful to develop the anti-inflammatory drug through percutaneous drug delivery.And the research and development of such drug will For psoriasis, leucoderma, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic loupus erythematosus, Crow The treatment of the cancers such as the autoimmune diseases such as grace disease and leukaemia, lymthoma, Huppert's disease provides new approach.This hair Bright compound shows splendid bioactivity as jak kinase inhibitor.

Summary of the invention

The present invention provides a kind of 2- (1- substituted pyrazolecarboxylic -4-) amino -4- substituted-amino -5- pyrimidinecarboxamides chemical combination Object and its be used as preparation treat or prevent caused by tyrosine kinase (such as JAK1, JAK2, JAK3, TYK2) or its mutation Disease drug purposes.

The present invention provides a kind of compound or its isomers, solvate or its pharmaceutically acceptable salt, or with The form of its effective polymorphous pharmaceutical composition provides, which has structure formula (I):

Wherein,

R¹Forn₁For 0-1, n₂For 0-1, n₃For 0-5,

L₁ForR⁴And/or R⁵For H, C₁-C₃Straight chained alkyl；

R²Forn₄For 0-3, n₅For 0-1, n₆For 0-5,

L₂ForR⁷And/or R⁸For H, C₁-C₃Straight chained alkyl.

Substituent R in compound formula (I)³Are as follows:

A) H, hydroxyl, cyano,

b)C₁-C₅Linear or branched alkyl group,

c)C₃-C₈Naphthenic base, more preferably C₃-C₇Naphthenic base,

d)C₁-C₅Straight or branched alkoxyl,

e)C₁-C₅Linear chain or branched chain alkylthio group,

F) 5-7 circle heterocyclic ring, the preferably described 5-7 circle heterocyclic ring contain 1-2 hetero atom, hetero atom be selected from O and/or N and/ Or S connects H or C on N when hetero atom is N₁-C₄Alkyl, C₁-C₃Acyl group, preferably acetyl group, trifluoroacetyl group, propiono, N, N- diformyl connect 0-2 oxygen atom on S when hetero atom is S,

G) substituted or non-substituted five member aromatic or heteroaryl, it is preferable that the substituted or non-substituted five member aromatic Or the structural formula of heteroaryl isWherein: J₁And/or J₂And/or J₃And/or J₄For C, N, S, O；R⁹For C₁-C₃ Linear or branched alkyl group,

Either the structural formula of the substituted or non-substituted five member aromatic or heteroaryl isIts In:

J₁、J₂、J₃、J₄It is each independently C, N, S, O,

R²⁰、R²¹It is each independently C₁-C₃Linear or branched alkyl group,

H) substituted or non-substituted hexa-atomic aryl or heteroaryl,

Preferably, the structural formula of the substituted or non-substituted hexa-atomic aryl or heteroaryl isWherein:

Q₁、Q₂、Q₃、Q₄、Q₅For N or C；

R¹⁰And/or R¹¹And/or R¹²Are as follows:

1)-F、-Cl、-Br、-CF₃、-OCF₃, cyano；

2)-NR'R ", R', R " are H, C₁-C₃Alkyl；

3)C₁-C₃Alkyl, C₂-C₅Alkynyl, C₃-C₅Naphthenic base；

4)SO₂R¹³, wherein R¹³For H, C₁-C₃Alkyl；

5)Wherein q is 0-2, M O, S, R¹⁴For H, C₁-C₅Straight chain

Or branched alkyl；

6)Wherein R¹⁵、R¹⁶For straight chained alkyl,

Alternatively, the structural formula of the substituted or non-substituted hexa-atomic aryl or heteroaryl isWherein:

Q₁、Q₂、Q₃、Q₄、Q₅For N or C；

R¹⁷、R¹⁸Each independently are as follows:

A)-H,

b)-F、-Cl、-Br、-CF₃、-OCF₃, cyano,

C)-NR'R ", R', R " are H, C₁-C₃Alkyl,

d)C₁-C₃Alkyl, C₂-C₅Alkynyl, C₂-C₅Alkenyl, C₃-C₅Naphthenic base,

e)SO₂R¹³, wherein R¹³For H, C₁-C₃Alkyl,

f)Wherein q is 0-2, M O, S, R¹⁴For H, C₁-C₅Linear or branched alkyl group,

g)Wherein R¹⁵、R¹⁶For C₁-C₃Straight chained alkyl,

h)-(CH₂)_t-R¹⁹, t 1-2, R¹⁹For C₃-C₅Naphthenic base；

I) containing the hexa-atomic aromatic ring of 0-3 hetero atom and five yuan or hexatomic ring or containing simultaneously five yuan of five yuan of hetero-aromatic rings of 1-3 hetero atom Or hexatomic ring, it preferably is selected from:

Substituent R in formula (I)⁶Are as follows:

A) H, hydroxyl,

B)-NR'R ", R', R " are H, C₁-C₃Alkyl,

c)C₁-C₅Linear or branched alkyl group,

d)C₃-C₈Naphthenic base,

e)C₁-C₅Straight or branched alkoxyl,

f)C₁-C₅Linear chain or branched chain alkylthio group,

G) heterocycle, it is preferable that the heterocycle be five yuan or hexa-atomic oxygen-containing and/or nitrogen heterocycle, such as

The present invention provides a kind of compound or its isomers, solvate or its pharmaceutically acceptable salt, the chemical combination Object has structure formula (I):

Wherein,

R¹Forn₁For 0-2, n₂For 0-1, n₃For 0-5,

L₁ForR⁴And/or R⁵For H, C₁-C₃Straight chained alkyl；

R²Forn₄For 0-3, n₅For 0-1, n₆For 0-5,

L₂ForR⁷And/or R⁸For H, C₁-C₃Straight chained alkyl；

R³For R²²Substituted C₁-C₃Alkoxy or R²²Substituted C₁-C₃Alkylthio group, R²²For hydroxyl, C₁-C₃Alkoxy, C₁- C₃The C that alkylthio group ,-NR'R ", hydroxyl replace₁-C₃The C that alkoxy, amino replace₁-C₃The C that alkoxy, hydroxyl replace₁-C₃Alkane sulphur The C that base, amino replace₁-C₃Alkylthio group, wherein R', R " are H, C₁-C₃Alkyl；

R⁶For a) H, hydroxyl,

B)-NR'R ", R', R " are H, C₁-C₃Alkyl,

c)C₁-C₅Linear or branched alkyl group,

d)C₃-C₈Naphthenic base,

e)C₁-C₅Straight or branched alkoxyl,

f)C₁-C₅Linear chain or branched chain alkylthio group, or

g)

It is clear that the compound of structure formula (I), isomers, crystallization or prodrug and its officinal salt may exist solvation Form and nonsolvated forms.Such as solvation form can be water-soluble form.The present invention includes the sum of all these solvations Unsolvated form.

One aspect of the present invention is a kind of pharmaceutical composition, and it includes the compounds of structure formula (I).This composition can Be applied to psoriasis, leucoderma, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic loupus erythematosus, The cancers such as the autoimmune diseases such as Crohn disease and leukaemia, lymthoma, Huppert's disease, including those processes Tofacitinib, Peficitinib, Decernotinib or other kinase inhibitor for treating have the class autoimmunity of drug resistance Disease, cancer etc..

A further object of the present invention is to be to provide a kind of method for treating autoimmune disease and cancer comprising A kind of method of the therapeutically effective amount of the composition containing the compound of the present invention is applied to subject.Can be treated in this way itself Immunological diseases, cancer can indicate in the other places this paper, including have to Tofacitinib, Peficitinib, Roxolitinib, Decernotinib or other kinase inhibitor for treating have the autoimmune disease of drug resistance, cancer etc..

Can also be applied in combination other one or more therapies in cancer treatment, including operation, radiotherapy (such as gamma-radiation, Neutron beam radiotherapy, electron beam evaporation treatment, proton therapeutic, plesioradiotherapy and body radioactivity isotope etc.), it is interior Secrete therapy, biological response modifier (for example, interferon, interleukin and tumor necrosis factor (TNF)), thermotherapy, cold therapy, Weaken any adverse effect (for example, antemetic) and other therapeutic agents.

The invention also includes the uses of the compound of the present invention or its pharmaceutically acceptable derivates, manufacture for treating Fundus oculi disease, xerophthalmia, psoriasis, rheumatoid arthritis, fash, eczema, alopecia areata, atheroma, pulmonary fibrosis, liver are fine The medicament of the diseases such as autoimmune diseases and tumour such as dimensionization, myelofibrosis, property enteritis, including those are treated as existed herein Drug resistant disease is generated to one or more other therapeutic agents pointed by other places.The compound of the present invention can also be used in drug In by inhibiting one or more kinases (such as JAK1, JAK2, JAK3, TYK2) mitigate or prevent disease.

The present invention also provides the methods of preparation respective compound, can specifically be prepared by following methods.Serial (I) changes The synthetic route for closing object is as follows:

Reagent and reaction condition: (a) DIEA, THF；(b) s-BuOH, TFA.

Specific embodiment

The synthetic method of intermediate is as follows:

The preparation of 1 1- of intermediate (2- methoxy ethyl) -1H- pyrazoles -4- amine:

Step 1): the preparation of 1- (2- methoxy ethyl) -4- nitro -1H- pyrazoles:

4- nitro -1H- pyrazoles (5g, 44.21mmol) is dissolved in DMF (20mL), K is added₂CO₃(9.1g, 65.85mmol) With the bromo- 2- Ethyl Methyl Ether (7.4g, 53.24mmol) of 1-, 50 DEG C are reacted 16 hours.Reaction solution pours into ice water, ethyl acetate Extraction, anhydrous sodium sulfate, which dries, filters, steams dry chromatography (petroleum ether: ethyl acetate=3:1), obtains brown oil 5g, produces Rate 66%.¹H NMR(400MHz,DMSO-d₆) δ 8.85 (s, 1H), 8.27 (s, 1H), 4.35 (t, J=5.1Hz, 2H), 3.73 (t, J=5.2Hz, 2H), 3.24 (s, 3H) .LCMS:m/z=172.1 (M+H)⁺.

Step 2): the preparation of 1- (2- methoxy ethyl) -1H- pyrazoles -4- amine:

1- (2- methoxy ethyl) -4- nitro -1H- pyrazoles (5g, 29.21mmol) is dissolved in ethyl alcohol (25mL) and acetic acid second It in ester (25mL), is added Raney's nickel (500mg), is reacted 5 hours under hydrogen environment.Diatomite filtering, filtrate are evaporated, and it is solid to obtain brown Body 3.6g, yield 87%.¹H NMR(400MHz,DMSO-d₆) δ 7.01 (s, 1H), 6.90 (s, 1H), 4.04 (t, J=5.4Hz, 2H), 3.89-3.63 (m, 2H), 3.58 (t, J=5.4Hz, 2H), 3.20 (s, 3H) .LCMS:m/z=142.1 (M+H)⁺.

The preparation of 2 1- of intermediate [2- (methyl mercapto) ethyl] -1H- pyrazoles -4- amine:

Step 1): the preparation of 1- [2- (methyl mercapto) ethyl] -4- nitro -1H- pyrazoles:

4- nitro -1H- pyrazoles (400mg, 3.54mmol) is dissolved in anhydrous tetrahydro furan (10mL), 2- (first sulphur is added Base) -1- ethyl alcohol (424mg, 4.60mmol), triphenylphosphine (1.4g, 5.32mmol), under 0 DEG C of argon gas protective condition, DIAD is added dropwise (1.13g, 5.60mmol), 25 DEG C are reacted 4 hours.Reaction solution saturated aqueous ammonium chloride is quenched, ethyl acetate extraction, anhydrous sulphur Sour sodium, which dries, filters, steams dry chromatography (petroleum ether: ethyl acetate=4:1), obtains yellow oil 180mg, yield 54%. LCMS:m/z=188.0 (M+H)⁺.

Step 2): the preparation of 1- [2- (methyl mercapto) ethyl] -1H- pyrazoles -4- amine:

1- [2- (methyl mercapto) ethyl] -4- nitro -1H- pyrazoles (300mg, 1.60mmol) is dissolved in ethyl alcohol (2mL) and second It in the mixed solution of acetoacetic ester (2mL), is added Raney's nickel (30mg), is reacted 5 hours under hydrogen environment.Diatomite filtering, filtrate It is evaporated, obtains brown oil 210mg, yield 83%.¹H NMR(400MHz,DMSO-d₆)δ7.06(s,1H),6.91(s,1H), 4.09 (t, J=6.9Hz, 2H), 3.81 (s, 2H), 2.79 (t, J=6.9Hz, 2H), 1.99 (s, 3H) .LCMS:m/z=158.1 (M+H)⁺.

The synthesis of 1 intermediate 3-22 of table (with reference to the synthetic method of intermediate 1 or 2)

The preparation of 23 1- cyclopropyl -1H- pyrazoles -4- amine of intermediate:

Step 1): the preparation of 1- cyclopropyl -4- nitro -1H- pyrazoles:

4- nitro -1H- pyrazoles (200mg, 1.77mmol) is dissolved in anhydrous methylene chloride (15mL), cyclopropyl boron is added Sour (320mg, 3.72mmol), copper acetate (326mg, 1.79mmol), pyridine (144mg, 1.82mmol), sodium carbonate (432mg, 4.08mmol), it under 70 DEG C of argon gas protective conditions, reacts 4 hours.Reaction solution evaporating column chromatography (petroleum ether: ethyl acetate=4: 1) yellow oil 110mg, yield 41%, are obtained.LCMS:m/z=154.1 (M+H)⁺.

Step 2): the preparation of 1- cyclopropyl -1H- pyrazoles -4- amine: by 1- cyclopropyl -4- nitro -1H- pyrazoles (110mg, It 0.72mmol) is dissolved in the mixed solution of ethyl alcohol (2mL) and ethyl acetate (2mL), is added Raney's nickel (15mg), under hydrogen environment Reaction 3 hours.Diatomite filtering, filtrate are evaporated, and obtain brown oil 90mg, yield 90%.¹H NMR(400MHz,DMSO-d₆) δ7.02(s,1H),6.86(s,1H),3.89–3.61(m,2H),3.50–3.45(m,1H),0.91–0.73(m,4H).LCMS: M/z=124.1 (M+H)⁺.

The preparation of 24 1- of intermediate (6- methoxyethyl) -1H- pyrazoles -4- amine:

Step 1): the preparation of 1- (6- bromohexane) -4- nitro -1H- pyrazoles:

4- nitro -1H- pyrazoles (200mg, 1.77mmol) is dissolved in DMF (8mL), K is added₂CO₃(732mg, 5.30mmol), 1,6- dibromo-hexane (864mg, 3.54mmol), 80 DEG C are reacted 3 hours.Reaction solution pours into ice water, acetic acid second Ester extraction, anhydrous sodium sulfate, which dries, filters, steams dry chromatography (petroleum ether: ethyl acetate=5:1), obtains colorless oil 300mg, yield 61%.LCMS:m/z=276.0 (M+H)⁺.

Step 2): the preparation of 1- (6- methoxyethyl) -4- nitro -1H- pyrazoles:

1- (6- bromohexane) -4- nitro -1H- pyrazoles (300mg, 1.09mmol) is dissolved in the methanol solution of sodium methoxide In (33%, 7mL), 25 DEG C are reacted 16 hours.Reaction solution saturated salt solution is quenched, and ethyl acetate extraction, anhydrous sodium sulfate is dry, Filtering is evaporated reversed phase column chromatography (petroleum ether: ethyl acetate=5:1), obtains colorless oil 230mg, yield 93%.LCMS:m/z= 228.1(M+H)⁺.

Step 3): the preparation of 1- (6- methoxyethyl) -1H- pyrazoles -4- amine:

1- (6- methoxyethyl) -4- nitro -1H- pyrazoles (230mg, 1.01mmol) is dissolved in ethyl alcohol (2mL) and acetic acid It in the mixed solution of ethyl ester (2mL), is added Raney's nickel (25mg), is reacted 3 hours under hydrogen environment.Diatomite filtering, filtrate are steamed It is dry, obtain brown oil 190mg, yield 95%.LCMS:m/z=198.2 (M+H)⁺.

The preparation of 25 4- methyl-1-pentene amine of intermediate:

3- methyl valeronitrile (400mg, 4.11mmol) is dissolved in anhydrous tetrahydro furan (5mL), 0 DEG C of argon gas protective condition Under, it is added lithium aluminium hydride reduction (235mg, 6.18mmol), rises to 25 DEG C naturally and stir 16 hours.It is down to 0 DEG C, sequentially adds 0.4mL Water, 0.4mL15% sodium hydroxide solution, 1.2mL water.After stirring 15 minutes, filtering, filtrate low temperature is evaporated, and obtains yellow oily Object 300mg, thick yield 72%.¹H NMR(400MHz,CDCl₃) δ 2.85 (t, J=7.6Hz, 2H), 1.60-1.46 (m, 3H), 1.14-1.08 (m, 2H), 0.95 (d, 6H) .LCMS:m/z=102.1 (M+H)⁺.

The synthesis of 2 intermediate 26-28 of table (with reference to the synthesis of intermediate 29)

The preparation of intermediate 29 [2- (methoxyl methyl) phenyl] methylamine:

Step 1): the preparation of 2- (methoxyl methyl) benzonitrile:

2- (chloromethyl) benzonitrile (500mg, 3.30mmol) is dissolved in the methanol solution (33%, 5mL) of sodium methoxide, 25 DEG C reaction 4 hours, saturated aqueous ammonium chloride is quenched, ethyl acetate extraction, anhydrous sodium sulfate dries, filters faint yellow Grease 450mg, thick yield 93%.LCMS:m/z=148.1 (M+H)⁺.

Step 2): the preparation of [2- (methoxyl methyl) phenyl] methylamine:

2- (methoxyl methyl) benzonitrile (450mg, 3.06mmol) is dissolved in anhydrous tetrahydro furan (15mL), 0 DEG C of argon gas Lithium aluminium hydride reduction (354mg, 9.32mmol) is added under protective condition, rises to 25 DEG C after ten minutes and reacts 16 hours.Successively add at 0 DEG C Enter 0.4mL water, 0.4mL15% sodium hydroxide solution and 1.2mL water, after ten minutes, filtering, filtrate is evaporated for stirring, obtains brown Grease 360mg, thick yield 78%.LCMS:m/z=152.1 (M+H)⁺.

The preparation of intermediate 30 (2- picoline -3- base) methylamine:

2- methylnicotinamide (200mg, 1.47mmol) is dissolved in anhydrous tetrahydro furan (5mL), under the conditions of 0 DEG C of argon gas, The tetrahydrofuran solution (1M, 7.4mL, 7.4mmol) of borine is added dropwise, after reaction 30 minutes, rises to 60 DEG C and reacts 8 hours.Saturation Aqueous ammonium chloride solution is quenched, and ethyl acetate extraction, anhydrous sodium sulfate dries, filters to obtain colorless oil 200mg, crude product It is directly used in and reacts in next step.LCMS:m/z=123.1 (M+H)⁺.

The preparation of intermediate 31 [3- (dimethylamino formoxyl) benzyl] semicarbazide hydrochloride:

3- (((tertbutyloxycarbonyl) amino) methyl) benzoic acid (400mg, 1.59mmol) is dissolved in tetrahydrofuran (5mL) In, be added carbonyl dimidazoles (337mg, 2.39mmol), stirring 3 hours after, be added dropwise dimethylamine tetrahydrofuran solution (2M, 3.2mL, 6.4mmol), 60 DEG C of tube sealing are reacted 16 hours.Reaction solution concentration, column chromatograph (petroleum ether: ethyl acetate=1:1).To In obtained white solid, the dioxane solution (4M, 4mL) of hydrogen chloride is added and is evaporated reaction solution after 25 DEG C are stirred 2 hours, Obtain white solid 263mg, yield 77%.LCMS:m/z=179.1 (M+H)⁺.

Embodiment

The preparation of 1 4- benzylamino -2- of embodiment [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide:

Step 1): the preparation of 2- chloro- 4- (benzylamino) pyrimidine -5- formamide:

2,4- dichloro pyrimidine -5- formamide (2g, 10.42mmol) is dissolved in tetrahydrofuran (20mL), benzyl is separately added into Amine (1.12g, 10.45mmol) and diisopropyl ethyl amine (4g, 31.01mmol), 25 DEG C are reacted 2 hours.Saturated common salt is added Water (200mL), after stirring 15 minutes, filtering, filter cake petroleum ether obtains white solid 2.1g, yield 77%.¹H NMR (400MHz,DMSO-d₆+DCl/D₂O) δ 8.84 (s, 1H), 7.48-7.33 (m, 5H), 4.82 (s, 2H) .LCMS:m/z=263.1 (M+H)⁺.

Step 2): the preparation of 4- benzylamino -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide:

2- chloro- 4- (benzylamino) pyrimidine -5- formamide (100mg, 0.38mmol) is dissolved in sec-butyl alcohol (3mL), is added Enter 1- methyl-1 H- pyrazoles -4- amine (40mg, 0.41mmol) and trifluoroacetic acid (0.1mL), 100 DEG C tube sealing reaction 2 hours.Reaction Liquid concentration, filtering, solid are washed with acetonitrile, obtain white solid 50mg, yield 41%.¹H NMR(300MHz,DMSO-d₆+ DCl/D₂O)δ8.75(s,1H),7.73(s,1H),7.55(s,1H),7.42–7.36(m,5H),4.79(s,2H),3.79(s, 3H) .LCMS:m/z=324.1 (M+H)⁺.

2 4- of embodiment [(2- methoxy-benzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- first The preparation of amide:

Step 1): the preparation of the chloro- 4- of 2- [(2- methoxy-benzyl) amino] pyrimidine -5- formamide:

2,4- dichloro pyrimidine -5- formamide (80mg, 0.42mmol) is dissolved in tetrahydrofuran (3mL), 2- is separately added into Methoxybenzylamine (57mg, 0.42mmol) and diisopropyl ethyl amine (161mg, 1.25mmol), 25 DEG C are reacted 2 hours.It is added Saturated salt solution (30mL), stirring are filtered after 15 minutes, and filter cake petroleum ether obtains white solid 116mg, yield 95%.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O) δ 8.84 (s, 1H), 7.42-7.35 (m, 2H), 7.11 (d, J=8.2Hz, 1H), 7.04–6.96(m,1H),4.79(s,2H),3.86(s,3H).；¹³C NMR(101MHz,DMSO-d₆+DCl/D₂O)δ166.77, 157.63,156.84,148.52,147.71,130.55,129.68,122.97,121.08,111.64,96.61,56.12, (42.39.LCMS:m/z=293.1 M+H)⁺.

Step 2): 4- [(2- methoxy-benzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- first The preparation of amide:

The chloro- 4- of 2- [(2- methoxy-benzyl) amino] pyrimidine -5- formamide (116mg, 0.40mmol) is dissolved in sec-butyl alcohol In (3mL), 1- methyl-1 H- pyrazoles -4- amine (39mg, 0.40mmol) and trifluoroacetic acid (0.1mL), 100 DEG C of tube sealing reactions are added 2 hours.Reaction solution concentration, column chromatograph (methylene chloride: methanol=95:5), and crude product is washed with acetonitrile, obtains white solid 15mg, yield 11%.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.68(s,1H),7.68(s,1H),7.50(s,1H), 7.32-7.22 (m, 1H), 7.11 (d, J=7.4Hz, 1H), 7.05 (d, J=8.2Hz, 1H), 6.95-6.82 (m, 1H), 4.66 (s,2H),3.83(s,3H),3.75(s,3H).¹³C NMR(101MHz,DMSO-d₆+DCl/D₂O)δ166.86,161.02, 157.36,149.69,144.70,131.25,129.45,128.42,124.82,123.12,120.85,119.52,111.38, (100.76,56.01,40.98,39.31.LCMS:m/z=354.2 M+H)⁺.

3 4- of embodiment [(the fluoro- 6- methoxy-benzyl of 2-) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] is phonetic The preparation of pyridine -5- formamide:

Step 1): the preparation of the chloro- 4- of 2- [(the fluoro- 6- methoxy-benzyl of 2-) amino] pyrimidine -5- formamide:

2,4- dichloro pyrimidine -5- formamide (210mg, 1.09mmol) is dissolved in tetrahydrofuran (8mL), is separately added into (the fluoro- 6- methoxyphenyl of 2-) methylamine (170mg, 1.09mmol) and diisopropyl ethyl amine (423mg, 3.27mmol), 25 DEG C Reaction 2 hours.It is added saturated salt solution (60mL), stirring is filtered after 15 minutes, and filter cake petroleum ether obtains white solid 75mg, yield 66%.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.82(s,1H),7.50–7.40(m,1H),7.03– 6.96 (m, 1H), 6.95-6.87 (m, 1H), 4.77 (s, 2H), 3.88 (s, 3H) .LCMS:m/z=311.1 (M+H)⁺.

Step 2): 4- [(the fluoro- 6- methoxy-benzyl of 2-) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine - The preparation of 5- formamide:

The chloro- 4- of 2- [(the fluoro- 6- methoxy-benzyl of 2-) amino] pyrimidine -5- formamide (75mg, 0.24mmol) is dissolved in secondary In butanol (3mL), 1- methyl-1 H- pyrazoles -4- amine (27mg, 0.28mmol) and trifluoroacetic acid (0.1mL), 100 DEG C of tube sealings are added Reaction 2 hours.Reaction solution thickening filtration, filter cake are washed with acetonitrile, obtain white solid 65mg, yield 73%.¹H NMR (400MHz,DMSO-d₆+DCl/D₂O)δ8.72(s,1H),8.03(s,1H),7.75(s,1H),7.45–7.34(m,1H), 7.03-6.93 (m, 1H), 6.93-6.83 (m, 1H), 4.83 (s, 2H), 3.89 (s, 3H), 3.88 (s, 3H) .LCMS:m/z= 372.2(M+H)⁺.

4 4- of embodiment [(2,6- dimethyl benzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- The preparation of formamide:

Step 1): the preparation of the chloro- 4- of 2- [(2,6- dimethyl benzyl) amino] pyrimidine -5- formamide:

2,4- dichloro pyrimidine -5- formamide (70mg, 0.36mmol) is dissolved in tetrahydrofuran (4mL), be separately added into (2, 6- 3,5-dimethylphenyl) methylamine (50mg, 0.37mmol) and diisopropyl ethyl amine (141mg, 1.09mmol), 25 DEG C of reactions 2 are small When.It is added saturated salt solution (30mL), stirring is filtered after 15 minutes, and filter cake petroleum ether obtains white solid 73mg, yield 69%.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.88(s,1H),7.31–7.18(m,1H),7.18–7.06(m, 2H),4.73(s,2H),2.34(s,6H)；¹³C NMR(101MHz,DMSO-d₆+DCl/D₂O)δ166.98,157.34, 148.46,147.77,137.93,131.33,129.36,129.10,96.61,41.68,19 .77.LCMS:m/z=291.1 (M +H)⁺.

Step 2): 4- [(2,6- dimethyl benzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- The preparation of formamide:

The chloro- 4- of 2- [(2,6- dimethyl benzyl) amino] pyrimidine -5- formamide (73mg, 0.25mmol) is dissolved in sec-butyl alcohol In (3mL), 1- methyl-1 H- pyrazoles -4- amine (30mg, 0.31mmol) and trifluoroacetic acid (0.1mL), 100 DEG C of tube sealing reactions are added 2 hours.Reaction solution thickening filtration, filter cake are washed with acetonitrile, obtain white solid 50mg, yield 57%.¹H NMR(400MHz, DMSO-d₆+DCl/D₂O) δ 8.76 (s, 1H), 8.08 (s, 1H), 7.75 (s, 1H), 7.18 (dd, J=8.6,6.3Hz, 1H), 7.14-7.08 (m, 2H), 4.74 (s, 2H), 3.90 (s, 3H), 2.32 (s, 6H) .LCMS:m/z=352.2 (M+H)⁺.

5 4- of embodiment [(2,6- dichloro benzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- first The preparation of amide:

Step 1): the chloro- 4- of 2- [(2,6- dichloro benzyl) amino] pyrimidine -5- formamide:

2,4- dichloro pyrimidine -5- formamide (70mg, 0.36mmol) is dissolved in tetrahydrofuran (4mL), be separately added into (2, 6- dichlorophenyl) methylamine (64mg, 0.36mmol) and diisopropyl ethyl amine (141mg, 1.09mmol), 25 DEG C are reacted 2 hours. It is added saturated salt solution (40mL), stirring is filtered after 15 minutes, and filter cake petroleum ether obtains white solid 110mg, yield 91%.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.93(s,1H),7.67–7.60(m,2H),7.60–7.50(m, 1H),5.03(s,2H).¹³C NMR(101MHz,DMSO-d₆+DCl/D₂O)δ167.05,157.86,149.16,147.94, (135.98,132.68,130.34,129.74,96.46,42.77.LCMS:m/z=331.0 M+H)⁺.

Step 2): 4- [(2,6- dichloro benzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- first The preparation of amide:

The chloro- 4- of 2- [(2,6- dichloro benzyl) amino] pyrimidine -5- formamide (112mg, 0.34mmol) is dissolved in sec-butyl alcohol In (3mL), 1- methyl-1 H- pyrazoles -4- amine (40mg, 0.41mmol) and trifluoroacetic acid (0.1mL), 100 DEG C of tube sealing reactions are added 2 hours.It is filtered after reaction solution concentration, filter cake is washed with acetonitrile, obtains white solid 110mg, yield 83%.¹H NMR (400MHz,DMSO-d₆+DCl/D₂O)δ8.80(s,1H),8.07(s,1H),7.74(s,1H),7.66–7.55(m,2H), 7.53-7.41 (m, 1H), 5.03 (s, 2H), 3.89 (s, 3H) .LCMS:m/z=392.1 (M+H)⁺.

6 4- of embodiment [(2,6- difluorobenzyl) amino] -2- [[1- (2- methoxy ethyl) -1H- pyrazoles -4- base] ammonia Base] pyrimidine -5- formamide preparation:

Step 1): the preparation of the chloro- 4- of 2- [(2,6- difluorobenzyl) amino] pyrimidine -5- formamide:

2,4- dichloro pyrimidine -5- formamide (210mg, 1.09mmol) is dissolved in tetrahydrofuran (8mL), is separately added into (2,6- difluorophenyl) methylamine (156mg, 1.09mmol) and diisopropyl ethyl amine (423mg, 3.27mmol), 25 DEG C of reactions 2 Hour.It being added saturated salt solution (80mL), stirring is filtered after 15 minutes, and filter cake petroleum ether obtains white solid 285mg, Yield 87%.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.90(s,1H),7.72–7.38(m,1H),7.38–7.08 (m, 2H), 4.93 (s, 2H) .LCMS:m/z=299.0 (M+H)⁺.

Step 2): 4- [(2,6- difluorobenzyl) amino] -2- [[1- (2- methoxy ethyl) -1H- pyrazoles -4- base] amino] The preparation of pyrimidine -5- formamide:

The chloro- 4- of 2- [(2,6- difluorobenzyl) amino] pyrimidine -5- formamide (94mg, 0.31mmol) is dissolved in sec-butyl alcohol In (3mL), addition 1- (2- methoxy ethyl) -1H- pyrazoles -4- amine (53mg, 0.38mmol) and trifluoroacetic acid (0.1mL), 100 DEG C tube sealing reaction 2 hours.It is filtered after reaction solution concentration, filter cake is washed with acetonitrile, obtains white solid 80mg, yield 63%.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.78(s,1H),8.09(s,1H),7.75(s,1H),7.58–7.39(m,1H), 7.19-7.14 (m, 2H), 4.90 (s, 2H), 4.32 (t, J=5.1Hz, 2H), 3.70 (t, J=5.1Hz, 2H), 3.21 (s, 3H) .LCMS:m/z=404.2 (M+H)⁺.

7 4- of embodiment [(the fluoro- 6- methoxy-benzyl of 2-) amino] -2- [[1- (2- methoxy ethyl) -1H- pyrazoles -4- Base] amino] pyrimidine -5- formamide preparation:

Step 2): 4- [(the fluoro- 6- methoxy-benzyl of 2-) amino] -2- [[1- (2- methoxy ethyl) -1H- pyrazoles -4- base] Amino] pyrimidine -5- formamide preparation:

The chloro- 4- of 2- [(the fluoro- 6- methoxy-benzyl of 2-) amino] pyrimidine -5- formamide (118mg, 0.38mmol) is dissolved in secondary In butanol (3mL), 1- (2- methoxy ethyl) -1H- pyrazoles -4- amine (64mg, 0.45mmol) and trifluoroacetic acid is added (0.1mL), 100 DEG C tube sealing reaction 2 hours.Reaction solution thickening filtration, is washed with acetonitrile, obtains white solid 100mg, yield 63%.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.75(s,1H),8.12(s,1H),7.82(s,1H),7.53–7.33 (m, 1H), 6.98 (d, J=8.4Hz, 1H), 6.95-6.73 (m, 1H), 4.83 (s, 2H), 4.32 (t, J=5.1Hz, 2H), 3.89 (s, 3H), 3.70 (t, J=5.1Hz, 2H), 3.21 (s, 3H) .LCMS:m/z=416.2 (M+H)⁺.

8 4- of embodiment [(5- Hydroxy pentyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formyl The preparation of amine:

Step 1): the preparation of the chloro- 4- of 2- [(5- Hydroxy pentyl) amino] pyrimidine -5- formamide

2,4- dichloro pyrimidine -5- formamide (100mg, 0.52mmol) is dissolved in tetrahydrofuran (4mL), 5- is separately added into Amino -1- amylalcohol (54mg, 0.52mmol) and diisopropyl ethyl amine (202mg, 1.56mmol), 25 DEG C are reacted 2 hours.It is added Saturated salt solution (40mL) crosses filter solid after stirring 15 minutes, and filter cake petroleum ether obtains white solid 80mg, yield 59%.LCMS:m/z=259.1 (M+H)⁺.

Step 2): 4- [(5- Hydroxy pentyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formyl The preparation of amine:

The chloro- 4- of 2- [(5- Hydroxy pentyl) amino] pyrimidine -5- formamide (80mg, 0.31mmol) is dissolved in sec-butyl alcohol In (3mL), 1- methyl-1 H- pyrazoles -4- amine (37mg, 0.38mmol) and trifluoroacetic acid (0.1mL), 100 DEG C of tube sealing reactions are added 2 hours.Reaction solution thickening filtration, filter cake are washed with acetonitrile, obtain white solid 70mg, yield 71%.¹H NMR(400MHz, DMSO-d₆+DCl/D₂O)δ8.68(s,1H),7.96(s,1H),7.68(s,1H),3.87(s,3H),3.60–3.47(m,2H), 3.39 (t, J=6.3Hz, 2H), 1.69-1.54 (m, 2H), 1.51-1.40 (m, 2H), 1.40-1.29 (m, 2H) .LCMS:m/z =320.2 (M+H)⁺.

9 4- of embodiment [(5- methoxypentyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- first The preparation of amide:

Step 1), step 2) are the same as embodiment 8

Step 3): 4- [(5- bromine amyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide Preparation:

By 4- [(5- Hydroxy pentyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide (60mg, 0.19mmol) is dissolved in anhydrous methylene chloride (4mL), under 0 DEG C of argon gas protective condition, sequentially adds carbon tetrabromide (187mg, 0.56mmol) and triphenylphosphine (148mg, 0.56mmol) rises to 25 DEG C and reacts 2 hours.Methanol is quenched, and is evaporated column It chromatographs (methylene chloride: methanol=10:1), obtains light yellow solid 70mg, yield 95%.LCMS:m/z=382.1 (M+H)⁺.

Step 4): 4- [(5- methoxypentyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- first The preparation of amide:

By 4- [(5- bromine amyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide (70mg, It 0.18mmol) is dissolved in the methanol solution (33%, 7mL) of sodium methoxide, 25 DEG C are reacted 16 hours.Reaction solution saturated common salt water quenching It goes out, ethyl acetate extraction, anhydrous sodium sulfate, which dries, filters, is evaporated reversed phase column chromatography (water: methanol=7:3), and crude product acetonitrile is washed It washs, obtains white solid 35mg, yield 57%.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.69(s,1H),8.02(s, 1H), 7.76 (s, 1H), 3.90 (s, 3H), 3.53 (t, J=6.7Hz, 2H), 3.31 (t, J=6.1Hz, 2H), 3.20 (s, 3H), 1.69-1.57 (m, 2H), 1.57-1.44 (m, 2H), 1.44-1.30 (m, 2H) .LCMS:m/z=334.2 (M+H)⁺.

10 4- of embodiment [(3- hydroxy-3-methyl butyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] is phonetic The preparation of pyridine -5- formamide:

Step 1): the preparation of 3- [(5- carbamyl -2- chlorine pyrimidine-4-yl) amino] methyl propionate

2,4- dichloro pyrimidine -5- formamide (100mg, 0.52mmol) is dissolved in tetrahydrofuran (4mL), ammonia is separately added into Base propionate hydrochloride (73mg, 0.52mmol) and diisopropyl ethyl amine (202mg, 1.56mmol), 25 DEG C of reactions 2 are small When.It is added saturated salt solution (40mL), stirring is filtered after 15 minutes, and filter cake petroleum ether obtains white solid 90mg, yield 67%.LCMS:m/z=259.1 (M+H)⁺.

Step 2): 3- [(5- carbamyl -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine-4-yl) amino] third The preparation of sour methyl esters:

3- [(5- carbamyl -2- chlorine pyrimidine-4-yl) amino] methyl propionate (90mg, 0.35mmol) is dissolved in sec-butyl alcohol In (3mL), 1- methyl-1 H- pyrazoles -4- amine (41mg, 0.42mmol) and trifluoroacetic acid (0.1mL), 100 DEG C of tube sealing reactions are added 2 hours.Reaction solution concentration, solid filtering, acetonitrile washing obtain white solid 80mg, yield 72%.LCMS:m/z=320.1 (M+H)⁺.

Step 3): 4- [(3- hydroxy-3-methyl butyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine - The preparation of 5- formamide:

By 3- [(5- carbamyl -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine-4-yl) amino] methyl propionate (80mg, 0.25mmol) is dissolved in anhydrous tetrahydro furan (2mL), under 0 DEG C of argon gas protective condition, dropwise addition methyl Grignard (1M, 0.75mL, 0.75mmol), 25 DEG C are reacted 16 hours.Saturated aqueous ammonium chloride is quenched, ethyl acetate extraction, saturated salt solution It washes, anhydrous sodium sulfate, which dries, filters, to be evaporated, and thin-layer chromatography (methylene chloride: methanol=10:1), crude product is washed with acetonitrile, is obtained To white solid 15mg, yield 19%.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.57(s,1H),8.01(s,1H), 7.62 (s, 1H), 3.78 (s, 3H), 3.63-3.47 (m, 2H), 1.71-1.56 (m, 2H), 1.08 (s, 6H) .LCMS:m/z= 320.2(M+H)⁺.

11 4- of embodiment [[(1- Acetylpiperidin -4- base) methyl] amino] -2- [(1- methyl-1 H- pyrazoles -4- base) ammonia Base] pyrimidine -5- formamide preparation:

Step 1): 4- [[(5- carbamoyl -2- chlorine pyrimidine-4-yl) amino] methyl] piperidines -1- t-butyl formate Preparation:

2,4- dichloro pyrimidine -5- formamide (100mg, 0.52mmol) is dissolved in tetrahydrofuran (4mL), 4- is separately added into (aminomethyl) piperidines -1- t-butyl formate (112mg, 0.52mmol) and diisopropyl ethyl amine (202mg, 1.57mmol), 25 DEG C reaction 2 hours.It is added saturated salt solution (40mL), stirring is filtered after 15 minutes, and filter cake petroleum ether obtains white solid 150mg, yield 79%.LCMS:m/z=370.2 (M+H)⁺.

Step 2): 4- [[(5- carbamoyl -2- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino] Methyl] piperidines -1- t-butyl formate preparation:

By 4- [[(5- carbamoyl -2- chlorine pyrimidine-4-yl) amino] methyl] piperidines -1- t-butyl formate (150mg, It 0.41mmol) is dissolved in sec-butyl alcohol (3mL), 1- methyl-1 H- pyrazoles -4- amine (48mg, 0.49mmol) and trifluoroacetic acid is added (0.1mL), 100 DEG C tube sealing reaction 2 hours.Reaction solution thickening filtration, filter cake petroleum ether obtain white solid 115mg, Yield 66%.LCMS:m/z=431.2 (M+H)⁺.

Step 3): 4- [[(1- Acetylpiperidin -4- base) methyl] amino] -2- [(1- methyl-1 H- pyrazoles -4- base) ammonia Base] pyrimidine -5- formamide preparation:

By 4- [[(5- carbamoyl -2- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino] methyl] Piperidines -1- t-butyl formate (115mg, 0.27mmol) is dissolved in methylene chloride (3mL), is slowly dropped into trifluoroacetic acid (1mL), 25 DEG C stirring 2 hours.Reaction solution is evaporated.Crude product is dissolved in methylene chloride (4mL), and under 0 DEG C of argon gas protective condition, three second are first added Amine (160mg, 1.58mmol) instills chloroacetic chloride (63mg, 0.80mmol) after stirring 2 minutes, and 25 DEG C are reacted 2 hours.Reaction solution Concentration, thin-layer chromatography chromatograph (methylene chloride: methanol=10:1), obtain white solid 30mg, two step yields 30%.¹H NMR (400MHz,DMSO-d₆+DCl/D₂O)δ8.72(s,1H),8.02(s,1H),7.75(s,1H),4.47–4.25(m,1H),3.90 (s, 3H), 3.48 (d, J=6.7Hz, 2H), 3.17-3.02 (m, 1H), 2.54 (s, 3H), 2.13-2.07 (m, 2H), 2.04- 1.89 (m, 1H), 1.80-1.63 (m, 2H), 1.32-1.05 (m, 2H) .LCMS:m/z=373.2 (M+H)⁺.

12 4- of embodiment [[2- (1- Acetylpiperidin -4- base) ethyl] amino] -2- [(1- methyl-1 H- pyrazoles -4- base) Amino] pyrimidine -5- formamide preparation:

Step 1): 4- [2- [(5- carbamoyl -2- chlorine pyrimidine-4-yl) amino] ethyl] piperidines -1- t-butyl formate Preparation:

2,4- dichloro pyrimidine -5- formamide (200mg, 1.04mmol) is dissolved in tetrahydrofuran (5mL), 4- is separately added into (2- aminoethyl) piperidines -1- t-butyl formate (238mg, 1.04mmol) and diisopropyl ethyl amine (404mg, 3.13mmol), 25 DEG C are reacted 2 hours.It is added saturated salt solution (50mL), stirring is filtered after 15 minutes, and filter cake petroleum ether obtains white solid Body 270mg, yield 68%.LCMS:m/z=384.2 (M+H)⁺.

Step 2): 4- [2- [(5- carbamoyl -2- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) ammonia Base] ethyl] piperidines -1- t-butyl formate preparation:

By 4- [2- [(5- carbamoyl -2- chlorine pyrimidine-4-yl) amino] ethyl] piperidines -1- t-butyl formate (270mg, 0.70mmol) is dissolved in sec-butyl alcohol (3mL), is added 1- methyl-1 H- pyrazoles -4- amine (83mg, 0.85mmol) and three Fluoroacetic acid (0.1mL), 100 DEG C tube sealing reaction 2 hours.Reaction solution concentration, solid filtering, acetonitrile washing obtain white solid 170mg, yield 54%.LCMS:m/z=445.3 (M+H)⁺.

Step 3): 4- [[2- (1- Acetylpiperidin -4- base) ethyl] amino] -2- [(1- methyl-1 H- pyrazoles -4- base) ammonia Base] pyrimidine -5- formamide preparation:

By 4- [2- [(5- carbamoyl -2- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine-4-yl) amino] second Base] piperidines -1- t-butyl formate (170mg, 0.38mmol) is dissolved in methylene chloride (6mL), it is slowly dropped into trifluoroacetic acid (2mL), 25 DEG C are stirred 2 hours.Reaction solution is evaporated.Crude product is dissolved in methylene chloride (6mL), under 0 DEG C of argon gas protective condition, first It is added triethylamine (176mg, 1.36mmol), after stirring 2 minutes, instills chloroacetic chloride (69mg, 0.88mmol), 25 DEG C of reactions 2 are small When.Reaction solution concentration, thin-layer chromatography chromatograph (methylene chloride: methanol=10:1), obtain light yellow solid 10mg, two step yields 7%.¹H NMR(400MHz,DMSO-d₆+DCl/D₂O)δ8.58(s,1H),7.90(s,1H),7.63(s,1H),4.34–4.08 (m,1H),3.79(s,3H),3.77–3.64(m,1H),3.53–3.37(m,2H),3.04–2.83(m,1H),2.45–2.38 (m, 1H), 1.98 (s, 3H), 1.69-1.55 (m, 2H), 1.52-1.37 (m, 3H), 1.11-0.79 (m, 2H) .LCMS:m/z= 387.2(M+H)⁺.

13 4- of embodiment [[4- amino -2- luorobenzyl] amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine - The preparation of 5- formamide:

Step 1): the preparation of the chloro- 4- of 2- [(the fluoro- 4- nitrobenzyl of 2-) amino] pyrimidine -5- formamide:

2,4- dichloro pyrimidine -5- formamide (100mg, 0.52mmol) is dissolved in tetrahydrofuran (4mL), is separately added into (the fluoro- 4- nitrobenzophenone of 2-) methylamine hydrochloride (108mg, 0.52mmol) and diisopropyl ethyl amine (202mg, 1.57mmol), 25 DEG C are reacted 2 hours.It is added saturated salt solution (40mL), after stirring 15 minutes, crosses filter solid, filter cake petroleum ether obtains yellow Color solid 120mg, yield 71%.LCMS:m/z=326.0 (M+H)⁺.

Step 2): 4- [[the fluoro- 4- nitrobenzyl of 2-] amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- The preparation of formamide:

The chloro- 4- of 2- [(the fluoro- 4- nitrobenzyl of 2-) amino] pyrimidine -5- formamide (120mg, 0.37mmol) is dissolved in Zhong Ding In alcohol (3mL), 1- methyl-1 H- pyrazoles -4- amine (43mg, 0.44mmol) is added and trifluoroacetic acid (0.1mL), 100 DEG C of tube sealings are anti- It answers 2 hours.Reaction solution concentration, solid filtering, acetonitrile washing obtain brown solid 80mg, yield 56%.LCMS:m/z= 387.1(M+H)⁺.

Step 3): 4- [[4- amino -2- luorobenzyl] amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- The preparation of formamide:

By 4- [[the fluoro- 4- nitrobenzyl of 2-] amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formyl Amine (80mg, 0.21mmol) is dissolved in the mixed solution of ethyl alcohol (3mL) and water (1mL), afterwards be added chloride solid (112mg, 2.10mmol) with iron powder (117mg, 2.10mmol), it is heated to 70 DEG C of reaction hours.Reaction solution is cooling, diatomite filtering, thin layer It chromatographs (methylene chloride: methanol=10:1), obtains yellow solid 52mg, yield 70%.¹H NMR(400MHz,DMSO-d₆+DCl/ D₂O)δ8.76(s,1H),7.70(s,1H),7.60–7.47(m,1H),7.47–7.34(m,2H),7.32–7.19(m,1H), 4.83 (s, 2H), 3.81 (s, 3H) .LCMS:m/z=357.2 (M+H)⁺.

The synthesis of remaining embodiment

The synthesis of subsequent specific embodiment is according to synthetic route as follows, in method similar to Example 1, using tool There is the raw material of different substituents, synthesize corresponding intermediate A and target compound B, as shown in the following table 3 and table 4.

Reaction condition: 1) R¹CH₂NH₂, DIEA, THF, 25 DEG C, 2~16h；2)TFA, s-BuOH, 60~ 100 DEG C, 2~16h.

The structure and characterization of the midbody compound A and target compound B of 3 embodiment 14-180 of table

The structure and characterization of the midbody compound A and target compound B of 4 embodiment 181-227 of table

The test of 1. the compounds of this invention of experimental example inhibition JAK1, JAK2, JAK3, TYK2 kinase activity

In the enzymatic reaction assembled in vitro, the compound test compound of various concentration is added to specific enzymatic reaction Inhibiting effect, the specific test method is as follows:

5. instrument for testing of table, material and reagent

Two, test methods

It is following will be by taking JAK3 as an example, the specific experiment condition of JAK1, JAK2, JAK3, TYK2 is shown in annex.

1. preparation of reagents:

EDTA (0.5M pH8.0) solution is prepared: precise 14.612g EDTA powder, constant volume arrives after ultrapure water is added 100mL (if having it is insoluble if be heated to 37 DEG C, with 1N NaOH solution tune pH to 8.0)

1 × Kinase Assay Buffer: 25mL HEPES solution (1M), 190.175mg are separately added into reagent bottle EGTA、5mL MgCl₂Solution (1M), 1mL DTT, 50 μ L Tween-20 add ultrapure water constant volume to 500mL (adjusting pH to 7.5).

1 × Detection Buffer: it takes 10 × Detection of 1mL Buffer that 9mL water is added and mixes.

4 × terminate liquid: by 0.8mL above-mentioned EDTA (0.5M, pH8.0) solution, 10 × Detection of 1mL Buffer and 8.2mL ultrapure water mixes.

4 × JAK3 kinase solution: diluting kinases stoste to concentration with 1 × Kinase Assay Buffer is 0.36nM, is mixed It is even, it saves on ice.

4 × substrate solution: substrate ULight is diluted with 1 × Kinase Assay Buffer^TM-labeled JAK-1 (Tyr1023) Peptide stoste is mixed to 200nM.

4 × ATP solution: diluting ATP stoste to concentration with 1 × Kinase Assay Buffer is 40 μM, is mixed.

4 × detection liquid: detection antibody Europium-anti-phospho- is diluted with 1 × Detection Buffer Tyrosine antibody (PT66) is 8nM to concentration, is mixed.

2 × substrate/ATP mixed liquor: 4 × substrate solution and 600 μ l 4 × ATP solution evens mix and (use preceding preparation).

2, experimental procedure

1) dilution of compound,

In 96 orifice plates, compound DMSO solution is pressed into 3 times of dilution proportions, forms 11 gradients, another pure DMSO is molten Liquid is as positive control；One piece of 96 new orifice plate is taken, above-mentioned solution ultrapure water is diluted into 25 times (DMSO concentration is 4%)

2) by compound turntable to 384 orifice plates

By the compound solution diluted in above-mentioned 96 orifice plate with ultrapure water according to the standard turntable of 2 multiple holes to 384 orifice plates In corresponding hole.

3) add 4 × kinase solution: taking the 2.5 above-mentioned 4 × kinase solutions of μ l to be added to the corresponding reacting hole of 384 orifice plates with the volley of rifle fire In, it mixes room temperature pre-reaction 5 minutes.

4) add 2 × substrate/ATP mixed liquor: taking the 5 above-mentioned 2 × substrates of μ l/ATP mixed liquor corresponding to 384 orifice plates with the volley of rifle fire In reacting hole.

5) negative control: being arranged negative control hole in 384 orifice plates, which is added 2.5 4 × substrates of the hole μ l/, 2.5 μ l 4 × enzyme solutions, 2.5 μ l 1 × Kinase Assay Buffer and 2.5 ultrapure waters of the μ l containing 4%DMSO.

6) centrifugation mixes, and is protected from light room temperature reaction 60min.

7) enzymatic reaction is terminated:

The 5 above-mentioned 4 × terminate liquids of μ l are drawn into 384 orifice plate corresponding apertures, centrifugation mixes, and reacts at room temperature 5 minutes.

8) chromogenic reaction:

It draws 5 μ l above-mentioned 4 × detection liquid to be added in 384 orifice plate mesoporous, centrifugation mixes, and reacts at room temperature 60min.

9) 384 orifice plates are put into plate reader, transfer corresponding Programmable detection signal.

10) inhibiting rate and IC₅₀It calculates:

Hole readings=10000*EU665 value/EU615 value

Inhibiting rate=[1- (experimental port readings-negative control hole readings)/(Positive control wells readings-negative control hole is read Value)] * 100%

Drug concentration and the input GraphPad Prism5 processing of corresponding inhibiting rate are calculated into corresponding IC₅₀Value.

Three, test conditions:

The test of JAK1 kinase activity:

JAK1 (final concentration 10nM)；ATP (10 μM of final concentration)；ULight^TM-labeled JAK-1(Tyr1023) Peptide (final concentration 100nM)；Time of enzymatic reacting is 2 hours.It is maximum final concentration of 2.5 μM of compound, dilute through 3 times of gradients Totally 11 concentration after releasing, minimum final concentration of 0.042nM.DMSO final concentration of 1%.

The test of JAK2 kinase activity:

JAK2 (final concentration 0.25nM)；ATP (5 μM of final concentration)；ULight^TM-labeled JAK-1(Tyr1023) Peptide (final concentration 50nM)；Time of enzymatic reacting is 1 hour.Maximum final concentration of 2.5 μM of compound, through 3 times of gradient dilutions Totally 11 concentration afterwards, minimum final concentration of 0.042nM.DMSO final concentration of 1%.

The test of JAK3 kinase activity:

JAK3 (final concentration 0.36nM)；ATP (10 μM of final concentration)；ULight^TM-labeled JAK-1(Tyr1023) Peptide (final concentration 50nM)；Time of enzymatic reacting is 1 hour.Maximum final concentration of 2.5 μM of compound, through 3 times of gradient dilutions Totally 11 concentration afterwards, minimum final concentration of 0.042nM.DMSO final concentration of 1%.

The test of TYK2 kinase activity:

TYK2 (final concentration 8nM)；ATP (20 μM of final concentration)；ULight^TM-labeled JAK-1(Tyr1023)Peptide (final concentration 100nM)；Time of enzymatic reacting is 2 hours.Maximum final concentration of 2.5 μM of compound, totally 11 after 3 times of gradient dilutions A concentration, minimum final concentration of 0.042nM.DMSO final concentration of 1%.

Table 6 lists in the present invention part of compounds to tyrosine kinase JAK1, JAK2, JAK3 and TYK2 inhibitory activity Measurement result.IC in following table₅₀Value indicates that compound concentration when enzyme highest inhibiting rate 50%, NT indicate corresponding without testing Enzyme.

Table 6, part of compounds of the present invention are to JAK1, JAK2, JAK3 and TYK2 tyrosine-kinase enzyme inhibition activity measurement result

2. the compounds of this invention of experimental example quantifies AlphaLISA detection to the phosphorylation of STAT5 in hel cell

Handle hel cell with Tofacitinib the and S1 part of compounds of various concentration, then with 100ng/mL IL-4 into It assassinates and uses AlphaLISA quantitative detection pSTAT5 signal after swashing, the specific test method is as follows:

7. test agent of table:

One, the dilution and configuration of related solution

1, Acceptor Mix: matching while using, by Reaction Buffer1, Reaction Buffer2, Activation Buffer, Acceptor Beads are mixed according to the ratio of 47:47:4:2, are placed on ice chest (in 30min Using)

Donor Mix: matching while using mixes Dilution Buffer and Donor Beads according to the ratio of 49:1, (dim light operation, 30min is interior to be used) is placed on ice chest.

2, Positive control lysate :+250 μ L water of freeze-dried powder is dispensed (every 10.5 μ L of pipe), is put It is saved in -20 DEG C.(having been used within one month)

Two, experimentation

1, hel cell is collected, is washed three times (1000rpm, 4min) with PBS centrifugation, according to 100,000 cell/ in 96 orifice plates (no phenol red) the progress cell inoculation of well/45 μ L DMEM, each concentration do two multiple holes, cultivate 1h；

2, the Tofacitinib of 15 μ L various concentrations is added in every hole, cultivates 1h after being mixed with the volley of rifle fire；

3, the IL-4 of 20 μ L 400ng/mL is added in every hole, mixes, and cultivates 15min；

4,20 μ L 5 × Lysis buffer then are added in every hole, are mixed on mixing elfin, 350rpm, 10min； After cracking, low-speed centrifugal, 800rpm, 1min；

5, above-mentioned 10 μ L of pyrolysis product is drawn to add to respectively in 384 plates；

6,5 μ L Acceptor Mix are added in every hole, and sealing is protected from light with masking foil package, mix 1-2min, incubation at room temperature 2h；(low speed shakes on mixing elfin when incubation)

7,5 μ L Donor Mix are added in every hole, and sealing is wrapped up with masking foil, mixes 1-2min, are incubated at room temperature 2h；(dim light Operation, low speed shakes on mixing elfin when incubation)

8, corresponding program is opened in multi-functional plate reading machine Envision read orifice plate readings.

9, inhibiting rate and IC₅₀It calculates:

Table 8. lists part of compounds of the present invention and quantifies AlphaLISA detection knot to the phosphorylation of STAT5 in hel cell Fruit.

Table 8, part of compounds of the present invention are to the phosphorylation quantitative detection result of STAT5 in hel cell

Test of 3. the compounds of this invention of experimental example to mouse spleen cell proliferation inhibitory activity

Steps are as follows for specific experiment:

1) diluted chemical compound: (this experiment makes totally 9 concentration after 3 times of gradient dilutions of progress since maximum concentration 5000nM The maximum final concentration of 5000nM, minimum final concentration of 0.76nM of drug).

2) culture dish for taking 6 centimetres of a diameter is sieved wherein placing the cell filtration that an aperture is 70 μm, then in sieve 2mL HBSS solution is added, it is made to infiltrate culture dish bottom；

3) adult Balb/c mouse is euthanized with carbon dioxide, is impregnated 1 minute in 75% alcohol, is put into safety cabinet, Osculum is cut off in the middle part of the left veutro of mouse, exposure stomach wall finds spleen；

4) spleen is taken, removes on the cell filtration sieve that spleen is put into culture dish after the adipose tissue of surrounding, suitably cuts It cuts；

5) it is lightly ground spleen with the top plat part of syringe piston, obtains cell suspending liquid；

6) cell suspension is collected from culture dish, and cell suspension is slowly added to fill 5ml Ficoll-Paque PLUS 15ml centrifuge tube in；

7) it with the speed of 400g, is centrifuged 30 minutes at room temperature；

8) after being centrifuged, upper layer is slowly removed with suction pipe, then middle layer, i.e. splenocyte is slowly sucked out；

9) splenocyte suspension of collection is placed in another 15ml centrifuge tube and 10ml RPMI1640 is added and cultivated completely Base, 300g, are centrifuged 4 minutes by 4 DEG C；

10) liquid is discarded supernatant, complete medium is added, cell is resuspended, then carry out cell count.Cell suspension presses the 9th Step repeats to wash primary；

11) cell is transferred in culture dish with the cell density of 2,000,000/mL to 5,000,000/mL (containing 2.5 μ g/mL sword beans Albumin A) overnight incubation；

12) second day, cell is transferred in 15mL centrifuge tube, 5min is centrifuged with the speed of 300g；

13) discard supernatant liquid, be added 1640 complete culture solution of 5mL RPMI, piping and druming uniformly, take 10 μ L cell suspending liquids and 10 μ L tires expect blue mixing, are counted with cell counter, and cell number and survival rate are recorded.

14) for cell suspension inoculation into 96 orifice plates, every hole is inoculated with 80 μ l cell suspensions, and density is 100000 cells/wells；

15) the corresponding above-mentioned 5 × compound solution diluted with culture solution of 20 μ L is added in every hole, mixes；

16) 10 μ L CCK-8 reagents are added in every hole after cultivating 72 hours, and be incubated for 2 hours (can adjust according to shade Save the reaction time)；

17) its OD value is read at 450nm in multi-functional plate reading machine.

18) data processing:

Cell survival rate (%)=[(As-Ab)/(Ac-Ab)] * 100%

As: the OD value of experimental port (containing cell culture medium, CCK-8, compound),

Ac: the OD value of control wells (containing cell culture medium, CCK-8),

Ab: the OD value of blank well (culture medium, CCK-8 without cell and compound),

Then numerical value importing Graphpad Prism5 software is carried out curve fitting, calculates IC50.

Table 9. lists the compounds of this invention to the test result of mouse spleen cell proliferation inhibitory activity, and wherein A indicates IC₅₀ IC is indicated less than or equal to 100nM, B₅₀Greater than 100nM but it is less than or equal to 500nM, C indicates IC₅₀Greater than 500nM but be less than or IC is indicated equal to 1000nM, D₅₀Greater than 1000nM.

Table 9, the compounds of this invention are to the test result of mouse spleen cell proliferation inhibitory activity

Purposes, preparation, administration

Medical usage, indication

Biological data provided by the present invention shows that the compound of the present invention is conducive to treat or prevent due to tyrosine Disease caused by kinases (JAK1, JAK2, JAK3, TYK2) exception.The compound of the present invention more than 1/5th is demonstrate,proved JAK tyrosine kinase activity can strongly be inhibited in fact, and the generation and transfer of jak kinase family and autoimmune disease and cancer There is substantial connection.Therefore, the compound of the present invention is conducive to treat autoimmune disease, including but not limited to: psoriasis, leucoderma Wind, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic loupus erythematosus, Crohn disease.Of the invention Compound also helps treating cancer, including primary and metastatic cancer, including solid tumor.Such cancer includes but unlimited In: non-small cell lung cancer, Small Cell Lung Cancer, breast cancer, cancer of pancreas, glioma, glioblastoma, oophoroma, uterus Neck cancer, colorectal cancer, melanoma, carcinoma of endometrium, prostate cancer, bladder cancer, leukaemia, gastric cancer, liver cancer, gastro-intestinal stromal Tumor, thyroid cancer, chronic myelocytic leukemia, acute myelocytic leukemia, non-Hodgkin lymphoma, nasopharyngeal carcinoma, cancer of the esophagus, Brain tumor, B cell and t cell lymphoma, lymthoma, Huppert's disease, biliary tract carcinosarcoma, cholangiocarcinoma.The compound of the present invention It also include the cancer for treating resistance to one or more other treatment methods.The compound of the present invention can also be used in JAK1 kinases and/ Or the related other diseases other than autoimmune disease and cancer of JAK2 and/or JAK3 kinases, including but not limited to eye Bottom disease, pulmonary fibrosis, liver fibrosis etc..The compound of the present invention can be used as monotherapy or conjoint therapy, can with it is more A the compound of the present invention drug combination or with the other drugs drug combination other than the present invention.

Pharmaceutical methods

Pharmaceutical methods of the invention include to needing the subject of the compounds of this invention to determine therapeutically effective amount." treatment has Imitate dosage " difference according to the stage of disease, progress or severity.The compound of the present invention and the daily dosage of composition will take Certainly in many factors of patient, the medicine of severity, used particular compound including the illness, the illness treated Effect, particular composition, age, weight, general health, gender and diet, the approach of administration and timetable, metabolism and/or Discharge rate, duration for the treatment of of the compound etc..In addition, dosage needed for the compound of the present invention with can pharmaceutically connect After medicament is made in the carrier received, people and other animals can be applied to.Mode of administration include oral, rectum, parenteral, in brain pond, In intravaginal, peritonaeum, part (such as by transdermal patch, pulvis, ointment or drops), sublingual, buccal or nose spray.This hair The effective dose of bright compound is usually measured with per kilogram patient's weight institute's formulation rate, is preferable over 0.1~125 milligram/thousand Gram weight, generally 0.01~500 mg/kg weight.Administration can be it is one or many, daily, weekly, every other day or Every more days or an intermittent schedule.For example, the compound can with daily administration, weekly administration (for example, on every Mondays), Indefinite duration administration or continued over many weeks administration (such as 4-10 weeks).The effective dose of the compound of the present invention will be according to usedization Close object, mode of administration, the seriousness of disease, institute's treatment condition and the various physical factors of relevant patient and change.More In number situation, when the daily dosage of preferred compounds of the invention is about 0.01~500 mg/kg, it can achieve and make us Satisfied therapeutic effect.Preferred dose is 0.1~125 mg/kg, and preferred dosage is 1~25 mg/kg.Stomach External administration dosage is usually the Oral dosage levels in about 10%-20%.When the compound of the present invention is used as being treated in combination When a part of scheme, the component of each composition will be administered during a required treatment.Either as independent Dosage device or include two kinds of components as single formulation, the component in composition can be administered simultaneously in treatment phase, It can also be applied in the different time in treatment phase or some can be used as another pretreatment application.

About compound

The compound of the present invention can be used to treat in a free form, or in the appropriate case with pharmaceutically acceptable Salt or other derivatives form for treating.As used herein, term " pharmaceutically acceptable salt " refers to of the invention The organic salt and inorganic salts of compound, this salt be suitable for the mankind and lower animal, no excessive toxicity, irritation, allergic reaction etc., With reasonable interests/Hazard ratio.The pharmaceutically acceptable salt of amine, carboxylic acid, phosphonate and other types of compound is in institute Category is well-known in field.The salt can be reacted by the compound isolated and purified in the present invention with suitable free alkali or acid It forms.

Pharmaceutical innocuous acid formed salt, including but not limited to, with inorganic acid for example hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, Perchloric acid or the amide formed with organic acid such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, or By using method well known in the art, such as ion-exchange, to obtain these salt.Other pharmaceutically acceptable salts include Adipate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, disulfate, borate, butyric acid Salt, camphor hydrochlorate, camsilate, citrate, pentamethylene, digluconate, lauryl sulfate, esilate, first Hydrochlorate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, heptan, caproate, hydriodate, 2- Isethionate, Lactobionate, lactate, laruate, lauryl sulfate, malate, maleate, malonic acid Salt, methane sulfonates, 2- naphthalene sulfonate, nicotinate, nitrate, oleate, oxalates, palmitate, embonate, pectin Hydrochlorate, crosses 3- phenylpropionic acid salt, phosphate, picrate, Pivalate, propionate, stearate, succinic acid at persulfate Salt, sulfate, tartrate, rhodanate, tosilate, undecanoate, valerate etc..Representative alkali or alkaline earth Metal salt include sodium, lithium, potassium, calcium, magnesium, etc..Other pharmaceutically acceptable salts include nontoxic ammonium appropriate, quaternary ammonium, and are made With such as halogen ion, hydroxyl, carboxylate radical, sulfate radical, phosphate radical, nitrate anion, low-grade alkane sulfonate and arylsulphonate shape At amido cation.

In addition, terms used herein " prodrug ", which refers to a compound in vivo, can be converted into shown in formula (I) of the present invention Compound.This conversion is to be hydrolyzed in blood by pro-drug or be converted into parent through enzyme effect in blood or tissue Compound.

Composition

Composition described in this patent is by any one compound described herein (or prodrug or its is pharmaceutically acceptable Salt or other pharmaceutically acceptable derivates) and one or more pharmaceutically acceptable carriers or excipient institute group At.These compositions can optionally further include one or more other therapeutic agents.The compound of the present invention can be with one kind Or a variety of other therapeutic schemes are (for example, Tofacitinib or other kinase inhibitors, interferon, bone-marrow transplantation, farnesyl turn Move enzyme inhibitor, diphosphonate, the application combination of Thalidomide, cancer vaccine, hormonotherapy, antibody, radiation etc.) it is co-administered In required patient.The pharmaceutical composition of compound can be one or more anti-inflammatory agents or anticancer agent.

As described herein, composition of the invention includes the compound of the present invention and pharmaceutically acceptable carrier, including Any and all solvents, diluent or other carriers, dispersion or suspension aids, surfactant, isotonic agent, thickener or emulsification Agent, preservative, solid binder, lubricant etc., to be suitable for required particular dosage form.Some pharmaceutically acceptable carrier materials The example of material includes, but are not limited to sugar, such as lactose, dextrose and saccharose；Starch such as cornstarch and potato starch；Fiber Element and its derivative such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate；Powdered tragacanth；Malt；Gelatin；Talcum Powder；Excipient, such as cocoa butter and suppository wax；Oil as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and Soybean oil；Ethylene glycol, such as propylene glycol；Esters such as ethyl oleate and ethyl laurate, agar；Buffer such as magnesium hydroxide and Aluminium hydroxide；Alginic acid；Apirogen water；Isotonic saline solution；Ringer's solution；Ethyl alcohol and phosphate buffer solution and other nontoxic Biocompatible lubricant such as NaLS and magnesium stearate and colorant, releasing agent, coating agent, sweetener, flavoring agent It can also may be present in composition with aromatic, preservative and antioxidant.Formula

Present invention also contemplates that reactive compound in the present invention and one or more pharmaceutically acceptable carriers and/or dilute Release agent and/or a kind of composition (collectively referred to herein as " carrier " material) that adjuvant is used in combination, and if necessary, It also include other active constituents.Reactive compound of the invention can be administered by any suitable approach, preferably to be suitble to this The form of the pharmaceutical composition of kind administration route is for effective dose needed for expected treatment.The compound of the present invention and composition Form of medication can be, take orally, mucous membrane, part, rectum is transpulmonary, such as spraying by sucking or parenteral including intravascular, Intravenously, subcutaneously, intramuscular in peritonaeum, in breastbone and infusion techniques.It is administered be subject to dosage unit dosage form and contain There are pharmaceutically acceptable carrier, adjuvant and excipient.For oral administration, pharmaceutical composition can be following form, example Such as, tablet, capsule, suspension or liquid.The example of the dosage unit is tablet or capsule.For example, they may include The amount of active constituent is 1 to 2000 milligram, and preferably 1 to 500 milligram, more common is 5 to 200 milligrams.One people or other The suitable daily dosage of mammal can be different according to patient and other factors, but conventional method can be used and come again really It is fixed.As previously mentioned, the amount of compound depends in the administration of compound according to the present invention and/or composition and dosage Many factors, the age including subject, weight, gender and medical condition, disease type, the disease severity, administration way Diameter and frequency and used specific compound.Therefore, dosage can vary greatly, but standard method can be used It determines.Typical daily dose is 0.01~500 mg kg of body weight, preferably 0.1~125 mg kg of body weight, more preferably It is 1~25 mg kg of body weight.

Reactive compound of the invention usually forms administration route with one or more adjuvants, excipient or carrier.Such as Fruit oral administration, the compound can be with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, cunning Stone, stearic acid, magnesium stearate, magnesia, phosphoric acid and sulfuric acid sodium and calcium salt, gelatin, acacin, mosanom, polyethylene pyrrole Pyrrolidone and/or polyvinyl alcohol mix, then tabletting or be made capsule with facilitate administration.Such capsule or tablet can be with Comprising a kind of controlled release preparation, reactive compound can be dispersed in hydroxypropyl methyl cellulose to provide.It is suitable for local administration Preparation include suitable for penetrate through skin liquid or semi-liquid preparations (such as liniment, lotion, ointment, cream or paste) and It is suitble to be applied to the dropping liquid of eye, ear or nose.The suitable local dosages of the compound of the present invention are 0.1~150 milligram, daily It is one to four time, 1 to 2 time preferably daily.For local administration, when using ointment, active constituent can be mixed with any paraffin or water Dissolubility ointment is matrix.Alternatively, active constituent can be configured to water-in-oil emulsion basic cream.If desired, emulsifiable paste matrix Water phase may include the polyalcohol of for example, at least 30% weight ratio, such as propylene glycol, butane -1,3- glycol, mannitol, sorbierite, sweet Oil, polyethylene glycol and their mixture.Topical formulations may include that can make to live by skin or the enhancing of other involved areas Property ingredient draws or the compound of infiltration.The example of such dermal permeation reinforcing agent includes dimethyl sulfoxide and related analogs. Compound can also be administered by transdermal device.It is preferred that cutaneous penetration will be used containing liquid storage device and multiple aperture plasma membrane or solid-based The patch of matter is realized.The oil of emulsion of the invention can be mutually made of in a known way principal component, include at least one cream Agent and fat or oily mixture or the mixture with the fat of the two and oil.Preferably, hydrophilic emulsifier can simultaneously with Lipophilic emulsifier as stabilizer shares, it is additionally preferred to be that it can also be shared with oil & fat.It is suitable in this hair Emulsifier used in bright preparation and emulsion stabilizer include polysorbate60, sorbester p17, cetostearyl alcohol, myristyl alcohol, single hard Glycerol, NaLS, single distearin or with its in the mixture of emulsifying wax or this field Well known other materials.Emulsifiable paste should preferably non-greasy, not colored and washable product, and have suitable consistency to avoid from It is leaked in pipe or other containers.Linear chain or branched chain, unitary or the different adipate ester of binary alkyl ester such as two, isocetyl stearic acid Ester, the propylene glycol diesters of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2- The ester of ethyl hexyl palmitat or mixed branch can also be used.Alternatively, high-melting-point lipid such as White soft paraffin and/or Atoleine or other mineral oil can use.Preparation suitable for local administration to eye further includes eye drops, wherein activity Ingredient dissolves or is suspended in suitable carrier, especially for the aqueous solvent of active constituent.Active constituent is in these formulations Weight ratio is preferably 0.5% to 20%, and more favorable ratio is 0.5~10%, most preferably about 1.5% concentration.Preparation is used for Parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solution or suspension.These solution and suspension Liquid by using the formulations for oral administration being mentioned herein or can use it from one or more aseptic powderies or particle The carrier or diluent of his suitable dispersing agent or wetting agent and suspending agent and prepare.Compound is soluble in water, poly- second two Alcohol, propylene glycol, ethyl alcohol, corn oil, cottonseed oil, peanut oil, sesame oil, benzylalcohol, sodium chloride, bassora gum, and/or various bufferings Liquid.Other adjuvants and administration mode are well-known in pharmaceutical field.

The active constituent can also include the combination of salt water, glucose or water by drug administration by injection, with suitable carrier Object or with cyclodextrin (Captisol), cosolvent solubilized (i.e. propylene glycol) or Micellar Solubilization (i.e. Tween 80).Preparation can be with It is aseptic injectable solution or the suspension in the nontoxic acceptable diluent of parenteral or solvent, such as 1,3-BDO. Workable solvent has water, Ringer's solution and isotonic sodium chlorrde solution.In addition, sterile, fixed oil is typically used as solvent Or suspension media.Any mild fixing oil for this purpose can use, list or two glyceride including synthesis.

For pulmonary administration, described pharmaceutical composition can be applied in aerosol or with inhalator, including dry powder Aerosol.For rectally suppository can by the way that drug is prepared with suitable nonirritant excipient, such as cocoa butter and Polyethylene glycol is solid at normal temperature, but is liquid in rectal temperature, therefore will melt in the rectum and release drug.The medicine Compositions can be added such as sterilizing of conventional pharmaceutical practice and/or can containing conventional adjuvant, as preservative, stabilizer, The tablet and pill of wetting agent, emulsifier, buffer etc. also can be used enteric coating to prepare.Such composition can also include assistant Agent, such as wetting agent, sweetener, corrigent and aromatic.

Pharmaceutical composition of the invention includes structure formula (I) compound described herein or its pharmaceutically acceptable salt, swashs Enzyme inhibitor (small molecule, polypeptide, antibody etc.), immunosuppressor, anticarcinogen, antivirotic, anti-inflammatory agent, antifungal agent, antibiosis The other activating agent of plain or anti-angiogenic antihyperproliferative compound；And any pharmaceutically acceptable carrier, adjuvant or figuration Agent.Alternative composition of the invention include with formula described herein (I) compound or its pharmaceutically acceptable salt and Pharmaceutically acceptable carrier, adjuvant or excipient.Such composition optionally including one or more additional therapeutic agents, Including for example, kinase inhibitor (small molecule, polypeptide, antibody etc.), immunosuppressor, anticancer agent, antivirotic, anti-inflammatory agent resist Epiphyte pharmaceutical, antibiotic or anti-angiogenic antihyperproliferative compound.

Term " pharmaceutically acceptable carrier or adjuvant " refers to that one kind can be administered to together with the compound of the present invention The carrier or adjuvant of patient, and it does not destroy pharmaceutical activity, and is nontoxic when dosage is enough to deliver administration therapeutic dose. Pharmaceutically acceptable carrier, adjuvant and excipient pharmaceutical composition for use in the present invention, including but not limited to, ion exchange Agent, aluminium oxide, aluminum stearate, lecithin, self-emulsifying drug delivery system (SEDDS), such as d-atocopHerol polyethylene glycol 1000 succinates, surfactant used in pharmaceutical dosage form, such as tween or other similar polymeric delivery matrices, serum Albumen such as human serum albumins, buffer substance such as phosphate, glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acid it is inclined Surfactant, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, phosphoric acid hydrogen are used in glyceride mixture Potassium, sodium chloride, zinc salt, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, the substance based on cellulose, poly- second two Alcohol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene block polymer, polyethylene glycol and lanolin.Ring Dextrin such as α-, β-and gamma-cyclodextrin or chemically modified derivative such as hydroxy alkyl, including 2 and 3- hydroxypropyl-cyclodextrin, or The derivative of the other dissolutions of person is also advantageously used for improving the compound for delivering structural formula described herein.Described pharmaceutical composition It can be arbitrarily administered orally using acceptable dosage form, including but not limited to capsule, tablet, emulsion and aqueous suspension, dispersion Body and solution.In the case where tablets for oral use, commonly utilized carrier includes lactose and cornstarch.Lubrication Agent is also typically added into such as such as magnesium stearate.For with the oral administration of capsule form, useful diluent includes lactose With dry cornstarch.When being administered orally using aqueous suspension and/or emulsion, active constituent can with emulsification and/or Suspending agent is suspended or dissolved in oily phase.If desired, certain sweeteners, corrigent and/or colorant can be added into.The medicine Compositions may include using liposome or microencapsulation technology, and different embodiments can be found in the literature.It is described Pharmaceutical composition can pass through nasal aerosol or inhalation.Such composition is according to the known technology in field of pharmaceutical preparations Preparation, and solution can be prepared into salt water, using benzyl alcohol or other suitable preservatives, sorbefacient is to mention High bioavilability, fluorocarbon and/or other solubilizer or dispersing agent, example are also well-known the prior art.

Drug combination

The compound of the present invention can be used as exclusive use, can also with one or more other the compound of the present invention or It is used with one or more other drug combinations.When being administered in combination, therapeutic agent can be configured to be administered simultaneously or sequentially exist Different time administrations or the therapeutic agent can be used as single composition administration.So-called " combination treatment ", refer to using The compound of the present invention is used together with another medicament, and administration mode is that co-administered or every kind of medicament are suitable simultaneously for every kind of medicament Sequence administration, no matter which kind of situation, purpose is all the optimum efficiency of drug to be reached.Co-administered includes while delivering dosage form, with And the independent dosage form of every kind of compound respectively.Therefore, the compound of the present invention administration can with known this field other Therapy uses simultaneously, for example, using radiotherapy or cytostatic agent, cytotoxic agent, Qi Takang in cancer treatment The adjunctive therapies such as cancer agent improve cancerous symptom.The present invention is not limited to the sequences of administration；The compound of the present invention can be applied previously With being administered simultaneously, or applied after other anticancer agents or cytotoxic agent.

The above is a preferred embodiment of the present invention, it is noted that for those skilled in the art For, under the premise of not departing from principle of the present invention, embodiments of the present invention can also make several improvements and modify, These improvement and modification also should be regarded as protection scope of the present invention.

Claims

1. a kind of compound or its isomers, solvate or its pharmaceutically acceptable salt, which has structural formula (I):

Wherein,

R¹Forn₁For 0-2, n₂For 0-1, n₃For 0-5,

L₁ForR⁴And/or R⁵For H, C₁-C₃Straight chained alkyl；

R²Forn₄For 0-3, n₅For 0-1, n₆For 0-5,

L₂ForR⁷And/or R⁸For H, C₁-C₃Straight chained alkyl；

R³For a) H, hydroxyl, cyano,

b)C₁-C₅Linear or branched alkyl group,

c)C₃-C₇Naphthenic base,

d)C₁-C₅Straight or branched alkoxyl,

e)C₁-C₅Linear chain or branched chain alkylthio group,

F) 5-7 circle heterocyclic ring,

G) substituted or non-substituted five member aromatic or heteroaryl,

H) substituted or non-substituted hexa-atomic aryl or heteroaryl,

I) containing the hexa-atomic aromatic ring of 0-3 hetero atom or hetero-aromatic ring and five yuan or hexatomic ring, or simultaneously containing five yuan of heteroaromatics of 1-3 hetero atom Five yuan or hexatomic ring, such as:

R⁶For a) H, hydroxyl,

B)-NR'R ", R', R " are H, C₁-C₃Alkyl,

c)C₁-C₅Linear or branched alkyl group,

d)C₃-C₈Naphthenic base,

e)C₁-C₅Straight or branched alkoxyl,

f)C₁-C₅Linear chain or branched chain alkylthio group,

G) heterocycle.

2. compound according to claim 1 or its isomers, solvate or its pharmaceutically acceptable salt, wherein The 5-7 circle heterocyclic ring contains 1-2 hetero atom, and hetero atom is selected from O and/or N and/or S, when hetero atom is N, connects H on N Or C₁-C₄Alkyl, C₁-C₃Acyl group, preferably acetyl group, trifluoroacetyl group, propiono, N, N- diformyl；When hetero atom is S, 0-2 oxygen atom is connected on S.

3. compound according to claim 1 or its isomers, solvate or its pharmaceutically acceptable salt, wherein The structural formula of the substituted five member aromatic or heteroaryl isWherein:

J₁And/or J₂And/or J₃And/or J₄For C, N, S, O,

R⁹For C₁-C₃Linear or branched alkyl group.

4. compound according to claim 1 or its isomers, solvate or its pharmaceutically acceptable salt, wherein The structural formula of the substituted or non-substituted five member aromatic or heteroaryl isWherein:

J₁、J₂、J₃、J₄It is each independently C, N, S, O,

R²⁰、R²¹It is each independently C₁-C₃Linear or branched alkyl group.

5. compound according to claim 1 or its isomers, solvate or its pharmaceutically acceptable salt, wherein The structural formula of the substituted or non-substituted hexa-atomic aryl or heteroaryl isWherein:

Q₁、Q₂、Q₃、Q₄、Q₅For N or C；

R¹⁰And/or R¹¹And/or R¹²Are as follows:

a)-F、-Cl、-Br、-CF₃、-OCF₃, cyano,

B)-NR'R ", R', R " are H, C₁-C₃Alkyl,

c)C₁-C₃Alkyl, C₂-C₅Alkynyl, C₃-C₅Naphthenic base,

d)SO₂R¹³, wherein R¹³For H, C₁-C₃Alkyl,

e)Wherein q is 0-2, M O, S, R¹⁴For H, C₁-C₅Linear or branched alkyl group,

f)Wherein R¹⁵、R¹⁶For straight chained alkyl.

6. compound according to claim 1 or its isomers, solvate or its pharmaceutically acceptable salt, wherein The structural formula of the substituted or non-substituted hexa-atomic aryl or heteroaryl isWherein:

Q₁、Q₂、Q₃、Q₄、Q₅For N or C；

R¹⁷、R¹⁸Each independently are as follows:

A)-H,

b)-F、-Cl、-Br、-CF₃、-OCF₃, cyano,

C)-NR'R ", R', R " are H, C₁-C₃Alkyl,

d)C₁-C₃Alkyl, C₂-C₅Alkynyl, C₂-C₅Alkenyl, C₃-C₅Naphthenic base,

e)SO₂R¹³, wherein R¹³For H, C₁-C₃Alkyl,

g)Wherein R¹⁵、R¹⁶For C₁-C₃Straight chained alkyl,

h)-(CH₂)_t-R¹⁹, t 1-2, R¹⁹For C₃-C₅Naphthenic base.

7. compound according to claim 1 or its isomers, solvate or its pharmaceutically acceptable salt, wherein The heterocycle be five yuan or hexa-atomic oxygen-containing and/or nitrogen heterocycle, such as:

8. a kind of compound or its isomers, solvate or its pharmaceutically acceptable salt, which has structural formula (I):

Wherein,

R¹Forn₁For 0-2, n₂For 0-1, n₃For 0-5,

L₁ForR⁴And/or R⁵For H, C₁-C₃Straight chained alkyl；

R²Forn₄For 0-3, n₅For 0-1, n₆For 0-5,

L₂ForR⁷And/or R⁸For H, C₁-C₃Straight chained alkyl；

R³For R²²Substituted C₁-C₃Alkoxy or R²²Substituted C₁-C₃Alkylthio group, R²²For hydroxyl, C₁-C₃Alkoxy, C₁-C₃Alkane The C that sulfenyl ,-NR'R ", hydroxyl replace₁-C₃The C that alkoxy, amino replace₁-C₃The C that alkoxy, hydroxyl replace₁-C₃Alkylthio group, The C that amino replaces₁-C₃Alkylthio group, wherein R', R " are H, C₁-C₃Alkyl；

R⁶For a) H, hydroxyl,

B)-NR'R ", R', R " are H, C₁-C₃Alkyl,

c)C₁-C₅Linear or branched alkyl group,

d)C₃-C₈Naphthenic base,

e)C₁-C₅Straight or branched alkoxyl,

f)C₁-C₅Linear chain or branched chain alkylthio group, or

9. a kind of compound or its isomers, solvate or its pharmaceutically acceptable salt, the compound are selected from:

4- benzylamino -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2- methoxy-benzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(the fluoro- 6- methoxy-benzyl of 2-) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2,6- dimethyl benzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2,6- dichloro benzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2,6- difluorobenzyl) amino] -2- [[1- (2- methoxy ethyl) -1H- pyrazoles -4- base] amino] pyrimidine -5- formyl Amine；

4- [(the fluoro- 6- methoxy-benzyl of 2-) amino] -2- [[1- (2- methoxy ethyl) -1H- pyrazoles -4- base] amino] pyrimidine - 5- formamide；

4- [[4- amino -2- luorobenzyl] amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- n-butyl amine base -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

2- [(1- methyl-1 H- pyrazoles -4- base) amino] -4- (pentylamine base) pyrimidine -5- formamide；

4- i-butylamino -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

2- [(1- methyl-1 H- pyrazoles -4- base) amino] new penta aminopyrimidine -5- formamide of -4-；

4- (isoamylamino) -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(3,3- dimethylbutyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

2- [(1- methyl-1 H- pyrazoles -4- base) amino] -4- [(4- methyl amyl) amino) pyrimidine -5- formamide；

4- [(Cvclopropvlmethvl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(cyclobutylmethyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(cyclopentyl-methyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(cyclohexyl methyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2- cyclopropylethyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2- cyclopentyl ethyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(4- luorobenzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(4- chlorobenzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(3- luorobenzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(3- chlorobenzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(3- methylbenzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2- luorobenzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

2- [(1- methyl-1 H- pyrazoles -4- base) amino] -4- [(2- methylbenzyl) amino] pyrimidine -5- formamide；

2- [(1- methyl-1 H- pyrazoles -4- base) amino] -4- [(2- Ethylbenzyl) amino] pyrimidine -5- formamide；

4- [(2- cyclopropyl benzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2- chlorobenzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

2- [(1- methyl-1 H- pyrazoles -4- base) amino] -4- [(2- trifluoromethyl benzyl) amino] pyrimidine -5- formamide；

4- [(2- cyanobenzyls) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2- ethoxy benzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2- isopropoxide benzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

2- [(1- methyl-1 H- pyrazoles -4- base) amino] -4- [(2- trifluoro-methoxybenzyl) amino] pyrimidine -5- formamide；

4- [[2- (methoxyl methyl) benzyl] amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2,3- difluorobenzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(the fluoro- 3- chlorobenzyl of 2-) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2,3- dichloro benzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(the chloro- 3- luorobenzyl of 2-) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2- methyl -3- chlorobenzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2,3- dimethyl benzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2,4- difluorobenzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(the fluoro- 4- chlorobenzyl of 2-) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(the chloro- 4- luorobenzyl of 2-) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2- methyl -4- luorobenzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2- methyl -4- chlorobenzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2- methoxyl group -4- luorobenzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2,5- difluorobenzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(the fluoro- 5- chlorobenzyl of 2-) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(the chloro- 5- luorobenzyl of 2-) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2- methyl -5- luorobenzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2- methyl-5-chloro benzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [[2- (trifluoromethyl) -5- luorobenzyl] amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formyl Amine；

4- [(2- methoxyl group -5- chlorobenzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2,5- dimethoxy-benzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2,6- difluorobenzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(the fluoro- 6- chlorobenzyl of 2-) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2- fluoro- 6- (trifluoromethyl) benzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formyl Amine；

4- [(2- methyl -6- chlorobenzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2,6- dimethoxy-benzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(3,5- difluorobenzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(3,5- dimethoxy-benzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2,3,6- trifluoro-benzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2,3,5- trifluoro-benzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(the fluoro- 3- methylbenzyl of 2,6- bis-) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(the chloro- 3,6- difluorobenzyl of 2-) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2,4,6- trifluoro-benzyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

2- [(1- methyl-1 H- pyrazoles -4- base) amino] -4- (benzene ethylamino) pyrimidine -5- formamide；

2- [(1- methyl-1 H- pyrazoles -4- base) amino] -4- [(3- methylphenethyl) amino] pyrimidine -5- formamide；

2- [(1- methyl-1 H- pyrazoles -4- base) amino] -4- [(3- methoxyphenethyl) amino] pyrimidine -5- formamide；

4- [(2- fluorobenzene ethyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2- methylphenethyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2- methoxyphenethyl) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(the fluoro- 6- chlorobenzene ethyl of 2-) amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

2- [(1- methyl-1 H- pyrazoles -4- base) amino] -4- [(pyridin-4-yl methyl) amino] pyrimidine -5- formamide；

4- [[(2- fluorine pyridin-3-yl) methyl] amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [[(2- methoxypyridine -3- base) methyl] amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- first Amide；

4- [[(2- ethoxy pyridine -3- base) methyl] amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- first Amide；

4- [[(2- tert-butoxy pyridin-3-yl) methyl] amino] -2- [(1- methyl-1 H- pyrazoles -4- base) amino] pyrimidine -5- Formamide；

2- [(1- methyl-1 H- pyrazoles -4- base) amino] -4- [[2- (pyridin-3-yl) ethyl] amino] pyrimidine -5- formamide；

2- [(1- methyl-1 H- pyrazoles -4- base) amino] -4- [[(2,3- dihydrobenzo [b] [1,4] dioxanes -5- base) methyl] Amino] pyrimidine -5- formamide；

2- [(1- methyl-1 H- pyrazoles -4- base) amino] -4- [[(1H- indol-3-yl) methyl] amino] pyrimidine -5- formamide；

(S) -2- [(1- methyl-1 H- pyrazoles -4- base) amino] -4- [(2- phenyl propyl) amino] pyrimidine -5- formamide；

(R) -2- [(1- methyl-1 H- pyrazoles -4- base) amino] -4- [(2- phenyl propyl) amino] pyrimidine -5- formamide；

4- benzylamino -2- [[1- (2- methoxy ethyl) -1H- pyrazoles -4- base] amino] pyrimidine -5- formamide；

2- [(1H- pyrazoles -4- base) amino] -4- [(2,6- difluorobenzyl) amino] pyrimidine -5- formamide；

4- [(2,6- difluorobenzyl) amino] -2- [(1- ethyl -1H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2,6- difluorobenzyl) amino] -2- [(1- isopropyl -1H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2,6- difluorobenzyl) amino] -2- [(1- cyclopropyl -1H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2,6- difluorobenzyl) amino] -2- [(1- cyclobutyl -1H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(2,6- difluorobenzyl) amino] -2- [[1- (tetrahydrofuran -3- base) -1H- pyrazoles -4- base) amino] pyrimidine -5- first Amide；

4- [(2,6- difluorobenzyl) amino] -2- [[1- (tetrahydro -2H- pyrans -4- base) -1H- pyrazoles -4- base) amino] pyrimidine - 5- formamide；

4- [(2,6- difluorobenzyl) amino] -2- [[1- ((tetrahydrofuran -2- base) methyl) -1H- pyrazoles -4- base] amino] is phonetic Pyridine -5- formamide；

4- [(2,6- difluorobenzyl) amino] -2- [[1- ((tetrahydrofuran -3- base) methyl) -1H- pyrazoles -4- base] amino] is phonetic Pyridine -5- formamide；

4- [(2,6- difluorobenzyl) amino] -2- [[1- ((tetrahydro -2H- pyrans -4- base) methyl) -1H- pyrazoles -4- base] amino] Pyrimidine -5- formamide；

4- [(2,6- difluorobenzyl) amino] -2- [[1- (2- ethoxy) -1H- pyrazoles -4- base] amino] pyrimidine -5- formamide；

4- [(2,6- difluorobenzyl) amino] -2- [[1- (2-methylmercaptoethyl) -1H- pyrazoles -4- base] amino] pyrimidine -5- formyl Amine；

4- [(2,6- difluorobenzyl) amino] -2- [[1- (2- (dimethylamino) ethyl) -1H- pyrazoles -4- base] amino] pyrimidine - 5- formamide；

4- [(2,6- difluorobenzyl) amino] -2- [[1- (2- (morpholine -1- base) ethyl) -1H- pyrazoles -4- base] amino] pyrimidine - 5- formamide；

4- [(2,6- difluorobenzyl) amino] -2- [[1- (2- hydroxy-2-methyl propyl) -1H- pyrazoles -4- base] amino] pyrimidine - 5- formamide；

4- [(the fluoro- 6- chlorobenzyl of 2-) amino] -2- [[1- (2- ethoxy) -1H- pyrazoles -4- base] amino] pyrimidine -5- formamide；

4- [(the fluoro- 6- chlorobenzyl of 2-) amino] -2- [[1- (2- methoxy ethyl) -1H- pyrazoles -4- base] amino] pyrimidine -5- first Amide；

4- [(the fluoro- 6- chlorobenzyl of 2-) amino] -2- [[1- (2- (dimethylamino) ethyl) -1H- pyrazoles -4- base] amino] is phonetic Pyridine -5- formamide；

2- [(1H- pyrazoles -4- base) amino] -4- [(the fluoro- 6- methoxy-benzyl of 2-) amino] pyrimidine -5- formamide；

4- [(the fluoro- 6- methoxy-benzyl of 2-) amino] -2- [(1- ethyl -1H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(the fluoro- 6- methoxy-benzyl of 2-) amino] -2- [(1- isopropyl -1H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(the fluoro- 6- methoxy-benzyl of 2-) amino] -2- [(1- cyclopropyl -1H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(the fluoro- 6- methoxy-benzyl of 2-) amino] -2- [(1- cyclobutyl -1H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(the fluoro- 6- methoxy-benzyl of 2-) amino] -2- [(1- cyclopenta -1H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(the fluoro- 6- methoxy-benzyl of 2-) amino] -2- [(1- cyclohexyl -1H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(the fluoro- 6- methoxy-benzyl of 2-) amino] -2- [(1- suberyl -1H- pyrazoles -4- base) amino] pyrimidine -5- formamide；

4- [(the fluoro- 6- methoxy-benzyl of 2-) amino] -2- [[1- (tetrahydro -2H- pyrans -4- base) -1H- pyrazoles -4- base) amino] Pyrimidine -5- formamide；

4- [(the fluoro- 6- methoxy-benzyl of 2-) amino] -2- [[1- (2- ethoxy) -1H- pyrazoles -4- base] amino] pyrimidine -5- first Amide；

4- [(the fluoro- 6- methoxy-benzyl of 2-) amino] -2- [[1- (2-methylmercaptoethyl) -1H- pyrazoles -4- base] amino] pyrimidine - 5- formamide；

4- [(the fluoro- 6- methoxy-benzyl of 2-) amino] -2- [[1- (2- (dimethylamino) ethyl) -1H- pyrazoles -4- base] amino] Pyrimidine -5- formamide；

4- [(the fluoro- 6- methoxy-benzyl of 2-) amino] -2- [1- (1- methyl piperazine -4- base) -1H- pyrazoles -4- base) amino] it is phonetic Pyridine -5- formamide；

4- [(the fluoro- 6- methoxy-benzyl of 2-) amino] -2- [[1- (2- (pyrroles -1- base) ethyl) -1H- pyrazoles -4- base] amino] Pyrimidine -5- formamide；

4- [(the fluoro- 6- methoxy-benzyl of 2-) amino] -2- [[1- (2- (piperidin-1-yl) ethyl) -1H- pyrazoles -4- base] amino] Pyrimidine -5- formamide；

4- [(the fluoro- 6- methoxy-benzyl of 2-) amino] -2- [[1- (2- (morpholine -1- base) ethyl) -1H- pyrazoles -4- base] amino] Pyrimidine -5- formamide；

4- [(the fluoro- 6- methoxy-benzyl of 2-) amino] -2- [[1- (6- methoxy hexyl) -1H- pyrazoles -4- base] amino] pyrimidine -5- Formamide；

4- [(the fluoro- 6- methoxy-benzyl of 2-) amino] -2- [[1- (2- hydroxy-2-methyl propyl) -1H- pyrazoles -4- base] amino] Pyrimidine -5- formamide；

4- [[2- fluoro- 6- (trifluoromethyl) benzyl] amino] -2- [[1- (2- ethoxy) -1H- pyrazoles -4- base] amino] pyrimidine - 5- formamide；

4- [(2- fluoro- 6- (trifluoromethyl) benzyl) amino] -2- [[1- (2- methoxy ethyl) -1H- pyrazoles -4- base] amino] is phonetic Pyridine -5- formamide；

4- [(2- fluoro- 6- (trifluoromethyl) benzyl) amino] -2- [[1- (2- (dimethylamino) ethyl) -1H- pyrazoles -4- base] Amino] pyrimidine -5- formamide；

4- [(2- methoxy-benzyl) amino] -2- [[1- (2- ethoxy) -1H- pyrazoles -4- base] amino] pyrimidine -5- formamide；

4- [(2- methoxyl group -5- chlorobenzyl) amino] -2- [[1- (2- ethoxy) -1H- pyrazoles -4- base] amino] pyrimidine -5- first Amide；

4- [(2,6- dimethyl benzyl) amino] -2- [[1- (2- ethoxy) -1H- pyrazoles -4- base] amino] pyrimidine -5- formyl Amine；

4- [(the chloro- 6- methylbenzyl of 2-) amino] -2- [[1- (2- ethoxy) -1H- pyrazoles -4- base] amino] pyrimidine -5- formyl Amine；

4- [(2,6- dichloro benzyl) amino] -2- [[1- (2- ethoxy) -1H- pyrazoles -4- base] amino] pyrimidine -5- formamide；

4- [(2,3,6- trifluoro-benzyl) amino] -2- [[1- (2- ethoxy) -1H- pyrazoles -4- base] amino] pyrimidine -5- formyl Amine；

4- [(the fluoro- 3- methylbenzyl of 2,6- bis-) amino] -2- [[1- (2- ethoxy) -1H- pyrazoles -4- base] amino] pyrimidine -5- Formamide；

4- [(the chloro- 3,6- difluorobenzyl of 2-) amino] -2- [[1- (2- ethoxy) -1H- pyrazoles -4- base] amino] pyrimidine -5- first Amide；

4- [[the fluoro- 3- methoxy-benzyl of 2-] amino] -2- [[1- (2- methoxy ethyl) -1H- pyrazoles -4- base] amino] pyrimidine - 5- formamide.

10. a kind of compound or its isomers, solvate or its pharmaceutically acceptable salt, the compound are selected from:

2- ((1- tert-butyl -1H- pyrazoles -4- base) amino) -4- (isoamylamino) pyrimidine -5- formamide；

4- (isoamylamino) -2- ((1- (tetrahydro -2H- pyrans -4- base) -1H- pyrazoles -4- base) amino) pyrimidine -5- formamide；

2- ((1- tert-butyl -1H- pyrazoles -4- base) amino) -4- ((2- (2- hydroxyl-oxethyl) ethyl) amino) pyrimidine -5- formyl Amine；

4- ((2- (2- hydroxyl-oxethyl) ethyl) amino) -2- ((1- (tetrahydro -2H- pyrans -4- base) -1H- pyrazoles -4- base) ammonia Base) pyrimidine -5- formamide；

2- ((1- ethyl -1H- pyrazoles -4- base) amino) -4- ((2- Ethylbenzyl) amino) pyrimidine -5- formamide；

4- ((2- Ethylbenzyl) amino) -2- ((1- propyl -1H- pyrazoles -4- base) amino) pyrimidine -5- formamide；

4- ((2- Ethylbenzyl) amino) -2- ((1- isopropyl -1H- pyrazoles -4- base) amino) pyrimidine -5- formamide；

2- ((1- cyclopropyl -1H- pyrazoles -4- base) amino) -4- ((2- Ethylbenzyl) amino) pyrimidine -5- formamide；

2- ((1- tert-butyl -1H- pyrazoles -4- base) amino) -4- ((2- Ethylbenzyl) amino) pyrimidine -5- formamide；

4- ((2- Ethylbenzyl) amino) -2- ((1- (tetrahydro -2H- pyrans -4- base) amino) pyrimidine -5- formamide；

2- ((1- methyl-1 H- pyrazoles -4- base) amino) -4- ((2- benzyl) amino) pyrimidine -5- formamide；

4- ((2- isopropyl benzyl) amino) -2- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine -5- formamide；

4- ((2- (Cvclopropvlmethvl) benzyl) amino) -2- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine -5- formamide；

2- ((1- tert-butyl -1H- pyrazoles -4- base) amino) -4- ((2- methoxy-benzyl) amino) pyrimidine -5- formamide；

2- ((1- tert-butyl -1H- pyrazoles -4- base) amino) -4- ((2,6- difluorobenzyl) amino) pyrimidine -5- formamide；

4- ((the chloro- 6- luorobenzyl of 2-) amino) -2- ((1- ethyl -1H- pyrazoles -4- base) amino) pyrimidine -5- formamide；

4- ((the chloro- 6- luorobenzyl of 2-) amino) -2- ((1- propyl -1H- pyrazoles -4- base) amino) pyrimidine -5- formamide；

4- ((the chloro- 6- luorobenzyl of 2-) amino) -2- ((1- isopropyl -1H- pyrazoles -4- base) amino) pyrimidine -5- formamide；

4- ((the chloro- 6- luorobenzyl of 2-) amino) -2- ((1- cyclopropyl -1H- pyrazoles -4- base) amino) pyrimidine -5- formamide；

2- ((1- tert-butyl -1H- pyrazoles -4- base) amino) -4- ((the chloro- 6- luorobenzyl of 2-) amino) pyrimidine -5- formamide；

4- ((the chloro- 6- luorobenzyl of 2-) amino) -2- ((1- cyclobutyl -1H- pyrazoles -4- base) amino) pyrimidine -5- formamide；

4- ((the chloro- 6- luorobenzyl of 2-) amino) -2- ((1- cyclopenta -1H- pyrazoles -4- base) amino) pyrimidine -5- formamide；

4- ((the chloro- 6- luorobenzyl of 2-) amino) -2- ((1- cyclohexyl -1H- pyrazoles -4- base) amino) pyrimidine -5- formamide；

4- ((the chloro- 6- luorobenzyl of 2-) amino) -2- ((1- (tetrahydro -2H- pyrans -4- base) -1H- pyrazoles -4- base) amino) pyrimidine - 5- formamide；

4- ((the bromo- 6- luorobenzyl of 2-) amino) -2- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine -5- formamide；

4- ((the bromo- 6- luorobenzyl of 2-) amino) -2- ((1- ethyl -1H- pyrazoles -4- base) amino) pyrimidine -5- formamide；

4- ((the fluoro- 6- methylbenzyl of 2-) amino) -2- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine -5- formamide；

4- ((the fluoro- 6- methylbenzyl of 2-) amino) -2- ((1- ethyl -1H- pyrazoles -4- base) amino) pyrimidine -5- formamide；

2- ((1- ethyl -1H- pyrazoles -4- base) amino) -4- ((2- fluoro- 6- (trifluoromethyl) benzyl) amino) pyrimidine -5- formyl Amine；

2- ((1- tert-butyl -1H- pyrazoles -4- base) amino) -4- ((2- fluoro- 6- (trifluoromethyl) benzyl) amino) pyrimidine -5- first Amide；

4- ((2- ethyl -6- luorobenzyl) amino) -2- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine -5- formamide；

2- ((1- ethyl -1H- pyrazoles -4- base) amino) -4- ((2- ethyl -6- luorobenzyl) amino) pyrimidine -5- formamide；

2- ((1- tert-butyl -1H- pyrazoles -4- base) amino) -4- ((2- ethyl -6- luorobenzyl) amino) pyrimidine -5- formamide；

2- ((1- tert-butyl -1H- pyrazoles -4- base) amino) -4- ((the fluoro- 6- methoxy-benzyl of 2-) amino) pyrimidine -5- formamide；

4- ((2,6- dimethyl benzyl) amino) -2- ((1- ethyl -1H- pyrazoles -4- base) amino) pyrimidine -5- formamide；

4- ((2,6- dimethyl benzyl) amino) -2- ((1- isopropyl -1H- pyrazoles -4- base) amino) pyrimidine -5- formamide；

2- ((1- tert-butyl -1H- pyrazoles -4- base) amino) -4- ((2,6- dimethyl benzyl) amino) pyrimidine -5- formamide；

4- ((2,6- dimethyl benzyl) amino) -2- ((1- (tetrahydro -2H- pyrans -4- base) -1H- pyrazoles -4- base) amino) is phonetic Pyridine -5- formamide；

4- ((2- acetenyl benzyl) amino) -2- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine -5- formamide；

2- ((1- methyl-1 H- pyrazoles -4- base) amino) -4- ((2- vinyl benzyl) amino) pyrimidine -5- formamide；

2- ((1- methyl-1 H- pyrazoles -4- base) amino) -4- ((2- (propyl -1- alkene -1- base) benzyl) amino) pyrimidine -5- formyl Amine；

4- ((2- allyl benzyl) amino) -2- ((1- methyl-1 H- pyrazoles -4- base) amino) pyrimidine -5- formamide.

11. according to claim 1 to 10 kinds of described in any item compounds or its isomers, solvate or its can pharmaceutically connect The salt received, wherein the salt includes: malate, hydrochloride, sulfate, mesylate, formates, acetate, citric acid Salt, tartrate, fumarate, gluconate, oxalates.

12. a kind of Pharmaceutical composition for the treatment of and tyrosine kinase JAK1, JAK2, JAK3, TYK2 related disease, is wanted by right The compound or its pharmaceutically acceptable salt of formula described in asking any one of 1 to 10 (I) or its hydrate or its solvate Or its prodrug is formed with pharmaceutically acceptable carrier or excipient.

13. a kind of Pharmaceutical composition: wherein comprising the compound or its medicine such as formula of any of claims 1-10 (I) Acceptable salt, hydrate, solvate or prodrug are as active constituent on, one or more of the other therapeutic agent, and One or more pharmaceutically acceptable carriers or excipient.

14. the compound or its pharmaceutically acceptable salt of formula (I) according to claim 1 to 10 or its before Medicine answering in the drug for treating autoimmune disease relevant to tyrosine kinase JAK1, JAK2, JAK3, TYK2 and cancer With wherein the disease includes: fundus oculi disease, xerophthalmia, psoriasis, leucoderma, dermatitis, alopecia areata, rheumatoid arthritis, knot Enteritis, multiple sclerosis, systemic loupus erythematosus, Crohn disease, atheroma, pulmonary fibrosis, liver fibrosis, myleo Change, non-small cell lung cancer, Small Cell Lung Cancer, breast cancer, cancer of pancreas, glioma, glioblastoma, oophoroma, uterus Neck cancer, colorectal cancer, melanoma, carcinoma of endometrium, prostate cancer, bladder cancer, leukaemia, gastric cancer, liver cancer, gastro-intestinal stromal Tumor, thyroid cancer, chronic myelocytic leukemia, acute myelocytic leukemia, non-Hodgkin lymphoma, nasopharyngeal carcinoma, cancer of the esophagus, Brain tumor, B cell and t cell lymphoma, lymthoma, Huppert's disease, biliary tract carcinosarcoma, cholangiocarcinoma.