CN101282945A - Compositions and methods for inhibition of the JAK pathway - Google Patents

Compositions and methods for inhibition of the JAK pathway Download PDF

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Publication number
CN101282945A
CN101282945A CNA200680020533XA CN200680020533A CN101282945A CN 101282945 A CN101282945 A CN 101282945A CN A200680020533X A CNA200680020533X A CN A200680020533XA CN 200680020533 A CN200680020533 A CN 200680020533A CN 101282945 A CN101282945 A CN 101282945A
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phenyl
amino
pyrimidinediamine
fluoro
sulfonyl
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Inventor
李慧
S·索塔
D·卡罗尔
A·阿加德
曹健云
A·斯兰
J·克罗格
H·凯姆
S·伯汉米迪帕提
V·泰勒
R·库珀
R·辛格
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Rigel Pharmaceuticals Inc
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Rigel Pharmaceuticals Inc
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Abstract

The invention encompasses compounds having formula (I-V) and the compositions and methods using these compounds in the treatment of conditions in which modulation of the JAK pathway or inhibition of JAK kinases, particularly JAK3, may be therapeutically useful.

Description

The composition and the method that suppress the JAK approach
I. the cross reference of related application
[0001] the application requires the U.S. Provisional Application sequence number 60/689 of submission on June 8th, 2005,032, the U.S. Provisional Application sequence number of submitting on August 8th, 2,005 60/706,638, U.S. Provisional Application sequence number 60/776,636 right of priority of submitting on February 24th, 2006.
II. introduce
A. invention field
[0002] disclosure relates to compound, prodrug and uses these compounds and prodrug treatment adjusting JAK approach or inhibition jak kinase, especially JAK3, has the method for the symptom of treatment benefit.
B. background of invention
[0003] protein kinase constituted involved enzyme on the structure of being responsible for various signal transduction processes in the control cell extended familys (referring to for example, Hardie and Hanks, The Protein Kinase Facts Book (real albumen Kinases), I and II, academic press (AcademicPress), SanDiego, CA, 1995).Because therefore the conservative property of protein kinase structure and catalysis thinks that they come from total ancestral gene.Nearly all kinases all contains a similar 250-300 amino acid whose catalyst structure domain.Can kinases be divided into some families (for example, protein-tyrosine, protein-serine/threonine, lipid etc.) by its phosphorylated substrate.Identified with each family basic corresponding sequence motifs (referring to, for example, Hanks ﹠amp; Hunter, (1995), FASEB is J.9:576-596; Knighton etc., (1991), Science 253:407-414; Hiles etc., (1992), Cell 70:419-429; Kunz etc., (1993), Cell 73:585-596; Garcia-Bustos etc., (1994), EMBO is J.13:2352-2361).
[0004] jak kinase (JAnus kinases) is a cytoplasmic protein matter family tyrosine kinase, comprises JAK1, JAK2, JAK3 and TYK2.Each jak kinase has selectivity to the acceptor of some cytokine, but multiple jak kinase may be subjected to the influence of the specific cells factor or signal transduction path.Studies show that JAK3 is relevant with general γ (γ c) chain of various cytokine receptors.JAK3 especially selective binding IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 acceptor and be the part of these cytokine signaling pathways.JAK1 especially with the acceptor interaction of cytokine IL-2, IL-4, IL-7, IL-9 and IL-21, and JAK2 especially with the acceptor interaction of IL-9 and TNF-.After some cytokine and their receptors bind (for example, IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21), acceptor generation oligomerization, thus cause the kytoplasm tail of relevant jak kinase mutual near helping the tyrosine residues on the jak kinase that trans phosphorylation takes place.This trans phosphorylation causes jak kinase to be activated.
[0005] jak kinase of phosphorylation is in conjunction with various STAT (signal transduction and transcription activating albumen) albumen.Stat protein is a kind of conjugated protein by tyrosine residues phosphorylation activated DNA, its function is signal transduction molecule and transcription factor, and it is final in conjunction with the dna sequence dna (Leonard etc. that are present in the cytokine effector promotor, (2000), J.Allergy Clin.Immunol.105:877-888).The many abnormal immunes of known JAK/STAT signal conduction mediation are replied, as transformation reactions, asthma, autoimmune disorder such as graft (allograft (allograft)) repulsion, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, and solid malignant and hematologic malignancies such as leukemia and lymphoma.For the drug intervention of looking back the JAK/STAT approach can be referring to Frank, (1999), Mol.Med.5:432:456 and Seidel etc., (2000), Oncogene19:2645-2656.
[0006] especially, JAK3 participates in multiple bioprocess.For example, known propagation and survival by IL-4 and IL-9 inductive muroid mastocyte depends on JAK3-and γ chain-signal conduction (Suzuki etc., (2000), Blood 96:2172-2180).JAK3 also brings into play keying action (Malaviya etc. in the receptor-mediated mastocyte threshing reaction of IgE, (1999), Biochem.Biophys.Res.Commun.257:807-813), known inhibition JAK3 kinases can prevent to comprise the I type allergy (Malaviya etc. of anaphylaxis, (1999), J.Biol.Chem.274:27028-27038).Also known inhibition JAK3 can cause to allograft rejection immunosuppression (Kirken, (2001), Transpl.Proc.33:3268-3270).JAK3 kinases mechanism also early stage with following disease and that late stage is related is relevant: and rheumatoid arthritis (Muller-Ladner etc., (2000), J.Immunal.164:3894-3901); Familial amyotrophic lateral sclerosis (Trieu etc., (2000), Biochem Biophys.Res.Commun.267:22-25); Leukemia (Sudbeck etc., (1999), Clin.Cancer Res.5:1569-1582); Mycosis fungoides; A kind of t cell lymphoma of form (Nielsen etc., (1997), Prac.Natl.Acad.Sci.USA94:6764-6769); And abnormal cell growth (Yu etc., (1997), J.Immunol.159:5206-5210; Catlett-Falcone etc., (1999), Immunity 10:105-115).
[0007] jak kinase, comprise JAK3, great expression in the children's that suffer from acute lymphoblastic leukemia elementary leukemia cell, this leukemia is a modal cancer form among the children, research (the Demoulin etc. that activation of STAT in some cell have been associated with the Signal Regulation apoptosis, (1996), Mol.Cell.Biol.16:4710-6; Jurlander etc., (1997), Blood.89:4146-52; Kaneko etc., (1997), Clin.Exp.Immun.109:185-193; With Nakamura etc., (1996), J.Biol.Chem.271:19483-8).Also known they be important for lymphocyte differentiation, function and survival.JAK-3 especially brings into play keying action in the function of lymphocyte, scavenger cell and mastocyte.Importance in view of this jak kinase, regulate the compound of JAK approach, comprise that those to JAK3 compound selectively, can be used for treating disease or symptom (Kudlacz etc., (2004) Am.J.Transplant 4:51-57 of relating to lymphocyte, scavenger cell or mastocyte function; Changelian (2003) Science 302:875-878).Target JAK approach or adjusting jak kinase, especially JAK3, the symptom that has the treatment benefit comprises: leukemia, lymphoma, (for example the pancreatic islets transplantation thing repels in transplant rejection, bone marrow transplantation is used (for example anti-host disease of the value of moving thing), autoimmune disorder (for example diabetes), and inflammation (for example asthma, transformation reactions).May benefit from the symptom that suppresses JAK3 below will discuss in more detail.
[0008] it seems the compound of this new adjusting JAK approach and use the method for these compounds as if to can be various patients substantial treatment benefit is provided from benefiting from the various symptoms that relate to the treatment of regulating the JAK approach.What provide here is new 2, and the pyrimidinediamine compounds that 4-replaces can be used for treating target JAK approach or suppresses jak kinase, especially JAK3, has the symptom of treatment benefit.
[0009] relating to patent and the patent application of regulating the JAK approach comprises: U.S. Patent number 5728536; 6080747; 6080748; 6133305; 6177433; 6210654; 6313130; 6316635; 6433018; 6486185; 6506763; 6528509; 6593357; 6608048; 6610688; 6635651; 6677368; 6683082; 6696448; 6699865; 6777417; 6784195; 6825190; U.S. Patent Application Publication No. 2001/0007033 A1; 2002/0026053 A1; 2002/0115173 A1; 2002/0137141 A1; 2002/0151574 A1; 2003/0040536 A1; 2003/0065180 A1; 2003/0069430 A1; 2003/0225151 A1; 2003/0236244 A1; 2004/0009996 A1; 2004/0072836 A1; 2004/0082631 A1; 2004/0102455 A1; 2004/0102506 A1; 2004/0127453 A1; 2004/0142404 A1; 2004/0147507 A1; 2004/0186157 A1; 2004/0205835 A1; With 2004/0214817 A1; And International Patent Application WO 95/03701A1; WO 99/15500A1; WO 00/00202A1; WO 00/10981A1; WO00/47583A1; WO 00/51587A2; WO 00/55159A2; WO 01/42246A2; WO01/45641A2; WO 01/52892A2; WO 01/56993A2; WO 01/57022A2; WO01/72758A1; WO 02/00661A1; WO 02/43735A1; WO 02/48336A2; WO02/060492A1; WO 02/060927A1; WO 02/096909A1; WO 02/102800A1; WO03/020698A2; WO 03/048162A1; WO 03/101989A1; WO 04/016597A2; WO04/041789A1; WO 04/041810A1; WO 04/041814A1; WO 04/046112A2; WO04/046120A2; WO 04/047843A1; WO 04/058749A1; WO 04/058753A1; WO04/085388A2; WO 04/092154A1; WO 05/009957A1; WO 05/016344A1; WO05/028475A2; With WO 05/033107A1.
[0010] patent and the patent application of the pyrimidinediamine compounds of description replacement comprise: U.S. Patent Application Publication No. 2004/0029902 A1; 2005/0234049 A1, and disclosed International Application No. WO 03/063794, WO04/014382 and WO 05/016893, its content is included this paper by reference in.The pyrimidinediamine compounds that replaces also is described in following international patent application application number: WO 02/059110, and WO 03/074515, and WO 03/106416, WO 03/066601, and WO 03/063794, and WO 04/046118, WO 05/016894, WO 05/0122294, and WO 05/066156, and WO 03/002542, WO 03/030909, WO 00/039101, and WO 05/037800, and U.S. Patent Publication No. 2003/0149064.
[0011] all above-mentioned publications are included this paper in by reference in full, and its degree is equal to one by one and mentions each publication separately and include in as a reference in full.
Summary of the invention
[0012] the present invention relates to compound, prodrug and use these compounds and prodrug treatment is regulated the JAK approach or suppressed jak kinase, especially JAK3, have the method for the symptom of treatment benefit.
[0013] an embodiment of the invention provide the compound of formula I or solvate, prodrug or the pharmacy acceptable salt of this compound:
Figure A20068002053300491
Wherein:
X is selected from: the alkynyl of the thiazolinyl of the amino of the alkoxyl group of the alkyl of alkyl, replacement, alkoxyl group, replacement, amino, replacement, carboxyl, carboxylic acid ester groups, cyano group, halogen, nitro, thiazolinyl, replacement, alkynyl and replacement;
R is selected from: the cycloalkyl of the alkynyl of the thiazolinyl of the alkyl of hydrogen, alkyl, replacement, thiazolinyl, replacement, alkynyl, replacement, cycloalkyl and replacement;
Ring A is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl group and heterocycle, and wherein encircling A is not indyl or benzimidazolyl-;
Y is selected from: key ,-NR 7-,-C (O) NR 7-,-NR 7C (O)-,-NR 7C (O) O-,-OC (O) NR 7-,-NR 7C (O) NR 7-, oxygen and sulphur, wherein R 7Independent is the alkyl of hydrogen, alkyl or replacement;
Alk is key or straight or branched alkylidene group, wherein R then when alk and Y respectively do for oneself key 1By a covalent bonds in the ring A;
R 1Be selected from: heterocycle, acyl group, aminoacyl oxygen base and the amino carbonyl amino of the heteroaryl of the aryl of cyano group, acyl amino, aminoacyl, aryl, replacement, carboxyl, carboxylic acid ester groups, carboxylic acid ester groups oxygen base, heteroaryl, replacement, heterocycle, replacement; Perhaps
R 1-alk-Y-is R 10-C (O)-S-alk-C (O)-, wherein alk in the literary composition definition and R 10It is the alkyl of alkyl or replacement; Perhaps
R 1-alk-Y-is R 11R 12NS (O) 2-, R wherein 11And R 12Independent is the alkyl of alkyl or replacement;
P is 0,1,2 or 3 when ring A is monocycle, and perhaps p is 0,1,2,3,4 or 5 when ring A comprises a plurality of ring;
Each R 2Independently be selected from: the heterocyclyloxy base of the heterocycle of the heteroaryloxy of the heteroaryl of the cycloalkyloxy of the cycloalkyl of the aryloxy of the aryl of the amino of the alkoxyl group of the alkyl of alkyl, replacement, alkoxyl group, replacement, amino, replacement, aryl, replacement, aryloxy, replacement, cyano group, cycloalkyl, replacement, cycloalkyloxy, replacement, heteroaryl, replacement, heteroaryloxy, replacement, heterocycle, replacement, heterocyclyloxy base, replacement, aminoacyl, aminoacyl oxygen base, carboxyl, carboxylic acid ester groups, carbonate group, nitro and halogen, two R on the perhaps same carbon atom 2The formation oxo (=O);
Z 1, Z 2And Z 3Independent separately is carbon or nitrogen, if Z wherein 1Be then Z of nitrogen 2And Z 3Be carbon, if Z 2Be then Z of nitrogen 1And Z 3Be carbon, and if Z 3Be then Z of nitrogen 1And Z 2Be carbon, if Z wherein 1, Z 2Or Z 3Be then SO of nitrogen 2R 4R 5Debond is in nitrogen;
Q is 0,1,2 or 3;
Each R 3Independently be selected from: the heterocycle of the cycloalkyl of the alkoxyl group of the alkyl of hydrogen, alkyl, replacement, alkoxyl group, replacement, cycloalkyl or replacement, halogen, heterocycle and replacement;
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement, acyl group and M +, M wherein +Be to be selected from K +, Na +, Li +Or +N (R 6) 4The metal counter ion, R wherein 6Be hydrogen or alkyl, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4Or R 5Be to be selected from Ca 2+, Mg 2+ or Ba 2+The divalence counter ion, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms; Perhaps
When q is 1,2 or 3, R 5Can with a R who is incorporated into its alpha position 3Group forms together suc as formula the condensed ring shown in the II:
Figure A20068002053300511
Wherein W is selected from: C 1-C 3The C of alkylidene group, replacement 1-C 3Alkylidene group, C 2-C 3The C of alkenylene and replacement 2-C 3Alkenylene, wherein one or more carbon atoms have been selected from oxygen, sulphur, S (O), S (O) 2, C (O) or NR 8Part replace R wherein 8Be selected from hydrogen or alkyl, perhaps R 8It is the key that participates in forming unsaturated-N=C＜site;
Prerequisite is:
When alk is key and Y when being key, R 1Not cyano group, carboxyl, carboxylic acid ester groups or amino carbonyl amino (aminoacarbonylamino);
When alk is-CH 2-, Y is an oxygen, R 1When being phenyl, ring A is not a cycloalkyl;
When alk is that key, Y are key and ring A when being phenyl, R 1Not the heterocycle or the aminoacyl oxygen base of heterocycle, replacement;
As Y or R 1-alk-Y-formation is connected to ring A's-NR 7C (O) O-or-NR 7C (O) NR 7-when directly connecting, R 7Be hydrogen; With
When Y is-C (O) NR 7-,-NR 7C (O)-,-OC (O) NR 7-,-NR 7C (O) O-or-NR 7C (O) NR 7-and alk when being key, R 1Not acyl group, acyl amino, aminoacyl or amino carbonyl amino.
[0014] another embodiment of the invention provides the compound of formula III or solvate, prodrug or the pharmacy acceptable salt of this compound:
Figure A20068002053300512
Wherein:
X is selected from: the alkynyl of the thiazolinyl of the amino of the alkoxyl group of the alkyl of alkyl, replacement, alkoxyl group, replacement, amino, replacement, carboxyl, carboxylic acid ester groups, cyano group, halogen, nitro, thiazolinyl, replacement, alkynyl and replacement;
R is selected from: the cycloalkyl of the alkynyl of the thiazolinyl of the alkyl of hydrogen, alkyl, replacement, thiazolinyl, replacement, alkynyl, replacement, cycloalkyl and replacement;
Ring A is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl group and heterocycle, and wherein encircling A is not indyl or benzimidazolyl-;
P is 0,1,2 or 3;
Each R 2Independently be selected from: alkyl, the alkyl that replaces, alkoxyl group, the alkoxyl group that replaces, amino, the amino that replaces, aryl, the aryl that replaces, aryloxy, the aryloxy that replaces, cyano group, cycloalkyl, the cycloalkyl that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryl, the heteroaryl that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocycle, the heterocycle that replaces, the heterocyclyloxy base, the heterocyclyloxy base that replaces, aminoacyl, aminoacyl oxygen base, carboxyl, carboxylic acid ester groups, carbonate group, alkylsulfonyl, oxo, nitro and halogen;
Z 1, Z 2And Z 3Independent separately is carbon or nitrogen, if Z wherein 1Be then Z of nitrogen 2And Z 3Be carbon, if Z 2Be then Z of nitrogen 1And Z 3Be carbon, and if Z 3Be then Z of nitrogen 1And Z 2Be carbon, if Z wherein 1, Z 2Or Z 3Be then SO of nitrogen 2R 4R 5Debond is in nitrogen;
Q is 0,1,2 or 3;
Each R 3Independently be selected from: the heterocycle of the cycloalkyl of the alkoxyl group of the alkyl of hydrogen, alkyl, replacement, alkoxyl group, replacement, cycloalkyl or replacement, halogen, heterocycle and replacement;
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement, acyl group and M +, M wherein +Be to be selected from K +, Na +, Li +Or +N (R 6) 4The metal counter ion, R wherein 6Be hydrogen or alkyl, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4Or R 5Be to be selected from Ca 2+, Mg 2+ or Ba 2+The divalence counter ion, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms; Perhaps
When q is 1,2 or 3, R 5Can with a R who is incorporated into its alpha position 3Group forms together suc as formula the condensed ring shown in the IV:
Figure A20068002053300521
Wherein W is selected from: C 1-C 3The C of alkylidene group, replacement 1-C 3Alkylidene group, C 2-C 3The C of alkenylene and replacement 2-C 3Alkenylene, wherein one or more carbon atoms have been selected from oxygen, sulphur, S (O), S (O) 2, C (O) or NR 8Part replace R wherein 8Be selected from hydrogen or alkyl, perhaps R 8It is the key that participates in forming unsaturated-N=C＜site;
Prerequisite is:
If p=0, then X is not a bromine;
If ring A is a cycloalkyl, then X is not a bromine;
If p=2 and each R 2Be methoxyl group, halogen, trihalogenmethyl or three halogen methoxyl group, then R 4And R 5Not a hydrogen and a methyl;
If p=2 and R 2Be fluorine and methyl, then R is not the thiazolinyl that replaces; With
If ring A is a phenyl, p=1 and R 2Be chlorine, R then 4And R 5Not a hydrogen and a methyl.
[0015] another embodiment more of the present invention provides the compound that is selected from down group:
Figure A20068002053300541
Figure A20068002053300551
Figure A20068002053300561
Figure A20068002053300571
Figure A20068002053300581
Figure A20068002053300591
Figure A20068002053300601
Figure A20068002053300611
Figure A20068002053300621
Figure A20068002053300631
Figure A20068002053300651
Figure A20068002053300661
Figure A20068002053300671
Figure A20068002053300681
Figure A20068002053300691
Figure A20068002053300701
Figure A20068002053300711
Figure A20068002053300731
Figure A20068002053300741
Figure A20068002053300751
Figure A20068002053300761
Figure A20068002053300781
Figure A20068002053300791
[0018] in another embodiment, the active method of a kind of inhibition jak kinase of the present invention, described method is included in the compound that the external JAK3 of making kinases contact effectively suppresses the active amount of jak kinase, and wherein said compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).
[0019] in another embodiment, the invention provides the method for the cell-mediated autoimmune disorder of a kind of T of treatment, described method comprises that the patient who suffers from this autoimmune disorder effectively treats the compound of the amount of described autoimmune disorder, and wherein said compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).
[0020] more in another embodiment, the invention provides the method for the cell-mediated autoimmune disorder of a kind of T of treatment, described method comprises that the patient who suffers from this autoimmune disorder effectively treats the compound of the amount of described autoimmune disorder, wherein said compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3), and described compound and IC 50Be that 10 μ M or the lower kinase whose compound combination of inhibition Syk give or auxiliary this compound.
[0021] in another embodiment, the invention provides the method for the allograft rejection in a kind of treatment or the prevention graft acceptor, described method comprises and gives the compound that the amount of described repulsion was effectively treated or prevented to the graft acceptor that wherein said compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).Described repulsion can be acute cellular rejection or chronic rejection.Described repulsion also can be by HVGR or GVHR mediation.In some embodiments, described allograft is selected from kidney, heart, liver or lung.Randomly, described compound can give or auxiliary a kind of immunosuppressor with a kind of immunosuppressor combination.Some preferred embodiment in, described immunosuppressor is selected from: ciclosporin, tacrolimus, sirolimus, IMPDH inhibitor, mycophenolate, mycophenlate mofetil (mycophanolate mofetil), anti--T cell antibody and OKT3.
[0022] in another embodiment, the invention provides the method for a kind of treatment or the allergy of prevention IV type, described method comprises and gives the compound that the amount of described allergy was effectively treated or prevented to object that wherein said compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).In preferred embodiment, described compound gave before the contact allergen.
[0023] in another embodiment, the invention provides the method for the signal transduction cascade that a kind of JAK3 of inhibition kinases plays a role therein, described method comprises makes a kind of compound of cells contacting of expressing the acceptor that participates in sort signal cascade amplification, and wherein said compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).
[0024] in another embodiment, the invention provides the method for the disease of a kind of treatment or the mediation of prevention jak kinase, described method comprises the compound of the amount of the disease that gives effective treatment of object or the mediation of prevention jak kinase, and wherein said compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).In preferred embodiment, the disease of described JAK mediation is selected from: HVGR, GVHR, acute allograft rejection and chronic allograft rejection.
[0025] in another embodiment, the invention provides a kind of pharmaceutical preparation, described pharmaceutical preparation comprises a kind of compound or its prodrug and at least a pharmaceutically acceptable vehicle, thinner, sanitas or stablizer or their mixture, and described compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).
[0026] in another embodiment, the invention provides a kind of medicine box, described medicine box comprises a kind of compound or its prodrug, packing and operation instruction, and described compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).In preferred embodiment, described medicine box comprises a kind of pharmaceutical preparation, packing and operation instruction, described pharmaceutical preparation comprises a kind of compound or its prodrug and at least a pharmaceutically acceptable vehicle, thinner, sanitas or stablizer or their mixture, and described compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).
IV. detailed Description Of The Invention
A. general introduction
[0027] the present invention includes the compound of formula I-V and adopt these compounds for treating to regulate JAK approach or suppress jak kinase, especially JAK3, have the composition and the method for the symptom of treatment benefit.
B. definition
[0028] in the literary composition, should adopt to give a definition except as otherwise noted.
[0029] " Alkyl" refer to have 1-10 carbon atom, the unit price representative examples of saturated aliphatic alkyl of preferred 1-6 carbon atom.This term comprises, for example, and straight chain and branched hydrocarbyl such as methyl (CH 3-), ethyl (CH 3CH 2-), n-propyl (CH 3CH 2CH 2-), sec.-propyl ((CH 3) 2CH-), normal-butyl (CH 3CH 2CH 2CH 2-), isobutyl-((CH 3) 2CHCH 2-), sec-butyl ((CH 3) (CH 3CH 2) CH-), the tertiary butyl ((CH 3) 3C-), n-pentyl (CH 3CH 2CH 2CH 2CH 2-) and neo-pentyl ((CH 3) 3CCH 2-).
[0030] " The alkyl that replaces" refer to have 1-5 hydrogen to be selected from down the alkyl of the substituting group replacement of group: alkoxyl group; the alkoxyl group of replacement; acyl group; acyl amino; acyloxy; amino; the amino that replaces; aminocarboxyl; amino thiocarbonyl; amino carbonyl amino; amino thio-carbonyl-amino; aminocarboxyl oxygen base; amino-sulfonyl; amino-sulfonyl oxygen base; amino-sulfonyl amino; amidino groups; aryl; the aryl that replaces; aryloxy; the aryloxy that replaces; arylthio; the arylthio that replaces; carboxyl; carboxylic acid ester groups (carboxyl ester); (carboxylic acid ester groups) amino; (carboxylic acid ester groups) oxygen base; cyano group; cycloalkyl; the cycloalkyl that replaces; cycloalkyl oxy; the cycloalkyl oxy that replaces; the cycloalkyl sulfo-; the cycloalkyl sulfo-that replaces; cycloalkenyl group; the cycloalkenyl group that replaces; cycloalkenyl oxy; the cycloalkenyl oxy that replaces; the cycloalkenyl group sulfo-; the cycloalkenyl group sulfo-that replaces; alkynyl; the alkynyl that replaces; guanidine radicals; the guanidine radicals that replaces; halogen; hydroxyl; heteroaryl; the heteroaryl that replaces; heteroaryloxy; the heteroaryloxy that replaces; the heteroaryl sulfo-; the heteroaryl sulfo-that replaces; heterocycle; the heterocycle that replaces; the heterocyclyloxy base; the heterocyclyloxy base that replaces; the heterocyclic radical sulfo-; the heterocyclic radical sulfo-that replaces; nitro; SO 3Alkylthio, silyl and the trialkylsilkl of H, alkylsulfonyl, alkylsulfonyl oxygen base, sulfo-acyl group, mercaptan, alkylthio, replacement, wherein said substituting group defines in the text.In some embodiments, alkyl has 1-3 above-mentioned group.In other embodiments, alkyl has 1-2 above-mentioned group.
[0031] " Alkylidene group" refer to preferably have 1-5, the more preferably divalence representative examples of saturated aliphatic alkyl of the straight or branched of 1-3 carbon atom.The example of this term such as methylene radical (CH 2-), ethylidene (CH 2CH 2-), positive propylidene (CH 2CH 2CH 2-), isopropylidene (CH 2CH (CH 3)-) or (CH (CH 3) CH 2-) etc.
[0032] " The alkylidene group that replaces" referring to have 1-3 hydrogen to be selected from down the alkylidene group of the substituting group replacement of group: the heterocycle of the heteroaryl of the cycloalkyl of the aryloxy of the aryl of the amino of the alkoxyl group of the alkyl of alkyl, replacement, alkoxyl group, replacement, acyl group, acyl amino, acyloxy, amino, replacement, aminoacyl, aryl, replacement, aryloxy, replacement, cyano group, halogen, hydroxyl, nitro, carboxyl, carboxylic acid ester groups, cycloalkyl, replacement, heteroaryl, replacement, heterocycle, replacement, wherein said substituting group defines in the text.In some embodiments, alkylidene group has 1-2 above-mentioned group.
[0033] " Alkoxyl group" refer to group-O-alkyl ,-the O-thiazolinyl and-the O-alkynyl, wherein alkyl, thiazolinyl and alkynyl in the literary composition definition.
[0034] " The alkoxyl group that replaces" refer to group-O-(alkyl of replacement) ,-O-(thiazolinyl of replacement) and-O-(alkynyl of replacement), wherein the alkynyl of the thiazolinyl of the alkyl of Qu Daiing, replacement and replacement in the literary composition definition.
[0035] " Acyl group" refer to group H-C (O)-; alkyl-C (O)-; the alkyl-C of replacement (O)-; thiazolinyl-C (O)-; the thiazolinyl-C of replacement (O)-; alkynyl-C (O)-, alkynyl-C (O)-cycloalkyl-C (O) that replaces-, cycloalkyl-the C (O) that replaces-, cycloalkenyl group-C (O)-, cycloalkenyl group-the C (O) that replaces-, aryl-C (O)-, aryl-the C (O) that replaces-, heteroaryl-C (O)-, heteroaryl-the C (O) that replaces-, heterocycle-C (O)-and heterocycle-C (O) of replacing-, alkyl wherein, the alkyl that replaces, thiazolinyl, the thiazolinyl that replaces, alkynyl, the alkynyl that replaces, cycloalkyl, the cycloalkyl that replaces, cycloalkenyl group, the cycloalkenyl group that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, the heterocycle of heterocycle and replacement in the literary composition definition.Acyl group comprises " ethanoyl " CH 3C (O)-.
[0036] " Acyl amino" refer to group-NR 20C (O) alkyl ,-NR 20The alkyl that C (O) replaces ,-NR 20C (O) cycloalkyl ,-NR 20The cycloalkyl that C (O) replaces ,-NR 20C (O) cycloalkenyl group ,-NR 20The cycloalkenyl group that C (O) replaces ,-NR 20C (O) thiazolinyl ,-NR 20The thiazolinyl that C (O) replaces ,-NR 20C (O) alkynyl ,-NR 20The alkynyl that C (O) replaces ,-NR 20C (O) aryl ,-NR 20The aryl that C (O) replaces ,-NR 20C (O) heteroaryl ,-NR 20The heteroaryl that C (O) replaces ,-NR 20C (O) heterocycle and-NR 20The heterocycle that C (O) replaces, wherein R 20Be the heterocycle of heteroaryl, heterocycle and replacement of aryl, heteroaryl, replacement of cycloalkenyl group, aryl, the replacement of cycloalkyl, cycloalkenyl group, the replacement of alkynyl, cycloalkyl, the replacement of thiazolinyl, alkynyl, the replacement of alkyl, thiazolinyl, the replacement of hydrogen or alkyl and wherein alkyl, replacement in the literary composition definition.
[0037] " Acyloxy" refer to group alkyl-C (O) O-; the alkyl-C of replacement (O) O-; thiazolinyl-C (O) O-; the thiazolinyl-C of replacement (O) O-; alkynyl-C (O) O-; the alkynyl-C of replacement (O) O-, aryl-C (O) O-, aryl-C (O) O-that replaces, cycloalkyl-C (O) O-, cycloalkyl-C (O) O-that replaces, cycloalkenyl group-C (O) O-, cycloalkenyl group-C (O) O-that replaces, heteroaryl-C (O) O-, heteroaryl-C (O) O-that replaces, heterocycle-C (O) O-of heterocycle-C (O) O-and replacement, wherein alkyl, the alkyl that replaces, thiazolinyl, the thiazolinyl that replaces, alkynyl, the alkynyl that replaces, cycloalkyl, the cycloalkyl that replaces, cycloalkenyl group, the cycloalkenyl group that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, the heterocycle of heterocycle and replacement in the literary composition definition.
[0038] " Amino" refer to group-NH 2
[0039] " The amino that replaces" refer to group-NR 21R 22, R wherein 21And R 22Independently be selected from down group: the heterocycle of the heteroaryl of the cycloalkenyl group of the cycloalkyl of the aryl of the alkynyl of the thiazolinyl of the alkyl of hydrogen, alkyl, replacement, thiazolinyl, replacement, alkynyl, replacement, aryl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, heteroaryl, replacement, heterocycle, replacement ,-SO 2-alkyl ,-SO 2The alkyl of-replacement ,-SO 2-thiazolinyl ,-SO 2The thiazolinyl of-replacement ,-SO 2-cycloalkyl ,-SO 2The cycloalkyl of-replacement ,-SO 2-cycloalkenyl group ,-SO 2The cycloalkenyl group of-replacement ,-SO 2-aryl ,-SO 2The aryl of-replacement ,-SO 2-heteroaryl ,-SO 2The heteroaryl of-replacement ,-SO 2-heterocycle and-SO 2The heterocycle of-replacement, and R wherein 21And R 22Can choose wantonly with the heterocyclic group of they institute's bonded nitrogen in conjunction with formation heterocycle or replacement, prerequisite is R 21And R 22Not all be hydrogen, and the heterocycle of heteroaryl, heterocycle and the replacement of the aryl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the thiazolinyl of the alkyl of alkyl wherein, replacement, thiazolinyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heteroaryl, replacement in the literary composition definition.Work as R 21Be hydrogen and R 22When being alkyl, the amino of this replacement be called as sometimes in the text " Alkylamino".Work as R 21And R 22When all making alkyl, the amino of this replacement be called as sometimes in the text " Dialkyl amido".When mentioning mono-substituted amino, be meant R 21Or R 22Be hydrogen but not all be hydrogen.When mentioning disubstituted amino, be meant R 21Or R 22Not hydrogen.
[0040] " Aminoacyl" refer to group-C (O) NR 21R 22, R wherein 21And R 22Independently be selected from down group: the heterocycle of the heteroaryl of the cycloalkenyl group of the cycloalkyl of the aryl of the alkynyl of the thiazolinyl of the alkyl of hydrogen, alkyl, replacement, thiazolinyl, replacement, alkynyl, replacement, aryl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, heteroaryl, replacement, heterocycle and replacement, wherein R 21And R 22Can choose wantonly with their institutes bonded nitrogen in conjunction with the heterocyclic group that forms heterocycle or replacement, and the heterocycle of heteroaryl, heterocycle and the replacement of the aryl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the thiazolinyl of the alkyl of alkyl wherein, replacement, thiazolinyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heteroaryl, replacement in the literary composition definition.
[0041] " Amino thiocarbonyl" refer to group-C (S) NR 21R 22, R wherein 21And R 22Independently be selected from down group: the heterocycle of the heteroaryl of the cycloalkenyl group of the cycloalkyl of the aryl of the alkynyl of the thiazolinyl of the alkyl of hydrogen, alkyl, replacement, thiazolinyl, replacement, alkynyl, replacement, aryl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, heteroaryl, replacement, heterocycle and replacement, wherein R 21And R 22Can choose wantonly with their institutes bonded nitrogen in conjunction with the heterocyclic group that forms heterocycle or replacement, and the heterocycle of heteroaryl, heterocycle and the replacement of the aryl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the thiazolinyl of the alkyl of alkyl wherein, replacement, thiazolinyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heteroaryl, replacement in the literary composition definition.
[0042] " Amino carbonyl amino" refer to group-NR 20C (O) NR 21R 22, R wherein 20Be hydrogen or alkyl, and R 21And R 22Independently be selected from down group: the heterocycle of the heteroaryl of the cycloalkenyl group of the cycloalkyl of the aryl of the alkynyl of the thiazolinyl of the alkyl of hydrogen, alkyl, replacement, thiazolinyl, replacement, alkynyl, replacement, aryl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, heteroaryl, replacement, heterocycle and replacement, wherein R 21And R 22Can choose wantonly with their institutes bonded nitrogen in conjunction with the heterocyclic group that forms heterocycle or replacement, and the heterocycle of heteroaryl, heterocycle and the replacement of the aryl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the thiazolinyl of the alkyl of alkyl wherein, replacement, thiazolinyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heteroaryl, replacement in the literary composition definition.
[0043] " Amino thio-carbonyl-amino" refer to group-NR 20C (S) NR 21R 22, R wherein 20Be hydrogen or alkyl, and R 21And R 22Independently be selected from down group: the heterocycle of the heteroaryl of the cycloalkenyl group of the cycloalkyl of the aryl of the alkynyl of the thiazolinyl of the alkyl of hydrogen, alkyl, replacement, thiazolinyl, replacement, alkynyl, replacement, aryl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, heteroaryl, replacement, heterocycle and replacement, wherein R 21And R 22Can choose wantonly with their institutes bonded nitrogen in conjunction with the heterocyclic group that forms heterocycle or replacement, and the heterocycle of heteroaryl, heterocycle and the replacement of the aryl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the thiazolinyl of the alkyl of alkyl wherein, replacement, thiazolinyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heteroaryl, replacement in the literary composition definition.
[0044] " Aminoacyl oxygen base" refer to group-O-C (O) NR 21R 22, R wherein 21And R 22Independently be selected from down group: the heterocycle of the heteroaryl of the cycloalkenyl group of the cycloalkyl of the aryl of the alkynyl of the thiazolinyl of the alkyl of hydrogen, alkyl, replacement, thiazolinyl, replacement, alkynyl, replacement, aryl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, heteroaryl, replacement, heterocycle and replacement, wherein R 21And R 22Can choose wantonly with their institutes bonded nitrogen in conjunction with the heterocyclic group that forms heterocycle or replacement, and the heterocycle of heteroaryl, heterocycle and the replacement of the aryl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the thiazolinyl of the alkyl of alkyl wherein, replacement, thiazolinyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heteroaryl, replacement in the literary composition definition.
[0045] " Amino-sulfonyl" refer to group-SO 2NR 21R 22, R wherein 21And R 22Independently be selected from down group: the heterocycle of the heteroaryl of the cycloalkenyl group of the cycloalkyl of the aryl of the alkynyl of the thiazolinyl of the alkyl of hydrogen, alkyl, replacement, thiazolinyl, replacement, alkynyl, replacement, aryl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, heteroaryl, replacement, heterocycle and replacement, wherein R 21And R 22Can choose wantonly with their institutes bonded nitrogen in conjunction with the heterocyclic group that forms heterocycle or replacement, and the heterocycle of heteroaryl, heterocycle and the replacement of the aryl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the thiazolinyl of the alkyl of alkyl wherein, replacement, thiazolinyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heteroaryl, replacement in the literary composition definition.
[0046] " Amino-sulfonyl oxygen base" refer to group-O-SO 2NR 21R 22, R wherein 21And R 22Independently be selected from down group: the heterocycle of the heteroaryl of the cycloalkenyl group of the cycloalkyl of the aryl of the alkynyl of the thiazolinyl of the alkyl of hydrogen, alkyl, replacement, thiazolinyl, replacement, alkynyl, replacement, aryl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, heteroaryl, replacement, heterocycle and replacement, wherein R 21And R 22Can choose wantonly with their institutes bonded nitrogen in conjunction with the heterocyclic group that forms heterocycle or replacement, and the heterocycle of heteroaryl, heterocycle and the replacement of the aryl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the thiazolinyl of the alkyl of alkyl wherein, replacement, thiazolinyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heteroaryl, replacement in the literary composition definition.
[0047] " Amino-sulfonyl amino" refer to group-NR 20-SO 2NR 21R 22, R wherein 20Be hydrogen or alkyl, and R 21And R 22Independently be selected from down group: the cycloalkenyl group of the cycloalkyl of the aryl of the alkynyl of the thiazolinyl of the alkyl of hydrogen, alkyl, replacement, thiazolinyl, replacement, alkynyl, replacement, aryl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement (cycloalkyenyl), the heterocycle of the heteroaryl of heteroaryl, replacement, heterocycle and replacement, wherein R 21And R 22Can choose wantonly with they institute's bonded nitrogen in conjunction with the heterocyclic group that forms heterocycle or replacement, and the cycloalkenyl group of the cycloalkyl of the alkynyl of the thiazolinyl of alkyl wherein, the alkyl of replacement, thiazolinyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, the heterocycle of the heteroaryl of the aryl of aryl, replacement, heteroaryl, replacement, heterocycle and replacement in the literary composition definition.
[0048] " Sulfuryl amino" refer to group-NR 21SO 2R 22, R wherein 21And R 22Independently be selected from down group: the heterocycle of the heteroaryl of the cycloalkenyl group of the cycloalkyl of the aryl of the alkynyl of the thiazolinyl of the alkyl of hydrogen, alkyl, replacement, thiazolinyl, replacement, alkynyl, replacement, aryl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, heteroaryl, replacement, heterocycle and replacement, wherein R 21And R 22Can choose wantonly with their institutes bonded nitrogen in conjunction with the heterocyclic group that forms heterocycle or replacement, and the heterocycle of heteroaryl, heterocycle and the replacement of the aryl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the thiazolinyl of the alkyl of alkyl wherein, replacement, thiazolinyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heteroaryl, replacement in the literary composition definition.
[0049] " Amidino groups" refer to group-C (=NR 20) R 21R 22, R wherein 20, R 21And R 22Independently be selected from down group: the heterocycle of the heteroaryl of the cycloalkenyl group of the cycloalkyl of the aryl of the alkynyl of the thiazolinyl of the alkyl of hydrogen, alkyl, replacement, thiazolinyl, replacement, alkynyl, replacement, aryl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, heteroaryl, replacement, heterocycle and replacement, wherein R 21And R 22Can choose wantonly with their institutes bonded nitrogen in conjunction with the heterocyclic group that forms heterocycle or replacement, and the heterocycle of heteroaryl, heterocycle and the replacement of the aryl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the thiazolinyl of the alkyl of alkyl wherein, replacement, thiazolinyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heteroaryl, replacement in the literary composition definition.
[0050] " Aryl" or " Ar" referring to have the monovalent aromatic family carbon ring group of 6-14 carbon atom of single ring (for example, phenyl) or a plurality of condensed ring (for example, naphthyl or anthryl); condensed ring wherein can yes or no aromatic (for example, 1,2; 3,4-tetraline etc.), and prerequisite is that tie point is positioned on the aromatic series carbon atom.Some representational examples comprise 1H-indenyl, 2,3-dihydro-1H-indenyl (indanyl), 1,2-dihydro naphthyl (tetralenyl), 1,4-dihydro naphthyl (tetralenyl), 1,2,3,4-tetrahydro naphthyl (tetralinyl), 9,10-dihydrophenanthrenyl, 9H-fluorenyl, 4a, 10-dihydro anthryl, 4a, 9,9a, 10-tetrahydrochysene anthryl, phenanthryl, anthryl, phenenyl (phenalenyl) etc.Preferred aryl groups comprises phenyl and naphthyl.
[0051] " The aryl that replaces" refer to have 1-5 hydrogen to be selected from down the aryl of the substituting group replacement of group: alkyl; the alkyl of replacement; thiazolinyl; the thiazolinyl of replacement; alkynyl; the alkynyl of replacement; alkoxyl group; the alkoxyl group that replaces; acyl group; acyl amino; acyloxy; amino; the amino that replaces; aminocarboxyl; amino thiocarbonyl; amino carbonyl amino; amino thio-carbonyl-amino; aminocarboxyl oxygen base; amino-sulfonyl; amino-sulfonyl oxygen base; amino-sulfonyl amino; amidino groups; aryl; the aryl that replaces; aryloxy; the aryloxy that replaces; arylthio; the arylthio that replaces; carboxyl; carboxylic acid ester groups; (carboxylic acid ester groups) amino; (carboxylic acid ester groups) oxygen base; cyano group; cycloalkyl; the cycloalkyl that replaces; cycloalkyl oxy; the cycloalkyl oxy that replaces; the cycloalkyl sulfo-; the cycloalkyl sulfo-that replaces; cycloalkenyl group; the cycloalkenyl group that replaces; cycloalkenyl oxy; the cycloalkenyl oxy that replaces; the cycloalkenyl group sulfo-; the cycloalkenyl group sulfo-that replaces; guanidine radicals; the guanidine radicals that replaces; halogen; hydroxyl; heteroaryl; the heteroaryl that replaces; heteroaryloxy; the heteroaryloxy that replaces; the heteroaryl sulfo-; the heteroaryl sulfo-that replaces; heterocycle; the heterocycle that replaces; the heterocyclyloxy base; the heterocyclyloxy base that replaces; the heterocyclic radical sulfo-; the heterocyclic radical sulfo-that replaces; nitro; SO 3The alkylthio of H, alkylsulfonyl, alkylsulfonyl oxygen base, sulfo-acyl group, mercaptan, alkylthio and replacement, wherein said substituting group defines in the text.In some embodiments, aryl has 1-3 above-mentioned group.In other embodiments, aryl has 1-2 above-mentioned group.In some embodiments, aryl has a plurality of condensed ring (for example, naphthyl or anthryl), and described condensed ring is can yes or no aromatic (for example, 1,2,3,4-tetralines etc.), except that substituting group defined above, described non-aromatic condensed ring can be chosen wantonly by oxygen and replace.
[0052] " Aryloxy" refer to group-O-aryl, aryl wherein in the literary composition definition, this group comprises, for example, phenoxy group, naphthyloxy etc.
[0053] " The aryloxy that replaces" refer to group-O-(aryl of replacement), wherein the aryl of Qu Daiing in the literary composition definition.
[0054] " Arylthio" refer to group-S-aryl, aryl wherein in the literary composition definition.
[0055] " The arylthio that replaces" refer to group-S-(aryl of replacement), wherein the aryl of Qu Daiing in the literary composition definition.
[0056] " Thiazolinyl" refer to have 2-6 carbon atom, preferred 2-4 carbon atom and have at least 1, the unit price unsaturated alkyl in the individual unsaturated site of preferred 1-2.The example of this group has vinyl, allyl group, fourth-3-alkene-1-base etc.
[0057] " The thiazolinyl that replaces" refer to have 1-3 and be selected from down the substituent thiazolinyl of organizing: alkoxyl group; the alkoxyl group of replacement; acyl group; acyl amino; acyloxy; amino; the amino that replaces; aminocarboxyl; amino thiocarbonyl; amino carbonyl amino; amino thio-carbonyl-amino; aminocarboxyl oxygen base; amino-sulfonyl; amino-sulfonyl oxygen base; amino-sulfonyl amino; amidino groups; aryl; the aryl that replaces; aryloxy; the aryloxy that replaces; arylthio; the arylthio that replaces; carboxyl; carboxylic acid ester groups; (carboxylic acid ester groups) amino; (carboxylic acid ester groups) oxygen base; cyano group; cycloalkyl; the cycloalkyl that replaces; cycloalkyl oxy; the cycloalkyl oxy that replaces; the cycloalkyl sulfo-; the cycloalkyl sulfo-that replaces; cycloalkenyl group; the cycloalkenyl group that replaces; cycloalkenyl oxy; the cycloalkenyl oxy that replaces; the cycloalkenyl group sulfo-; the cycloalkenyl group sulfo-that replaces; guanidine radicals; the guanidine radicals that replaces; halogen; hydroxyl; heteroaryl; the heteroaryl that replaces; heteroaryloxy; the heteroaryloxy that replaces; the heteroaryl sulfo-; the heteroaryl sulfo-that replaces; heterocycle; the heterocycle that replaces; the heterocyclyloxy base; the heterocyclyloxy base that replaces; the heterocyclic radical sulfo-; the heterocyclic radical sulfo-that replaces; nitro; SO 3The alkylthio of H, alkylsulfonyl, alkylsulfonyl oxygen base, sulfo-acyl group, mercaptan, alkylthio and replacement, wherein said substituting group defines in the text and prerequisite is, and any hydroxyl substituent is not attached to vinyl (undersaturated) carbon atom.In some embodiments, thiazolinyl has 1-2 above-mentioned group.
[0058] " Alkenylene" refer to have 2-10 carbon atom, preferred 2-6 carbon atom and have at least 1, the preferred divalence unsaturated alkyl in the unsaturated site of 1-2 vinyl (two key).Term " alkenylene " comprises any and all combinations owing to unsaturated cis that produces and trans-isomer(ide).
[0059] " The alkenylene that replaces" referring to have 1-3 substituent divalence alkenylene that is selected from down group: the heterocycle of the heteroaryl of the cycloalkyl of the aryloxy of the aryl of the amino of the alkoxyl group of the alkyl of alkyl, replacement, alkoxyl group, replacement, acyl group, acyl amino, amino, replacement, aminoacyl, aryl, replacement, aryloxy, replacement, cyano group, halogen, hydroxyl, nitro, carboxyl, carboxylic acid ester groups, cycloalkyl, replacement, heteroaryl, replacement, heterocycle and replacement, prerequisite are that any hydroxyl substituent is not on the vinyl carbon atom.In some embodiments, alkenylene has 1-2 above-mentioned group.
[0060] " Alkynyl" refer to have 2-6 carbon atom, preferred 2-3 carbon atom and have at least 1, the preferred unit price unsaturated alkyl in 1-2 the unsaturated site of triple bond.
[0061] " The alkynyl that replaces" refer to have 1-3 and be selected from down the substituent alkynyl of organizing: alkoxyl group; the alkoxyl group of replacement; acyl group; acyl amino; acyloxy; amino; the amino that replaces; aminocarboxyl; amino thiocarbonyl; amino carbonyl amino; amino thio-carbonyl-amino; aminocarboxyl oxygen base; amino-sulfonyl; amino-sulfonyl oxygen base; amino-sulfonyl amino; amidino groups; aryl; the aryl that replaces; aryloxy; the aryloxy that replaces; arylthio; the arylthio that replaces; carboxyl; carboxylic acid ester groups; (carboxylic acid ester groups) amino; (carboxylic acid ester groups) oxygen base; cyano group; cycloalkyl; the cycloalkyl that replaces; cycloalkyl oxy; the cycloalkyl oxy that replaces; the cycloalkyl sulfo-; the cycloalkyl sulfo-that replaces; cycloalkenyl group; the cycloalkenyl group that replaces; cycloalkenyl oxy; the cycloalkenyl oxy that replaces; the cycloalkenyl group sulfo-; the cycloalkenyl group sulfo-that replaces; guanidine radicals; the guanidine radicals that replaces; halogen; hydroxyl; heteroaryl; the heteroaryl that replaces; heteroaryloxy; the heteroaryloxy that replaces; the heteroaryl sulfo-; the heteroaryl sulfo-that replaces; heterocycle; the heterocycle that replaces; the heterocyclyloxy base; the heterocyclyloxy base that replaces; the heterocyclic radical sulfo-; the heterocyclic radical sulfo-that replaces; nitro; SO 3The alkylthio of H, alkylsulfonyl, alkylsulfonyl oxygen base, sulfo-acyl group, mercaptan, alkylthio and replacement, wherein said substituting group defines in the text and prerequisite is, and any hydroxyl substituent is not attached to the acetylene carbon atom.In some embodiments, alkynyl has 1-2 above-mentioned group.
[0062] " Carboxyl" refer to-COOH or its salt.
[0063] " Carboxylic acid ester groups" refer to group-C (O) O-alkyl; the alkyl that-C (O) O-replaces ;-C (O) O-thiazolinyl; the thiazolinyl that-C (O) O-replaces ;-C (O) O-alkynyl; the alkynyl that-C (O) O-replaces,-C (O) O-aryl, the aryl that-C (O) O-replaces,-C (O) O-cycloalkyl, the cycloalkyl that-C (O) O-replaces,-C (O) O-cycloalkenyl group, the cycloalkenyl group that-C (O) O-replaces,-C (O) O-heteroaryl, the heteroaryl that-C (O) O-replaces,-C (O) O-heterocycle and-heterocycle that C (O) O-replaces, wherein alkyl, the alkyl that replaces, thiazolinyl, the thiazolinyl that replaces, alkynyl, the alkynyl that replaces, cycloalkyl, the cycloalkyl that replaces, cycloalkenyl group, the cycloalkenyl group that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, the heterocycle of heterocycle and replacement in the literary composition definition.
[0064] " (carboxylic acid ester groups) amino" refer to group-NR-C (O) O-alkyl; replacement-NR-C (O) O-alkyl ;-NR-C (O) O-thiazolinyl; the thiazolinyl that-NR-C (O) O-replaces ;-NR-C (O) O-alkynyl; the alkynyl that-NR-C (O) O-replaces,-NR-C (O) O-aryl, the aryl that-NR-C (O) O-replaces,-NR-C (O) O-cycloalkyl, the cycloalkyl that-NR-C (O) O-replaces,-NR-C (O) O-cycloalkenyl group, the cycloalkenyl group that-NR-C (O) O-replaces,-NR-C (O) O-heteroaryl, the heteroaryl that-NR-C (O) O-replaces,-NR-C (O) O-heterocycle and-heterocycle that NR-C (O) O-replaces, wherein R is alkyl or hydrogen and alkyl, the alkyl that replaces, thiazolinyl, the thiazolinyl that replaces, alkynyl, the alkynyl that replaces, cycloalkyl, the cycloalkyl that replaces, cycloalkenyl group, the cycloalkenyl group that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, the heterocycle of heterocycle and replacement in the literary composition definition.
[0065] " (carboxylic acid ester groups) oxygen base" refer to group-O-C (O) O-alkyl; replacement-O-C (O) O-alkyl ;-O-C (O) O-thiazolinyl; the thiazolinyl that-O-C (O) O-replaces ;-O-C (O) O-alkynyl; the alkynyl that-O-C (O) O-replaces,-O-C (O) O-aryl, the aryl that-O-C (O) O-replaces,-O-C (O) O-cycloalkyl, the cycloalkyl that-O-C (O) O-replaces,-O-C (O) O-cycloalkenyl group, the cycloalkenyl group that-O-C (O) O-replaces,-O-C (O) O-heteroaryl, the heteroaryl that-O-C (O) O-replaces,-O-C (O) O-heterocycle and-heterocycle that O-C (O) O-replaces, wherein alkyl, the alkyl that replaces, thiazolinyl, the thiazolinyl that replaces, alkynyl, the alkynyl that replaces, cycloalkyl, the cycloalkyl that replaces, cycloalkenyl group, the cycloalkenyl group that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, the heterocycle of heterocycle and replacement in the literary composition definition.
[0066] " Carbonate group" refer to group-OC (O) O-alkyl; the alkyl that-OC (O) O-replaces ;-OC (O) O-thiazolinyl; the thiazolinyl that-OC (O) O-replaces ;-OC (O) O-alkynyl; the alkynyl that-OC (O) O-replaces,-OC (O) O-aryl, the aryl that-OC (O) O-replaces,-OC (O) O-cycloalkyl, the cycloalkyl that-OC (O) O-replaces,-OC (O) O-cycloalkenyl group, the cycloalkenyl group that-OC (O) O-replaces,-OC (O) O-heteroaryl, the heteroaryl that-OC (O) O-replaces,-OC (O) O-heterocycle and-heterocycle that OC (O) O-replaces, wherein alkyl, the alkyl that replaces, thiazolinyl, the thiazolinyl that replaces, alkynyl, the alkynyl that replaces, cycloalkyl, the cycloalkyl that replaces, cycloalkenyl group, the cycloalkenyl group that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, the heterocycle of heterocycle and replacement in the literary composition definition.
[0067] " Cyano group" refer to group-CN.
[0068] " Cycloalkyl" referring to have the cycloalkyl of 3-10 carbon atom of one or more rings, described ring comprises condensed ring, bridged ring and volution system.The example of suitable cycloalkyl comprises, for example, and adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, ring octyl group etc.
[0069] " Cycloalkenyl group" refer to have one or more rings and have at least one＞the non-aromatic cycloalkyl of 3-10 the carbon atom in the unsaturated site of C=C＜encircle, preferred 1-2＞C=C＜unsaturated site of ring.
[0070] " The cycloalkyl that replaces" and " The cycloalkenyl group that replaces" refer to have 1-5 and be selected from down substituent cycloalkyl or the cycloalkenyl group of organizing: oxo; sulfo-; alkyl; the alkyl of replacement; thiazolinyl; the thiazolinyl of replacement; alkynyl; the alkynyl that replaces; alkoxyl group; the alkoxyl group that replaces; acyl group; acyl amino; acyloxy; amino; the amino that replaces; aminocarboxyl; amino thiocarbonyl; amino carbonyl amino; amino thio-carbonyl-amino; aminocarboxyl oxygen base; amino-sulfonyl; amino-sulfonyl oxygen base; amino-sulfonyl amino; amidino groups; aryl; the aryl that replaces; aryloxy; the aryloxy that replaces; arylthio; the arylthio that replaces; carboxyl; carboxylic acid ester groups; (carboxylic acid ester groups) amino; (carboxylic acid ester groups) oxygen base; cyano group; cycloalkyl; the cycloalkyl that replaces; cycloalkyl oxy; the cycloalkyl oxy that replaces; the cycloalkyl sulfo-; the cycloalkyl sulfo-that replaces; cycloalkenyl group; the cycloalkenyl group that replaces; cycloalkenyl oxy; the cycloalkenyl oxy that replaces; the cycloalkenyl group sulfo-; the cycloalkenyl group sulfo-that replaces; guanidine radicals; the guanidine radicals that replaces; halogen; hydroxyl; heteroaryl; the heteroaryl that replaces; heteroaryloxy; the heteroaryloxy that replaces; the heteroaryl sulfo-; the heteroaryl sulfo-that replaces; heterocycle; the heterocycle that replaces; the heterocyclyloxy base; the heterocyclyloxy base that replaces; the heterocyclic radical sulfo-; the heterocyclic radical sulfo-that replaces; nitro; SO 3The alkylthio of H, alkylsulfonyl, alkylsulfonyl oxygen base, sulfo-acyl group, mercaptan, alkylthio and replacement, wherein said substituting group defines in the text.In some embodiments, cycloalkyl or cycloalkenyl group have 1-3 above-mentioned group.
[0071] " Cycloalkyloxy" refer to-the O-cycloalkyl.
[0072] " The cycloalkyloxy that replaces" refer to-O-(cycloalkyl of replacement).
[0073] " The cycloalkyl sulfo-" refer to-the S-cycloalkyl.
[0074] " The cycloalkyl sulfo-that replaces" refer to-S-(cycloalkyl of replacement).
[0075] " Cycloalkenyl oxy" refer to-the O-cycloalkenyl group.
[0076] " The cycloalkenyl oxy that replaces" refer to-O-(cycloalkenyl group of replacement).
[0077] " The cycloalkenyl group sulfo-" refer to-the S-cycloalkenyl group.
[0078] " The cycloalkenyl group sulfo-that replaces" refer to-S-(cycloalkenyl group of replacement).
[0079] " Guanidine radicals" refer to group-NHC (=NH) NH 2
[0080] " The guanidine radicals that replaces" refer to-NRC (=NR) N (R) 2Wherein each R independently is selected from: the heterocycle of the heteroaryl of the aryl of the alkyl of hydrogen, alkyl, replacement, aryl, replacement, heteroaryl, replacement, heterocycle and replacement, and two R bases that are connected on the shared guanidine radicals nitrogen-atoms can be chosen wantonly with they institute's bonded nitrogen in conjunction with the heterocyclic group that forms heterocycle or replacement, prerequisite is that at least one R is not a hydrogen, and wherein said substituting group in the literary composition definition.
[0081] " Halogen" or " Halogen" refer to fluorine, chlorine, bromine and iodine, preferably fluorine or chlorine.
[0082] " Hydroxyl" refer to group-OH.
[0083] " Heteroaryl" refer to contain 5-15 annular atoms, comprising 1-4 heteroatomic aromatic group that is selected from oxygen, nitrogen or sulphur.This heteroaryl (for example can have single ring, pyridyl or furyl) or a plurality of condensed ring is (for example, indolizinyl or benzothienyl (benzothienyl)), condensed ring wherein is can yes or no aromatic and/or contain or do not contain heteroatoms, and prerequisite is that tie point is the atom of aromatic series heteroaryl.In one embodiment, the nitrogen of heteroaryl and/or sulphur annular atoms are optional oxidized so that N-oxide compound (N → O), sulfinyl or alkylsulfonyl part to be provided.In preferred embodiment, heteroaryl is a 5-14 unit heteroaryl, the first heteroaryl of especially preferred 5-10.Preferred heteroaryl comprises pyridyl, pyrimidyl, pyrazinyl, piperazinyl (pyridizinyl), triazine (base), pyrryl, indyl, thienyl and furyl.
[0084] " The heteroaryl that replaces" refer to by 1-5 heteroaryl that is selected from down the substituting group replacement of group: with the identical group of substituting group that in the aryl that replaces, defines.In some embodiments, heteroaryl has 1-3 above-mentioned group.In other embodiments, heteroaryl has 1-2 above-mentioned group.In some embodiments, heteroaryl has a plurality of condensed ring, and described condensed ring is can yes or no aromatic, except with above be the identical group of substituting group of the aryl definition that replaces, described non-aromatic condensed ring can be chosen wantonly by oxygen and replace.
[0085] " Heteroaryloxy" refer to-the O-heteroaryl.
[0086] " The heteroaryloxy that replaces" refer to group-O-(heteroaryl of replacement).
[0087] " The heteroaryl sulfo-" refer to group-S-heteroaryl.
[0088] " The heteroaryl sulfo-that replaces" refer to group-S-(heteroaryl of replacement).
[0089] " Heterocycle" or " Heterocyclic" or " Heterocyclylalkyl" or " Heterocyclic radical" referring to have 1-10 carbon atom being arranged and 1-4 heteroatomic saturated or undersaturated group that is selected from nitrogen, sulphur or oxygen being arranged of single ring or a plurality of condensed ring in ring; described condensed ring comprises condensed bridge ring systems and volution system; wherein; the intrasystem one or more rings of condensed ring can be cycloalkyl, aryl or heteroaryl, and prerequisite is that tie point is the non-aromatic annular atoms.In one embodiment, the nitrogen of heterocyclic group and/or sulphur atom can be chosen wantonly oxidized so that N-oxide compound, sulfinyl, alkylsulfonyl part to be provided.
[0090] " The heterocycle that replaces" or " The Heterocyclylalkyl that replaces" or " The heterocyclic radical that replaces" refer to that by the heterocyclic group of 1-5 substituting group replacement described substituting group is identical with the substituting group that defines for the cycloalkyl that replaces.In some embodiments, heterocyclic radical has 1-3 above-mentioned group.
[0091] " The heterocyclyloxy base" refer to group-O-heterocyclic radical.
[0092] " The heterocyclyloxy base that replaces" refer to group-O-(heterocyclic radical of replacement).
[0093] " The heterocyclic radical sulfo-" refer to group-S-heterocyclic radical.
[0094] " The heterocyclic radical sulfo-that replaces" refer to group-S-(heterocyclic radical of replacement).
[0095] example of heterocycle and heteroaryl includes but not limited to: acridine, azetidine, the pyrroles, imidazoles, pyrazoles, pyridine, piperazine, pyrimidine, pyridazine, indolizine, isoindole, indoles, indoline, indazole, purine, quinolizine, isoquinoline 99.9, quinoline, phthalazines, the naphthyl pyridine, quinoxaline, quinazoline, cinnolines, pteridine, carbazole, carboline, phenanthridines, acridine, phenanthroline, isothiazole, azophenlyene isoxazole Fen oxazine, thiodiphenylamine, imidazolidine, tetrahydroglyoxaline, piperidines, piperazine, indoline, phthalic imidine, 1,2,3, the 4-tetrahydroisoquinoline, 4,5,6,7-tetrahydro benzo [b] thiophene, thiazole, thiazolidine, thiophene, benzo [b] thiophene, morpholinyl, thio-morpholinyl (being also referred to as thiomorpholine base (thiamorpholinyl)), 1,1-dioxo thio-morpholinyl, piperidyl, tetramethyleneimine, tetrahydrofuran base etc.
[0096] typical heteroaryl includes but not limited to derived from following group: acridine, azetidine, benzoglyoxaline, benzoisoxazole, benzo [b] thiophene, benzodiazole, benzodioxan, cumarone, benzopyrone, diazosulfide, benzothiazole, benzotriazole benzoxazine benzoxazole benzoxazole quinoline, carbazole, carboline, β-Ka Lin, look alkane, chromene, cinnolines, indoline, 1,1-dioxo thio-morpholinyl, furans, imidazoles, imidazolidine, tetrahydroglyoxaline, indazole, indoles, indoline, indolizine, isobenzofuran, heterochromatic alkene, isoindole, isoindoline, isoquinoline 99.9, isothiazole isoxazole, morpholinyl, the naphthyl pyridine, 1,5-naphthyridine oxadiazole oxazole, perimidine, phenanthridines, phenanthroline, azophenlyene, thiodiphenylamine Fen oxazine, phthalazines, phthalic imidine, piperazine, piperidines, pteridine, pteridine, purine, pyrans, piperazine, pyrazoles, pyridazine, pyridine, pyrimidine, the pyrroles, pyrrolidone, pyrroles's piperazine (pyrrolizine), quinazoline, quinoline, quinolizine, quinoxaline, 4,5,6,7-tetrahydro benzo [b] thiophene, tetrahydrofuran base, 1,2,3, the 4-tetrahydroisoquinoline, tetrazolium, thiadiazoles, thiazole, thiazolidine, thio-morpholinyl (being also referred to as the thiomorpholine base), thiophene, triazole, ton etc., and their various hydrogenation variants.
[0097] " Nitro" refer to group-NO 2
[0098] " Oxo" refer to atom (=O).
[0099] " Spiro cycloalkyl group" refer to have the cyclic group of 3-10 carbon atom of the cycloalkyl ring that has spiral shell structure (this structure is formed by the alkylidene bridge of alkylidene group or replacement, and its two ends are incorporated in the chain or the single atom in another loop systems part), shown in following structure:
Figure A20068002053300911
[0100] " Alkylsulfonyl" refer to group-SO 2-alkyl ,-SO 2The alkyl of-replacement ,-SO 2-thiazolinyl ,-SO 2The thiazolinyl of-replacement ,-SO 2-cycloalkyl ,-SO 2The cycloalkyl of-replacement ,-SO 2-cycloalkenyl group ,-SO 2The cycloalkenyl group of-replacement ,-SO 2-aryl ,-SO 2The aryl of-replacement ,-SO 2-heteroaryl ,-SO 2The heteroaryl of-replacement ,-SO 2-heterocycle ,-SO 2-the heterocycle that replaces, wherein the heterocycle of the heteroaryl of the aryl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the thiazolinyl of the alkyl of alkyl, replacement, thiazolinyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heteroaryl, replacement, heterocycle and replacement in the literary composition definition.Alkylsulfonyl comprises such as methyl-SO 2-, phenyl-SO 2-and 4-aminomethyl phenyl-SO 2-group.
[0101] " Alkylsulfonyl oxygen base" refer to group-OSO 2-alkyl ,-OSO 2The alkyl of-replacement ,-OSO 2-thiazolinyl ,-OSO 2The thiazolinyl of-replacement ,-OSO 2-cycloalkyl ,-OSO 2The cycloalkyl of-replacement ,-OSO 2-cycloalkenyl group ,-OSO 2The cycloalkenyl group of-replacement ,-OSO 2-aryl ,-OSO 2The aryl of-replacement ,-OSO 2-heteroaryl ,-OSO 2The heteroaryl of-replacement ,-OSO 2-heterocycle ,-OSO 2-the heterocycle that replaces, wherein the heterocycle of the heteroaryl of the aryl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the thiazolinyl of the alkyl of alkyl, replacement, thiazolinyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heteroaryl, replacement, heterocycle and replacement in the literary composition definition.
[0102] " The sulfo-acyl group" refer to group H-C (S)-; alkyl-C (S)-; the alkyl-C of replacement (S)-; thiazolinyl-C (S)-; the thiazolinyl-C of replacement (S)-; alkynyl-C (S)-, alkynyl-the C (S) that replaces-, cycloalkyl-C (S)-, cycloalkyl-the C (S) that replaces-, cycloalkenyl group-C (S)-, cycloalkenyl group-the C (S) that replaces-, aryl-C (S)-, aryl-the C (S) that replaces-, heteroaryl-C (S)-, heteroaryl-the C (S) that replaces-, heterocycle-C (S)-and heterocycle-C (S) of replacing-, alkyl wherein, the alkyl that replaces, thiazolinyl, the thiazolinyl that replaces, alkynyl, the alkynyl that replaces, cycloalkyl, the cycloalkyl that replaces, cycloalkenyl group, the cycloalkenyl group that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, the heterocycle of heterocycle and replacement in the literary composition definition.
[0103] " Mercaptan" refer to group-SH.
[0104] " Sulfo-" refer to atom (=S).
[0105] " Alkylthio" refer to group-S-alkyl, wherein alkyl in the literary composition definition.
[0106] " Silyl" refer to group-SiH 3" Trialkylsilkl" refer to group-SiR 3, wherein each R independently is the alkyl of alkyl or replacement.
[0107] " The alkylthio that replaces" refer to group-S-(alkyl of replacement), wherein the alkyl of Qu Daiing in the literary composition definition.
[0108] " Steric isomer" refer to the different compound of chirality of one or more stereocenters.Steric isomer comprises enantiomorph and diastereomer.
[0109] " Tautomer" refer to other form of the molecule that the proton position is different; as enol-ketone and imine-enamine tautomerism body; or contain the tautomeric form of the heteroaryl that is incorporated into ring-NH-part and ring=N-annular atoms partly, as pyrazoles, imidazoles, benzoglyoxaline, triazole and tetrazolium.
[0110] " The patient" refer to people and non-human animal.
[0111] " Pharmacy acceptable salt" referring to the salt of pharmaceutically acceptable compound, this salt can be derived from various organic and inorganic counter ion well known in the art, and comprise, only for instance, sodium, potassium, calcium, magnesium, ammonium, tetra-allkylammonium etc.; And the salt that when molecule contains alkaline functionality, comprises organic or mineral acid, example hydrochloric acid salt, hydrobromate, tartrate, mesylate, acetate, maleate, oxalate etc.
[0112] " Prodrug" refer to may need under working conditions as in vivo to transform to discharge activity 2, the activity 2 of 4-pyrimidinediamine medicine, the derivative of 4-pyrimidinediamine compounds (medicine).Prodrug does not have pharmacological activity usually before changing into active medicine, but needn't be like this.For obtaining prodrug, usually shelter active 2 with preceding group (definition hereinafter), be considered in the 4-pyrimidinediamine medicine partly discharge functional group and activity 2, the precursor portions (promoiety) of 4-pyrimidinediamine medicine to be formed under the specific working conditions through transforming (as excision) for active required one or more functional groups.The excision of precursor portions can spontaneously be carried out, for example, perhaps can or induce by another kind of reagent catalysis by hydrolysis reaction, and for example by enzyme, light, acid or alkali, perhaps can be by changing or contact physics or environmental parameter, as changing temperature.Described reagent can be present in the working conditions, as uses the enzyme that exists in the acidic conditions of the cell of prodrug or stomach, and perhaps described reagent also can be provided by the outside.
[0113] " Preceding group" refer to one type protecting group, active 2 when sheltering with this protecting group, the functional group in the 4-pyrimidinediamine medicine and medicine can be changed into prodrug when forming precursor portions.Before group usually by can cut key under specific working conditions being connected to the functional group of medicine.Therefore, preceding group is the part of precursor portions, and it is can be under specific working conditions cut and discharge functional group.Its object lesson is for comprising preceding group-C (O) CH 3Formula-NH-C (O) CH 3Shown amide precursor part.More particularly, of the present invention 2, one or more sulfamyl of 4-pyrimidinediamine compounds are protected with formation-SO by acyl group 2N (H) C (O) CH 3Deng.
[0114] " Medicine effective quantity" or " treatment significant quantity " refer to be enough to treat particular disorder or disease or its one or more symptoms and/or prevent described disease or the amount of the compound that illness takes place.With regard to the tumorigenicity proliferative disorders, medicine or treatment significant quantity comprise the amount that tumour reduced or reduce tumor growth rate of being enough to.
[0115] " Solvate" refer to solvent molecule is mixed the compound that forms with solute molecule or ion.Described solvent can be the organic or inorganic compound.Some examples of solvent include but not limited to: methyl alcohol, N, dinethylformamide, tetrahydrofuran (THF), methyl-sulphoxide, water etc.
[0116] except as otherwise noted, the substituent name that does not clearly define in the text is to name adjacent functionality to obtain towards tie point then by the terminal portions of name functionality.For example, substituting group " arylalkyl oxygen base carbonyl " refer to group (aryl)-(alkyl)-O-C (O)-.
[0117] should understand, in the above in Ding Yi all substituting groups, by further replacing polymkeric substance that substituting group obtains with substituting group (for example, the aryl that replaces has the aryl of replacement as substituting group, and this substituting group itself can replace by substituted aryl, the latter can replace by substituted again aryl again, and the rest may be inferred) be not included in herein.In this case, this substituent maximum number is 3.For example, the aryl of the continuous replacement of the aryl of replacement aryl-(aryl of replacement)-replacement of only limiting to-replacing.
[0118] similarly, should be understood that top definition does not comprise unallowed substitute mode (for example, methyl is replaced by 5 fluorine).This unallowed substitute mode is that one of ordinary skill in the art is understood easily.
C. compound of the present invention
[0119] the invention provides new 2, the pyrimidinediamine compounds that 4-replaces, the prodrug of this compound, make the method for this compound and use these compounds for treating target JAK approach or suppress jak kinase, especially JAK3 has the method for the symptom of treatment benefit.These symptoms include but not limited to aging and pathogenic disease and influence children simultaneously and adult illness, for example have: neoplastic disease such as leukemia comprise for example leukemia of children, lymphoma, autoimmunization symptom such as transplant rejection, and other symptom described in the literary composition.Consider the seriousness of these symptoms and the misery that causes, the new treatment of these symptoms of research treatment is important.
In [0120] one embodiment, the invention provides compound, its prodrug, its solvate or its pharmacy acceptable salt of formula I:
Figure A20068002053300931
Wherein
X is selected from: the alkynyl of the thiazolinyl of the amino of the alkoxyl group of the alkyl of alkyl, replacement, alkoxyl group, replacement, amino, replacement, carboxyl, carboxylic acid ester groups, cyano group, halogen, nitro, thiazolinyl, replacement, alkynyl and replacement;
R is selected from: the cycloalkyl of the alkynyl of the thiazolinyl of the alkyl of hydrogen, alkyl, replacement, thiazolinyl, replacement, alkynyl, replacement, cycloalkyl and replacement;
Ring A is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl group and heterocycle, and wherein encircling A is not indyl or benzimidazolyl-;
Y is selected from: key ,-NR 7-,-C (O) NR 7-,-NR 7C (O)-,-NR 7C (O) O-,-OC (O) NR 7-,-NR 7C (O) NR 7-, oxygen and sulphur, wherein R 7Independent is the alkyl of hydrogen, alkyl or replacement;
Alk is key or straight or branched alkylidene group, wherein R then when alk and Y respectively do for oneself key 1By a covalent bonds in the ring A;
R 1Be selected from: heterocycle, acyl group, aminoacyl oxygen base and the amino carbonyl amino of the heteroaryl of the aryl of cyano group, acyl amino, aminoacyl, aryl, replacement, carboxyl, carboxylic acid ester groups, carboxylic acid ester groups oxygen base, heteroaryl, replacement, heterocycle, replacement; Perhaps
R 1-alk-Y-is R 10-C (O)-S-alk-C (O)-, wherein alk in the literary composition definition and R 10It is the alkyl of alkyl or replacement; Perhaps
R 1-alk-Y-is R 11R 12NS (O) 2-, R wherein 11And R 12Independent is the alkyl of alkyl or replacement;
P is 0,1,2 or 3 when ring A is monocycle, and perhaps p is 0,1,2,3,4 or 5 when ring A comprises a plurality of ring;
Each R 2Independently be selected from: the heterocyclyloxy base of the heterocycle of the heteroaryloxy of the heteroaryl of the cycloalkyloxy of the cycloalkyl of the aryloxy of the aryl of the amino of the alkoxyl group of the alkyl of alkyl, replacement, alkoxyl group, replacement, amino, replacement, aryl, replacement, aryloxy, replacement, cyano group, cycloalkyl, replacement, cycloalkyloxy, replacement, heteroaryl, replacement, heteroaryloxy, replacement, heterocycle, replacement, heterocyclyloxy base, replacement, aminoacyl, aminoacyl oxygen base, carboxyl, carboxylic acid ester groups, carbonate group, nitro and halogen, perhaps two R on the same carbon 2The formation oxo (=O);
Z 1, Z 2And Z 3Independent separately is carbon or nitrogen, if Z wherein 1Be then Z of nitrogen 2And Z 3Be carbon, if Z 2Be then Z of nitrogen 1And Z 3Be carbon, and if Z 3Be then Z of nitrogen 1And Z 2Be carbon, if Z wherein 1, Z 2Or Z 3Be then SO of nitrogen 2R 4R 5Debond is in nitrogen;
Q is 0,1,2 or 3;
Each R 3Independently be selected from: the heterocycle of the cycloalkyl of the alkoxyl group of the alkyl of hydrogen, alkyl, replacement, alkoxyl group, replacement, cycloalkyl or replacement, halogen, heterocycle and replacement;
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement, acyl group and M +, M wherein +Be to be selected from K +, Na +, Li +Or +N (R 6) 4The metal counter ion, R wherein 6Be hydrogen or alkyl, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4Or R 5Be to be selected from Ca 2+, Mg 2+ or Ba 2+The divalence counter ion, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms; Perhaps
When q is 1,2 or 3, R 5Can with a R who is incorporated into its alpha position 3Group forms together suc as formula the condensed ring shown in the II:
Figure A20068002053300941
Wherein W is selected from: C 1-C 3The C of alkylidene group, replacement 1-C 3Alkylidene group, C 2-C 3The C of alkenylene and replacement 2-C 3Alkenylene, wherein one or more carbon atoms have been selected from oxygen, sulphur, S (O), S (O) 2, C (O) or NR 8Part replace R wherein 8Be selected from hydrogen or alkyl, perhaps R 8It is the key that participates in forming unsaturated-N=C＜site;
Prerequisite is:
When alk is key and Y when being key, R 1Not cyano group, carboxyl, carboxylic acid ester groups or amino carbonyl amino;
When alk is-CH 2-, Y is an oxygen, R 1When being phenyl, ring A is not a cycloalkyl;
When alk is that key, Y are key and ring A when being phenyl, R 1Not the heterocycle or the aminoacyl oxygen base of heterocycle, replacement;
As Y or R 1-alk-Y-formation is connected to ring A's-NR 7C (O) O-or-NR 7C (O) NR 7-when directly connecting, R 7Be hydrogen; With
When Y is-C (O) NR 7,-NR 7C (O)-,-OC (O) NR 7-,-NR 7C (O) O-or-NR 7C (O) NR 7-and alk when being key, R 1Not acyl group, acyl amino, aminoacyl or amino carbonyl amino.
[0121] works as R 4Or R 5Be to be selected from Ca 2+, Mg 2+Or Ba 2+The divalence counter ion time, the nitrogen portability negative charge of sulphonamide, but these counter ion will be relevant with two kinds of parent molecule ions, perhaps ring is gone up and is existed another that another anionic group can be provided.For example, chlorine or similar negatively charged ion can be used to satisfy the electric charge of divalent metal (as Mg ++Cl -Deng).
[0122] some embodiment of the present invention provides compound, its prodrug, its solvate or its pharmacy acceptable salt with structure shown in the formula IA:
Figure A20068002053300951
Wherein:
X is selected from: the alkynyl of the thiazolinyl of the amino of the alkoxyl group of the alkyl of alkyl, replacement, alkoxyl group, replacement, amino, replacement, carboxyl, carboxylic acid ester groups, cyano group, halogen, nitro, thiazolinyl, replacement, alkynyl and replacement;
R is selected from: the cycloalkyl of the alkynyl of the thiazolinyl of the alkyl of hydrogen, alkyl, replacement, thiazolinyl, replacement, alkynyl, replacement, cycloalkyl and replacement;
Ring A is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl group and heterocycle, and wherein encircling A is not indyl or benzimidazolyl-;
Alk is key or straight or branched alkylidene group;
R 1Be selected from: heterocycle, acyl group, aminoacyl oxygen base and the amino carbonyl amino of the heteroaryl of the aryl of cyano group, acyl amino, aminoacyl, aryl, replacement, carboxyl, carboxylic acid ester groups, carboxylic acid ester groups oxygen base, heteroaryl, replacement, heterocycle, replacement;
P is 0,1,2 or 3 when ring A is monocycle, and perhaps p is 0,1,2,3,4 or 5 when ring A comprises a plurality of ring;
Each R 2Independently be selected from: alkyl, the alkyl that replaces, alkoxyl group, the alkoxyl group that replaces, amino, the amino that replaces, aryl, the aryl that replaces, aryloxy, the aryloxy that replaces, cyano group, cycloalkyl, the cycloalkyl that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryl, the heteroaryl that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocycle, the heterocycle that replaces, the heterocyclyloxy base, the heterocyclyloxy base that replaces, aminoacyl, aminoacyl oxygen base, carboxyl, carboxylic acid ester groups, carbonate group, nitro and halogen;
Q is 0,1,2 or 3;
Each R 3Independently be selected from: the heterocycle of the cycloalkyl of the alkoxyl group of the alkyl of hydrogen, alkyl, replacement, alkoxyl group, replacement, cycloalkyl or replacement, halogen, heterocycle and replacement;
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement, acyl group and M +, M wherein +Be to be selected from K +, Na +, Li +Or +N (R 6) 4The metal counter ion, R wherein 6Be hydrogen or alkyl, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4Or R 5Be to be selected from Ca 2+, Mg 2+Or Ba 2+The divalence counter ion, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms; Perhaps
When q is 1,2 or 3, R 5Can with a R who is incorporated into its alpha position 3Group forms together suc as formula the condensed ring A shown in the II:
Figure A20068002053300961
Wherein W is selected from: C 1-C 3The C of alkylidene group, replacement 1-C 3Alkylidene group, C 2-C 3The C of alkenylene and replacement 2-C 3Alkenylene, wherein one or more carbon atoms have been selected from oxygen, sulphur, S (O), S (O) 2, C (O) or NR 8Part replace R wherein 8Be selected from hydrogen or alkyl, perhaps R 8It is the key that participates in forming unsaturated-N=C＜site.
[0123] preferably encircling A is phenyl.
[0124] other embodiment comprises compound and prodrug, its solvate or its pharmacy acceptable salt with structure shown in the formula IB:
Wherein:
Ring A is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl group and heterocycle, and wherein encircling A is not indyl or benzimidazolyl-;
Alk is key or straight or branched alkylidene group;
R 1Be selected from: heterocycle, acyl group, aminoacyl oxygen base and the amino carbonyl amino of the heteroaryl of the aryl of cyano group, acyl amino, aminoacyl, aryl, replacement, carboxyl, carboxylic acid ester groups, carboxylic acid ester groups oxygen base, heteroaryl, replacement, heterocycle, replacement;
P is 0,1,2 or 3 when ring A is monocycle, and perhaps p is 0,1,2,3,4 or 5 when ring A comprises a plurality of ring;
Each R 2Independently be selected from: alkyl, the alkyl that replaces, alkoxyl group, the alkoxyl group that replaces, amino, the amino that replaces, aryl, the aryl that replaces, aryloxy, the aryloxy that replaces, cyano group, cycloalkyl, the cycloalkyl that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryl, the heteroaryl that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocycle, the heterocycle that replaces, the heterocyclyloxy base, the heterocyclyloxy base that replaces, aminoacyl, aminoacyl oxygen base, carboxyl, carboxylic acid ester groups, carbonate group, nitro and halogen;
Q is 0,1,2 or 3;
Each R 3Independently be selected from: the heterocycle of the cycloalkyl of the alkoxyl group of the alkyl of hydrogen, alkyl, replacement, alkoxyl group, replacement, cycloalkyl or replacement, halogen, heterocycle and replacement;
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement, acyl group and M +, M wherein +Be to be selected from K +, Na +, Li +Or +N (R 6) 4The metal counter ion, R wherein 6Be hydrogen or alkyl, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms.
[0125] other embodiment provides compound, its prodrug, its solvate or its pharmacy acceptable salt with structure shown in the formula IC again:
Figure A20068002053300971
Wherein:
Alk is key or straight or branched alkylidene group;
R 1Be selected from: heterocycle, acyl group, aminoacyl oxygen base and the amino carbonyl amino of the heteroaryl of the aryl of cyano group, acyl amino, aminoacyl, aryl, replacement, carboxyl, carboxylic acid ester groups, carboxylic acid ester groups oxygen base, heteroaryl, replacement, heterocycle, replacement;
P is 0,1,2 or 3 when ring A is monocycle, and perhaps p is 0,1,2,3,4 or 5 when ring A comprises a plurality of ring;
Each R 2Independently be selected from: alkyl, the alkyl that replaces, alkoxyl group, the alkoxyl group that replaces, amino, the amino that replaces, aryl, the aryl that replaces, aryloxy, the aryloxy that replaces, cyano group, cycloalkyl, the cycloalkyl that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryl, the heteroaryl that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocycle, the heterocycle that replaces, the heterocyclyloxy base, the heterocyclyloxy base that replaces, aminoacyl, aminoacyl oxygen base, carboxyl, carboxylic acid ester groups, carbonate group, nitro and halogen;
Q is 0,1,2 or 3;
Each R 3Independently be selected from: the heterocycle of the cycloalkyl of the alkoxyl group of the alkyl of hydrogen, alkyl, replacement, alkoxyl group, replacement, cycloalkyl or replacement, halogen, heterocycle and replacement;
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement, acyl group and M +, M wherein +Be to be selected from K +, Na +, Li +Or +N (R 6) 4The metal counter ion, R wherein 6Be hydrogen or alkyl, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms.
[0126] other embodiment comprises compound, its prodrug, its solvate or its pharmacy acceptable salt with structure shown in the formula ID:
Figure A20068002053300972
ID
Wherein:
Ring A is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl group and heterocycle, and wherein encircling A is not indyl or benzimidazolyl-;
Alk is key or straight or branched alkylidene group;
R 1Be selected from: heterocycle, acyl group, aminoacyl oxygen base and the amino carbonyl amino of the heteroaryl of the aryl of cyano group, acyl amino, aminoacyl, aryl, replacement, carboxyl, carboxylic acid ester groups, carboxylic acid ester groups oxygen base, heteroaryl, replacement, heterocycle, replacement;
P is 0,1,2 or 3 when ring A is monocycle, and perhaps p is 0,1,2,3,4 or 5 when ring A comprises a plurality of ring;
Each R 2Independently be selected from: the heterocyclyloxy base of the heterocycle of the heteroaryloxy of the heteroaryl of the cycloalkyloxy of the cycloalkyl of the aryloxy of the aryl of the amino of the alkoxyl group of the alkyl of alkyl, replacement, alkoxyl group, replacement, amino, replacement, aryl, replacement, aryloxy, replacement, cyano group, cycloalkyl, replacement, cycloalkyloxy, replacement, heteroaryl, replacement, heteroaryloxy, replacement, heterocycle, replacement, heterocyclyloxy base, replacement, aminoacyl, aminoacyl oxygen base, carboxyl, carboxylic acid ester groups, carbonate group, nitro and halogen, two R on the perhaps same carbon atom 2The formation oxo (=O);
Q is 0,1,2 or 3;
Each R 3Independently be selected from: the heterocycle of the cycloalkyl of the alkoxyl group of the alkyl of hydrogen, alkyl, replacement, alkoxyl group, replacement, cycloalkyl or replacement, halogen, heterocycle and replacement;
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement, acyl group and M +, M wherein +Be to be selected from K +, Na +, Li +Or +N (R 6) 4The metal counter ion, R wherein 6Be hydrogen or alkyl, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4Or R 5Be to be selected from Ca 2+, Mg 2+ or Ba 2+The divalence counter ion, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms.
[0127] the present invention again other preferred implementation compound, its prodrug, its solvate or its pharmacy acceptable salt with structure shown in the formula IE is provided:
Figure A20068002053300981
Wherein:
Alk is key or straight or branched alkylidene group;
R 1Be selected from: heterocycle, acyl group, aminoacyl oxygen base and the amino carbonyl amino of the heteroaryl of the aryl of cyano group, acyl amino, aminoacyl, aryl, replacement, carboxyl, carboxylic acid ester groups, carboxylic acid ester groups oxygen base, heteroaryl, replacement, heterocycle, replacement;
P is 0,1,2 or 3;
Each R 2Independently be selected from: the heterocyclyloxy base of the heterocycle of the heteroaryloxy of the heteroaryl of the cycloalkyloxy of the cycloalkyl of the aryloxy of the aryl of the amino of the alkoxyl group of the alkyl of alkyl, replacement, alkoxyl group, replacement, amino, replacement, aryl, replacement, aryloxy, replacement, cyano group, cycloalkyl, replacement, cycloalkyloxy, replacement, heteroaryl, replacement, heteroaryloxy, replacement, heterocycle, replacement, heterocyclyloxy base, replacement, aminoacyl, aminoacyl oxygen base, carboxyl, carboxylic acid ester groups, carbonate group, nitro and halogen, two R on the perhaps same carbon atom 2The formation oxo (=O);
Q is 0,1,2 or 3;
Each R 3Independently be selected from: the heterocycle of the cycloalkyl of the alkoxyl group of the alkyl of hydrogen, alkyl, replacement, alkoxyl group, replacement, cycloalkyl or replacement, halogen, heterocycle and replacement;
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement, acyl group and M +, M wherein +Be to be selected from K +, Na +, Li +Or +N (R 6) 4The metal counter ion, R wherein 6Be hydrogen or alkyl, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4Or R 5Be to be selected from Ca 2+, Mg 2+ or Ba 2+The divalence counter ion, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms.
[0128] the present invention again other preferred implementation compound, its prodrug, its solvate or its pharmacy acceptable salt with structure shown in the formula III is provided:
Figure A20068002053300991
Wherein:
X is selected from: the alkynyl of the thiazolinyl of the amino of the alkoxyl group of the alkyl of alkyl, replacement, alkoxyl group, replacement, amino, replacement, carboxyl, carboxylic acid ester groups, cyano group, halogen, nitro, thiazolinyl, replacement, alkynyl and replacement;
R is selected from: the cycloalkyl of the alkynyl of the thiazolinyl of the alkyl of hydrogen, alkyl, replacement, thiazolinyl, replacement, alkynyl, replacement, cycloalkyl and replacement;
Ring A is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl group and heterocycle, and wherein encircling A is not indyl or benzimidazolyl-;
P is 0,1,2 or 3;
Each R 2Independently be selected from: alkyl, the alkyl that replaces, alkoxyl group, the alkoxyl group that replaces, amino, the amino that replaces, aryl, the aryl that replaces, aryloxy, the aryloxy that replaces, cyano group, cycloalkyl, the cycloalkyl that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryl, the heteroaryl that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocycle, the heterocycle that replaces, the heterocyclyloxy base, the heterocyclyloxy base that replaces, aminoacyl, aminoacyl oxygen base, carboxyl, carboxylic acid ester groups, carbonate group, alkylsulfonyl, oxo, nitro and halogen;
Z 1, Z 2And Z 3Independent separately is carbon or nitrogen, if Z wherein 1Be then Z of nitrogen 2And Z 3Be carbon, if Z 2Be then Z of nitrogen 1And Z 3Be carbon, and if Z 3Be then Z of nitrogen 1And Z 2Be carbon, if Z wherein 1, Z 2Or Z 3Be then SO of nitrogen 2R 4R 5Debond is in nitrogen;
Q is 0,1,2 or 3;
Each R 3Independently be selected from: the heterocycle of the cycloalkyl of the alkoxyl group of the alkyl of hydrogen, alkyl, replacement, alkoxyl group, replacement, cycloalkyl or replacement, halogen, heterocycle and replacement;
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement, acyl group and M +, M wherein +Be to be selected from K +, Na +, Li +Or +N (R 6) 4The metal counter ion, R wherein 6Be hydrogen or alkyl, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4Or R 5Be to be selected from Ca 2+, Mg 2+ or Ba 2+The divalence counter ion, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms; Perhaps
When q is 1,2 or 3, R 5Can with a R who is incorporated into its alpha position 3Group forms together suc as formula the condensed ring shown in the IV:
Figure A20068002053301001
Wherein W is selected from: C 1-C 3The C of alkylidene group, replacement 1-C 3Alkylidene group, C 2-C 3The C of alkenylene and replacement 2-C 3Alkenylene, wherein one or more carbon atoms have been selected from oxygen, sulphur, S (O), S (O) 2, C (O) or NR 8Part replace R wherein 8Be selected from hydrogen or alkyl, perhaps R 8It is the key that participates in forming unsaturated-N=C＜site;
Prerequisite is:
If p=0, then X is not a bromine;
If ring A is a cycloalkyl, then X is not a bromine;
If p=2 and each R 2Be methoxyl group, halogen, trihalogenmethyl or three halogen methoxyl group, then R 4And R 5Not a hydrogen and a methyl;
If p=2 and R 2Be fluorine and methyl, then R is not the thiazolinyl that replaces; With
If ring A is a phenyl, p=1 and R 2Be chlorine, R then 4And R 5Not a hydrogen and a methyl.
[0129] the present invention again other preferred implementation compound, its prodrug, its solvate or its pharmacy acceptable salt with structure shown in the formula III A is provided:
Figure A20068002053301002
Wherein:
X is selected from: the alkynyl of the thiazolinyl of the amino of the alkoxyl group of the alkyl of alkyl, replacement, alkoxyl group, replacement, amino, replacement, carboxyl, carboxylic acid ester groups, cyano group, halogen, nitro, thiazolinyl, replacement, alkynyl and replacement;
Ring A is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl group and heterocycle, and wherein encircling A is not indyl or benzimidazolyl-;
P is 0,1,2 or 3;
Each R 2Independently be selected from: alkyl, the alkyl that replaces, alkoxyl group, the alkoxyl group that replaces, amino, the amino that replaces, aryl, the aryl that replaces, aryloxy, the aryloxy that replaces, cyano group, cycloalkyl, the cycloalkyl that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryl, the heteroaryl that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocycle, the heterocycle that replaces, the heterocyclyloxy base, the heterocyclyloxy base that replaces, aminoacyl, aminoacyl oxygen base, carboxyl, carboxylic acid ester groups, carbonate group, nitro and halogen;
Q is 0,1,2 or 3;
Each R 3Independently be selected from: the heterocycle of the cycloalkyl of the alkoxyl group of the alkyl of hydrogen, alkyl, replacement, alkoxyl group, replacement, cycloalkyl or replacement, halogen, heterocycle and replacement;
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement, acyl group and M +, M wherein +Be to be selected from K +, Na +, Li +Or +N (R 6) 4The metal counter ion, R wherein 6Be hydrogen or alkyl, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4Or R 5Be to be selected from Ca 2+, Mg 2+ or Ba 2+The divalence counter ion, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4And R 5Form each R of heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms 2Independently be selected from: alkyl; the alkyl that replaces; alkoxyl group; the alkoxyl group that replaces; amino; the amino that replaces; aryl; the aryl that replaces; aryloxy; the aryloxy that replaces; cyano group; cycloalkyl; the cycloalkyl that replaces; cycloalkyloxy; the cycloalkyloxy that replaces; heteroaryl; the heteroaryl that replaces; heteroaryloxy; the heteroaryloxy that replaces; heterocycle; the heterocycle that replaces; the heterocyclyloxy base; the heterocyclyloxy base that replaces; aminoacyl; aminoacyl oxygen base; carboxyl; carboxylic acid ester groups; carbonate group; nitro and halogen.
[0130] the present invention again other preferred implementation compound, its prodrug, its solvate or its pharmacy acceptable salt with structure shown in the formula III A is provided, wherein:
Ring A is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl group and heterocycle, and wherein encircling A is not indyl or benzimidazolyl-;
P is 0,1,2 or 3;
Each R 2Independently be selected from: alkyl, the alkyl that replaces, alkoxyl group, the alkoxyl group that replaces, amino, the amino that replaces, aryl, the aryl that replaces, aryloxy, the aryloxy that replaces, cyano group, cycloalkyl, the cycloalkyl that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryl, the heteroaryl that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocycle, the heterocycle that replaces, the heterocyclyloxy base, the heterocyclyloxy base that replaces, aminoacyl, aminoacyl oxygen base, carboxyl, carboxylic acid ester groups, carbonate group, nitro and halogen;
Q is 0,1,2 or 3;
Each R 3Independently be selected from: the heterocycle of the cycloalkyl of the alkoxyl group of the alkyl of hydrogen, alkyl, replacement, alkoxyl group, replacement, cycloalkyl or replacement, halogen, heterocycle and replacement;
[0131] X is fluorine or methyl; With
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement and acyl group; Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms.
[0132] the present invention again other preferred implementation compound, its prodrug, its solvate or its pharmacy acceptable salt with structure shown in the formula III A is provided, wherein:
Ring A is a phenyl;
P is 0,1,2 or 3;
Each R 2Independently be selected from: alkyl, the alkyl that replaces, alkoxyl group, the alkoxyl group that replaces, amino, the amino that replaces, aryl, the aryl that replaces, aryloxy, the aryloxy that replaces, cyano group, cycloalkyl, the cycloalkyl that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryl, the heteroaryl that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocycle, the heterocycle that replaces, the heterocyclyloxy base, the heterocyclyloxy base that replaces, aminoacyl, aminoacyl oxygen base, carboxyl, carboxylic acid ester groups, carbonate group, nitro and halogen;
Q is 0,1,2 or 3;
Each R 3Independently be selected from: the heterocycle of the cycloalkyl of the alkoxyl group of the alkyl of hydrogen, alkyl, replacement, alkoxyl group, replacement, cycloalkyl or replacement, halogen, heterocycle and replacement;
[0133] X is fluorine or methyl; With
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement and acyl group; Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms.
[0134] the present invention again other preferred implementation compound, its prodrug, its solvate or its pharmacy acceptable salt with structure shown in the formula IVA is provided:
Figure A20068002053301021
Wherein:
X is selected from: the alkynyl of the thiazolinyl of the amino of the alkoxyl group of the alkyl of alkyl, replacement, alkoxyl group, replacement, amino, replacement, carboxyl, carboxylic acid ester groups, cyano group, halogen, nitro, thiazolinyl, replacement, alkynyl and replacement;
Ring A is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl group and heterocycle, and wherein encircling A is not indyl or benzimidazolyl-;
P is 0,1,2 or 3;
Each R 2Independently be selected from: alkyl, the alkyl that replaces, alkoxyl group, the alkoxyl group that replaces, amino, the amino that replaces, aryl, the aryl that replaces, aryloxy, the aryloxy that replaces, cyano group, cycloalkyl, the cycloalkyl that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryl, the heteroaryl that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocycle, the heterocycle that replaces, the heterocyclyloxy base, the heterocyclyloxy base that replaces, aminoacyl, aminoacyl oxygen base, carboxyl, carboxylic acid ester groups, carbonate group, alkylsulfonyl, oxo, nitro and halogen;
Each R 3Independently be selected from: the heterocycle of the cycloalkyl of the alkoxyl group of the alkyl of hydrogen, alkyl, replacement, alkoxyl group, replacement, cycloalkyl or replacement, halogen, heterocycle and replacement;
R 4Independently be selected from: the alkyl of hydrogen, alkyl, replacement, acyl group and M +, M wherein +Be to be selected from K +, Na +, Li +Or +N (R 6) 4The metal counter ion, R wherein 6Be hydrogen or alkyl and SO 2NR 4Nitrogen be N -Perhaps
R 4Be to be selected from Ca 2+, Mg 2+ or Ba 2+The divalence counter ion, and SO 2NR 4Nitrogen be N -
Q-1 is 0,1 or 2; With
W is selected from: C 1-C 3The C of alkylidene group, replacement 1-C 3Alkylidene group, C 2-C 3The C of alkenylene and replacement 2-C 3Alkenylene, wherein one or more carbon atoms have been selected from oxygen, sulphur, S (O), S (O) 2, C (O) or NR 8Part replace R wherein 8Be selected from hydrogen or alkyl, perhaps R 8It is the key that participates in forming unsaturated-N=C＜site;
Prerequisite is:
If p=0, then X is not a bromine;
If ring A is a cycloalkyl, then X is not a bromine;
If p=2 and each R 2Be methoxyl group, halogen, trihalogenmethyl or three halogen methoxyl group, then R 4And R 5Not a hydrogen and a methyl;
If p=2 and R 2Be fluorine and methyl, then R is not the thiazolinyl that replaces; With
If ring A is a phenyl, p=1 and R 2Be chlorine, R then 4And R 5Not a hydrogen and a methyl.
[0135] the present invention again other preferred implementation compound, its prodrug, its solvate or its pharmacy acceptable salt with structure shown in the formula IVA is provided, wherein:
X is selected from: the alkynyl of the thiazolinyl of the amino of the alkoxyl group of the alkyl of alkyl, replacement, alkoxyl group, replacement, amino, replacement, carboxyl, carboxylic acid ester groups, cyano group, halogen, nitro, thiazolinyl, replacement, alkynyl and replacement;
Ring A is a phenyl;
P is 0,1,2 or 3;
Each R 2Independently be selected from: alkyl, the alkyl that replaces, alkoxyl group, the alkoxyl group that replaces, amino, the amino that replaces, aryl, the aryl that replaces, aryloxy, the aryloxy that replaces, cyano group, cycloalkyl, the cycloalkyl that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryl, the heteroaryl that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocycle, the heterocycle that replaces, the heterocyclyloxy base, the heterocyclyloxy base that replaces, aminoacyl, aminoacyl oxygen base, carboxyl, carboxylic acid ester groups, carbonate group, alkylsulfonyl, oxo, nitro and halogen;
Each R 3Independently be selected from: the heterocycle of the cycloalkyl of the alkoxyl group of the alkyl of hydrogen, alkyl, replacement, alkoxyl group, replacement, cycloalkyl or replacement, halogen, heterocycle and replacement;
R 4Independently be selected from: the alkyl of hydrogen, alkyl, replacement, acyl group and M +, M wherein +Be to be selected from K +, Na +, Li +Or +N (R 6) 4The metal counter ion, R wherein 6Be hydrogen or alkyl, and SO 2NR 4Nitrogen be N -Perhaps
R 4Be to be selected from Ca 2+, Mg 2+ or Ba 2+The divalence counter ion, and SO 2NR 4Nitrogen be N -
Q-1 is 0,1 or 2; With
W is selected from: C 1-C 3The C of alkylidene group, replacement 1-C 3Alkylidene group, C 2-C 3The C of alkenylene and replacement 2-C 3Alkenylene, wherein one or more carbon atoms have been selected from oxygen, sulphur, S (O), S (O) 2, C (O) or NR 8Part replace R wherein 8Be selected from hydrogen or alkyl, perhaps R 8It is the key that participates in forming unsaturated-N=C＜site;
Prerequisite is:
If p=0, then X is not a bromine;
If ring A is a cycloalkyl, then X is not a bromine;
If p=2 and each R 2Be methoxyl group, halogen, trihalogenmethyl or three halogen methoxyl group, then R 4And R 5Not a hydrogen and a methyl;
If p=2 and R 2Be fluorine and methyl, then R is not the thiazolinyl that replaces; With
If ring A is a phenyl, p=1 and R 2Be chlorine, R then 4And R 5Not a hydrogen and a methyl.
[0136] the present invention again other preferred implementation compound, its prodrug, its solvate or its pharmacy acceptable salt with structure shown in the formula III B is provided:
Figure A20068002053301041
Wherein:
X is selected from: the alkynyl of the thiazolinyl of the amino of the alkoxyl group of the alkyl of alkyl, replacement, alkoxyl group, replacement, amino, replacement, carboxyl, carboxylic acid ester groups, cyano group, halogen, nitro, thiazolinyl, replacement, alkynyl and replacement;
Ring A is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl group and heterocycle, and wherein encircling A is not indyl or benzimidazolyl-;
P is 0,1,2 or 3;
Each R 2Independently be selected from: alkyl, the alkyl that replaces, alkoxyl group, the alkoxyl group that replaces, amino, the amino that replaces, aryl, the aryl that replaces, aryloxy, the aryloxy that replaces, cyano group, cycloalkyl, the cycloalkyl that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryl, the heteroaryl that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocycle, the heterocycle that replaces, the heterocyclyloxy base, the heterocyclyloxy base that replaces, aminoacyl, aminoacyl oxygen base, carboxyl, carboxylic acid ester groups, carbonate group, nitro and halogen;
Q is 0,1,2 or 3;
Each R 3Independently be selected from: the heterocycle of the cycloalkyl of the alkoxyl group of the alkyl of hydrogen, alkyl, replacement, alkoxyl group, replacement, cycloalkyl or replacement, halogen, heterocycle and replacement;
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement, acyl group and M +, M wherein +Be to be selected from K +, Na +, Li +Or +N (R 6) 4The metal counter ion, R wherein 6Be hydrogen or alkyl, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4Or R 5Be to be selected from Ca 2+, Mg 2+ or Ba 2+The divalence counter ion, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms.
[0137] the present invention again other preferred implementation compound, its prodrug, its solvate or its pharmacy acceptable salt with structure shown in the formula III B is provided, wherein:
X is fluorine or methyl;
Ring A is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl group and heterocycle, and wherein encircling A is not indyl or benzimidazolyl-;
P is 0,1,2 or 3;
Each R 2Independently be selected from: alkyl, the alkyl that replaces, alkoxyl group, the alkoxyl group that replaces, amino, the amino that replaces, aryl, the aryl that replaces, aryloxy, the aryloxy that replaces, cyano group, cycloalkyl, the cycloalkyl that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryl, the heteroaryl that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocycle, the heterocycle that replaces, the heterocyclyloxy base, the heterocyclyloxy base that replaces, aminoacyl, aminoacyl oxygen base, carboxyl, carboxylic acid ester groups, carbonate group, nitro and halogen;
Q is 0,1,2 or 3;
Each R 3Independently be selected from: the heterocycle of the cycloalkyl of the alkoxyl group of the alkyl of hydrogen, alkyl, replacement, alkoxyl group, replacement, cycloalkyl or replacement, halogen, heterocycle and replacement;
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement and acyl group; Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms.
[0138] the present invention again other preferred implementation compound, its prodrug, its solvate or its pharmacy acceptable salt with structure shown in the formula III B is provided, wherein:
X is fluorine or methyl;
Ring A is a phenyl;
P is 0,1,2 or 3;
Each R 2Independently be selected from: alkyl, the alkyl that replaces, alkoxyl group, the alkoxyl group that replaces, amino, the amino that replaces, aryl, the aryl that replaces, aryloxy, the aryloxy that replaces, cyano group, cycloalkyl, the cycloalkyl that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryl, the heteroaryl that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocycle, the heterocycle that replaces, the heterocyclyloxy base, the heterocyclyloxy base that replaces, aminoacyl, aminoacyl oxygen base, carboxyl, carboxylic acid ester groups, carbonate group, nitro and halogen;
Q is 0,1,2 or 3;
Each R 3Independently be selected from: the heterocycle of the cycloalkyl of the alkoxyl group of the alkyl of hydrogen, alkyl, replacement, alkoxyl group, replacement, cycloalkyl or replacement, halogen, heterocycle and replacement;
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement and acyl group; Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms.
[0139] the present invention again other preferred implementation compound, its prodrug, its solvate or its pharmacy acceptable salt with structure shown in the formula V is provided, wherein:
Figure A20068002053301061
Wherein:
X is selected from: the alkynyl of the thiazolinyl of the amino of the alkoxyl group of the alkyl of alkyl, replacement, alkoxyl group, replacement, amino, replacement, carboxyl, carboxylic acid ester groups, cyano group, halogen, nitro, thiazolinyl, replacement, alkynyl and replacement;
R is selected from: the cycloalkyl of the alkynyl of the thiazolinyl of the alkyl of hydrogen, alkyl, replacement, thiazolinyl, replacement, alkynyl, replacement, cycloalkyl and replacement;
Z 1, Z 2And Z 3Independent separately is carbon or nitrogen, if Z wherein 1Be then Z of nitrogen 2And Z 3Be carbon, if Z 2Be then Z of nitrogen 1And Z 3Be carbon, and if Z 3Be then Z of nitrogen 1And Z 2Be carbon, if Z wherein 1, Z 2Or Z 3Be then SO of nitrogen 2R 4R 5Debond is in nitrogen;
Q is 0,1,2 or 3;
Each R 3Independently be selected from: the heterocycle of the cycloalkyl of the alkoxyl group of the alkyl of hydrogen, alkyl, replacement, alkoxyl group, replacement, cycloalkyl or replacement, halogen, heterocycle and replacement;
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement, acyl group and M +, M wherein +Be to be selected from K +, Na +, Li +Or +N (R 6) 4The metal counter ion, R wherein 6Be hydrogen or alkyl, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4Or R 5Be to be selected from Ca 2+, Mg 2+ or Ba 2+The divalence counter ion, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms; Perhaps
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement and acyl group; Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms;
R 7Be selected from: the alkyl of hydrogen, alkyl or replacement; With
V is selected from: C 1-C 3The C of alkylidene group, replacement 1-C 3Alkylidene group, C 2-C 3The C of alkenylene and replacement 2-C 3Alkenylene, wherein one or more carbon atoms have been selected from oxygen, sulphur, S (O), S (O) 2Or NR 8Heteroatoms replace R wherein 8Be selected from hydrogen or alkyl, perhaps R 8It is the key that participates in forming unsaturated-N=C＜site.
[0140] the present invention again other preferred implementation compound, its prodrug, its solvate or its pharmacy acceptable salt with structure shown in the formula VA is provided, wherein:
Figure A20068002053301071
Wherein:
X is fluorine or methyl;
Q is 0,1,2 or 3;
Each R 3Independently be selected from: the heterocycle of the cycloalkyl of the alkoxyl group of the alkyl of hydrogen, alkyl, replacement, alkoxyl group, replacement, cycloalkyl or replacement, halogen, heterocycle and replacement;
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement, acyl group and M +, M wherein +Be to be selected from K +, Na +, Li +Or +N (R 6) 4The metal counter ion, R wherein 6Be hydrogen or alkyl, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4Or R 5Be to be selected from Ca 2+, Mg 2+ or Ba 2+The divalence counter ion, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms; Perhaps
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement and acyl group; Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms;
R 7Be selected from: the alkyl of hydrogen, alkyl or replacement; With
V is selected from: C 1-C 3The C of alkylidene group, replacement 1-C 3Alkylidene group, C 2-C 3The C of alkenylene and replacement 2-C 3Alkenylene, wherein one or more carbon atoms have been selected from oxygen, sulphur, S (O), S (O) 2Or NR 8Heteroatoms replace R wherein 8Be selected from hydrogen or alkyl, perhaps R 8It is the key that participates in forming unsaturated-N=C＜site.
[0141] the present invention again other preferred implementation compound, its prodrug, its solvate or its pharmacy acceptable salt with structure shown in the formula VB is provided, wherein:
Figure A20068002053301072
Wherein:
X is fluorine or methyl;
Q is 0,1,2 or 3;
Each R 3Independently be selected from: the heterocycle of the cycloalkyl of the alkoxyl group of the alkyl of hydrogen, alkyl, replacement, alkoxyl group, replacement, cycloalkyl or replacement, halogen, heterocycle and replacement;
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement, acyl group and M +, M wherein +Be to be selected from K +, Na +, Li +Or +N (R 6) 4The metal counter ion, R wherein 6Be hydrogen or alkyl, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4Or R 5Be to be selected from Ca 2+, Mg 2+ or Ba 2+The divalence counter ion, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms; Perhaps
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement and acyl group; Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms;
R 7Be selected from: the alkyl of hydrogen, alkyl or replacement; With
V is selected from: C 1-C 3The C of alkylidene group, replacement 1-C 3Alkylidene group, C 2-C 3The C of alkenylene and replacement 2-C 3Alkenylene, wherein one or more carbon atoms have been selected from oxygen, sulphur, S (O), S (O) 2Or NR 8Heteroatoms replace R wherein 8Be selected from hydrogen or alkyl, perhaps R 8It is the key that participates in forming unsaturated-N=C＜site.
[0142] those are proficient in and those skilled in the art will appreciate that described herely 2, and the pyrimidinediamine compounds that 4-replaces can contain the functional group of being sheltered by preceding group to produce prodrug.This prodrug did not have pharmacological activity usually before changing into their active medicine form, but must be not so.In fact, many of the present invention 2, the pyrimidinediamine compounds that 4-replaces is included in hydrolyzable or resectable precursor portions under the working conditions.For example, ester group can be produced parent carboxylic by acid-catalyzed hydrolysis usually when being exposed to the acidic conditions of stomach, perhaps when being exposed to the alkaline condition of enteron aisle or blood by alkali catalyzed hydrolysis.Therefore, when to the object oral administration, comprise 2 of ester moiety, the pyrimidinediamine compounds that 4-replaces can be considered to the prodrug of their corresponding carboxylic acid, and no matter whether this ester-formin has pharmacological activity.
[0143] metabolic mechanism to preceding group does not require, and for example, can be hydrolyzed metabolism under the acidic conditions of stomach as mentioned above, and/or by the enzymes metabolism that exists in digestive tube and/or bodily tissue or the organ.In fact, privileged site group before the metabolism selectively in the body.For example, many esters are cut under the acidic conditions of stomach.Be designed to be become activity 2 by chemical chop under one's belt, the prodrug of the pyrimidinediamine that 4-replaces can adopt the preceding group that comprises this ester.Perhaps, preceding group can be designed to enzyme such as esterase, Ntn hydrolase, lipase, comprise ATP enzyme and kinases Phosphoric acid esterase etc. in the presence of by metabolism.Contain in vivo and can be known, for example include but not limited to ether, thioether, silyl ether, silylthio-ether, ester, thioesters, carbonic ether, thiocarbonic ester, carbamate, thiocarbamate, urea, thiocarbamide, carboxylic acid amides etc. by the preceding group of metabolic key.Under the certain situation, but can select the Cytochrome P450 of oxidized enzyme such as liver to be oxidized to " precursor " group of metabolism group.
[0144] in prodrug, any available functional moiety can be sheltered to produce prodrug by preceding group.Can by the preceding group in the precursor portions shelter 2, the functional group in the pyrimidinediamine compounds that 4-replaces includes but not limited to: amine (primary amine and secondary amine), hydroxyl, sulfane base (mercaptan), carboxyl etc.Be fit to shelter activity 2, the functional group in the 4-pyrimidinediamine compounds is well known in the art with many preceding group and the gained characteristic that produces prodrug.For example, hydroxy functional group can masked one-tenth sulfonate, ester or carbonate precursor part, and these precursor portions can be hydrolyzed in vivo so that hydroxyl to be provided.Amido functional group can masked one-tenth acid amides, carbamate, imines, urea, phosphenyl, phosphoryl or sulfinyl precursor portions, and these precursor portions can be hydrolyzed in vivo provides amino.Carboxyl can masked one-tenth ester (comprising silyl ester and thioesters), acid amides or hydrazides precursor portions, and these precursor portions can be hydrolyzed in vivo carboxyl is provided.The preceding group that other is suitable and the object lesson of their representative precursor portions are that to be proficient in those skilled in the art conspicuous.Group can individually or be combined in the present prodrug before all these.
[0145] 2, in some embodiments of the pyrimidinediamine compounds that 4-replaces and the using method of this compound, preceding group can be connected in any available primary amine or secondary amine, for example comprise 2, the N2 nitrogen-atoms, 2 of 4-pyrimidinediamine part, the N4 nitrogen-atoms and/or 2 of 4-pyrimidinediamine part, contained uncle or secondary nitrogen-atoms in the 4-pyrimidinediamine compounds substituting group.
[0146] 2, in the embodiment of the pyrimidinediamine compounds that 4-replaces and the using method of this compound, prodrug described here is 2, be substituted on the N4 nitrogen of 4-pyrimidinediamine part or unsubstituted nitrogenous two cyclosubstituted 2, the pyrimidinediamine compounds that 4-replaces, group these nitrogenous two rings contain at least one on following one or more positions before: bicyclic nitrogen-atoms, 2, the N2 nitrogen and/or 2 of 4-pyrimidinediamine part, the N4 nitrogen of 4-pyrimidinediamine part.
[0147] as mentioned above, the character of preceding group is not required, if it can be under required working conditions as under the acidic conditions under one's belt and/or the enzymes metabolism of finding in by body produce bio-active group, for example described here 2, the pyrimidinediamine that 4-replaces.Therefore, those skilled in the art will understand, and preceding group can comprise any known or unknown hydroxyl, amine or mercaptan protecting group in fact.The non-limitative example of appropriate protection base can be at for example Protective Groups in OrganicSynthesis (organic synthesis protecting group), Greene ﹠amp; Wuts, second edition, (the John Wiley ﹠amp of John Wiley Publishing Company; Sons), New York finds in 1991 (especially 10-142 page or leaf (alcohol), 277-308 page or leaf (mercaptan) and 309-405 page or leaf (amine), its content is included this paper by reference in).
[0148] in addition, can select to give the prodrug desired characteristic the character of preceding group.For example, lipophilic group can be used to reduce water-soluble and hydrophilic radical can be used to improve water-soluble.Adopt this method can obtain the prodrug that selected mode of administration is specifically adjusted.Also can be designed to give prodrug other characteristic preceding group, as intestinal absorption, the protection of improved passive intestinal absorption, improved transhipment (transport) mediation exempt from that tachymetabolism (slowly-releasing prodrug), tissue selectivity are sent, passive enrichment in the target tissue, targeting specific vehicle etc.Can give the group of these characteristics of prodrug and know, and be described in, for example, Ettmayer etc., 2004, J.Med.Chem.47 (10): 2393-2404), its content is included this paper by reference in.All groups of describing in these bibliographys can be used for prodrug described here.
[0149] as mentioned above, also can select so that the water-soluble active medicine that is higher than of prodrug preceding group.This preceding group can comprise or can be to be fit to give the water miscible group that drug molecule improves.This group is known, its example includes but not limited to hydrophilic radical, as the alkyl of being mixed by the alkyl of the one or more replacements in amine, alcohol, carboxylic acid, phosphoric acid, sulfoxide, sugar, amino acid, mercaptan, polyvalent alcohol, ether, thioether and the quaternary ammonium salt, aryl, arylalkyl or ring.
[0150] by any specific preceding suitability of group in required mode of administration of biochemical test susceptible of proof.For example, if give specific tissue or organ with prodrug by injection, and the characteristic of the various enzymes of expressing in this tissue or organ is known, then can detect the metabolism situation of specific prodrug in biochemical test with isolating enzyme.Perhaps, available tissue and/or opzyme detect specific prodrug and are metabolized to activity 2, the situation of the pyrimidinediamine compounds that 4-replaces.When the characteristic of the enzyme of in target tissue or organ, expressing for unknown, or can't obtain isolating enzyme easily the time, adopt tissue and/or opzyme especially convenient.Those skilled in the art can select to have the preceding group of the metabolic characteristic (as dynamics) of suitable application-specific easily by this in vitro tests.Certainly, also can in external animal model, detect the pathways metabolism that is fit to specific prodrug.
[0151] many reference have been lectured the application of prodrug and synthetic, comprising, for example, Ettmayer etc., the same and Bungaard etc., (1989) J.Med.Chem.32 (12): 2503-2507.In addition, the U.S. Provisional Patent Application 60/654 that is entitled as " Pyrimidinediamine Prodrugs and their Uses (pyrimidinediamine prodrug and application thereof) " that on February 18th, 2005 submitted to, 620 have especially told about 2, the preparation and the application of 4-pyrimidinediamine prodrug, its content is included this paper by reference in.
[0152] is proficient in and those skilled in the art will appreciate that chemical compound lot and prodrug thereof and all cpds kind of describing especially and/or exemplifying can demonstrate tautomerism, conformational isomerism, rotamerism and/or enantiomerism here.For example, compound of the present invention and prodrug can comprise one or more chiral centres and/or two key, the possibility of result occurs with steric isomer, as double bond isomer (geometrical isomer just), enantiomorph, diastereomer and their mixture, as racemic mixture.Another example is that compound of the present invention and prodrug may exist with multiple tautomeric forms, comprise enol form, keto-acid and their mixture.Name with chemical compound lot is the same, formula that in specification sheets and claim, proposes and figure, only represent a kind of in possible tautomer, conformer, optical isomer or the geometrical isomer, should know to the present invention includes any tautomer, conformer, optical isomer and/or the geometrical isomer with prodrug of one or more application described herein, and the various mixtures of these different isomerization bodies.Atropisomer is owing to being restricted the steric isomer that produces around single bonded rotation, thus this moment to the obstruction of rotation enough height can separate conformer (Eliel, E.L.; Wilen, S.H.Stereochemistry of Organic Compounds (stereochemistry of organic compound); Wiley ﹠amp; Sons:New York, 1994; The 14th chapter).It is significant that isomery is changeed in resistance, because it can not exist the stereochemistry atomic time to introduce chiral element.For example when around 2, the key between 4-pyrimidinediamine core texture and its group that is connected perhaps for example centers on and has Z 1-3A ring and corresponding group that it is connected between the rotation of key when being restricted, the present invention also comprises atropisomer.Except isomeric form, the included compound of the present invention also must be chemically stable and can be isolating.
[0153] according to the characteristic of various substituents, of the present invention 2,4-pyrimidinediamine compounds and prodrug can be the forms of salt.This salt comprises drug salt (" pharmacy acceptable salt ") and is suitable for salt of animal doctor's use or the like.As known in this area, such salt can be derived from acid or alkali.
In [0154] one embodiment, described salt is pharmacy acceptable salt.Usually, pharmacy acceptable salt is fully to keep one or more needed pharmacological activities of parent compound and suitable salt to the human body administration.Pharmacy acceptable salt comprises the acid salt that is formed by mineral acid or organic acid.The mineral acid that is fit to the formation pharmaceutically-acceptable acid addition includes but not limited to haloid acid (for example, hydrochloric acid, Hydrogen bromide, hydrogen iodide or the like), thiosulfonic acid, nitric acid and phosphoric acid etc.The suitable organic acid that forms pharmaceutically-acceptable acid addition comprises but does not limit acetate, trifluoroacetic acid, propionic acid, caproic acid, the pentamethylene propionic acid, oxyacetic acid, oxalic acid, pyruvic acid, lactic acid, propanedioic acid, succsinic acid, hydroxy-butanedioic acid, maleic acid, FUMARIC ACID TECH GRADE, tartrate, citric acid, palmitinic acid, M-nitro benzoic acid, 3-(4-oxybenzene formic acid) M-nitro benzoic acid, vinylbenzene acid, phenylglycolic acid, alkylsulphonic acid (for example, methylsulfonic acid, ethyl sulfonic acid, 1,2-ethane-disulfonic acid, 2-ethylenehydrinsulfonic acid etc.), aryl sulfonic acid (for example, phenylbenzimidazole sulfonic acid, 4-chloro-phenyl-sulfonic acid, the 2-naphthene sulfonic acid, 4-tolyl sulfonic acid, cycloalkyl sulfonic acid (as camphorsulfonic acid), 4-methyl bicyclic [2.2.2]-octane-2-alkene-1-carboxylic acid octane, glucoheptonic acid, the 3-phenylpropionic acid, trimethylacetic acid, tert.-butylacetic acid, dodecane alcohol radical sulfonic acid, gluconic acid, L-glutamic acid, hydroxynaphthoic acid, Whitfield's ointment, stearic acid and muconic acid etc.).
[0155] the pharmacy acceptable salt salt that comprises also that the sour proton that is present in the parent compound is replaced by metal ion (as alkaline metal ions, alkaline-earth metal ions or aluminum ion) or form with organic bases (as thanomin, diethanolamine, trolamine, N-methylglucosamine, morpholine, piperidines, dimethylamine, diethylamine, triethylamine, ammoniacal liquor etc.) coordination.
[0156] as known in the art, described 2,4-pyrimidinediamine compounds and prodrug thereof with and salt also can be hydrate, solvate and N-oxide form.
[0157] in another embodiment, the invention provides compound or its steric isomer, tautomer, prodrug, solvate or the pharmacy acceptable salt that is selected from Table I-XI.
Figure A20068002053301121
Figure A20068002053301131
Figure A20068002053301141
Figure A20068002053301151
Figure A20068002053301161
Figure A20068002053301171
Figure A20068002053301181
Figure A20068002053301201
Figure A20068002053301211
Figure A20068002053301221
Figure A20068002053301231
Figure A20068002053301241
Figure A20068002053301251
Figure A20068002053301261
Figure A20068002053301271
Figure A20068002053301281
Figure A20068002053301291
Figure A20068002053301311
Figure A20068002053301341
Figure A20068002053301351
Figure A20068002053301361
Figure A20068002053301371
Figure A20068002053301391
Figure A20068002053301401
Figure A20068002053301411
Figure A20068002053301421
Figure A20068002053301441
Figure A20068002053301451
Method of the present invention
[0158] the invention provides as described hereinly 2, pyrimidinediamine compounds that 4-replaces and prodrug thereof are to be used for the treatment of symptom as herein described.The present invention also provides compound of the present invention to be used for the treatment of target JAK approach or to suppress jak kinase, especially JAK3 in manufacturing, has the application in the medicine of symptom of treatment benefit.These symptoms comprise the symptom that relates to lymphocyte, scavenger cell or mastocyte function.Target JAK approach or inhibition jak kinase, especially JAK3, the symptom that has the treatment benefit comprises: leukemia, lymphoma, transplant rejection (for example the pancreatic islets transplantation thing repels), bone marrow transplantation are used in (for example anti-host disease of the value of moving thing), autoimmune disorder (for example rheumatoid arthritis etc.), inflammation (for example asthma etc.) and the literary composition other symptom of detailed description more.
[0159] as mentioned above, many symptoms can be with described here 2, and the pyrimidinediamine compounds that 4-replaces, its prodrug and methods of treatment are handled.In the literary composition, and understood by this area, " treatment " is the useful or required result of a kind of acquisition, comprises the method for clinical effectiveness.For purposes of the present invention, useful or required result include but not limited to following one or more: alleviate or improve one or more symptoms, mitigation symptoms (comprising disease) degree, stable (promptly not making its deterioration) symptom (comprising disease) state, the diffusion that wards off disease, postpone or slow down symptom (comprising disease, progress), improvement or mitigation symptoms (comprising disease, state) and alleviation (partly or entirely) can detect or undetectable symptom.Preferred compound is strong and can low-down dosage topical administration, can make the systemic adverse reactions minimum like this.
[0160] compound described here is a jak kinase effective as selective inhibitor, and especially has selectivity for the cytokine signaling approach that comprises JAK3.This active result is, this compound can be used in various external, the bodies and in the body of earlier external back purposes amplify with the signal cascade of regulating or suppressing jak kinase activity, jak kinase and participate in and be subjected to the biological response that the sort signal cascade is amplified to be influenced.For example, in the embodiment, this compound can be used on external or the interior jak kinase that suppresses of body, in fact can suppress the cell type of any expression jak kinase.For example, the expression of JAK3 occupies advantage in hematopoietic cell.They also can be used to regulate the especially signal transduction cascade that plays a role of JAK3 of jak kinase.This JAK-dependent signals transductory cascade includes but not limited to: comprise the cytokine receptor of general γ chain such as the signal cascade of IL-4, IL-7, IL-5, IL-9, IL-15 and IL-21 and amplify, perhaps the signal cascade of IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 acceptor amplifies.This compound also is used in external or the interior adjusting of body, especially suppresses the cell or the biological response that influenced by this JAK-dependent signals transductory cascade.This cell or biological response include but not limited to: the T cell proliferation that IL-4/ramos CD23 raises, IL-2 mediates etc.Importantly, thus this compound can be used for suppressing jak kinase as treatment or prevention wholly or in part by the disease of the active mediation of jak kinase (be called in the literary composition " Jak kinase is situated between The disease of leading") methods of treatment.The non-limitative example of the disease of the jak kinase mediation of available this compounds for treating or prevention includes but not limited to: transformation reactions, asthma, autoimmune disorder such as transplant rejection (for example, kidney, heart, lung, liver, pancreas, skin; Host versus graft response (HVGR), graft-vs-host reaction (GVHR) etc.), rheumatoid arthritis, amyotrophic lateral sclerosis, autoimmune disorder that T is cell-mediated such as multiple sclerosis, psoriatic and xerodermosteosis, II type inflammatory diseases such as vascular inflammation (comprise vasculitis, arterial pressure, atherosclerosis and coronary artery disease), the disease of central nervous system such as apoplexy, tuberculosis such as bronchitis obliterans and primary pulmonary hypertension, the allergy of delaying type IV type, and solid malignant or hematologic malignancies such as leukemia and lymphoma.
[0161] including but not limited to the example of small part of treatment of available the inventive method or prevention: transformation reactions by the disease of jak kinase mediation, asthma, autoimmune disorder such as transplant rejection are (for example, kidney, heart, lung, liver, pancreas, skin, host versus graft response (HVGR) etc.), rheumatoid arthritis, amyotrophic lateral sclerosis, multiple sclerosis, psoriatic and xerodermosteosis, II type inflammatory diseases such as vascular inflammation (comprise vasculitis, arterial pressure, atherosclerosis and coronary artery disease), the disease of central nervous system such as apoplexy, tuberculosis such as bronchitis obliterans and primary pulmonary hypertension, that postpone or cell-mediated IV type allergy, and solid malignant or hematologic malignancies such as leukemia and lymphoma.
[0162] disease of jak kinase mediation comprises that for example, cell proliferation disorders such as blood tumor comprise lymphoma and myelomatosis." Cell proliferation disorders" refer to cellular abnormality propagation to be the disease of feature.Proliferative disease does not imply any restriction of cell growth speed, and only hypodactylia influences the normal control of cell growth and differentiation.Therefore, in some embodiments, the cell that proliferative disease takes place can have the cytodifferentiation rate identical with normal cell, but the signal of this growth of response limits not." cell proliferation disorders " comprises knurl or tumour, and this is a kind of tissue abnormalities growth.Cancer refers to can invade surrounding tissue and/or to transfer to any malignant tumour that the cell proliferation of newly settling down the position is feature.
[0163] " Blood tumor" refer to that hematopoiesis is the cell proliferation disorders that cell causes.Usually, hemopoietic is that undifferentiated cell or stem cell become the various cells physiological processes in the peripheral blood.In the initial period of growing, hemopoietic stem cell (normally in the marrow) forms the multipotency progenitor cells through a series of cytodifferentiation, and the multipotency progenitor cell experiences two kinds of main development pathways again: lymphatic system and myeloid lineage.The committed progenitor of myeloid lineage is divided into three main inferior, comprising red corpuscle, megalokaryocyte and granulocyte/monocyte development pathway.Another approach forms the dendritic cell that participate in antigen presentation.Erythron produces red blood cell, and megakaryocytic series produces thrombocyte.Granulocyte/monocytic committed cell divides myeloblast or monocyte development pathway again, and last approach forms neutrophil leucocyte, eosinophilic granulocyte and basophilic granulocyte, and then an approach forms blood mononuclear cell and scavenger cell.
[0164] committed progenitor of lymphatic system develops into B cellular pathways, T cellular pathways or non-T/B cellular pathways.As if similar with myeloid lineage, another kind of lymph approach produces the dendritic cell that relate to antigen presentation.B cell progenitor cell develops into pre B cell (pre-B), and it is divided into the B cell of being responsible for producing immunoglobulin (Ig).The progenitor cell of T clone is divided into pre-T cell (pre-T), and this cell develops into cytotoxic T cell or the helper cell/suppressor T cell that participates in cellular immunization according to the influence of some cytokine.Non-T/B cellular pathways produces natural killer (NK) cell.The hematopoietic cell knurl can relate to any stages of cell of hemopoietic, comprises hemopoietic stem cell, multipotency progenitor cell, few energy committed progenitor, precursor cell and sophisticated noble cells.Usually can according to be proficient in description that those skilled in the art adopts and Case definition to blood tumor classify (referring to, for example, the International Classification of disease and associated health problems (ICD 10), world health organization (2003)).Also can characterize blood tumor according to characterization of molecules, the cell phenotype and/or the Philadelphia chromosome of the distinctive chromosome aberration of some blood tumor (for example, disappearance, transposition, insertion etc.) that demonstrate as cell surface marker and allelic expression, abnormal T cell as in chronic granulocytic leukemia, finding.Other classification comprises National Cancer Institute job classification method (National CancerInstitute Working Formulation) (Cancer, 1982,49:2112-2135) with the American-European lymphoma classification of revising (REAL, Revised European-American Lymphoma Classification).
[0165] " Lymphoma" proliferative disease of reference and hemopoietic lymphoid lineage cell.Lymphoma can be caused by hemopoietic stem cell and lymph committed progenitor, precursor cell and terminally differentiated cells.Can be according to paracytic phenotypic characteristic or the paracytic differentiation state lymphoma of further classifying.Wherein, can further be categorized into B glucagonoma, T glucagonoma, NK glucagonoma and Hodgkin lymphoma.
[0166] " Myelomatosis" refer to the proliferative disease of hemopoietic myeloid lineage.Myelomatosis can be caused by hemopoietic stem cell, marrow committed progenitor, precursor cell and terminally differentiated cells.Can be according to paracytic phenotypic characteristic or the paracytic differentiation state myelomatosis of further classifying.Wherein, can further be categorized into myeloproliferative disease, myeloproliferative disorder/myeloproliferative disease, myelodysplastic syndrome, acute myeloid leukaemia and leukemia acute biphenotypic.
[0167] common, it is the disease of feature with the abnormal cell proliferation that the cell proliferation disorders of available compounds for treating described here relates to any.Tumour and cancer comprising various optimum or pernicious, transitivitys or non-metastatic.Can treat specific cancer feature with method described here, invade or shift as tissue.Cell proliferation disorders comprises various cancers, comprising mammary cancer, ovarian cancer, the rectum cancer, gastrointestinal cancer, kidney, bladder cancer, carcinoma of the pancreas, squamous cell lung carcinoma and gland cancer.
[0168] in some embodiments, the cell proliferation disorders of being treated is a blood tumor, i.e. the misgrowth of hemopoietic system cell.Hematologic malignancies can originate from the terminally differentiated cells that multipotential stem cell, multipotency progenitor cell, few energy committed progenitor, precursor cell and participation hemocyte form.Some hematologic malignancies be considered to originate from can self hemopoietic stem cell.For example, the cell that can develop into the specific hypotype of acute myeloid leukaemia (AML) demonstrates the cell surface marker of hemopoietic stem cell when translation, illustrate that hemopoietic stem cell is leukemia cell's source.As if the parent cell that does not have the cell marking feature of hemopoietic stem cell do not produce tumour (Blaire etc., 1997, Blood 89:3104-3112) when transplanting.Following discovery supports that also stem cell is the source of some hematologic malignancies, can find the specific chromosome abnormalty relevant with specific type of leukemia in the normal cell of hematopoiesis system and lymphoblast.For example, reciprocal translocation t (9q34; 22q11) relevant with the chronic granulocytic leukemia that exists in about 95% myeloid lineage, red system and the lymphoid lineage cell, illustrate that chromosome aberration originates from hemopoietic stem cell.Cell subsets in some CML type demonstrates the cell marking phenotype of hemopoietic stem cell.
[0169] although blood tumor originates from stem cell usually, the growth of committed progenitor or end differentiation more eventually is that cell also may be some leukemic sources.For example, make fusion rotein Bcr/Abl (relevant) expression in the common progenitor cell of marrow or granulocyte/scavenger cell progenitor cell can cause leukemia sample symptom with chronic granulocytic leukemia.In addition, some chromosome aberrations relevant with the leukemia hypotype are undiscovered in the cell mass with hemopoietic stem cell mark phenotype, but showing that the hematopoiesis approach is found (Turhan etc., 1995, Blood 85:2154-2161) in the cell mass of differentiation state mark more.Therefore, because committed progenitor and other noble cells may have only limited cytodifferentiation potential, the leukemia cell may obtain the energy for growth do not regulated, can simulate the self characteristic (Passegue etc. of hemopoietic stem cell in some instances, Proc.Natl.Acad.Sci.USA, 2003,100:11842-9).
[0170] in some embodiments, be lymphoma by the blood tumor of being treated, this moment abnormal cells derived from and/or the feature phenotype of showing lymphoid lineage cell.Lymphoma can be subdivided into B glucagonoma, T cell and NK glucagonoma and Hodgkin lymphoma.The B glucagonoma can further be subdivided into precursor B glucagonoma and maturation/periphery B glucagonoma.Exemplary B glucagonoma has precursor B-lymphoblastic leukemia/lymphoma (precursor B cell acute lymphoblastic leukemia), and exemplary maturation/periphery B glucagonoma has B cell lymphocytic leukemia/small lymphocytic lymphoma, B cell PL, lymphoma lymphoplasmacytic, the splenic marginal zone B cell lymphoma, hairy cell, plasma cell myeloma/plasmoma, MALT type extranodal marginal zone B cell lymphoma, joint marginarium B cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, the mediastinum large B cell lymphoid tumor, lymphoma primary effusion and Burkitt lymphoma/leukemia Burkitt cell.T cell and Nk glucagonoma can be further divided into precursor T glucagonoma and maturation (periphery) T glucagonoma.Exemplary precursor T glucagonoma has precursor T-lymphoblastic lymphoma/leukemia (precursor T cell acute lymphoblastic leukemia), and exemplary maturation (periphery) T glucagonoma has T cell PL, T cell pellets cell lymphocyte leukemia, the NK chronic myeloid leukemia of progress, adult T cell lymphoma/leukemia (HTLV-1), lymphoma extranodal NK/Tcell, the nose type, enteropathy-type T cell lymphoma, liver spleen γ-delta T cells lymphoma, subcutaneous pimelitis sample t cell lymphoma, mycosis fungoides/Sezary syndrome, primary cutaneous type, lymphoma peripheral T cell (T/ null cell, lymphoma anaplastic large cell), lymphoma peripheral T cell (not having other features), angioimmunoblastic T cell lymphoma, primary cutaneous type ((T/ null cell, primary general type).The 3rd class lymphoma is a Hodgkin lymphoma, is also referred to as Hodgkin's disease.The such exemplary disease of available described compounds for treating comprises the various classical field formalisms of nodositas lymphocyte dominance Hodgkin lymphoma and Hodgkin's disease, its example nodosity sclerotic type Hodgkin lymphoma (1 grade and 2 grades), the classical Hodgkin lymphoma based on lymphocyte, hodgkin lymphoma mixed cellularity type and LD Hodgkin lymphoma.In various embodiments, with the active relevant all available Syk inhibition of any lymphoma compounds for treating of unusual Syk.
[0171] in some embodiments, the blood tumor of being treated is a myelomatosis.Myelomatosis comprises that a big class relates to or show the cell proliferation disorders of myeloid lineage cell characteristic phenotype.Myelomatosis can be subdivided into myeloproliferative disease, myeloproliferative disorder/myeloproliferative disease, myelodysplastic syndrome and acute myeloid leukaemia.Exemplary myeloproliferative disease has chronic granulocytic leukemia, and (for example, (t (9 for the Philadelphia chromosome positive; 22) (qq34; Q11)), chronic neutrophilic leukemia, chronic EL/Eosinophilia's property syndrome, chronic idiopathic myelofibrosis, polycythemia vera and essential thrombocythemia.Exemplary myeloproliferative disorder/myeloproliferative disease has chronic myelomonocytic leukemia, atypical chronic granulocytic leukemia and juvenile form bone marrow mononuclear cell leukemia.Exemplary myelodysplastic syndrome has refractory anemia with sideroblasts and refractory anemia without sideroblasts, intractable cytopenia (myelodysplastic syndrome) companion polyphyly heteroplasia, refractory anemia (myelodysplastic syndrome) companion protoblast is too much, 5q syndrome and myelodysplastic syndrome companion t (9; 12) (q22; P12) (TEL-Syk merges; Referring to, for example, Kuno etc., 2001, Blood 97:1050).In various embodiments, with the active relevant all available Syk inhibition of any myelomatosis compounds for treating of unusual Syk.
[0172] in some embodiments, described Syk inhibition compound can be used to treat acute myeloid leukaemia (AML), comprising the myelomatosis that can further segment of a big class.These subclass comprise: the transposition of AML companion recurrent cytogenetics, AML companion polyphyly heteroplasia, and other non-classified AML.Exemplary AML companion recurrent cytogenetics transposition comprises: AML accompanies t (8; 21) (q22; Q22), AML1 (CBF-α)/ETO, (AML accompanies t (15 to acute promyelocytic leukemia; 17) (q22; Q11-12) and variant, PML/RAR-α), (inv (16) (p13q22) or t (16 for AML companion abnormal marrow oxyphie; 16) (p13; Q11), CBFb/MYH11X) and AML companion 11q23 (MLL) unusual.Exemplary AML companion polyphyly heteroplasia is those and the relevant or incoherent AML of myelodysplastic syndrome before.Other acute myeloid leukaemia that is not referred to any definable kind comprises minimum differentiated AML, prematurity type AML, adult form AML, acute myelomonocytic leukemia, acute monocytic leukemia, acute fragility of erythrocytes leukemia, acute megakaryoblastic leukemia, acute basophilic leukemia and acute panmyelosis companion myelofibrosis.
[0173] disease of Jak mediation also comprises various autoimmune disorders.This autoimmune disorder includes but not limited to: be commonly called those autoimmune disorders of single organ or unicellular type systemic autoimmune disease and those autoimmune disorders that are commonly called systemic autoimmune disorder.The non-limitative example that is commonly called single organ or unicellular type systemic autoimmune disease comprises: Hashimoto thyroiditis, autoimmune hemolytic anemia, autoimmunity pernicious anemia atrophic gastritis, the autoimmunity encephalomyelitis, autoimmunity orchitis, goodpasture's disease, autoimmunity thrombopenia, sympathetic ophthalmia, myasthenia gravis, Graves disease, primary biliary cirrhosis, chronic active hepatitis, ulcerative colitis and membranous glomerulopathy.The non-limitative example that is commonly called those diseases of systemic autoimmune disorder comprises: systemic lupus erythematous, rheumatoid arthritis, xerodermosteosis, Reiter syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid.Other autoimmune disorder can be based on β cell (body fluid) or based on the T cell, comprise cogan's syndrome, ankylosing spondylitis, Wegner granulomatosis, autoimmunity alopecia, I type or juvenile onset diabetes and thyroiditis.
[0174] type of the autoimmune disorder of available JAK inhibition compounds for treating described here or prevention generally includes those and tissue injury diseases associated, and described tissue injury is as taking place at the antigenic body fluid in immunogen or endogenous and/or exogenous source and/or cell-mediated response result.This disease is commonly called nonallergic (being II type, III type and/or IV type) allergy.
[0175] allergy of I type is normally learned active substance and is caused as histamine owing to mastocyte and/or basophilic leukocyte release of pharmacologically behind the specific exogenous antigen of contact.This I type is reflected in the multiple disease that comprises complaisance asthma, rhinallergosis etc. and plays a role.II type allergy (being also referred to as the allergy of cell toxicant, cytolytic component dependency or cytositimulation) takes place in the antigenicity component of immunoglobulin (Ig) and cell or tissue or when interacting with the tight link coupled antigen of cell or tissue or haptens.Common and II type allergy diseases associated includes but not limited to: autoimmune hemolytic anemia, EBF and goodpasture's disease.III type allergy (being also referred to as toxicity mixture, soluble complex or immunocomplex allergy) causes owing to solubility circulating antigen-immunoglobulin complex deposits in blood vessel or tissue, and the while is with the acute inflammatory response at immune complex deposit position.The non-limitative example of prototype III type reaction disease comprises glomerulonephritis, multiple sclerosis and the bullous pemphigoid of arthus reaction, rheumatoid arthritis, serum sickness, systemic lupus erythematous, some type.IV type allergy (being commonly referred to cell, cell-mediated, postpone or tuberculin type allergy) is to be caused by the T lymphocyte of sensitization by the contact specific antigen.The non-limitative example that relates to the disease of IV type reaction is contact dermatitis and allograft rejection.
[0176] autoimmune disorder relevant with any above-mentioned nonallergic allergy can be with jak kinase inhibitor for treating of the present invention or prevention.Specifically, this method can be used for treating or prevents those is the autoimmune disorder of feature with the autoimmune disorder of single organ or unicellular type usually, comprising but be not limited to: Hashimoto thyroiditis, autoimmune hemolytic anemia, autoimmunity pernicious anemia atrophic gastritis, the autoimmunity encephalomyelitis, autoimmunity orchitis, goodpasture's disease, the autoimmunity thrombopenia, sympathetic ophthalmia, myasthenia gravis, Graves disease, primary biliary cirrhosis, chronic active hepatitis, ulcerative colitis and membranous glomerulopathy, and those are usually relating to the autoimmune disorder that systemic autoimmune disorder is a feature, comprising but be not limited to: systemic lupus erythematous (SLE), rheumatoid arthritis, xerodermosteosis, Reiter syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid.
[0177] those skilled in the art will understand, and many above-mentioned autoimmune disorders are relevant with serious symptom, even if described autoimmune disorder is not eased, but the alleviation of these symptoms can provide significant treatment benefit.
[0178] disease of JAK mediation also comprises inflammation and inflammatory diseases (for example, osteoarthritis, inflammatory bowel, ulcerative colitis, Crohn's disease, idiopathic inflammatory bowel diseases, irritable bowel syndrome syndrome, spastic colon etc.), rudimentary cicatrization is (for example, scleroderma, fibrosis increases, keloid, operation back scar, pulmonary fibrosis, vascular spasm, migraine, reperfusion injury and back myocardial infarction), and sicca complex or sjogren syndrome.All available method described here treatment of all these diseases or prevention.
In [0179] one embodiment, the invention provides the active method of a kind of inhibition jak kinase, this method comprises the compound that makes the jak kinase contact effectively suppress the active amount of jak kinase, and wherein said compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).
[0180] in another embodiment, the invention provides the active method of a kind of inhibition jak kinase, this method is included in the compound that the external JAK3 of making kinases contact effectively suppresses the active amount of jak kinase, wherein said compound is selected from: compound of the present invention as described herein (comprising the compound described in Table I-X), and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).In some embodiment of methods described herein, this method is carried out in vivo.
[0181] in concrete embodiment, described compound can be used for treating and/or preventing the repulsion (promptly treating and/or preventing allograft rejection) in organ and/or the tissue grafts acceptor.Allograft can be by repelling at the antigenic cell-mediated or humoral immune reaction of the graft that is presented to donorcells film surface (histocompatibility) that acceptor produces.The strongest antigen is subjected to being called the antigenic genetic loci mixture domination of people A type white corpuscle (HLA).The same with abo blood group antigen, they are detectable main graft antigen in the mankind.Preferably, compound of the present invention uses with prevention with the transplanting of kidney, heart, lung, liver, pancreas, small intestine, large intestine, skin or alleviates host versus graft response (HVGR) or graft-vs-host reaction (GVHR).
[0182] repulsion after the transplanting can be divided into three classes usually: super acute, after transplanting, take place in a few hours to a couple of days; Acute, a couple of days takes place in some months after transplanting; With chronic, some months took place in several years after transplanting.
[0183] hyperacute rejection causes mainly due to the host's antibody that has produced the attack graft tissue.In hyperacute rejection, in the graft blood vessel, observe antibody immediately after the transplanting.Blood vessel takes place in the very short time afterwards solidify, this causes ischemic and finally causes and death.Known immunosuppressive therapy is invalid to graft infarction.Since can be at external evaluation HLA antigen, screening can be used to significantly reduce hyperacute rejection before transplanting.This results of screening is that nowadays hyperacute rejection is relatively not general.
[0184] acute cellular rejection is considered to antigen atopy cell in graft tissue inner accumulated mediation.What T was cell-mediated is the main mechanism of acute cellular rejection at these antigenic immune responses (being HVGR or GVHR).These cells gather the damage that causes graft tissue.It is believed that CD4+ helper cell and CD8+ cytotoxic T cell all participate in this process, and antigen is presented by donor and host's dendritic cell.The CD4+ helper cell helps to raise other effector cell for graft, as scavenger cell and eosinophilic granulocyte.Also relate to the signal transduction cascade (for example, CD28, CD40L and CD2 cascade) of palp t cell activation.
[0185] by the reinforced immunological treatment, can reverse cell-mediated acute cellular rejection as a rule.Success can be cured graft by the major injury element by fibrosis after reversing, and remaining graft shows normally.Solved after the acute cellular rejection the low-down level that the dosage of immunosuppressive drug can be fallen.
[0186] chronic rejection is the peculiar problem in the renal transplantation, although immunosuppressant therapy is constantly strengthened its development of still hiding.Think that this overwhelming majority is because cell-mediated IV type allergy causes.Its pathological characters is different from acute cellular rejection.It relates generally to arterial endothelium, arterial endothelium hyper-proliferative and artery-clogging flow gradually, thus cause ischemic, fibrosis, intimal thickening and atherosclerosis to change.Chronic rejection is mainly due to the carrying out property obturation of graft vascular system, and is similar to vasculitis process slowly.
[0187] in the allergy of IV type, when cd8 cell poison T cell and CD4 helper cell can be discerned in the born of the same parents or synthetic antigen outside the born of the same parents with I class or II class MHC molecule compound tense respectively.The function of scavenger cell is as antigen presenting cell and discharges IL-1 that IL-1 can promote helper cell propagation.Helper cell discharges interferon-gamma and IL-2, and they are regulated together by the superactivity reaction of the delay of macrophage activation mediation with by the cell-mediated immunity of T.In organ transplantation, cytotoxic T cell destroys the graft cell that touches.
[0188] because jak kinase is played the part of keying action in the activation of T cell, therefore described here 2, the pyrimidinediamine compounds that 4-replaces can be used for treating and/or preventing many aspects of transplant rejection, and especially can be used for treating and/or preventing the rejection that is added to by the T cell to small part, as HVGR or GVHR.2, the pyrimidinediamine compounds that 4-replaces also can be used for treating and/or preventing graft acceptor, the especially chronic rejection of renal transplantation thing acceptor.
[0189] in another embodiment, the invention provides the method for the cell-mediated autoimmune disorder of a kind of T of treatment, this method comprises that the patient who suffers from this autoimmune disorder effectively treats the compound of the amount of described autoimmune disorder, and wherein said compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).In some embodiment of this method, described autoimmune disorder is multiple sclerosis (MS), psoriatic or xerodermosteosis.
[0190] adopts described here 2, the therapy of the pyrimidinediamine compounds that 4-replaces can be used separately, perhaps can assist with other common immunosuppressive therapy combined administration or as it, these therapies for example have: purinethol, cortical steroid such as prednisone, methylprednisolone and prednisolone, alkylating agent such as endoxan, neurocalcin inhibitor such as ciclosporin, sirolimus and tacrolimus, inosine monophosphate dehydrogenase (IMPDH) inhibitor such as mycophenolate, mycophenlate mofetil and azathioprine, and be designed for the medicament that suppresses cellular immunization and keep the humoral immune reaction of acceptor, comprise various antibody (for example, antilymphocyte globulin (ALG) (ALG), antithymocyte globulin (ATG), monoclonal anti-T cell antibody (OKT3)) and radiation.These different medicaments can use according to indicated their standard or routine dose in the incidental prescription information of medicine commercial form (also can referring to Prescription information in The Physician ' s Desk Reference (doctor's desk reference) version in 2006), its content is included this paper by reference in.(Salix Pharmaceuticals Inc.) obtains azathioprine from Sai Likesi pharmaceutical Co. Ltd with trade(brand)name AZASAN at present; (GatePharmaceuticals Inc.) obtains purinethol from giving special medicine company limited with trade(brand)name THOL at present; (RoxaneLaboratories Inc.) obtains from the gloomy laboratory of Roc company limited at present for prednisone and prednisolone; Methylprednisolone obtains from Pfizer (Pfizer) at present; Sirolimus (rapamycin) obtains from Hui Shi-A Yesite company (Wyeth-Ayerst) with trade(brand)name RAPAMUNE at present; Tacrolimus obtains from rattan pool company (Fujisawa) with trade(brand)name PROGRAF at present; Ciclosporin obtains from Novartis Co.,Ltd (Novartis) with trade(brand)name SANDIMMUNE at present, and obtains from Abbott (Abbott) with GENGRAF; IMPDH inhibitor such as mycophenlate mofetil and Mycophenolic Acid obtain from Luo Shi (Roche) with trade(brand)name CELLCEPT at present, and obtain from Novartis Co.,Ltd (Novartis) with trade(brand)name MYFORTIC; Azathioprine obtains from Ge Lansu-SmithKline company (Glaxo SmithKline) with trade(brand)name IMURAN at present; Antibody can obtain from the many biotech companies of Austria (Ortho Biotech) by trade(brand)name ORTHOCLONE at present, obtain from Novartis Co.,Ltd (Novartis) with trade(brand)name SIMULECT (basiliximab), and obtain from Luo Shi (Roche) with trade(brand)name ZENAPAX (daclizumab).
[0191] in another embodiment, 2, the pyrimidinediamine compounds that 4-replaces can give with the combination of Syk kinase inhibitor or be auxiliary as it.The Syk kinases is a kind of Tyrosylprotein kinase, known its brought into play keying action in conduction of Fc γ receptor signal and the amplification of other signal cascade, as relate to those (Tumer etc. of B-cell receptor signal conduction, (2000), ImmunologyToday 21:148-154) and those (Mocsavi etc. that relate to integrin β (1) in the neutrophilic leukocyte, β (2) and β (3), (2002), Immunity 16:547-558).For example, the Syk kinases causes activating in mastocyte and discharges subsequently in the high-affinity IgE receptor signal conduction of the number of chemical medium cause that allergy is attacked and brings into play keying action.Yet different with the jak kinase that helps adjusting participation IV type allergy approach that postpone or cell-mediated, the Syk kinases helps to regulate the type of the I immediately allergy approach that participation IgE-mediates.Some compound that influences the Syk approach can influence or not influence the JAK approach.
[0192] suitable Syk inhibition compound is described in, for example, and the sequence number 10/355,543 (publication number 2004/0029902) that on January 31st, 2003 submitted to; WO 03/063794; The sequence number 10/631,029 that on July 29th, 2003 submitted to; WO 2004/014382; The sequence number 10/903,263 that on July 30th, 2004 submitted to; The PCT/US2004/24716 (WO005/016893) that on July 30th, 2004 submitted to; The sequence number 10/903,870 that on July 30th, 2004 submitted to; The PCT/US2004/24920 that on July 30th, 2004 submitted to; The sequence number 60/630,808 that on November 24th, 2004 submitted to; The sequence number 60/645,424 that on January 19th, 2005 submitted to; With the sequence number 60/654,620 that on February 18th, 2005 submitted to, its content is included this paper by reference in.Describe in the literary composition 2, pyrimidinediamine and Syk inhibition compound that 4-replaces can use separately, perhaps can repel methods of treatment with one or more above-mentioned conventional graft and be used in combination.
[0193] in concrete embodiment, 2, the pyrimidinediamine compounds that 4-replaces can be used for treatment or intravital these diseases of prevention patient, described patient is for Syk inhibition compounds for treating or to one of other existing therapy of specified disease reactionless at the very start (patience), it is reactionless perhaps to become.Can be with 2, the pyrimidinediamine compounds that 4-replaces gives that with Syk inhibition compound the Syk compound is had patience or unresponsive patient.Can be with 2, the suitable Syk inhibition compound that the pyrimidinediamine compounds that 4-replaces gives together is as mentioned above.
[0194] in another embodiment, the invention provides the method for the cell-mediated autoimmune disorder of a kind of T of treatment, this method comprises that the patient who suffers from this autoimmune disorder effectively treats the compound of described autoimmune disorder amount, wherein said compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3), and described compound and IC 50The kinase whose compound combination of inhibition Syk that scope is at least 10 μ M gives or auxiliary this compound.
[0195] in another embodiment, the invention provides the method for the allograft rejection in a kind of treatment or the prevention graft acceptor, this method comprises and gives the compound that the amount of described repulsion was effectively treated or prevented to the graft acceptor that wherein said compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).
[0196] in another embodiment, the invention provides the method for the allograft rejection in a kind of treatment or the prevention graft acceptor, wherein said repulsion is an acute cellular rejection, this method comprises and gives the compound that the amount of described repulsion was effectively treated or prevented to the graft acceptor that wherein said compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).
[0197] in another embodiment, the invention provides the method for the allograft rejection in a kind of treatment or the prevention graft acceptor, wherein said repulsion is chronic rejection, this method comprises and gives the compound that the amount of described repulsion was effectively treated or prevented to the graft acceptor that wherein said compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).
[0198] in another embodiment, the invention provides the method for the allograft rejection in a kind of treatment or the prevention graft acceptor, wherein said repulsion is by HVGR or GVHR mediation, this method comprises and gives the compound that the amount of described repulsion was effectively treated or prevented to the graft acceptor that wherein said compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).
[0199] in another embodiment, the invention provides the method for the allograft rejection in a kind of treatment or the prevention graft acceptor, wherein said allograft is selected from kidney, heart, liver or lung, this method comprises and gives the compound that the amount of described repulsion was effectively treated or prevented to the graft acceptor that wherein said compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).
[0200] in another embodiment, the invention provides the method for the allograft rejection in a kind of treatment or the prevention graft acceptor, wherein said allograft is selected from kidney, heart, liver or lung, this method comprises and gives the compound that the amount of described repulsion was effectively treated or prevented to the graft acceptor, wherein said compound is selected from: compound of the present invention as described herein and (the CAS accession number 845817-97-2 of the compound among the Table X I, CAS accession number 841290-42-4 and CAS accession number 841290-41-3), wherein said compound and the combination of another kind of immunosuppressor give or auxiliary another kind of immunosuppressor.
[0201] in another embodiment, the invention provides the method for the allograft rejection in a kind of treatment or the prevention graft acceptor, wherein said allograft is selected from kidney, heart, liver or lung, this method comprises and gives the compound that the amount of described repulsion was effectively treated or prevented to the graft acceptor, wherein said compound is selected from: compound of the present invention as described herein and (the CAS accession number 845817-97-2 of the compound among the Table X I, CAS accession number 841290-42-4 and CAS accession number 841290-41-3), wherein said compound and the combination of another kind of immunosuppressor give or auxiliary another kind of immunosuppressor, and wherein said immunosuppressor is selected from: ciclosporin, tacrolimus, sirolimus, the IMPDH inhibitor, mycophenolate, mycophenlate mofetil, anti--T cell antibody and OKT3.
[0202] described here 2, the pyrimidinediamine compounds that 4-replaces is the cytokine modulators of IL-4 signal conduction.Consequently, 2, the pyrimidinediamine compounds that 4-replaces can slow down replying the allergy of I type.Therefore, in concrete embodiment, 2, the pyrimidinediamine compounds that 4-replaces can be used for prophylactically handling this reaction, so preventability ground handle relevant with this allergy (for example, transformation reactions), by its mediation or the disease that causes.For example, transformation reactions patient can take in outbreak or the progress of one or more JAK alternative cpds described here with the delayed allergy reaction before estimating the contact allergen, perhaps eliminate this reaction fully.
[0203] when being used for the treatment of or prevent this disease, 2, the pyrimidinediamine compounds that 4-replaces can give separately, as one or more 2, the mixture of the pyrimidinediamine compounds that 4-replaces gives or mixes or make up with the other medicines that are used for the treatment of this disease and/or this disease related symptom to give.2, the pyrimidinediamine compounds that 4-replaces also can give with medicament mixed that is used for the treatment of other illness or disease or combination, and described medicine comprises for example steroid, membrane stabilizer, 5-lipoxidase (5LO) inhibitor, synthetic and the acceptor inhibitor of leukotriene, IgE isotype switch or IgE synthetic inhibitor, IgG isotype switch or IgG synthetic inhibitor, β-excitomotor, tryptase inhibitors, Asprin, cyclo-oxygenase (COX) inhibitor, methotrexate, the anti-TNF medicine, the auspicious suffering (retuxin) that is coated with, the PD4 inhibitor, the p38 inhibitor, PDE4 inhibitor and antihistaminic.2, the pyrimidinediamine compounds itself that 4-replaces can give by prodrug forms, perhaps gives as the pharmaceutical composition that comprises active compound or prodrug.
[0204] in another embodiment, the invention provides the method for a kind of treatment or the allergy of prevention IV type, this method comprises and gives the compound that the amount of described allergy was effectively treated or prevented to object that wherein said compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).
[0205] in another embodiment, the invention provides the method for a kind of treatment or the allergy of prevention IV type, this method is a therapeutic or preventative, it comprises and gives the compound that the amount of described allergy was effectively treated or prevented to object, wherein said compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3), and described compound gave before the contact allergen.
[0206] in another embodiment, the invention provides the method for the signal transduction cascade that a kind of JAK3 of inhibition kinases plays a role therein, this method comprises makes a kind of compound of cells contacting of expressing the acceptor that participates in sort signal cascade amplification, and wherein said compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).
[0207] in another embodiment, the invention provides the method for the disease of a kind of treatment or the mediation of prevention jak kinase, this method comprises the compound of the amount of the disease that gives effective treatment of object or the mediation of prevention jak kinase, and wherein said compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).
[0208] in another embodiment, the invention provides the method for the disease of a kind of treatment or the mediation of prevention jak kinase, the disease of wherein said JAK mediation is HVGR or GVHR, this method comprises the compound of the amount of the disease that gives effective treatment of object or the mediation of prevention jak kinase, and wherein said compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).
[0209] in another embodiment, the invention provides the method for the disease of a kind of treatment or the mediation of prevention jak kinase, the disease of wherein said JAK mediation is acute allograft rejection, this method comprises the compound of the amount of the disease that gives effective treatment of object or the mediation of prevention jak kinase, and wherein said compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).
[0210] in another embodiment, the invention provides the method for the disease of a kind of treatment or the mediation of prevention jak kinase, the disease of wherein said JAK mediation is chronic allograft rejection, this method comprises the compound of the amount of the disease that gives effective treatment of object or the mediation of prevention jak kinase, and wherein said compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).
[0211] active compound of the present invention suppresses the JAK/Stat approach usually.Can be in external or interior evaluating specific compound activity as the jak kinase inhibitor.In some embodiments, can detect the activity of specific compound by test cell line.Suitable test comprises determines that jak kinase suppresses the test of phosphorylation activity or atpase activity.Therefore, if certain compound with about 20 μ M or lower IC 50Suppress the phosphorylation or the ART enzymic activity of jak kinase, can say that then this compound can suppress the jak kinase activity.
[0212] measuring this inhibiting a kind of method is to detect 2, and the pyrimidinediamine compounds that 4-replaces is to the effect of up-regulated gene product upstream.In Ramos/IL4 test, with cytokine interleukin element-4 (IL-4) thus stimulate the B cell to cause JAK family kinase JAK1 and JAK3 by phosphorylation activation JAK/Stat approach, this causes transcription factor Stat-6 by phosphorylation and activation again.The gene that the Stat-6 that is activated raises is low affinity IgE acceptor CD23.To JAK1 and the kinase whose effect of JAK3, personnel selection IL-4 stimulates people Ramos B cell for research inhibitor (for example, described here 2, the pyrimidinediamine compounds that 4-replaces).Stimulating pair cell after 20-24 hour to dye analyzes with the rise of understanding CD23 and with flow cytometry (FACS).Compare with collating condition, the amount minimizing of the CD23 of appearance shows that test compounds initiatively suppresses the jak kinase approach.Such a kind of exemplary test will be described in embodiment 41 in further detail.
[0213] can be described here 2 by detecting, the pyrimidinediamine compounds that 4-replaces further characterizes the activity of active compound of the present invention to the influence of primary human T cell proliferative response.In this test, elementary human T-cell also stimulates to activate in advance with TXi Baoshouti and CD28 from peripheral blood, and they respond cytokine interleukin element-2 (IL-2) and breed when cultivating.This proliferative response depends on can phosphorylation and the JAK1 of activating transcription factor Stat-5 and the activation of JAK3 Tyrosylprotein kinase.With elementary human T-cell and 2, the pyrimidinediamine compounds that 4-replaces was cultivated 72 hours together when having IL-2, and ATP concentration is to estimate cell survival in test endpoint is measured born of the same parents.Compare the cell proliferation minimizing with collating condition and show that the jak kinase approach is suppressed.Such exemplary test is described in embodiment 42 in further detail.
[0214] described here 2 by detecting, the pyrimidinediamine compounds that 4-replaces can further characterize the activity of The compounds of this invention to the influence of A549 pulmonary epithelial cells and U937 cell.A549 pulmonary epithelial cells and the various different stimulated of U937 cellular response and raise the surface expression of ICAM-1 (CD54).Therefore, but express as of the influence of reading evaluation test compound with ICAM-1 unlike signal pathway in the same cell type.Cause ICAM-1 to be raised with IL-1 β thorn activating signal activation IL-1 beta receptor and then activation TRAF6/NF kB pathway.Thereby IFN γ induces the JAK1/JAK2 approach to be activated raises ICAM-1.Can quantize the rise of ICAM-1 and calculate EC by flow cytometry according to the dose curve of compound 50Value.Such exemplary test is described in detail in embodiment 43 and 44 more.
[0215] active compound as herein described is usually with about 1mM or lower IC 50Suppress the jak kinase approach, described IC 50Value test determination described herein.Certainly, those skilled in the art will understand, and have low IC 50, for example 100 μ M, 75 μ M, 50 μ M, 40 μ M, 30 μ M, 20 μ M, 15 μ M, 10 μ M, 5 μ M, 1 μ M, 500nM, 100nM, 10nM, 1nM or lower compound may be more useful in treatment is used.When requiring that particular cell types had activity, available required cell type detects the active of this compound and oppositely screens to obtain that other cell type is lacked active compound.Required " non-activity " degree in this reverse screening, perhaps active required ratio with non-activity according to circumstances are not both and can change, and can be selected by the user.
The pyrimidinediamine active compound that [0216] 2,4-replaces also suppresses the expression of the CD23 that IL-4 stimulates in the B cell, its IC usually 50Be about 20 μ M or lower, be about 10 μ M, 1 μ M, 500nM, 100nM, 10nM, 1nM or lower usually.Adoptable a kind of suitable test is the test of describing during embodiment 41 " detects the test of the Ramos B clone of IL-4 stimulation ".In some embodiments, activity 2, the IC of pyrimidinediamine compounds in embodiment 41 described tests that 4-replaces 50For be less than or equal to 5 μ M, greater than 5 μ M but less than 20 μ M, greater than 20 μ M or greater than 20 μ M but less than 50 μ M.
[0217] in addition, 2, the pyrimidinediamine active compound that 4-replaces also suppresses the elementary T cell activity of people, its IC usually 50Be about 20 μ M or lower, be about 10 μ M, 1 μ M, 500nM, 100nM, 10nM, 1nM or lower usually.The elementary T cell of available isolating people adopts the IC of the outer test determination of standard body at the elementary T cell of people 50Adoptable a kind of suitable test is the test of describing among the embodiment 42 " the primary human T cell proliferation test that stimulated by IL-2 ".In some embodiments, activity 2, the IC of pyrimidinediamine compounds in embodiment 42 described tests that 4-replaces 50For be less than or equal to 5 μ M, greater than 5 μ M but less than 20 μ M, greater than 20 μ M or greater than 20 μ M but less than 50 μ M.
The pyrimidinediamine active compound that [0218] 2,4-replaces also suppresses the expression of inductive ICAM1 (CD54) owing to contact IFN γ in U937 or the A549 cell, its IC usually 50Be about 20 μ M or lower, be about 10 μ M, 1 μ M, 500nM, 100nM, 10nM, 1nM or lower usually.Available isolating A549 or U937 clone are utilized the IC that expresses at ICAM (CD54) in the functional cell test determination IFN γ stimulated cells 50Adoptable suitable test is respectively the test of describing among embodiment 43 " the A549 epithelial cell line that stimulated by IFN γ " or the embodiment 44 " U937IFN γ ICAM1 FACS test ".In some embodiments, embodiment 43 or embodiment 44 have described IC in test 50Be less than or equal to 20 μ M, greater than 20 μ M, greater than 20 μ M but less than the activity 2 of 50 μ M, the pyrimidinediamine compounds that 4-replaces.
E. pharmaceutical composition of the present invention
[0219] contain described herely 2, the pharmaceutical composition of the pyrimidinediamine compounds (or its prodrug) that 4-replaces can be by traditional mixing, molten, the granulation of disappearing, make drageeing, grinding, emulsification, formation capsule, trapping or freeze dried process produces.These compositions can use one or more physiologically acceptable carriers, thinner, vehicle in a conventional manner or help that active compound is processed in the pharmacy auxiliary of spendable preparation and allocate out.
Pyrimidinediamine compounds or prodrug that [0220] 2,4-replaces can be made into pharmaceutical composition itself, perhaps make the form of hydrate, solvate or pharmacy acceptable salt, and be as described herein.Usually, the corresponding free bronsted lowry acids and bases bronsted lowry solution more soluble in water of this salt ratio, but also can be made into the salt that solubleness is lower than corresponding free bronsted lowry acids and bases bronsted lowry.
In [0221] one embodiment, pharmaceutical preparation provided by the invention comprises a kind of compound or its prodrug and at least a pharmaceutically acceptable vehicle, thinner, sanitas or stablizer or their mixture, and described compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).
[0222] in another embodiment, can put into practice the methods of treatment of this method as treatment symptom described here.Therefore, in concrete embodiment, 2, pyrimidinediamine compounds (and the various forms described here that 4-replaces, comprise the pharmaceutical preparation that contains this compound (with various forms)) can be used for treatment of animal subjects, comprise the symptom described here among the mankind.This method generally includes and gives described object effectively compound or its salt of the present invention, prodrug, hydrate or the N-oxide compound of the amount of the described symptom of treatment.In one embodiment, described object is a Mammals, comprising but be not limited to ox, horse, cat, dog, rodents or primates.In another embodiment, described object is behaved.
[0223] described compound can various preparations and formulation provide.Described compound can pharmaceutically acceptable form provide, and is comprising described compound or prodrug being mixed with pharmaceutical composition itself or being the form of hydrate, solvate, N-oxide compound or pharmacy acceptable salt, as described herein.Usually, this salt still also may form the salt than the poor solubility in corresponding free bronsted lowry acids and bases bronsted lowry than corresponding free bronsted lowry acids and bases bronsted lowry solution more soluble in water.Should be understood that and in the middle of the preparation discussion, mention compound, 2, when the pyrimidinediamine compounds that 4-replaces or " activity ", be proficient in it should be appreciated by those skilled in the art, also comprise 2 when appropriate, the preparation of the pyrimidinediamine compounds prodrug that 4-replaces.
In [0224] one embodiment, described compound provides with pharmaceutically acceptable non-toxic salt, as mentioned above.The pharmacy acceptable salt of suitable The compounds of this invention comprises the acid salt that is formed by hydrochloric acid, fumaric acid, tosic acid, toxilic acid, succsinic acid, acetate, citric acid, tartrate, carbonic acid or phosphoric acid.The salt of amido also comprises quaternary ammonium salt, and wherein amino nitrogen atom carries suitable organic group, as alkyl, thiazolinyl, alkynyl or aralkyl moiety.In addition, when compound of the present invention carried acidic moiety, its suitable pharmacy acceptable salt can comprise the salt of metal, as an alkali metal salt, and for example sodium salt or sylvite; And alkaline earth salt, for example calcium salt and magnesium salts.
[0225] can form pharmacy acceptable salt of the present invention by ordinary method, for example described salt can't the dissolved solvent or medium in or in solvent, make free alkali form and one or more normal suitable acid-respons of product such as water, then under vacuum or by lyophilize or the negatively charged ion of existing salt and another kind of anionresin are desolvated to remove.
[0226] the present invention includes 2, pyrimidinediamine compounds and the solvate of salt, for example hydrate that 4-replaces.
The pyrimidinediamine compounds that [0227] 2,4-replaces can have one or more asymmetric centers, therefore can correspondingly exist with enantiomorph and diastereomer.Should be understood that all this isomer and their mixture are included in the scope of the invention.
[0228] 2, the pyrimidinediamine compounds that 4-replaces can be by oral, parenteral (for example, intramuscular, intraperitoneal, intravenously, ICV, intracisternal injection or inculcate, subcutaneous injection or transplant), by sucking spraying, nose, vagina, rectum, hypogloeeis, urethra (for example urethral suppositories) or the topical approach (for example, gel, ointment, emulsifiable paste, aerosol etc.) give, and can be made the proper dosage unit formulation that contains the nontoxic vehicle of pharmaceutically acceptable routine, adjuvant, vehicle and the carrier that are fit to various route of administration separately or together.Except treating warm-blooded animal such as mouse, rat, horse, ox, sheep, dog, cat, monkey etc., compound of the present invention can be effective to the mankind.
[0229] be used to give 2, the pharmaceutical composition of the pyrimidinediamine compounds that 4-replaces can exist also and can make by the method that any pharmacy field is known by dosage unit form usually.For example, solid carrier or the two even and thorough mixing of activeconstituents and liquid vehicle or segmentation can be made product shaping become required preparation then if necessary, thereby makes pharmaceutical composition.The content of active target compound is enough to produce required result of treatment in the pharmaceutical composition.For example, pharmaceutical composition of the present invention can adopt the form that is fit to any administering mode in fact, comprise, as local, eye, oral, contain clothes, systematicness, nose, injection, skin, rectum, vagina administration mode or the like, or suitable suction or be blown into the form of administration.
[0230] use for the part, described JAK alternative cpd or prodrug can be made into solution well known in the art, gel, ointment, emulsifiable paste, suspension or the like.
[0231] the general formulation comprise those be injection (as in subcutaneous, intravenously, intramuscular, the sheath or peritoneal injection) formulation of design, and the formulation that those be transdermal, saturating mucous membrane is oral or pulmonary administration designs.
[0232] useful injectable formulation comprises sterile suspensions, solution or the emulsion of active compound in water-based or the oiliness carrier.Described composition also can comprise blender, as suspension agent, stablizer and/or dispersion agent.Injectable dosage forms can be the form of unitary dose, as the form of ampoule or multi-dose container, and can comprise other sanitass.
[0233] or, injectable dosage forms can provide with form of powder, with appropriate carriers reconstruct, described carrier includes but not limited to: aseptic apirogen water, damping fluid, glucose solution or the like before being used for using.At last, described active compound can adopt any technology known in the art (as freeze-drying) drying, and reconstruct before use.
[0234], in this formulation, uses the permeate agent that is fit to see through this barrier for transmucosal administration.Such permeate agent is known in the art.
[0235] for oral administration, pharmaceutical composition can be taked as lozenge, tablet or capsular form, these are by traditional mode, with acceptable vehicle such as tackiness agent on the pharmacopedics (pre-gelatinization W-Gum, polyvinylpyrrolidone or Vltra tears); Weighting agent (as lactose, Microcrystalline Cellulose or secondary calcium phosphate); Slipping agent (as Magnesium Stearate, talcum powder or ground silica); Decomposition agent (as yam starch or sodium starch glycollate); Wetting agent (as dodecanol sodium sulfate) prepares.Described tablet can be by the method for knowing in this area, with for example sugar, film or casing bag quilt.In addition, contain 2 with what suitable oral form occurred, the pyrimidinediamine that 4-replaces also comprises as the pharmaceutical composition of activeconstituents or its prodrug, for example, and lozenge, lozenge, water-based or oily suspensions, dispersible powder or particle, emulsion, hard or soft capsule or syrup or elixir.Can prepare according to the method for any manufacturing pharmaceutical composition known in the art for oral composition, and this composition can contain one or more reagent that are selected from sweeting agent, seasonings, staining agent or sanitas so that attractive in appearance and good to eat pharmaceutical preparation to be provided.Contain activeconstituents (comprising prodrug) and the suitable pharmaceutically acceptable non-toxic excipients of making tablet in the tablet.These vehicle can be, for example, and inert diluent such as lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granule and dispersion agent (for example, W-Gum or Lalgine); Tackiness agent (for example, starch, gelatin or gum arabic); And lubricant (for example, Magnesium Stearate, stearic acid or talcum).Thereby described tablet can be not dressing or available currently known methods dressing provide slow releasing function in a long time with disintegration and the absorption that postpones in gi tract.For example, can adopt time-delay material such as Zerol Stearic diglyceride.Also can adopt U.S. Patent number 4,256,108; 4,166,452; With 4,265, the technology of describing in 874 is carried out dressing to form slowly-releasing osmotic therapeutic tablet to them.Pharmaceutical composition of the present invention also can be taked the form of oil-in-water emulsion.
[0236] liquid preparation that is used for oral administration can be taked the form as elixir, solution, syrup or suspension, perhaps can have use and water or other suitable carriers reconstruct with the form of desciccate.This liquid preparation can be used pharmaceutically acceptable additive such as suspension agent (as Sorbitol Powder syrup, derivatived cellulose or sclerosis edible-fat) by traditional method; Emulsifying agent (Yelkin TTS or Sudan Gum-arabic); Nonaqueous carrier is (as Prunus amygdalus oil, grease, ethyl alcoh(ol), cremophore TMPerhaps fractionated vegetables oil); Sanitas (as methyl or propyl group-to Para Hydroxy Benzoic Acid or Sorbic Acid) prepares.Said composition also can contain buffering salt, sanitas, seasonings, pigment and sweeting agent as required.
[0237] well-known, the preparation that can suitably prepare oral administration is to realize the controllable release of active compound or prodrug.
[0238] is used to contain tablet or the lozenge form that the composition of obeying administration can be taked traditional form.
[0239] for rectum and vagina administration path, described active compound can be prepared to the solution that contains traditional suppository alkali such as theobroma oil or other glyceryl ester (for enema lasting) suppository or ointment dosage form.
[0240] for nasal administration or by sucking or be blown into administration, described active compound or prodrug can be sent in the mode of aerosol injection from inflating bag or atomizer easily by using suitable pressurized gas (as Refrigerant 12, trichlorofluoromethane, dichloro tetrafluoro ethane, fluorocarbon, carbonic acid gas or other gas).Under the situation of pressurization aerosol, dose unit can be determined by the valve that discharges metered amount is provided.Capsule that uses in sucker or insufflator and cartridge case (as capsule and the cartridge case of being made up of gel) can be mixed with the formulation of the powdered mixture of compound as described in containing and suitable powder basis thing (as lactose or starch).
[0241] described pharmaceutical composition also can be the form of water-based or butyrous sterile injectable suspension.Can adopt above-mentioned those suitable dispersion agents or wetting agent and suspension agent to prepare this suspension according to methods known in the art.The sterile injectable goods can also be sterile injectable solution or the suspension with acceptable nontoxic thinner of parenteral or solvent allotment.Adoptable acceptable carrier and solvent have water, Ringer's solution and isotonic sodium chlorrde solution.2, the pyrimidinediamine compounds that 4-replaces also can suppository form be used to give medicine by rectum or urethra.In concrete embodiment, described compound can be made into urethral suppositories, for example is used to handle the especially male sex's fertility disease, as the treatment testicular dysfunction.
[0242] according to the present invention, 2, the pyrimidinediamine compounds that 4-replaces can be used for making composition or medicine, comprising the medicine that is fit to rectum or urethra administration.The invention still further relates to make the suitable urethra comprise suppository or rectal administration form contain 2, the method for compositions of the pyrimidinediamine compounds that 4-replaces.
[0243], can adopt and contain 2, emulsifiable paste, ointment, jelly, gelifying agent, solution or the suspension of the pyrimidinediamine compounds that 4-replaces for topical application.In some embodiments, can be with 2, the pyrimidinediamine compounds that 4-replaces is made the form that is fit to topical with polyoxyethylene glycol (PEG).These preparations can be chosen wantonly and contain other pharmaceutically acceptable composition, as thinner, stablizer and/or adjuvant.In concrete embodiment, the form of topical formulations is fit to treatment complaisance symptom and/or skin symptom, comprising psoriatic, contact dermatitis and atopic dermatitis.
[0244] according to the present invention, 2, the pyrimidinediamine compounds that 4-replaces can be used for making composition or medicine, comprising the medicine that is fit to topical application.What the invention still further relates to the suitable topical form of manufacturing contains 2, the method for compositions of the pyrimidinediamine compounds that 4-replaces.
[0245] according to the present invention, also can send 2 by any suction apparatus known in the art and method, the pyrimidinediamine compounds that 4-replaces is comprising for example: U.S. Patent number 6,241,969; U.S. Patent number 6,060,069; U.S. Patent number 6,238,647; U.S. Patent number 6,335,316; U.S. Patent number 5,364,838; U.S. Patent number 5,672,581; WO96/32149; WO95/24183; U.S. Patent number 5,654,007; U.S. Patent number 5,404,871; U.S. Patent number 5,672,581; U.S. Patent number 5,743,250; U.S. Patent number 5,419,315; U.S. Patent number 5,558,085; WO98/33480; U.S. Patent number 5,364,833; U.S. Patent number 5,320,094; U.S. Patent number 5,780,014; U.S. Patent number 5,658,878; 5,518,998; 5,506,203; U.S. Patent number 5,661,130; U.S. Patent number 5,655,523; U.S. Patent number 5,645,051; U.S. Patent number 5,622,166; U.S. Patent number 5,577,497; U.S. Patent number 5,492,112; U.S. Patent number 5,327,883; U.S. Patent number 5,277,195; Application No. 20010041190; Application No. 20020006901; With Application No. 20020034477.
[0246] can be used for using 2, the device of the specific examples of the pyrimidinediamine compounds that 4-replaces comprise well known in the art those, as metered-dose inhaler, liquid dispenser, Diskus, atomizer, hot vaporizer etc.Be used to use specific 2, other appropriate technology of the pyrimidinediamine compounds that 4-replaces comprises electronic aerosol producer.
[0247] in addition, suction apparatus preferably practical, be easy to use, enough little so that carry, can provide multidose and be durable.Some object lessons of commercially available suction apparatus are: Turbohaler (Ai Site company (Astra), Wilmington, DE), Rotahaler (Ge Lansu (Glaxo), Research Triangle Park, NC), Diskus (Ge Lansu (Glaxo), Research Triangle Park, NC), Ultravent atomizer (Mai Linke Roche Co.,Ltd (Mallinckrodt)), Acorn II atomizer (horse Koster Therapy Products Inc. (Marquest Medical Products), Totowa, NJ), breathe heavily happy peaceful metered-dose inhaler (Ge Lansu (Glaxo), Research Triangle Park, NC) or the like.In one embodiment, 2, the pyrimidinediamine compounds that 4-replaces is sent by Diskus or atomizer.
[0248] those are proficient in and those skilled in the art will appreciate that 2, and formulation, the amount of formulation of sending of the pyrimidinediamine compounds that 4-replaces and the time length that gives single dose are depended on the type and the other factors of the suction apparatus that is adopted.For some aerosol delivery systems such as atomizer, administration frequency and the time span that activates this system will depend in the aerosol 2, the concentration of the pyrimidinediamine compounds that 4-replaces.For example, administration time is short then can adopt 2 of higher concentration, the pyrimidinediamine compounds that 4-replaces in atomizer solution.Device such as metered-dose inhaler can produce higher aerosol load, but therefore operates within a short period of time in some embodiments to send 2 of aequum, the pyrimidinediamine compounds that 4-replaces.Device transmissibility active agents such as Diskus is discharged from this device up to the medicament of specified rate.In such sucker, in the specified rate powder 2, the amount of the pyrimidinediamine compounds that 4-replaces has determined the dosage that single administration is sent.Select 2, the formulation of the pyrimidinediamine that 4-replaces is to obtain the required granularity of selected suction apparatus.
[0249] is used for 2 of Diskus, the formulation of the pyrimidinediamine compounds that 4-replaces generally includes and contains 2, the dry powder of the segmentation of the pyrimidinediamine compounds that 4-replaces, but also can comprise filler, buffer reagent, carrier, vehicle, other additive etc. in this powder.2, can comprise additive in the pyrimidinediamine compounds dry powder formulations that 4-replaces, for example, so that according to from the requirement of particular powder sucker drug delivery dilution powder, with the processing of convenient preparation so as to provide the favourable powder characteristics of preparation in case help powder from suction apparatus disperse in case stabilization formulations (for example, antioxidant or buffer reagent) so that for preparation provides taste, or the like.Typical additive comprises monose, disaccharides and polysaccharide; Sugar alcohol and other polyvalent alcohol are as lactose, glucose, raffinose, melizitose, Saccharum lactis, Xylitol, trehalose, sucrose, N.F,USP MANNITOL, starch or its mixture; Tensio-active agent is as sorbyl alcohol, two phosphatidylcholines or Yelkin TTS; Or the like.
[0250] the invention still further relates to and be fit to contain 2, the pharmaceutical composition of the pyrimidinediamine compounds that 4-replaces by inhalation.According to the present invention, 2, the pyrimidinediamine compounds that 4-replaces can be used for making composition or medicine, comprises the medicine that is fit to by inhalation.The invention still further relates to and make to be fit to administration, to comprise and contain 2, the method for compositions of the pyrimidinediamine compounds that 4-replaces by the inhalation form.For example, can adopt routine techniques to make dry powder formulations by number of ways, these technical descriptions are in for example above-mentioned any open source literature (its content is included this paper by reference in) and the U.S. Patent number 5,700,904 (its complete content is included this paper by reference in) of Baker etc. for example.Can obtain to have the size range of maximum deposition at lower respiratory tract by methods such as micronize, grindings.With 2, the pyrimidinediamine compounds that 4-replaces is dissolved in the suitable solvent that contains buffer reagent or other vehicle, as water, can make liquid preparation under suitable pH.
[0251] contain described herely 2, the pharmaceutical composition of the pyrimidinediamine compounds (or its prodrug) that 4-replaces can be by traditional mixing, molten, the granulation of disappearing, make drageeing, grinding, emulsification, formation capsule, trapping or freeze dried process produces.These compositions can use one or more physiologically acceptable carriers, thinner, vehicle in a conventional manner or help that active compound is processed in the pharmacy auxiliary of spendable preparation and allocate out.
[0252] for ocular administration, 2, pyrimidinediamine compounds that 4-replaces or prodrug can be the formulations of the solution that is fit to eye usefulness, emulsion, suspension etc.Various being fit to known in the art with the carrier of compound to ocular administration.Concrete non-limitative example is described in U.S. Patent number 6,261,547; U.S. Patent number 6,197,934; U.S. Patent number 6,056,950; U.S. Patent number 5,800,807; U.S. Patent number 5,776,445; U.S. Patent number 5,698,219; U.S. Patent number 5,521,222; U.S. Patent number 5,403,841; U.S. Patent number 5,077,033; U.S. Patent number 4,882,150; With U.S. Patent number 4,738,851.
[0253] for sustained release delivery, 2, pyrimidinediamine compounds that 4-replaces or prodrug can be mixed with as the formulation of deposit preparation by implantation or intramuscularly administration.Described activeconstituents can with suitable polymerization or hydrophobic material (as in acceptable oil with the emulsion form) or ion exchange resin preparation formulation, or the derivative form of low-solubility (as low-solubility salt).Perhaps, can utilize the transdermal administration system, it is made into to be used for the dish with viscosity or the sheet of the described active compound of slow release of Transdermal absorption.At last, can use penetrating reinforcing agent to improve the penetrating quality that active compound passes skin.Suitable transdermal pastes and is described in for example U.S. Patent number 5,407,713; U.S. Patent number 5,352,456; U.S. Patent number 5,332,213; U.S. Patent number 5,336,168; U.S. Patent number 5,290,561; U.S. Patent number 5,254,346; U.S. Patent number 5,164,189; U.S. Patent number 5,163,899; U.S. Patent number 5,088,977; U.S. Patent number 5,087,240; U.S. Patent number 5,008,110; With U.S. Patent number 4,921,475.
[0254] or, also can use the other drug transmission system.Liposome and emulsion are the examples of the delivery vector that can be used for delivery of active compounds or prodrug known.Though be cost with higher toxicity usually, also can use some organic solvent such as methyl-sulphoxide (DMSO).
[0255] if desired, described pharmaceutical composition may reside in the packing or divider that can comprise one or more unitary doses that contain active compound.Described packing can for example be made up of metal or plastic tab, as blister.Described packing or divider can have takes explanation.
[0256] described here 2, pyrimidinediamine compounds that 4-replaces or prodrug or its composition will use with the amount that effectively reaches required result usually, for example effectively treat or prevent the amount of specific symptoms to be processed.Treatability gives described compound realizing the treatment benefit, perhaps preventatively gives described compound to realize the prevention benefit.The treatment benefit is meant the potential illness of eradicating or improving the disease of being treated, and/or eradicates or improve the one or more symptoms of following potential disease, makes the patient report that sensation or symptom take a turn for the better, although the patient may still be subjected to the torment of potential disease.For example, with a kind of compound to suffering from allergic patient's administration, not only when strain responses is eradicated or improved, and when the patient claimed that the seriousness of symptom relevant with transformation reactions after contacting allergen or time length alleviate, described administration provided the treatment benefit.Another example is, the treatment of asthma benefit is included in breath state after the asthma attack improves or frequency or seriousness that asthma takes place reduces.Another concrete example is, the treatment benefit of transplant rejection comprised can alleviate the acute cellular rejection incident, as HVGR or GVHR, perhaps can prolong the interval between outbreak of acute cellular rejection incident and/or the chronic rejection outbreak.The treatment benefit also comprises the progress of the time-out or the disease that slows down and no matter whether has realized improvement.
[0257] consumption of compound depends on multiple factor, comprises as the severity of the symptom that will treat concrete symptom, mode of administration, will treat and patient's age and body weight, bioavailability of concrete active compound or the like.How to determine effective dose be proficient in well-known to those having ordinary skill in the art.
[0258] it is known 2 to be proficient in those skilled in the art, and the preferred dose of the pyrimidinediamine compounds that 4-replaces will depend on by the seriousness of individual age, body weight, general health and symptom of treatment.Dosage also must adapt to individual sex and/or adapt to individual lung volume when by inhalation.Also can be individuality or those the individuality customization dosage of suffering from more than one symptoms with other symptom (as pulmonary emphysema, bronchitis, pneumonia, respiratory tract infection etc.) that can influence lung volume and eupnea ability.The dosage of compound or its prodrug and administration frequency will depend on also whether this compound is made into to be used for the treatment of the acute events of symptom or is used for preventative processing disease.For example, the acute events of complaisance symptom (comprising the asthma that transformation reactions is relevant), transplant rejection etc.Those skilled in the art can be identified for the optimal dose of particular individual.
[0259] in preventive administration, this compound can be given the patient of the risk that one of above-mentioned symptom takes place.For example, if whether do not know the patient, then can before using this medicine, give described compound to avoid or to alleviate anaphylaxis to medicine to certain drug allergy.Perhaps, can adopt preventive administration to produce symptom to avoid the patient who is diagnosed with potential disease.For example, can before contacting allergen, the transformation reactions patient give this compound.Also this compound prophylactically can be given to contact repeatedly notified the reagent that causes one of above-mentioned disease healthy individual to prevent the generation of this disease.For example, compound can be given contact repeatedly to notify and induce allergic strain former, so that prevent this individuality generation transformation reactions as the latex healthy individual.Perhaps, can before the activity that participates in initiation asthma, give asthmatic patient to alleviate or to avoid fully the seriousness of symptoms of asthma with compound.
[0260] in transplant rejection, this compound can be given patient that acute rejection does not take place to be repelled avoiding, and/or gives before the chronic rejection clinical indication occurring.
[0261] amount of institute's administered compound depends on multiple factor, comprise as to treat concrete symptom, mode of administration, whether required income is preventative or the bioavailability of the severity of therapeutic, the symptom that will treat and patient's age and body weight, concrete active compound or the like.How to determine effective dose be proficient in well-known to those having ordinary skill in the art.
[0262] effective dose begins and can estimate from vitro tests.For example, the predose that is used for animal can be to make the blood circulation of active compound or plasma concentration meet or exceed the IC of the specific compound that in vitro tests records 50Consider the bioavailability of specific compound, calculating the circulation dosage that reaches this blood circulation or plasma concentration is that those skilled in the art know.For obtaining instructing, the reader can be with reference to the The Pharmaceutical Basis ofTherapeutics (the medicine basis of treatment) of Goodman and Gilman, latest edition, Pagamonon Press, the General Principles (rule) that the 1st chapter 1-46 page or leaf Fingl and Woodbury write and the reference of wherein quoting.
[0263] predose also can be estimated from data in the body such as animal model.It is well known in the art being used for the test compounds treatment or preventing the animal model of the effect of above-mentioned various diseases.Allergy or allergic suitable animal model are described in Foster, and 1995, Allergy 50 (supplementary issue 21): 6-9 discusses 34-38 and Tumas etc., and 2001, J.Allergy Clin.Immunol.107 (6): 1025-1033.The suitable animal model of allergic rhinitis is described in Szelenyi etc., and 2000, Arzneimittelforschung 50 (11): 1037-42; Kawaguchi etc., 1994, Clin.Exp.Allergy 24 (3): 238-244 and Sugimoto etc., 2000, Immunopharmacology 48 (1): 1-7.The suitable animal model of anaphylaxis conjunctivitis is described in Carreras etc., and 1993, Br.J.Ophthalmol.77 (8): 509-514; Saiga etc., 1992, OphthalmicRes.24 (1): 45-50; With Kunert etc., 2001, Invest.Ophthalmol.Vis.Sci.42 (11): 2483-2489.The suitable animal model of systemic mastocytosis is described in O ' Keefe etc., and 1987, J.Vet.Intern.Med.1 (2): 75-80 and Bean-Knudsen etc., 1989, Vet.Pathol.26 (1): 90-92.The syndromic suitable animal model of super IgE is described in Claman etc., and 1990, Clin.Immunol.Immunopathol.56 (1): 46-53.The suitable animal model of B cell lymphoma is described in Hough etc., and 1998, Proc.Natl.Acad.Sci.USA 95:13853-13858 and Hakim etc., 1996, J.Immunol.157 (12): 5503-5511.The suitable animal model of atopic disorder such as atopic dermatitis, atopic eczema and atopic asthma is described in Chan etc., 2001, J.Invest.Dermatol.117 (4): 977-983 and Suto etc., 1999, Int.Arch.Allergy Immunol.120 (supplementary issue 1): 70-75.The suitable animal model of transplant rejection such as HVGR model description are in O ' Shea etc., (2004), Nature Reviews Drug Discovery 3:555-564; Cetkovic-Curlje ﹠amp; Tibbles, (2004), Current Pharmaceutical Design 10:1767-1784; With Chengelian etc., (2003), Science 302:875-878.Those skilled in the art can determine suitable dosage to people's administration according to this information usually.
[0264] dosage range be generally about 0.0001mg/kg/ days, 0.001mg/kg/ days or 0.01mg/kg/ days to about 100mg/kg/ days, but can be higher or lower, this depends on activity, its bioavailability, mode of administration and the above-mentioned various other factors of compound except other factors.Can regulate dosage and at interval so that the blood plasma level of the compound that is enough to keep treatment or preventive effect to be provided according to the individual.For example, compound can give weekly to give once, weekly several times (for example per two days once), once a day or every day repeatedly, this depends on mode of administration, the concrete illness of being treated and prescription doctor's judgement except other factors.When local administration or selectivity absorption, during as topical, effective partial concn of active compound may be irrelevant with plasma concentration.Those skilled in the art do not need the undo experimentation just can the effective local dose of optimizing.
[0265] preferably, this compound will provide treatment or prevention benefit and can not cause substantive toxicity.The toxicity available standards pharmacy program of compound is determined.The dosage ratio of toxic effect and treatment (or prevention) effect is a therapeutic index.The compound that preferably has high therapeutic index.
[0266] top with 2, the relevant description of the pyrimidinediamine compounds dosage demand that 4-replaces is relevant with the required dosage of prodrug, understand after this point, it is evident that for those of skill in the art, the amount of the prodrug of being used also will depend on various factors, comprising the transformation efficiency and the efficient that change into active pharmaceutical compounds under the bioavailability of for example specific prodrug, the selected route of administration.How to determine concrete use and mode of administration under the effective dose of prodrug be proficient in well-known to those having ordinary skill in the art.
[0267] effective dose begins and can estimate from external activity and metabolic test.For example, the predose that is used for the prodrug of animal can be to make the blood circulation of metabolite active compound or plasma concentration meet or exceed the IC of the specific compound that in vitro tests records 50Other in vitro tests of describing in described in vitro tests such as external CHMC or BMMC and the following document: the U. S. application sequence number 10/355 that on January 31st, 2003 submitted to, 543 (US2004/0029902A1), the international application serial PCT/US03/03022 (WO 03/063794) that on January 31st, 2003 submitted to, the U. S. application sequence number 10/631 that on July 29th, 2003 submitted to, 029, international application serial PCT/US03/24087 (WO2004/014382), the U. S. application sequence number 10/903 that on July 30th, 2004 submitted to, 263 (US2005/0234049), and international application serial PCT/US2004/24716 (WO005/016893).Consider the bioavailability of specific compound, calculating the circulation dosage that reaches this blood circulation or plasma concentration is that those skilled in the art know.For obtaining instructing, the reader can be with reference to the The Pharmaceutical Basis of Therapeutics (the medicine basis of treatment) of Goodman and Gilman, latest edition, Pagamonon Press, the General Principles (rule) that the 1st chapter 1-46 page or leaf Fingl and Woodbury write and the reference of wherein quoting.
[0268] also provides and be used to give 2, pyrimidinediamine, its prodrug that 4-replaces or contain the medicine box of the pharmaceutical preparation of this compound, at least a 2 of dose amount can be housed in this medicine box, the pyrimidinediamine that 4-replaces or contain at least a described herein 2, the composition of the pyrimidinediamine that 4-replaces.Also can comprise the suitable packing and/or the operation instruction of compound in the medicine box.Also can comprise at least a 2 in the medicine box, the pyrimidinediamine that 4-replaces or contain at least a 2, the delivery apparatus of the composition of the pyrimidinediamine that 4-replaces, as sucker, spray dispenser (for example nasal spray), the compression packing of injection syringe or capsule, tablet, suppository, other device perhaps as herein described.
[0269] in addition, compound of the present invention also can constitute the form of medicine box.This medicine box can provide compound and reagent to supply with the composition of medicine with preparation.Described composition can be drying or freeze dried form or be solution form, especially sterile solution.When described composition was dried forms, it is acute with preparation liquid that described reagent can comprise pharmaceutically acceptable thinner.This medicine box can comprise and be used to use or the device of dispersive composition, and described device includes but not limited to that syringe, suction pipe, transdermal paste or sucker.
[0270] described medicine box can comprise other therapeutic compound of uniting use with compound described here.In one embodiment, described therapeutical agent is the compound of immunosuppressor or anti-allergen.These compounds can provide separately or with compound of the present invention.
[0271] described medicine box will comprise about preparation of compositions and use, the side effect of composition and the suitable indication of other relevant information.Described indication can be any appropriate form, comprising but be not limited to printing material, video-tape, computer readable disk or CD.
In [0272] one embodiment, the invention provides a kind of medicine box, a kind of compound or its prodrug, packing and operation instruction are housed in this medicine box, and described compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).
[0273] in another embodiment, the invention provides a kind of medicine box, the pharmaceutical preparation, packing and the operation instruction that contain a kind of compound or its prodrug and at least a pharmaceutically acceptable vehicle, thinner, sanitas or stablizer or their mixture are housed in this medicine box, and described compound is selected from: compound of the present invention as described herein and the compound among the Table X I (CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3).
[0274] in another aspect of this invention, provide to be used for the treatment of and suffered from or the medicine box of the individuality of susceptible symptom described herein, one container and operation instruction are housed in the described medicine box, comprise 2 of dose amount in the container, pyrimidinediamine that 4-replaces or composition described here.Container can adopt known in the art and suitable storage and send oral, intravenously, part, rectum, urethra or suck any form of preparation.
[0275] also 2 of enough dose can be housed in the medicine box, pyrimidinediamine or composition that 4-replaces are so that provide the effective treatments of long period as 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks or 8 weeks or longer time for individuality.
F. the general synthetic method of The compounds of this invention
[0276] of the present invention 2,4-pyrimidinediamine compounds and prodrug can adopt marketable material and/or the raw material by conventional synthetic method preparation to synthesize through various different route of synthesis.Usually be applicable to synthetic of the present inventionly 2, the suitable illustrative methods of 4-pyrimidinediamine compounds and prodrug can be at U.S. Patent number 5,958, finds in 935, and its content is included this paper by reference in.Therefore, describe numerously 2,4-pyrimidinediamine compounds and prodrug and intermediate synthetic object lesson are described in the U. S. application sequence number of submitting on January 31st, 2,003 10/355,543 (US2004/0029902A1) that awaits the reply, and its content is included this paper by reference in.Be generally used for and/or be applicable to composite reactive 2, the international application serial PCT/US03/03022 (WO 03/063794) that the suitable illustrative methods of the pyrimidinediamine compounds that 4-replaces also can be submitted on January 31st, 2003, the U. S. application sequence number 10/631 that on July 29th, 2003 submitted to, 029, international application serial PCT/US03/24087 (WO2004/014382), the U. S. application sequence number 10/903 that on July 30th, 2004 submitted to, 263, and find among the international application serial PCT/US2004/24716 (WO005/016893), its content is included this paper by reference in.All compounds described here (comprising prodrug) can prepare by these methods being carried out the routine change.
[0277] described here 2, the concrete exemplary synthetic method of the pyrimidinediamine that 4-replaces also is described in the following examples 1-10.Those are proficient in those skilled in the art also can change these embodiment easily with synthetic described here other 2, the pyrimidinediamine that 4-replaces.
[0278] can be used for synthetic of the present inventionly 2, the various exemplary route of synthesis of 4-pyrimidinediamine compounds is described in following scheme (I)-(VII).Can carry out conventional changing with synthetic described here 2 pyrimidinediamine compounds and prodrug that 4-replaces to these methods.
[0279] in an illustrative embodiments, shown in following scheme (I), can synthesize this compound from replacement or unsubstituted uridylic:
Scheme (I)
[0280] in scheme (I), ring A, R 1, (R 2) p, alk, (R 3) q, R 4, R 5, X, Y and Z in the literary composition definition.According to scheme (I), under standard conditions, use standard halogenating agent such as POCl 3(or other standard halogenating agent) with the 2-of uridylic A-1 and 4-position dihalide to generate 2,4-dichloro pyrimidine A-2.According to the X substituting group among the pyrimidinediamine A-2, the muriate of C4 position is better than the muriate of C2 position to the reactivity of nucleophilic reagent.But utilize this activity difference Synthetic 2,4-pyrimidinediamine A-7, method is at first to make 2,4-dichloro pyrimidine A-2 and 1 equivalent amine A-3 reaction produce 4N-replacement-2-chloro-4-PYRIMITHAMINE A-4, produce 2 with amine A-5 reaction then, 4-pyrimidinediamine derivative A-6, N4 nitrogen wherein can be by the selectivity alkylation to obtain the compound of formula A-7.
[0281] common, shown in this scheme, C4 halogenide has more reactivity to nucleophilic reagent.Yet those skilled in the art will understand, and the substituent homogeny of X can change this reactivity.For example, when being trifluoromethyl, X will obtain 50: 50 the 4N-replacement-4-PYRIMITHAMINE A-4 and the mixture of corresponding 2N-replacement-2-PYRIMITHAMINE.As known in the art, by regulating the also regioselectivity of may command reaction of solvent and other synthesis condition (as temperature).
[0282] the described reaction of scheme (I) can be carried out quickly when by the microwave heating reaction mixture.Can adopt following condition when heating in this way: (175 ℃ were heated 5-20 minute in the inherent ethanol of tube sealing Sweden) (pressure is 20 crust) for individual chemical company (Personal Chemistry), Uppsala at the Smith reactor.
[0283] uridylic 1 raw material can prepare available from chemical feedstocks or with the standard technique of organic chemistry.The commercially available uridylic that can be used as the raw material of scheme (I) comprises, for example, but is not limited to: uridylic (Aldrich #13,078-8; CAS accession number 66-22-8); 5-bromouracil (Aldrich #85,247-3; CAS accession number 51-20-7; 5 FU 5 fluorouracil (Aldrich #85,847-1; CAS accession number 51-21-8); 5-iodouracil (Aldrich #85,785-8; CAS accession number 696-07-1); 5-nitrouracil (Aldrich #85,276-7; CAS accession number 611-08-5); 5-(trifluoromethyl)-uridylic (Aldrich #22,327-1; CAS accession number 54-20-6).The uridylic that other 5-replaces can available from Canada general intermediate company limited (GeneralIntermediates of Canada, Inc.), Edmonton, CA and/or Yin Tekaimu company (Interchim), Cedex, France, perhaps available standards technology preparation.The textbook bibliography of the suitable synthetic method of many professors hereinafter is provided.
[0284] amine A-3 and A-5 can or can utilize standard technique synthetic available from commercial source.For example, can adopt standard chemical process from the synthetic suitable amine of nitro precursor.Concrete exemplary reaction provides in the embodiment part.Also can be referring to Vogel, 1989, Practical Organic Chemistry (practical organic chemistry), company limited of Ai Dishengweisili Longman (Addison Wesley Longman, Ltd.) and (the John Wiley of John Wiley Publishing Company; Sons, Inc.).
[0285] those skilled in the art will understand, and in some cases, the substituent X on amine A-3 and A-5 and/or the uridylic A-1 can be included in the functional group that needs protection in the building-up process.The definite character of any protecting group that adopts will depend on the characteristic of the functional group that will protect, and be that to be proficient in those skilled in the art conspicuous.About the selection and the connection of appropriate protection base or remove the guidance of their synthesis strategy can be at for example Greene ﹠amp; The Protective Groupsin Organic Synthesis (organic synthesis protecting group) of Wuts, the third edition, (the John Wiley ﹠amp of John Wiley Publishing Company; Sons, Inc.), New York (1999) and the bibliography of wherein quoting (are called " Greene ﹠amp later on; Wuts ") in find.
[0286] therefore, protecting group refers to one group of atom, when they are connected on the reactive functional groups of a molecule, will shield, reduces or stop the reactivity of this functional group.Be typically, in the synthetic process, as required, can optionally remove a protecting group.The example of protecting group is at Greene and Wuts (as mentioned above) and Harrison etc., Compendium of Synthetic Organic Methods (summary of methodology of organic synthesis), the 1-8 volume, 1971-1996, (the John Wiley ﹠amp of John Wiley Publishing Company; Sons), can find among the NY.The example of representative amino protecting group includes but not limited to: the trityl of formyl radical, ethanoyl, trifluoroacetyl group, benzyl, benzyl oxygen base carbonyl (" CBZ "), tert-butoxycarbonyl (" Boc "), trimethyl silyl (" TMS "), 2-trimethyl silyl-ethane alkylsulfonyl (" TES "), trityl and replacement, allyloxy carbonyl, 9-fluorenyl methyl oxygen base carbonyl (" FMOC "), nitro-3,4-veratryl carbonyl (" NVOC ") etc.The example of representative hydroxyl protecting group includes but not limited to: those hydroxyls are become acetic ester or benzoic ether by acidylate or are alkylated into benzyl and the group of trityl ether and alkyl oxide, tetrahydropyranyl ethers, trialkylsilyl ethers (for example TMS or TIPPS) and allyl ethers.
[0287] embodiment of scheme (I) utilize 5 FU 5 fluorouracil (Aldrich #32,937-1) as raw material, shown in following scheme (Ia):
Scheme (Ia)
Figure A20068002053301701
[0288] in scheme (Ia), ring A, R 1, (R 2) p, alk, (R 3) q, R 4, R 5, Y and Z be as mentioned to the definition of scheme (I).Can make 2,4-two chloro-5-fluorine pyrimidine A-9 and 1 equivalent amine A-3 reaction (with generate that 2-chloro-N4-replaces-5-fluoro-4-PYRIMITHAMINE A-10) and then with one or more normal amine A-5 reactions to obtain asymmetric 2N, 4N-is dibasic-5-fluoro-2, and 4-pyrimidinediamine A-11.
[0289] in another illustrative embodiments, of the present invention 2, the 4-pyrimidinediamine compounds can from replace or unsubstituted cytosine(Cyt) synthetic, as following scheme (IIa) with (IIb):
Scheme (IIa)
Figure A20068002053301702
Figure A20068002053301711
[0290] in scheme (IIa) with (IIb), ring A, R 1, (R 2) p, alk, (R 3) q, R 4, R 5, X, Y and Z be as mentioned to the definition of scheme (I), PG represents protecting group.Reference scheme (IIa), at first the cytosine(Cyt) A-13 that protects with generation N4-with the C4 exocyclic amine of suitable protecting group PG protection cytosine(Cyt) A-12.For obtaining can be referring to Vorbr ü ggen and Ruh-Pohlenz about the concrete guide of useful in this article protecting group, 2001, Handbook of Nucleoside Synthesis (nucleosides synthesizes handbook), (the John Wiley ﹠amp of John Wiley Publishing Company; Sons), NY, 1-631 page or leaf (" Vorbr ü ggen ").Under standard conditions with the standard halogenating agent with the C2 position halogenation of the cytosine(Cyt) A-13 of protection with generate 2-chloro-4N-protection-4-PYRIMITHAMINE A-14.Obtain A-15 with amine A-5 reaction, go protection to obtain A-16 its C4 exocyclic amine.Make A-16 and amine A-3 reaction obtain 2,4-pyrimidinediamine derivative A-6.
[0291] or, reference scheme (IIb), can make cytosine(Cyt) A-12 respectively with the amine A-19 of amine A-3 or protection reaction to generate cytosine(Cyt) A-17 or the A-20 that N4-replaces.The cytosine(Cyt) of these replacements then can be as mentioned above by halogenation, go protection (the cytosine(Cyt) A-20 that replaces for N4-) and with amine A-5 reaction to obtain 2,4-pyrimidinediamine A-11.
[0292] the commercially available cytosine(Cyt) that can be used as scheme (IIa) and raw material (IIb) includes but not limited to: cytosine(Cyt) (Aldrich#14,201-8; CAS accession number 71-30-7); N 4-ethanoyl cytosine(Cyt) (Aldrich #37,791-0; CAS accession number 14631-20-0); 5-flurocytosine (Aldrich #27,159-4; CAS accession number 2022-85-7); And 5-(trifluoromethyl)-cytosine(Cyt).Other the suitable cytosine(Cyt) that can be used as the raw material of scheme (IIa) can be available from (the General Intermediates of Canada of Canada general intermediate company limited, Inc.), Edmonton, CA and/or Yin Tekaimu company (Interchim), Cedex, France, perhaps available standards technology preparation.The textbook bibliography of the suitable synthetic method of many professors hereinafter is provided.
[0293] again in another illustrative embodiments, of the present invention 2, the 4-pyrimidinediamine compounds can from replace or unsubstituted 2-amino-4-ancymidol (pyrimidinol) synthetic, shown in following scheme (III):
Scheme (III)
Figure A20068002053301721
[0294] at scheme (III), ring A, R 1, (R 2) p, alk, (R 3) q, R 4, R 5, X, Y and Z be as mentioned to the definition of scheme (I), LG is the leavings group as going through more among the scheme IV below.Reference scheme (III), make 2-amino-4-ancymidol A-22 and arylating agent A-23 reaction with generate that N2-replaces-4-ancymidol A-24, then as mentioned above with the A-24 halogenation with generate that N2-replaces-4-halogen-2-PYRIMITHAMINE A-25.Obtain 2,4-pyrimidinediamine derivative A-6 with amine A-3 reaction again.
[0295] can be used as the suitable commercially available 2-amino-4-ancymidol A-22 of the raw material of scheme (III) can be available from (the General Intermediates of Canada of Canada general intermediate company limited, Inc.), Edmonton, CA and/or Yin Tekaimu company (Interchim), Cedex, France, perhaps available standards technology preparation.The textbook bibliography of the suitable synthetic method of many professors hereinafter is provided.
[0296] or, of the present invention 2, the 4-pyrimidinediamine compounds can be from replacing or unsubstituted 4-amino-2-ancymidol preparation, shown in following scheme (IV):
Scheme (IV)
Figure A20068002053301722
[0297] at scheme (IV), ring A, R 1, (R 2) p, alk, (R 3) q, R 4, R 5, X, Y and Z be as mentioned to the definition of scheme (I).Reference scheme (IV), the C2-hydroxyl of 4-amino-2-ancymidol A-26 is better than C4-amino to the reactivity of nucleophilic reagent, therefore obtains-2 of N2-replacement, 4-pyrimidinediamine A-27 with amine A-5 reaction.Generate 2,4-pyrimidinediamine derivative A-6 with compd A-28 (can comprise suitable leavings group) or amine A-3 reaction subsequently.Compd A-28 in fact can comprise any can by N2-replace-2, the amino alternate leavings group of the C4-of 4-pyrimidinediamine A-27.Suitable leavings group includes but not limited to: halogen, methylsulfonyl oxygen base (methylsulfonyl oxygen; " OM "), trifyl oxygen base (" OTf ") and ptoluene-sulfonyl oxygen base (tolylsulfonyl oxygen; " OT "), benzenesulfonyl oxygen base (" benzene sulfonate ") and-oil of mirbane alkylsulfonyl oxygen base (" nosylate ").Other suitable leavings group will be that to be proficient in those skilled in the art conspicuous.
[0298] the 4-amino of Qu Daiing-2-ancymidol raw material also can be by commercial acquisition or synthetic with standard technique.The textbook bibliography of the suitable synthetic method of many professors hereinafter is provided.
[0299] again in another illustrative embodiments, of the present invention 2, the 4-pyrimidinediamine compounds can be from 2-chloro-4-aminopyrimidine or 2-amino-4-chloropyrimide preparation, shown in following scheme (V):
Scheme (V)
Figure A20068002053301731
[0300] at scheme (V), ring A, R 1, (R 2) p, alk, (R 3) q, R 4, R 5, X, Y and Z be as the definition in scheme (I), leavings group is as the definition in scheme (IV).Reference scheme (V) makes 2-amino-4-chloropyrimide A-29 and amine A-3 reaction to generate-2 of 4N-replacement, and 4-pyrimidinediamine A-30 makes A-30 and compd A-23 or amine A-5 reaction obtain N2, N4-2,4-pyrimidinediamine derivative A-6 then.Perhaps, can make the reaction of 2-chloro-4-amino-pyrimidine A-31 and compd A-28 to obtain compd A-32, A-32 and amine A-5 reaction obtain A-6.
[0301] is suitable as the various pyrimidine A-29 of raw material of scheme (V) and A-31 available from (the General Intermediates of Canada of Canada general intermediate company limited, Inc.), Edmonton, CA and/or Yin Tekaimu company (Interchim), Cedex, France, perhaps available standards technology preparation.The textbook bibliography of the suitable synthetic method of many professors hereinafter is provided.
[0302] or, 4-chloro-2-PYRIMITHAMINE A-29 can be according to the description of scheme (Va) preparation:
Scheme (Va)
Figure A20068002053301741
[0303] in scheme (Va), X in the scheme I definition.In scheme (Va), dialdehyde A-33 and guanidine reaction generate 2-PYRIMITHAMINE A-34.And peracid as-the chlorine peroxybenzoic acid, the reaction of trifluoro Peracetic Acid or urea peroxide mixture produces N-oxide compound A-35, then the A-35 halogenation is obtained 4-chloro-2-PYRIMITHAMINE A-29.Available suitable halogenating agent obtains corresponding 4-halogen-2-PYRIMITHAMINE.
[0304] again in another illustrative embodiments, of the present invention 2, the 4-pyrimidinediamine compounds can be from replacing or the preparation of unsubstituted uridine, shown in following scheme (VI):
Figure A20068002053301742
[0305] in scheme (VI), ring A, R 1, (R 2) p, alk, (R 3) q, R 4, R 5, X, Y and Z be as mentioned to the definition of scheme (I), PG represents the protecting group discussed as in the scheme (IIb).According to scheme (VI), uridine A-36 has the C4 reactive center, and it can generate the cytidine A-37 or the A-38 of N4-replacement respectively with the amine A-19 reaction of amine A-3 or protection.A-37 or A-38 that N4-is replaced carry out the acid catalyzed cytosine(Cyt) A-39 that goes protection (when " PG " represents the acid labile protecting group) to obtain the N4-replacement; can react to produce 2,4-pyrimidinediamine derivative A-6 with the C2-position halogenation of A-39 and with amine A-5 subsequently.
[0306] cytidine can be used as the raw material of similar approach, shown in following scheme (VII):
Figure A20068002053301751
[0307] at scheme (VII), ring A, R 1, (R 2) p, alk, (R 3) q, R 4, R 5, X, Y and the Z definition in scheme (I) as mentioned, PG represents protecting group discussed above.Reference scheme (VII), A-36 is similar with uridine, and cytidine A-40 has the C4 reactive center, therefore can obtain the cytidine A-37 or the A-38 of N4-replacement respectively with the amine A-19 reaction of amine A-3 or protection.Before using then in scheme (VI) the method for description handle these cytidines A-37 and A-38 to generate 2,4-pyrimidinediamine derivative A-6.
[0308] although scheme (VI) and (VII) be example with the ribonucleoside, but those skilled in the art should understand, corresponding 2 '-dezyribonucleoside and 2 ', 3 '-dideoxy ribonucleoside and contain sugar except that ribose or the nucleosides of sugar analogue also is useful.
[0309] many uridine and cytidines that can be used as scheme (VI) and raw material (VII) are known in the art, comprising, such as but not limited to: 5-trifluoromethyl-2 '-Deoxyribose cytidine (Chem.Sources #ABCR F07669; CAS accession number 66,384-66-5); 5-broxuridine (Chem.Sources Int ' l 2000; CAS accession number 957-75-5); 5-iodo-2 '-deoxyuridine (Aldrich #1-775-6; CAS accession number 54-42-2); 5-floxuridine (Aldrich #32,937-1; CAS accession number 316-46-1); 5-ioduria glycosides (Aldrich #85,259-7; CAS accession number 1024-99-3); 5-(trifluoromethyl) uridine (Chem.Sources Int ' l 2000; CAS accession number 70-00-8); 5-trifluoromethyl-2 '-deoxyuridine (Chem.Sources Int ' l 2000; CAS accession number 70-00-8).Other uridine and the cytidine that can be used as scheme (VI) and raw material (VII) can be available from (the General Intermediates of Canada of Canada general intermediate company limited, Inc.), Edmonton, CA and/or Yin Tekaimu company (Interchim), Cedex, France, perhaps available standards technology preparation.The textbook bibliography of the suitable synthetic method of many professors hereinafter is provided.
[0310] although above-mentioned many synthetic schemess do not illustrate the use of protecting group, those skilled in the art will understand, in some cases, and some substituting group such as R 2And/or R 4Can comprise the functional group that needs protection.The definite character of protecting group will depend on the reaction conditions that adopts in the characteristic of the functional group that will protect and the specific synthetic schemes, and be that to be proficient in those skilled in the art conspicuous.Can be about the selection of the protecting group that is fit to application-specific and their connection or the guidance of removing at for example Greene ﹠amp; Find among the Wuts (the same).
[0311] can carry out conventional the modification to aforesaid method to prepare prodrug described here.Perhaps, can be with 2 of due care, 4-pyrimidinediamine 6 prepares with suitable preceding radical reaction.Carry out this reaction and go to protect condition to know product to produce prodrug described here.
[0312] bibliography of the conventional synthetic method of many professor's pyrimidines and the described raw material of scheme (I)-(VII) is known in the art.Be concrete understanding, the reader can be with reference to following document: Brown, D.J., " The Pyrimidines (pyrimidine) ", be selected from The Chemistry of Heterocyclic Compounds (chemistry of heterocyclic compound), the 16th volume (Weissberger, A. compiles), 1962, ((the John Wiley ﹠amp of John Wiley Publishing Company of international scientific press (Interscience Publishers); Sons) New York (" Brown I ") branch office); Brown, D.J., " The Pyrimidines (pyrimidine) ", be selected from The Chemistryof Heterocyclic Compounds (chemistry of heterocyclic compound), the 16th volume, supplementary issue I (Weissberger, A. and Taylor, E.C. compile), 1970, Willie-international scientific company (Wiley-Interscience) ((the John Wiley ﹠amp of John Wiley Publishing Company; Sons) New York (" Brown II ") branch office); Brown, D.J., " The Pyrimidines (pyrimidine) ", be selected from The Chemistry of Heterocyclic Compounds (chemistry of heterocyclic compound), the 16th volume, supplementary issue II (Weissberger, A. and Taylor, E.C. compile), 1985, ((the John Wiley ﹠amp of John Wiley Publishing Company of international scientific publishing company (An Interscience Publication); Sons)), New York (" Brown III "); Brown, D.J., " The Pyrimidines (pyrimidine) ", be selected from The Chemistry of Heterocyclic Compounds (chemistry of heterocyclic compound), the 52nd volume (Weissberger, A. and Taylor, E.C. compile), 1994, (the John Wiley ﹠amp of John Wiley Publishing Company; Sons, Inc.), New York, the 1-1509 page or leaf (Brown IV "); Kenner, G.W. and Todd, A. is selected from HeterocyclicCompounds (heterogeneous ring compound, the 6th volume, (Elderfield, R.C. compiles), 1957, John Wiley, New York, the 7th chapter (pyrimidine); Paquette, L.A., Principles of Modern Heterocyclic Chemistry (contemporary heterocyclic chemistry principle), 1968, and Benjamin company limited (W.A.Benjjamin, Inc.), New York, (the synthetic of uridylic sees the 313rd, 315 page to the 1-401 page or leaf; Pyrimidinediamine synthetic sees the 313-316 page or leaf; The synthetic of aminopyrimidine diamines sees the 315th page); Joule, J.A., Mills, K. and Smith, G.F., Heterocyclic Chemistry (heterocyclic chemistry), the third edition, 1995, Cha Puman-Hall company (Chapman and Hall), London, UK, 1-516 page or leaf; Vorbr ü ggen, H. and Ruh-Pohlenz, C., Handbook of Nucleoside Synthesis (nucleosides synthesizes handbook), (the John Wiley ﹠amp of John Wiley Publishing Company; Sons), New York, 2001, the 1-631 pages or leaves (are seen the 90-91 page or leaf by acylations protection pyrimidine; The 91-93 page or leaf is seen in the silylanizing of pyrimidine); Joule, J.A., Mills, K. and Smith, G.F., HeterocyclicChemistry (heterocyclic chemistry), the 4th edition, 2000, Bu Laikeweier science company limited (Blackwell Science, Ltd), Oxford, UK, 1-589 page or leaf; And Comprehensive Organic Synthesis (organic synthesis general introduction), 1-9 volume (I. compiles for Trost, B.M. and Fleming), 1991, Pa Jiameng press (Pergamon Press), Oxford, UK.
[0313] those are proficient in and those skilled in the art will appreciate that described herely 2, and the pyrimidinediamine compounds that 4-replaces can contain the functional group of being sheltered by preceding group to produce prodrug.This prodrug did not have pharmacological activity usually before changing into their active medicine form, but needn't be like this.In fact, many of the present invention 2, the pyrimidinediamine compounds that 4-replaces is included in hydrolyzable or resectable precursor portions under the working conditions.For example, ester group can be produced parent carboxylic by acid-catalyzed hydrolysis usually when being exposed to the acidic conditions of stomach, perhaps when being exposed to the alkaline condition of enteron aisle or blood by alkali catalyzed hydrolysis.Therefore, when to the object oral administration, comprise 2 of ester moiety, the pyrimidinediamine compounds that 4-replaces can be considered to the prodrug of their corresponding carboxylic acid, and no matter whether this ester-formin has pharmacological activity.
[0314] metabolic mechanism to preceding group does not require, and for example, can be hydrolyzed metabolism under the acidic conditions of stomach as mentioned above, and/or by the enzymes metabolism that exists in digestive tube and/or bodily tissue or the organ.In fact, privileged site group before the metabolism selectively in the body.For example, many esters are cut under the acidic conditions of stomach.Be designed to be become activity 2 by chemical chop under one's belt, the prodrug of the pyrimidinediamine that 4-replaces can adopt the preceding group that comprises this ester.Perhaps, preceding group can be designed to enzyme such as esterase, Ntn hydrolase, lipase, comprise ATP enzyme and kinases Phosphoric acid esterase etc. in the presence of by metabolism.Contain in vivo and can be known, for example include but not limited to ether, thioether, silyl ether, silylthio-ether, ester, thioesters, carbonic ether, thiocarbonic ester, carbamate, thiocarbamate, urea, thiocarbamide, carboxylic acid amides etc. by the preceding group of metabolic key.Under the certain situation, but can select the Cytochrome P450 of oxidized enzyme such as liver to be oxidized to " precursor " group of metabolism group.
[0315] in prodrug, any available functional moiety can be sheltered to produce prodrug by preceding group.Can by the preceding group in the precursor portions shelter 2, the functional group in the pyrimidinediamine compounds that 4-replaces includes but not limited to: amine (primary amine and secondary amine), hydroxyl, sulfane base (mercaptan), carboxyl etc.Being fit to shelter this functional group is well known in the art with the many preceding group that is created in characteristic that can be cut under the required working conditions.Group can individually or be combined in the present prodrug before all these.
[0316] 2, in some embodiments of the pyrimidinediamine compounds that 4-replaces and the using method of this compound, preceding group can be connected in any available primary amine or secondary amine, for example comprise 2, the N2 nitrogen-atoms, 2 of 4-pyrimidinediamine part, the N4 nitrogen-atoms and/or 2 of 4-pyrimidinediamine part, contained uncle or secondary nitrogen-atoms in the 4-pyrimidinediamine compounds substituting group.
[0317] 2, in the embodiment of the pyrimidinediamine compounds that 4-replaces and the using method of this compound, prodrug described here is 2, be substituted on the N4 nitrogen of 4-pyrimidinediamine part or unsubstituted nitrogenous two cyclosubstituted 2, the pyrimidinediamine compounds that 4-replaces, group these nitrogenous two rings contain at least one on following one or more positions before: bicyclic nitrogen-atoms, 2, the N2 nitrogen and/or 2 of 4-pyrimidinediamine part, the N4 nitrogen of 4-pyrimidinediamine part.
[0318] as mentioned above, the character of preceding group is not required, if it can be under required working conditions as under the acidic conditions under one's belt and/or the enzymes metabolism of finding in by body produce bio-active group, for example described here 2, the pyrimidinediamine that 4-replaces.Therefore, those skilled in the art will understand, and preceding group can comprise any known or unknown hydroxyl, amine or mercaptan protecting group in fact.The non-limitative example of appropriate protection base can be at for example Protective Groups in OrganicSynthesis (organic synthesis protecting group), Greene ﹠amp; Wuts, second edition, (the John Wiley ﹠amp of John Wiley Publishing Company; Sons), New York finds in 1991 (especially 10-142 page or leaf (alcohol), 277-308 page or leaf (mercaptan) and 309-405 page or leaf (amine), its content is included this paper by reference in).
[0319] in addition, can select to give the prodrug desired characteristic the character of preceding group.For example, lipophilic group can be used to reduce water-soluble and hydrophilic radical can be used to improve water-soluble.Adopt this method can obtain the prodrug that selected mode of administration is specifically adjusted.Also can be designed to give prodrug other characteristic preceding group, as intestinal absorption, the protection of improved passive intestinal absorption, improved transhipment (transport) mediation exempt from that tachymetabolism (slowly-releasing prodrug), tissue selectivity are sent, passive enrichment in the target tissue, targeting specific vehicle etc.Can give the group of these characteristics of prodrug and know, and be described in, for example, Ettmayer etc., 2004, J.Med.Chem.47 (10): 2393-2404), its content is included this paper by reference in.All groups of describing in these bibliographys can be used for prodrug described here.
[0320] as mentioned above, also can select so that the water-soluble active medicine that is higher than of prodrug preceding group.This preceding group can comprise or can be to be fit to give the water miscible group that drug molecule improves.This group is known, its example includes but not limited to hydrophilic radical, as the alkyl of being mixed by the alkyl of the one or more replacements in amine, alcohol, carboxylic acid, phosphoric acid, sulfoxide, sugar, amino acid, mercaptan, polyvalent alcohol, ether, thioether and the quaternary ammonium salt, aryl, arylalkyl or ring.
[0321] by any specific preceding suitability of group in required mode of administration of biochemical test susceptible of proof.For example, if give specific tissue or organ with prodrug by injection, and the characteristic of the various enzymes of expressing in this tissue or organ is known, then can detect the metabolism situation of specific prodrug in biochemical test with isolating enzyme.Perhaps, available tissue and/or opzyme detect specific prodrug and are metabolized to activity 2, the situation of the pyrimidinediamine compounds that 4-replaces.When the characteristic of the enzyme of in target tissue or organ, expressing for unknown, or can't obtain isolating enzyme easily the time, adopt tissue and/or opzyme especially convenient.Those skilled in the art can select to have the preceding group of the metabolic characteristic (as dynamics) of suitable application-specific easily by this in vitro tests.Certainly, also can in external animal model, detect the pathways metabolism that is fit to specific prodrug.
[0322] many reference have been lectured the application of prodrug and synthetic, comprising, for example, Ettmayer etc., the same and Bungaard etc., (1989) J.Med.Chem.32 (12): 2503-2507.In addition, the U.S. Provisional Patent Application 60/654 that is entitled as " Pyrimidinediamine Prodrugs and their Uses (pyrimidinediamine prodrug and application thereof) " that on February 18th, 2005 submitted to, 620 have especially told about 2, the preparation and the application of 4-pyrimidinediamine prodrug, its content is included this paper by reference in.
Embodiment
[0323] will be further understood that the present invention by following examples, these embodiment only are for illustration the present invention.The invention is not restricted to the scope of illustrative embodiments, these embodiments have only exemplified one aspect of the present invention.The method of any function equivalence is included within the scope of the invention.Except described here those, by top description and accompanying drawing, various versions of the present invention are conspicuous for being proficient in those skilled in the art.This modification also falls within the scope of accessory claim.
[0324] in embodiment below and the whole specification sheets, below Suo Xie implication is as follows.Undefined term has its common received implication.
TFA=trifluoroacetic acid
MeOH=methyl alcohol
EtOH=ethanol
ML=milliliter
Mmol=mmole
DCM or CH 2Cl 2=methylene dichloride
M=mole
DMSO=methyl-sulphoxide
S=unimodal
D=bimodal
T=three peaks
Q=four peaks
M=multimodal
Dd=two are bimodal
Br=widen
MS=mass spectrum
LC=liquid chromatography
Pd/C=carbon carries palladium
HCl=hydrochloric acid
UL=microlitre
H=hour
K 2CO 3=salt of wormwood
G=gram
D=sky
RT or rt=room temperature
Mg=milligram
Aq=aqueous solution
THF=tetrahydrofuran (THF)
NaOH=sodium hydroxide
EtOAc=ethyl acetate
NH 3=ammonia
DMF=dimethyl formamide
DMAP=dimethyl aminopyridine
TEA=triethylamine
TBuOH=trimethyl carbinol
Cs 2CO 3=cesium carbonate
IPrOH=Virahol
H 2O 2=hydrogen peroxide
HPLC=high performance liquid chromatography
Na 2SO 4=sodium sulfate
Psi=pound per square inch
NH 4Cl=ammonium chloride
Cu 2O=Red copper oxide
N=just
NH 4OH=ammonium hydroxide
POCl 3=phosphorus oxychloride
H 2O=water
NaOMe=sodium methylate
NaHCO 3=sodium bicarbonate
μ M=micromole
Embodiment 1
Figure A20068002053301801
5-methyl-3-(4-nitrophenoxy methyl) isoxazole (3, X=H)
[0325] is being equipped with reflux exchanger, magnetic stirring bar and having N 2Add in the exsiccant reaction flask of rubber septum of inlet the 4-nitrophenols (2, X=H) (1.57g, 11.36mmol), anhydrous K 2GO 3(1.58g, 12mmol), iodate tetramethyl-ammonium (200mg) and anhydrous propanone (100mL).With reaction mixture stirring at room 30 minutes.Under the room temperature, (2.0g 11.36mmol) spends the night reaction mixture refluxed then to add 3-(brooethyl)-5-methyl-isoxazole in this uneven mixture.It is cooled to room temperature after-filtration reaction mixture, with the filtrate of acetone (50mL) washing and concentrating under reduced pressure merging.The gained solid carries out wash-out with the hexane class, then by the silicagel column purifying, polarity increases gradually, carry out wash-out up to hexane solution with 40%EtOAc, with obtain 2.59 the gram (97%) required 5-methyl-3-(4-nitrophenoxy methyl) isoxazole (and 3, X=H). 1H?NMR(CDCl 3)：δ8.19(d，2H，J＝9.3Hz)，7.04(d，2H，J＝9.6Hz)，6.18(s，1H)，5.20(s，2H)，2.44(s，3H)；LCMS(m/z)：235(MH +)。
3-(4-amino-benzene oxygen methyl)-5-methyl-isoxazole (4, X=H)
[0326] ((3, X=H) (2.59g 11.07mmol) is dissolved in MeOH: CH to 4-nitrophenoxy methyl) isoxazole with 5-methyl-3- 2Cl 2(1: 1,600mL).With under nitrogen, dropwise added in 30 minutes V-Brite B (11.93g, 68.5mmol) and K 2CO 3(9.55g, aqueous solution 69mmol) (77mL).The reactant room temperature is stirred 2 hours (2h), and organic solvent is removed in decompression, and CH is used in water (200mL) dilution 2Cl 2(anhydrous Na is used in 3 * 300mL) extractions 2SO 4Dry also removal of solvent under reduced pressure.Products therefrom finally under high vacuum dry with provide 1.03 gram (46%) 5-methyl-3-(4-amino-benzene oxygen methyl) isoxazole (and 4, X=H). 1H?NMR(CDCl 3)：δ6.78(d，2H，J＝8.7Hz)，6.61(d，2H，J＝8.4Hz)，6.07(s，1H)，5.01(s，2H)，3.44(s，2H)，2.40(s，3H)；LCMS(m/z)：205(MH +)。
[0327] following compound prepares according to mode similar to Example 1.
5-methyl-3-(2-methyl-4-nitrophenoxy methyl) isoxazole (3, X=CH 3)
[0328] 1H?NMR(CDCl 3)：δ8.08(d，1H，J＝2.7Hz)，8.04(s，1H)，6.96(d，1H，J＝8.7Hz)，6.08(s，1H)，5.21(s，2H)，2.44(s，3H)，2.30(s，3H)；LCMS(m/z)：249(MH +)。
3-(2-fluoro-4-nitrophenoxy methyl)-5-methyl-isoxazole (3, X=F)
[0329] LCMS: purity: 98%; MS (m/e): 254 (MH+).
3-(4-amino-2-methyl phenoxymethyl)-5-methyl-isoxazole (4, X=CH 3)
[0330] 1H NMR (CDCl 3): δ 6.70 (d, 1H, J=8.7Hz), 6.52 (d, 1H, J=2.7Hz), 6.45 (dd, 1H, J=2.7 and 8.4Hz), 6.07 (s, 1H), 5.00 (s, 2H), 3.39 (s, 2H), 2.41 (s, 3H), 2.17 (s, 3H); LCMS (m/z): 219 (MH +).
3-(4-amino-2-fluorophenoxy methyl)-5-methyl-isoxazole (4, X=F)
[0331] LCMS: purity: 89%; MS:224 (MH+).
Embodiment 2
Figure A20068002053301811
4-methyl-3-methoxycarbonyl methylene radical oxygen base oil of mirbane (6)
[0332] in the reaction flask that is equipped with reflux exchanger, magnetic stirring bar and nitrogen inlet, add 2-methyl-5-nitro phenol (5) (5.0g, 32.6mmol), K 2CO 3(4.51g, 32.6mmol) and acetone (35mL).Under the room temperature, (2.7mL 29.34mmol), refluxed 24 hours then to add methyl bromoacetate in this uneven mixture.After the cooling reaction mixture poured into frozen water (200mL).The solid of separating out is leached, and (3 * 50mL) washings are also dry to obtain 7.0 gram 4-methyl-3-methoxycarbonyl methylene radical oxygen base oil of mirbane (6) under high vacuum for water.LCMS: purity: 95%; MS (m/z): 226 (MH +).
4-methyl-3-methylamino carbonyl methylene radical oxygen base oil of mirbane (7)
[0333] with 4-methyl-3-methoxycarbonyl methylene radical oxygen base oil of mirbane (6) (7.0g, 31mmol), methylamine hydrochloride (20.93g, 310mmol), diisopropylethylamine (DIPEA) (28mL, 155mmol) and the mixture of methyl alcohol (100mL) in vitro stirred 6 hours at pressure in 90 ℃.Make reactant be cooled to room temperature and water (1 liter) dilution.The gained solid is leached, and (3 * 150mL) washings are also dry to obtain 6 gram 4-methyl-3-methylamino carbonyl methylene radical oxygen base oil of mirbane (7) for water.LCMS: purity: 98%; MS (m/z): 225 (MH +).
4-methyl-3-methylamino carbonyl methylene radical oxygen base aniline (8)
[0334] during 40PSI in methyl alcohol (50mL) with 10%Pd/C (100mg) with (1.0g) hydrogenation 4 hours of 4-methyl-3-methylamino carbonyl methylene radical oxygen base oil of mirbane (7), obtain 0.8 gram 4-methyl-3-methylamino carbonyl methylene radical oxygen base aniline (8) after elimination catalyzer and the removal of solvent under reduced pressure.LCMS: purity: 93%; MS (m/e): 195 (MH+).
4-methyl-3-(2-methylamino) ethyl oxygen base oil of mirbane (9)
[0335] in being equipped with the dry reaction flask of reflux exchanger, magnetic stirring bar and nitrogen inlet, add 4-methyl-3-methylamino carbonyl methylene radical oxygen base oil of mirbane (7) (0.5g, 2.23mmol) and THF (5mL).Gained suspension is cooled to 0 ℃, and (3.3mL 2M), makes reaction mixture reply room temperature and refluxed 2 hours then with 5 minutes it to be added borine-methyl-sulfide mixture.It is (careful to remove the careful methyl alcohol that adds in the back of desolvating under vacuum! Methyl alcohol and remnants/unreacted borine-methyl-sulfide mixture vigorous reaction).With gained methanol solution stirring at room 30 minutes, methyl alcohol and volatile matter were removed in decompression then.This process repeats twice.Methanol solution uses 4N HCl (to be dissolved in that diox (4.4mmol, 1.1mL)) is handled and 60 ℃ of heating 2.5 hours then.Removal of solvent under reduced pressure.Mixture 2M NH 3(8.8mmol 4.4mL) handles, then removal of solvent under reduced pressure/methyl alcohol.Residual product is carried out chromatographic separation (silica gel is used the hexane elution, uses the hexane solution wash-out of 20% ethyl acetate then) to obtain 0.350 gram 4-methyl-3-(2-methylamino) ethyl oxygen base oil of mirbane (9).LCMS: purity: 92%; MS (m/z): 211 (MH +).
4-methyl-3-(2-methylamino) ethyl oxygen base aniline (10)
[0336] during 40psi in methyl alcohol (20mL) with 10%Pd/C (50mg) with 4-methyl-3-(2-methylamino) ethyl oxygen base oil of mirbane (9) (0.5g) hydrogenation 4 hours to obtain 0.350 gram 4-methyl-3-(2-methylamino) ethyl oxygen base aniline (10).LCMS: purity: 90%; MS (m/z): 181 (MH +).
Embodiment 3
Figure A20068002053301821
The acetyl amidoxime. triethylamine hydrochloride (11)
[0337] under the room temperature, acetonitrile (2.0g, 2.54mL, add while stirring in MeOH 48.72mmol) (10mL) solution hydroxy amine hydrochloric acid salt (3.38g, 48.64mmol) and triethylamine (NEt 3) (5.1g, 7.0mL 50.4mmol), refluxed 3 days then.Removal of solvent under reduced pressure, dry so that the acetyl amidoxime triethylamine hydrochloride (11) of required white crystalline solid shape to be provided under high vacuum then.
3-methyl-5-(4-nitrophenoxy methyl)-1,2,4-oxadiazole (13a)
[0338] with 4-nitrophenoxy acetate (12) (2.25g, 11.4mmol), acetyl amidoxime triethylamine hydrochloride (11,5.85g, 27.62mmol), EDCl.HCl (4.37g, 22.79mmol) and diisopropyl ethyl amine (7.42g, 10mL, mixture 57.40mmol) refluxed 18 hours in (250mL) at anhydrous tetrahydro furan (THF).Uneven brown reaction mixture water cancellation is then also used EtOAc (3 * 300mL) extractions.The organic layer that merges is used sodium bicarbonate aqueous solution (NaHCO successively 3) and the salt water washing.Gained organic phase anhydrous Na 2SO 4Dry and remove with rotatory evaporator and to desolvate.The gained resistates by purification by silica gel column chromatography with produce 1.62 the gram (60%) white solid required product 3-methyl-5-(4-nitrophenoxy methyl)-1,2,4-oxadiazole (13a). 1H?NMR(CDCl 3，300MHz)：δ8.24(d，2H，J＝8.8Hz)，7.08(d，2H，J＝8.8Hz)，5.36(s，2H)，2.44(s，3H)；LCMS(m/z)：236(MH +)。
5-(4-amino-benzene oxygen methyl)-3-methyl isophthalic acid, 2,4-oxadiazole (14a)
[0339] according to embodiment 1 described process preparation. 1H?NMR(CDCl 3)：δ6.82(d，2H，J＝8.8Hz)，6.63(d，2H，J＝8.8Hz)，5.15(s，2H)，3.38(br?s，2H)，2.41(s，3H)；LCMS(m/z)：206(MH +)。
[0340] following compound prepares according to mode similar to Example 3.
3-methyl-5-(3-nitro-phenoxy methyl)-1,2,4-oxadiazole (13b)
[0341] 1H NMR (CDCl 3, 300MHz): δ 7.92 (dd, 1H, J=0.9 and 1.9Hz), 7.89 (dd, 1H, J=0.9 and 2.1Hz), 7.83 (t, 1H, J=2.1Hz), 7.33 (m, 1H), 5.34 (s, 2H), 2.44 (s, 3H); LCMS (m/z): 236 (MH +).
5-(3-amino-benzene oxygen methyl)-3-methyl isophthalic acid, 2,4-oxadiazole (14b)
[0342] 1H?NMR(CDCl 3)：δ7.05(t，1H，J＝8.4Hz)，6.36-6.29(m，3H)，5.19(s，2H)，3.69(br?s，2H)，2.42(s，3H)；LCMS(m/z)：206(MH +)。
3-methyl-5-(4-oil of mirbane ethyl)-1,2, the 4-oxadiazole
[0343] 1H NMR (DMSO-d 6): δ 8.15-8.12 (d, J=9.0Hz, 2H), 7.56-7.53 (d, J=9.0Hz, 2H), 3.28-3.26 (m, 2H), 3.22-3.20 (m, 2H) and 2.28 (s, 3H).
4-[2-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) ethyl] aniline
[0344] LCMS: purity: 91%; MS (m/e): 204 (M+).
Embodiment 4
Figure A20068002053301841
1-benzyl-3-methylpyrazole-5-carboxylic acid, ethyl ester (16)
[0345] with 3-methyl isophthalic acid H-pyrazoles-5-carboxylic acid, ethyl ester (15) (0.50g.3.2mmol), bromotoluene (0.48mL, 4.0mmol) and K 2CO 3(0.90g, acetonitrile 6.5mmol) (8.0mL) mixture stirred overnight at room temperature.Reaction mixture water (50mL) dilutes and uses dichloromethane extraction.The organic layer that merges is with the salt water washing and use anhydrous magnesium sulfate drying.After the removal of solvent under reduced pressure, resistates restrains 1-benzyl-3-methylpyrazole-5-carboxylic acid, ethyl ester (16) by hurried column chromatography [silica gel is with mixture (from 0% to the 15%EtOAc/ hexane) wash-out of ethyl acetate and hexane] purifying to produce 0.30. 1H NMR (CDCl 3): δ 7.30-7.22 (m, 5H), 6.65 (s, 1H), 5.71 (s, 2H), 4.28 (q, J=7.2Hz, 2H), 2.32 (s, 3H), 1.32 (t, J=7.2Hz, 3H); LCMS: purity: 99%; MS (m/z): 345 (MH +).
4-[(1-benzyl-3-methylpyrazole-5-yl) methylene radical oxygen base] oil of mirbane (18)
In the time of [0346] 0 ℃, (0.30g dropwise adds diisobutyl aluminium hydride (DIBAL-H) (1M prepares with toluene for 3.4mL, 3.4mmol) solution in dry toluene 1.2mmol) (6.0mL) suspension at 1-benzyl-3-methylpyrazole-5-carboxylic acid, ethyl ester (16).Then with reaction mixture stirring at room 1 hour.Reaction mixture is with ether (50mL) dilution, and (50mL is 0.5M) and in room temperature vigorous stirring 2 hours to add Rochelle salt.Extract once more with the water layer separation and with ether.The organic layer that merges is with the salt water washing and use anhydrous magnesium sulfate drying.The crude product 17 (0.23g) that concentrates the back acquisition need not to be further purified just and can use.
[0347] with product 17 (0.23g, 1.0mmol) be suspended in anhydrous methylene chloride (8.0mL), and in this solution, add triethylamine (0.29mL, 2.1mmol), 4-dimethylaminopyridine (5mg, 0.04mmol) and p-toluenesulfonyl chloride (0.21g, 1.1mmol).Then the reaction mixture stirring at room was also used methylene dichloride (10mL) and saturated NH in 3.5 hours 4Cl (15mL) washing.Organic layer is separated, use anhydrous magnesium sulfate drying, and vacuum concentration.Make crude product pass through silicagel pad, with the tosylate (0.135g) of mixture (from 0% to 5%EtOAc/ hexane) wash-out to obtain yellow oily of ethyl acetate and hexane.Anhydrous dimethyl formamide (DMF) (2.0mL) in tosylate (0.135g, 0.379mmol) with the 4-nitrophenols (66mg, 0.47mmol) and K 2CO 3(0.10g 0.76mmol) mixes.Then mixture is spent the night 65 ℃ of stirrings.Reaction mixture be cooled to room temperature and pour in the water (20mL),, obtain the 4-[(1-benzyl-3-methylpyrazole-5-yl of white solid by the separating obtained solid product of suction filtration) methylene radical oxygen base] oil of mirbane (18) is (0.155g). 1H NMR (CDCl 3): δ 8.16 (d, J=9.0Hz, 2H), 7.29-7.25 (m, 3H), 7.11-7.06 (m, 2H), 6.83 (d, J=9.0Hz, 2H), 6.20 (s, 1H), 5.39 (s, 2H), 4.96 (s, 2H) and 2.34 (s, 3H).
4-[(1-benzyl-3-methylpyrazole-5-yl) methylene radical oxygen base] aniline (19, the Y=benzyl)
[0348] LCMS: purity: 85%; MS (m/e): 294 (MH+).
Embodiment 5
Figure A20068002053301851
4-aminocarboxyl methylene radical oxygen base oil of mirbane (20)
[0349] with 4-nitrophenols (10g), bromoacetamide (10g) and K 2CO 3(15g) be suspended in acetone (30mL).With yellow solution stirring at room 3 days.Reaction mixture is removed acetone with distilled water diluting and decompression.By filter collecting faint yellow precipitation, water (3 * 100mL) washings and dry with the 4-aminocarboxyl methylene radical oxygen base oil of mirbane (20) that obtains the beige solid shape (11.5g).
4-(aminocarboxyl methylene radical oxygen base) aniline (21)
[0350] 4-aminocarboxyl methylene radical oxygen base oil of mirbane (20) (5g) is dissolved in methyl alcohol (50mL) and also adds 10%Pd-C (500mg) therein.Reaction mixture was reacted 1 hour down at hydrogen (about 40psi).Leach catalyzer by Celite pad.With concentrated 4-(aminocarboxyl methoxyl group) aniline (21) of filtrate decompression to obtain white solid.
Embodiment 6
Figure A20068002053301852
4-cyano group methylene radical oxygen base oil of mirbane (22)
[0351] with 4-nitrophenols (10g), bromoacetonitrile (6mL) and K 2CO 3(15g) be suspended in acetone (100mL).With the yellow solution stirred overnight at room temperature.Acetone is removed in reaction mixture water (100mL) dilution and decompression.Faint yellow precipitation is collected by filtering, and (3 * 100mL) washings are also dry to obtain 4-cyano group methylene radical oxygen base oil of mirbane (22) with distilled water.
4-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl) methylene radical oxygen base oil of mirbane (23)
[0352] 4-cyano group methylene radical oxygen base oil of mirbane (22) (8g) is dissolved in methyl alcohol (50mL) and add oxyamine HCl (3.4g) and triethylamine (9.4mL) in solution.With reaction mixture refluxed 4 days and removal of solvent under reduced pressure.Resistates heavily is dissolved in THF (50mL).In solution, add Acetyl Chloride 98Min. (AcCl) (23mL) and triethylamine (50mL).The reaction mixture stirred overnight at room temperature adds entry (30mL) and NaOH (18g) then.The reaction soln backflow is spent the night and water (200mL) dilution.(2 * 150mL) extract the aqueous solution with EtOAc.After the separation, the EtOAc layer anhydrous sodium sulfate drying of merging, removal of solvent under reduced pressure then.The gained resistates by hurried column chromatography (EtOAc/ hexane (hexanes)=1/2 (v/v), 1/1, EtOAc) with from EtOAc and hexane recrystallization purifying to obtain 4-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl) methylene radical oxygen base oil of mirbane (23).
4-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl) anisidine (24)
[0353] 4-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl) methylene radical oxygen base oil of mirbane (1g) is dissolved in THF (40mL) and water (40mL).In solution, add sodium bisulfite (3.8g), sodium bicarbonate (1.4g) and K 2CO 3(1.8g).With solution stirring at room 30 minutes and water (80mL) dilution.(2 * 100mL) extract the aqueous solution with EtOAc.Merge organic layer then, with anhydrous sodium sulfate drying and removal of solvent under reduced pressure to obtain 4-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl) anisidine (24).
Embodiment 7
Figure A20068002053301861
3-chlorosulfonyl-4-fluoro-5-methyl oil of mirbane (26)
[0354] in being equipped with the dry reaction flask of stirring rod, reflux exchanger and nitrogen inlet, add 4-fluoro-3-methyl oil of mirbane (25) (3.10g, 20mmol).In the time of 0 ℃, with dropwise added therein in 15 minutes chlorsulfonic acid (5.29mL, 80mmol).Make solution get back to room temperature behind the homogeneous, and stirred 24 hours at 110 ℃.Then the gained soup compound is poured into frozen water (100gm), (3 * 75mL) extractions, anhydrous sodium sulfate drying is used in organic phase water (75mL) washing then with diethyl ether.Removal of solvent under reduced pressure is to provide corresponding sulfonyl chloride derivatives (26) then, and this material need not purifying just can be continued to use.
3-amino-sulfonyl-4-fluoro-5-methyl oil of mirbane (27)
[0355] gained oiliness resistates compound 26 is added ethyl acetate (100mL) and with ammonium hydroxide (100mL, 30% aqueous solution) stirred overnight at room temperature together.Use ethyl acetate (2 * 50mL) aqueous layer extracted after the separating ethyl acetate layer.Organic layer is merged, remove with anhydrous sodium sulfate drying and under vacuum and desolvate.The oiliness resistates of dark color is carried out chromatography (silica gel, hexane are 10%, 20% then, the hexane solution of the ethyl acetate until 50%) so that 3-amino-sulfonyl-4-fluoro-5-methyl oil of mirbane (27) to be provided.LCMS: purity: 89%; MS (m/z): 235 (MH +).
Synthetic 3-amino-sulfonyl-4-fluoro-5-monomethylaniline (28)
[0356] under the room temperature, 3-amino-sulfonyl-4-fluoro-5-methyl oil of mirbane (27) (0.5g, ethanol 2mmol): add in the inhomogeneous solution of water (each 50mL) iron powder (1.08g, 20mmol) and ammonium chloride (1.08g, 20mmol).The gained heterogeneous mixture stirred 2 hours at 60 ℃ then, by diatomite filtration (while hot), with ethanol (2 * 50mL) washing, removal of solvent under reduced pressure then.Residue diluted with water, use then ethyl acetate (3 * 50mL) extractions, organic phase with anhydrous sodium sulfate drying and concentrating under reduced pressure to obtain 3-amino-sulfonyl-4-fluoro-5-monomethylaniline (28).LCMS: purity: 85%; MS (m/z): 205 (MH +).
3-amino-sulfonyl-4-fluoroaniline
[0357] 3-amino-sulfonyl-4-fluoronitrobenzene (360mg, add 10%Pd/C (36mg) in methylene dichloride 1.62mmol) (6mL) and methyl alcohol (3mL) solution and under 50psi hydrogen the vibration 15 minutes.Mixture is by diatomite filtration, and filter cake washs with methyl alcohol (5mL).Obtaining crude product, this material is by hurried column chromatography (ethyl acetate: hexane 1: 1) be further purified 5-amino-2-fluorobenzene sulphonamide to obtain 240mg faint yellow solid shape with the organic solvent concentrating under reduced pressure that merges.
1H?NMR(DMSO-d 6)：δ7.38(s，2H)，7.03-6.94(m，2H)，6.70-6.66(m，1H)，5.33(s，1H)。
[0358] following compound prepares according to mode similar to Example 7.
3-amino-sulfonyl-4-methyl oil of mirbane
[0359] LCMS: purity: 95%; MS (m/e): 217 (MH+).
3-amino-sulfonyl-4-fluoronitrobenzene
[0360] 1H NMR (DMSO-d 6): δ 8.53-8.50 (m, 2H), 8.04 (s, 2H), and 7.77-7.70 (m, 1H).
3-amino-sulfonyl-4-chloro-5-methyl oil of mirbane
[0361] LCMS: purity: 86%; MS (m/e): 252 (MH+).
3-amino-sulfonyl-5-chloro-4-methyl oil of mirbane
[0362] LCMS: purity: 96%; MS (m/e): 252 (MH+).
3-amino-sulfonyl-4-monomethylaniline
[0363] LCMS: purity: 87%; MS (m/e): 187 (MH+).
3-amino-sulfonyl-4-chloro-5-monomethylaniline
[0364] LCMS: purity: 98%; MS (m/e): 222 (MH+).
3-amino-sulfonyl-5-chloro-4-monomethylaniline
[0365] LCMS: purity: 97%; MS (m/e): 222 (MH+).
3-amino-sulfonyl-4-chloroaniline
[0366] LCMS: purity: 98%; MS (m/e): 239 (MH+).
Embodiment 8
Figure A20068002053301871
6-bromo-3-hydroxyl-2-nitropyridine (30)
[0367] in being equipped with the dry reaction flask of magnetic stirring bar and nitrogen inlet, add 3-hydroxyl-2-nitropyridine (29) (28g, 200mmol) and methyl alcohol (560mL).Under the room temperature, (25wt% prepares with methyl alcohol to add sodium methylate with 30 minutes in this uniform mixture; 181mmol, 46.15mL).With gained solution be cooled to 0 ℃ and with added therein in 15 minutes bromine (10.31mL, 200mmol).Then with reaction mixture 0 ℃ of restir 30 minutes.With Glacial acetic acid (3.5mL) termination reaction, then reaction mixture is concentrated into dried, water (1 liter) dilution then.The gained solid leached and water (2 * 100mL) washings are to obtain 6-bromo-3-hydroxyl-2-nitropyridine (30): 4,60: 40 mixtures of 6-two bromo-3-hydroxyls-2-nitropyridine (31).LCMS:MS (m/z): be respectively 219 (MH +) and 297 (MH +).6-bromo-3-hydroxyl-2-nitropyridine (30): 4,60: 40 mixtures of 6-two bromo-3-hydroxyls-2-nitropyridine (31) are directly used in following test.
6-bromo-3-methoxyl group-2-nitropyridine (32)
[0368] at 6-bromo-3-hydroxyl-2-nitropyridine (30): 4,60: 40 mixtures of 6-two bromo-3-hydroxyls-2-nitropyridine (31) (2.18g, 10mmol), K 2CO 3(2.08g, 15mmol) and N, (1.13mL 12mmol), and stirs the gained mixture 24 hours in 60 ℃ to add methyl-sulfate (DMS) in dinethylformamide (DMF) heterogeneous mixture (20mL).Pour reaction mixture into frozen water (100mL), with ethyl acetate (3 * 50mL) extractions, organic phase anhydrous sodium sulfate drying.Removal of solvent under reduced pressure is to provide 6-bromo-3-methoxyl group-2-nitropyridine (32) then.LCMS: purity: 92%; MS (m/z): 233 (MH +).
2-amino-6-bromo-3-Methoxy Pyridine (33)
[0369] under the room temperature, 6-bromo-3-methoxyl group-2-nitropyridine (32) (2.32g, 10mmol) and ethanol: add in the inhomogeneous solution of water (each 40mL) iron powder (2.8g, 50mmol), add then ammonium chloride (2.64g, 50mmol).The gained heterogeneous mixture stirred 15 minutes at 70-75 ℃ then, by diatomite filtration (while hot), with washing with alcohol (2 * 50mL), removal of solvent under reduced pressure then.The dilute with water resistates to be to obtain solid, by this solid of filtering separation to obtain 2-amino-6-bromo-3-Methoxy Pyridine (33).LCMS: purity: 95%, MS (m/z): 203 (MH +).
6-bromo-2-(tertiary butyl carbonyl) amino-3-Methoxy Pyridine (34)
[0370] in being equipped with the dry reaction flask of nitrogen inlet and magnetic stirring bar, add 2-amino-6-bromo-3-Methoxy Pyridine (33) (0.170g, 0.84mmol), pyridine (0.126mL, 1.26mmol) and CH 2Cl 2(5mL).(0.113mL is 0.92mmol) then with the reaction mixture stirred overnight at room temperature to add pivalyl chloride in the time of 0 ℃ therein.Water (25mL) termination reaction is used CH then 2Cl 2(2 * 25mL) extractions, with anhydrous sodium sulfate drying and removal of solvent under reduced pressure so that 6-bromo-2-(tertiary butyl carbonyl) amino-3-Methoxy Pyridine (34) to be provided.LCMS: purity: 80%; MS (m/z): 287 (MH +).
6-amino-2-(tertiary butyl carbonyl) amino-3-Methoxy Pyridine (35)
[0371] in the pressure test tube, add 6-bromo-2-(tertiary butyl carbonyl) amino-3-Methoxy Pyridine (34) (0.287g), ethylene glycol (3mL) and Cu 2O (0.028g) also is cooled to-78 ℃.In this mixture, add 1mL liquefied ammonia (in-78 ℃), the sealing load test tube, stirring at room is 24 hours then.Again reaction mixture is cooled to-78 ℃, removes sealing and water (10mL) diluted reaction mixture.(3 * 50mL) extractions are with anhydrous sodium sulfate drying and removal of solvent under reduced pressure with ethyl acetate for the aqueous solution.The gained resistates is carried out chromatographic separation (silica gel, CH 2Cl 2, be 1%2NNH then 3The CH of/MeOH 2Cl 2Solution) to obtain 6-amino-2-(tertiary butyl carbonyl) amino-3-Methoxy Pyridine (35).LCMS: purity: 94%; MS (m/z): 224 (MH +).
Embodiment 9
Figure A20068002053301891
3-(4-nitrophenyl) propionitrile (38)
[0372] under the room temperature, 4-oil of mirbane methyl alcohol (37) (1g, 6.53mmol) and (cyano methyl) trimethylammonium iodate phosphorus (36) (4g, add in mixture 16.32mmol) propionitrile (32mL) and diisopropyl ethyl amine (2.5g, 19.58mmol).Mixture was heated 24 hours at about 100 ℃.Water (1mL) termination reaction adds dense HCl (5mL) then.(the salt water washing is used in 3 * 100mL) extractions to the gained reaction mixture, uses anhydrous sodium sulfate drying, and concentrating under reduced pressure is to obtain dark brown solid then with ethyl acetate.Rough solid product is by hurried column chromatography (silica gel, ethyl acetate: 3-(4-nitrophenyl) propionitrile (38) of purifying to obtain 740 milligrams of light orange solid state hexane 1: 1). 1H NMR (DMSO-d 6): δ 8.20-8.17 (dd, J=8.7Hz, 2H), 7.59-7.56 (d, J=9.0Hz, 2H), and 3.06-3.01 (m, 2H).
3-(4-aminophenyl) propionitrile (39)
[0373] (740mg is 4.2mmol) to provide 3-(4-aminophenyl) propionitrile (39) as catalyst reduction 3-(4-nitrophenyl) propionitrile (38) with 10%Pd/C in methyl alcohol (100mL) with embodiment 5 described methods. 1H NMR (DMSO-d 6): δ 6.91-6.88 (d, J=9.0Hz, 2H), 6.49-6.46 (d, J=9.0Hz, 2H), 4.92 (s, 2H) and 2.66 (s, 4H).
(cyano methyl) trimethylammonium iodate phosphorus
[0374] under 0 ℃, nitrogen, with toluene (the 1mol L of triphenylphosphine -1, 40mL, 40mmol) solution adds the mixture of toluene (20mL) and tetrahydrofuran (THF) (20mL).Dropwise add then iodomethyl cyanide (2.8mL, 38.7mmol) and vigorous stirring.Remove ice bath then and mixture was at room temperature stirred 40 hours again.Mixture is filtered, solid with toluene wash and drying under reduced pressure to obtain (cyano methyl) trimethylammonium iodate phosphorus of 8 gram faint yellow solid shapes.LCMS(m/z)：243.03(M +)。
Embodiment 10
2-(4-nitrophenoxy) acethydrazide (41)
[0375] (5g, (11.8mL 38mmol), refluxes the mixture room temperature 1 hour then to add hydrazine hydrate in methyl alcohol 24mmol) (75mL) solution in 2-(4-nitrophenoxy) ethyl acetate (40).So that resistates to be provided, this resistates is used the washing of distilled water (30mL) and ether (30mL) then with methylene dichloride (30mL) washing with the reactant removal of solvent under reduced pressure.With gained solid drying under reduced pressure to obtain 2-(4-nitrophenoxy) acethydrazide (41) of 5.7 gram faint yellow solid shapes. 1H?NMR(DMSO-d 6)：δ9.41(s，1H)，8.20-8.17(d，J＝9.0Hz，2H)，7.15-7.12(d，J＝9.0Hz，2H)，4.65(s，2H)，4.34(d，J＝6.0Hz，2H)。
N '-ethanoyl-2-(4-nitrophenoxy) acethydrazide (42)
[0376] under the room temperature, 2-(4-nitrophenoxy) acethydrazide (41) (5.7g, add in ethanol 29.5mmol) (500mL) solution diacetyl oxide (3.9mL, 41.3mmol) and triethylamine (6.17mL, 44.3mmol).Then with reaction mixture refluxed 1 hour and be cooled to room temperature.The gained precipitation is collected by filtration and (2 * 50mL) washings are to produce N '-ethanoyl-2-(4-nitrophenoxy) acethydrazide (42) of 7.5 gram Off-white solid shapes with cold ethanol. 1H?NMR(DMSO-d 6)：δ9.84(s，1H)，8.21-8.18(d，J＝9.0Hz，2H)，7.17-7.14(d，J＝9.0Hz，2H)，4.77(s，2H)，1.90(brs，3H)。
2-methyl-5-[(4-nitro-phenoxy) methyl]-1,3,4-oxadiazole (43)
[0377] (7.5g, mixture 29.4mmol) add Tripyrophosphoric acid (162mL) and heated 1 hour at 120 ℃ with N '-ethanoyl-2-(4-nitrophenoxy) acethydrazide (42).Then reaction mixture is poured in the trash ice also with ethyl acetate (3 * 300mL) extractions.Organic layer is with anhydrous sodium sulfate drying and removal of solvent under reduced pressure.The gained resistates is dissolved in methylene dichloride (500mL), with sodium bicarbonate aqueous solution and salt water washing.Remove methylene dichloride to obtain crude product with decompression after the anhydrous sodium sulfate drying, crude product is by hurried column chromatography (ethyl acetate: hexane 3: 1v/v) purifying is to obtain the 2-methyl-5-[(4-nitro-phenoxy of 2.4 gram white solid) methyl]-1,3,4-oxadiazole (43). 1H NMR (DMSO-d 6): δ 8.23-8.20 (d, J=9.0Hz, 2H), 7.28-7.25 (d, J=9.0Hz, 2H), 5.54 (s, 2H) and 2.52 (s, 3H).
The 4-[(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) methylene radical oxygen base] aniline (44)
[0378] according to embodiment 5 described method reductase 12-methyl-5-[(4-nitro-phenoxies) methyl]-1,3, (1.21g is 5.13mmol) to obtain the 4-[(5-methyl isophthalic acid of 1.02 gram light brown oilies for 4-oxadiazole (43), 3,4-oxadiazole-2-yl) methylene radical oxygen base] aniline (44). 1H NMR (CDCl 3): δ 6.85-6.82 (d, J=9.0Hz, 2H), 6.65-6.62 (d, J=9.0Hz, 2H), 5.132 (s, 2H) and 2.56 (s, 3H).
Embodiment 11
Figure A20068002053301901
3-(N-4-methyl piperidine-1-yl) amino-sulfonyl oil of mirbane (47)
In the time of [0379] 0 ℃; at 3-chlorosulfonyl oil of mirbane (45) (2.21g; add diisopropylethylamine (1.93mL in tetrahydrofuran (THF) 10mmol) (100mL) solution; 15mmol); add N-methyl-4-amino piperidine (46) (1.36g then; 12mmol), then with reaction mixture stirring at room 2 hours.Water (50mL) termination reaction stirred 30 minutes and the separation of tetrahydrofuran layer.Concentrating under reduced pressure organic solution.The gained resistates is added methylene dichloride (200mL), with sodium bicarbonate aqueous solution (2 * 100mL) and the salt water washing.Organic layer with anhydrous sodium sulfate drying and removal of solvent under reduced pressure to provide required product, 3-(N-4-methyl piperidine-1-yl) amino-sulfonyl oil of mirbane (47).LCMS: purity: 93%; MS (m/e): 300 (MH+).
[0380] following compound is according to mode similar to Example 3 or by method described here or the known method preparation of those of skill in the art.
3-(N-4-methyl piperidine-1-yl) amino-sulfonyl aniline (48)
[0381] LCMS: purity: 87%; MS (m/e): 270 (MH+).
3-(N-ethoxy carbonyl methylene radical) amino-sulfonyl oil of mirbane
[0382] LCMS: purity: 94%; MS (m/e): 289 (MH+).
3-(N-ethoxy carbonyl methylene radical) amino-sulfonyl aniline
[0383] LCMS: purity: 88%; MS (m/e): 259 (MH+).
4-(2-N, N-diethylamino ethyl) amino-sulfonyl oil of mirbane
[0384] 1H?NMR(CDCl 3)：δ8.35(d，2H，J＝8.4Hz)，8.05(d，2H，J＝8.4Hz)，5.02(brs，1H)，3.01(t，2H，J＝6.0Hz)，2.53(t，2H，J＝6.0Hz)，2.42(q，4H，J＝7.2Hz)，0.94(t，6H，J＝6.9Hz)，LCMS(m/z)：302(MH +)。
3-(2-N, N-diethylamino ethyl) amino-sulfonyl oil of mirbane
[0385] 1H?NMR(CDCl 3)：δ8.69(t，1H，J＝1.5Hz)，8.41(m，1H)，8.18(m，1H)，7.72(t，1H，J＝7.8Hz)，2.99(t，2H，J＝6.3Hz)，2.50(t，2H，J＝5.4Hz)，2.39(q，4H，J＝7.2Hz)，0.92(t，6H，J＝6.9Hz)，LCMS(m/z)：302(MH +)。
4-(2-N, N-diethylamino ethyl) amino-sulfonyl aniline
[0386] 1H?NMR(CDCl 3)：δ7.62(d，2H，J＝8.4Hz)，6.67(d，2H，J＝8.4Hz)，4.09(s，2H)，2.91(t，2H，J＝6.3Hz)，2.47(t，2H，J＝5.4Hz)，2.38(q，4H，J＝7.2Hz)，0.92(t，6H，J＝7.2Hz)，LCMS(m/z)：272(MH +)。
3-(2-N, N-diethylamino ethyl) amino-sulfonyl aniline
[0387] 1H?NMR(CDCl 3)：δ7.27-7.13(m，3H)，6.82(m，1H)，3.91(s，2H)，2.94(t，2H，J＝5.7Hz)，2.45(t，2H，J＝5.7Hz)，2.36(q，4H，J＝7.2Hz)，0.91(t，6H，J＝7.2Hz)，LCMS(m/z)：272(MH +)。
Embodiment 12
Figure A20068002053301911
2-(4-nitrophenoxy) methyl isobutyrate (49)
[0388] with 4-nitrophenols (5g), 2-isobutyl bromide methyl esters (5.6mL), K 2CO 3(7.5g) and the heterogeneous mixture of acetone (60mL) reflux and to spend the night.Water (150mL) diluted reaction mixture is also with ethyl acetate (2 * 100mL) extractions then.Organic layer is evaporated to obtain 2-(4-nitrophenoxy) methyl isobutyrate (49).
2-(4-nitrophenoxy) isopropylformic acid (50)
[0389] under the room temperature, adds sodium hydroxide (5g) in 2-(4-nitrophenoxy) methyl isobutyrate (49) solution in methyl alcohol (50mL) and water (50mL).With solution stirring at room 30 minutes, use 1N HCl acidified aqueous solution then to pH about 3.(2 * 100mL) extract the aqueous solution with ethyl acetate.Organic layer is merged, with anhydrous sodium sulfate drying and removal of solvent under reduced pressure to obtain 2-(4-nitrophenoxy) isopropylformic acid (50).
2-(4-nitrophenoxy)-2-methyl propanamide (51)
[0390] with 2-(4-nitrophenoxy) isopropylformic acid (50) (5g), the mixture stirring at room of isobutyl chlorocarbonate (4.36mL), triethylamine (8mL) and methylene dichloride (20mL) 1 hour.Methyl alcohol (20mL) solution that in solution, adds 2.0M ammonia then.With gained solution stirring at room 2 hours removal of solvent under reduced pressure then.Mixture from EtOAc recrystallization purifying hexane to obtain 2-(4-nitrophenoxy)-2-methyl propanamide (51).
2-(4-amino-benzene oxygen)-2-methyl propanamide (52)
[0391] 2-(4-nitrophenoxy)-2-methyl propanamide (51) is dissolved in methyl alcohol (50mL) and adds 10%Pd-C (500mg) in solution.Reaction mixture was reacted 1 hour down at hydrogen (about 40psi).Then by diatomite elimination catalyzer.With 2-(4-the amino-benzene oxygen)-2-methyl propanamide (52) of filtrate evaporated under reduced pressure to obtain white solid.
Embodiment 13
Figure A20068002053301921
4-(Propargyl oxygen base) oil of mirbane (X=H, Y=H)
[0392] with the 4-nitrophenols (1.00g, 7.19mmol), (80wt% prepares with toluene propargyl bromide; 0.788mL, 7.09mmol) and K 2CO 3(1.08g 7.84mmol) stirred 18 hours in 60 ℃ in acetone (16.0mL).Reaction mixture is cooled to room temperature and water (200mL) dilution.Isolate 4-(the Propargyl oxygen base) oil of mirbane (1.12g) of white solid by suction filtration. 1H?NMR(CDCl 3)：δ8.22(d，J＝9.0Hz，2H)，7.05(d，J＝9.0Hz，2H)，4.80(d，J＝2.4Hz，2H)，2.59(t，J＝2.4Hz，1H)。
4-(Propargyl oxygen base) aniline (X=H, Y=H)
[0393] with 4-(Propargyl oxygen base) oil of mirbane (0.910g, 5.13mmol), iron (1.42g, 25.3mmol) and NH 4Cl (0.719g, 12.8mmol) EtOH/ water (1: 1,55mL) in 70 ℃ of vigorous stirring 15 minutes.Reaction mixture is passed through diatomite heat filtering and vacuum concentration.Resistates is suspended in the dichloromethane solution of 10%2N ammonia methyl alcohol, ultrasonic, and pass through diatomite filtration.Concentrate and obtain brown buttery 4-(Propargyl oxygen base) aniline, this material need not to be further purified just and can use.Usually, isolating Propargyl oxygen base aniline is unsettled, therefore need use immediately after filtering for the second time. 1H?NMR(CDCl 3)：δ6.82(d，J＝8.7Hz，2H)，6.64(d，J＝8.7Hz，2H)，4.61(d，J＝2.4Hz，2H)，2.50(t，J＝2.4Hz，1H)。
[0394] following compound prepares according to mode similar to Example 13.
3-methyl-4-(Propargyl oxygen base) oil of mirbane (X=Me, Y=H)
[0395] 1H NMR (CDCl 3): δ 8.10 (dd, J=3.0 and 9.0Hz, 1H), 7.01 (d, J=9.0Hz, 1H), 4.83 (d, J=2.4Hz, 2H), 2.58 (t, J=2.4Hz, 1H), 2.31 (s, 3H).
3-chloro-4-(Propargyl oxygen base) oil of mirbane (X=Cl, Y=H)
[0396] 1H NMR (CDCl 3): δ 8.31 (d, J=2.7Hz, 1H), 8.17 (dd, J=2.7 and 9.0Hz, 1H), 7.17 (d, J=9.0Hz, 1H), 4.90 (d, J=2.7Hz, 2H), 2.63 (t, J=2.7Hz, 1H).
3-fluoro-4-(Propargyl oxygen base) oil of mirbane (X=F, Y=H)
[0397] 1H NMR (CDCl 3): δ 8.07 (ddd, J=1.5,2.7, and 9.3Hz, 1H), 8.01 (dd, J=2.7 and 10.5Hz, 1H), 7.20 (t, J=8.7Hz, 1H), 4.89 (d, J=2.1Hz, 2H), 6.23 (t, J=2.1Hz, 1H).
4-(fourth-2-alkynyloxy base) oil of mirbane (X=H, Y=Me)
[0398] 1H?NMR(CDCl 3)：δ8.21(d，J＝9.0Hz，2H)，7.03(d，J＝9.0Hz，2H)，4.75(q，J＝2.4Hz，2H)，1.88(t，J＝2.4Hz，3H)。
3-(Propargyl oxygen base) oil of mirbane
[0399] 1H NMR (CDCl 3): δ 7.87 (ddd, J=0.9,2.1, and 8.1Hz, 1H), 7.83 (t, J=2.1Hz, 1H), 7.46 (t, J=8.4Hz, 1H), 7.30 (ddd, J=0.6,2.4, and 8.4Hz, 1H), 4.79 (d, J=2.4Hz, 2H), 2.58 (t, J=2.4Hz, 1H).
Embodiment 14
Figure A20068002053301931
2-aminocarboxyl-5-nitrobenzofuran
[0400] in being equipped with the dry reaction flask of magnetic stirring bar, nitrogen inlet and rubber septum, add 2-carboxyl-5-nitrobenzofuran (0.414g, 2mmol) and CH 2Cl 2(100mL).Add DMF (0.1mL) therein, then 0 ℃ with slowly added therein in 5 minutes oxalyl chloride (0.519mL, 6mmol).With reaction mixture restir 30 minutes, observed settled solution and formed.With gained settled solution concentrating under reduced pressure and under high vacuum dry 30 minutes.The gained resistates is suspended in EtOAc (25mL), is cooled to 10 ℃, add NH therein 4OH (30% solution, 25mL) and stirring at room 24 hours.Organic phase is separated and use anhydrous sodium sulfate drying, except that desolvating to obtain 2-aminocarboxyl-5-nitrobenzofuran. 1H NMR (DMSO-d 6): δ 8.75 (d, 1H, J=2.7Hz), 8.28 (m, 2H), 7.86 (d, 1H, J=9.0Hz), 7.83 (bs, 1H), 7.72 (s, 1H); LCMS: purity: 93%, MS (m/e): 206 (M +).
2-cyano group-5-nitrobenzofuran
[0401] with uneven 2-aminocarboxyl-5-nitrobenzofuran (0.206g, POCl 1mmol) 3(5mL) solution heats 24 to obtain settled solution at 100 ℃.The gained settled solution is carefully poured in the frozen water to obtain solid matter, and this solid matter washes with water to obtain 2-cyano group-5-nitrobenzofuran subsequently by filtering separation. 1H NMR (DMSO-d 6): δ 8.80 (d, 1H, J=2.4Hz), 8.42 (dd, 1H, J=2.7 and 9.0Hz), 8.27 (s, 1H), 7.99 (d, 1H, J=8.7Hz); LCMS: purity: 98%, MS (m/e): 189 (MH +).
5-amino-2-cyano group cumarone
[0402] with 2-cyano group-5-nitrobenzofuran (0.150g, 0.789mmol), iron powder (0.220g, 3.9mmol), NH 4Cl (0.221g, 3.9mmol) and EtOH/H 2The inhomogeneous reaction mixture of O (each 5mL) was 60-70 ℃ of vigorous stirring 1 hour.Gained solution is used methanol wash then by the Celite pad filtered while hot.Filtrate is concentrated into dry doubling is resuspended in H under vacuum 2O (20mL), solution reaches capacity, by the filtering separation solid to obtain 5-amino-2-cyano group cumarone.
1H NMR (DMSO-d 6): δ 7.80 (s, 1H), 7.36 (d, 1H, J=8.7Hz), 6.86 (dd, 1H, J=2.7 and 9.0Hz), 6.76 (d, 1H, J=2.1Hz), 5.16 (bs, 2H); LCMS: purity: 95%, MS (m/e): 159 (MH +).
Embodiment 15
Figure A20068002053301941
3-amino-sulfonyl-4-methoxyl group-5-methyl-aniline
Under [0403] 0 ℃, (6.20g 40mmol), adds chlorsulfonic acid (10.60mL then to add 2-fluoro-5-nitrotoluene in being equipped with the dry reaction flask of magnetic stirring bar, nitrogen inlet and reflux exchanger, 160mmol), then reactant was stirred 24 hours at 100 ℃.It is cooled to after the room temperature reactant to be poured into frozen water (careful! ) and use ethyl acetate (3 * 200mL) extractions.Removal of solvent under reduced pressure obtains 3-chlorosulfonyl-4-fluoro-5-methyl oil of mirbane intermediate, with this intermediate at EtOAc (50mL) and NH 4OH (30%, 50mL) the middle stirring 2-3 hour.Evaporate isolating organic phase then so that thick material to be provided, this material by column chromatography (silica gel, hexane are used the hexane solution of 10-20%EtOAc then) purifying so that 3-amino-sulfonyl-4-fluoro-5-methyl oil of mirbane to be provided.LCMS: purity: 96%; MS (m/e): 235 (MH +).
[0404] (0.940g 4mmol) spends the night in 60 ℃ of stirrings in 25% methyl alcohol NaOMe (1.00mL) with gained 3-amino-sulfonyl-4-fluoro-5-methyl oil of mirbane.Gained solution is filtered by Celite pad then, with methanol wash and concentrated methanol solution to obtain 3-amino-sulfonyl-4-methoxyl group-5-methyl oil of mirbane.LCMS: purity: 100%, MS (m/e): 247 (MH +).
In the time of [0405] 60 ℃, at ethanol (100mL): in the water (25mL) with iron powder (0.81g, 15mmol), NH 4(0.81g, 15mmol) (0.740g, 3mmol) reduction is 1 hour, filters by Celite pad then, obtains the aqueous solution of alcohol with 3-amino-sulfonyl-4-methoxyl group-5-methyl oil of mirbane for Cl.With this solution concentration then dilute with water to obtain solid matter, by this solid matter of filtering separation to obtain 3-amino-sulfonyl-4-methoxyl group-5-monomethylaniline. 1H NMR (DMSO-d 6): δ 6.90 (bs, 1H), 6.55 (bs, 1H), 5.1 (bs, 2H), 3.65 (s, 3H), 2.15 (s, 3H), LCMS: purity: 94%, MS (m/e): 217 (MH +).
[0406] following compound is according to preparing with method described here or the similar mode of those of skill in the art's currently known methods.
4-(4-nitrophenoxy methyl)-2-methylthiazol
[0407] 1H?NMR(CDCl 3，300MHz)：δ8.19(d，2H，J＝9.0Hz)，7.17(s，1H)，7.04(d，2H，J＝9.3Hz)，5.22(s，2H)，2.74(s，3H)；LCMS(m/z)：251(MH +)。
The 3-[(4-nitro-phenoxy) methyl] pyridine
[0408] 1H NMR (CDCl 3, 300MHz): δ 8.68 (d, 1H, J=2.1Hz), 8.62 (dd, 1H, J=1.5 and 4.8Hz), 8.21 (d, 2H, J=9.0Hz), 7.76 (m, 1H), 7.35 (dd, 1H, J=4.5 and 7.8Hz), 7.03 (d, 2H, J=9.0Hz), 5.17 (s, 2H); LCMS (m/z): 231 (MH +).
The 2-[(4-nitro-phenoxy) methyl] pyridine
[0409] 1H?NMR(CDCl 3，300MHz)：δ8.61(d，1H，J＝4.8Hz)，8.19(d，2H，J＝9.0Hz)，7.72(m，2H)，7.46(d，1H，J＝7.8Hz)，7.25(m，1H)，7.05(d，2H，J＝9.3Hz)，5.28(s，2H)；LCMS(m/z)：231(MH +)。
The 2-[(4-nitro-phenoxy) methyl] pyridine
[0410] 1H?NMR(CDCl 3，300MHz)：δ8.60(d，1H，J＝4.5Hz)，8.04(m，2H)，7.73(m，1H)，7.48(d，1H，J＝8.1Hz)，7.25(m，1H)，6.92(d，1H，J＝9.3Hz)，5.30(s，2H)，2.39(s，3H)；LCMS(m/z)：245(MH +)。
The 3-[(3-nitro-phenoxy) methyl] pyridine
[0411] 1H?NMR(CDCl 3，300MHz)：δ8.69(d，1H，J＝2.1Hz)，8.61(d，1H，J＝4.5Hz)，7.81(m，3H)，7.45(t，1H，J＝8.1Hz)，7.36-7.24(m，2H)，5.15(s，2H)；LCMS(m/z)：231(MH +)。
The 4-[(4-nitro-phenoxy) methyl] pyridine
[0412] 1H?NMR(CDCl 3，300MHz)：δ8.61(d，2H，J＝5.4Hz)，8.21(d，2H，J＝9.0Hz)，7.33(d，2H，J＝5.4Hz)，7.02(d，2H，J＝9.0Hz)，5.18(s，2H)；LCMS(m/z)：231(MH +)。
Embodiment 16
Figure A20068002053301961
7-nitro-4-(3-pyridylmethyl) benzo [1,4] oxazine
[0413] is being equipped with reflux exchanger, magnetic stirring bar and having N 2Add in the dry reaction flask of rubber septum of inlet 7-nitro benzo [1,4] oxazine (1.0g, 5.55mmol), tertiary butyl chlorination ammonium (56mg), NaOH powder (0.58g) and dry DMF (10mL).With reaction mixture stirring at room 30 minutes.Adding 3-(brooethyl)-pyridine hydrobromide (1.40g, 5.55mmol).Reaction mixture 80 ℃ of heated overnight, is cooled to room temperature, pours in the water (200mL), left standstill 2 hours, add ethyl acetate (200mL).The organic layer water (2 * 200mL) and salt solution (200mL) washing, dry (Na 2SO 4) and concentrate.Solid restrains (44%) required 7-nitro-4-(3-pyridylmethyl) benzo [1,4] oxazine with the EtOAc wash-out to obtain 0.67 by the silicagel column purifying. 1H NMR (CDCl 3, 300MHz): δ 8.56 (d, 1H, J=4.8Hz), 8.53 (s, 1H), 7.72 (m, 2H), 7.53 (m, 1H), 7.28 (dd, 1H, J=5.1 and 7.8Hz), 6.57 (d, 1H, J=9.0Hz), 4.61 (s, 2H), 4.29 (t, 2H, J=4.2Hz), 3.59 (t, 2H, J=4.5Hz); LCMS (m/z): 272 (MH +).
Embodiment 17
Figure A20068002053301962
4-(4-pyridyl oxygen base)-1-oil of mirbane
[0414] (4.42g is 45.8mmol) with 1-fluoro-4-oil of mirbane (4.89mL, disposable adding anhydrous K in dry DMF 45.8mmol) (50mL) solution at the 4-pyridone 2CO 3(13.0g, 91.6mmol).Mixture heated under reflux temperature stirred simultaneously 24 hours, be cooled to room temperature and pour in the water (300mL).The solid that filtration is separated out, wash with water and under high vacuum thorough drying with produce 8.9 the gram (90%) required products, 4-(4-pyridyl oxygen base)-1-oil of mirbane. 1H?NMR(CDCl 3，300MHz)：δ8.36(d，2H，J＝9.0Hz)，8.11(d，2H，J＝8.1Hz)，7.83(d，2H，J＝9.0Hz)，6.27(d，2H，J＝7.8Hz)；LCMS(m/z)：217(MH +)。
Embodiment 18
Figure A20068002053301971
4-(4-oil of mirbane formyl) thiomorpholine (X=S)
In the time of [0415] 0 ℃, thiomorpholine (2.00mL, 20mmol) and Et 3The CH of N (5.0mL) 2Cl 2(60mL) dropwise add 4-nitrobenzoyl chloride (3.71g, CH 20mmol) in the solution while stirring 2Cl 2(50mL) solution.Reactant answer room temperature and stirring are spent the night, use saturated NaHCO then 3((2 * 75mL) washings are with CH for 2 * 75mL) water for solution 2Cl 2Dry (the Na of layer 2SO 4), filter and concentrate.Dry so that 5.027 gram (99%) 4-(4-oil of mirbane formyl) thiomorpholines to be provided under high vacuum at last. 1H?NMR(CDCl 3，300MHz)：δ8.28(d，2H，J＝9.0Hz)，7.54(d，2H，J＝8.7Hz)，4.04(br?s，2H)，3.61(br?s，2H)，2.75(br?s，2H)，2.57(br?s，2H)；LCMS(m/z)：253(MH +)。
[0416] following compound is according to mode similar to Example 18, method described here or the preparation of those of skill in the art's currently known methods.
1-methylsulfonyl-4-(4-oil of mirbane formyl) piperazine
[0417] 1H?NMR(CDCl 3，300MHz)：δ8.29(d，2H，J＝8.4Hz)，7.58(d，2H，J＝8.4Hz)，3.91(br?s，2H)，3.52(br?s，2H)，3.33(br?s，2H)，3.23(br?s，2H)，2.83(s，3H)；LCMS(m/z)：314(MH +)。
4-(4-oil of mirbane formyl) thiomorpholine-1, the 1-dioxide
[0418] 1H?NMR(CDCl 3，300MHz)：δ8.32(d，2H，J＝8.4Hz)，7.60(d，2H，J＝9.0Hz)，4.08(br?s，4H)，3.08(br?s，4H)；LCMS(m/z)：285(MH +)。
1-ethanoyl-4-(4-oil of mirbane formyl) piperazine
[0419] 1H?NMR(CDCl 3，300MHz)：δ8.29(d，2H，J＝8.7Hz)，7.58(d，2H，J＝8.4Hz)，3.59(m，8H)，2.14(s，3H)；LCMS(m/z)：277(MH +)。
4-(4-amino-benzene oxygen methyl)-2-methylthiazol
[0420] 1H?NMR(CDCl 3，300MHz)：δ7.10(s，1H)，6.81(d，2H，J＝8.7Hz)，6.62(d，2H，J＝9.0Hz)，5.06(s，2H)，3.43(s，2H)，2.72(s，3H)；LCMS(m/z)：221(MH +)。
The 3-[(4-amino-benzene oxygen) methyl] pyridine
[0421] 1H NMR (CDCl 3, 300MHz): δ 8.63 (d, 1H, J=2.1Hz), 8.54 (d, 1H, J=5.1Hz), 7.74 (d, 1H, J=7.5Hz), 7.29 (dd, 1H, J=5.1 and 7.8Hz), 6.79 (d, 2H, J=8.7Hz), 6.63 (d, 2H, J=8.7Hz), 4.99 (s, 2H), 3.44 (br s, 2H); LCMS (m/z): 201 (MH +).
The 3-[(3-amino-benzene oxygen) methyl] pyridine
[0422] 1H NMR (CDCl 3, 300MHz): δ 8.64 (d, 1H, J=2.1Hz), 7.75 (m, 1H), 7.29 (dd, 1H, J=4.8 and 7.8Hz), 7.05 (t, 1H, J=8.4Hz), 6.33 (m, 3H), 5.02 (s, 2H), 3.67 (br s, 2H); LCMS (m/z): 201 (MH +).
The 2-[(4-amino-benzene oxygen) methyl] pyridine
[0423] 1H?NMR(CDCl 3，300MHz)：δ8.56(m，1H)，7.67(m，1H)，7.49(d，1H，J＝7.8Hz)，7.18(m，1H)，6.80(d，2H，J＝8.7Hz)，6.62(d，2H，J＝8.7Hz)，5.12(s，2H)，3.43(br?s，2H)；LCMS(m/z)：201(MH +)。
The 4-[(4-amino-benzene oxygen) methyl] pyridine
[0424] 1H?NMR(CDCl 3，300MHz)：δ8.56(d，2H，J＝6.0Hz)，7.31(d，2H，J＝6.0Hz)，6.76(d，2H，J＝8.7Hz)，6.62(d，2H，J＝8.6Hz)，5.01(s，2H)，3.31(br?s，2H)；LCMS(m/z)：201(MH +)。
2-[(4-amino-benzene oxygen-2-methyl) methyl] pyridine
[0425] 1H NMR (CDCl 3, 300MHz): δ 8.55 (d, 1H, J=4.8Hz), 7.68 (m, 1H), 7.53 (d, 1H, J=7.5Hz), 7.18 (m, 1H), 6.67 (d, 1H, J=8.4Hz), 6.55 (d, 1H, J=3.0Hz), 6.44 (dd, 1H, J=2.7 and 8.5Hz), 5.11 (s, 2H), 3.23 (br s, 2H), 2.26 (s, 3H); LCMS (m/z): 215 (MH +).
7-amino-4-(3-pyridylmethyl) benzo [1,4] oxazine
[0426]LCMS(m/z)：242(MH +)。
Embodiment 19
Figure A20068002053301981
4-(4-aminobenzoyl) thiomorpholine
[0427] (1.26g 5mmol) adds NH while stirring in the solution at 4-(the 4-oil of mirbane formyl) thiomorpholine with ethanol (80mL) and water (20mL) preparation 4Cl (2.65g) also is heated to 80 ℃ with reactant.In this uneven reaction mixture, add iron powder (2.75g) vigorous stirring under nitrogen simultaneously in the time of 80 ℃ in batches, continue afterwards to stir 2 hours.Reaction mixture is also used the methanol wash filter bed by the Celite pad filtered while hot.Filtrate is concentrated, and dilute with water is used CH 2Cl 2(3 * 75mL) extractions, dry (Na 2SO 4), filter and concentrate.Dry so that 1.11 gram (100%) 4-(4-aminobenzoyl) thiomorpholines to be provided under high vacuum at last. 1H?NMR(CDCl 3，300MHz)：δ7.21(d，2H，J＝8.4Hz)，6.64(d，2H，J＝8.1Hz)，3.86(br?s，6H)，2.64(t，4H，J＝4.5Hz)；LCMS(m/z)：223(MH +)。
[0428] following compound prepares according to mode similar to Example 19.
1-methylsulfonyl-4-(4-aminobenzoyl) piperazine
[0429] 1H?NMR(CDCl 3，300MHz)：δ7.26(d，2H，J＝7.8Hz)，6.65(d，2H，J＝8.4Hz)，3.92(br?s，2H)，3.75(t，4H，J＝4.8Hz)，3.23(t，4H，J＝4.8Hz)，2.79(s，3H)；LCMS(m/z)：284(MH +)。
4-(4-aminobenzoyl) thiomorpholine-1, the 1-dioxide
[0430] 1H?NMR(CDCl 3，300MHz)：δ7.27(d，2H，J＝8.7Hz)，6.65(d，2H，J＝8.7Hz)，4.09(t，4H，J＝5.4Hz)，3.97(s，2H)，3.05(t，4H，J＝5.1Hz)，；LCMS(m/z)：255(MH +)。
1-ethanoyl-4-(4-aminobenzoyl) piperazine
[0431] 1H?NMR(CDCl 3，300MHz)：δ7.26(d，2H，J＝7.2Hz)，6.65(d，2H，J＝7.8Hz)，3.90(s，2H)，3.60(m，8H)，2.12(s，3H)；LCMS(m/z)：248(MH +)。
4-(4-pyridyl oxygen base) aniline
[0432] 1H?NMR(DMSO?d 6，，300MHz)：δ7.76(br?s，2H)，7.10(br?s，2H)，6.61(br?s，2H)，6.13(br?s，2H)，5.37(s，2H)；LCMS(m/z)：187(MH +)。
1-cyano group methoxyl group-2,3-dimethoxy-5-oil of mirbane
[0433] under the room temperature,, adds 7.8 gram cesium carbonates in acetone (25mL) solution of 3-dimethoxy-5-nitrophenols (1.5 gram) and dropwise add the 0.75mL bromoacetonitrile then lentamente in (±)-2.Reaction mixture is filtered, and evaporated filtrate also distributes the gained resistates between 1N HCl solution and EtOAc.Water extracts with EtOAc, and the organic layer of merging is used MgSO then with bicarbonate solution and salt water washing 4Dry.Except that desolvating, (hexane/EtOAc) purifying restrains (productive rate 78%) required product 1-cyano group methoxyl groups-2,3-dimethoxy-5-oil of mirbane to produce 1.4 to thick material by column chromatography by rotary evaporation. 1HNMR (DMSO-d 6): δ 7.78 (d, 2H, J=4.5Hz), 7.64 (d, 2H, J=4.5Hz), 5.38 (s, 2H), 3.92 (s, 3H), 3.82 (s, 3H); LCMS: purity 93%; MS (m/e): 239 (MH +).
3-cyano group methoxyl group-4, the 5-dimethoxyaniline
[0434] with 1-cyano group methoxyl group-2, ethanol (75mL) solution of 3-dimethoxy-5-oil of mirbane (1.4 gram) refluxed 4 hours with 1.65 gram iron and 1.65 gram ammonium chlorides, be cooled to room temperature (RT), dilute with DCM, filter, with the DCM extraction, the organic layer of merging restrains (82%) required product 3-cyano group methoxyl group-4 with dried over sodium sulfate and evaporation to obtain 1, the 5-dimethoxyaniline, MS (m/e): 209 (MH +).
[0435] following compound prepares according to mode similar to the above embodiments.
3-(2-fluoro-4-nitrophenyl) propionitrile
[0436] 1H?NMR(DMSO-d 6)：
Figure A20068002053302001
8.12-8.06(t，2H)，7.72-7.66(t，1H)，3.07-3.02(t，2H)，2.91-2.86(t，2H)，LCMS：196.10(MH +)。
3-(4-amino-2-fluorophenyl) propionitrile
[0437] 1H?NMR(DMSO-d 6)：
Figure A20068002053302002
8.41(s，2H)，7.13-7.07(t，1H)，6.57-6.54(d，J＝10.5Hz，2H)，2.77-2.71(m，4H)，LCMS：164.02(MH +)。
3-(2-methyl-4-nitrophenyl) propionitrile
[0438] 1H?NMR(DMSO-d 6)： 8.06(s，1H)，8.03-8.00(d，J＝8.4Hz，1H)，7.50-7.48(d，J＝8.1Hz，1H)，3.03-2.98(t，2H)，2.88-2.83(t，2H)，2.41(s，3H)，LCMS：193.12(MH+)。
3-(2-chloro-4-nitrophenyl) propionitrile
[0439]LCMS：211.11(MH+)。
3-(4-amino-2-chloro-phenyl-) propionitrile
[0440]LCMS：181.04(MH +)。
Embodiment 20
Figure A20068002053302004
2-chloro-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-the 4-PYRIMITHAMINE (54, X=H)
[0441] with 5-methyl-3-(4-amino-benzene oxygen methyl) isoxazole (4, X=H, 1.94g) 2,4-two chloro-5-fluorine pyrimidines (53) (4.0g) are dissolved in MeOH: H 2O (9: 1, v/v, 400mL).Reactant was at room temperature stirred 24 hours, and MeOH is removed in decompression, and resistates alkalizes with saturated sodium bicarbonate aqueous solution (100mL), and water (300mL) is with EA (3 * 300mL) extractions, dry (Na 2SO 4) and removal of solvent under reduced pressure.The gained resistates by purification by silica gel column chromatography with provide 1.93 the gram white solid 2-chloro-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-the 4-PYRIMITHAMINE (54, X=H). 1HNMR(DMSO-d 6)：δ9.85(s，1H)，8.24(d，1H，J＝3.6Hz)，7.54(d，2H，J＝8.7Hz)，7.02(d，2H，J＝9.0Hz)，6.31(s，1H)，5.12(s，2H)，2.40(s，3H)；LCMS(m/z)：335(MH +)。
[0442] following compound prepares according to mode similar to Example 20.
2-chloro-5-fluoro-N4-[3-methyl-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-the 4-PYRIMITHAMINE (54, X=CH 3)
[0443] 1H NMR (CDCl 3): δ 7.99 (d, 1H, J=3.0Hz), 7.42 (dd, 1H, J=2.4 and 8.7Hz), 7.30 (d, 1H, J=2.4Hz), 6.89 (d, 2H, J=8.4Hz), 6.09 (s, 1H), 5.10 (s, 2H), 2.44 (s, 3H), 2.26 (s, 3H); LCMS (m/z): 350 (MH +).
2-chloro-5-fluoro-N4-[3-fluoro-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-the 4-PYRIMITHAMINE (54, X=F)
[0444] LCMS: purity: 93%; MS (m/e): 354 (MH+).
2-chloro-5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-4-PYRIMITHAMINE (11)
[0445] 1H?NMR(DMSO-d 6)：δ9.91(s，1H)，8.26(d，1H，J＝3.5Hz)，7.56(d，2H，J＝8.8Hz)，7.05(d，2H，J＝8.8Hz)，5.46(s，2H)，2.34(s，3H)；LCMS(m/z)：336(MH +)。
2-chloro-5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) ethylidene phenyl]-the 4-PYRIMITHAMINE
[0446] 1H?NMR(DMSO-d 6)：δ9.92(s，1H)8.28-8.27(d，J＝3.0Hz，1H)，7.57-7.54(d，J＝9.0Hz，2H)，7.25-7.22(d，J＝9.0Hz，2H)3.23-3.18(m，2H)，3.07-3.02(m，2H)，2.29(s，3H)；LCMS(m/z)：334.27(M +)。
2-chloro-N4-(3-cyano group-4-aminomethyl phenyl)-5-fluoro-4-PYRIMITHAMINE
[0447]LCMS：263.23(MH +)。
2-chloro-N4-(3-chloro-4-fluorophenyl)-5-fluoro-4-PYRIMITHAMINE
[0448]LCMS：(m/z)：276.16(MH +)。
2-chloro-N4-(3-cyano group-4-fluorophenyl)-5-fluoro-4-PYRIMITHAMINE
[0449]LCMS(m/z)：267.20(MH +)。
2-chloro-5-fluoro-N4-(2 methyl indole-5-methylene)-4-PYRIMITHAMINE
[0450]LCMS(m/z)：291.32(MH +)。
Embodiment 21
Figure A20068002053302011
N4-(4-aminocarboxyl methylene radical oxygen base) phenyl-2-chloro-5-fluoro-4-PYRIMITHAMINE (55)
[0451] (5g) and 2,6-two chloro-5-fluorine pyrimidines (53) mixture (6g) stirred overnight at room temperature in methyl alcohol (10mL) and water (1mL) with 4-(aminocarboxyl methylene radical oxygen base) aniline (21).Methyl alcohol is removed in decompression then.1N HCl (80mL) acidifying of remainder water solution.White precipitate is collected by filtering, and (3 * 50mL) washings are also dry to obtain N4-(4-aminocarboxyl methylene radical oxygen base) phenyl-2-chloro-5-fluoro-4-PYRIMITHAMINE (55) for water. 1H?NMR(CDCl 3)：δ8.07(d，1H，J＝2.7Hz)，7.52(t，1H，J＝2.4Hz)，7.30(d，1H，J＝8.1Hz)，7.19(m，1H)，6.96(br?s，1H)，6.79(m，1H)，5.29(s，2H)，2.44(s，3H)；LCMS(m/z)：336(MH +)。
2-chloro-N4-(4-cyano group methylene radical oxygen base) phenyl-5-fluoro-4-PYRIMITHAMINE (56)
[0452] under the room temperature, in N4-(4-aminocarboxyl methylene radical oxygen base) phenyl-2-chloro-5-fluoro-4-PYRIMITHAMINE (55) THF (20mL) solution (2g), adds trifluoroacetic anhydride (1.9mL) and pyridine (1.65mL).With the reaction soln stirred overnight at room temperature, use ethyl acetate (100mL) dilution then.Organic layer with wet chemical (2 * 100mL), 1N HCl (100mL) and water (100mL) washs.The separating ethyl acetate layer, with anhydrous sodium sulfate drying and with solvent removed under reduced pressure to obtain 2-chloro-N4-(4-cyano group methylene radical oxygen base) phenyl-5-fluoro-4-PYRIMITHAMINE (56).
[0453] following compound is according to preparing with embodiment 21 similar modes.
[0454] 2-chloro-5-fluoro-N4-[4-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl) methoxyl group] phenyl-4-PYRIMITHAMINE
[0455] N4-[4-(1-aminocarboxyl-1-methyl) oxyethyl group] phenyl-2-chloro-5-fluoro-4-PYRIMITHAMINE
[0456] 2-chloro-N4-[4-(1-cyano group-1-methyl) oxyethyl group] phenyl-5-fluoro-4-PYRIMITHAMINE
[0457] 2-chloro-N4-[4-(cyano group ethylidene) phenyl]-5-fluoro-4-PYRIMITHAMINE
N4-[4-(1-benzyl-3-methyl-(1H)-pyrazoles-5-yl) methylene radical oxygen base phenyl]-2-chloro-5-fluoro-4-PYRIMITHAMINE
[0458] LCMS: purity: 95%; MS (m/e): 424 (MH+).
2-chloro-N4-[4-(1, the 3-dimethyl-(1H)-and pyrazoles-5-yl) methylene radical oxygen base phenyl]-5-fluoro-4-PYRIMITHAMINE
[0459] LCMS: purity: 95%; MS (m/e): 424 (MH+).
2-chloro-5-fluoro-N4-[4-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) methylene radical oxygen base phenyl]-the 4-PYRIMITHAMINE
[0460] 1H NMR (CDCl 3): δ 8.04-8.03 (d, J=3.0Hz, 1H), 7.56-7.53 (d, J=9.0Hz, 2H), 7.06-7.03 (d, J=9.0Hz, 2H), 5.24 (s, 2H) and 2.58 (s, 3H).
N4-[2-(tertiary butyl carbonyl) amino-3-Methoxy Pyridine-6-yl]-2-chloro-5-fluoro-4-PYRIMITHAMINE (65)
[0461] (1.5g, 6.72mmol), 2, (1.68g, 10mmol) at methyl alcohol: the uniform mixture in the water (each 20mL) stirred 48 hours in 60 ℃ 4-two chloro-5-fluorine pyrimidines (53) with 6-amino-2-(tertiary butyl carbonyl) amino-3-Methoxy Pyridine (35).Water (100mL) diluted reaction mixture obtains solid, by this solid of filtering separation to obtain N4-[2-(tertiary butyl carbonyl) amino-3-Methoxy Pyridine-6-yl]-2-chloro-5-fluoro-4-PYRIMITHAMINE.LCMS: purity: 89%; MS (m/z): 354 (MH +).
Embodiment 22
Figure A20068002053302021
2-chloro-5-fluoro-N4-[4-(Propargyl oxygen base) phenyl]-the 4-PYRIMITHAMINE (X=H, Y=H)
[0462] (0.750g, 5.10mmol) with 2, (1.27g, 0.760mmol) (4: 1,35mL) middle stirring at room was 18 hours at MeOH/ water for 4-two chloro-5-fluorine pyrimidines with rough 4-(Propargyl oxygen base) aniline.Reaction mixture washs with EtOAc (200mL) dilution and with 1N HCl (50mL) and salt solution (50mL).With organic layer drying (MgSO 4), filter and vacuum concentration.Resistates by column chromatography (silica gel, hexane are to EtOAc: hexane (1: 10)) purifying is to provide 2-chloro-5-fluoro-N4-[4-(the Propargyl oxygen base) phenyl of light brown solid state]-4-PYRIMITHAMINE (0.514g). 1H NMR (CDCl 3): δ 8.03 (d, J=2.7Hz, 1H), 7.53 (d, J=8.7Hz, 2H), 7.02 (d, J=8.7Hz, 2H), 6.86 (s, 1H), 4.71 (d, J=2.4Hz, 2H), 2.55 (t, J=2.4Hz, 1H); LCMS: purity: 99%; MS (m/e): 279 (MH +).
[0463] following compound according to embodiment 22 similar modes, method described here or the preparation of those of skill in the art's currently known methods.
2-chloro-5-fluoro-N4-[3-methyl-4-(Propargyl oxygen base) phenyl]-the 4-PYRIMITHAMINE (X=Me, Y=H)
[0464] 1H NMR (CDCl 3): δ 8.01 (d, J=2.7Hz, 1H), 7.50 (dd, J=2.7 and 8.7Hz, 1H), 7.50 (dd, J=2.7 and 8.7Hz, 1H), 7.28 (d, J=2.1Hz, 1H), 6.97 (d, J=8.7Hz, 1H), 6.82 (s, 1H), 4.72 (d, J=2.4Hz, 2H), 2.53 (t, J=2.4Hz, 1H), 2.28 (s, 3H); LCMS: purity: 99%; MS (m/e): 293 (MH +).
2-chloro-N4-[3-chloro-4-(Propargyl oxygen base) phenyl]-5-fluoro-4-PYRIMITHAMINE (X=Cl, Y=H)
[0465] 1H NMR (CDCl 3): δ 8.06 (d, J=2.7Hz, 1H), 7.66 (d, J=2.7Hz, 1H), 7.54 (dd, J=3.0 and 9.3Hz, 1H), 7.12 (d, J=9.3Hz, 1H), 6.86 (s, 1H), 4.79 (d, J=2.4Hz, 2H), 2.57 (t, J=2.4Hz, 1H); LCMS: purity: 98%; MS (m/e): 313 (MH +).
2-chloro-5-fluoro-N4-[3-fluoro-4-(Propargyl oxygen base) phenyl]-the 4-PYRIMITHAMINE (X=F, Y=H)
[0466] 1H NMR (CDCl 3): δ 8.07 (d, J=2.7Hz, 1H), 7.59 (dd, J=2.7 and 12.6Hz, 1H), 7.28-7.24 (m, 1H), 7.13 (t, J=8.7Hz, 1H), 6.89 (s, 1H), 4.78 (d, J=2.4Hz, 2H), 2.56 (t, J=2.4Hz, 1H); LCMS: purity: 99%; MS (m/e): 297 (MH +).
N4-[4-(fourth-2-alkynyloxy base) phenyl]-2-chloro-5-fluoro-4-PYRIMITHAMINE (X=H, Y=Me)
[0467] 1H NMR (CDCl 3): δ 8.02 (d, J=2.7Hz, 1H), 7.52 (d, J=9.0Hz, 2H), 7.00 (d, J=9.0Hz, 2H), 6.85 (s, 1H), 4.66 (q, J=2.4Hz, 2H), 1.89 (t, J=2.4Hz, 3H); LCMS: purity: 98%; MS (m/e): 293 (MH +).
2-chloro-5-fluoro-N4-[3-(Propargyl oxygen base) phenyl]-the 4-PYRIMITHAMINE
[0468] 1H NMR (CDCl 3): δ 8.08 (d, J=2.7Hz, 1H), 7.49 (t, J=2.1Hz, 1H), 7.31 (t, J=8.1Hz, 1H), 7.16 (ddd, J=0.9,2.1, and 8.1Hz, 1H), 6.94 (s, 1H), 6.80 (ddd, J=0.9,2.4, and 8.1Hz, 1H), 4.74 (d, J=2.4Hz, 2H), 2.57 (t, J=2.4Hz, 1H); LCMS: purity: 98%; MS (m/e): 279 (MH +).
2-chloro-N4-(2-cyano group cumarone-5-yl)-5-fluoro-4-PYRIMITHAMINE
[0469] 1H NMR (DMSO-d 6): δ 10.14 (s, 1H), 8.32 (d, 1H, J=3.6Hz), 8.14 (s, 1H), 8.12 (d, 1H, J=1.8Hz), 7.77 (m, 2H); LCMS: purity: 94%, MS (m/e): 290 (MH +).
2-chloro-5-fluoro-N-[4-(3-pyridylmethyl) benzo [1,4] oxazine-7-y]-4-PYRIMITHAMINE
[0470] 1H NMR (CDCl 3, 300MHz): δ 8.56 (d, 1H, J=1.8Hz), 8.52 (dd, 1H, J=1.5 and 4.6Hz), 7.95 (d, 1H, J=3.0Hz), 7.62 (m, 1H), 7.26 (m, 1H), 7.11 (d, 1H, J=2.7Hz), 6.98 (dd, 1H, J=2.4 and 8.5Hz), 6.90 (d, 1H, J=2.1Hz), 6.60 (d, 1H, J=8.7Hz), 4.29 (m, 2H), 3.36 (m, 2H); LCMS (m/z): 372 (MH +).
2-chloro-5-fluoro-N-[4-(3-pyridyl) methylene radical oxygen base phenyl]-the 4-PYRIMITHAMINE
[0471] 1H NMR (CDCl 3, 300MHz): δ 8.66 (s, 1H), 8.58 (d, 1H, J=4.8Hz), 8.00 (d, 1H, J=2.1Hz), 7.77 (d, 1H, J=8.1Hz), 7.52 (d, 2H, J=9.0Hz), 7.32 (dd, 1H, J=5.1 and 7.6Hz), 6.98 (d, 3H, J=8.4Hz), 5.08 (s, 2H); LCMS (m/z): 331 (MH +).
2-chloro-5-fluoro-N-[4-(4-pyridylmethyl) phenyl]-the 4-PYRIMITHAMINE
[0472] 1H?NMR(CDCl 3，300MHz)：δ8.49(d，2H，J＝6.0Hz)，8.04(d，1H，J＝3.0Hz)，7.58(d，2H，J＝8.4Hz)，7.19(d，2H，J＝8.1Hz)，7.09(d，3H，J＝5.4Hz)，3.96(s，2H)；LCMS(m/z)：315(MH +)。
2-chloro-5-fluoro-N-[3-(3-pyridyl) methylene radical oxygen base phenyl]-the 4-PYRIMITHAMINE
[0473]LCMS(m/z)：331(MH +)。
2-chloro-5-fluoro-N-[4-(2-methylthiazol-4-yl) methylene radical oxygen base phenyl]-the 4-PYRIMITHAMINE
[0474] 1H?NMR(CDCl 3，300MHz)：δ8.00(d，1H，J＝2.1Hz)，7.50(d，2H，J＝9.0Hz)，7.15(s，1H)，6.99(d，2H，J＝9.0Hz)，6.89(br?s，1H)，5.14(s，2H)，2.73(s，3H)；LCMS(m/z)：351(MH +)。
2-chloro-5-fluoro-N-[4-(2-pyridyl) methylene radical oxygen base phenyl]-the 4-PYRIMITHAMINE
[0475] 1H?NMR(CDCl 3，300MHz)：δ8.58(d，1H，J＝4.5Hz)，8.00(d，1H，J＝3.0Hz)，7.71(m，1H)，7.49(m，3H)，7.22(m，1H)，6.99(d，2H，J＝9.0Hz)，6.96(br?s，1H)，5.19(s，2H)；LCMS(m/z)：331(MH +)。
2-chloro-5-fluoro-N-[4-(4-pyridyl) methylene radical oxygen base phenyl]-the 4-PYRIMITHAMINE
[0476] 1H?NMR(CDCl 3，300MHz)：δ8.60(d，2H，J＝6.0Hz)，8.01(d，1H，J＝2.7Hz)，7.52(d，2H，J＝9.0Hz)，7.35(m，2H)，6.96(d，2H，J＝9.0Hz)，6.92(br?s，1H)，5.10(s，2H)；LCMS(m/z)：331(MH +)。
2-chloro-5-fluoro-N-[4-(1-imidazolyl methyl) phenyl]-the 4-PYRIMITHAMINE
[0477] 1H?NMR(DMSO-d 6，300MHz)：δ9.99(s，1H)，8.29(d，1H，J＝3.6Hz)，7.72(s，1H)，7.62(d，2H，J＝8.4Hz)，7.25(d，2H，J＝8.1Hz)，7.17(s，1H)，6.88(s，1H)，5.15(s，2H)；LCMS(m/z)：304(MH +)。
2-chloro-5-fluoro-N-[4-(4-pyridyl oxygen base) phenyl]-the 4-PYRIMITHAMINE
[0478] the method preparation of describing according to embodiment 20. 1H?NMR(DMSO-d 6，300MHz)：δ7.89(d，2H，J＝7.5Hz)，7.55(s，1H)，7.41(d，2H，J＝7.8Hz)，7.27(d，2H，J＝6.9Hz)，6.16(d，2H，J＝6.3Hz)，4.09(s，1H)；LCMS(m/z)：317(MH +)。
2-chloro-5-fluoro-N-[4-(4-thio-morpholinyl) carbonyl phenyl]-the 4-PYRIMITHAMINE
[0479] 1H?NMR(DMSO-d 6，300MHz)：δ10.11(s，1H)，8.35(d，1H，J＝3.3Hz)，7.77(d，2H，J＝8.7Hz)，7.40(d，2H，J＝8.7Hz)，3.71(br?s，4H)，2.64(br?s，4H)；LCMS(m/z)：353(MH +)。
2-chloro-5-fluoro-N-[4-(1-methylsulfonyl-4-piperazinyl) carbonyl phenyl]-the 4-PYRIMITHAMINE
[0480] 1H?NMR(DMSO-d 6，300MHz)：δ10.14(s，1H)，8.35(d，1H，J＝2.7Hz)，7.79(d，2H，J＝8.1Hz)，7.45(d，2H，J＝7.8Hz)，3.59(br?s，4H)，3.16(br?s，4H)，2.89(s，3H)；LCMS(m/z)：414(MH +)。
2-chloro-5-fluoro-N-[4-(1-ethanoyl-4-piperazinyl) carbonyl phenyl]-the 4-PYRIMITHAMINE
[0481] 1H?NMR(DMSO-d 6，300MHz)：δ10.12(s，1H)，8.35(d，1H，J＝3.3Hz)，7.78(d，2H，J＝8.4Hz)，7.44(d，2H，J＝8.7Hz)，3.47(br?s，8H)，2.01(s，3H)；LCMS(m/z)：378(MH +)。
2-chloro-5-fluoro-N-[4-(1,1-dioxo-4-thio-morpholinyl) carbonyl phenyl]-the 4-PYRIMITHAMINE
[0482] 1H?NMR(DMSO-d 6，300MHz)：δ10.14(s，1H)，8.35(d，1H，J＝3.3Hz)，7.79(d，2H，J＝8.4Hz)，7.51(d，2H，J＝7.5Hz)，3.86(br?s，4H)，3.25(br?s，4H)；LCMS(m/z)：385(MH +)。
2-chloro-5-fluoro-N-[4-(2-pyridyl)-3-methyl methylene radical oxygen base phenyl]-the 4-PYRIMITHAMINE
[0483] 1H?NMR(DMSO-d 6，300MHz)：δ9.80(s，1H)，8.65(d，1H，J＝5.1Hz)，8.23(d，1H，J＝4.5Hz)，8.04(t，1H，J＝7.8Hz)，7.69(d，1H，J＝7.8Hz)，7.51(t，1H，J＝6.3Hz)，7.42(d，2H，J＝9.0Hz)，7.00(d，1H，J＝8.4Hz)，5.27(s，2H)，2.24(s，3H)；LCMS(m/z)：345(MH +)。
2-chloro-N4-[3-chloro-4-(2-cyano ethyl) phenyl]-5-fluoro-4-PYRIMITHAMINE
[0484]LCMS：311.35(MH +)。
2-chloro-5-fluoro-N4-(quinoline-8-yl)-4-PYRIMITHAMINE
[0485]LCMS：275.22(MH +)。
2-chloro-5-fluoro-N4-(quinoline-2-yl)-4-PYRIMITHAMINE
[0486]LCMS：275.36(MH +)。
2-chloro-5-fluoro-N4-(quinoline-6-yl)-4-PYRIMITHAMINE
[0487]LCMS：275.28(MH +)。
2-chloro-5-fluoro-N4-(quinoline-3-yl)-4-PYRIMITHAMINE
[0488]LCMS：275.25(MH +)。
2-chloro-5-fluoro-N4-(2-toluquinoline-6-yl)-4-PYRIMITHAMINE
[0489]LCMS：289.38(MH +)。
N4-(thionaphthene-5-yl)-2-chloro-5-fluoro-4-PYRIMITHAMINE
[0490]LCMS：280.26(MH +)。
2-chloro-5-fluoro-N4-(2-toluquinoline-8-yl)-4-PYRIMITHAMINE
[0491]LCMS：289.43(MH +)。
2-chloro-N4-[4-(2-cyano ethyl) phenyl]-5-methyl-4-PYRIMITHAMINE
[0492]LCMS：275.28(MH +)。
N4-[(2S, 4R)-1-tert-butoxycarbonyl-2-methoxycarbonyl-tetramethyleneimine-4-yl]-2-chloro-5-fluoro-4-PYRIMITHAMINE
[0493]LCMS：375.01(MH +)。
N4-[(2S, 4S)-1-tert-butoxycarbonyl-2-methyl carboxylic acids ester group (methylcarboxylate)-tetramethyleneimine]-2-chloro-5-fluoro-4-PYRIMITHAMINE
[0494]LCMS：375.02(MH +)。
2-chloro-5-fluoro-N4-[(2S, 4R)-2-methoxycarbonyl tetramethyleneimine-4-yl]-the 4-PYRIMITHAMINE
[0495]LCMS：275.36(MH +)。
2-chloro-5-fluoro-N4-[(2S, 4S)-2-methoxycarbonyl tetramethyleneimine-4-yl]-the 4-PYRIMITHAMINE
[0496]LCMS：275.39(MH +)。
2-chloro-N4-[(2S, 4R)-1-(2-cyano group ethanoyl)-2-methoxycarbonyl tetramethyleneimine-4-yl]-5-fluoro-4-PYRIMITHAMINE
[0497] 1H?NMR(DMSO-d 6)：
Figure A20068002053302061
8.38-8.36(d，J＝7.2Hz，1H)，8.13-8.11(d，J＝3.3Hz，1H)，4.61-4.59(m，1H)，4.52-4.47(m，1H)，4.06-4.04(d，J＝7.2Hz，1H)，3.85-3.80(m，1H)，3.64(s，3H)，3.51-3.46(m，1H)，2.43-2.34(m，1H)，2.20-2.13(m，1H)，LCMS：342.01(MH +)。
2-chloro-N4-[(2S, 4S)-1-(2-cyano group ethanoyl)-2-methoxycarbonyl tetramethyleneimine-4-yl]-5-fluoro-4-PYRIMITHAMINE
[0498] 1H?NMR(DMSO-d 6)：
Figure A20068002053302062
8.20-8.18(d，J＝6.9Hz，1H)，8.13(bs，1H)，4.66-4.61(m，1H)，4.37-4.33(m，1H)，4.06-4.04(bs，2H)，3.90-3.84(m，1H)，3.63(s，3H)，3.47-3.37(m，1H)，2.56-2.54(m，1H)，2.07-1.98(m，1H)，LCMS：341.99(MH +)。
2-chloro-N4-[4-(2-cyano ethyl)-3-aminomethyl phenyl]-5-fluoro-4-PYRIMITHAMINE
[0499]LCMS：291.05(MH +)。
2-chloro-N4-[4-(2-cyano ethyl)-3-aminomethyl phenyl]-5-fluoro-4-PYRIMITHAMINE
[0500]LCMS：291.05(MH +)。
Embodiment 23
2-chloro-N4-(3-cyano group methylene radical oxygen base-4,5-Dimethoxyphenyl)-5-fluoro-4-PYRIMITHAMINE
[0501] will be with the 3-cyano group methoxyl group-4 of 4: 1 EtOH/THF of 70mL preparation, 5-dimethoxyaniline (1.5g), 2, the suspension stirred overnight at room temperature of 4-two chloro-5-fluorine pyrimidines and sodium bicarbonate (1.3g) is with 1N HCl solution dilution.Precipitation is collected by suction filtration, and drying is ground with ether, collects also dry to produce 1.3 gram (80%) required product 2-chloro-N4-(3-cyano group methoxyl group-4,5-Dimethoxyphenyl)-5-fluoro-4-PYRIMITHAMINE again by suction filtration. 1H NMR (DMSO-d 6): δ 8.18 (d, 1H, J=2.1Hz), 7.28 (d, 1H, J=4.3Hz), 7.18 (d, 1H, J=4.3Hz), 5.09 (s, 2H), 3.77 (s, 3H), 3.64 (s, 3H); LCMS: purity 97%; MS (m/e): 339 (MH +).
Embodiment 24
2-chloro-5-methyl-N4-oxo-benzo [1,4] oxazine-6-yl)-the 4-PYRIMITHAMINE
[0502] with 250 milligrams of 6-amino-3-oxo-4H-benzo [1,4] oxazine and 460 milligram 2, the mixture stirred overnight at room temperature of 4-two chloro-5-methylpyrimidines in 15mL methyl alcohol reduces volume by rotary evaporation.Filtering solution, filtrate water dilute and neutralize with sodium bicarbonate.Precipitation is collected by suction filtration, wash with water and on funnel dry with produce 75 milligrams of (20%) required product 2-chloro-5-methyl-N4-oxo-benzos [1,4] oxazine-6-yl)-the 4-PYRIMITHAMINE. 1H NMR (DMSO-d 6): δ 7.98 (s, 1H), 7.08 (m, 2H), 6.91 (d, 1H J=6Hz), 4.54 (s, 2H), 2.11 (s, 3H) purity 97%; MS (m/e) 291 (MH +).
Embodiment 25
2-chloro-5-methyl-N4-(4-methyl-3-oxo-benzo [1,4] thiazine-6-yl)-4-PYRIMITHAMINE
[0503] with 1.3 gram 6-amino-4-methyl-3-oxo-benzo [1,4] thiazine and 3.3 grams 2, the mixture stirring at room RT of 4-two chloro-5-methylpyrimidines in 100mL methyl alcohol spends the night, and reduces volume by rotary evaporation.Filtering solution, filtrate water dilute and neutralize with sodium bicarbonate.Precipitation is collected by suction filtration, washes with water and dry to produce 660 milligrams of (13%) required product 2-chloro-5-methyl-N4-(4-methyl-3-oxo-benzo [1,4] thiazine-6-yl)-4-PYRIMITHAMINE on funnel. 1H NMR (DMSO-d 6): δ 8.93 (s, 1H), 8.06 (m, 2H), 7.62 (s, 1H), 7.37 (s, 1H), 3.51 (s, 2H), 2.16 (s, 3H) purity 97%; MS (m/e) 321 (MH +).
[0504] following compound according to the similar mode of embodiment 20-25, method described here or the preparation of those of skill in the art's currently known methods.
2-chloro-N4-(4-cyano group ethylidene-2-aminomethyl phenyl)-5-fluoro-4-PYRIMITHAMINE
[0505] 1H?NMR(DMSO-d 6)：δ9.711(s，1H)，8.235-8.219(d，J＝4.8Hz，1H)，7.251-7.226(d，J＝7.5Hz，1H)，7.162-7.122(m，2H)，2.852-2.790(m，4H)，2.130(s，3H)，LCMS：291.36(MH+)。
2-chloro-N4-(4-cyano group ethylidene-3-p-methoxy-phenyl)-5-fluoro-4-PYRIMITHAMINE
[0506] 1H?NMR(DMSO-d 6)：δ9.959(s，1H)，8.305-8.293(d，J＝3.6Hz，1H)，7.410(s，1H)，7.285-7.262(d，J＝6.9Hz，1H)，7.192-7.164(d，J＝8.4Hz，1H)，3.784(s，3H)，2.808-2.726(m，4H)，LCMS：307.04(MH+)。
2-chloro-5-fluoro-N4-(5-methoxycarbonyl-thiophene-2-yl)-4-PYRIMITHAMINE
[0507] 1H?NMR(DMSO-d 6)：δ11.809(s，1H)，8.442-8.432(d，J＝3.0Hz，1H)，7.665-7.649(d，J＝4.8Hz，1H)，7.017-7.001(d，J＝4.8Hz，1H)，3.793(s，3H)，LCMS：288.25(MH+)。
2-chloro-5-fluoro-N4-(2-hydroxy-4-methyl quinoline-6-yl)-4-PYRIMITHAMINE
[0508] 1H?NMR(DMSO-d 6)：δ11.599(s，1H)，10.077(s，1H)，8.291-8.280(d，J＝3.3Hz，1H)，8.064(s，1H)，7.766-7.736(d，J＝9Hz，1H)，7.295-7.266(d，J＝8.7Hz，1H)，6.410(s，1H)，2.389(s，3H)。
2-chloro-N4-(4-cyano group ethylidene-3-trifluoromethyl)-5-fluoro-4-PYRIMITHAMINE
[0509] 1H?NMR(DMSO-d 6)：δ10.223(s，1H)，8.372-8.360(d，J＝3.6Hz，1H)，8.138(s，1H)，8.004-7.975(d，J＝8.7Hz，1H)，7.599-7.571(d，J＝8.4Hz，1H)，3.047-2.999(t，2H)，2.885-2.837(t，2H)，LCMS：344.93(MH+)。
N4-[4-(2-carboxyl ethylidene) phenyl]-2-chloro-5-fluoro-4-PYRIMITHAMINE
[0510] 1H?NMR(DMSO-d 6)：δ12.075(s，1H)，9.908(s，1H)，8.271-8.260(d，J＝3.3Hz，1H)，7.548-7.520(d，J＝8.4Hz，2H)，7.221-7.193(d，J＝8.4Hz，2H)，2.818-2.767(t，2H)，2.549-2.497(t，2H)。
N4-[4-(the amino carboxyl ethylidene of 2-) phenyl]-2-chloro-5-fluoro-4-PYRIMITHAMINE
[0511] 1H?NMR(DMSO-d 6)：δ8.269-8.257(d，J＝3.6Hz，1H)，7.540-7.512(d，J＝8.4Hz，2H)，7.266(s，1H)，7.197-7.169(d，J＝8.4Hz，2H)，6.740(s，1H)，2.796-2.745(t，2H)，2.365-2.313(t，2H)，LCMS：295.30(MH+)。
2-chloro-N4-[3, the 4-dihydro-(1H)-quinoline-2-one--6-yl]-5-fluoro-4-PYRIMITHAMINE
[0512] 1H?NMR(DMSO-d 6)：δ9.963(s，1H)，7.919(s，1H)，7.260-7.215(m，2H)，6.766-6.739(d，J＝8.1Hz，1H)，2.845-2.796(t，2H)，2.442-2.392(t，2H)，LCMS：293.01(MH+)。
2-chloro-N4-(2-N, N '-dimethylamino yl-quinoline-6-yl)-5-fluoro-4-PYRIMITHAMINE
[0513] 1H?NMR(DMSO-d 6)：δ10.015(s，1H)，8.273-8.261(d，J＝3.6Hz，1H)，7.955-7.925(m，2H)，7.705(s，1H)，7.532-7.502(d，J＝9Hz，1H)，7.077-7.047(d，J＝9.0Hz，1H)，3.138(s，6H)。
N4-[(4R)-1-tert-butoxycarbonyl-tetramethyleneimine-4-yl]-2-chloro-5-fluoro-4-PYRIMITHAMINE
[0514] 1H?NMR(DMSO-d 6)：δ8.330-8.309(d，J＝6.3Hz，1H)，8.093-8.081(d，J＝3.6Hz，1H)，4.462-4.444(m，1H)，3.587-3.528(m，1H)，3.436-3.378(m，1H)，3.208-3.154(m，1H)，2.138-2.095(m，1H)，1.958-1.914(m，1H)，1.395(s，9H)。
2-chloro-N4-[(4R)-1-(2-cyano group ethanoyl)-tetramethyleneimine-4-yl]-5-fluoro-4-PYRIMITHAMINE
[0515] 1H?NMR(DMSO-d 6)：δ8.320(s，1H)，8.113-8.092(d，J＝6.3Hz，1H)，4.543-4.001(m，1H)，3.908(s，2H)，3.718-3.543(m，1H)，3.520-3.299(m，3H)，2.208-1.979(m，2H)，LCMS：284.29(MH+)。
N4-(2-cyano group ethylidene-thionaphthene-5-yl)-2-chloro-5-fluoro-4-PYRIMITHAMINE
[0516] 1H?NMR(DMSO-d 6)：δ11.104(s，1H)，8.326-8.308(d，J＝5.4Hz，1H)，7.963-7.934(d，J＝8.7Hz，1H)，7.813(s，1H)，7.391-7.355(d，J＝9Hz，1H)，7.313(s，1H)，3.248-3.202(t，2H)，2.969-2.922(t，2H)。
[0517]
Embodiment 26
Figure A20068002053302081
I-230:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine (59, X=H)
[0518] make 2-chloro-5-fluoro-N-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-4-PYRIMITHAMINE (54, X=H) (100mg, 0.298mmol), the 3-aminobenzene sulfonamide (51.2mg, 0.298mmol) and the mixture of MeOH (2mL) solution of trifluoroacetic acid (TFA) (2) the sealing reaction tube in 100 ℃ the reaction 24 hours.[silicagel column is used CH to product by column chromatography 2Cl 2: 2M NH 3MeOH solution (1-3%) wash-out] purifying to be to provide N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine (59, X=H).This reaction also can well be carried out when not having trifluoroacetic acid. 1H?NMR(DMSO-d 6)：δ9.46(s，1H)，9.28(s，1H)，8.06(d，2H，J＝1.2Hz)，7.93(m，1H)，7.69(d，2H，J＝9.3Hz)，7.33(m，2H)，7.26(s，2H)，6.98(d，2H，J＝9.0Hz)，6.32(s，1H)，5.13(s，2H)，2.40(s，3H)；LCMS(m/z)：471(MH +)。
[0519] following compound is according to preparing with embodiment 26 similar modes.
I-219:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0520] 1H NMR (CD 3OD): δ 8.08 (d, J=2.7Hz, 1H), 7.87 (d, J=3.6Hz, 1H), 7.72 (dd, J=2.4 and 8.4Hz, 1H), 7.57 (d, J=8.7Hz, 2H), 7.16 (d, J=8.1Hz, 1H), 6.99 (d, J=8.7Hz, 2H), 6.25 (s, 1H), 5.13 (s, 2H), 2.60 (s, 3H), 2.44 (s, 3H); LCMS: purity: 94%; MS (m/z): 485 (MH +).
I-220:N2-(3-amino-sulfonyl-4-chloro-phenyl-)-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0521] 1H NMR (DMSO-d 6): δ 9.59 (s, 1H), 9.31 (s, 1H), 8.27 (d, J=1.8Hz, 1H), 8.08 (d, J=3.6Hz, 1H), 8.04-7.98 (m, 1H), 7.68 (d, J=9.0Hz, 2H), 7.46 (s, 2H), 7.40 (d, J=8.7Hz, 1H), 6.99 (d, J=9.0Hz, 2H), 6.33 (s, 1H), 5.13 (s, 2H), 2.41 (s, 3H); LCMS: purity: 89%; MS (m/z): 506 (MH +).
I-221:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[3-chloro-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-5-fluoro-2, the 4-pyrimidinediamine
[0522] 1H NMR (DMSO-d 6): δ 9.44 (s, 1H), 9.36 (s, 1H), 8.08 (d, J=3.6Hz, 1H), 8.06-8.02 (m, 1H), 7.91-7.85 (m, 1H), 7.84 (d, J=1.8Hz, 1H), 7.74 (dd, J=2.7 and 9.0Hz, 1H), 7.26-7.13 (m, 4H), 6.33 (s, 1H), 5.22 (s, 2H), 2.59 (s, 3H), 2.41 (s, 3H); LCMS: purity: 99%; MS (m/z): 520 (MH +).
I-222:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-fluoro-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0523] 1H NMR (DMSO-d 6): δ 9.46 (s, 1H), 9.39 (s, 1H), 8.13-8.06 (m, 2H), 7.93-7.84 (m, 2H), 7.52 (d, J=9.3Hz, 1H), 7.28-7.22 (m, 2H), 7.18 (d, J=8.4Hz, 1H), 6.34 (s, 1H), 5.20 (s, 2H), 2.50 (s, 3H), 2.41 (s, 3H); LCMS: purity: 95%; MS (m/z): 503 (MH +).
I-233:N2-(3-amino-sulfonyl-4-fluorophenyl)-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0524] 1H?NMR(DMSO-d 6)：δ9.42(s，1H)，9.27(s，1H)，8.05(d，2H，J＝3.3Hz)，7.95(m，1H)，7.66(d，2H，J＝9.0Hz)，7.54(s，2H)，7.21(t，1H，J＝9.3Hz)，6.98(d，2H，J＝8.7Hz)，6.32(s，1H)，5.12(s，2H)，2.40(s，3H)；LCMS(m/z)：489(MH +)。
I-234:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-methyl-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0525] 1H?NMR(DMSO-d 6)：δ9.33(s，1H)，9.15(s，1H)，8.05(s，1H)，8.02(d，1H，J＝3.3Hz)，7.90(d，1H，J＝8.7Hz)，7.52(m，2H)，7.22(s，2H)，7.12(d，1H，J＝8.4Hz)，6.98(d，1H，J＝8.7Hz)，6.33(s，1H)，5.13(s，2H)，2.49(s，3H)，2.41(s，3H)，2.16(s，3H)；LCMS(m/z)：499(MH +)。
I-235:5-fluoro-N2-[3-(N-methyl) amino-sulfonyl-4-aminomethyl phenyl]-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0526] 1H?NMR(DMSO?d 6)：δ9.42(s，1H)，9.31(s，1H)，8.11(d，1H，J＝3.0Hz)，8.06(s，1H)，7.99(d，1H，J＝8.4Hz)，7.75(d，2H，J＝8.4Hz)，7.38(q，1H，J＝4.8Hz)，7.24(d，1H，J＝8.4Hz)，7.04(d，2H，J＝8.7Hz)，6.38(s，1H)，5.18(s，2H)，2.55(d，3H，J＝1.8Hz)，2.52(s，3H)，2.46(s，3H)；LCMS(m/z)：499(MH +)。
I-237:N2-(3-amino-sulfonyl-4-fluorophenyl)-5-fluoro-N4-[3 methyl-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine:
[0527] 1H?NMR(DMSO-d 6)：δ9.41(s，1H)，9.19(s，1H)，8.01(m，3H)，7.46(m，3H)，7.18(t，1H，J＝9.6Hz)，7.00(d，2H，J＝9.0Hz)，6.34(s，1H)，5.14(s，2H)，2.41(s，3H)，2.17(s，3H)；LCMS(m/z)：503(MH +)。
I-223:N2-(3-amino-sulfonyl-5-chloro-4-aminomethyl phenyl)-5-fluoro-N4-[3-fluoro-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0528] 1H NMR (DMSO-d 6): δ 9.71 (s, 1H), 9.50 (s, 1H), 8.25 (d, J=2.4Hz, 1H), 8.14 (d, J=3.9Hz, 1H), 8.04 (d, J=2.4Hz, 1H), 7.79 (dd, J=2.7 and 13.5Hz, 1H), and 7.53-7.40 (m, 3H), 7.20 (t, J=9.3Hz, 1H), 6.32 (s, 1H), 5.18 (s, 2H), 3.51 (s, 3H), 2.41 (s, 3H); LCMS: purity: 93%; MS (m/z): 538 (MH +).
I-224:N2-(3-amino-sulfonyl-4-fluoro-5-aminomethyl phenyl)-5-fluoro-N4-[3-fluoro-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0529] 1H NMR (DMSO-d 6): δ 9.57 (s, 1H), 8.12 (d, J=4.2Hz, 1H), 7.88-7.82 (m, 1H), 7.81-7.73 (m, 2H), 7.49-7.42 (m, 1H), 7.20 (t, J=9.0Hz, 1H), 6.32 (s, 1H), 5.18 (s, 2H), 2.41 (s, 3H), 2.19 (s, 3H); LCMS: purity: 94%; MS (m/z): 521 (MH +).
I-238:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[3-methyl-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0530] 1H?NMR(DMSO-d 6)：δ9.45(s，1H)，9.19(s，1H)，8.05(d，1H，J＝3.6Hz)，8.02-7.96(m，2H)，7.51(m，2H)，7.31(d，2H，J＝4.8Hz)，7.24(s，2H)，6.99(d，1H，J＝8.4Hz)，6.33(s，1H)，5.13(s，2H)，2.41(s，3H)，2.17(s，3H)；LCMS(m/z)：485(MH +)。
I-216:N2-(3-amino-sulfonyl-5-chloro-4-aminomethyl phenyl)-5-fluoro-N4-[3-methyl-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0531] LCMS: purity: 96%, MS (m/e): 520 (MH+).
I-217:N2-(3-amino-sulfonyl-4-fluoro-5-aminomethyl phenyl)-5-fluoro-N4-[3-methyl-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0532] LCMS: purity: 99%, MS (m/e): 504 (MH+).
V-1:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[2-(5-methyl-isoxazole-3-yl) methylene radical oxygen yl pyridines-5-yl]-2, the 4-pyrimidinediamine
[0533] 1H NMR (DMSO-d 6): δ 9.33 (s, 1H), 9.21 (s, 1H), 8.14 (d, J=2.4Hz, 1H), 8.05 (s, J=2.4Hz, 2H), 7.81 (dd, J=2.4 and 8.7Hz, 1H), 7.71 (dd, J=2.7 and 9.6Hz, 1H), 7.24 (s, 2H), 7.12 (d, J=8.4Hz, 1H), 6.46 (d, J=9.6Hz, 1H), 6.11 (s, 1H), 5.13 (s, 2H), 2.48 (s, 3H), 2.34 (s, 3H); LCMS: purity: 87%; MS (m/z): 486 (MH +).
I-240:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[3 methyl-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0534] 1H?NMR(DMSO?d 6，300MHz)：δ9.56(s，1H)，9.27(s，1H)，8.09(d，1H，J＝3.6Hz)，7.78(d，2H，J＝8.7Hz)，7.59(d，2H，J＝8.4Hz)，7.51(s，1H)，7.43(d，1H，J＝8.7Hz)，7.12(s，2H)，7.02(d，1H，J＝8.4Hz)，6.35(s，1H)，5.14(s，2H)，2.41(s，3H)，2.19(s，3H)；LCMS(m/z)：485(MH +)。
I-214:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[3-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0535] 1H NMR (DMSO-d 6): δ 9.45 (s, 1H), 9.37 (s, 1H), 8.14-8.05 (m, 2H), 7.93 (d, J=9.0Hz, 1H), 7.53-7.49 (m, 1H), 7.46 (d, J=9.0Hz, 1H), 7.27-7.20 (m, 3H), 7.16 (d, J=8.1Hz, 1H), 6.73 (d, J=9.3Hz, 1H), 6.31 (s, 1H), 5.12 (s, 2H), 2.49 (s, 3H), 2.40 (s, 3H); LCMS: purity: 96%; MS (m/z): 485 (MH +).
I-206:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-morpholino ethyl oxygen base) phenyl-2, the 4-pyrimidinediamine
[0536] LCMS: purity: 93%; MS (m/z): 489 (MH +).
I-207:5-fluoro-N2-(3-morpholino alkylsulfonyl phenyl)-N4-[4-(2-morpholino ethyl oxygen base) phenyl]-2, the 4-pyrimidinediamine
[0537] 1H NMR (DMSO-d 6): δ 9.56 (s, 1H), 9.32 (s, 1H), 8.10 (d, 1H, J=3.9Hz), 7.80 (d, 2H, J=8.1Hz), (7.60 3H, dd, J=2.4Hz and 2.1Hz), 7.12 (s, 2H), 6.96 (d, 2H, J=8.7Hz), 3.58 (m, 3H), 3.32 (m, 8H), 3.30 (m, 8H), 2.70 (t, 2H, J=5.7Hz); LCMS: purity: 93%; MS (m/z): 559 (MH +).
I-208:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-methyl-3-(2-morpholino carbonyl methylene radical oxygen base) phenyl]-2, the 4-pyrimidinediamine
[0538] 1H NMR (DMSO-d 6): δ 9.68 (s, 1H), 9.53 (s, 1H), 8.15 (d, 1H, J=3.9Hz), 8.10 (s, 1H), 7.92 (m, 1H), 7.46 (s, 1H), 7.40 (m, 2H), 7.23 (m, 2H), 7.10 (d, 1H, J=8.4Hz), 4.82 (s, 2H), 3.75 (bs, 4H), 3.50 (bs, 4H), 2.16 (s, 3H); LCMS: purity: 90%; MS (m/z): 503 (MH +).
I-209:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-methyl-3-(2-morpholino carbonyl methylene radical oxygen base) phenyl]-2, the 4-pyrimidinediamine
[0539] 1H NMR (DMSO-d 6): δ 9.85 (s, 1H), 9.64 (s, 1H), 8.18 (d, 1H, J=3.6Hz), 7.80 (d, 2H, J=8.4Hz), 7.65 (d, 2H, J=8.7Hz), 7.38 (s, 1H), 7.16 (m, 2H), 4.80 (s, 2H), 3.51 (s, 4H), 3.43 (s, 4H), 2.18 (s.3H); LCMS: purity: 88%; MS (m/z): 517 (MH +).
I-203:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-methyl-3-(2-morpholino ethyl oxygen base) phenyl]-2, the 4-pyrimidinediamine
[0540] 1H NMR (DMSO-d 6): δ 9.48 (s, 1H), 9.26 (s, 1H), 8.10 (d, 1H, J=3.9Hz), 7.97 (d, 1H, J=6.9Hz), 7.36 (m, 3H), 7.25 (s, 2H), 7.09 (s, 1H), 4.03 (m, 2H), 3.55 (bs, 4H), 3.31 (bs, 4H), 2.71 (m, 2H), 2.13 (s, 3H); LCMS: purity: 87%; MS (m/z): 503 (MH +).
VII-51:N2-(3-amino-sulfonyl phenyl)-N4-[2,2-dimethyl-3-oxo-4H-5-pyrido [1,4] oxazine-7-yl]-5-fluoro-2,4-pyrimidinediamine
[0541] 1H NMR (DMSO-d 6): δ 11.11 (s, 1H), 9.63 (s, 1H), 9.48 (s, 1H), 8.42 (t, 1H, J=2.1Hz), 8.13 (t, 2H, J=3.3Hz), 7.95 (d, 1H, J=7.8Hz), 7.87 (d, 1H, J=2.1Hz), 7.41 (m, 2H), 7.25 (s, 1H), 1.45 (s, 6H); LCMS: purity: 92%; MS (m/z): 460 (MH +).
VII-52:N2-(4-amino-sulfonyl phenyl)-N4-[2,2-dimethyl-3-oxo-4H-5-pyrido [1,4] oxazine-7-yl]-5-fluoro-2,4-pyrimidinediamine
[0542] 1H NMR (DMSO-d 6): δ 11.14 (s, 1H), 9.70 (s, 1H), 9.53 (s, 1H), 8.16 (s, 1H), 7.81 (d, 2H, J=8.4Hz), 7.66 (d, 2H, J=8.4Hz), 7.11 (s, 2H), 1.45 (s, 6H); LCMS: purity: 95%; MS (m/z): 460 (MH +).
VII-42:N2-(3-amino-sulfonyl phenyl)-N4-[2,2,4-trimethylammonium-3-oxo-5-pyrido [1,4] oxazine-7-yl]-5-fluoro-2,4-pyrimidinediamine
[0543] 1H NMR (DMSO-d 6): δ 9.64 (s, 1H), 8.62 (s, 1H), 8.15 (d, 2H, J=3.9Hz), 7.93 (t, 2H, J=7.2Hz), 7.37 (m, 3H), 2.43 (s, 3H), 1.45 (s, 6H); LCMS: purity: 94%; MS (m/z): 474 (MH +).
VII-43:N2-(4-amino-sulfonyl phenyl)-N4-[2,2,4-trimethylammonium-3-oxo-5-pyrido [1,4] oxazine-5-yl]-5-fluoro-2,4-pyrimidinediamine
[0544] 1H NMR (DMSO-d 6): δ 11.14 (s, 1H), 9.70 (s, 1H), 9.53 (s, 1H), 8.16 (s, 1H), 7.81 (d, 2H, J=8.4Hz), 7.66 (d, 2H, J=8.4Hz), 7.11 (s, 2H), 2.43 (s, 3H), 1.45 (s, 6H); LCMS: purity: 90%; MS (m/z): 474 (MH +).
I-204:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-methyl-3-(2-morpholino ethyl oxygen base) phenyl] 2, the 4-pyrimidinediamine
[0545] 1H?NMR(DMSO-d 6)：δ9.38(s，1H)，9.22(s，1H)，8.09(d，1H，J＝1.5Hz)，7.92(d，1H，J＝2.4Hz)，7.40(d，2H，J＝8.1Hz)，7.26(s，2H)，7.15(s，1H)，4.10(t，2H，J＝5.7Hz)，3.54(bs，4H)，2.69(bs，2H)，2.49(s，6H)，2.12(s，4H)。
VI-111:N2-(3-amino-sulfonyl-4-chloro-phenyl-)-5-fluoro-N4-[4-(2-methoxyl group ethyleneoxy group) phenyl]-2, the 4-pyrimidinediamine
[0546] LCMS: purity: 94%; MS (m/z): 468 (MH +).
V-14:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[2,2-dimethyl-3-oxo-4-cyano methyl-5-pyrido [1,4] oxazine-7-yl]-5-fluoro-2,4-pyrimidinediamine
[0547] 1H NMR (DMSO-d 6): δ 8.65 (s, 1H), 8.15 (d, 1H, J=3.6Hz), 8.09 (s, 1H), 8.01 (s, 1H), 7.91 (m, 2H), 5.10 (s, 2H), 2.07 (s, 3H), 1.50 (s, 6H); LCMS: purity: 96%; MS (m/z): 513 (MH +).
V-15:N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-[2,2-dimethyl-3-oxo-4-cyano methyl-5-pyrido [1,4] oxazine-7-yl]-5-fluoro-2,4-pyrimidinediamine
[0548] 1H NMR (DMSO-d 6): δ 8.66 (d, 1H, J=2.4Hz), 8.27 (d, 1H, J=3.6Hz), 8.19 (d, 1H, J=3.6Hz), 8.10 (m, 1H), 7.48 (d, 2H, J=1.8Hz), 5.10 (s, 2H), 1.52 (s, 6H); LCMS: purity: 96%; MS (m/z): 533 (MH +).
VI-112:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(2-methoxyl group ethyleneoxy group) phenyl]-2, the 4-pyrimidinediamine
[0549] LCMS: purity: 91%; MS (m/z): 448 (MH +).
I-205:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-morpholino ethyl oxygen base) phenyl)-2, the 4-pyrimidinediamine
[0550] LCMS: purity: 87%; MS (m/z): 489 (MH +).
VII-26: racemize N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[2-(N, N-dimethylamino carbonyl)-2,3-Dihydrobenzofuranes-5-yl]-5-fluoro-2, the 4-pyrimidinediamine:
[0551] 1H NMR (DMSO-d 6): δ 8.17 (d, 1H, J=4.8Hz), 7.86 (s, 1H), 7.82 (d, 1H, J=2.1Hz), 7.50 (s, 1H), 7.27 (t, 2H, J=8.4Hz), 6.79 (d, 1H, J=8.4Hz), 5.67 (t, 2H, J=8.1Hz), 2.88 (s, 6H), 2.49 (s, 3H); LCMS: purity: 90%; MS (m/z): 487 (MH +).
VII-27: racemize N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-[2-(N, N-dimethylamino carbonyl)-2,3-Dihydrobenzofuranes-5-yl]-5-fluoro-2, the 4-pyrimidinediamine
[0552] 1H NMR (DMSO-d 6): δ 7.95 (dd, 2H, J=2.7Hz and 2.4Hz), 7.30 (dd, 3H, J=2.4Hz and 2.4Hz), 6.80 (d, 2H, J=8.7Hz), 5.67 (t, 2H, J=7.5Hz), 2.88 (s, 6H); LCMS: purity: 90%; MS (m/z): 507 (MH +).
IX-9:N4-[3-(aminocarboxyl)-1H-indoles-6-yl]-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0553] 1H NMR (DMSO-d 6): δ 7.83 (d, 2H, J=7.8Hz), 7.41 (s, 2H), 7.26 (s, 2H), 7.10 (d, 2H, J=8.4Hz), 2.45 (s, 3H); LCMS: purity: 96%; MS (m/z): 456 (MH +).
IX-10:N4-[3-(aminocarboxyl)-1H-indoles-6-yl]-N2-(3-amino-sulfonyl-4-chloro-phenyl-)-5-fluoro-2, the 4-pyrimidinediamine
[0554] 1H NMR (DMSO-d 6): δ 8.18 (s, 1H), 8.12 (s, 1H), 8.03 (m, 2H), 7.44 (m, 3H), 7.15 (d, 1H, J=9.0Hz); LCMS: purity: 87%; MS (m/z): 476 (MH +).
IX-11:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3-cyano methyl-1H-indoles-6-yl)-5-fluoro-2, the 4-pyrimidinediamine
[0555] 1H NMR (DMSO-d 6): δ 7.95 (d, 1H, J=8.4Hz), 7.64 (s, 1H), 7.55 (d, 1H, J=8.4Hz), 7.41 (m, 1H), 7.29 (s, 1H), 7.20 (s, 2H), 7.06 (d, 1H, J=8.7Hz), 4.04 (s, 2H), 2.45 (s, 3H); LCMS: purity: 96%; MS (m/z): 452 (MH +).
IX-12:N2-(3-amino-sulfonyl phenyl)-N4-(3-cyano methyl-1H-indoles-6-yl)-5-fluoro-2, the 4-pyrimidinediamine
[0556] 1H NMR (DMSO-d 6): δ 8.08 (t, 1H, J=3.3Hz), 8.01 (d, 1H, J=3.0Hz), 7.65 (s, 1H), 7.55 (d, 2H, J=8.4Hz), 7.43 (d, 1H, J=8.1Hz), 7.26 (m, 3H), 4.04 (s, 2H); LCMS: purity: 93%; MS (m/z): 438 (MH +).
IX-13:N2-(3-amino-sulfonyl phenyl)-N4-(3-cyano methyl-1H-indoles-5-yl)-5-fluoro-2, the 4-pyrimidinediamine
[0557] 1H NMR (DMSO-d 6): δ 8.06 (d, 1H, J=3.9Hz), 7.96 (d, 1H, J=8.4Hz), 7.87 (s, 1H), 7.35 (m, 5H), 4.02 (s, 2H); LCMS: purity: 96%; MS (m/z): 438 (MH +).
IX-14:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3-cyano methyl-1H-indoles-5-yl)-5-fluoro-2, the 4-pyrimidinediamine
[0558] 1H NMR (DMSO-d 6): δ 8.07 (s, 1H), 8.02 (d, 1H, J=3.9Hz), 7.87 (s, 2H), 7.41 (s, 1H), 7.37 (s, 1H), 7.35 (s, 1H), 7.20 (s, 1H), 4.01 (s, 2H), 2.42 (s, 3H); LCMS: purity: 97%; MS (m/z): 452 (MH +).
I-244:N2-[3-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[3-methyl-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0559] 1H?NMR(DMSO?d 6，300MHz)：δ9.45(s，1H)，9.20(s，1H)，8.05(m，3H)，7.50(m，2H)，7.34(t，1H，J＝7.5Hz)，7.26(d，2H，J＝7.8Hz)，7.00(d，1H，J＝9.3Hz)，6.33(s，1H)，5.13(s，2H)，2.79(t，2H，J＝7.8Hz)，2.41(s，3H)，2.38(m，6H)，2.17(s，3H)，0.85(t，6H，J＝6.9Hz)；LCMS(m/z)：584(MH +)。
I-245:N2-[4-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[3-methyl-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0560] 1H NMR (DMSO d 6): δ 9.62 (s, 1H), 9.28 (s, 1H), 8.09 (d, 1H, J=3.3Hz), 7.80 (d, 2H, J=8.7Hz), 7.55 (d, 2H, J=8.7Hz), 7.52 (d, 1H, J=2.7Hz), 7.40 (dd, 1H, J=2.4 and 8.5Hz), 7.17 (br s, 1H), 7.01 (d, 1H, J=8.7Hz), 6.34 (s, 1H), 5.13 (s, 2H), 2.71 (t, 2H, J=7.8Hz), 2.41 (s, 3H), 2.38 (m, 6H), 2.18 (s, 3H), 0.83 (t, 6H, J=6.9Hz); LCMS (m/z): 584 (MH +).
I-239:5-fluoro-N2-[3-N-(methyl) amino-sulfonyl-4-aminomethyl phenyl]-N4-[3-methyl-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0561] 1H?NMR(DMSO?d 6)：δ9.34(s，1H)，9.16(s，1H)，8.03(d，1H，J＝3.9Hz)，7.96(m，2H)，7.50(m，2H)，7.32(q，1H，J＝4.5Hz)，7.15(d，1H，J＝9.0Hz)，6.99(d，1H，J＝8.4Hz)，6.33(s，1H)，5.13(s，2H)，2.45(s，3H)，2.41(d，3H，J＝3.3Hz)，2.40(s，3H)，2.16(s，3H)；LCMS(m/z)：513(MH +)。
I-241:N2-[3-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0562] 1H?NMR(DMSO?d 6)：δ9.45(s，1H)，9.28(s，1H)，8.05(m，2H)，7.98(d，1H，J＝8.4Hz)，7.67(d，2H，J＝9Hz)，7.36(t，1H，J＝8.1Hz)，7.26(d，2H，J＝8.1Hz)，6.98(d，2H，J＝9.0Hz)，6.32(s，1H)，5.12(s，2H)，2.79(t，2H，J＝8.1Hz)，2.40(s，3H)，2.37(m，6H)，0.84(t，6H，J＝6.9Hz)；LCMS(m/z)：570(MH +)。
I-246:N2-[4-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0563] 1H?NMR(DMSO?d 6)：δ9.60(s，1H)，9.34(s，1H)，8.10(d，1H，J＝3.9Hz)，7.81(d，2H，J＝9.0Hz)，7.63(d，2H，J＝9.0Hz)，7.57(d，2H，J＝8.7Hz)，7.15(br?s，1H)，7.01(d，2H，J＝9.3Hz)，6.32(s，1H)，5.12(s，2H)，2.73(t，2H，J＝7.5Hz)，2.40(s，3H)，2.36(m，6H)，0.84(t，6H，J＝6.9Hz)；LCMS(m/z)：570(MH +)。
Figure A20068002053302151
I-252:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2,4-pyrimidinediamine (60)
[0564] 1H?NMR(DMSO-d 6)：δ9.51(s，1H)，9.39(s，1H)，8.13(d，1H，J＝2.1Hz)，8.09(s，1H)，7.98(d，1H，J＝6.9Hz)，7.51(br?s，2H)，7.41-7.25(m，4H)，6.73(d，2H，J＝7.5Hz)，5.45(s，2H)，2.35(s，3H)；LCMS(m/z)：472(MH +)。
I-253:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[3-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0565] 1H?NMR(DMSO?d 6，300MHz)：δ9.62(s，1H)，9.46(s，1H)，8.16(d，1H，J＝2.1Hz)，7.82(d，2H，J＝7.5Hz)，7.62(d，2H，J＝7.2Hz)，7.49(d，1H，J＝8.1Hz)，7.43(s，1H)，7.26(t，1H，J＝8.1Hz)，7.11(br?s，2H)，6.76(d，1H，J＝8.1Hz)，5.46(s，2H)，2.34(s，3H)；LCMS(m/z)：472(MH +)。
I-231:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0566] 1H?NMR(DMSO-d 6)：δ9.62(s，1H)，9.46(s，1H)，8.16(d，1H，J＝2.1Hz)，7.82(d，2H，J＝7.5Hz)，7.62(d，2H，J＝7.2Hz)，7.49(d，1H，J＝8.1Hz)，7.43(s，1H)，7.26(t，1H，J＝8.1Hz)，7.11(br?s，2H)，6.76(d，1H，J＝8.1Hz)，5.46(s，2H)，2.34(s，3H)；LCMS(m/z)：472(MH +)。
I-259:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0567] 1H?NMR(DMSO?d 6)：δ9.35(s，1H)，9.26(s，1H)，8.08(s，1H)，8.04(d，1H，J＝3.3Hz)，7.86(d，1H，J＝7.5Hz)，7.71(d，2H，J＝8.7Hz)，7.22(s，2H)，7.13(d，1H，J＝8.4Hz)，6.99(d，2H，J＝9.0Hz)，5.45(s，2H)，2.49(s，3H)，2.36(s，3H)；LCMS(m/z)：486(MH +)。
I-258:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0568] 1H?NMR(DMSO?d 6)：δ9.47(s，1H)，9.31(s，1H)，8.07(d，2H，J＝3.0Hz)，7.90(d，1H，J＝6.6Hz)，7.70(d，2H，J＝8.7Hz)，7.33(m，2H)，7.25(s，2H)，7.00(d，2H，J＝9.0Hz)，5.46(s，2H)，2.49(s，3H)，2.36(s，3H)；LCMS(m/z)：472(MH +)。
I-254:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0569] 1H NMR (DMSO d 6): δ 9.41 (s, 1H), 9.35 (s, 1H), 8.09 (m, 2H), 7.92 (dd, 2H, J=2.1 and 8.1Hz), 7.51 (m, 2H), 7.22 (m, 5H), 6.74 (dd, 2H, J=2.1 and 8.2Hz), 5.45 (s, 2H), 2.45 (s, 3H); LCMS (m/z): 486 (MH +).
III-14:N2-(3-amino-sulfonyl phenyl)-N4-[4-(cyano group ethylidene) phenyl]-5-fluoro-2, the 4-pyrimidinediamine
[0570] 1H?NMR(DMSO-d 6)：δ9.52(s，1H)，9.37(s，1H)，8.11-8.10(d，J＝3Hz，2H)，7.98-7.95(d，J＝9.0Hz，1H)，7.77-7.74(d，J＝9.0Hz，2H)，7.39-7.32(m，2H)，7.26(s，2H)，7.23(s，2H)，2.86-2.79(m，4H)；LCMS(m/z)：412.97(MH +)。
III-15:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[4-(cyano group ethylidene) phenyl]-5-fluoro-2, the 4-pyrimidinediamine
[0571] 1H?NMR(DMSO-d 6)：δ9.40(s，1H)，9.32(s，1H)，8.10-8.06(m，2H)，7.92(brs，1H)，7.25-7.17(m，5H)，2.48(s，3H)；LCMS(m/z)：427.01(MH +)。
III-16:N2-(3-amino-sulfonyl-4-fluorophenyl)-N4-[4-(cyano group ethylidene) phenyl]-5-fluoro-2, the 4-pyrimidinediamine
[0572] 1H?NMR(DMSO-d 6)：δ9.47(s，1H)，9.36(s，1H)，8.09-8.08(d，J＝3.0Hz，1H)8.06-8.04(m，1H)，8.02-7.98(m，1H)，7.75-7.72(d，J＝9.0Hz，2H)，7.54(s，2H)，7.28-7.22(m，3H)，2.86-2.81(m，4H)；LCMS：(m/z)：430.98(MH +)。
III-106:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) ethylidene phenyl]-2, the 4-pyrimidinediamine
[0573] 1H?NMR(DMSO-d 6)：δ9.50(s，1H)，9.33(s，1H)，8.10(br?s，2H)，7.97-7.94(bd，J＝9.0Hz，1H)，7.73-7.70(d，J＝9.0Hz，2H)，7.35(m，2H)，7.25(s，2H)，7.21-7.18(d，J＝9.0Hz，2H)，3.23-3.19(m，2H)，3.06-3.01(m，2H)，2.30(s，3H)；LCMS(m/z)：469.88(MH +)。
I-267:N2-(3-amino-sulfonyl-4-fluorophenyl)-5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) ethylidene phenyl]-2, the 4-pyrimidinediamine
[0574] 1H?NMR(DMSO-d 6)：δ9.411(s，1H)，9.30(br?s，1H)，8.07-8.06(d，J＝3Hz，1H)，8.01(m，1H)，7.95(m，1H)，7.71-7.68(d，J＝9.0Hz，2H)，7.21-7.18(d，J＝9.0Hz，2H)，3.23-3.18(m，2H)，3.05-3.00(m，2H)，2.29(s，3H)；LCMS(m/z)：488.41(MH +)。
I-266:N2-(3-amino-sulfonyl-4-fluorophenyl)-5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0575] 1H?NMR(DMSO-d 6)：δ9.52(s，1H)，9.44(s，1H)，8.08-8.07(d，J＝3Hz，1H)，8.01-7.99(m，1H)，7.95-7.92(m，1H)，7.68-7.65(d，J＝9.0Hz，2H)，7.55(s，2H)，7.28-7.20(m，1H)，7.03-7.00(d，J＝9.0Hz，2H)，5.46(s，2H)，2.36(s，3H)；LCMS(m/z)：490.36(MH +)。
I-260:5-fluoro-N2-[3-N-(methyl) amino-sulfonyl-4-aminomethyl phenyl)-and N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine:
[0576] 1H NMR (DMSO d 6): δ 9.35 (s, 1H), 9.27 (s, 1H), 8.05 (d, 1H, J=3.6Hz), 8.00 (d, 1H, J=2.4Hz), 7.92 (dd, 1H, J=2.4 and 8.2Hz), 7.71 (d, 2H, J=9.0Hz), 7.31 (q, 1H, J=4.8Hz), 7.18 (d, 1H, J=8.1Hz), 7.00 (d, 2H, J=9.3Hz), 5.45 (s, 2H), 2.45 (s, 3H), 2.41 (d, 3H, J=4.8Hz), 2.35 (s, 3H), 2.46 (s, 3H); LCMS (m/z): 500 (MH +).
I-255:5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-[3-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine:
[0577] 1H NMR (DMSO d 6): δ 9.41 (s, 1H), 9.36 (s, 1H), 8.11 (d, 1H, J=3.6Hz), 7.99 (m, 2H), 7.50 (m, 2H), 7.32 (q, 1H, J=4.8Hz), 7.22 (t, 2H, J=8.1Hz), 6.72 (dd, 1H, J=2.4 and 8.1Hz), 5.43 (s, 2H), 2.44 (s, 3H), 2.41 (d, 3H, J=4.5Hz), 2.35 (s, 3H); LCMS (m/z): 500 (MH +).
I-261:N2-[3-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[3-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0578] 1H?NMR(DMSO?d 6)：δ9.54(s，1H)，9.41(s，1H)，8.14(d，1H，J＝3.3Hz)，8.07(s，1H)，8.03(d，1H，J＝8.4Hz)，7.50(m，2H)，7.41(t，1H，J＝8.1Hz)，7.34(brs，1H)，7.25(d，2H，J＝8.1Hz)，6.74(d，1H，J＝6.9Hz)，5.45(s，2H)，2.79(t，2H，J＝7.5Hz)，2.35(m，9H)，0.84(t，6H，J＝6.9Hz)；LCMS(m/z)：571(MH +)。
I-256:N2-[4-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[3-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0579] 1H NMR (DMSO d 6): δ 9.68 (s, 1H), 9.47 (s, 1H), 8.17 (d, 1H, J=3.6Hz), 7.85 (d, 2H, J=9.0Hz), 7.60 (d, 2H, J=9.0Hz), 7.44 (m, 2H), 7.27 (t, 2H, J=8.4Hz), (6.76 dd, 1H, J=2.4 and 8.1Hz), 5.46 (s, 2H), 2.74 (t, 2H, J=7.8Hz), 2.41 (m, 6H), 2.34 (s, 3H), 0.86 (t, 6H, J=7.2Hz); LCMS (m/z): 571 (MH +).
I-262:N2-[3-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0580] 1H?NMR(DMSO?d 6)：δ9.47(s，1H)，9.31(s，1H)，8.08(d，1H，J＝3.9Hz)，8.05(s，1H)，7.98(d，1H，J＝8.4Hz)，7.70(d，2H，J＝9.0Hz)，7.37(t，2H，J＝7.8Hz)，7.26(d，1H，J＝8.1Hz)，5.46(s，2H)，2.79(t，2H，J＝7.5Hz)，2.36(m，9H)，0.85(t，6H，J＝6.9Hz)；LCMS(m/z)：571(MH +)。
Figure A20068002053302181
VIII-1:5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-N2-(sugar-6-yl)-2, the 4-pyrimidinediamine:
[0581] 1H?NMR(DMSO?d 6，300MHz)：δ10.07(s，1H)，9.44(s，1H)，8.46(s，1H)，8.18(d，1H，J＝3.6Hz)，7.84(d，1H，J＝8.4Hz)，7.70(d，1H，J＝8.7Hz)，7.60(d，2H，J＝9.3Hz)，7.05(d，2H，J＝9.0Hz)，6.45(br?s，1H)，6.33(s，1H)，5.15(s，2H)，2.41(s，3H)；LCMS(m/z)：497(MH +)。
Figure A20068002053302182
I-198:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[4-(1, the 3-dimethyl-(1H)-and pyrazoles-5-yl) methylene radical oxygen base phenyl]-5-fluoro-2, the 4-pyrimidinediamine
[0582] 1H NMR (DMSO-d 6): δ 9.33 (s, 1H), 9.22 (s, 1H), 8.09 (d, J=2.4Hz, 1H), 8.03 (d, J=3.6Hz, 1H), 7.85 (dd, J=2.1 and 8.4Hz, 1H), 7.67 (d, J=8.7Hz, 1H), 7.21 (s, 2H), 7.14 (d, J=8.1Hz, 1H), 6.99 (d, J=8.7Hz, 2H), 6.12 (s, 1H), 5.08 (s, 2H), 3.74 (s, 3H), 2.48 (s, 3H), 2.10 (s, 3H); LCMS: purity: 98%; MS (m/z): 498 (MH +).
I-199:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[4-(1-benzyl-3-methyl-(1H)-pyrazoles-5-yl) methylene radical oxygen base phenyl]-5-fluoro-2, the 4-pyrimidinediamine
[0583] 1H NMR (DMSO-d 6): δ 9.39 (s, 1H), 9.29 (s, 1H), 8.07 (d, J=2.1Hz, 1H), 8.04 (d, J=3.9Hz, 1H), 7.84 (dd, J=2.1 and 8.4Hz, 1H), 7.64 (d, J=9.0Hz, 2H), 7.33-7.22 (m, 5H), 7.18-7.11 (m, 3H), 6.90 (d, J=9.0Hz, 2H), 6.19 (s, 1H), 5.28 (s, 2H), 5.06 (s, 2H), 2.49 (s, 3H), 2.13 (s, 3H); LCMS: purity: 98%; MS (m/z): 575 (MH +).
I-197:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(the 3-methyl-(1H)-pyrazoles-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0584] with N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[4-(1-benzyl-3-methyl-(1H)-pyrazoles-5-yl) methylene radical oxygen base phenyl]-5-fluoro-2; 4-pyrimidinediamine (63; the Y=benzyl; 50mg; 0.087mmol), 10%Pd/C (20mg) and 4NHCl (30 μ L; 0.12mmol) methyl alcohol (1.0mL) suspension under vacuum, outgas, recharge with hydrogen, and under hydrogen stirring at room 24 hours.Then reaction mixture is passed through diatomite filtration, filter cake washs with methyl alcohol (10mL).Under vacuum, remove N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-that methyl alcohol obtains 43 milligrams of Off-white solid shapes (3-methyl-(1H)-pyrazoles-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine (63, Y=H). 1H NMR (DMSO-d 6): δ 12.45 (s, 1H), 9.33 (s, 1H), 9.21 (s, 1H), 8.09 (d, J=1.5Hz, 1H), 8.02 (d, J=3.9Hz, 1H), 7.86 (dd, J=2.1 and 8.1Hz, 1H), 7.66 (d, J=9.0Hz, 2H), 7.29-7.19 (m, 2H), 7.14 (d, J=8.1Hz, 1H), 6.96 (d, J=9.0Hz, 2H), 6.05 (s, 1H), 4.95 (s, 2H), 2.49 (s, 3H), 2.20 (s, 3H); LCMS: purity: 95%; MS (m/z): 484 (MH +).
Embodiment 27
Figure A20068002053302191
I-16:N2-(4-amino-sulfonyl) phenyl-N4-(4-cyano group methoxyl group) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0585] with 4-nitrophenols (10g), bromoacetamide (10g) and K 2CO 3(15g) be suspended in acetone (30mL).With yellow solution stirring at room 3 days.Acetone is removed in reaction mixture dilute with water and decompression.Faint yellow precipitation is collected by filtering, and washes with water and dry O-amino carbonyl methyl-4-nitrophenols (11.5g) to obtain the beige solid shape.
[0586] O-amino carbonyl methyl-4-nitrophenols (5g) is dissolved in methyl alcohol (50mL) and adds 10%Pd-C (500mg) in solution.Reaction mixture was reacted 1 hour down at hydrogen (about 40psi).Leach catalyzer by diatomite.With 4-(aminocarboxyl methoxyl group) aniline (analine) of filtrate evaporation to obtain white solid.
[0587] with 4-(aminocarboxyl methoxyl group) aniline (5g) and 2,6-two chloro-5-fluorine pyrimidines (6g) are dissolved in methyl alcohol (10mL) and water (1mL).With the reaction soln stirred overnight at room temperature.Methyl alcohol is removed in decompression then.The 1N HCl aqueous solution (80mL) acidifying of remainder water solution.White precipitate is collected by filtering, and washes with water and dry N4-(4-aminocarboxyl methoxyl group) phenyl-2-chloro-5-fluoro-4-PYRIMITHAMINE to obtain solid state.
[0588] N4-(4-aminocarboxyl methoxyl group) phenyl-2-chloro-5-fluoro-4-PYRIMITHAMINE (2g) is dissolved in THF (20mL).In this solution, add trifluoroacetic anhydride (1.9mL) and pyridine (1.65mL).With the reaction soln stirred overnight at room temperature.Use ethyl acetate (100mL) dilution then.Organic layer K 2CO 3The aqueous solution (2 * 100mL), the washing of the 1N HCl aqueous solution (100mL) and water (100mL).Ethyl acetate layer is separated dry and 2-chloro-N4-(the 4-cyano group methoxyl group) phenyl-5-fluoro-4-PYRIMITHAMINE of evaporation to obtain white solid.
[0589] 2-chloro-N4-(4-cyano group methoxyl group) phenyl-5-fluoro-4-PYRIMITHAMINE (100mg) and sulfanilamide (SN) (100mg) are dissolved in Virahol (1mL).Solution is used methyl alcohol (5mL) dilution and ultrasonic then 100 ℃ of heated overnight.Precipitation is leached, with methanol wash and dry N2-(4-amino-sulfonyl) phenyl-N4-(4-cyano group methoxyl group) phenyl-5-fluoro-2,4-pyrimidinediamine to obtain the beige solid shape. 1H NMR (DMSO-d 6): δ 5.16 (s, 2H), 7.07 (d, J=9.0Hz, 2H), 7.16 (br, 2H), 7.64 (d, J=8.7Hz, 2H), 7.69 (d, J=9.0Hz, 2H), 7.75 (d, J=8.7Hz, 2H), 8.17 (d, J=4.2Hz, 1H), 9.71 (br, 1H), 9.85 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.19; LCMS: purity: 95.05%; MS (m/e): 415.01 (MH +).
[0590] following compound is according to preparing with embodiment 27 similar modes.
I-17:N2-(3-amino-sulfonyl) phenyl-N4-(4-cyano group methoxyl group) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0591] 1H NMR (DMSO-d 6): δ 5.16 (s, 2H), 7.06 (d, J=9.3Hz, 2H), 7.31 (br, 2H), 7.42 (m, 2H), 7.68 (d, J=9.0Hz, 2H), 7.87 (m, 1H), 7.94 (s, 1H), 8.19 (d, J=4.2Hz, 1H), 9.90 (br, 1H), 9.97 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-200.94; LCMS: purity: 93.17%; MS (m/e): 415.54 (MH +).
I-91:N4-(3-aminocarboxyl methoxyl group) phenyl-N2-(4-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0592] 1H NMR (DMSO-d 6): δ 4.43 (s, 2H), 6.72 (dd, J=2.1,7.5Hz, 1H), 7.16 (br, 2H), 7.26 (t, J=8.1Hz, 1H), 7.36 (d, J=9.0Hz, 1H), 7.44 (m, 2H), 7.54 (s, 1H), 7.65 (d, J=9.0Hz, 2H), 7.79 (d, J=9.0Hz, 2H), 8.22 (d, J=4.2Hz, 1H), 9.82 (br, 1H), 9.91 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-200.39; LCMS: purity: 91.64%; MS (m/e): 433.00 (MH +).
I-88:N4-(3-aminocarboxyl methoxyl group) phenyl-N2-(3-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0593] 1H NMR (DMSO-d 6): δ 4.41 (s, 2H), 6.66 (dd, J=2.4,8.4Hz, 1H), 7.23 (t, J=8.1Hz, 1H), 7.26 (br, 2H), 7.35-7.54 (m, 6H), 7.94 (d, J=8.1Hz, 1H), 8.09 (s, 1H), 8.16 (d, J=4.2Hz, 1H), 9.62 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-201.09; LCMS: purity: 94.82%; MS (m/e): 433.46 (MH +).
I-3:N2-(4-amino-sulfonyl) phenyl-N4-(3-cyano group methoxyl group) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0594] 1H NMR (DMSO-d 6): δ 5.14 (s, 2H), 6.81 (dd, J=2.7,8.4Hz, 1H), 7.13 (br, 2H), 7.32 (t, J=8.1Hz, 1H), 7.49 (t, J=2.1Hz, 1H), 7.54 (d, J=8.1Hz, 1H), 7.63 (d, J=8.7Hz, 2H), 7.80 (d, J=9.0Hz, 2H), 8.18 (d, J=3.6Hz, 1H), 9.55 (br, 1H), 9.62 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.17; LCMS: purity: 93.10%; MS (m/e): 415.56 (MH +).
I-4:N2-(3-amino-sulfonyl) phenyl-N4-(3-cyano group methoxyl group) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0595] 1H NMR (DMSO-d 6): δ 5.14 (s, 2H), 6.81 (dd, J=2.4,8.4Hz, 1H), 7.29 (br, 2H), 7.32 (t, J=8.1Hz, 1H), 7.40 (m, 2H), 7.52 (m, 2H), 7.92 (m, 1H), 8.01 (s, 1H), 8.20 (d, J=4.2Hz, 1H), 9.78 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-200.81; LCMS: purity: 88.73%; MS (m/e): 415.58 (MH +).
III-3:N2-(4-amino-sulfonyl) phenyl-N4-(4-cyano methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0596] 1H NMR (DMSO-d 6): δ 4.01 (s, 2H), 7.15 (br, 2H), 7.32 (d, J=9.0Hz, 2H), 7.65 (d, J=8.7Hz, 2H), 7.78 (d, J=8.7Hz, 2H), 7.78 (d, J=9.0Hz, 2H), 8.19 (d, J=3.6Hz, 1H), 9.70 (br, 1H), 9.78 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-200.85; LCMS: purity: 89.03%; MS (m/e): 399.54 (MH +).
III-4:N2-(3-amino-sulfonyl) phenyl-N4-(4-cyano methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0597] 1H NMR (DMSO-d 6): δ 4.00 (s, 2H), 7.29 (br, 2H), 7.30 (d, J=8.4Hz, 2H), 7.39 (m, 2H), 7.78 (d, J=8.1Hz, 2H), 7.89 (m, 1H), 8.02 (s, 1H), 8.18 (d, J=3.9Hz, 1H), 9.80 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-201.02; LCMS: purity: 98.20%; MS (m/e): 399.53 (MH +).
I-18:N4-(4-cyano group methoxyl group) phenyl-5-fluoro-N2-[4-(4-methylpiperazine-1-yl) alkylsulfonyl] phenyl-2, the 4-pyrimidinediamine
[0598] LCMS: purity: 99.80%; MS (m/e): 498.06 (MH +).
I-19:N4-(4-cyano group methoxyl group) phenyl-5-fluoro-N2-[3-(4-methylpiperazine-1-yl) alkylsulfonyl] phenyl-2, the 4-pyrimidinediamine
[0599] 1H NMR (DMSO-d 6): δ 2.12 (s, 3H), 2.34 (t, 4H), 2,87 (t, 4H), 5.15 (s, 2H), 7.05 (d, J=9.0Hz, 2H), 7.18 (d, J=8.1Hz, 1H), 7.45 (t, J=8.1Hz, 1H), 7.74 (d, J=8.7Hz, 2H), 7.98 (s, 1H), 8.11 (d, J=7.8Hz, 1H), 8.11 (d, J=3.6Hz, 1H), 9.38 (br, 1H), 9.53 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.15; LCMS: purity: 93.41%; MS (m/e): 498.39 (MH +).
I-89:N4-(3-aminocarboxyl methoxyl group) phenyl-5-fluoro-N2-[3-(4-methylpiperazine-1-yl) alkylsulfonyl] phenyl-2, the 4-pyrimidinediamine
[0600] 1H NMR (DMSO-d 6): δ 2.12 (s, 3H), 2.34 (t, 4H), 2.88 (t, 4H), 4.42 (s, 2H), 6.66 (dd, J=2.7,8.4Hz, 1H), 7.18-7.25 (m, 2H), 7.41-7.56 (m, 5H), 8.10 (m, 2H), 8.15 (d, J=3.9Hz, 1H), 9.44 (br, 1H), 9.51 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.35; LCMS: purity: 86.95%; MS (m/e): 516.11 (MH +).
I-5:N4-(3-cyano group methoxyl group) phenyl-5-fluoro-N2-[3-(4-methylpiperazine-1-yl) alkylsulfonyl] phenyl-2, the 4-pyrimidinediamine
[0601] 1H NMR (DMSO-d 6): δ 2.12 (s, 3H), 2.34 (t, 4H), 2.87 (t, 4H), 5.14 (s, 2H), 6.78 (dd, J=2.4,8.1Hz, 1H), 7.20 (d, J=8.7Hz, 1H), 7.31 (t, J=8.1Hz, 1H), 7.46 (t, J=8.1Hz, 1H), 7.54 (m, 2H), 8.00 (s, 1H), 8.10 (d, J=8.4Hz, 1H), 8.16 (d, J=3.6Hz, 1H), 9.48 (br, 1H), 9.55 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.35; LCMS: purity: 91.89%; MS (m/e): 498.06 (MH +).
III-5:N4-(4-cyano methyl) phenyl-5-fluoro-N2-[3-(4-methylpiperazine-1-yl) alkylsulfonyl] phenyl-2, the 4-pyrimidinediamine
[0602] 1H NMR (DMSO-d 6): δ 2.12 (s, 3H), 2.34 (t, 4H), 2,87 (t, 4H), 3.99 (s, 2H), 7.19 (d, J=7.5Hz, 1H), 7.30 (d, J=8.7Hz, 2H), 7.46 (t, J=8.1Hz, 1H), 7.81 (d, J=8.4Hz, 2H), 8.00 (s, 1H), 8.10 (dd, J=1.5,8.1Hz, 1H), 8.14 (d, J=3.6Hz, 1H), 9.48 (br, 1H), 9.56 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.59; LCMS: purity: 93.12%; MS (m/e): 482.06 (MH +).
RI-6:N4-(3-cyano group methoxyl group) phenyl-5-fluoro-N2-[4-(4-methylpiperazine-1-yl) alkylsulfonyl] phenyl-2, the 4-pyrimidinediamine
[0603] LCMS: purity: 99.63%; MS (m/e): 498.05 (MH +).
III-6:N4-(4-cyano methyl) phenyl-5-fluoro-N2-[4-(4-methylpiperazine-1-yl) alkylsulfonyl] phenyl-2, the 4-pyrimidinediamine
[0604] LCMS: purity: 96.81%; MS (m/e): 482.03 (MH +).
I-115:N4-(4-aminocarboxyl methoxyl group) phenyl-N2-(4-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0605] 1H NMR (DMSO-d 6): δ 4.43 (s, 2H), 6.95 (d, J=8.7Hz, 2H), 7.17 (br, 2H), 7.36 (br, 1H), 7.55 (br, 1H), 7.58 (d, J=9.3Hz, 2H), 7.62 (d, J=8.4Hz, 2H), 7.74 (d, J=8.7Hz, 2H), 8.16 (d, J=3.9Hz, 1H), 9.70 (br, 1H), 9.86 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.26; LCMS: purity: 95.49%; MS (m/e): 433.36 (MH +).
I-111:N4-(4-aminocarboxyl methoxyl group) phenyl-N2-(3-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0606] 1H NMR (DMSO-d 6): δ 4.42 (s, 2H), 6.93 (d, J=8.7Hz, 2H), 7.31 (br, 2H), 7.41 (m, 3H), 7.52 (br, 1H), 7.60 (d, J=8.7Hz, 2H), 7.87 (m, 1H), 7.94 (s, 1H), 8.17 (d, J=4.2Hz, 1H), 9.84 (br, 1H), 9.94 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.04; LCMS: purity: 96.23%; MS (m/e): 433.39 (MH +).
I-112:N4-(4-aminocarboxyl methoxyl group) phenyl-5-fluoro-N2-[3-(4-methylpiperazine-1-yl) alkylsulfonyl] phenyl-2, the 4-pyrimidinediamine
[0607] 1H NMR (DMSO-d 6): δ 2.12 (s, 3H), 2.34 (t, 4H), 2.86 (t, 4H), 4.41 (s, 2H), 6.92 (d, J=9.0Hz, 2H), 7.18 (d, J=8.4Hz, 1H), 7.38 (br, 1H), 7.43 (t, J=8.1Hz, 1H), 7.51 (br, 1H), 7.65 (d, J=9.0Hz, 2H), 7.97 (s, 1H), 8.08 (d, J=3.6Hz, 1H), 8.11 (d, J=8.4Hz, 1H), 9.30 (br, 1H), 9.50 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.33; LCMS: purity: 77.73%; MS (m/e): 516.44 (MH +).
I-65: racemize N2-(3-amino-sulfonyl) phenyl-N4-[4-(1-cyano group) oxyethyl group] phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0608] 1H NMR (DMSO-d 6): δ 1.69 (d, J=6.6Hz, 3H), 5.41 (q, J=6.6Hz, 1H), 7.06 (d, J=9.0Hz, 2H), 7.25 (br, 2H), 7.31-7.41 (m, 2H), 7.77 (d, J=8.7Hz, 2H), 7.94 (d, J=8.1Hz, 1H), 8.09 (m, 2H), 9.35 (br, 1H), 9.49 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.36; LCMS: purity: 91.76%; MS (m/e): 429.05 (MH +).
I-66: racemize N2-(4-amino-sulfonyl) phenyl-N4-[4-(1-cyano group) oxyethyl group] phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0609] 1H NMR (DMSO-d 6): δ 1.70 (d, J=6.6Hz, 3H), 5.43 (q, J=6.6Hz, 1H), 7.09 (d, J=9.0Hz, 2H), 7.13 (br, 2H), 7.63 (d, J=8.7Hz, 2H), 7.71 (d, J=9.0Hz, 2H), 7.77 (d, J=8.7Hz, 2H), 8.16 (d, J=3.9Hz, 1H), 9.61 (br, 1H), 9.76 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.42; LCMS: purity: 96.39%; MS (m/e): 429.39 (MH +).
I-116: racemize N4-[4-(1-aminocarboxyl) oxyethyl group] phenyl-N2-(4-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0610] 1H NMR (DMSO-d 6): δ 1.46 (d, J=6.6Hz, 3H), 4.63 (q, J=6.6Hz, 1H), 6.92 (d, J=9.0Hz, 2H), 7.19 (br, 3H), 7.57 (d, J=7.8Hz, 2H), 7.58 (br, 1H), 7.63 (d, J=9.0Hz, 2H), 7.73 (d, J=7.5Hz, 2H), 8.17 (d, J=4.2Hz, 1H), 9.76 (br, 1H), 9.93 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.11; LCMS: purity: 94.25%; MS (m/e): 447.40 (MH +).
I-117: racemize N4-[4-(1-aminocarboxyl) oxyethyl group] phenyl-N2-(3-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0611] 1H NMR (DMSO-d 6): δ 1.44 (d, J=6.6Hz, 3H), 4.60 (q, J=6.6Hz, 1H), 6.89 (d, J=8.7Hz, 2H), 7.25 (br, 1H), 7.31 (br, 2H), 7.42 (m, 2H), 7.51 (br, 1H), 7.59 (d, J=8.7Hz, 2H), 7.88 (m, 1H), 7.95 (s, 1H), 8.16 (d, J=4.5Hz, 1H), 9.79 (br, 1H), 9.89 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.17; LCMS: purity: 95.18%; MS (m/e): 447.44 (MH +).
I-125:N4-[4-(1-aminocarboxyl-1-methyl) oxyethyl group] phenyl-N2-(4-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0612] 1H NMR (DMSO-d 6): δ 1.43 (s, 6H), 6.91 (d, J=8.7Hz, 2H), 7.16 (br, 2H), 7.22 (br, 1H), 7.57 (br, 1H), 7.59 (d, J=8.7Hz, 2H), 7.62 (d, J=9.9Hz, 2H), 7.74 (d, J=8.4Hz, 2H), 8.17 (d, J=4.9Hz, 1H), 9.72 (br, 1H), 9.89 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.14; LCMS: purity: 98.31%; MS (m/e): 461.33 (MH +).
I-21:N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(4-cyano group methoxyl group) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0613] 1H NMR (DMSO-d 6): δ 5.16 (s, 2H), 7.06 (d, J=8.4Hz, 2H), 7.42 (d, J=8.1Hz, 1H), 7.47 (br, 2H), 7.74 (d, J=9.0Hz, 2H), 8.02 (d, J=8.7Hz, 1H), 8.10 (d, J=2.4Hz, 1H), 8.26 (s, 1H), 9.42 (br, 1H), 9.63 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.94; LCMS: purity: 96.69%; MS (m/e): 449.34 (MH +).
III-7:N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-(4-cyano methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0614] 1H NMR (DMSO-d 6): δ 2.51 (s, 3H), 4.00 (s, 2H), 7.21 (d, J=8.1Hz, 1H), 7.29 (br, 2H), 7.30 (d, J=8.4Hz, 2H), 7.76 (d, J=8.4Hz, 2H), 7.81 (dd, J=2.1,8.4Hz, 1H), 8.01 (s, 1H), 8.16 (d, J=4.5Hz, 1H), 9.75 (br s, 1H), 9.82 (br s, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.31; LCMS: purity: 96.68%; MS (m/e): 413.66 (MH +).
III-8:N2-(3-amino-sulfonyl-4-chlorine) phenyl-N4-(4-cyano methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0615] 1H NMR (DMSO-d 6): δ 4.01 (s, 2H), 7.32 (d, J=7.8Hz, 2H), 7.44 (d, J=8.7Hz, 1H), 7.49 (br, 2H), 7.79 (d, J=7.8Hz, 2H), 8.00 (d, J=8.7Hz, 1H), 8.16 (d, J=3.9Hz, 1H), 8.24 (s, 1H), 9.68 (br s, 1H), 9.79 (br s, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.00; LCMS: purity: 90.19%; MS (m/e): 433.00 (MH +).
I-75:N2-(4-amino-sulfonyl) phenyl-N4-[4-(1-cyano group-1-methyl) oxyethyl group] phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0616] 1H NMR (DMSO-d 6): δ 1.70 (s, 6H), 7.14 (br, 2H), 7.16 (d, J=9.0Hz, 2H), 7.63 (d, J=8.4Hz, 2H), 7.78 (d, J=9.0Hz, 2H), 7.79 (d, J=8.7Hz, 2H), 8.18 (d, J=3.9Hz, 1H), 9.63 (br s, 1H), 9.74 (br s, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.30; LCMS: purity: 94.43%; MS (m/e): 443.64 (MH +).
I-274:5-fluoro-N4-[4-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl) methoxyl group] phenyl-N2-[3-(4-methylpiperazine-1-yl) alkylsulfonyl] phenyl-2, the 4-pyrimidinediamine
[0617] with 4-nitrophenols (10g), bromoacetonitrile (6mL) and K 2CO 3(15g) be suspended in acetone (100mL).With the yellow solution stirred overnight at room temperature.Acetone is removed in reaction mixture water (100mL) dilution and decompression.Faint yellow precipitation is collected by filtering, and washes with water also dry to obtain O-cyano methyl-4-nitrophenols.
[0618] O-cyano methyl-4-nitrophenols (8g) is dissolved in methyl alcohol (50mL) and in solution, adds oxyamine HCl (3.4g) and triethylamine (9.4mL).With reaction mixture refluxed 4 days and removal of solvent under reduced pressure.Resistates heavily is dissolved in THF (50mL).In solution, add AcCl (23mL) and triethylamine (50mL).With the reaction mixture stirred overnight at room temperature, add entry (30mL) and NaOH (18g) then.The reaction soln backflow is spent the night water (200mL) dilution then.(2 * 150mL) extract the aqueous solution with EtOAc.With the EtOAc layer drying that merges, evaporate after the separation.Resistates by hurried column chromatography (EtOAc/ hexane=1/2,1/1, EtOAc) with from EtOAc and hexane recrystallization purifying to obtain O-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl) methyl-4-nitrophenols.
[0619] O-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl) methyl-4-nitrophenols (1g) is dissolved in THF (40mL) and water (40mL).In solution, add sodium bisulfite (3.8g), sodium bicarbonate (1.4g), K 2CO 3(1.8g).With its stirring at room 30 minutes, water (80mL) dilution then.(2 * 100mL) extract the aqueous solution with EtOAc.Organic layer is merged, drying, evaporation is to obtain 4-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl) anisidine.
[0620] with 4-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl) anisidine and 2,6-two chloro-5-fluorine pyrimidines (1g) are dissolved in methyl alcohol (5mL) and water (1mL).With reaction soln stirring at room 3 days.Water (100mL) diluting soln is also with ethyl acetate (2 * 100mL) extractions then.Organic layer is evaporated to obtain 2-chloro-5-fluoro-N4-[4-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl) methoxyl group] phenyl-4-PYRIMITHAMINE.
[0621] with 2-chloro-5-fluoro-N4-[4-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl) methoxyl group] phenyl-4-PYRIMITHAMINE (80mg) and [3-(4-methylpiperazine-1-yl) alkylsulfonyl] aniline (80mg) is dissolved in Virahol (1mL) and adds TFA (5).Solution evaporates then 100 ℃ of heated overnight.Resistates by hurried column chromatography (the DCM solution of 2.0M NH3/ methyl alcohol=1-3%) and from ethyl acetate and hexane recrystallization purifying to obtain 5-fluoro-N4-[4-(5-methyl isophthalic acid; 2; 4-oxadiazole-3-yl) methoxyl group] phenyl-N2-[3-(4-methylpiperazine-1-yl) alkylsulfonyl] phenyl-2, the 4-pyrimidinediamine. 1H NMR (DMSO-d 6): δ 2.12 (s, 3H), 2.35 (t, 4H), 2.61 (s, 3H), 2,87 (t, 4H), 5.22 (s, 2H), 7.01 (d, J=9.3Hz, 2H), 7.18 (d, J=8.4Hz, 1H), 7.43 (t, J=8.1Hz, 1H), 7.68 (d, J=9.0Hz, 2H), 7.98 (s, 1H), 8.10 (m, 2H), 9.32 (br, 1H), 9.51 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.24; LCMS: purity: 76.41%; MS (m/e): 555.37 (MH +).
[0622] following compound prepares according to mode similar to the above.
I-275:N2-(4-amino-sulfonyl) phenyl-5-fluoro-N4-[4-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl) methoxyl group] phenyl-2, the 4-pyrimidinediamine
[0623] LCMS: purity: 87.52%; MS (m/e): 472.33 (MH +).
I-276:N2-(3-amino-sulfonyl) phenyl-5-fluoro-N4-[4-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl) methoxyl group] phenyl-2, the 4-pyrimidinediamine
[0624] LCMS: purity: 84.90%; MS (m/e): 472.31 (MH +).
I-20:N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-(4-cyano group methoxyl group) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0625] 2-chloro-N4-(4-cyano group methoxyl group) phenyl-5-fluoro-4-PYRIMITHAMINE (1g) and 2-methyl-5-amino-benzene sulfanilamide (SN) (1g) are dissolved in Virahol (10mL) and TFA (10).Solution is used DMF (30mL) dilution then 100 ℃ of heated overnight.Solution is heated to 50 ℃ and add entry up to slight floss occurring.Solution is slowly cooled to room temperature, cream-coloured precipitation is leached, wash with water and drying.Solid is resuspended in methyl alcohol and ultrasonic.Solid is leached, with methanol wash and dry to obtain N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-(4-cyano group methoxyl group) phenyl-5-fluoro-2,4-pyrimidinediamine (1.3g). 1HNMR (DMSO-d 6): δ 2.50 (s, 3H), 5.16 (s, 2H), 7.05 (d, J=9.0Hz, 2H), 7.20 (d, J=8.4Hz, 1H), 7.26 (br, 2H), 7.72 (d, J=9.0Hz, 2H), 7.85 (d, J=8.7Hz, 1H), 8.03 (s, 1H), 8.96 (d, J=3.0Hz, 1H), 9.56 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-202.34; LCMS: purity: 95.79%; MS (m/e): 429.51 (MH +).
I-76 945941:N2-(3-amino-sulfonyl) phenyl-N4-[4-(1-cyano group-1-methyl) oxyethyl group] phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0626] with 4-nitrophenols (5g), 2-isobutyl bromide methyl esters (5.6mL) and K 2CO 3(7.5g) be suspended in acetone (60mL).The yellow solution backflow is spent the night.Reaction mixture water (150mL) dilutes and (2 * 100mL) extract with ethyl acetate.Organic layer is evaporated to obtain 2-(4-nitrophenoxy) methyl isobutyrate.
[0627] 2-(4-nitrophenoxy) methyl isobutyrate is dissolved in methyl alcohol (50mL) and water (50mL).Add sodium hydroxide (5g).Solution stirring at room 30 minutes, about with 1N HCl acidified aqueous solution then to pH.(2 * 100mL) extract the aqueous solution with ethyl acetate.Organic layer is evaporated to obtain 2-(4-nitrophenoxy) isopropylformic acid.
[0628] with 2-(4-nitrophenoxy) isopropylformic acid (5g), isobutyl chlorocarbonate (4.36mL) and triethylamine (8mL) stirring at room 1 hour in methylene dichloride (20mL).Methyl alcohol (20mL) solution that in solution, adds 2.0M ammoniacal liquor then.With solution stirring at room 2 hours and evaporation.Mixture from EtOAc and hexane recrystallization purifying to obtain 2-(4-nitrophenoxy)-2-methyl propanamide.
[0629] 2-(4-nitrophenoxy)-2-methyl propanamide is dissolved in methyl alcohol (50mL) and in solution, add 10%Pd-C (500mg).Reaction mixture was reacted 1 hour down at hydrogen (about 40psi).Leach catalyzer by diatomite.With 2-(4-the amino-benzene oxygen)-2-methyl propanamide of filtrate evaporation to obtain white solid.
[0630] with 2-(4-amino-benzene oxygen)-2-methyl propanamide and 2,6-two chloro-5-fluorine pyrimidines (2g) are dissolved in methyl alcohol (20mL) and water (10mL).With the reaction soln stirred overnight at room temperature.Solution with water (100mL) dilution is also ultrasonic.White precipitate is collected by filtering, and washes with water and dry N4-[4-(1-aminocarboxyl-1-methyl) oxyethyl group to obtain solid state] phenyl-2-chloro-5-fluoro-4-PYRIMITHAMINE.
[0631] with N4-[4-(1-aminocarboxyl-1-methyl) oxyethyl group] phenyl-2-chloro-5-fluoro-4-PYRIMITHAMINE (900mg) is dissolved in THF (20mL).In this solution, add trifluoroacetic anhydride (0.8mL) and pyridine (0.7mL).With the reaction soln stirred overnight at room temperature.Use ethyl acetate (100mL) dilution then.Organic layer K 2CO 3The aqueous solution (2 * 100mL), (2 * 100mL) washings of the 1N HCl aqueous solution (100mL) and water.Ethyl acetate layer is separated dry and 2-chloro-N4-[4-(1-cyano group-1-methyl) oxyethyl group of evaporation to obtain white solid] phenyl-5-fluoro-4-PYRIMITHAMINE.
[0632] with 2-chloro-N4-[4-(1-cyano group-1-methyl) oxyethyl group] phenyl-5-fluoro-4-PYRIMITHAMINE (100mg) and 3-aminobenzene sulfonamide (100mg) be dissolved in Virahol (1mL) and TFA (5).Solution is used methyl alcohol (3mL) dilution and ultrasonic then 100 ℃ of heated overnight.Precipitation is leached, with methanol wash and dry N2-(3-amino-sulfonyl) phenyl-N4-[4-(1-cyano group-1-methyl) oxyethyl group to obtain the beige solid shape] phenyl-5-fluoro-2, the 4-pyrimidinediamine. 1H NMR (DMSO-d 6): δ 1.69 (s, 6H), 7.13 (d, J=7.5Hz, 2H), 7.29 (br, 2H), 7.38 (m, 2H), 7.80 (d, J=8.1Hz, 2H), 7.91 (d, J=6.6Hz, 1H), 8.02 (s, 1H), 8.16 (d, J=2.1Hz, 1H), 9.70 (br, 1H), 9.75 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.30; LCMS: purity: 81.69%; MS (m/e): 443.02 (MH +).
[0633] following compound is according to preparing with the similar mode of above embodiment or by method described here or those of skill in the art's currently known methods.
I-126:N4-[4-(1-aminocarboxyl-1-methyl) oxyethyl group] phenyl-N2-(3-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0634] 1H NMR (DMSO-d 6): δ 1.41 (s, 6H), 6.88 (d, J=9.3Hz, 2H), 7.25 (br, 2H), 7.34 (m, 3H), 7.53 (br, 1H), 7.69 (d, J=9.0Hz, 2H), 7.95 (d, J=7.2Hz, 1H), 8.07 (d, J=3.9Hz, 1H), 8.09 (s, 1H), 9.29 (br, 1H), 9.47 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.34; LCMS: purity: 95.58%; MS (m/e): 461.31 (MH +).
I-73:N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-[4-(1-cyano group-1-methyl) oxyethyl group] phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0635] 1H NMR (DMSO-d 6): δ 1.69 (s, 6H), 2.49 (s, 3H), 7.12 (d, J=9.0Hz, 2H), 7.18 (d, J=8.4Hz, 1H), 7.24 (br, 2H), 7.83 (d, J=9.0Hz, 2H), 7.91 (d, J=8.1Hz, 1H), 8.08 (s, 1H), 8.08 (d, J=2.7Hz, 1H), 9.39 (br, 1H), 9.42 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.64; LCMS: purity: 97.27%; MS (m/e): 457.14 (MH +).
I-67: racemize N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-[4-(1-cyano group) oxyethyl group] phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0636] 1H NMR (DMSO-d 6): δ 1.70 (d, J=6.6Hz, 3H), 2.48 (s, 3H), 5.41 (q, J=6.6Hz, 1H), 7.05 (d, J=9.0Hz, 2H), 7.17 (d, J=8.7Hz, 1H), 7.22 (br, 2H), 7.76 (d, J=9.0Hz, 2H), 7.89 (dd, J=2.4,8.4Hz, 1H), 8.07 (m, 2H), 9.32 (br, 1H), 9.39 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.64; LCMS: purity: 95.10%; MS (m/e): 443.46 (MH +).
I-22:N2-(4-amino-sulfonyl) phenyl-N4-(4-cyano group methoxyl group-3-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0637] 1H NMR (DMSO-d 6): δ 2.20 (s, 3H), 5.16 (s, 2H), 7.05 (d, J=9.0Hz, 1H), 7.10 (br, 2H), 7.50 (dd, J=2.7,8.7Hz, 1H), 7.58 (d, J=2.7Hz, 1H), 7.60 (d, J=8.7Hz, 2H), 7.79 (d, J=8.4Hz, 2H), 8.11 (d, J=3.3Hz, 1H), 9.33 (br, 1H), 9.58 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.06; LCMS: purity: 95.53%; MS (m/e): 429.51 (MH +).
I-23:N2-(3-amino-sulfonyl) phenyl-N4-(4-cyano group methoxyl group-3-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine:
[0638] 1H NMR (DMSO-d 6): δ 2.17 (s, 3H), 5.17 (s, 2H), 7.07 (d, J=9.0Hz, 1H), 7.30 (br, 2H), 7.40 (d, J=5.4Hz, 2H), 7.51 (s, 1H), 7.55 (dd, J=2.7,8.7Hz, 1H), 7.93 (m, 2H), 8.17 (d, J=4.5Hz, 1H), 9.80 (br, 1H), 9.92 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.02; LCMS: purity: 98.05%; MS (m/e): 429.64 (MH +).
I-24:N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-(4-cyano group methoxyl group-3-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine:
[0639] 1H NMR (DMSO-d 6): δ 2.17 (s, 3H), 2.49 (s, 3H), 5.16 (s, 2H), 7.05 (d, J=8.7Hz, 1H), 7.17 (d, J=8.4Hz, 1H), 7.25 (br, 2H), 7.52 (d, J=2.1Hz, 1H), 7.57 (d, J=8.7Hz, 1H), 7.87 (dd, J=2.4,8.4Hz, 1H), 7.98 (s, 1H), 8.08 (d, J=3.9Hz, 1H), 9.49 (br, 1H), 9.56 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.28; LCMS: purity: 96.81%; MS (m/e): 443.75 (MH +).
I-113:N4-(4-aminocarboxyl methoxyl group-3-methyl) phenyl-N2-(4-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0640] 1H NMR (DMSO-d 6): δ 2.24 (s, 3H), 4.45 (s, 2H), 6.81 (d, J=9.0Hz, 1H), 7.16 (br, 2H), 7.36 (br, 2H), 7.38 (dd, J=2.1,8.4Hz, 1H), 7.46 (d, J=2.7Hz, 1H), 7.62 (d, J=8.7Hz, 2H), 7.74 (d, J=9.0Hz, 2H), 8.15 (d, J=4.2Hz, 1H), 9.66 (br, 1H), 9.88 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.17; LCMS: purity: 82.30%; MS (m/e): 447.04 (MH +).
I-92:N4-(4-aminocarboxyl methoxyl group-3-methyl) phenyl-N2-(3-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0641] 1H NMR (DMSO-d 6): δ 2.22 (s, 3H), 4.43 (s, 2H), 6.80 (d, J=8.4Hz, 1H), 7.28 (br, 2H), 7.39 (m, 4H), 7.45 (br, 1H), 7.47 (dd, J=2.4Hz, 1H), 7.94 (m, 2H), 8.12 (d, J=4.2Hz, 1H), 9.62 (br, 1H), 9.78 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.45; LCMS: purity: 92.52%; MS (m/e): 447.44 (MH +).
I-114:N4-(4-aminocarboxyl methoxyl group-3,5-dimethyl) phenyl-N2-(4-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0642] 1H NMR (DMSO-d 6): δ 2.24 (s, 6H), 4.14 (s, 2H), 7.17 (br, 2H), 7.34 (s, 2H), 7.48 (br, 1H), 7.59 (br, 1H), 7.62 (d, J=9.0Hz, 2H), 7.76 (d, J=8.7Hz, 2H), 8.16 (d, J=3.9Hz, 1H), 9.53 (br, 1H), 9.81 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.12; LCMS: purity: 93.05%; MS (m/e): 461.43 (MH +).
I-93:N4-(4-aminocarboxyl methoxyl group-3,5-dimethyl) phenyl-N2-(3-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0643] 1H NMR (DMSO-d 6): δ 2.23 (s, 6H), 4.13 (s, 2H), 7.25 (s, 2H), 7.33-7.40 (m, 4H), 7.47 (br, 1H), 7.59 (br, 1H), 7.99 (s, 1H), 8.04 (d, J=7.2Hz, 1H), 8.08 (d, J=3.9Hz, 1H), 9.19 (br, 1H), 9.48 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.22; LCMS: purity: 73.18%; MS (m/e): 461.58 (MH +).
I-25:N2-(4-amino-sulfonyl) phenyl-N4-(4-cyano group methoxyl group-3,5-dimethyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0644] 1H NMR (DMSO-d 6): δ 2.26 (s, 6H), 4.91 (s, 2H), 7.17 (br, 2H), 7.38 (s, 2H), 7.63 (d, J=8.7Hz, 2H), 7.73 (d, J=8.7Hz, 2H), 8.20 (d, J=4.2Hz, 1H), 9.70 (br, 1H), 9.96 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-200.66; LCMS: purity: 96.84%; MS (m/e): 443.05 (MH +).
I-26:N2-(3-amino-sulfonyl) phenyl-N4-(4-cyano group methoxyl group-3,5-dimethyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0645] 1H NMR (DMSO-d 6): δ 2.26 (s, 6H), 4.90 (s, 2H), 7.25 (s, 2H), 7.32 (d, J=8.4Hz, 1H), 7.37 (t, J=7.8Hz, 1H), 7.44 (s, 2H), 7.99 (s, 1H), 8.04 (d, J=7.8Hz, 1H), 8.09 (d, J=3.6Hz, 1H), 9.25 (br, 1H), 9.50 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.11; LCMS: purity: 93.34%; MS (m/e): 443.04 (MH +).
I-27:N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-(4-cyano group methoxyl group-3,5-dimethyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0646] 1H NMR (DMSO-d 6): δ 2.25 (s, 6H), 2.49 (s, 3H), 4.90 (s, 2H), 7.16 (d, J=8.1Hz, 1H), 7.22 (s, 2H), 7.43 (s, 2H), 7.94 (dd, J=2.1,8.1Hz, 1H), 8.01 (d, J=2.4Hz, 1H), 8.06 (d, J=3.6Hz, 1H), 9.21 (br, 1H), 9.38 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-217.5; LCMS: purity: 96.48%; MS (m/e): 457.39 (MH +).
I-28:N2-(4-amino-sulfonyl-3-p-methoxy-phenyl)-N4-(4-cyano group methoxyl group) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0647] 1H NMR (DMSO-d 6): δ 3.67 (s, 3H), 5.14 (s, 2H), 6.80 (s, 2H), 7.04 (d, J=9.0Hz, 2H), 7.37 (m, 1H), 7.51 (m, 2H), 7.70 (d, J=9.3Hz, 2H), 8.12 (d, 1H), 9.40 (br, 1H), 9.52 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.82; LCMS: purity: 89.30%; MS (m/e): 445.37 (MH +).
III-9:N2-(4-amino-sulfonyl-3-methoxyl group) phenyl-N4-(4-cyano methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0648] 1H NMR (DMSO-d 6): δ 3.70 (s, 3H), 4.00 (s, 2H), 6.82 (s, 2H), 7.30 (d, J=8.7Hz, 2H), 7.39 (d, J=8.7Hz, 1H), 7.52 (m, 2H), 7.78 (d, J=8.4Hz, 2H), 8.17 (d, J=3.0Hz, 1H), 9.51 (br, 1H), 9.56 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.21; LCMS: purity: 89.37%; MS (m/e): 429.14 (MH +).
I-70: racemize N2-(4-amino-sulfonyl-3-methoxyl group) phenyl-N4-[4-(1-cyano group) oxyethyl group] phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0649] 1H NMR (DMSO-d 6): δ 3.69 (s, 3H), 5.41 (q, J=6.6Hz, 1H), 6.80 (s, 2H), 7.06 (d, J=8.7Hz, 2H), 7.37 (d, J=8.7Hz, 1H), 7.50 (m, 2H), 7.72 (d, J=9.0Hz, 2H), 8.13 (d, J=3.3Hz, 1H), 9.41 (br, 1H), 9.53 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.75; LCMS: purity: 93.14%; MS (m/e): 459.17 (MH +).
I-60: racemize N2-(4-amino-sulfonyl) phenyl-N4-[4-(1-cyano group) oxyethyl group-3-methyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0650] 1H NMR (DMSO-d 6): δ 1.72 (d, J=6.6Hz, 3H), 2.20 (s, 3H), 5.37 (q, J=6.6Hz, 1H), 7.11 (d, J=8.7Hz, 1H), 7.13 (br, 2H), 7.48 (dd, J=2.7,8.4Hz, 1H), 7.58 (d, J=2.7Hz, 1H), 7.63 (d, J=9.0Hz, 2H), 7.74 (d, J=8.7Hz, 2H), 8.18 (d, J=4.2Hz, 1H), 9.70 (br, 1H), 9.90 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-200.99; LCMS: purity: 97.08%; MS (m/e): 443.15 (MH +).
I-61: racemize N2-(3-amino-sulfonyl) phenyl-N4-[4-(1-cyano group) oxyethyl group-3-methyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0651] 1H NMR (DMSO-d 6): δ 1.72 (d, J=6.6Hz, 3H), 2.18 (s, 3H), 5.36 (q, J=6.6Hz, 1H), 7.10 (d, J=8.4Hz, 1H), 7.29 (br, 2H), 7.40 (d, J=5.1Hz, 2H), 7.53 (s, 1H), 7.56 (dd, J=2.1,9.0Hz, 1H), 7.94 (m, 2H), 8.17 (d, J=3.9Hz, 1H), 9.75 (br, 1H), 9.89 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.06; LCMS: purity: 95.36%; MS (m/e): 443.64 (MH +).
I-62: racemize N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-[4-(1-cyano group) oxyethyl group-3-methyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0652] 1H NMR (DMSO-d 6): δ 1.72 (d, J=6.6Hz, 3H), 2.16 (s, 3H), 2.50 (s, 3H), 5.36 (q, J=6.6Hz, 1H), 7.10 (d, J=8.7Hz, 1H), 7.21 (d, J=8.4Hz, 1H), 7.29 (br, 2H), 7.50 (s, 1H), 7.54 (d, J=8.7Hz, 1H), 7.82 (dd, J=2.1,8.1Hz, 1H), 7.90 (d, 1H), 8.16 (d, J=4.5Hz, 1H), 9.89 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-201.19; LCMS: purity: 93.72%; MS (m/e): 457.18 (MH +).
I-94:N4-(4-aminocarboxyl methoxyl group) phenyl-N2-(3-amino-sulfonyl-4-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0653] 1H NMR (DMSO-d 6): δ 2.49 (s, 3H), 4.40 (s, 2H), 6.91 (d, J=9.0Hz, 2H), 7.15 (d, J=8.7Hz, 1H), 7.22 (s, 2H), 7.38 (br, 1H), 7.51 (br, 1H), 7.67 (d, J=9.0Hz, 2H), 7.87 (d, J=6.6Hz, 1H), 8.03 (d, J=3.9Hz, 1H), 8.09 (s, 1H), 9.23 (br, 1H), 9.35 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-203.07; LCMS: purity: 62.07%; MS (m/e): 447.05 (MH +).
I-90:N4-(3-aminocarboxyl methoxyl group) phenyl-N2-(3-amino-sulfonyl-4-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine:
[0654] 1H NMR (DMSO-d 6): δ 2.49 (s, 3H), 4.42 (s, 2H), 6.64 (dd, J=2.7,8.4Hz, 1H), 7.22 (m, 4H), 7.43 (m, 2H), 7.49 (s, 1H), 7.58 (s, 1H), 7.91 (dd, J=1.8,8.7Hz, 1H), 8.09 (d, J=3.0Hz, 1H), 8.16 (d, J=1.8Hz, 1H), 9.34 (br, 1H), 9.36 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.17; LCMS: purity: 83.29%; MS (m/e): 447.13 (MH +).
I-118:N4-[4-(1-aminocarboxyl) oxyethyl group] phenyl-N2-(3-amino-sulfonyl-4-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0655] 1H NMR (DMSO-d 6): δ 1.44 (d, J=6.6Hz, 3H), 2.53 (s, 3H), 4.60 (q, J=6.6Hz, 1H), 6.88 (d, J=8.7Hz, 2H), 7.21 (d, J=8.1Hz, 1H), 7.24 (br, 1H), 7.30 (s, 2H), 7.51 (br, 1H), 7.57 (d, J=9.0Hz, 2H), 7.76 (d, J=8.1Hz, 1H), 7.92 (s, 1H), 8.15 (d, J=4.8Hz, 1H), 9.95 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-201.03; LCMS: purity: 89.00%; MS (m/e): 461.09 (MH +).
I-127:N4-[4-(1-aminocarboxyl-1-methyl) oxyethyl group] phenyl-N2-(3-amino-sulfonyl-4-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0656] 1H NMR (DMSO-d 6): δ 1.41 (s, 6H), 2.49 (s, 3H), 6.88 (d, J=8.7Hz, 2H), 7.14 (d, J=8.7Hz, 1H), 7.22 (s, 2H), 7.24 (s, 1H), 7.52 (s, 1H), 7.69 (d, J=9.0Hz, 2H), 7.88 (dd, J=2.4,8.1Hz, 1H), 8.04 (d, J=3.6Hz, 1H), 8.09 (d, J=1.8Hz, 1H), 9.25 (br, 1H), 9.35 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.91; LCMS: purity: 92.68%; MS (m/e): 475.18 (MH +).
I-95:N4-(4-aminocarboxyl methoxyl group-3-methyl) phenyl-N2-(3-amino-sulfonyl-4-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0657] 1H NMR (DMSO-d 6): δ 2.22 (s, 3H), 2.49 (s, 3H), 4.42 (s, 2H), 6.78 (d, J=8.7Hz, 1H), 7.14 (d, J=8.4Hz, 1H), 7.20 (s, 2H), 7.35 (s, 1H), 7.39 (s, 1H), 7.48 (m, 2H), 7.90 (dd, J=2.4,8.4Hz, 1H), 8.01 (d, J=3.6Hz, 1H), 8.06 (d, J=2.4Hz, 1H), 9.14 (br, 1H), 9.32 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-203.12; LCMS: purity: 93.67%; MS (m/e): 461.16 (MH +).
I-119: racemize N4-[4-(1-aminocarboxyl) oxyethyl group-3-methyl] phenyl-N2-(4-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0658] 1H NMR (DMSO-d 6): δ 1.47 (d, J=6.6Hz, 3H), 2.22 (s, 3H), 4.64 (q, J=6.6Hz, 1H), 6.80 (d, J=8.7Hz, 1H), 7.18 (s, 1H), 7.27 (br, 2H), 7.32 (dd, J=2.4,8.4Hz, 1H), 7.42 (d, J=2.4Hz, 1H), 7.51 (s, 1H), 7.66 (s, 4H), 8.29 (d, J=5.1Hz, 1H), 10.32 (br, 1H), 10.63 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-199.40; LCMS: purity: 88.84%; MS (m/e): 461.14 (MH +).
I-120: racemize N4-[4-(1-aminocarboxyl) oxyethyl group-3-methyl] phenyl-N2-(3-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0659] 1H NMR (DMSO-d 6): δ 1.45 (d, J=6.6Hz, 3H), 2.19 (s, 3H), 4.58 (q, J=6.6Hz, 1H), 6.76 (d, J=8.7Hz, 1H), 7.26 (s, 1H), 7.31 (s, 2H), 7.41 (m, 5H), 7.86 (s, 1H), 7.93 (d, J=7.5Hz, 1H), 8.17 (d, J=4.5Hz, 1H), 9.87 (br, 1H), 10.03 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-200.79; LCMS: purity: 87.27%; MS (m/e): 461.08 (MH +).
I-96:N4-(4-aminocarboxyl methoxyl group-3,5-dimethyl) phenyl-N2-(3-amino-sulfonyl-4-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0660] 1H NMR (DMSO-d 6): δ 2.21 (s, 6H), 2.48 (s, 3H), 4.12 (s, 2H), 7.14 (d, J=8.4Hz, 1H), 7.23 (s, 2H), 7.38 (s, 2H), 7.46 (br, 1H), 7.60 (br, 1H), 7.91 (dd, J=8.4Hz, 1H), 7.99 (d, 1H), 8.03 (d, J=3.6Hz, 1H), 9.15 (br, 1H), 9.33 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.71; LCMS: purity: 83.51%; MS (m/e): 475.19 (MH +).
I-121: racemize N4-[4-(1-aminocarboxyl) oxyethyl group-3-methyl] phenyl-N2-(3-amino-sulfonyl-4-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0661] 1H NMR (DMSO-d 6): δ 1.45 (d, J=6.6Hz, 3H), 2.18 (s, 3H), 2.52 (s, 3H), 4.58 (q, J=6.6Hz, 1H), 6.76 (d, J=9.6Hz, 1H), 7.20 (d, J=8.4Hz, 1H), 7.24 (s, 1H), 7.31 (s, 2H), 7.40 (br, 3H), 7.80 (d, J=8.4Hz, 1H), 7.86 (s, 1H), 8.16 (d, J=4.8Hz, 1H), 10.02 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-200.86; LCMS: purity: 87.82%; MS (m/e): 475.06 (MH +).
I-122: racemize N4-[4-(1-aminocarboxyl) oxyethyl group-3, the 5-dimethyl] phenyl-N2-(4-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0662] 1H NMR (DMSO-d 6): δ 1.33 (d, J=6.6Hz, 3H), 2.24 (s, 6H), 4.29 (q, J=6.6Hz, 1H), 7.15 (br, 2H), 7.28 (br, 1H), 7.34 (s, 2H), 7.55 (br, 1H), 7.60 (d, J=9.0Hz, 2H), 7.77 (d, J=9.0Hz, 2H), 8.13 (d, J=3.9Hz, 1H), 9.39 (br, 1H), 9.70 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.52; LCMS: purity: 89.76%; MS (m/e): 475.09 (MH +).
I-123: racemize N4-[4-(1-aminocarboxyl) oxyethyl group-3, the 5-dimethyl] phenyl-N2-(3-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0663] 1H NMR (DMSO-d 6): δ 1.32 (d, J=6.6Hz, 3H), 2.22 (s, 6H), 4.27 (q, J=6.6Hz, 1H), 7.25 (s, 2H), 7.28 (br, 1H), 7.33 (m, 2H), 7.40 (s, 2H), 7.53 (br, 1H), 7.98 (s, 1H), 8.05 (m, 1H), 8.07 (d, J=3.6Hz, 1H), 9.17 (br, 1H), 9.48 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.22; LCMS: purity: 90.76%; MS (m/e): 475.12 (MH +).
I-124: racemize N4-[4-(1-aminocarboxyl) oxyethyl group-3, the 5-dimethyl] phenyl-N2-(3-amino-sulfonyl-4-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0664] 1H NMR (DMSO-d 6): δ 1.32 (d, J=6.6Hz, 3H), 2.22 (s, 6H), 2.49 (s, 3H), 4.27 (q, J=6.6Hz, 1H), 7.13 (d, J=8.4Hz, 1H), 7.23 (s, 2H), 7.28 (s, 1H), 7.39 (s, 2H), 7.54 (s, 1H), 7.94 (dd, J=2.1,8.4Hz, 1H), 8.01 (d, J=2.4Hz, 1H), 8.04 (d, J=3.6Hz, 1H), 9.13 (br, 1H), 9.36 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.79; LCMS: purity: 96.27%; MS (m/e): 489.17 (MH +).
I-63: racemize N2-(4-amino-sulfonyl) phenyl-N4-[4-(1-cyano group) oxyethyl group-3, the 5-dimethyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0665] 1H NMR (DMSO-d 6): δ 1.71 (d, J=6.6Hz, 3H), 2.27 (s, 6H), 5.01 (q, J=6.6Hz, 1H), 7.16 (br, 2H), 7.39 (s, 2H), 7.64 (d, J=9.0Hz, 2H), 7.74 (d, J=9.3Hz, 2H), 8.20 (d, J=3.9Hz, 1H), 9.72 (br, 1H), 9.98 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-200.54; LCMS: purity: 97.32%; MS (m/e): 457.15 (MH +).
I-71: racemize N2-(3-amino-sulfonyl) phenyl-N4-[4-(1-cyano group) oxyethyl group-3, the 5-dimethyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0666] 1H NMR (DMSO-d 6): δ 1.71 (d, J=6.6Hz, 3H), 2.25 (s, 6H), 5.01 (q, J=6.6Hz, 1H), 7.31 (s, 2H), 7.40 (s, 4H), 7.87 (s, 1H), 7.99 (m, 1H), 8.20 (d, J=4.2Hz, 1H), 9.78 (br, 1H), 9.98 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-200.67; LCMS: purity: 99.05%; MS (m/e): 457.59 (MH +).
I-72: racemize N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-[4-(1-cyano group) oxyethyl group-3, the 5-dimethyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0667] 1H NMR (DMSO-d 6): δ 1.71 (d, J=6.6Hz, 3H), 2.25 (s, 6H), 2.50 (s, 3H), 5.01 (q, J=6.6Hz, 1H), 7.21 (d, J=8.4Hz, 1H), 7.30 (s, 2H), 7.40 (s, 2H), 7.89 (m, 2H), 8.16 (d, J=4.5Hz, 1H), 9.74 (br, 1H), 9.83 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.19; LCMS: purity: 97.45%; MS (m/e): 471.60 (MH +).
I-7:N2-(4-amino-sulfonyl-3-methoxyl group) phenyl-N4-(3-cyano group methoxyl group) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0668] 1H NMR (DMSO-d 6): δ 3.72 (s, 3H), 5.13 (s, 2H), 6.80 (dd, J=9.3Hz, 1H), 6.82 (br, 2H), 7.31 (t, J=8.1Hz, 1H), 7.39 (d, 1H), 7.51 (m, 4H), 8.18 (d, J=3.6Hz, 1H), 9.51 (br, 1H), 9.55 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.04; LCMS: purity: 91.71%; MS (m/e): 445.00 (MH +).
I-77:N2-(4-amino-sulfonyl-3-methoxyl group) phenyl-N4-[4-(1-cyano group-1-methyl) oxyethyl group] phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0669] 1H NMR (DMSO-d 6): δ 1.70 (s, 6H), 3.72 (s, 3H), 6.80 (s, 2H), 7.13 (d, J=8.7Hz, 2H), 7.43 (m, 1H), 7.49 (m, 2H), 7.80 (d, J=8.7Hz, 2H), 8.15 (d, J=3.6Hz, 1H), 9.48 (br, 1H), 9.56 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.44; LCMS: purity: 84.88%; MS (m/e): 473.10 (MH +).
I-29:N2-(4-amino-sulfonyl-3-methoxyl group) phenyl-N4-(4-cyano group methoxyl group-3-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0670] 1H NMR (DMSO-d 6): δ 2.17 (s, 3H), 3.66 (s, 3H), 5.16 (s, 2H), 6.80 (br, 2H), 7.04 (d, J=8.4Hz, 1H), 7.38 (s, 1H), 7.51 (m, 4H), 8.11 (d, J=3.6Hz, 1H), 9.33 (br, 1H), 9.52 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.86; LCMS: purity: 70.82%; MS (m/e): 459.02 (MH +).
I-32:N2-(4-amino-sulfonyl-3-methoxyl group) phenyl-N4-(4-cyano group methoxyl group-3,5-dimethyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0671] 1H NMR (DMSO-d 6): δ 2.24 (s, 6H), 3.68 (s, 3H), 4.89 (s, 2H), 6.81 (s, 2H), 7.36 (dd, J=1.8,8.4Hz, 1H), 7.41 (s, 2H), 7.44 (d, J=1.5Hz, 1H), 7.51 (d, J=8.7Hz, 1H), 8.12 (d, J=3.9Hz, 1H), 9.30 (br, 1H), 9.53 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.49; LCMS: purity: 70.55%; MS (m/e): 472.94 (MH +).
I-64: racemize N2-(4-amino-sulfonyl-3-methoxyl group) phenyl-N4-[4-(1-cyano group) oxyethyl group-3-methyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0672] 1H NMR (DMSO-d 6): δ 1.71 (d, J=6.6Hz, 3H), 2.18 (s, 3H), 3.67 (s, 3H), 5.34 (q, J=6.6Hz, 1H), 6.80 (br, 2H), 7.08 (d, J=8.4Hz, 1H), 7.36 (d, J=8.7Hz, 1H), 7.53 (m, 4H), 8.12 (d, J=2.7Hz, 1H), 9.34 (br, 1H), 9.53 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.78; LCMS: purity: 77.96%; MS (m/e): 473.14 (MH +).
I-33:N2-(3-amino-sulfonyl-4-fluorine) phenyl-N4-(4-cyano group methoxyl group) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0673] 1H NMR (DMSO-d 6): δ 5.16 (s, 2H), 7.07 (d, J=9.3Hz, 2H), 7.31 (t, J=9.3Hz, 1H), 7.61 (s, 2H), 7.64 (d, J=8.7Hz, 2H), 7.88 (m, 2H), 8.20 (d, J=4.8Hz, 1H), 10.04 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-200.77 ,-158.04; LCMS: purity: 97.97%; MS (m/e): 433.69 (MH +).
III-10:N2-(3-amino-sulfonyl-4-fluorine) phenyl-N4-(4-cyano methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0674] 1H NMR (DMSO-d 6): δ 4.00 (s, 2H), 7.28 (t, J=9.3Hz, 1H), 7.31 (d, J=8.4Hz, 2H), 7.59 (s, 2H), 7.75 (d, J=8.7Hz, 2H), 7.92 (dd, J=3.6,8.1Hz, 1H), 7.97 (d, J=3.9Hz, 1H), 8.17 (d, J=3.9Hz, 1H), 9.77 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-201.13 ,-159.13; LCMS: purity: 99.78%; MS (m/e): 417.57 (MH +).
I-68: racemize N2-(3-amino-sulfonyl-4-fluorine) phenyl-N4-[4-(1-cyano group) oxyethyl group] phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0675] LCMS: purity: 89.22%; MS (m/e): 447.79 (MH +).
I-74:N2-(3-amino-sulfonyl-4-fluorine) phenyl-N4-[4-(1-cyano group-1-methyl) oxyethyl group] phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0676] 1H NMR (DMSO-d 6): δ 1.69 (s, 6H), 7.14 (d, J=9.0Hz, 2H), 7.28 (t, J=9.3Hz, 1H), 7.59 (s, 2H), 7.75 (d, J=8.7Hz, 2H), 7.94 (m, 2H), 8.17 (d, J=3.9Hz, 1H), 9.81 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-201.14 ,-159.13; LCMS: purity: 100%; MS (m/e): 461.72 (MH +).
I-34:N2-(3-amino-sulfonyl-4-fluorine) phenyl-N4-(4-cyano group methoxyl group-3-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0677] 1H NMR (DMSO-d 6): δ 2.16 (s, 3H), 5.17 (s, 2H), 7.07 (d, J=8.7Hz, 1H), 7.27 (t, J=9.3Hz, 1H), 7.46 (d, J=2.1Hz, 1H), 7.54 (dd, J=2.4,8.7Hz, 1H), 7.60 (s, 2H), 7.92 (m, 2H), 8.16 (d, J=4.2Hz, 1H), 9.82 (br, 1H), 9.90 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.08 ,-158.67; LCMS: purity: 99.77%; MS (m/e): 447.69 (MH +).
I-35:N2-(3-amino-sulfonyl-4-fluorine) phenyl-N4-(4-cyano group methoxyl group-3,5-dimethyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0678] LCMS: purity: 96.22%; MS (m/e): 461.84 (MH +).
I-69: racemize N2-(3-amino-sulfonyl-4-fluorine) phenyl-N4-[4-(1-cyano group) oxyethyl group-3-methyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0679] 1H NMR (DMSO-d 6): δ 1.72 (d, J=6.6Hz, 3H), 2.17 (s, 3H), 5.36 (q, J=6.6Hz, 1H), 7.11 (d, J=9.0Hz, 1H), 7.26 (t, J=9.3Hz, 1H), 7.49 (s, 1H), 7.59 (m, 3H), 7.92 (m, 2H), 8.14 (d, J=4.2Hz, 1H), 9.73 (br, 1H), 9.82 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.28 ,-158.94; LCMS: purity: 99.33%; MS (m/e): 461.74 (MH +).
Embodiment 28
VII-9:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[2-amino-3-Methoxy Pyridine-6-yl]-5-fluoro-2,4-pyrimidinediamine (66)
[0680] with the N4-[2-in the methyl alcohol (1mL) (tertiary butyl carbonyl) amino-3-Methoxy Pyridine-6-yl]-(25mg, 0.07mmol) mixture with 3-amino-sulfonyl-4-monomethylaniline (15mg) vibrated 48 hours in 100 ℃ in tube sealing 2-chloro-5-fluoro-4-PYRIMITHAMINE (65).Then with reaction mixture chromatographic separation (silica gel, CH 2Cl 2, 2-4%2N NH then 3The CH of/MeOH 2Cl 2Solution) to obtain N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(2-amino-3-Methoxy Pyridine-6-yl)-5-fluoro-2,4-pyrimidinediamine (66).(note: N-tertiary butyl carbonyl is cut to obtain the free amine functional group in this reaction).LCMS: purity: 90%; MS (m/z): 420 (MH +).
[0681] following compound is according to preparing with embodiment 28 similar modes.
VII-7:N2-(3-amino-sulfonyl phenyl)-N4-(2-amino-3-Methoxy Pyridine-6-yl)-5-fluoro-2, the 4-pyrimidinediamine
[0682] LCMS: purity: 92%; MS (m/z): 406 (MH +).
VII-8:N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(2-amino-3-Methoxy Pyridine-6-yl)-5-fluoro-2, the 4-pyrimidinediamine
[0683] LCMS: purity: 92%; MS (m/z): 440 (MH +).
VII-10:N4-(2-amino-3-Methoxy Pyridine-6-yl)-N2-[3-(ethoxy carbonyl methylene radical) amino-sulfonyl phenyl)-and 5-fluoro-2, the 4-pyrimidinediamine
[0684] LCMS: purity: 93%; MS (m/z): 526 (MH +).
VI-96:N2-(3-butyl amino-sulfonyl phenyl)-N4-(3-cyano group-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0685] 1H?NMR(DMSO-d 6)：δ9.63(s，1H)，9.60(s，1H)，8.20-8.19(d，J＝3.0Hz，1H)，8.17-8.16(d，J＝3.0Hz，1H)，8.02-7.99(d，J＝9.0Hz，2H)，7.48-7.38(m，3H)，7.30-7.27(d，J＝9.0Hz，2H)，2.74-2.70(m，2H)，2.45(s，3H)，1.36-1.31(m，2H)，1.26-1.18(m，2H)，0.81-0.76(m，3H)；LCMS(m/z)：455.02(M +)。
VI-97:N2-(3-butyl amino-sulfonyl phenyl)-N4-(3-chloro-4-fluorophenyl) 5-fluoro-2, the 4-pyrimidinediamine
[0686] 1H?NMR(DMSO-d 6)：δ9.60(s，1H)，9.55(s，1H)，8.17-8.16(d，J＝3.0Hz，1H)，8.03-8.00(m，2H)，7.97(br?s，1H)，7.82-7.76(m，1H)，7.48-7.44(m，1H)，7.42(s，1H)，7.39-7.33(m，1H)，7.30-7.27(br?d，J＝9.0Hz，1H)，2.76-2.70(m，2H)，1.37-1.29(m，2H)，1.26-1.18(m，2H)，0.81-0.76(m，3H)；LCMS(m/z)：470.33(M +)。
VI-98:N2-(3-amino-sulfonyl phenyl)-N4-(3-cyano group-4-fluorophenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0687] 1H?NMR(DMSO-d 6)：δ9.72(s，1H)，9.66(s，1H)，8.39-8.36(m，1H)，8.20-8.19(d，J＝3.0Hz，1H)，8.08(br?s，2H)，7.93-7.90(d，J＝9.0Hz，1H)，7.51-7.34(m，3H)，7.27(s，2H)；LCMS(m/z)：403.18(M +)。
VI-99:N2-(3-amino-sulfonyl phenyl)-N4-(3-cyano group-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0688] 1H?NMR(DMSO-d 6)：δ9.63(s，1H)，9.59(s，1H)，8.21-8.20(d，J＝3.0Hz，1H)，8.17-8.16(d，J＝3.0Hz，1H)，8.07(s，1H)，8.00-7.94(m，2H)，7.45-7.34(m，3H)，7.27(s，2H)，2.45(s，3H)；LCMS(m/z)：399.32(M +)。
X-3:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(2 methyl indole-5-methylene)-2, the 4-pyrimidinediamine
[0689] 1H?NMR(DMSO-d 6)：δ10.77(s，1H)，9.36(s，1H)，8.27(s，1H)，7.99(m，1H)，7.88-7.87(d，J＝3Hz，1H)，7.83-7.81(d，J＝6.0Hz，1H)，7.35-6.88(m，4H)，6.70-6.66(d，J＝12Hz，2H)，6.03(s，1H)，4.66-4.64(d，J＝6Hz，2H)，2.33(s，3H)；LCMS(m/z)：427.20(M +)。
Embodiment 29
I-30:N4-(4-cyano group methylene radical oxygen base) phenyl-5-fluoro-N2-(4-methyl-3-propionyl amino-sulfonyl) phenyl-2,4-pyrimidinediamine (68)
[0690] with N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-(4-cyano group methylene radical oxygen base) phenyl-5-fluoro-2; 4-pyrimidinediamine (67) (400mg), propionic anhydride (0.24mL), N, N-dimethyl aminopyridine (DMAP) is (60mg) and triethylamine (0.16mL) stirred overnight at room temperature in THF (15mL).Solution dilutes with ethyl acetate (100mL) and water (100mL) and salt solution (100mL) washing.Evaporate organic layer then.Resistates from EtOAc and hexane recrystallization to obtain N4-(4-cyano group methylene radical oxygen base) phenyl-5-fluoro-N2-(4-methyl-3-propionyl amino-sulfonyl) phenyl-2,4-pyrimidinediamine (68). 1H NMR (DMSO-d 6): δ 0.88 (t, J=7.5Hz, 3H), 2.24 (q, J=7.5Hz, 2H), 2.49 (s, 3H), 5.15 (s, 2H), 7.04 (d, J=9.3Hz, 2H), 7.20 (d, J=8.1Hz, 1H), 7.75 (d, J=9.0Hz, 2H), 8.00 (dd, J=2.1,8.1Hz, 1H), 8.08 (d, J=3.9Hz, 1H), 8.14 (s, 1H), 9.35 (br, 1H), 9.48 (br, 1H), 12.02 (br, 1H); 19F NMR (DMSO-d 6): δ-202.71; LCMS: purity: 95.67%; MS (m/z): 485.09 (MH +).
I-31:N4-(4-cyano group methylene radical oxygen base) phenyl-5-fluoro-N2-(4-methyl-3-propionyl amino-sulfonyl) phenyl-2,4-pyrimidinediamine sodium salt (69)
[0691] with N4-(4-cyano group methoxyl group) phenyl-5-fluoro-N2-(4-methyl-3-propionyl amino-sulfonyl) phenyl-2,4-pyrimidinediamine (68) (583.5mg) is dissolved in methyl alcohol (5mL) and water (1mL).In solution, add the 1N NaOH aqueous solution (1.2mL).Then with solution evaporation and freeze-drying to obtain N4-(4-cyano group methylene radical oxygen base) phenyl-5-fluoro-N2-(4-methyl-3-propionyl amino-sulfonyl) phenyl-2,4-pyrimidinediamine sodium salt (69). 1H NMR (DMSO-d 6): δ 0.85 (t, J=7.5Hz, 3H), 1.90 (q, J=7.5Hz, 2H), 2.42 (s, 3H), 5.13 (s, 2H), 6.94 (d, J=8.1Hz, 1H), 7.04 (d, J=9.0Hz, 2H), 7.70 (d, J=7.5Hz, 1H), 7.78 (d, J=9.0Hz, 2H), 7.85 (d, J=2.1Hz, 1H), 8.02 (d, J=3.9Hz, 1H), 9.17 (br, 1H), 9.22 (br, 1H); 19F NMR (DMSO-d 6): δ-203.90; LCMS: purity: 100%; MS (m/z): 485.39 (MH +).
[0692] following compound is according to preparing with embodiment 29 similar modes.
I-36:N2-(3-acetylamino alkylsulfonyl-4-methyl) phenyl-N4-(4-cyano group methylene radical oxygen base) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[0693] 1H NMR (DMSO-d 6): δ 1.94 (s, 3H), 2.47 (s, 3H), 5.15 (s, 2H), 7.04 (d, J=9.0Hz, 2H), 7.21 (d, J=8.4Hz, 1H), 7.75 (d, J=9.0Hz, 2H), 8.02 (dd, J=2.4,8.4Hz, 1H), 8.08 (d, J=3.6Hz, 1H), 8.12 (d, J=2.1Hz, 1H), 9.34 (br, 1H), 9.48 (br, 1H), 12.06 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.71; LCMS: purity: 99.34%; MS ((m/z): 471.71 (MH +).
I-37:N4-(4-cyano group methylene radical oxygen base) phenyl-5-fluoro-N2-(3-isobutyryl amino-sulfonyl-4-methyl) phenyl-2, the 4-pyrimidinediamine
[0694] 1H NMR (DMSO-d 6): δ 0.94 (d, J=6.9Hz, 6H), 2.47 (m, 1H), 2.47 (s, 3H), 5.15 (s, 2H), 7.04 (d, J=8.7Hz, 2H), 7.19 (d, J=8.7Hz, 1H), 7.75 (d, J=9.3Hz, 2H), 7.97 (dd, J=2.4,8.4Hz, 1H), 8.07 (d, J=3.6Hz, 1H), 8.15 (d, J=2.1Hz, 1H), 9.34 (br, 1H), 9.47 (br, 1H), 12.02 (br, 1H); 19F NMR (DMSO-d 6): δ-202.77; LCMS: purity: 94.84%; MS (m/z): 499.74 (MH +).
I-38:N2-(3-acetylamino alkylsulfonyl-4-methyl) phenyl-N4-(4-cyano group methylene radical oxygen base) phenyl-5-fluoro-2,4-pyrimidinediamine sodium salt
[0695] 1H NMR (DMSO-d 6): δ 1.63 (s, 3H), 2.42 (s, 3H), 5.13 (s, 2H), 6.95 (d, J=8.4Hz, 1H), 7.03 (d, J=9.3Hz, 2H), 7.71 (d, J=8.1Hz, 1H), 7.78 (d, J=9.3Hz, 2H), 7.84 (d, J=2.4Hz, 1H), 8.02 (d, J=3.6Hz, 1H), 9.18 (br, 1H), 9.22 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-203.87; LCMS: purity: 91.01%; MS (m/z): 471.18 (MH +).
I-39:N4-(4-cyano group methylene radical oxygen base) phenyl-5-fluoro-N2-(3-isobutyryl amino-sulfonyl-4-methyl) phenyl-2,4-pyrimidinediamine sodium salt
[0696] 1H NMR (DMSO-d 6): δ 0.88 (d, J=6.9Hz, 6H), 2.09 (p, J=6.9Hz, 1H), 2.42 (s, 3H), 5.13 (s, 2H), 6.94 (d, J=7.8Hz, 1H), 7.04 (d, J=8.7Hz, 2H), 7.68 (d, J=5.7Hz, 1H), 7.78 (d, J=9.3Hz, 2H), 7.86 (s, 1H), 8.02 (d, J=3.9Hz, 1H), 9.17 (br, 1H), 9.22 (br, 1H); 19F NMR (DMSO-d 6): δ-203.93; LCMS: purity: 91.73%; MS (m/z): 499.38 (MH +).
I-48:N4-(4-cyano group methoxyl group-3-fluorophenyl)-5-fluoro-N2-(4-methyl-3-propionyl amino-sulfonyl phenyl)-2, the 4-pyrimidinediamine
[0697] 1H NMR (DMSO-d 6): δ 0.89 (t, J=7.5Hz, 3H), 2.24 (q, J=7.5Hz, 2H), 2.48 (s, 3H), 5.20 (s, 2H), 7.25 (m, 2H), 7.58 (d, J=9.9Hz, 1H), 7.94 (dd, J=2.7,13.8Hz, 1H), 8.02 (dd, J=2.7,8.4Hz, 1H), 8.12 (d, J=3.6Hz, 1H), 8.16 (d, J=2.1Hz, 1H), 9.50 (br, 1H), 9.58 (br, 1H), 12.03 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-171.26 ,-202.29; LCMS: purity: 95.69%; MS (m/e): 503.74 (MH +).
I-49:N4-(4-cyano group methoxyl group-3-fluorophenyl)-5-fluoro-N2-(4-methyl-3-propionyl amino-sulfonyl phenyl)-2,4-pyrimidinediamine sodium salt
[0698] 1H NMR (DMSO-d 6): δ 0.85 (t, J=7.5Hz, 3H), 1.93 (q, 2H), 2.43 (s, 3H), 5.19 (s, 2H), 6.98 (d, J=7.8Hz, 1H), 7.27 (t, J=9.3Hz, 1H), 7.66 (d, J=9.9Hz, 1H), 7.75 (d, 1H), 7.88 (m, 1H), 7.95 (d, 1H), 8.07 (d, J=3.6Hz, 1H), 9.32 (br, 1H), 9.38 (br, 1H); LCMS: purity: 84.54%; MS (m/e): 503.45 (MH +).
VI-12:N2-[3-(N-ethanoyl) amino-sulfonyl-4-chloro-phenyl-]-N4-(3-chloro-4-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0699] LCMS: purity: 89%, MS (m/e): 501 (MH +).
I-264:5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-3-yl) methylene radical oxygen base phenyl]-the N2-[(3-N-propionamido) the alkylsulfonyl phenyl)]-2, the 4-pyrimidinediamine
[0700] 1H?NMR(DMSO?d 6，300MHz)：δ11.96(s，1H)，9.56(s，1H)，9.33(s，1H)，8.17(s，1H)，8.07(m，2H)，7.69(d，2H，J＝8.7Hz)，7.37(m，2H)，7.01(d，2H，J＝9.0Hz)，5.46(s，2H)，2.36(s，3H)，2.22(q，2H，J＝7.5Hz)，0.88(t，3H，J＝7.5Hz)；LCMS(m/z)：528(MH +)。
I-273:5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-3-yl) methylene radical oxygen base phenyl]-the N2-[(3-N-propionamido) the alkylsulfonyl phenyl)]-2,4-pyrimidinediamine sodium salt
[0701] 1H?NMR(D 2O，300MHz)：δ7.61(s，1H)，7.51(s，1H)，7.45(d，1H，J＝7.5Hz)，7.26(d，1H，J＝7.5Hz)，7.11(d，2H，J＝6.9Hz)，7.00(t，1H，J＝7.8Hz)，6.67(d，2H，J＝7.5Hz)，5.16(s，2H)，2.26(s，3H)，2.03(q，2H，J＝7.5Hz)，0.86(t，3H，J＝7.8Hz)；LCMS(m/z)：528(MH +)。
III-68:5-fluoro-N4-[4-(4-pyridylmethyl) phenyl]-the N2-[(3-N-propionamido) the alkylsulfonyl phenyl)]-2, the 4-pyrimidinediamine
[0702] 1H?NMR(DMSO?d 6，300MHz)：δ11.95(s，1H)，9.55(s，1H)，9.37(s，1H)，8.44(d，2H，J＝4.8Hz)，8.17(s，1H)，8.09(d，1H，J＝3.3Hz)，8.04(d，1H，J＝7.5Hz)，7.70(d，2H，J＝8.4Hz)，7.34(m，2H)，7.22(m，4H)，3.94(s，2H)，2.21(q，2H，J＝7.5Hz)，0.88(t，3H，J＝7.2Hz)；LCMS(m/z)：507(MH +)。
III-69:5-fluoro-N4-[4-(4-pyridylmethyl) phenyl]-the N2-[(3-N-propionamido) the alkylsulfonyl phenyl)]-2,4-pyrimidinediamine sodium salt
[0703] 1H?NMR(D 2O，300MHz)：δ8.06(s，2H)，7.46(d，1H，J＝3.6Hz)，7.33(m，2H)，7.08(d，1H，J＝7.8Hz)，6.79(br?s，3H)，6.50(d，2H，J＝8.1Hz)，6.41(t，2H，J＝7.8Hz)，3.44(s，2H)，2.01(q，2H，J＝7.5Hz)，0.84(t，3H，J＝7.2Hz)；LCMS(m/z)：507(MH +).＝
I-232:N2-(3-kharophen alkylsulfonyl phenyl)-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0704] 1H?NMR(DMSO?d 6，300MHz)：δ12.05(br?s，1H)，9.60(s，1H)，9.36(s，1H)，8.21(s，1H)，8.12(s，1H)，8.12(s，1H)，7.73(d，2H，J＝8.7Hz)，7.33(m，2H)，7.42(s，2H)，7.15(s，1H)，7.04(d，2H，J＝8.7Hz)，6.38(s，1H)，5.18(s，2H)，2.45(s，3H)，1.96(s，3H)；LCMS(m/z)：513(MH +)。
I-236:5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-N2-(3-N-propionamido) alkylsulfonyl phenyl)]-2, the 4-pyrimidinediamine
[0705] 1H?NMR(DMSO?d 6，300MHz)：δ11.96(s，1H)，9.55(s，1H)，9.31(s，1H)，8.17(s，1H)，8.06(m，2H)，7.68(d，2H，J＝9.0Hz)，7.37(d，2H，J＝5.1Hz)，6.99(d，2H，J＝9.0Hz)，6.33(s，1H)，5.13(s，2H)，2.41(s，3H)，2.21(q，2H，J＝7.8Hz)，0.88(t，3H)，2.46(s，3H?J＝7.5Hz)；LCMS(m/z)：527(MH +)。
I-242:5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-N2-(3-N-propionamido) alkylsulfonyl phenyl)]-2,4-pyrimidinediamine sodium salt
[0706] 1H?NMR(D 2O)：δ7.54(d，1H，J＝2.1Hz)，7.42(br?s，2H)，7.21(d，1H，J＝7.2Hz)，6.98(d，2H，J＝6.9Hz)，6.83(t，1H，J＝6.3Hz)，6.55(d，2H，J＝6.9Hz)，5.99(s，1H)，4.86(s，2H)，2.23(s，3H)，2.01(q，2H，J＝7.8Hz)，0.83(t，3H，)，2.46(s，3H?J＝7.5Hz)；LCMS(m/z)：527(MH +)。
I-243:N2-(3-kharophen alkylsulfonyl phenyl)-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2,4-pyrimidinediamine sodium salt
[0707] 1H?NMR(D 2O)：δ7.59(s，1H)，7.47(s，2H)，7.22(d，1H，J＝7.2Hz)，7.08(d，2H，J＝7.0Hz)，6.94(t，1H，J＝6.3Hz)，6.67(d，2H，J＝7.8Hz)，6.05(s，1H)，4.94(s，2H)，2.24(s，3H)，1.77(s，3H)；LCMS(m/z)：513(MH +)。
I-228:5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-N2-(4-methyl-3-propionyl amino-sulfonyl phenyl)-2, the 4-pyrimidinediamine
[0708] 1H NMR (DMSO-d 6): δ 12.00 (s, 1H), 9.43 (s, 1H), 9.25 (s, 1H), 8.16-8.13 (m, 1H), 8.04 (d, J=3.6Hz, 1H), 8.00-7.95 (m, 1H), 7.68 (d, J=9.0Hz, 2H), 7.17 (d, JH=9.0Hz, 1H), 6.97 (d, J=9.0Hz, 2H), 6.31 (s, 1H), 5.12 (s, 2H), 2.49 (s, 3H), 2.23 (q, J=7.2Hz, 2H), 0.88 (t, J=7.2Hz, 2H); LCMS: purity: 97%; MS (m/e): 542 (MH +).
I-229:5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-N2-(4-methyl-3-(2-methylpropionyl) amino-sulfonyl phenyl)-2, the 4-pyrimidinediamine
[0709] 1H NMR (DMSO-d 6): δ 12.00 (s, 1H), 9.43 (s, 1H), 9.25 (s, 1H), 8.18-7.15 (m, 1H), 8.04 (d, J=3.6Hz, 1H), 7.99-7.09 (m, 1H), 7.68 (d, J=9.0 hour, 2H), 7.17 (d, J=8.7Hz, 1H), 6.97 (d, J=9.0Hz, 2H), 6.31 (s, 1H), 5.12 (s, 2H), 2.48-2.46 (m, 4H), 2.41 (s, 3H), 0.93 (d, J=6.9Hz, 6H); LCMS: purity: 94%; MS (m/e): 556 (MH +).
Embodiment 30
Figure A20068002053302401
I-277:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) methylene radical oxygen base phenyl]-2,4-pyrimidinediamine (71)
[0710] with 2-chloro-5-fluoro-N4-[4-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) methylene radical oxygen base phenyl]-4-PYRIMITHAMINE (70) (100mg, 0.3mmol) the adding trimethyl carbinol (1mL), add 3-aminobenzene sulfonamide (61.5mg then, 0.35mmol) and the acetate (10%, in mole) of catalytic amount.With mixture in 100 ℃ of heated overnight and removal of solvent under reduced pressure.Resistates is dissolved in ethyl acetate and washs with saturated sodium bicarbonate.Organic layer is separated, use dried over sodium sulfate, then concentrating under reduced pressure.Crude product is by column chromatography (silica gel; ethyl acetate: N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(the 5-methyl isophthalic acid of purifying hexane 3: 1) to obtain 20 milligrams of white solid; 3,4-oxadiazole-2-yl) methylene radical oxygen base phenyl]-2,4-pyrimidinediamine (71). 1HNMR(DMSO-d 6)：δ9.47(s，1H)，9.30(s，1H)，8.08(br?s，2H)，7.94(br?s，1H)，7.73-7.70(bd，J＝9.0Hz，2H)，7.39-7.36(d，J＝9.0Hz，2H)，7.25(br?s，2H)，7.04-7.01(br?s，J＝9.0Hz，2H)，5.33(br?s，2H)，2.55(s，3H)；LCMS(m/z)：472.13(MH +)。
[0711] following compound is according to preparing with embodiment 30 similar modes.
I-278:N2-(3-amino-sulfonyl-4-fluorophenyl)-5-fluoro-N4-[4-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0712] 1H?NMR(DMSO-d 6)：δ9.431(s，1H)，9.30(s，1H)，8.05(br?s，2H)，7.97-7.94(m，1H)，7.71-7.68(d，J＝9.0Hz，2H)，7.54(s，2H)，7.27-7.21(m，1H)，7.05-7.02(d，J＝9.0Hz，2H)，5.34(s，2H)，2.53(s，3H)；LCMS(m/z)：489.91(MH +)。
I-279:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) p-methoxy-phenyl]-2, the 4-pyrimidinediamine
[0713] 1H?NMR(DMSO-d 6)：δ9.36(s，1H)，9.26(s，1H)，8.09(s，1H)，8.05-8.04(d，J＝3.0Hz，1H)，7.89-7.86(d，J＝9.0Hz，1H)，7.73-7.70(d，J＝9.0Hz，2H)，7.22(s，2H)，7.18-7.15(d，J＝9.0Hz，1H)，7.03-7.00(d，J＝9.0Hz，2H)，5.33(s，2H)，2.53(s，3H)；LCMS(m/z)：486.16(MH +)。
Embodiment 31
I-225:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-methyl-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine:
[0714] at N2-chloro-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-the 4-PYRIMITHAMINE (54,0.33g, N 1mmol), dinethylformamide (DMF) (1mL) adds Cs in the solution 2CO 3And methyl-sulfate (DMS) (each 1.5 equivalents) and the reactant room temperature stirred 24 hours.The water termination reaction and by filter collecting the gained solid to obtain N2-chloro-5-fluoro-N4-methyl-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-4-PYRIMITHAMINE (72); method according to embodiment 18 is reacted to obtain N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-methyl-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl it again with 3-amino-sulfonyl-4-monomethylaniline]-2,4-pyrimidinediamine (73). 1H NMR (DMSO-d 6): δ 9.46 (s, 1H), 8.46 (s, 1H), 7.90 (d, J=5.4Hz, 1H), 7.65 (d, J=6.6Hz, 1H), 7.30-7.12 (m, 5H), 7.01 (d, J=8.4Hz, 2H), 6.33 (s, 1H), 5.14 (s, 2H), 3.42 (s, 3H), 3.31 (s, 3H), 2.41 (s, 3H); LCMS: purity: 98%; MS (m/z): 499 (MH +).
[0715] following compound is according to preparing with embodiment 31 similar modes.
I-227:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-methoxycarbonyl methyl-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine:
[0716] 1H NMR (CDCl 3): δ 8.29 (d, J=2.1Hz, 1H), 7.78-7.52 (m, 2H), 7.21-7.15 (m, 3H), 7.06 (d, J=8.1Hz, 1H), 6.87 (d, J=9.0Hz, 2H), 6.03 (s, 1H), 5.46 (bs, 2H), 5.03 (s, 2H), 4.48 (s, 2H), 3.47 (s, 3H), 2.53 (s, 3H), 2.36 (s, 3H); LCMS: purity: 90%; MS (m/z): 557 (MH +).
I-226:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-fluoro-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-N4-methyl-2, the 4-pyrimidinediamine:
[0717] 1H NMR (DMSO-d 6): δ 9.50 (s, 1H), 8.45 (d, J=2.1Hz, 1H), 7.95 (d, J=5.7Hz, 1H), 7.64 (dd, J=2.4 and 8.4Hz, 1H), 7.32 (dd, J=2.7 and 12.3Hz, 1H), 7.29-7.14 (m, 4H), 7.10 (d, J=9.0Hz, 1H), 6.34 (s, 1H), 5.23 (s, 2H), 3.43 (s, 3H), 2.49 (s, 3H), 2.41 (s, 3H); LCMS: purity: 99%; MS (m/z): 517 (MH +).
Embodiment 32
5-chloromethyl-2,4-dihydro-1,2,4-triazole-3-ketone (74)
[0718] with Urea,amino-.HCl (5g, 89mmol), 2-chloro-1,1, the 1-trimethoxy-ethane (12.07mL, 179mmol) and methyl alcohol (50mL) mixes and stirring at room 3 days, by 1H NMR monitoring reaction.Add 2-chloro-1,1 again, 1-trimethoxy-ethane (8.77mL) is to finish reaction.Under vacuum, remove methyl alcohol then.(2 * 100mL) wash the gained resistates with ethyl acetate (500mL) extraction and with 1N HCl.(5 * 100mL) strip water with ethyl acetate.Merge organic layer then, use anhydrous sodium sulfate drying, and removal of solvent under reduced pressure is to obtain the 5-chloromethyl-2 of 3.1 gram white powder, 4-dihydro-1,2,4-triazole-3-ketone (74). 1H?NMR(DMSO-d 6)：δ11.65(s，1H)，11.50(s，1H)，4.48(s，2H)；LCMS(m/z)：133.90(M +)。
I-200:N2-(3-amino-sulfonyl-4-fluorophenyl)-5-fluoro-N4-[4-(2,4-dihydro-3-oxo-1,2,4-triazole-5-yl) methylene radical oxygen base phenyl]-2,4-pyrimidinediamine (76)
[0719] at 5-chloromethyl-2; 4-dihydro-1; 2; 4-triazole-3-ketone (35mg; 0.26mmol) 2-butanone solution in add N2-(3-amino-sulfonyl-4-fluorophenyl)-5-fluoro-N4-(4-hydroxy phenyl)-2; the 4-pyrimidinediamine (100mg, 0.25mmol) and salt of wormwood (35mg, 0.25mmol).The gained mixture is in 140 ℃ of microwaves 5 hours, and then adds 5-chloromethyl-2 as required, 4-dihydro-1,2,4-triazole-3-ketone.Reaction solvent is removed in decompression; resistates is by column chromatography (silica gel; methylene dichloride: methyl alcohol 8: 2v/v) N2-(3-amino-sulfonyl-4-the fluorophenyl)-5-fluoro-N4-[4-(2 of purifying to obtain 25 milligrams of faint yellow solid shapes; 4-dihydro-3-oxo-1; 2; 4-triazole-5-yl) p-methoxy-phenyl]-2,4-pyrimidinediamine (76). 1H?NMR(D 2O)：δ7.90-7.89(d，J＝3Hz，1H)，7.60-7.58(d，J＝6Hz，1H)，7.34(bs，2H)，7.24-7.18(m，2H)，7.05-7.02(d，J＝9.0Hz，2H)，6.65-6.62(d，J＝9.0Hz，2H)，5.11(br?s，2H)；LCMS(m/z)：491.05(MH +)。
[0720] following compound is according to preparing with embodiment 32 similar modes or by method described here or those of skill in the art's currently known methods.
VI-100:N2-(3-amino-sulfonyl-4-fluorophenyl)-5-fluoro-N4-(4-hydroxy phenyl)-2, the 4-pyrimidinediamine
[0721] 1H?NMR(DMSO-d 6)：δ7.99-7.97(d，J＝5.4Hz，1H)，7.80-7.77(m，1H)，7.74-7.69(m，1H)，7.34-7.31(d，J＝6.9Hz，2H)，7.27-7.21(t，2H)，6.81-6.78(d，J＝6.9Hz，2H)，LCMS：394.34(MH +)。
VI-101:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(4-hydroxy phenyl)-2, the 4-pyrimidinediamine
[0722] 1H?NMR(DMSO-d 6)：δ7.99-7.97(d，J＝5.4Hz，1H)，7.81-7.78(m，1H)，7.74-7.69(m，1H)，7.34-7.31(d，J＝6.9Hz，2H)，7.27-7.21(t，2H)，6.81-6.78(d，J＝6.9Hz，2H)，LCMS：376.38(MH +)。
VI-102:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-hydroxy phenyl]-2, the 4-pyrimidinediamine
[0723] 1H?NMR(DMSO-d 6)：δ7.96-7.94(d，J＝5.7Hz，1H)，7.87-7.86(d，J＝2.4Hz，1H)，7.62-7.58(d，J＝8.4Hz，1H)，7.37-7.29(m，4H)，6.80-6.77(d，J＝6.6Hz，2H)，2.66(s，3H)，LCMS：390.39(MH +)。
I-201:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2,4-dihydro-3-oxo-1,2,4-triazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0724] 1H?NMR(CD 3OD)：δ7.91-7.89(d，J＝4.0Hz，1H)，7.61-7.52(m，2H)，7.41-7.39(m，2H)，7.31-7.28(d，J＝9.0Hz，2H)，6.63-6.60(d，J＝9.0Hz，2H)，5.03(s，2H)；LCMS：473.58(M +)。
I-202:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(2,4-dihydro-3-oxo-1,2,4-triazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0725] 1H?NMR(CD 3OD)：δ7.95-7.94(d，J＝3.0Hz，1H)，7.74(s，1H)，7.32-7.2(m，4H)，6.65-6.0(m，2H)，5.05(s，2H)，2.67(s，3H)；LCMS(m/z)：487.53(M +)。
IX-44:N2-(4-amino-sulfonyl phenyl)-N4-[3,5-dimethyl-4-(4-methylpiperazine-1-yl] phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0726] LCMS: purity: 94.62%; MS (m/e): 486.14 (MH +).
I-40:N4-(4-cyano group methoxyl group-3,5-3,5-dimethylphenyl)-5-fluoro-N2-[4-(4-methylpiperazine-1-yl) alkylsulfonyl phenyl]-2, the 4-pyrimidinediamine:
[0727] LCMS: purity: 92.80%; MS (m/e): 526.65 (MH +).
I-41:N2-(4-amino-sulfonyl phenyl)-N4-(3-chloro-4-cyano group p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0728] 1H NMR (DMSO-d 6): δ 5.25 (s, 2H), 7.12 (br, 2H), 7.27 (d, J=9.0Hz, 1H), 7.64 (d, J=8.7Hz, 2H), 7.70 (dd, J=2.7,9.0Hz, 1H), 7.78 (d, J=8.7Hz, 2H), 7.95 (d, J=2.4Hz, 1H), 8.16 (d, J=3.6Hz, 1H), 9.52 (br, 1H), 9.67 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.71; LCMS: purity: 75.54%; MS (m/e): 449.36 (MH +).
I-42:N2-(3-amino-sulfonyl phenyl)-N4-(3-chloro-4-cyano group p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0729] 1H NMR (DMSO-d 6): δ 5.25 (s, 2H), 7.28 (m, 3H), 7.38 (m, 2H), 7.78 (dd, J=2.4,8.7Hz, 1H), 7.89 (d, J=2.4Hz, 1H), 7.95 (d, J=7.8Hz, 1H), 7.99 (s, 1H), 8.17 (d, J=3.6Hz, 1H), 9.66 (br, 1H), 9.74 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.64; LCMS: purity: 88.17%; MS (m/e): 449.39 (MH +).
I-43:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3-chloro-4-cyano group p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0730] 1H NMR (DMSO-d 6): δ 2.49 (s, 3H), 5.25 (s, 2H), 7.24 (m, 4H), 7.79 (dd, J=2.7,9.0Hz, 1H), 7.87 (m, 1H), 7.88 (d, J=2.7Hz, 1H), 8.02 (d, J=2.1Hz, 1H), 8.12 (d, J=3.9Hz, 1H), 9.54 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-202.43; LCMS: purity: 91.27%; MS (m/e): 463.40 (MH +).
I-97:N4-(4-aminocarboxyl methoxyl group-3-chloro-phenyl-)-N2-(4-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0731] 1H NMR (DMSO-d 6): δ 4.56 (s, 2H), 7.01 (d, J=8.7Hz, 1H), 7.16 (br, 2H), 7.39 (br, 1H), 7.41 (br, 1H), 7.57 (dd, J=2.4,9.0Hz, 1H), 7.66 (d, J=8.7Hz, 2H), 7.75 (d, J=8.7Hz, 2H), 7.83 (d, J=2.4Hz, 1H), 8.19 (d, J=3.9Hz, 1H), 9.76 (br, 1H), 9.92 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.07; LCMS: purity: 82.15%; MS (m/e): 467.36 (MH +).
I-98:N4-(4-aminocarboxyl methoxyl group-3-chloro-phenyl-)-N2-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0732] 1H NMR (DMSO-d 6): δ 4.54 (s, 2H), 7.00 (d, J=8.7Hz, 1H), 7.28 (br, 2H), 7.39 (m, 4H), 7.67 (dd, J=2.4,8.7Hz, 1H), 7.79 (d, J=2.4Hz, 1H), 7.94 (dd, J=2.4,7.2Hz, 1H), 7.97 (s, 1H), 8.15 (d, J=3.9Hz, 1H), 9.64 (br, 1H), 9.75 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.59; LCMS: purity: 82.05%; MS (m/e): 467.37 (MH +).
I-99:N4-(4-aminocarboxyl methoxyl group-3-chloro-phenyl-)-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0733] 1H NMR (DMSO-d 6): δ 2.51 (s, 3H), 4.54 (s, 2H), 6.99 (d, J=9.0Hz, 1H), 7.23 (dd, J=3.3,8.7Hz, 1H), 7.28 (br, 2H), 7.36 (br, 1H), 7.45 (br, 1H), 7.66 (d, J=9.0Hz, 1H), 7.79 (d, J=2.4Hz, 1H), 7.82 (dd, J=2.4,8.1Hz, 1H), 7.96 (s, 1H), 8.15 (d, J=4.2Hz, 1H), 9.76 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-201.70; LCMS: purity: 80.53%; MS (m/e): 481.38 (MH +).
I-100:N4-(4-aminocarboxyl methoxyl group-3-fluorophenyl)-N2-(4-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0734] 1H NMR (DMSO-d 6): δ 4.52 (s, 2H), 7.04 (t, J=9.0Hz, 1H), 7.16 (br, 2H), 7.40 (m, 2H), 7.49 (br, 1H), 7.65 (d, J=8.7Hz, 2H), 7.75 (d, J=2.7Hz, 1H), 7.78 (d, J=9.0Hz, 2H), 8.18 (d, J=3.6Hz, 1H), 9.70 (br, 1H), 9.85 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-171.66 ,-201.16; LCMS: purity: 94.57%; MS (m/e): 451.63 (MH +).
I-101:N4-(4-aminocarboxyl methoxyl group-3-fluorophenyl)-N2-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0735] 1H NMR (DMSO-d 6): δ 4.50 (s, 2H), 7.02 (t, J=9.0Hz, 1H), 7.29 (br, 2H), 7.40 (m, 3H), 7.46 (m, 2H), 7.78 (dd, J=2.4,13.5Hz, 1H), 7.94 (m, 1H), 8.02 (s, 1H), 8.16 (d, J=4.2Hz, 1H), 9.69 (br, 1H), 9.79 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-171.60 ,-201.45; LCMS: purity: 91.91%; MS (m/e): 451.59 (MH +).
I-102:N4-(4-aminocarboxyl methoxyl group-3-fluorophenyl)-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0736] 1H NMR (DMSO-d 6): δ 2.51 (s, 3H), 4.50 (s, 2H), 7.01 (t, J=9.3Hz, 1H), 7.22 (m, 1H), 7.26 (br, 2H), 7.45 (m, 3H), 7.78 (dd, J=14.1Hz, 1H), 7.84 (dd, J=2.4,8.4Hz, 1H), 8.02 (s, 1H), 8.12 (d, J=4.2Hz, 1H), 9.68 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-171.61 ,-201.86; LCMS: purity: 83.32%; MS (m/e): 465.67 (MH +).
I-44:N2-(4-amino-sulfonyl phenyl)-N4-(4-cyano group methoxyl group-3-fluorophenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0737] 1H NMR (DMSO-d 6): δ 5.22 (s, 2H), 7.15 (br, 2H), 7.28 (t, J=9.0Hz, 1H), 7.51 (d, J=8.1Hz, 1H), 7.66 (d, J=8.7Hz, 2H), 7.79 (d, J=9.0Hz, 2H), 7.91 (dd, J=2.4,13.5Hz, 1H), 8.20 (d, J=3.9Hz, 1H), 9.74 (br, 1H), 9.84 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-171.30 ,-201.07; LCMS: purity: 96.50%; MS (m/e): 433.69 (MH +).
I-103:N4-(4-aminocarboxyl methoxyl group-3-p-methoxy-phenyl)-N2-(4-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0738] 1H NMR (DMSO-d 6): δ 3.73 (s, 3H), 4.41 (s, 2H), 6.91 (d, J=8.4Hz, 1H), 7.16 (br, 2H), 7.28 (m, 2H), 7.37 (br, 2H), 7.61 (d, J=8.7Hz, 2H), 7.76 (d, J=7.8Hz, 2H), 8.16 (d, 1H), 9.59 (br, 1H), 9.79 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.39; LCMS: purity: 86.59%; MS (m/e): 463.57 (MH +).
I-104:N4-(4-aminocarboxyl methoxyl group-3-p-methoxy-phenyl)-N2-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0739] 1H NMR (DMSO-d 6): δ 3.72 (s, 3H), 4.40 (s, 2H), 6.89 (d, J=8.7Hz, 1H), 7.27-7.41 (m, 8H), 7.93 (dd, J=2.4,5.7Hz, 1H), 7.99 (s, 1H), 8.13 (d, J=4.2Hz, 1H), 9.60 (br, 1H), 9.73 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.60; LCMS: purity: 83.79%; MS (m/e): 463.01 (MH +).
I-105:N4-(4-aminocarboxyl methoxyl group-3-p-methoxy-phenyl)-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0740] 1H NMR (DMSO-d 6): δ 2.50 (s, 3H), 3.71 (s, 3H), 4.40 (s, 2H), 6.89 (d, J=8.7Hz, 1H), 7.16 (d, J=8.4Hz, 1H), 7.26 (br, 2H), 7.28 (d, J=2.4Hz, 1H), 7.33 (m, 2H), 7.40 (br, 1H), 7.83 (dd, J=2.4,8.1Hz, 1H), 8.02 (s, 1H), 8.09 (d, J=3.9Hz, 1H), 9.59 (br, 2H); LCMS: purity: 88.10%; MS (m/e): 477.53 (MH +).
I-45:N2-(4-amino-sulfonyl phenyl)-N4-(4-cyano group methoxyl group-3-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0741] 1H NMR (DMSO-d 6): δ 3.72 (s, 3H), 5.09 (s, 2H), 7.08 (d, J=8.7Hz, 1H), 7.17 (br, 2H), 7.32 (dd, J=2.4,8.7Hz, 1H), 7.36 (d, J=2.4Hz, 1H), 7.63 (d, J=9.0Hz, 2H), 7.75 (d, J=8.7Hz, 2H), 8.20 (d, J=4.2Hz, 1H), 9.80 (br, 1H), 9.96 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-200.85; LCMS: purity: 98.23%; MS (m/e): 445.64 (MH +).
I-46:N2-(3-amino-sulfonyl phenyl)-N4-(4-cyano group methoxyl group-3-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0742] 1H NMR (DMSO-d 6): δ 3.73 (s, 3H), 5.08 (s, 2H), 7.06 (d, J=8.7Hz, 1H), 7.28 (br, 2H), 7.37 (m, 4H), 7.93 (m, 1H), 8.00 (s, 1H), 8.15 (d, J=4.2Hz, 1H), 9.62 (br, 1H), 9.72 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.58; LCMS: purity: 97.98%; MS (m/e): 445.10 (MH +).
I-47:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(4-cyano group methoxyl group-3-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0743] 1H NMR (DMSO-d 6): δ 2.49 (s, 3H), 3.73 (s, 3H), 5.08 (s, 2H), 7.05 (d, J=8.7Hz, 1H), 7.17 (d, J=9.0Hz, 1H), 7.25 (br, 2H), 7.36 (d, J=2.1Hz, 1H), 7.43 (dd, J=2.4,8.4Hz, 1H), 7.87 (dd, J=2.1,7.8Hz, 1H), 8.04 (d, 1H), 8.09 (d, J=3.9Hz, 1H), 9.51 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-202.45; LCMS: purity: 92.72%; MS (m/e): 459.50 (MH +).
I-106:N4-(4-aminocarboxyl methoxyl group-3-hydroxymethyl phenyl)-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0744] 1H NMR (DMSO-d 6): δ 2.49 (s, 3H), 4.46 (s, 2H), 4.56 (d, J=5.4Hz, 2H), 5.11 (t, J=5.4Hz, 1H), 6.86 (d, J=8.7Hz, 1H), 7.14 (d, J=8.1Hz, 1H), 7.20 (br, 2H), 7.40 (br, 1H), 7.49 (br, 1H), 7.58 (d, J=2.7Hz, 1H), 7.67 (dd, J=2.7,9.0Hz, 1H), 7.89 (dd, J=2.1,8.1Hz, 1H), 8.02 (d, J=3.6Hz, 1H), 8.06 (d, J=1.2Hz, 1H), 9.23 (br, 1H), 9.29 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.97; LCMS: purity: 82.44%; MS (m/e): 477.03 (MH +).
I-50:N2-(3-amino-sulfonyl phenyl)-N4-(4-cyano group methoxyl group-3-hydroxymethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine:
[0745] 1H NMR (DMSO-d 6): δ 4.51 (d, J=5.4Hz, 2H), 5.12 (t, J=5.4Hz, 1H), 5.17 (s, 2H), 7.07 (d, J=8.7Hz, 1H), 7.25 (br, 2H), 7.35 (m, 2H), 7.64 (d, J=2.7Hz, 1H), 7.79 (dd, J=2.4,8.7Hz, 1H), 7.98 (d, J=8.1Hz, 1H), 8.04 (s, 1H), 8.08 (d, J=3.6Hz, 1H), 9.37 (br, 1H), 9.45 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.27; LCMS: purity: 82.62%; MS (m/e): 445.10 (MH +).
I-51:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(4-cyano group methoxyl group-3-hydroxymethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0746] 1H NMR (DMSO-d 6): δ 2.48 (s, 3H), 4.51 (d, J=5.7Hz, 2H), 5.10 (t, J=5.4Hz, 1H), 5.16 (s, 2H), 7.06 (d, J=8.7Hz, 1H), 7.16 (d, J=8.7Hz, 1H), 7.21 (br, 2H), 7.62 (d, J=2.7Hz, 1H), 7.78 (dd, J=2.7,9.0Hz, 1H), 7.91 (dd, J=2.4,8.4Hz, 1H), 8.04 (d, J=3.6Hz, 2H), 9.32 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-202.87; LCMS: purity: 87.82%, MS (m/e): 459.12 (MH +).
I-52:N2-(4-amino-sulfonyl phenyl)-N4-[4-cyano group methoxyl group-3-(1-cyano methyl pyrazole-3-yl) phenyl]-5-fluoro-2, the 4-pyrimidinediamine
[0747] 1H NMR (DMSO-d 6): δ 5.25 (s, 2H), 5.48 (s, 2H), 6.80 (d, J=2.4Hz, 1H), 7.06 (br, 2H), 7.23 (d, J=9.0Hz, 1H), 7.52 (d, J=8.7Hz, 2H), 7.78 (d, J=9.0Hz, 2H), 7.90 (m, 2H), 8.06 (d, J=2.7Hz, 1H), 8.13 (d, J=3.6Hz, 1H), 9.53 (br, 1H), 9.56 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.76; LCMS: purity: 92.05%; MS (m/e): 520.46 (MH +).
I-53:N2-(3-amino-sulfonyl phenyl)-N4-[4-cyano group methoxyl group-3-(1-cyano methyl pyrazole-3-yl) phenyl]-5-fluoro-2, the 4-pyrimidinediamine
[0748] 1H NMR (DMSO-d 6): δ 5.26 (s, 2H), 5.50 (s, 2H), 6.79 (d, J=1.5Hz, 1H), 7.19-7.35 (m, 5H), 7.92 (m, 4H), 8.02 (d, J=2.4Hz, 1H), 8.17 (d, J=3.9Hz, 1H), 9.82 (br, 1H), 9.89 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.13; LCMS: purity: 94.31%; MS (m/e): 520.16 (MH +).
I-54:N2-(3-amino-sulfonyl-4-aminomethyl phenyl]-N4-[4-cyano group methoxyl group-3-(1-cyano methyl pyrazole-3-yl) phenyl]-5-fluoro-2, the 4-pyrimidinediamine
[0749] 1H NMR (DMSO-d 6): δ 2.45 (s, 3H), 5.25 (s, 2H), 5.50 (s, 2H), 6.79 (d, J=2.4Hz, 1H), 6.98 (d, J=8.1Hz, 1H), 7.23 (m, 3H), 7.86 (dd, J=2.4,8.1Hz, 1H), 7.92 (d, J=2.4Hz, 1H), 7.97 (m, 2H), 8.02 (d, J=2.7Hz, 1H), 8.09 (d, J=4.2Hz, 1H), 9.53 (br, 1H), 9.66 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.24; LCMS: purity: 95.42%; MS (m/e): 534.28 (MH +).
I-107:N4-(4-aminocarboxyl methoxyl group-3-hydroxymethyl phenyl]-N2-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0750] 1H NMR (DMSO-d 6): δ 4.47 (s, 2H), 4.56 (d, J=5.4Hz, 2H), 5.12 (t, J=5.7Hz, 1H), 6.86 (d, J=8.7Hz, 1H), 7.24 (br, 2H), 7.32 (m, 2H), 7.41 (br, 1H), 7.49 (br, 1H), 7.59 (d, J=2.4Hz, 1H), 7.67 (dd, J=3.0,9.3Hz, 1H), 7.97 (d, J=7.8Hz, 1H), 8.05 (m, 2H), 9.28 (br, 1H), 9.42 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.45; LCMS: purity: 99.96%; MS (m/e): 463.68 (MH +).
I-55:N2-(3-amino-sulfonyl pyridin-4-yl)-N4-(4-cyano group p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0751] 1H NMR (DMSO-d 6): δ 5.17 (s, 2H), 7.11 (d, J=9.0Hz, 2H), 7.20 (d, J=7.5Hz, 1H), 7.66 (d, J=8.7Hz, 2H), 8.53 (d, J=3.3Hz, 1H), 9.04 (dd, J=1.8,7.5Hz, 1H), 9.49 (d, J=1.8Hz, 1H), 9.96 (br, 1H), 10.33 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-191.46; LCMS: purity: 90.38%; MS (m/e): 416.91 (MH +).
I-143:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-(4-methylamino carbonyl p-methoxy-phenyl)-2, the 4-pyrimidinediamine
[0752] 1H NMR (DMSO-d 6): δ 2.66 (d, J=4.5Hz, 3H), 4.46 (s, 2H), 6.96 (d, J=9.0Hz, 2H), 7.17 (br, 2H), 7.60 (d, J=8.7Hz, 2H), 7.63 (d, J=8.7Hz, 2H), 7.74 (d, J=8.7Hz, 2H), 8.05 (q, J=4.5Hz, 1H), 8.16 (d, J=4.2Hz, 1H), 9.70 (br, 1H), 9.87 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.19; LCMS: purity: 97.92%; MS (m/e): 447.73 (MH +).
I-144:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(4-methylamino carbonyl p-methoxy-phenyl)-2, the 4-pyrimidinediamine
[0753] 1H NMR (DMSO-d 6): δ 2.66 (d, J=4.8Hz, 3H), 4.44 (s, 2H), 6.93 (d, J=8.7Hz, 2H), 7.27 (br, 2H), 7.37 (m, 2H), 7.63 (d, J=8.4Hz, 2H), 7.89 (q, J=3.6Hz, 1H), 8.00 (br, 2H), 8.11 (d, J=3.9Hz, 1H), 9.58 (br, 1H), 9.68 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.64; LCMS: purity: 98.07%; MS (m/e): 447.62 (MH +).
I-145:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(4-methylamino carbonyl p-methoxy-phenyl)-2, the 4-pyrimidinediamine
[0754] 1H NMR (DMSO-d 6): δ 2.52 (s, 3H), 2.65 (d, J=4.8Hz, 3H), 4.45 (s, 2H), 6.93 (d, J=9.0Hz, 2H), 7.21 (d, J=8.4Hz, 1H), 7.29 (br, 2H), 7.61 (d, J=9.0Hz, 2H), 7.78 (dd, J=2.1,8.1Hz, 1H), 7.95 (s, 1H), 8.02 (q, J=4.5Hz, 1H), 8.13 (d, J=4.5Hz, 1H), 9.80 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-201.31; LCMS: purity: 94.30%; MS (m/e): 461.73 (MH +).
I-128:N2-(4-amino-sulfonyl phenyl)-N4-(4-dimethylamino carbonyl p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine:
[0755] 1H NMR (DMSO-d 6): δ 2.85 (s, 3H), 3.00 (s, 3H), 4.80 (s, 2H), 6.91 (d, J=8.7Hz, 2H), 7.17 (br, 2H), 7.53 (d, J=8.4Hz, 2H), 7.63 (d, J=8.4Hz, 2H), 7.72 (d, J=8.4Hz, 2H), 8.16 (d, J=3.9Hz, 1H), 9.76 (br, 1H), 9.93 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.18; LCMS: purity: 95.72%; MS (m/e): 461.70 (MH +).
I-129:N2-(3-amino-sulfonyl phenyl)-N4-(4-dimethylamino carbonyl p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0756] 1H NMR (DMSO-d 6): δ 2.85 (s, 3H), 3.00 (s, 3H), 4.78 (s, 2H), 6.88 (d, J=8.4Hz, 2H), 7.24 (br, 2H), 7.33 (m, 2H), 7.62 (d, J=8.7Hz, 2H), 7.92 (d, J=7.8Hz, 1H), 8.06 (d, J=2.7Hz, 1H), 8.09 (s, 1H), 9.26 (br, 1H), 9.45 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.67; LCMS: purity: 89.45%; MS (m/e): 461.77 (MH +).
I-130:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(4-dimethylamino carbonyl p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0757] 1H NMR (DMSO-d 6): δ 2.51 (s, 3H), 2.85 (s, 3H), 3.00 (s, 3H), 4.79 (s, 2H), 6.88 (d, J=9.0Hz, 2H), 7.21 (d, J=8.4Hz, 1H), 7.28 (br, 2H), 7.56 (d, J=9.0Hz, 2H), 7.77 (dd, J=2.4,8.4Hz, 1H), 7.97 (d, J=2.1Hz, 1H), 8.11 (d, J=4.5Hz, 1H), 9.74 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-201.85; LCMS: purity: 97.67%; MS (m/e): 475.80 (MH +).
I-56:N2-(3-amino-sulfonyl-4-p-methoxy-phenyl)-N4-(4-cyano group p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0758] 1H NMR (DMSO-d 6): δ 3.87 (s, 3H), 5.14 (s, 2H), 7.03 (br, 2H), 7.06 (d, J=9.3Hz, 2H), 7.10 (d, J=8.7Hz, 1H), 7.67 (d, J=9.0Hz, 2H), 7.76 (dd, J=2.4,9.0Hz, 1H), 7.83 (s, 1H), 8.13 (d, J=4.2Hz, 1H), 9.70 (br, 1H), 9.89 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.85; LCMS: purity: 90.15%; MS (m/e): 445.73 (MH +).
I-57:N2-(4-amino-sulfonyl phenyl)-N4-(4-cyano group p-methoxy-phenyl-5)-methyl-2, the 4-pyrimidinediamine
[0759] 1H NMR (DMSO-d 6): δ 2.16 (s, 3H), 5.18 (s, 2H), 7.12 (d, J=9.0Hz, 2H), 7.24 (br, 2H), 7.52 (d, J=8.7Hz, 2H), 7.58 (d, J=8.7Hz, 2H), 7.64 (d, J=8.7Hz, 2H), 7.91 (s, 1H), 9.64 (br, 1H), 10.38 (br, 1H); LCMS: purity: 96.78%; MS (m/e): 411.70 (MH +).
I-58:N2-(3-amino-sulfonyl phenyl)-N4-(4-cyano group p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine
[0760] 1H NMR (DMSO-d 6): δ 2.10 (s, 3H), 5.15 (s, 2H), 7.04 (d, J=9.0Hz, 2H), 7.23 (br, 2H), 7.29 (m, 2H), 7.67 (d, J=9.0Hz, 2H), 7.87 (s, 1H), 7.99 (d, J=7.8Hz, 1H), 8.04 (s, 1H), 8.28 (br, 1H), 9.27 (br, 1H); LCMS: purity: 95.23%; MS (m/e): 411.18 (MH+).
I-59:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(4-cyano group p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine
[0761] 1H NMR (DMSO-d 6): δ 2.09 (s, 3H), 2.47 (s, 3H), 5.15 (s, 2H), 7.04 (d, J=9.0Hz, 2H), 7.12 (d, J=8.4Hz, 1H), 7.20 (br, 2H), 7.67 (d, J=8.7Hz, 2H), 7.84 (s, 1H), 7.92 (dd, J=2.7,8.1Hz, 1H), 8.04 (d, J=2.1Hz, 1H), 8.26 (br, 1H), 9.17 (br, 1H); LCMS: purity: 92.97%; MS (m/e): 425.72 (MH +).
I-108:N4-(4-aminocarboxyl p-methoxy-phenyl)-N2-(4-amino-sulfonyl phenyl)-5-methyl-2, the 4-pyrimidinediamine:
[0762] 1H NMR (DMSO-d 6): δ 2.16 (s, 3H), 4.48 (s, 2H), 7.01 (d, J=8.1Hz, 2H), 7.26 (br, 2H), 7.34 (br, 1H), 7.42 (d, J=8.4Hz, 2H), 7.57 (d, J=8.4Hz, 2H), 7.58 (br, 1H), 7.63 (d, J=8.4Hz, 2H), 7.91 (s, 1H), 9.73 (br, 1H), 10.56 (br, 1H); LCMS: purity: 96.73%; MS (m/e): 429.17 (MH +).
I-109:N4-(4-aminocarboxyl p-methoxy-phenyl)-N2-(3-amino-sulfonyl phenyl)-5-methyl-2, the 4-pyrimidinediamine
[0763] 1H NMR (DMSO-d 6): δ 2.16 (s, 3H), 4.45 (s, 2H), 6.97 (d, J=9.0Hz, 2H), 7.39 (m, 6H), 7.52 (d, J=7.5Hz, 2H), 7.64 (s, 1H), 7.78 (d, J=9.3Hz, 1H), 7.88 (s, 1H), 9.70 (br, 1H), 10.49 (br, 1H); LCMS: purity: 93.75%; MS (m/e): 429.22 (MH +).
I-110:N4-(4-aminocarboxyl p-methoxy-phenyl)-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-methyl-2, the 4-pyrimidinediamine
[0764] 1H NMR (DMSO-d 6): δ 2.15 (s, 3H), 2.54 (s, 3H), 4.45 (s, 2H), 6.96 (d, J=8.7Hz, 2H), 7.19 (d, J=8.4Hz, 1H), 7.35 (br, 2H), 7.39 (br, 1H), 7.41 (d, J=9.0Hz, 2H), 7.54 (br, 1H), 7.64 (dd, J=2.1,8.1Hz, 1H), 7.70 (d, J=2.1Hz, 1H), 7.84 (s, 1H), 9.65 (br, 1H), 10.35 (br, 1H); LCMS: purity: 94.04%; MS (m/e): 443.12 (MH +).
I-157:N4-(4-allyl amino carbonyl p-methoxy-phenyl)-N2-(4-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0765] 1H NMR (DMSO-d 6): δ 3.77 (t, J=5.4Hz, 2H), 4.50 (s, 2H), 5.02-5.13 (m, 2H), 5.78 (m, 1H), 6.96 (d, J=9.3Hz, 2H), 7.11 (br, 2H), 7.60 (d, J=8.4Hz, 2H), 7.63 (d, J=8.4Hz, 2H), 7.79 (d, J=8.7Hz, 2H), 8.09 (d, J=3.6Hz, 1H), 8.27 (t, J=5.7Hz, 1H), 9.34 (br, 1H), 9.56 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.14; LCMS: purity: 92.65%; MS (m/e): 473.14 (MH +).
I-158:N4-(4-allyl amino carbonyl p-methoxy-phenyl)-N2-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0766] 1H NMR (DMSO-d 6): δ 3.76 (t, J=5.4Hz, 2H), 4.49 (s, 2H), 5.02-5.13 (m, 2H), 5.80 (m, 1H), 6.94 (d, J=9.3Hz, 2H), 7.27 (br, 2H), 7.37 (m, 2H), 7.65 (d, J=9.0Hz, 2H), 7.90 (td, J=2.1,6.6Hz, 1H), 8.01 (s, 1H), 8.10 (d, J=4.2Hz, 1H), 8.26 (t, J=4.5Hz, 1H), 9.52 (br, 1H), 9.64 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.86; LCMS: purity: 98.60%; MS (m/e): 473.22 (MH +).
I-159:N4-(4-allyl amino carbonyl p-methoxy-phenyl)-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0767] 1H NMR (DMSO-d 6): δ 2.51 (s, 3H), 3.76 (t, J=5.4Hz, 2H), 4.50 (s, 2H), 5.00-5.12 (m, 2H), 5.79 (m, 1H), 6.94 (d, J=9.3Hz, 2H), 7.20 (d, J=9.0Hz, 1H), 7.28 (br, 2H), 7.62 (d, J=9.0Hz, 2H), 7.79 (dd, J=2.7,8.4Hz, 1H), 7.97 (s, 1H), 8.11 (d, J=4.2Hz, 1H), 8.26 (t, J=6.0Hz, 1H), 9.72 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-201.73; LCMS: purity: 92.70%; MS (m/e): 487.80 (MH +).
I-131:N2-(4-amino-sulfonyl phenyl)-N4-(3-chloro-4-dimethylamino carbonyl p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0768] 1H NMR (DMSO-d 6): δ 2.85 (s, 3H), 3.01 (s, 3H), 4.92 (s, 2H), 6.98 (d, J=9.0Hz, 1H), 7.11 (br, 2H), 7.54 (dd, J=2.7,9.3Hz, 1H), 7.63 (d, J=8.7Hz, 2H), 7.77 (d, J=8.7Hz, 2H), 7.78 (s, 1H), 8.12 (d, J=3.3Hz, 1H), 9.40 (br, 1H), 9.62 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.11; LCMS: purity: 92.42%; MS (m/e): 495.42 (MH +).
I-132:N2-(3-amino-sulfonyl phenyl)-N4-(3-chloro-4-dimethylamino carbonyl p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0769] 1H NMR (DMSO-d 6): δ 2.85 (s, 3H), 3.00 (s, 3H), 4.92 (s, 2H), 6.96 (d, J=9.0Hz, 1H), 7.27 (br, 2H), 7.38 (m, 2H), 7.61 (dd, J=2.4,9.0Hz, 1H), 7.74 (d, J=2.4Hz, 1H), 7.93 (d, J=7.5Hz, 1H), 7.98 (s, 1H), 8.13 (d, J=4.2Hz, 1H), 9.56 (br, 1H), 9.69 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.89; LCMS: purity: 96.46%; MS (m/e): 495.04 (MH +).
I-133:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3-chloro-4-dimethylamino carbonyl p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0770] 1H NMR (DMSO-d 6): δ 2.49 (s, 3H), 2.85 (s, 3H), 3.00 (s, 3H), 4.92 (s, 2H), 6.95 (d, J=9.0Hz, 1H), 7.19 (d, J=8.4Hz, 1H), 7.24 (br, 2H), 7.62 (dd, J=3.0,9.3Hz, 1H), 7.75 (d, J=2.4Hz, 1H), 7.85 (dd, J=2.4,8.4Hz, 1H), 8.01 (d, J=2.4Hz, 1H), 8.09 (d, J=3.6Hz, 1H), 9.47 (br, 1H), 9.53 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.56; LCMS: purity: 93.71%; MS (m/e): 509.06 (MH +).
I-210:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-morpholine-4-base-2-oxo-oxyethyl group) phenyl]-2, the 4-pyrimidinediamine
[0771] 1H NMR (DMSO-d 6): δ 3.47 (m, 4H), 3.54-3.60 (m, 4H), 4.83 (s, 2H), 6.93 (d, J=9.0Hz, 2H), 7.16 (br, 2H), 7.55 (d, J=9.0Hz, 2H), 7.63 (d, J=9.0Hz, 2H), 7.73 (d, J=8.7Hz, 2H), 8.16 (d, J=4.2Hz, 1H), 9.72 (br, 1H), 9.90 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.25; LCMS: purity: 95.60%; MS (m/e): 503.81 (MH +).
I-211:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-morpholine-4-base-2-oxo-oxyethyl group) phenyl]-2, the 4-pyrimidinediamine
[0772] 1H NMR (DMSO-d 6): δ 3.46 (m, 4H), 3.56-3.60 (m, 4H), 4.82 (s, 2H), 6.90 (d, J=9.0Hz, 2H), 7.30 (br, 2H), 7.40 (m, 2H), 7.57 (d, J=9.0Hz, 2H), 7.85 (m, 1H), 7.95 (s, 1H), 8.15 (d, J=4.5Hz, 1H), 9.78 (br, 1H), 9.87 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.26; LCMS: purity: 94.18%; MS (m/e): 503.75 (MH +).
I-212:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(2-morpholine-4-base-2-oxo-oxyethyl group) phenyl]-2, the 4-pyrimidinediamine
[0773] 1H NMR (DMSO-d 6): δ 3.46 (m, 4H), 3.56-3.61 (m, 4H), 4.82 (s, 2H), 6.89 (d, J=9.0Hz, 2H), 7.22 (d, J=8.4Hz, 1H), 7.29 (br, 2H), 7.56 (d, J=9.0Hz, 2H), 7.75 (dd, J=2.7,8.4Hz, 1H), 7.94 (s, 1H), 8.14 (d, J=4.2Hz, 1H), 9.86 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-201.34; LCMS: purity: 91.60%; MS (m/e): 517.75 (MH +).
III-119:N2-(4-amino-sulfonyl phenyl)-N4-(4-ethylamino carbonylamino aminomethyl phenyl]-5-fluoro-2, the 4-pyrimidinediamine
[0774] 1H NMR (DMSO-d 6): δ 1.00 (t, J=7.2Hz, 3H), 3.03 (q, J=7.2Hz, 2H), 4.18 (s, 2H), 7.16 (br, 2H), 7.22 (d, J=8.7Hz, 2H), 7.63 (d, J=8.7Hz, 4H), 7.76 (d, J=9.0Hz, 2H), 8.16 (d, J=3.6Hz, 1H), 9.63 (br, 1H), 9.76 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.17; LCMS: purity: 100%; MS (m/e): 460.54 (MH +).
III-120:N2-(3-amino-sulfonyl phenyl]-N4-(4-ethylamino carbonylamino aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0775] 1H NMR (DMSO-d 6): δ 1.00 (t, J=7.2Hz, 3H), 3.03 (q, J=7.2Hz, 2H), 4.16 (s, 2H), 7.20 (d, J=8.4Hz, 2H), 7.28 (br, 2H), 7.38 (m, 2H), 7.66 (d, J=8.4Hz, 2H), 7.92 (m, 1H), 8.00 (s, 1H), 8.14 (d, J=4.2Hz, 1H), 9.66 (br, 1H), 9.74 (br, 1H); 19FNMR (282MHz, DMSO-d 6): δ-201.25; LCMS: purity: 97.96%; MS (m/e): 460.17 (MH +).
III-121:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(4-ethylamino carbonylamino aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0776] 1H NMR (DMSO-d 6): δ 1.00 (t, J=7.2Hz, 3H), 3.03 (p, J=7.2Hz, 2H), 4.16 (d, J=5.7Hz, 2H), 5.85 (t, J=5.4Hz, 1H), 6.24 (t, J=6.0Hz, 1H), 7.16 (d, J=6.9Hz, 1H), 7.18 (d, J=8.1Hz, 2H), 7.22 (br, 2H), 7.71 (d, J=8.4Hz, 2H), 7.90 (dd, J=2.4,8.1Hz, 1H), 8.06 (d, J=3.9Hz, 1H), 8.10 (d, J=2.1Hz, 1H), 9.30 (br, 1H), 9.37 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.63; LCMS: purity: 88.98%; MS (m/e): 474.75 (MH +).
I-146:N2-(4-amino-sulfonyl phenyl)-N4-(3-chloro-4-methylamino carbonyl p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0777] 1H NMR (DMSO-d 6): δ 2.67 (d, J=4.8Hz, 3H), 4.57 (s, 2H), 7.02 (d, J=9.0Hz, 1H), 7.14 (br, 2H), 7.60 (dd, J=2.7,9.0Hz, 1H), 7.65 (d, J=9.0Hz, 2H), 7.77 (d, J=9.0Hz, 2H), 7.86 (d, J=2.7Hz, 1H), 7.91 (d, J=5.1Hz, 1H), 8.16 (d, J=3.9Hz, 1H), 9.58 (br, 1H), 9.75 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.52; LCMS: purity: 97.14%; MS (m/e): 481.41 (MH +).
I-147:N2-(3-amino-sulfonyl phenyl)-N4-(3-chloro-4-methylamino carbonyl p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0778] 1H NMR (DMSO-d 6): δ 2.67 (d, J=4.5Hz, 3H), 4.56 (s, 2H), 7.00 (d, J=8.7Hz, 1H), 7.28 (br, 2H), 7.39 (m, 2H), 7.68 (dd, J=2.4,8.7Hz, 1H), 7.80 (d, J=2.4Hz, 1H), 7.89 (d, J=4.2Hz, 1H), 7.94 (d, J=2.1,7.2Hz, 1H), 7.98 (s, 1H), 8.15 (d, J=3.9Hz, 1H), 9.62 (br, 1H), 9.73 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.68; LCMS: purity: 97.93%; MS (m/e): 481.40 (MH +).
I-148:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3-chloro-4-methylamino carbonyl p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0779] 1H NMR (DMSO-d 6): δ 2.51 (s, 3H), 2.67 (d, J=4.8Hz, 3H), 4.56 (s, 2H), 7.00 (d, J=9.3Hz, 1H), 7.22 (d, J=8.7Hz, 1H), 7.28 (br, 2H), 7.65 (dd, J=2.4,8.7Hz, 1H), 7.79 (d, J=2.7Hz, 1H), 7.82 (dd, J=2.4,8.1Hz, 1H), 7.89 (d, J=4.2Hz, 1H), 7.95 (d, J=2.4Hz, 1H), 8.15 (d, J=4.5Hz, 1H), 9.79 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-201.59; LCMS: purity: 93.21%; MS (m/e): 495.44 (MH +).
I-213:5-fluoro-N4-(4-methoxycarbonyl p-methoxy-phenyl)-N2-(4-methyl-3-propionyl amino-sulfonyl phenyl)-2, the 4-pyrimidinediamine
[0780] LCMS: purity: 94.24%; MS (m/e): 518.82 (MH +).
I-134:N2-(4-amino-sulfonyl phenyl)-N4-(3-chloro-4-dimethylamino carbonyl p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine
[0781] 1H NMR (DMSO-d 6): δ 2.15 (s, 3H), 2.86 (s, 3H), 3.01 (s, 3H), 4.97 (s, 2H), 7.03 (d, J=9.3Hz, 1H), 7.24 (br, 2H), 7.37 (dd, J=2.4,9.0Hz, 1H), 7.58 (d, J=9.0Hz, 2H), 7.65 (d, J=3.0Hz, 1H), 7.69 (d, J=8.7Hz, 2H), 7.93 (s, 1H), 9.66 (br, 1H), 10.53 (br, 1H); LCMS: purity: 93.31%; MS (m/e): 491.44 (MH +).
I-135:N2-(3-amino-sulfonyl phenyl)-N4-(3-chloro-4-dimethylamino carbonyl p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine
[0782] 1H NMR (DMSO-d 6): δ 2.14 (s, 3H), 2.86 (s, 3H), 3.01 (s, 3H), 4.96 (s, 2H), 7.00 (d, J=9.0Hz, 1H), 7.34 (br, 2H), 7.40-7.49 (m, 3H), 7.59 (d, J=2.7Hz, 1H), 7.70 (s, 1H), 7.84 (d, J=7.2Hz, 1H), 7.89 (s, 1H), 9.44 (br, 1H), 10.24 (br, 1H); LCMS: purity: 96.97%; MS (m/e): 491.47 (MH +).
I-136:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3-chloro-4-dimethylamino carbonyl p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine
[0783] 1H NMR (DMSO-d 6): δ 2.13 (s, 3H), 2.52 (s, 3H), 2.86 (s, 3H), 3.01 (s, 3H), 4.96 (s, 2H), 6.98 (d, J=9.0Hz, 1H), 7.24 (d, J=8.7Hz, 1H), 7.34 (br, 2H), 7.42 (dd, J=2.4,8.4Hz, 1H), 7.59 (d, J=2.4Hz, 1H), 7.71 (d, J=8.4Hz, 1H), 7.75 (s, 1H), 7.84 (s, 1H), 9.40 (br, 1H), 10.13 (br, 1H); LCMS: purity: 93.42%; MS (m/e): 505.10 (MH +).
I-137:N2-(4-amino-sulfonyl phenyl)-N4-(4-dimethylamino carbonyl methoxyl group-3-fluorophenyl)-5-methyl-2, the 4-pyrimidinediamine
[0784] 1H NMR (DMSO-d 6): δ 2.15 (s, 3H), 2.86 (s, 3H), 3.00 (s, 3H), 4.93 (s, 2H), 7.06 (t, J=9.0Hz, 1H), 7.23 (d, J=16.2Hz, 1H), 7.26 (br, 2H), 7.50 (d, J=12.9Hz, 1H), 7.59 (d, J=8.7Hz, 2H), 7.66 (d, J=8.7Hz, 2H), 7.92 (s, 1H), 9.66 (br, 1H), 10.51 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-172.68; LCMS: purity: 98.26%; MS (m/e): 475.63 (MH +).
I-138:N2-(3-amino-sulfonyl phenyl)-N4-(4-dimethylamino carbonyl methoxyl group-3-fluorophenyl)-5-methyl-2, the 4-pyrimidinediamine
[0785] 1H NMR (DMSO-d 6): δ 2.15 (s, 3H), 2.86 (s, 3H), 3.00 (s, 3H), 4.93 (s, 2H), 7.04 (t, J=9.3Hz, 1H), 7.23 (d, J=8.7Hz, 1H), 7.36 (br, 2H), 7.39-7.49 (m, 3H), 7.69 (s, 1H), 7.83 (d, J=6.9Hz, 1H), 7.89 (s, 1H), 9.57 (br, 1H), 10.36 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-172.80; LCMS: purity: 98.80%; MS (m/e): 475.57 (MH +).
I-139:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(4-dimethylamino carbonyl methoxyl group-3-fluorophenyl)-5-methyl-2, the 4-pyrimidinediamine
[0786] 1H NMR (DMSO-d 6): δ 2.14 (s, 3H), 2.53 (s, 3H), 2.85 (s, 3H), 3.00 (s, 3H), 4.92 (s, 2H), 7.02 (t, J=9.0Hz, 1H), 7.24 (d, J=8.1Hz, 2H), 7.34 (br, 2H), 7.48 (d, J=12.9Hz, 1H), 7.71 (d, J=8.4Hz, 1H), 7.76 (s, 1H), 7.84 (s, 1H), 9.44 (br, 1H), 10.17 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-172.82; LCMS: purity: 96.33%; MS (m/e): 489.12 (MH +).
I-149:N2-(4-amino-sulfonyl phenyl)-N4-(3-chloro-4-methylamino carbonyl p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine
[0787] 1H NMR (DMSO-d 6): δ 2.15 (s, 3H), 2.68 (d, J=4.5Hz, 3H), 4.61 (s, 2H), 7.08 (d, J=9.0Hz, 1H), 7.26 (br, 2H), 7.42 (dd, J=2.7,9.0Hz, 1H), 7.60 (d, J=9.0Hz, 2H), 7.68 (d, J=8.7Hz, 2H), 7.71 (d, J=1.8Hz, 1H), 7.93 (s, 2H), 9.60 (br, 1H), 10.45 (br, 1H); LCMS: purity: 90.13%; MS (m/e): 476.99 (MH +).
I-150:N2-(3-amino-sulfonyl phenyl)-N4-(3-chloro-4-methylamino carbonyl p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine
[0788] 1H NMR (DMSO-d 6): δ 2.15 (s, 3H), 2.68 (d, J=4.8Hz, 3H), 4.60 (s, 2H), 7.04 (d, J=9.0Hz, 1H), 7.36 (br, 2H), 7.46 (m, 4H), 7.63 (d, J=2.4Hz, 1H), 7.83 (d, J=8.7Hz, 1H), 7.92 (s, 2H), 9.66 (br, 1H), 10.50 (br, 1H); LCMS: purity: 85.98%; MS (m/e): 476.96 (MH +).
I-151:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3-chloro-4-methylamino carbonyl p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine
[0789] 1H NMR (DMSO-d 6): δ 2.14 (s, 3H), 2.67 (d, J=4.5Hz, 3H), 4.60 (s, 2H), 7.03 (d, J=9.3Hz, 1H), 7.24 (d, J=7.8Hz, 1H), 7.36 (br, 2H), 7.45 (d, J=9.3Hz, 1H), 7.63 (d, J=2.4Hz, 1H), 7.69 (d, J=9.3Hz, 1H), 7.71 (s, 1H), 7.86 (s, 1H), 7.91 (d, J=4.8Hz, 1H), 9.60 (br, 1H), 10.32 (br, 1H); LCMS: purity: 98.01%; MS (m/e): 491.00 (MH +).
Embodiment 33
Figure A20068002053302541
VI-82:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-fluoropropyl) phenyl]-2, the 4-pyrimidinediamine
[0790] 3-phenyl-1-propyl alcohol (1mL) and (diethylamino) sulfur trifluoride (1.2mL) are dissolved in methylene dichloride (10mL).With reaction soln stirring at room 3 days.Make reaction mixture by lacking silicagel column and using washed with dichloromethane.With the solution evaporation collected to obtain the 1-fluoro-3-phenyl-propane of faint yellow oily. 1H?NMR(DMSO-d 6)：δ1.84-2.02(m，2H)，2.65(t，J＝7.5Hz，2H)，4.34(t，J＝5.7Hz，1H)，4.50(t，J＝5.7Hz，1H)，7.20(m，5H)； 19F?NMR(282MHz，DMSO-d 6)：δ-79.22。
In the time of [0791] 0 ℃ 1-fluoro-3-phenyl-propane is dissolved in diacetyl oxide (10mL) and adds acetate (1mL) and nitrosonitric acid (1mL) in solution.Reaction mixture is at room temperature reacted and, use ethyl acetate (100mL) dilution then 60 ℃ of reactions 1 hour.(3 * 100mL) and salt solution (100mL) washing, evaporation is to obtain 1-fluoro-3-(4-nitrophenyl) propane for the organic solution water.
[0792] 1-fluoro-3-(4-nitrophenyl) propane is dissolved in methyl alcohol (50mL) and adds 10%Pd-C in solution.Reaction mixture was reacted 1 hour down at hydrogen (about 40psi).Leach catalyzer with diatomite.Filtrate is evaporated to obtain 4-(3-fluoropropyl) aniline.
[0793] with 4-(3-fluoropropyl) aniline and 2,6-two chloro-5-fluorine pyrimidines (1.5g) are dissolved in methyl alcohol (5mL) and water (1mL).With reaction soln stirring at room 3 days.Reaction soln water (100mL) dilutes and (2 * 100mL) extract with ethyl acetate.With organic layer evaporation and by hurried column chromatography (EtOAc/ hexane=1/4,1/2) purifying to obtain 2-chloro-5-fluoro-N4-[4-(3-fluoropropyl) phenyl]-the 4-PYRIMITHAMINE.
[0794] with 2-chloro-5-fluoro-N4-[4-(3-fluoropropyl) phenyl]-4-PYRIMITHAMINE (100mg) and sulfanilamide (SN) (100mg) is suspended in Virahol (1mL) and TFA (5).Solution is 100 ℃ of heated overnight.With solution evaporation, by hurried column chromatography (2.0MNH 3/ MeOH in methylene dichloride=1-3%) and from the re-crystallizing in ethyl acetate purifying to obtain N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-fluoropropyl) phenyl]-2, the 4-pyrimidinediamine. 1H NMR (DMSO-d 6): δ 1.89-2.02 (m, 2H), 2.67 (t, J=8.1Hz, 2H), 4.38 (t, J=5.7Hz, 1H), 4.53 (t, J=5.7Hz, 1H), 7.11 (br, 2H), 7.19 (d, J=8.1Hz, 2H), 7.60 (d, J=8.7Hz, 2H), 7.65 (d, J=8.1Hz, 2H), 7.80 (d, J=8.7Hz, 2H), 8.12 (d, J=3.9Hz, 1H), 9.38 (br, 1H), 9.57 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.79; LCMS: purity: 91.96%; MS (m/e): 420.74 (MH +).
[0795] following compound is according to mode similar to the above embodiments or by method described here or the preparation of those of skill in the art's currently known methods.
VI-83:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-fluoropropyl) phenyl]-2, the 4-pyrimidinediamine
[0796] 1H NMR (DMSO-d 6): δ 1.88-2.01 (m, 2H), 2.65 (t, J=7.8Hz, 2H), 4.37 (t, J=6.0Hz, 1H), 4.52 (t, J=6.0Hz, 1H), 7.17 (d, J=8.4Hz, 2H), 7.24 (br, 2H), 7.37 (m, 2H), 7.70 (d, J=8.7Hz, 2H), 7.95 (d, J=7.8Hz, 1H), 8.09 (d, J=3.3Hz, 2H), 9.32 (br, 1H), 9.48 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.10; LCMS: purity: 93.78%; MS (m/e): 420.78 (MH +).
VI-84:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(3-fluoropropyl) phenyl]-2, the 4-pyrimidinediamine
[0797] 1H NMR (DMSO-d 6): δ 1.88-1.98 (m, 2H), 2.65 (t, J=7.8Hz, 2H), 4.36 (t, J=6.0Hz, 1H), 4.52 (t, J=6.0Hz, 1H), 7.17 (m, 5H), 7.70 (d, J=8.1Hz, 2H), 7.88 (dd, J=2.4,8.4Hz, 1H), 8.05 (d, J=3.9Hz, 1H), 8.10 (d, J=2.1Hz, 1H), 9.27 (br, 1H), 9.37 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.68; LCMS: purity: 97.85%; MS (m/e): 434.92 (MH +).
VI-85:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-hydroxypropyl) phenyl]-2, the 4-pyrimidinediamine
[0798] 1H NMR (DMSO-d 6): δ 1.72 (p, J=7.2Hz, 2H), 2.61 (t, J=7.5Hz, 2H), 3.42 (t, J=6.3Hz, 2H), 4.47 (br, 1H), 7.11 (br, 2H), 7.16 (d, J=8.4Hz, 2H), 7.60 (d, J=9.0Hz, 2H), 7.62 (d, J=8.4Hz, 2H), 7.80 (d, J=9.0Hz, 2H), 8.11 (d, J=3.9Hz, 1H), 9.36 (br, 1H), 9.57 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.84; LCMS: purity: 97.76%; MS (m/e): 418.20 (MH +).
VI-86:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-hydroxypropyl) phenyl]-2, the 4-pyrimidinediamine
[0799] 1H NMR (DMSO-d 6): δ 1.71 (p, J=7.5Hz, 2H), 2.58 (t, J=7.5Hz, 2H), 3.41 (q, J=6.0Hz, 2H), 4.44 (t, J=5.1Hz, 1H), 7.14 (d, J=7.8Hz, 2H), 7.24 (br, 2H), 7.34 (m, 2H), 7.67 (d, J=8.1Hz, 2H), 7.95 (d, J=7.2Hz, 1H), 8.08 (d, J=3.6Hz, 2H), 9.29 (br, 1H), 9.47 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.16; LCMS: purity: 89.77%; MS (m/e): 418.18 (MH +).
VI-87:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(3-hydroxypropyl) phenyl]-2, the 4-pyrimidinediamine
[0800] LCMS: purity: 94.51%; MS (m/e): 432.66 (MH +).
I-152:N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(3-chloro-4-methylamino carbonyl p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0801] 1H NMR (DMSO-d 6): δ 2.67 (d, J=4.8Hz, 3H), 4.56 (s, 2H), 7.01 (d, J=9.0Hz, 1H), 7.42 (d, J=8.7Hz, 1H), 7.47 (br, 2H), 7.69 (dd, J=2.7,8.7Hz, 1H), 7.80 (d, J=2.4Hz, 1H), 7.88 (br, 1H), 8.02 (dd, J=2.7,8.7Hz, 1H), 8.12 (d, J=3.9Hz, 1H), 8.20 (d, J=2.4Hz, 1H), 9.51 (br, 1H), 9.72 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.67; LCMS: purity: 91.37%; MS (m/e): 515.31 (MH +).
I-140:N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(3-chloro-4-dimethylamino carbonyl p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0802] 1H NMR (DMSO-d 6): δ 2.85 (s, 3H), 3.01 (s, 3H), 4.93 (s, 2H), 6.96 (d, J=9.0Hz, 1H), 7.41 (d, J=9.0Hz, 1H), 7.46 (br, 2H), 7.61 (dd, J=2.4,9.0Hz, 1H), 7.72 (d, J=2.7Hz, 1H), 8.01 (dd, J=2.7,9.0Hz, 1H), 8.10 (d, J=3.6Hz, 1H), 8.20 (d, J=2.4Hz, 1H), 9.43 (br, 1H), 9.67 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.04; LCMS: purity: 91.74%; MS (m/e): 529.35 (MH +).
I-141:N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(3-chloro-4-dimethylamino carbonyl p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine
[0803] 1H NMR (DMSO-d 6): δ 2.13 (s, 3H), 2.87 (s, 3H), 3.01 (s, 3H), 4.97 (s, 2H), 7.00 (d, J=8.7Hz, 1H), 7.44 (d, J=8.7Hz, 2H), 7.54 (br, 2H), 7.58 (d, J=2.4Hz, 1H), 7.88 (m, 2H), 7.96 (s, 1H), 9.26 (br, 1H), 10.12 (br, 1H); LCMS: purity: 97.43%; MS (m/e): 525.37 (MH +).
I-142:N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(4-dimethylamino carbonyl methoxyl group-3-fluorophenyl)-5-methyl-2, the 4-pyrimidinediamine
[0804] 1H NMR (DMSO-d 6): δ 2.14 (s, 3H), 2.86 (s, 3H), 3.00 (s, 3H), 4.94 (s, 2H), 7.04 (t, J=9.3Hz, 1H), 7.25 (d, J=8.7Hz, 1H), 7.45 (d, J=9.0Hz, 1H), 7.46 (dd, 1H), 7.55 (br, 2H), 7.89 (m, 2H), 7.96 (s, 1H), 9.39 (br, 1H), 10.26 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-172.86; LCMS: purity: 99.33%; MS (m/e): 509.19 (MH +).
I-153:N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(3-chloro-4-methylamino carbonyl p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine
[0805] 1H NMR (DMSO-d 6): δ 2.09 (s, 3H), 2.68 (d, J=4.5Hz, 3H), 4.56 (s, 2H), 7.00 (d, J=9.0Hz, 1H), 7.35 (d, J=9.0Hz, 1H), 7.43 (br, 2H), 7.67 (d, J=8.7Hz, 1H), 7.71 (s, 1H), 7.89 (s, 2H), 8.07 (d, J=8.7Hz, 1H), 8.21 (s, 1H), 8.33 (s, 1H), 9.44 (br, 1H); LCMS: purity: 98.98%; MS (m/e): 511.34 (MH +).
VI-88:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-hydroxybutyl) phenyl]-2, the 4-pyrimidinediamine
[0806] 1H NMR (DMSO-d 6): δ 1.44 (m, 2H), 1.60 (m, 2H), 2.57 (t, J=7.5Hz, 2H), 3.41 (q, J=6.0Hz, 2H), 4.37 (t, J=5.1Hz, 1H), 7.11 (br, 2H), 7.16 (d, J=8.7Hz, 2H), 7.60 (d, J=8.7Hz, 2H), 7.62 (d, J=8.4Hz, 2H), 7.80 (d, J=9.0Hz, 2H), 8.11 (d, J=3.6Hz, 1H), 9.36 (br, 1H), 9.57 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.84; LCMS: purity: 90.99%; MS (m/e): 432.24 (MH +).
VI-89:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-hydroxybutyl) phenyl]-2, the 4-pyrimidinediamine
[0807] 1H NMR (DMSO-d 6): δ 1.43 (m, 2H), 1.59 (m, 2H), 2.55 (t, J=7.5Hz, 2H), 3.40 (q, J=5.8Hz, 2H), 4.36 (t, J=4.8Hz, 1H), 7.13 (d, J=8.4Hz, 2H), 7.21 (br, 2H), 7.33 (m, 2H), 7.67 (d, J=8.4Hz, 2H), 7.95 (d, J=6.9Hz, 1H), 8.08 (d, J=3.9Hz, 2H), 9.29 (br, 1H), 9.47 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.14; LCMS: purity: 92.80%; MS (m/e): 432.24 (MH +).
VI-90:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(4-hydroxybutyl) phenyl]-2, the 4-pyrimidinediamine
[0808] LCMS: purity: 91.08%; MS (m/e): 446.51 (MH +).
VI-91:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-fluorine butyl) phenyl]-2, the 4-pyrimidinediamine
[0809] 1H NMR (DMSO-d 6): δ 1.64-1.69 (m, 4H), 2.62 (t, J=6.9Hz, 2H), 4.38 (t, J=5.7Hz, 1H), 4.54 (t, J=6.0Hz, 1H), 7.11 (br, 2H), 7.18 (d, J=8.7Hz, 2H), 7.60 (d, J=9.3Hz, 2H), 7.63 (d, J=8.4Hz, 2H), 7.80 (d, J=9.0Hz, 2H), 8.12 (d, J=3.9Hz, 1H), 9.37 (br, 1H), 9.58 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.85; LCMS: purity: 89.65%; MS (m/e): 434.59 (MH +).
VI-92:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-fluorine butyl) phenyl]-2, the 4-pyrimidinediamine
[0810] 1H NMR (DMSO-d 6): δ 1.64-1.68 (m, 4H), 2.59 (t, J=6.9Hz, 2H), 4.37 (t, J=6.3Hz, 1H), 4.53 (t, J=5.4Hz, 1H), 7.15 (d, J=8.1Hz, 2H), 7.24 (br, 2H), 7.34 (m, 2H), 7.68 (d, J=7.8Hz, 2H), 7.95 (d, J=7.2Hz, 1H), 8.08 (d, J=2.4Hz, 2H), 9.30 (br, 1H), 9.47 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.13; LCMS: purity: 91.90%; MS (m/e): 434.60 (MH +).
VI-93:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(4-fluorine butyl) phenyl]-2, the 4-pyrimidinediamine
[0811] 1H NMR (DMSO-d 6): δ 1.63-1.68 (m, 4H), 2.60 (t, J=6.9Hz, 2H), 4.37 (t, J=5.7Hz, 1H), 4.53 (t, J=5.1Hz, 1H), 7.16 (d, J=8.7Hz, 2H), 7.18 (d, J=8.1Hz, 1H), 7.26 (br, 2H), 7.61 (d, J=8.4Hz, 2H), 7.80 (d, J=7.5Hz, 1H), 7.98 (s, 1H), 8.13 (d, J=4.5Hz, 1H), 9.75 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-201.39; LCMS: purity: 84.96%; MS (m/e): 448.68 (MH +).
I-154:N2-(4-amino-sulfonyl phenyl)-N4-(3-fluoro-4-methylamino carbonyl p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine
[0812] 1H NMR (DMSO-d 6): δ 2.15 (s, 3H), 2.66 (d, J=4.2Hz, 3H), 4.58 (s, 2H), 7.10 (t, J=9.0Hz, 1H), 7.26 (br, 3H), 7.57 (dd, J=2.4,12.9Hz, 1H), 7.61 (d, J=8.7Hz, 2H), 7.66 (d, J=9.3Hz, 2H), 7.93 (s, 1H), 8.02 (d, J=3.9Hz, 1H), 9.59 (br, 1H), 10.44 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-171.80; LCMS: purity: 99.32%; MS (m/e): 461.58 (MH +).
I-155:N2-(3-amino-sulfonyl phenyl)-N4-(3-fluoro-4-methylamino carbonyl p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine
[0813] 1H NMR (DMSO-d 6): δ 2.15 (s, 3H), 2.66 (d, J=4.5Hz, 3H), 4.56 (s, 2H), 7.06 (t, J=9.3Hz, 1H), 7.29 (d, J=8.7Hz, 1H), 7.34 (br, 2H), 7.40 (t, J=7.8Hz, 1H), 7.50 (d, J=7.5Hz, 1H), 7.53 (d, J=12.0Hz, 1H), 7.72 (s, 1H), 7.84 (d, J=8.4Hz, 1H), 7.90 (s, 1H), 7.98 (d, 1H), 9.50 (br, 1H), 10.26 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-171.83; LCMS: purity: 99.44%; MS (m/e): 461.52 (MH +).
I-156:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3-fluoro-4-methylamino carbonyl p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine
[0814] 1H NMR (DMSO-d 6): δ 2.14 (s, 3H), 2.54 (s, 3H), 2.65 (d, J=4.8Hz, 3H), 4.56 (s, 2H), 7.06 (t, J=9.0Hz, 1H), 7.22 (d, J=8.7Hz, 1H), 7.28 (d, J=8.4Hz, 1H), 7.36 (br, 2H), 7.51 (dd, J=10.8Hz, 1H), 7.69 (d, J=7.8Hz, 1H), 7.72 (s, 1H), 7.86 (s, 1H), 7.99 (d, 1H), 9.58 (br, 1H), 10.35 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-171.83; LCMS: purity: 98.38%; MS (m/e): 475.67 (MH +).
III-32:N4-(4-amino carbonyl amino aminomethyl phenyl)-N2-(4-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0815] 1H NMR (DMSO-d 6): δ 4.17 (s, 2H), 6.47 (br, 1H), 7.17 (br, 2H), 7.23 (d, J=8.7Hz, 2H), 7.62 (d, J=9.0Hz, 2H), 7.63 (d, J=8.4Hz, 2H), 7.77 (d, J=9.0Hz, 2H), 8.15 (d, J=3.9Hz, 1H), 9.60 (br, 1H), 9.73 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.32; LCMS: purity: 96.25%; MS (m/e): 432.11 (MH +).
III-33:N4-(4-amino carbonyl amino aminomethyl phenyl)-N2-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0816] 1H NMR (DMSO-d 6): δ 4.15 (s, 2H), 6.46 (br, 1H), 7.21 (d, J=8.1Hz, 2H), 7.28 (br, 2H), 7.39 (d, J=4.8Hz, 2H), 7.67 (d, J=7.5Hz, 2H), 7.92 (m, 1H), 8.01 (s, 1H), 8.15 (d, J=3.6Hz, 1H), 9.68 (br, 1H), 9.75 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.24; LCMS: purity: 95.09%; MS (m/e): 432.51 (MH +).
III-34:N4-(4-amino carbonyl amino aminomethyl phenyl)-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0817] 1H NMR (DMSO-d 6): δ 2.52 (s, 3H), 4.15 (s, 2H), 6.42 (br, 1H), 7.20 (d, J=8.4Hz, 1H), 7.21 (d, J=8.1Hz, 2H), 7.26 (br, 2H), 7.66 (d, J=8.4Hz, 2H), 7.83 (d, J=8.1Hz, 1H), 8.01 (s, 1H), 8.13 (d, J=4.2Hz, 1H), 9.70 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-201.66; LCMS: purity: 85.70%; MS (m/e): 446.65 (MH +).
IX-41:N4-(4-ethanoyl sulphomethyl carbonyl phenyl)-N2-(4-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0818] 1H NMR (DMSO-d 6): δ 2.36 (s, 3H), 4.11 (s, 2H), 7.15 (br, 2H), 7.27 (d, J=8.4Hz, 2H), 7.63 (d, J=8.7Hz, 2H), 7.65 (d, J=8.7Hz, 2H), 7.76 (d, J=9.0Hz, 2H), 8.18 (d, J=3.9Hz, 1H), 9.69 (br, 1H), 9.81 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-200.96; LCMS: purity: 78.34%; MS (m/e): 448.42 (M-28).
IX-42:N4-(4-ethanoyl sulphomethyl carbonyl phenyl)-N2-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0819] 1H NMR (DMSO-d 6): δ 2.35 (s, 3H), 4.09 (s, 2H), 7.24 (d, J=8.4Hz, 2H), 7.25 (br, 2H), 7.36 (m, 2H), 7.70 (d, J=8.7Hz, 2H), 7.91 (m, 1H), 8.05 (s, 1H), 8.13 (d, J=3.6Hz, 1H), 9.53 (br, 1H), 9.60 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.56; LCMS: purity: 84.49%; MS (m/e): 448.41 (M-28).
IX-43:N4-(4-ethanoyl sulphomethyl carbonyl phenyl)-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0820] 1H NMR (DMSO-d 6): δ 2.36 (s, 3H), 4.10 (s, 2H), 7.20 (d, J=8.1Hz, 1H), 7.25 (d, J=8.4Hz, 2H), 7.28 (br, 2H), 7.64 (d, J=8.7Hz, 2H), 7.79 (dd, J=2.4,8.4Hz, 1H), 7.96 (s, 1H), 8.17 (d, J=4.2Hz, 1H), 9.86 (br, 1H), 9.89 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.03; LCMS: purity: 85.44%; MS (m/e): 462.21 (M-28).
III-44:N4-(4-propenyl amido aminomethyl phenyl)-N2-(4-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0821] 1H NMR (DMSO-d 6): δ 4.33 (d, J=6.0Hz, 2H), 5.61 (dd, J=2.4,9.9Hz, 1H), 6.11 (dd, J=2.4,17.1Hz, 1H), 6.27 (dd, J=9.6,17.1Hz, 1H), 7.12 (br, 2H), 7.23 (d, J=8.7Hz, 2H), 7.62 (d, J=8.7Hz, 2H), 7.70 (d, J=8.1Hz, 2H), 7.81 (d, J=8.7Hz, 2H), 8.13 (d, J=3.6Hz, 1H), 8.59 (t, J=5.7Hz, 1H), 9.43 (br, 1H), 9.58 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.60; LCMS: purity: 93.70%; MS (m/e): 443.22 (MH +).
III-45:N4-(4-propenyl amido aminomethyl phenyl)-N2-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0822] 1H NMR (DMSO-d 6): δ 4.32 (d, J=6.0Hz, 2H), 5.61 (dd, J=2.1,9.9Hz, 1H), 6.11 (dd, J=2.4,17.1Hz, 1H), 6.28 (dd, J=10.2,17.4Hz, 1H), 7.22 (d, J=8.1Hz, 2H), 7.25 (br, 2H), 7.34 (m, 2H), 7.74 (d, J=8.4Hz, 2H), 7.95 (d, J=7.5Hz, 1H), 8.10 (s, 1H), 8.10 (d, J=3.6Hz, 1H), 8.57 (t, 1H), 9.38 (br, 1H), 9.49 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.04; LCMS: purity: 91.76%; MS (m/e): 443.57 (MH +).
III-46:N4-(4-propenyl amido aminomethyl phenyl)-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0823] 1H NMR (DMSO-d 6): δ 4.32 (d, J=6.3Hz, 2H), 5.61 (dd, J=2.4,9.9Hz, 1H), 6.12 (dd, J=2.4,17.1Hz, 1H), 6.28 (dd, J=9.9,17.1Hz, 1H), 7.15 (d, J=8.1Hz, 1H), 7.21 (d, J=8.4Hz, 2H), 7.22 (br, 2H), 7.74 (d, J=8.4Hz, 2H), 7.89 (dd, J=2.1,8.1Hz, 1H), 8.07 (d, J=3.9Hz, 1H), 8.10 (d, J=2.1Hz, 1H), 8.56 (t, J=5.4Hz, 1H), 9.34 (br, 1H), 9.38 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.59; LCMS: purity: 88.19%; MS (m/e): 457.48 (MH +).
IX-15:N2-(3-amino-sulfonyl phenyl)-N4-(3-cyano methyl-1H-indoles-7-yl)-5-fluoro-2, the 4-pyrimidinediamine
[0824] 1H NMR (DMSO-d 6): δ 8.07 (s, 1H), 7.88 (s, 1H), 7.50 (d, 1H, J=8.1Hz), 7.16 (m, 6H), 4.08 (s, 2H); LCMS: purity: 93%; MS (m/e): 438 (MH +).
IX-16:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3-cyano methyl-1H-indoles-7-yl)-5-fluoro-2, the 4-pyrimidinediamine
[0825] 1H NMR (DMSO-d 6): δ 8.05 (d, 1H, J=3.3Hz), 7.88 (s, 1H), 7.50 (d, 1H, J=7.5Hz), 7.39 (d, 1H, J=7.8Hz), 7.28 (s, 1H), 7.23 (d, 2H, J=7.8Hz), 7.07 (t, 1H, J=7.8Hz), 6.75 (d, 1H, J=8.4Hz), 4.08 (s, 2H), 2.39 (s, 3H); LCMS: purity: 92%; MS (m/e): 452 (MH +).
I-9:N2-[3-amino-sulfonyl-4-(4-methylpiperazine-1-yl) phenyl]-5-fluoro-N4-(4-cyano group methylene radical oxygen base phenyl)-2, the 4-pyrimidinediamine
[0826] 1H NMR (DMSO-d 6): δ 8.07 (d, 1H, J=4.62Hz), 7.95 (bs, 1H), 7.70 (bs, 2H), 7.44 (d, 1H, J=9.3Hz), 7.06 (d, 2H, J=9Hz), 5.14 (s, 2H), 3.15 (s, 4H), 2.90 (bs, 4H), 2.27 (s, 3H); LCMS: purity: 91%; MS (m/e): 514 (MH +).
I-251:N2-[3-amino-sulfonyl-4-(4-methylpiperazine-1-yl) phenyl]-5-fluoro-N4-[2-fluoro-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0827] 1H NMR (DMSO-d 6): δ 8.07 (bs, 1H), 7.98 (d, 1H, J=9Hz), 7.87 (d, 1H, J=13.8Hz), 7.53 (d, 1H, J=9.3Hz), 7.42 (d, 1H, J=8.7Hz), 7.20 (t, 1H, J=9Hz), 6.33 (s, 1H), 5.18 (s, 2H), 3.15 (s, 4H), 2.90 (s, 4H), 2.41 (s, 3H), 2.28 (s, 3H); LCMS: purity: 98%; MS (m/e): 588 (MH +).
I-10:N2-[3-amino-sulfonyl-4-(4-methylpiperazine-1-yl) phenyl]-5-fluoro-N4-(4-cyano group methylene radical oxygen base-3-fluorophenyl)-2, the 4-pyrimidinediamine
[0828] 1H NMR (DMSO-d 6): δ 8.10 (t, 2H, J=3.6Hz), 7.92 (m, 2H), 7.58 (d, 1H, J=3.3Hz), 7.45 (d, 1H, J=8.7Hz), 7.26 (t, 1H, J=8.7Hz), 5.19 (s, 2H), 3.15 (s, 4H), 2.90 (s, 4H), 2.22 (s, 3H); LCMS: purity: 94%; MS (m/e): 531 (MH +).
I-11:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(4-cyano group methylene radical oxygen base-3-fluorophenyl)-2, the 4-pyrimidinediamine
[0829] 1H NMR (DMSO-d 6): δ 8.10 (t, 2H, J=3.6Hz), 7.92 (m, 2H), 7.59 (d, 1H, J=9.0Hz), 7.24 (m, 2H), 5.20 (s, 2H), 2.45 (s, 3H); LCMS: purity: 94%; MS (m/e): 447 (MH +).
I-12:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(4-cyano group methylene radical oxygen base-3-fluorophenyl)-2, the 4-pyrimidinediamine
[0830] 1H NMR (DMSO-d 6): δ 8.13 (t, 1H, J=3.9Hz), 8.10 (s, 1H), 7.95 (m, 2H), 7.60 (d, 1H, J=8.7Hz), 7.36 (m, 3H), 5.20 (s, 2H); LCMS: purity: 95%; MS (m/e): 433 (MH +).
IX-20:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3-cyano methyl-1-methyl-indoles-5-yl)-5-fluoro-2, the 4-pyrimidinediamine
[0831] 1H NMR (DMSO-d 6): δ 9.32 (s, 1H), 9.21 (s, 1H), 8.08 (s, 1H), 8.02 (d, 1H, J=3.9Hz), 7.89 (s, 2H), 7.46 (s, 1H), 7.34 (s, 1H), 7.21 (s, 2H), 4.02 (s, 2H), 3.75 (s, 3H), 2.47 (s, 3H); LCMS: purity: 99%; MS (m/e): 467 (MH +).
III-103:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(4-N-morpholino methylene radical phenyl)-2, the 4-pyrimidinediamine
[0832] 1H NMR (DMSO-d 6): δ 8.10 (m, 2H), 7.96 (m, 2H), 7.76 (d, 1H, J=8.1Hz), 7.35 (m, 1H), 7.25 (m, 2H), J=5.7Hz), 3.57 (bs, 4H), 3.43 (bs, 2H), 2.28 (bs, 4H); LCMS: purity: 96%; MS (m/e): 459 (MH +).
III-104:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(4-N-morpholino methylene radical phenyl)-2, the 4-pyrimidinediamine
[0833] 1H NMR (DMSO-d 6): δ 8.08 (t, 1H, J=3.6Hz), 7.92 (d, 1H, J=8.1Hz), 7.57 (d, 1H, J=8.1Hz), 7.25 (d, 1H, J=7.5Hz), 7.16 (d, 1H, J=8.1Hz), 3.57 (bs, 4H), 3.44 (s, 2H), 2.36 (s, 4H), 2.07 (s, 3H); LCMS: purity: 99%; MS (m/e): 473 (MH +).
III-105:N2-(3-amino-sulfonyl-4-methylene radical oxygen base phenyl)-5-fluoro-N4-(4-N-morpholino methylene radical phenyl)-2, the 4-pyrimidinediamine
[0834] 1H NMR (DMSO-d 6): δ 8.05 (d, 1H, J=3.6Hz), 7.98 (m, 1H), 7.89 (m, 1H), 7.59 (d, 1H, J=8.4Hz), 7.24 (d, 1H, J=8.1Hz), 7.06 (m, 1H), 6.97 (s, 2H), 3.85 (s, 3H), 3.56 (bs, 4H), 3.42 (s, 2H), 2.34 (bs, 4H); LCMS: purity: 95%; MS (m/e): 489 (MH +).
III-110:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-{4-[(1,1-dioxo thiomorpholine-4-base-) methyl] phenyl-2, the 4-pyrimidinediamine
[0835] 1H NMR (DMSO-d 6): δ 8.12 (d, 2H, J=3.6Hz), 7.95 (m, 1H), 7.78 (d, 2H, J=8.4Hz), 7.37 (m, 2H), 7.28 (d, 2H), 3.64 (s, 2H), 3.10 ((bs, 4H), 2.87 (bs, 4H); LCMS: purity: 97%; MS (m/e): 507 (MH +).
III-111:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-{4-[(1,1-dioxo thiomorpholine-4-base-) methyl] phenyl-2, the 4-pyrimidinediamine
[0836] 1H NMR (DMSO-d 6): δ 8.1 (d, 2H, J=2.4Hz), 8.08 (d, 1H, J=3.9Hz), 7.90 (m, 1H), 7.78 (d, 2H, J=8.7Hz), 7.22 (m, 3H), 3.64 (s, 2H), 3.10 (bs, 4H), 2.45 (s, 3H), 2.88 (bm, 4H); LCMS: purity: 98%; MS (m/e): 521 (MH +).
III-112:N2-(3-amino-sulfonyl-4-methyl oxygen base phenyl)-5-fluoro-N4-{4-[(1,1-dioxo thiomorpholine-4-base-) methyl] phenyl-2, the 4-pyrimidinediamine
[0837] 1H NMR (DMSO-d 6): δ 8.06 (d, 1H, J=3.6Hz), 7.99 (bs, 1H), 7.97 (m, 2H), 7.28 (d, 2H, J=7.8Hz), 7.08 (d, 1H, J=9Hz), 6.96 (s, 1H), 3.85 (s, 3H), 3.65 (s, 2H), 3.12 (s, 4H), 2.90 (s, 4H); LCMS: purity: 91%; MS (m/e): 537 (MH +).
III-107:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(the 4-thiomorpholine is for the methylene radical phenyl)-2, the 4-pyrimidinediamine
[0838] 1H NMR (DMSO-d 6): δ 8.10 (m, 2H), 7.95 (m, 1H), 7.75 (d, 2H, J=8.4Hz), 7.36 (d, 2 hours, J=7.2Hz), 7.24 (t, 2H, J=8.7Hz), 3.46 (s, 2H), 2.6 (s, 4H), 2.48 (s, 4H); LCMS: purity: 96%; MS (m/e): 475 (MH+).
III-108:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(the 4-thiomorpholine is for the methylene radical phenyl)-2, the 4-pyrimidinediamine
[0839] 1H NMR (DMSOd-6): δ 8.07 (t, 2H, J=5.1Hz), 7.89 (dd, 1H, J=8.4Hz, J=1.8Hz), 7.50 (d, 2H, J=8.4Hz), 7.23 (d, 2H, J=8.4Hz), 7.16 (d, 1H, J=8.1Hz), 3.46 (s, 2H), 2.6 (s, 4H), 2.49 (s, 3H), 2.48 (s, 4H); LCMS: purity: 88%; MS (m/e): 489 (MH +).
III-109:N2-(3-amino-sulfonyl-4-p-methoxy-phenyl)-5-fluoro-N4-(the 4-thiomorpholine is for the methylene radical phenyl)-2, the 4-pyrimidinediamine
[0840] 1H NMR (DMSO-d 6): δ 8.08 (d, 1H, J=8.06Hz), 7.87 (bs, 1H), 7.78 (bs, 1H), 7.73 (d, 1H, J=8.1Hz), 7.23 (d, 1H, J=8.1Hz), 7.01 (s, 2H), 3.77 (s, 3H), 3.45 (s, 2H), 2.60 (s, 4H), 2.21 (s, 4H); LCMS: purity: 99%; MS (m/e): 505 (MH +).
II-9:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(N-methylpyrrolidin-3-base oxygen base phenyl)-2, the 4-pyrimidinediamine
[0841] 1H NMR (DMSO-d 6): δ 8.07 (t., 2H, J=4.8Hz), 7.94 (d, 1H, J=6.6Hz), 7.66 (d, 2H, J=8.4Hz), 7.33 (d, 2H, J=7.5Hz), 7.25 (s, 1H), 6.85 (d, 2H, J=8.1Hz), 4.83 (s, 1H), 2.76 (m, 2H), 2.62 (m, 2H), 2.35 (m, 2H), 2.26 (s, 3H); LCMS: purity: 90%; MS (m/e): 446 (MH +)
II-10:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(N-methylpyrrolidin-3-base oxygen base phenyl)-2, the 4-pyrimidinediamine
[0842] 1H NMR (DMSOd-6): δ 8.06 (m, 2H), 7.93 (d, 1H, J=6.9Hz), 7.66 (d, 2H, J=9.3Hz), 7.33 (m, 2H), 6.85 (d, 2H, J=9.0Hz), 4.83 (s, 1H), 2.75 (m, 2H), 2.62 (m, 2H), 2.49 (s, 3H), 2.35 (m, 2H), 2.25 (s, 3H); LCMS: purity: 90%; MS (m/e): 473 (MH +).
IX-27:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(4-methylpiperazine-1-base carbonyl) phenyl]-2, the 4-pyrimidinediamine
[0843] 1H NMR (DMSO-d 6): δ 9.53 (s, 1H), 9.46 (s, 1H), 8.12 (s, 2H), 7.89 (t, 3H, J=9.0Hz), 7.25 (m, 3H), 3.49 (s, 4H), 2.31 (s, 3H), 2.19 (s, 3H); LCMS: purity: 92%; MS (m/e): 500 (MH +).
IX-28:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-methylpiperazine-1-base carbonyl) phenyl]-2, the 4-pyrimidinediamine
[0844] 1H NMR (DMSO-d 6): d 95.3 (s, 1H), 8.16 (d, 1H, J=11.4Hz), 7.92 (d, 2H, J=8.1Hz), 7.35 (m, 3H), 7.26 (s, 3Hz), 3.49 (s, 4H), 2.2 (s, 3H); LCMS: purity: 86%; MS (m/e): 486 (MH +)
II-5:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-{3-methyl-4-[(1-methyl piperidine-4-yl) oxygen base] phenyl }-2, the 4-pyrimidinediamine
1H NMR (CD 3OD): δ 6.92 (d, J=2.4Hz, 1H), 6.73 (d, J=3.9Hz, 1H), 6.61 (dd, J=2.4 and 8.4Hz, 1H), 6.29 (dd, J=2.7 and 8.4Hz, 1H), 6.23-6.20 (m, 1H), 6.01 (d, J=8.4Hz, 1H), 5.79 (d, J=8.7Hz, 1H), 3.35-3.25 (m, 1H), 1.69-1.56 (m, 2H), 1.46 (s, 3H), 1.38-1.27 (m, 2H), 1.21 (s, 3H), 1.09 (s, 3H), 0.96-0.86 (m, 2H), 0.81-0.70 (m, 2H); LCMS: purity: 92%, MS (m/e): 501 (MH +).
II-6:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-{4-[(1-methyl piperidine-4-yl) oxygen base]-the 3-trifluoromethyl }-2, the 4-pyrimidinediamine
[0845] 1H NMR (DMSO-d 6): δ 9.39 (s, 1H), 9.37 (s, 1H), 8.09-8.01 (m, 3H), 7.81 (dd, J=2.4 and 8.7Hz, 1H), 7.77 (d, J=2.7Hz, 1H), 7.27-7.21 (m, 3H), 7.11 (d, J=8.4Hz, 1H), 4.62-4.51 (m, 1H), 2.57-2.42 (m, 5H), 2.28-2.00 (m, 2H), 2.16 (s, 3H), 1.98-1.86 (m, 2H), 1.75-1.63 (m, 2H); LCMS: purity: 97% (m/e): 555 (MH +).
II-7:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-{4-[(1-methyl piperidine-4-yl) oxygen base] phenyl }-2, the 4-pyrimidinediamine
[0846] 1H NMR (DMSO-d 6): δ 9.31 (s, 1H), 9.18 (s, 1H), 8.07 (d, J=2.4Hz, 1H), 8.02 (d, J=3.9Hz, 1H), 7.85 (dd, J=2.7 and 8.4Hz, 1H), 7.62 (d, J=8.7Hz, 2H), 7.21 (s, 2H), 7.13 (d, J=8.7Hz, 1H), 6.90 (d, J=8.7Hz, 2H), 4.34-4.25 (m, 1H), 2.65-2.57 (m, 2H), 2.49 (s, 3H), 2.17 (s, 3H), 2.20-2.10 (m, 2H), 1.98-1.87 (m, 2H), 1.69-1.55 (m, 2H); LCMS: purity: 95MS (m/e): 487 (MH +).
II-3: racemize N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-{3-chloro-4-[(1-methyl piperidine-3-yl) oxygen base] phenyl }-5-fluoro-2, the 4-pyrimidinediamine
[0847] 1H NMR (CD 3OD): δ 8.04 (d, J=2.4Hz, 1H), 7.89 (d, J=3.6Hz, 1H), 7.76 (dd, J=2.4 and 8.4Hz, 1H), 7.71 (d, J=2.7Hz, 1H), 7.55 (dd, J=2.7 and 9.0Hz, 1H), 7.18 (d, J=8.4Hz, 1H), 7.07 (d, J=9.0Hz, 1H), 4.36-4.27 (m, 1H), 3.03-2.95 (m, 1H), 2.71-2.64 (m, 1H), 2.59 (s, 3H), 2.32 (s, 3H), 2.30-2.25 (m, 1H), 2.24-2.12 (m, 1H), 2.10-2.02 (m, 1H), 1.96-1.84 (m, 1H), 1.72-1.48 (m, 2H); LCMS: purity: 90% (m/e): 522 (MH +).
II-4: racemize N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-{4-[(1-methyl piperidine-3-yl) oxygen base] phenyl }-2, the 4-pyrimidinediamine
[0848] 1H NMR (CD 3OD): δ 8.05 (d, J=2.4Hz, 1H), 7.83 (d, J=3.6Hz, 1H), 7.71 (dd, J=2.4 and 8.1Hz, 1H), 7.51 (d, J=9.3Hz, 2H), 7.11 (d, J=8.1Hz, 1H), 6.90 (d, J=9.0Hz, 2H), 4.41-4.30 (m, 1H), 2.89-2.78 (m, 1H), 2.58 (s, 3H), 2.35-2.18 (m, 5H), and 2.00-1.80 (m, 3H), 1.68-1.46 (m, 2H); LCMS: purity: 96% (m/e): 487 (MH +).
II-8:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-{3-chloro-4-[(1-methyl piperidine-4-yl) oxygen base] phenyl }-2, the 4-pyrimidinediamine
[0849] 1H NMR (DMSO-d 6): δ 9.41 (s, 1H), 9.31 (bs, 1H), 8.07 (d, J=3.6Hz, 1H), 8.04 (d, J=2.1Hz, 1H), 7.86 (dd, J=2.1 and 8.1Hz, 1H), 7.80 (d, J=2.4Hz, 1H), 7.66 (dd, J=2.7 and 9.0Hz, 1H), 7.23 (bs, 2H), 7.18-7.12 (m, 2H), 4.43-4.35 (m, 1H), 2.64-2.55 (m, 2H), 2.50 (s, 3H), 2.24-2.14 (m, 5H), and 1.96-1.86 (m, 2H), 1.74-1.63 (m, 2H); LCMS: purity: 98%; MS (m/e): 522 (MH +).
II-1: racemize N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-{3-[(1-methyl piperidine-3-yl) oxygen base] phenyl }-2, the 4-pyrimidinediamine
[0850] 1H NMR (DMSO-d 6): δ 9.40 (s, 1H), 9.27 (s, 1H), 8.09 (d, J=3.6Hz, 1H), 8.06 (d, J=2.4Hz, 1H), 7.93 (dd, J=2.4 and 8.4Hz, 1H), 7.57-7.49 (m, 1H), 7.32 (t, J=2.1Hz, 1H), 7.23 (s, 2H), 7.17 (dd, J=2.4 and 8.4Hz, 2H), 6.63 (dd, J=1.8 and 7.8Hz, 1H), 4.36-4.24 (m, 1H), 2.94-2.84 (m, 1H), 2.61-2.52 (m, 1H), 2.49 (s, 3H), 2.17 (S, 3H), 2.06-1.91 (m, 2H), 1.76-1.63 (m, 1H), 1.58-1.42 (m, 1H), 1.40-1.19 (m, 2H); LCMS: purity: 90%; (m/e): 487 (MH +).
II-2:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-{3-[(1-methyl piperidine-4-yl) oxygen base] phenyl }-2, the 4-pyrimidinediamine
[0851] 1H NMR (DMSO-d 6): δ 9.42 (s, 1H), 9.25 (s, 1H), 8.10-8.07 (m, 2H), 7.92 (dd, J=2.4Hz, 1H), 7.56-7.50 (m, 1H), 7.28 (t, J=1.8Hz, 1H), 7.22 (s, 2H), 7.20-7.15 (m, 4H), 6.63 (dd, J=2.4 and 8.1Hz, 1H), 4.31-4.20 (m, 1H), 2.67-2.55 (m, 2H), 2.50 (s, 3H), 2.15-2.05 (m, 2H), and 1.98-1.86 (m, 2H), 1.68-1.54 (m, 2H); LCMS: purity: 98%; MS (m/e): 487 (MH +).
VII-16:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-2, the 4-pyrimidinediamine
[0852] 1H NMR (DMSO-d 6): δ 9.35 (s, 1H), 9.19 (s, 1H), 8.07 (d, J=2.4Hz, 1H), 8.04 (d, J=3.3,1H), 7.90 (dd, J=1.8 and 8.1Hz, 1H), 7.46 (dd, J=2.1 and 8.4Hz, 1H), 7.42-7.38 (m, 1H), 7.22 (bs, 2H), 7.16 (d, J=8.4Hz, 1H), 6.99 (d, J=8.7Hz, 1H), 5.74 (s, 1H), 3.81 (s, 2H), 2.95 (t, J=6.0Hz, 2H), 2.43 (s, 3H); LCMS: purity: 97%; MS (m/e): 429 (MH +).
VII-17:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[2-(methylamino carbonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl]-2, the 4-pyrimidinediamine
[0853] 1H NMR (DMSO-d 6): δ 9.81-9.69 (m, 2H), 8.14 (d, J=4.5Hz, 1H), 7.95 (d, J=1.5Hz, 1H), 7.84 (dd, J=2.4 and 8.1Hz, 1H), 7.51-7.44 (m, 2H), 7.27 (s, 2H), 7.23 (d, J=8.4Hz, 1H), 7.10 (d, J=8.7Hz, 1H), 4.43 (s, 2H), 3.52 (t, J=5.7Hz, 2H), 2.73 (t, J=5.7Hz, 2H), 2.59 (s, 3H), 2.46 (s, 3H); LCMS: purity: 92%; MS (m/e): 487 (MH +).
VII-18:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[2-(dimethylamino carbonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl]-2, the 4-pyrimidinediamine
[0854] 1H NMR (DMSO-d 6): δ 9.72-9.63 (m, 2H), 8.13 (d, J=4.2Hz, 1H), 7.97 (s, 1H), 7.85 (dd, J=2.4 and 8.1Hz, 1H), 7.57 (s, 1H), 7.48-7.44 (m, 1H), 7.27 (s, 2H), 7.20 (d, J=8.1Hz, 1H), 7.10 (d, J=8.1Hz, 1H), 4.26 (s, 2H), 3.39 (t, J=5.4Hz, 2H), 2.81 (t, J=5.4Hz, 2H), 2.78 (s, 6H), 2.46 (s, 3H); LCMS: purity: 98%; MS (m/e): 501 (MH +).
VII-3: racemize N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(1-benzyl-4-methyl piperidine-3-yl)-5-fluoro-2, the 4-pyrimidinediamine
[0855] 1H NMR (CDCl 3): δ 8.56 (d, J=2.1Hz, 1H), 7.62 (d, J=3.6Hz, 1H), 7.25 (dd, J=2.1 and 8.4Hz, 1H), 7.21-7.10 (m, 5H), 7.07 (d, J=8.1Hz, 1H), 5.81-5.70 (m), 5.35-5.22 (m), 4.46-4.37 (m), 3.47 (d, J=13.2Hz), 3.35 (d, J=13.2Hz), 2.79-2.68 (m), 2.67-2.56 (m), 2.51 (s), 2.27 (d, J=11.1Hz), 2.14-2.00 (m), 1.85-1.69 (m), 1.49-1.38 (m), 1.24-1.15 (m), 0.89-0.86 (m); LCMS: purity: 98%; MS (m/e): 485 (MH +).
VII-4: racemize N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(4-methyl piperidine-3-yl)-2, the 4-pyrimidinediamine
[0856] 1H NMR (CD 3OD): δ 8.67 (d, J=2.4Hz, 1H), 7.75 (d, J=3.9Hz, 1H), 7.43 (dd, J=2.4Hz, 1H), 7.21 (d, J=8.7Hz, 1H), 4.63-4.57 (m), 3.06-2.95 (m), 2.94-2.88 (m), 2.74-2.63 (m), 2.49 (s), 2.14-2.00 (m), 1.66-1.55 (m), 1.52-1.40 (m), 1.32-1.26 (m), 0.99-0.88 (m); LCMS: purity: 98%; MS (m/e): 395 (MH +).
VII-5: racemize N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(1-cyano group methylene radical carbonyl-4-methyl piperidine-3-yl)-5-fluoro-2, the 4-pyrimidinediamine
[0857] 1H NMR (DMSO-d 6): δ 9.30 (s, 1H), 8.53-8.48 (m, 1H), 8.24 (s, 1H), 7.89 (d, J=3.9Hz, 1H), 7.62-7.56 (m, 1H), and 7.22-7.14 (m, 3H), 4.51-4.42 (m), 4.21-4.14 (m), 4.10-4.02 (m), 3.99-3.90 (m), 3.66-3.52 (m), 3.35-3.28 (m), 3.15-3.00 (m), 2.96-2.84 (m), 2.49 (s), 2.14-1.99 (m), 1.86-1.62 (m), 1.53-1.40 (m), 0.87 (d, J=6.6Hz); LCMS: purity: 99%; MS (m/e): 463 (MH +).
VI-49:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-(methylamino ketonic oxygen ylmethyl) phenyl]-2, the 4-pyrimidinediamine
[0858] 1H NMR (DMSO-d 6): δ 9.72 (s, 1H), 9.66 (s, 1H), 8.16 (d, J=4.2Hz, 1H), 7.99 (s, 1H), 7.85 (dd, J=1.8 and 8.4Hz, 1H), 7.74 (d, J=7.8Hz, 1H), 7.68 (s, 1H), 7.32 (t, J=7.8Hz, 1H), 7.27 (s, 2H), 7.19 (d, J=8.1Hz, 1H), 7.12-7.04 (m, 2H), 4.98 (s, 2H), 2.57 (d, J=4.2Hz, 3H), 2.50 (s, 3H); LCMS: purity: 96%; MS (m/e): 461 (MH +).
VII-19:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[1-(methylamino carbonyl)-1,2,3,4-tetrahydroquinoline-6-yl]-2, the 4-pyrimidinediamine
[0859] 1H NMR (DMSO-d 6): δ 9.98-9.84 (m, 2H), 8.16 (d, J=4.8Hz, 1H), 7.92-7.88 (m, 1H), 7.81 (dd, J=2.1 and 8.1Hz, 1H), 7.46-7.38 (m, 3H), 7.31 (s, 2H), 7.24 (d, J=8.1Hz, 1H), 6.60 (s, 1H), 3.55 (t, J=6.0Hz, 2H), 2.64 (s, 3H), 2.59 (t, J=6.0Hz, 2H), 2.52 (s, 3H), 1.812 (t, J=6.0Hz, 2H); LCMS: purity: 94%; MS (m/e): 487 (MH +).
VI-50:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(4-trifluoromethyl)-2, the 4-pyrimidinediamine
[0860] 1H NMR (DMSO-d 6): δ 9.70 (s, 1H), 9.49 (s, 1H), 8.17 (d, J=3.6Hz, 1H), 8.13 (s, 1H), 8.07 (d, J=8.7Hz, 2H), 7.84 (d, J=8.4Hz, 1H), 7.63 (d, J=8.5Hz, 2H), 7.28-7.18 (m, 3H), 2.50 (s, 3H); LCMS: purity: 99%; MS (m/e): 442 (MH +).
VI-51:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(4-trifluoromethyl)-2, the 4-pyrimidinediamine
[0861] 1H NMR (DMSO-d 6): δ 9.74 (s, 1H), 9.61 (s, 1H), 8.21 (d, J=3.6Hz, 1H), 8.13 (s, 1H), 8.07 (d, J=8.7Hz, 2H), 7.89 (d, J=7.8Hz, 2H), 7.64 (d, J=8.78Hz, 2H), 7.45-7.34 (m, 2H), 7.27 (s, 2H); LCMS: purity: 99%; MS (m/e): 428 (MH +).
VI-52:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(4-hydroxymethyl phenyl)-2, the 4-pyrimidinediamine
[0862] 1H NMR (DMSO-d 6): δ 9.38 (s, 1H), 9.30 (s, 1H), 8.11 (d, J=2.4Hz, 1H), 8.07 (d, J=3.9Hz, 1H), 7.90 (dd, J=2.4 and 8.4Hz, 1H), 7.75 (d, J=8.4Hz, 2H), 7.26 (d, J=8.4Hz, 2H), 7.23 (s, 2H), 7.177 (d, J=8.7Hz, 1H), 5.10 (t, J=5.7Hz, 1H), 4.46 (d, J=5.7Hz, 2H) 2.50 (s, 3H); LCMS: purity: 95%; MS (m/e): 404 (MH +).
VI-53:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(Propargyl oxygen base) phenyl]-2, the 4-pyrimidinediamine
[0863] in tube sealing with 2-chloro-5-fluoro-N4-[4-(Propargyl oxygen base) phenyl]-4-PYRIMITHAMINE (0.514g; 1.85mmol), 3-(amino-sulfonyl)-4-monomethylaniline (0.689g; 3.70mmol) and trifluoroacetic acid (0.186mL; 2.41mmol) mix with iPrOH (6.0mL), and heat 3h down at 100 ℃.Reaction mixture is cooled to room temperature, and dilutes with 1N HCl (80mL).Separate N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(Propargyl oxygen base) phenyl by suction filtration]-2,4-pyrimidinediamine VI-53), be white solid (0.703g). 1H NMR (DMSO-d 6): δ 10.08 (bs, 2H), 8.19 (d, J=4.5Hz, 1H), 7.89 (s, 1H), 7.74 (dd, J=2.4 and 8.4Hz, 1H), 7.58 (d, J=8.7Hz, 2H), 7.32 (bs, 2H), 7.23 (d, J=8.4Hz, 1H), 6.97 (d, J=8.4Hz, 2H), 4.79 (d, J=2.1Hz, 2H), 3.59-3.55 (m, 1H), 2.53 (s, 3H); LCMS: purity: 97%; MS (m/e): 428 (MH +).
VI-54:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(4-ethenylphenyl)-2, the 4-pyrimidinediamine
[0864] 1H NMR (DMSO-d 6): δ 9.42 (s, 1H), 9.40 (s, 1H), 8.12 (d, J=2.4Hz, 1H), 8.09 (d, J=3.3Hz, 1H), 7.89 (dd, J=2.4 and 8.4Hz, 1H), 7.82 (d, J=8.4Hz, 2H), 7.42 (d, J=8.4Hz, 2H), 7.23 (s, 2H), 7.18 (d, J=8.4Hz, 1H), 7.23 (s, 2H), 7.18 (d, J=8.4Hz, 1H), 6.69 (dd, J=10.8 and 17.4Hz, 1H), 5.73 (d, J=17.4Hz, 1H), 5.16 (d, J=11.4Hz, 1H), 2.50 (s, 3H); LCMS: purity: 96%; MS (m/e): 400 (MH +).
VI-55:N2-(3-amino-sulfonyl-4-chloro-phenyl-)-5-fluoro-N4-[4-(Propargyl oxygen base) phenyl]-2, the 4-pyrimidinediamine
[0865] 1H NMR (DMSO-d 6): δ 9.58 (s, 1H), 9.31 (s, 1H), 8.26 (d, J=2.4Hz, 1H), 8.06 (d, J=3.6Hz, 1H), 8.02 (dd, J=2.4 and 9.0Hz, 1H), 7.68 (d, J=8.7Hz, 2H), 7.45 (s, 2H), 7.39 (d, J=8.7Hz, 1H), 6.96 (d, J=9.0Hz, 2H), 4.78 (d, J=2.4Hz, 2H), 3.55 (t, J=2.4Hz, 1H); LCMS: purity: 97%; MS (m/e): 449 (MH +).
VII-20:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[1-(methylamino carbonyl)-1,2,3,4-tetrahydroquinoline-6-yl]-2, the 4-pyrimidinediamine
[0866] 1H NMR (CD 3OD): δ 8.17 (t, J=1.5Hz, 1H), 7.93 (d, J=3.9Hz, 1H), 7.79 (ddd, J=1.2,2.4, and 8.1Hz, 1H), 7.56 (dd, J=2.4 and 8.7Hz, 1H), 7.48-7.34 (m, 4H), 7.30 (d, J=9.0Hz, 1H), 3.67 (t, J=6.3Hz, 2H), 2.80 (s, 3H), 2.73 (t, J=6.3Hz, 2H), 1.91 (t, J=6.3Hz, 2H); LCMS: purity: 99%; MS (m/e): 472 (MH +).
III-59:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-{4-[2-(methylamino ketonic oxygen base) ethyl] phenyl }-2, the 4-pyrimidinediamine
[0867] 1H NMR (DMSO-d 6): δ 9.44 (s, 1H), 9.37 (s, 1H), 8.10-8.05 (m, 2H), 7.87 (dd, J=2.1 and 8.1Hz, 1H), 7.69 (d, J=8.4Hz, 1H), 7.22 (s, 2H), 7.21-7.14 (m, 3H), and 6.96-6.90 (m, 1H), 4.13 (t, J=6.6Hz, 2H), 2.82 (t, J=6.6Hz, 2H), 2.54 (d, J=4.5Hz, 3H), 2.50 (s, 3H); LCMS: purity: 94%; MS (m/e): 476 (MH +).
III-60:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-{4-[2-(methylamino ketonic oxygen base) ethyl] phenyl }-2, the 4-pyrimidinediamine
[0868] 1H NMR (DMSO-d 6): δ 9.85 (s, 1H), 9.75 (s, 1H), 8.17 (d, J=3.9Hz, 1H), 7.98 (s, 1H), 7.93-7.87 (m, 1H), 7.65 (d, J=8.1Hz, 2H), 7.42-7.38 (m, 2H), 7.29 (s, 2H), 7.21 (d, J=7.8Hz, 2H), 6.97-6.90 (m, 1H), 4.13 (t, J=6.6Hz, 2H), 2.83 (t, J=6.6Hz, 2H), 2.54 (d, J=3.6Hz, 3H); LCMS: purity: 98%; MS (m/e): 461 (MH +).
III-61:N2-(3-amino-sulfonyl-4-chloro-phenyl-)-5-fluoro-N4-{4-[2-(methylamino ketonic oxygen base) ethyl] phenyl }-2, the 4-pyrimidinediamine
[0869] 1H NMR (DMSO-d 6): δ 9.60 (s, 1H), 9.36 (s, 1H), 8.29 (d, J=2.7Hz, 1H), 8.10 (d, J=3.3Hz, 1H), 8.03 (dd, J=2.4 and 9.0Hz, 1H), 7.70 (d, J=8.1Hz, 2H), 7.45 (s, 2H), 7.41 (d, J=8.7Hz, 1H), 7.20 (d, J=8.1Hz, 2H), 6.96-6.90 (m, 1H), 4.13 (t, J=7.2Hz, 2H), 2.83 (t, J=6.9Hz, 2H), 2.54 (d, J=4.5Hz, 3H); LCMS: purity: 95%; MS (m/e): 496 (MH +).
III-56:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-{4-[2-(dimethylamino ketonic oxygen base) ethyl] phenyl }-5-fluoro-2, the 4-pyrimidinediamine
[0870] 1H NMR (DMSO-d 6): δ 9.71 (bs, 2H), 8.13 (d, J=4.2Hz, 1H), 8.01 (s, 1H), 7.81 (dd, J=1.8 and 7.8Hz, 1H), 7.66 (d, J=8.1Hz, 2H), 7.27 (s, 2H), 7.24-7.16 (m, 3H), 4.15 (t, J=6.6Hz, 2H), 2.86 (t, J=6.6Hz, 2H), 2.78 (s, 6H), 2.51 (s, 3H); LCMS: purity: 98%; MS (m/e): 490 (MH +).
III-57:N2-(3-amino-sulfonyl phenyl)-N4-{4-[2-(dimethylamino ketonic oxygen base) ethyl] phenyl }-5-fluoro-2, the 4-pyrimidinediamine
[0871] 1H NMR (DMSO-d 6): δ 9.77 (s, 1H), 9.67 (s, 1H), 8.16 (d, J=4.2Hz, 1H), 8.01 (s, 1H), 7.94-7.86 (m, 1H), 7.67 (d, J=8.1Hz, 2H), 7.41-7.36 (m, 2H), 7.29 (s, 2H), 7.21 (d, J=8.7Hz, 2H), 4.14 (t, J=6.6Hz, 2H), 2.85 (t, J=6.6Hz, 2H), 2.79 (s, 6H); LCMS: purity: 97%; MS (m/e): 475 (MH +).
III-58:N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-{4-[2-(dimethylamino ketonic oxygen base) ethyl] phenyl }-5-fluoro-2, the 4-pyrimidinediamine
[0872] 1H NMR (DMSO-d 6): δ 9.87 (s, 1H), 9.68 (s, 1H), 8.20 (d, J=2.7Hz, 1H), 8.16 (d, J=4.2Hz, 1H), 7.97 (dd, J=2.7 and 8.7Hz, 1H), 7.66 (d, J=8.4Hz, 2H), 7.49 (s, 2H), 7.42 (d, J=9.0Hz, 1H), 7.22 (d, J=8.7Hz, 2H), 4.15 (t, J=6.6Hz, 2H), 2.86 (t, J=6.6Hz, 2H), 2.78 (s, 6H); LCMS: purity: 98%; MS (m/e): 510 (MH +).
III-53:N4-{4-[2-(aminocarboxyl oxygen base) ethyl] phenyl }-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0873] 1H NMR (DMSO-d 6): δ 10.00 (s, 2H), 8.19 (d, J=4.5Hz, 1H), 7.93 (d, J=2.1Hz, 1H), 7.77 (dd, J=2.1 and 8.4Hz, 1H), 7.62 (d, J=8.4Hz, 2H), 7.30 (s, 2H), 7.22 (d, J=8.4Hz, 3H), 6.44 (bs, 2H), 4.10 (t, J=6.6Hz, 2H), 2.84 (t, J=6.6Hz, 2H), 2.53 (s, 3H); LCMS: purity: 96%; MS (m/e): 461 (MH +).
III-54:N4-{4-[2-(aminocarboxyl oxygen base) ethyl] phenyl }-N2-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0874] 1H NMR (DMSO-d 6): δ 9.77 (s, 1H), 9.67 (s, 1H), 8.16 (d, J=4.2Hz, 1H), 8.01 (s, 1H), 7.96-7.89 (m, 1H), 7.67 (d, J=8.4Hz, 2H), 7.44-7.36 (m, 2H), 7.29 (s, 2H), 7.21 (d, J=8.1Hz, 2H), 4.09 (t, J=6.6Hz, 2H), 2.83 (t, J=6.6Hz, 2H); LCMS: purity: 93%; MS (m/e): 447 (MH +).
III-55:N4-{4-[2-(aminocarboxyl oxygen base) ethyl] phenyl }-N2-(3-amino-sulfonyl-4-chloro-phenyl-)-5-fluoro-2, the 4-pyrimidinediamine
[0875] 1H NMR (DMSO-d 6): δ 9.76 (s, 1H), 9.56 (s, 1H), 8.24 (d, J=2.4Hz, 1H), 8.13 (d, J=3.9Hz, 1H), 7.99 (dd, J=2.4 and 8.7Hz, 1H), 7.68 (d, J=8.7Hz, 2H), 7.48 (s, 2H), 7.43 (d, J=9.0Hz, 1H), 7.22 (d, J=8.4Hz, 2H), 4.10 (t, J=6.6Hz, 2H), 2.83 (t, J=6.6Hz, 2H); LCMS: purity: 97%; MS (m/e): 482 (MH +).
III-56:5-fluoro-N2-(4-methyl-3-propionyl amino-sulfonyl phenyl)-N4-[4-(Propargyl oxygen base) phenyl]-2, the 4-pyrimidinediamine
[0876] 1H NMR (DMSO-d 6): δ 12.01 (s, 1H), 9.44 (s, 1H), 9.26 (s, 1H), 8.16 (d, J=2.4Hz, 1H), 8.06 (dd, J=0.3 and 3.3Hz, 1H), 8.00 (dd, J=2.1 and 7.8Hz, 1H), 7.69 (d, J=8.7Hz, 2H), 7.19 (d, J=8.4Hz, 1H), 6.95 (d, J=8.7Hz, 2H), 4.77 (d, J=2.1Hz, 2H), 3.56 (t, J=2.1Hz, 1H), 2.49 (s, 3H), 2.24 (q, J=7.2Hz, 2H), 0.89 (t, J=7.2Hz, 3H); LCMS: purity: 98%; MS (m/e): 484 (MH +).
VI-57:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-(Propargyl oxygen base) phenyl]-2, the 4-pyrimidinediamine
[0877] 1H NMR (DMSO-d 6): δ 9.45 (s, 1H), 9.35 (s, 1H), 8.12-8.07 (m, 2H), 7.93 (dd, J=2.1 and 8.4Hz, 1H), 7.49 (d, J=8.1Hz, 1H), 7.42 (t, J=2.1Hz, 1H), 7.27-7.16 (m, 4H), 6.69 (dd, J=2.7 and 8.7Hz, 1H), 4.77 (d, J=2.4Hz, 2H), 3.58 (t, J=2.4Hz, 1H), 2.49 (s, 3H); LCMS: purity: 98%; MS (m/e): 428 (MH +).
VI-58:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-methyl-4-(Propargyl oxygen base) phenyl]-2, the 4-pyrimidinediamine
[0878] 1H NMR (DMSO-d 6): δ 10.09-9.90 (m, 2H), 8.17 (d, J=4.5Hz, 1H), 7.87 (s, 1H), 7.80 (dd, J=2.1 and 8.4Hz, 1H), 7.49-7.42 (m, 2H), 7.32 (s, 2H), 7.20 (d, J=8.1Hz, 1H), 6.99 (d, J=8.4Hz, 1H), 4.81 (d, J=2.1Hz, 2H), 3.57 (t, J=2.1Hz, 1H), 2.52 (s, 3H), 2.13 (s, 3H); LCMS: purity: 99%; MS (m/e): 442 (MH +).
VI-59:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[3-chloro-4-(Propargyl oxygen base) phenyl]-5-fluoro-2, the 4-pyrimidinediamine
[0879] 1H NMR (DMSO-d 6): δ 10.06 (s, 1H), 8.22 (d, J=4.5Hz, 1H), 7.89 (d, J=2.1Hz, 1H), 7.82-7.75 (m, 2H), 7.65 (dd, J=2.4 and 9.0Hz, 1H), 7.32 (s, 2H), 7.24 (d, J=8.1Hz, 1H), 7.19 (d, J=8.7Hz, 1H), 4.90 (d, J=2.1Hz, 2H), 3.63 (t, J=2.1Hz, 1H), 2.52 (s, 3H); LCMS: purity: 99%; MS (m/e): 463 (MH +).
VI-60:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-fluoro-4-(Propargyl oxygen base) phenyl]-2, the 4-pyrimidinediamine
[0880] 1H NMR (DMSO-d 6): δ 9.94 (s, 2H), 8.19 (d, J=4.5Hz, 1H), 7.96 (s, 1H), 7.82 (d, J=8.4Hz, 1H), 7.75 (d, J=13.2Hz, 1H), 7.48 (d, J=8.7Hz, 1H), 7.31 (s, 2H), 7.23 (d, J=7.8Hz, 1H), 7.17 (d, J=9.6Hz, 1H), 4.88-4.86 (m, 2H), 3.64-3.61 (m, 1H), 2.53 (s, 3H); LCMS: purity: 98%; MS (m/e): 446 (MH +).
VI-61:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[4-(fourth-2-alkynyloxy base) phenyl]-5-fluoro-2, the 4-pyrimidinediamine
[0881] 1H NMR (DMSO-d 6): δ 10.10 (s, 2H), 8.19 (d, J=4.8Hz, 1H), 7.90 (d, J=2.1Hz, 1H), 7.73 (dd, J=1.8 and 8.1Hz, 1H), 7.57 (d, J=9.0Hz, 2H), 7.32 (s, 2H), 7.23 (d, J=8.1Hz, 1H), 6.95 (d, J=9.0Hz, 2H), 4.74-4.70 (m, 2H), 2.53 (s, 3H), 1.83 (t, J=2.1Hz, 3H); LCMS: purity: 98%; MS (m/e): 442 (MH +).
VIII-2:N4-(3-chloro-4-cyano group methylene radical oxygen base phenyl)-5-fluoro-N2-(5-methyl-2H-1,1-dioxy-1,2,4-benzothiadiazine-7-yl)-2, the 4-pyrimidinediamine
[0882] 1H NMR (DMSO-d 6): δ 11.50 (bs, 1H), 9.57 (s, 1H), 8.17 (d, 1H, J=2.7Hz), 8.04 (s, 1H), 7.88 (d, 1H), 7.79 (m, 2H), 7.57 (dd, 1H, J=1.2 and 9.0Hz), 7.27 (t, 1H, J=9.6Hz), 5.20 (s, 2H), 2.31 (s, 3H); LCMS: purity: 100%; MS (m/e): 472 (MH +).
VI-26:N2-(3-amino-sulfonyl phenyl)-5-bromo-N4-(3-chloro-4-p-methoxy-phenyl)-2, the 4-pyrimidinediamine
[0883] 1H NMR (DMSO-d 6): δ 9.61 (s, 1H), 8.64 (s, 1H), 8.21 (s, 1H), 7.91 (m, 2H), 7.63 (d, 1H, J=2.7Hz), 7.53 (dd, 1H, J=2.4 and 6.3Hz), 7.30 (m, 3H), 7.13 (d, 1H, J=9.3Hz), 3.86 (s, 3H); LCMS: purity: 100%, MS (m/e): 484 (M +), 486 (M+2).
VI-27:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-bromo-N4-(3-chloro-4-p-methoxy-phenyl)-2, the 4-pyrimidinediamine
[0884] 1H NMR (DMSO-d 6): δ 10.01 (s, 1H), 9.15 (s, 1H), 8.28 (s, 1H), 7.84 (s, 1H), (7.72 dd, 1H, J=1.8 and 8.4Hz), 7.61 (d, 1H, J=2.4Hz), 7.47 (dd, 1H, J=2.1 and 9.0Hz), 7.29 (bs, 2H), 7.12 (m, 2H), 3.86 (s, 3H); LCMS: purity: 97%, MS (m/e): 498 (M +), 500 (M+2).
VI-28:N2-(3-amino-sulfonyl phenyl)-N4-(3-chloro-4-p-methoxy-phenyl)-5-trimethyl silyl acetylene-2, the 4-pyrimidinediamine
[0885] LCMS: purity: 98%, MS (m/e): 502 (M +).
VII-82:(1R, 2R, 3S, 4S) N4-(3-aminocarboxyl two ring [2.2.1] heptan-5-alkene-2-yl)-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2,4-pyrimidinediamine
[0886] 1H NMR (DMSO-d 6): δ 9.30 (s, 1H), 8.19 (d, 1H, J=1.5Hz), 7.88 (m, 2H), 7.68 (bs, 1H), 7.46 (bd, 1H, J=7.8Hz), 7.19 (m, 4H), 6.30 (bs, 2H), 4.13 (t, 1H, J=7.5Hz), 2.85 (bs, 1H), 2.77 (bs, 1H), 2.53 (m, 1H), 2.12 (d, 1H, J=8.4Hz), 1.40 (d, 1H, J=8.1Hz); LCMS: purity: 97%, MS (m/e): 433 (MH +).
I-13:N2-(3-amino-sulfonyl phenyl)-5-bromo-N4-(4-cyano group methylene radical oxygen base phenyl)-2, the 4-pyrimidinediamine
[0887] 1H NMR (DMSO-d 6): δ 9.91 (s, 1H), 9.02 (s, 1H), 8.27 (d, 1H, J=0.9Hz), 7.85 (m, 2H), 7.53 (d, 2H, 8.1Hz), 7.34 (m, 4H), 7.07 (d, 2H, J=8.1Hz), 5.18 (s, 2H); LCMS: purity: 100%, MS (m/e): 475 (M +), 477 (M+2).
I-14:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-bromo-N4-(4-cyano group methylene radical oxygen base phenyl)-2, the 4-pyrimidinediamine
[0888] 1H NMR (DMSO-d 6): δ 10.05 (s, 1H), 9.23 (s, 1H), 8.28 (s, 1H), 7.82 (s, 1H), 7.74 (dd, 1H, J=2.1 and 8.4Hz), 7.51 (d, 2H, J=8.7Hz), 7.29 (bs, 2H), 7.11 (m, 3H), 5.11 (s, 2H), 2.45 (s, 3H); LCMS: purity: 98%, MS (m/e): 491 (M+2).
VI-29:N2-(3-amino-sulfonyl-4-p-methoxy-phenyl)-N4-(3-chloro-4-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0889] 1H NMR (DMSO-d 6): δ 9.03 (s, 1H), 9.33 (s, 1H), 8.09 (s, 1H), 7.12 (d, 1H, J=1.8Hz), 7.07 (d, 1H, J=2.1Hz), 7.01 (m, 2H), 6.80 (dd, 1H, J=1.2 and 9.0Hz), 6.60 (d, 1H, J=8.7Hz), 4.22 (s, 3H), 4.15 (s, 3H); LCMS: purity: 99%, MS (m/e): 453 (M+).
I-15:N2-(3-amino-sulfonyl phenyl)-N4-(4-cyano group methylene radical oxygen base phenyl)-5-trimethyl silyl acetylene-2, the 4-pyrimidinediamine
[0890] 1H NMR (DMSO-d 6): δ 9.48 (s, 1H), 8.08 (s, 1H), 7.93 (s, 1H), 7.67 (m, 2H), 7.29 (m, 3H), 7.07 (m, 3H), 6.82 (m, 2H), 4.91 (s, 2H), 0.00 (s, 9H); LCMS: purity: 89%, MS (m/e): 494 (MH +).
VII-38:N2-(3-amino-sulfonyl-4-methoxyl group-5-aminomethyl phenyl)-N4-(2,2-two fluoro-4H-benzo [1,4] oxazine-3-ketone-6-yls)-5-fluoro-2, the 4-pyrimidinediamine
[0891] 1H NMR (DMSO-d 6): δ 9.55 (s, 1H), 9.29 (s, 1H), 8.10 (bd, 1H), 7.82 (bs, 1H), 7.86 (bs, 1H), 7.57 (bd, 1H, J=8.1Hz), 7.42 (bs, 2H), 7.25 (bd, 1H, J=8.7Hz), 7.02 (bs, 2H), 3.75 (s, 3H), 2.16 (s, 3H); LCMS: purity: 88%, MS (m/e): 511 (MH +).
VI-30:N2-(3-amino-sulfonyl-4-methoxyl group-5-aminomethyl phenyl)-N4-(3-chloro-4-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0892] 1H NMR (DMSO-d 6): δ 9.31 (bs, 2H), 8.06 (bd, 1H, J=3.6Hz), 7.39 (m, 4H), 7.11 (d, 1H, J=8.7Hz), 7.02 (bs, 2H), 3.83 (s, 3H), 3.76 (s, 3H), 2.18 (s, 3H); LCMS: purity: 100%, MS (m/e): 468 (M +).
VII-83:(1R, 2R, 3S, 4S) N2-(3-amino-sulfonyl-4-methoxyl group-5-aminomethyl phenyl)-N4-(3-aminocarboxyl two ring [2.2.1] heptan-5-alkene-2-yl)-5-fluoro-2,4-pyrimidinediamine
[0893] 1H NMR (DMSO-d 6): δ 9.20 (s, 1H), 7.96 (d, 1H ,=2.1Hz), 7.86 (d, 1H, J=3.3Hz), 7.78 (d, 1H, J=2.1Hz), 7.65 (bs, 1H), 7.40 (bdd, 1H, J=7.8Hz), 7.16 (bs, 1H), 6.98 (bs, 2H), 6.28 (bs, 2H), 4.16 (t, 1H, J=7.5Hz), 3.76 (s, 3H), 2.84 (s, 1H), 2.74 (s, 1H), 2.53 (m, 1H), 2.25 (s, 3H), 2.13 (d, 1H, J=8.4Hz), 1.39 (d, 1H, J=8.1Hz); LCMS: purity: 100%, MS (m/e): 463 (MH +).
VI-31:N2-(3-amino-sulfonyl pyridin-4-yl)-N4-(3-chloro-4-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0894] LCMS: purity: 100%, MS (m/e): 425 (MH+).
II-19:N2-(3-aminocarboxyl-5-aminomethyl phenyl)-5-fluoro-N2-[4-(1-methylpyrazole-3-yl) amido phenyl)-2, the 4-pyrimidinediamine
[0895] 1H NMR (DMSO-d 6): δ 10.67 (s, 1H), 9.70 (s, 1H), 9.63 (s, 1H), 8.18 (d, 1H, J=3.6Hz), 8.11 (d, 1H, J=2.4Hz), 7.97 (m, 4H), 7.90 (dd, 1H, J=2.4 and 8.4Hz), 7.58 (d, 1H, J=2.1Hz), 7.27 (m, 2H), 7.24 (m, 1H), 6.58 (d, 1H, J=2.1Hz), 3.78 (s, 3H), 2.52 (s, 3H); LCMS: purity: 91%, MS (m/e): 497 (MH +).
II-20:N2-(3-aminocarboxyl-5-aminomethyl phenyl)-5-fluoro-N2-[4-(1-ethyl pyrazoles-5-yl) amido phenyl)-2, the 4-pyrimidinediamine
[0896] LCMS: purity: 97%, MS (m/e): 511 (M+).
II-21:N2-(3-aminocarboxyl-5-aminomethyl phenyl)-5-fluoro-N2-[4-(1-methylpyrazole-5-yl) amido phenyl)-2, the 4-pyrimidinediamine
[0897] 1H NMR (DMSO-d 6): δ 10.21 (s, 1H), 9.91 (s, 1H), 9.77 (s, 1H), 8.22 (d, 1H, J=2.4Hz), 8.07 (s, 1H), 7.96 (m, 6H), 7.38 (d, 1H, J=1.5Hz), 7.27 (m, 3H), 6.23 (s, 1H), 2.52 (s, 3H), 2.49 (s, 3H); LCMS: purity: 96%, MS (m/e): 497 (M +).
II-22:N2-(3-aminocarboxyl-5-aminomethyl phenyl)-5-fluoro-N2-[4-(1H-pyrazoles-5-yl) amido phenyl)-2, the 4-pyrimidinediamine
[0898] LCMS: purity: 91%, MS (m/e): 483 (MH +).
VI-24:N2-(3-amino-sulfonyl phenyl)-5-carbonyl oxyethyl group-N4-(N-carbonyl oxyethyl group methylene radical-N-3-chloro-4-p-methoxy-phenyl)-2, the 4-pyrimidinediamine
[0899] LCMS: purity: 94%; MS (m/e): 564 (M +).
VI-25:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-carbonyl oxyethyl group-N4-(N-carbonyl oxyethyl group methylene radical-N-3-chloro-4-p-methoxy-phenyl)-2, the 4-pyrimidinediamine
[0900] LCMS: purity: 97%, MS (m/e): 579 (MH +).
VIII-3:N4-(3-chloro-4-p-methoxy-phenyl)-5-fluoro-N2-(5-methyl-2H-1,1-dioxo-1,2,4-benzothiadiazine-7-yl)-2, the 4-pyrimidinediamine
[0901] LCMS: purity: 96%, MS (m/e): 463 (M +).
VI-33:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(4-Trifluoromethoxyphen-l)-2, the 4-pyrimidinediamine
[0902] 1H NMR (DMSO-d 6): δ 9.57 (s, 1H), 9.55 (s, 1H), 8.15 (d, 1H, J=3.6Hz), 8.12 (bs, 1H), 7.92 (m, 3H), 7.36 (m, 6H); LCMS: purity: 98%, MS (m/e): 444 (MH +).
VII-53:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(2-cyano group cumarone-5-yl)-5-fluoro-2, the 4-pyrimidinediamine
[0903] 1H NMR (DMSO-d 6): δ 9.53 (s, 1H), 9.42 (s, 1H), 8.29 (d, 1H, J=1.8Hz), 8.10 (m, 2H), 7.90 (m, 2H), 7.69 (d, 1H, J=9.0Hz), 7.23 (bs, 1H), 7.13 (d, 1H, J=8.1Hz), 7.10 (m, 2H), 5.23 (s, 2H), 2.37 (s, 3H); LCMS: purity: 97%, MS (m/e): 439 (MH +).
VI-32:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(4-Trifluoromethoxyphen-l)-2, the 4-pyrimidinediamine
[0904] LCMS: purity: 100%, MS (m/e): 458 (MH+).
I-263:N2-[4-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0905] 1H?NMR(DMSO?d 6，300MHz)：δ9.61(s，1H)，9.36(s，1H)，8.11(d，1H，J＝3.6Hz)，7.82(d，2H，J＝8.7Hz)，7.66(d，2H，J＝8.7Hz)，7.58(d，2H，J＝8.7Hz)，7.15(br?s，1H)，7.03(d，2H，J＝8.7Hz)，5.46(s，2H)，2.74(br?s，2H)，2.36(m，9H)，0.85(t，6H，J＝6.6Hz)；LCMS(m/z)：571(MH +)。
I-280:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(2-methylthiazol-4-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0906] 1H NMR (DMSO d 6, 300MHz): δ 9.32 (s, 1H), 9.21 (d, 1H, J=1.8Hz), 8.02 (d, 1H, J=3.9Hz), 7.87 (dd, 1H, J=2.1 and 8.2Hz), 7.68 (d, 2H, J=9.0Hz), 7.52 (s, 1H), 7.21 (s, 2H), 7.13 (m, 1H), 6.98 (d, 2H, J=8.7Hz), 5.08 (s, 2H), 2.65 (s, 3H), 2.48 (s, 3H); LCMS (m/z): 501 (MH +).
I-281:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-methylthiazol-4-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0907] 1H?NMR(DMSO?d 6，300MHz)：δ9.44(s，1H)，9.25(s，1H)，8.06(d，2H，J＝3.9Hz)，7.93(m，1H)，7.67(d，1H，J＝9.0Hz)，7.52(s，1H)，7.32(m，2H)，7.24(s，2H)，6.99(d，2H，J＝8.7Hz)，5.08(s，2H)，2.66(s，3H)；LCMS(m/z)：487(MH +)。
I-282:5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-[4-(2-methylthiazol-4-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0908] 1H NMR (DMSO d 6, 300MHz): δ 9.34 (s, 1H), 9.22 (s, 1H), 8.04 (d, 1H, J=3.6Hz), 8.00 (d, 1H, J=1.8Hz), 7.93 (dd, 1H, J=2.4 and 8.1Hz), 7.67 (d, 2H, J=9.0Hz), 7.52 (s, 1H), 7.31 (q, 1H, J=5.1Hz), 7.18 (d, 1H, J=8.4Hz), 6.99 (d, 2H, J=9.0Hz), 5.08 (s, 2H), 2.65 (s, 3H), 2.45 (s, 3H), 2.41 (d, 3H, J=4.5Hz); LCMS (m/z): 515 (MH +).
I-283:N2-[3-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[4-(2-methylthiazol-4-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0909] 1H?NMR(DMSO?d 6，300MHz)：δ9.46(s，1H)，9.26(s，1H)，8.06(d，2H，J＝5.1Hz)，7.99(m，1H)，7.66(d，2H，J＝9.0Hz)，7.52(s，1H)，7.36(t，1H，J＝8.1Hz)，7.26(m，2H)，6.99(d，2H，J＝9.0Hz)，5.08(s，2H)，2.78(t，2H，J＝7.8Hz)，2.65(s，3H)，2.37(m，6H)，0.84(t，6H，J＝6.9Hz)；LCMS(m/z)：586(MH +)。
I-284:N2-[4-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[4-(2-methylthiazol-4-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0910] 1H?NMR(DMSO?d 6，300MHz)：δ9.59(s，1H)，9.32(s，1H)，8.09(d，1H，J＝3.6Hz)，7.82(d，2H，J＝9.0Hz)，7.58(m，5H)，7.15(br?s，1H)，7.01(d，2H，J＝9.0Hz)，5.09(s，2H)，2.72(br?s，2H)，2.65(s，3H)，2.38(m，6H)，0.84(t，6H，J＝6.9Hz)；LCMS(m/z)：586(MH +)。
I-265:N2-(3-amino-sulfonyl-4-chloro-5-aminomethyl phenyl)-5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0911] 1H?NMR(DMSO?d 6，300MHz)：δ9.50(s，1H)，9.31(s，1H)，8.07(m，2H)，8.00(s，1H)，7.67(d，2H，J＝8.7Hz)，7.40(s，2H)，7.00(d，2H，J＝9.3Hz)，5.44(s，2H)，2.36(s，3H)，2.24(s，3H)；LCMS(m/z)：520(MH +)。
I-285:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-methylthiazol-4-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0912] 1H?NMR(DMSO?d 6，300MHz)：δ9.57(s，1H)，9.34(s，1H)，8.09(d，1H，J＝3.9Hz)，7.79(d，2H，J＝8.7Hz)，7.63(d，2H，J＝6.3Hz)，7.60(d，2H，J＝6.6Hz)，7.54(s，1H)，7.13(s，2H)，7.02(d，2H，J＝9.0Hz)，5.09(s，2H)，2.66(s，3H)；LCMS(m/z)：487(MH +)。
III-70:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-pyridylmethyl) phenyl]-2, the 4-pyrimidinediamine
[0913] 1H?NMR(DMSO?d 6，300MHz)：δ9.47(s，1H)，9.36(s，1H)，8.44(d，2H，J＝5.7Hz)，8.09(d，1H，J＝3.6Hz)，8.07(s，1H)，7.93(m，1H)，7.71(d，2H，J＝8.4Hz)，7.25(m，8H)，3.94(s，2H)；LCMS(m/z)：451(MH +)。
III-74:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(4-pyridylmethyl) phenyl]-2, the 4-pyrimidinediamine
[0914] 1H NMR (DMSO d 6, 300MHz): δ 9.35 (s, 1H), 9.31 (s, 1H), 8.44 (d, 2H, J=5.7Hz), 8.07 (d, 1H, J=2.4Hz), 8.06 (d, 1H, J=3.6Hz), 7.87 (dd, 1H, J=2.4 and 8.1Hz), 7.71 (d, 2H, J=8.4Hz), 7.20 (m, 5H), 7.09 (m, 2H), 3.93 (s, 2H), 2.36 (s, 3H); LCMS (m/z): 465 (MH +).
III-75:5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-5-fluoro-N4-[4-(4-pyridylmethyl) phenyl]-2, the 4-pyrimidinediamine
[0915] 1H NMR (DMSO d 6, 300MHz): δ 9.37 (s, 1H), 9.33 (s, 1H), 8.44 (d, 2H, J=5.7Hz), 8.07 (d, 1H, J=3.6Hz), 7.98 (d, 1H, J=2.1), (7.93 dd, 1H, J=2.1 and 8.4Hz), 7.70 (d, 2H, J=8.1Hz), 7.32 (q, 1H, J=4.8Hz), 7.24 (d, 2H, J=5.4Hz), 7.19 (d, 2H, J=8.1Hz), 7.11 (d, 1H, J=8.1Hz), 3.94 (s, 2H), 2.44 (s, 3H), 2.40 (d, 3H, J=5.1Hz); LCMS (m/z): 479 (MH +).
III-71:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-pyridylmethyl) phenyl]-2, the 4-pyrimidinediamine
[0916] 1H?NMR(DMSO?d 6，300MHz)：δ9.58(s，1H)，9.42(s，1H)，8.45(d，2H，J＝6.0Hz)，8.13(d，1H，J＝3.9Hz)，7.79(d，2H，J＝8.7Hz)，7.67(d，2H，J＝8.4Hz)，7.61(d，2H，J＝9.0Hz)，7.24(m，4H)，7.14(br?s，2H)，3.96(s，2H)；LCMS(m/z)：451(MH +)。
I-188:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0917] 1H NMR (DMSO d 6, 300MHz): δ 9.46 (s, 1H), 9.27 (s, 1H), 8.66 (s, 1H), 8.53 (d, 1H, J=3.6Hz), 8.06 (d, 2H, J=2.7Hz), 7.93 (m, 1H), 7.86 (d, 1H, J=8.1Hz), 7.68 (d, 2H, J=9.0Hz), 7.41 (dd, 1H, J=4.8 and 7.6Hz), 7.32 (m, 2H), 7.25 (s, 2H), 7.00 (d, 2H, J=9.3Hz), 5.15 (s, 2H); LCMS (m/z): 467 (MH +).
I-189:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(3-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0918] 1H NMR (DMSO d 6, 300MHz): δ 9.30 (s, 1H), 9.27 (s, 1H), 8.66 (s, 1H), 8.53 (d, 1H, J=3.6Hz), 8.08 (d, 1H, J=1.5Hz), 8.03 (d, 1H, J=3.6Hz), 7.86 (d, 2H, J=8.4Hz), 7.69 (d, 2H, J=9.0Hz), 7.42 (dd, 1H, J=5.1 and 7.8Hz), 7.22 (s, 1H), 7.11 (m, 2H), 6.99 (d, 2H, J=8.7Hz), 5.15 (s, 2H), 2.36 (s, 3H); LCMS (m/z): 481 (MH +).
I-190:5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-5-fluoro-N4-[4-(3-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0919] 1H NMR (DMSO d 6, 300MHz): δ 9.29 (s, 1H), 9.18 (s, 1H), 8.60 (s, 1H), 8.46 (d, 1H, J=4.5Hz), 7.98 (d, 1H, J=3.6Hz), 7.93 (s, 1H), 7.87 (d, 1H, J=8.4Hz), 7.80 (d, 1H, J=7.5Hz), 7.62 (d, 2H, J=8.7Hz), 7.35 (dd, 1H, J=4.5 and 7.6Hz), 7.26 (q, 1H, J=5.1Hz), 7.10 (d, 1H, J=8.4Hz), 6.93 (d, 2H, J=8.7Hz), 5.08 (s, 2H), 2.39 (s, 3H), 2.35 (d, 3H, J=4.8Hz); LCMS (m/z): 495 (MH +).
III-1:5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-5-fluoro-N4-(4-cyano methyl phenyl)-2, the 4-pyrimidinediamine
[0920] 1H NMR (DMSO d 6, 300MHz): δ 9.41 (s, 2H), 8.11 (d, 1H, J=3.6Hz), 8.02 (d, 1H, J=2.1Hz), 7.95 (dd, 1H, J=1.8 and 8.2Hz), 7.82 (d, 2H, J=8.7Hz), 7.29 (d, 3H, J=8.4Hz), 7.21 (d, 1H, J=8.1Hz), 3.99 (s, 2H), 2.46 (s, 3H), 2.42 (d, 3H, J=2.4Hz); LCMS (m/z): 427 (MH +).
I-182:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[3-(3-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0921] 1H NMR (DMSO d 6, 300MHz): δ 9.52 (s, 1H), 9.34 (s, 1H), 8.65 (d, 1H, J=1.8Hz), 8.53 (dd, 1H, J=1.5 and 4.6Hz), 8.12 (d, 1H, J=3.6Hz), 8.08 (s, 1H), 7.98 (d, 1H, J=7.8Hz), 7.84 (d, 1H, J=7.8Hz), 7.47 (s, 2H), 7.41 (m, 1H), 7.32 (m, 2H), 7.24 (m, 3H), 6.75 (m, 1H), 5.13 (s, 2H); LCMS (m/z): 467 (MH +).
I-183:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-(3-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0922] 1H NMR (DMSO d 6, 300MHz): δ 9.42 (s, 1H), 9.31 (s, 1H), 8.65 (d, 1H, J=2.1Hz), 8.52 (dd, 1H, J=1.5 and 4.7Hz), 8.09 (m, 2H), 7.93 (dd, 1H, J=2.7 and 8.4Hz), 7.84 (d, 1H, J=7.5Hz), 7.47 (m, 2H), 7.41 (dd, 1H, J=4.8 and 7.6Hz), 7.21 (m, 3H), 7.14 (d, 1H, J=8.4Hz), 6.73 (m, 1H), 5.11 (s, 2H), 2.44 (s, 3H); LCMS (m/z): 481 (MH +).
I-184:5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-5-fluoro-N4-[3-(3-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0923] 1H?NMR(DMSO?d 6，300MHz)：δ9.42(s，1H)，9.33(s，1H)，8.64(s，1H)，8.52(d，1H，J＝4.5Hz)，8.11(d，1H，J＝3.6Hz)，7.98(d，2H，J＝8.1Hz)，7.83(d，1H，J＝7.5Hz)，7.47(s，2H)，7.41(m，1H)，7.31(q，1H，J＝4.8Hz)，7.23(t，1H，J＝8.1Hz)，7.17(d，1H，J＝8.1Hz)，6.73(d，1H，J＝9.0Hz)，5.10(s，2H)，2.49(s，3H)，2.41(d，3H，J＝4.5Hz)，；LCMS(m/z)：495(MH +)。
III-2:N2-[4-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-(4-cyano methyl phenyl)-2, the 4-pyrimidinediamine
[0924] 1H?NMR(DMSO?d 6，300MHz)：δ9.67(s，1H)，9.52(s，1H)，8.16(d，1H，J＝3.3Hz)，7.85(d，2H，J＝8.7Hz)，7.79(d，2H，J＝8.1Hz)，7.61(d，2H，J＝8.7Hz)，7.31(d，2H，J＝8.4Hz)，7.16(br?s，1H)，4.01(s，2H)，2.74(t，2H，J＝7.2Hz)，2.36(q，6H，J＝7.2Hz)，0.85(t，6H，J＝6.9Hz)；LCMS(m/z)：498(MH +)。
VII-55:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-pyridylmethyl) benzo [1,4] oxazine-7-yl]-2, the 4-pyrimidinediamine
[0925] 1H NMR (DMSO d 6, 300MHz): δ 9.41 (s, 1H), 9.07 (s, 1H), 8.56 (s, 1H), 7.47 (d, 1H, J=3.9Hz), 8.01 (m, 3H), 7.72 (d, 1H, J=8.1Hz), 7.36 (dd, 1H, J=4.5 and 7.6Hz), 7.31-7.11 (m, 6H), 6.65 (d, 1H, J=8.7Hz), 4.51 (s, 2H), 4.25 (t, 2H, J=4.5Hz), 3.39 (t, 2H, J=4.2Hz); LCMS (m/z): 508 (MH +).
VII-56:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-pyridylmethyl) benzo [1,4] oxazine-7-yl]-2, the 4-pyrimidinediamine
[0926] 1H NMR (DMSO d 6, 300MHz): δ 9.30 (s, 1H), 9.03 (s, 1H), 8.56 (s, 1H), 8.46 (d, 1H, J=3.6Hz), 8.05 (d, 1H, J=1.8Hz), 7.98 (d, 1H, J=3.6Hz), 7.91 (dd, 1H, J=2.1 and 8.4Hz), 7.71 (d, 1H, J=7.5Hz), (7.35 dd, 1H, J=4.5 and 9.7Hz), 7.21 (s, 2H), and 7.19-7.05 (m, 3H), 6.64 (d, 1H, J=8.7Hz), 4.49 (s, 2H), 4.24 (t, 2H, J=4.5Hz), 3.37 (t, 2H, J=4.5Hz), 2.47 (s, 3H); LCMS (m/z): 522 (MH +).
I-185:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[3-(3-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0927] 1H?NMR(DMSO?d 6，300MHz)：δ9.64(s，1H)，9.42(s，1H)，8.64(s，1H)，8.51(d，1H，J＝4.5Hz)，8.16(d，1H，J＝3.6Hz)，7.84(m，3H)，7.63(d，2H，J＝8.7Hz)，7.42(m，3H)，7.26(t，1H，J＝7.8Hz)，7.13(s，2H)，6.77(d，1H，J＝8.1Hz)，5.13(s，2H)，LCMS(m/z)：467(MH +)。
I-186:N2-[4-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[3-(3-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0928] 1H?NMR(DMSO?d 6，300MHz)：δ9.69(s，1H)，9.43(s，1H)，8.64(s，1H)，8.51(d，1H，J＝4.5Hz)，8.16(d，1H，J＝3.6Hz)，7.84(m，3H)，7.59(d，2H，J＝8.7Hz)，7.40(m，3H)，7.26(t，1H，J＝8.1Hz)，7.18(br?s，1H)，6.78(d，1H，J＝8.1Hz)，5.13(s，2H)，2.72(s，2H)，2.37(q，6H，J＝6.9Hz)，0.85(t，6H，J＝6.9Hz)，LCMS(m/z)：566(MH +)。
I-160 942988:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(2-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0929] 1H NMR (DMSO d 6, 300MHz): δ 9.32 (s, 1H), 9.21 (s, 1H), 8.56 (d, 1H, J=4.5Hz), 8.09 (d, 1H, J=2.1Hz), 8.02 (d, 1H, J=3.6Hz), 7.83 (m, 2H), 7.68 (d, 2H, J=9.0Hz), 7.50 (d, 1H, J=7.8Hz), 7.33 (dd, 1H, J=5.1 and 7.0Hz), 7.21 (s, 2H), 7.12 (d, 1H, J=8.4Hz), 6.98 (d, 1H, J=8.7Hz), 5.73 (s, 2H), 2.48 (s, 3H); LCMS (m/z): 481 (MH +).
I-191:N2-[4-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[4-(3-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0930] 1H NMR (DMSO d 6, 300MHz): δ 9.61 (s, 1H), 9.34 (s, 1H), 8.66 (s, 1H), 8.53 (d, 1H, J=3.9Hz), 8.10 (d, 1H, J=3.6Hz), 7.86 (d, 1H, J=9.3Hz), 7.81 (d, 2H, J=8.7Hz), 7.62 (d, 2H, J=9.0Hz), 7.56 (d, 1H, J=9.0Hz), 7.41 (dd, 1H, J=5.1 and 7.8Hz), 7.21 (br s, 1H), 7.02 (d, 2H, J=9.0Hz), 5.18 (s, 2H), 2.72 (bs s, 2H), 2.34 (m, 6H), 0.83 (t, 6H, J=7.5Hz); LCMS (m/z): 566 (MH +).
III-66:N2-(3-amino-sulfonyl-4-p-methoxy-phenyl)-5-fluoro-N4-[4-(4-pyridylmethyl) phenyl]-2, the 4-pyrimidinediamine
[0931] 1H?NMR(DMSO?d 6，300MHz)：δ9.27(s，1H)，9.17(s，1H)，8.44(d，2H，J＝4.2Hz)，8.04(d，1H，J＝3.9Hz)，7.97(s，1H)，7.86(d，1H，J＝8.7Hz)，7.72(d，2H，J＝8.1Hz)，7.24(d，2H，J＝4.5Hz)，7.19(d，2H，J＝8.1Hz)，7.01(d，1H，J＝9.0Hz)，6.95(s，2H)，3.93(s，2H)，3.83(s，3H)；LCMS(m/z)：481(MH +)。
III-67:N2-[4-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[4-(4-pyridylmethyl) phenyl]-2, the 4-pyrimidinediamine
[0932] 1H?NMR(DMSO?d 6，300MHz)：δ9.47(s，1H)，9.36(s，1H)，8.44(d，2H，J＝5.1Hz)，8.09(d，1H，J＝3.3Hz)，8.05(s，1H)，7.98(d，1H，J＝7.5Hz)，7.71(d，2H，J＝7.8Hz)，7.25(m，7H)，3.94(s，2H)，2.79(t，2H，J＝7.2Hz)，2.37(q，6H，J＝6.9Hz)，0.85(t，6H，J＝6.6Hz)；LCMS(m/z)：550(MH +)。
I-161:5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-5-fluoro-N4-[4-(2-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0933] 1H NMR (DMSO d 6, 300MHz): δ 9.33 (s, 1H), 9.23 (s, 1H), 8.57 (d, 1H, J=4.8Hz), 8.04 (d, 1H, J=3.9Hz), 8.01 (d, 1H, J=2.1Hz), (7.93 dd, 1H, J=2.4 and 8.1Hz), 7.82 (m, 1H), 7.68 (d, 2H, J=8.7Hz), 7.51 (d, 1H, J=7.8Hz), 7.32 (m, 2H), 7.16 (d, 1H, J=8.4Hz), 6.98 (d, 2H, J=8.7Hz), 5.17 (s, 2H), 2.46 (s, 3H), 2.42 (d, 3H, J=4.8Hz); LCMS (m/z): 495 (MH +).
I-162:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0934] 1H?NMR(DMSO?d 6，300MHz)：δ9.43(s，1H)，9.25(s，1H)，8.57(d，1H，J＝5.4Hz)，8.06(d，2H，J＝3.9Hz)，7.93(m，1H)，7.82(m，1H)，7.68(d，2H，J＝9.0Hz)，7.51(d，1H，J＝7.8Hz)，7.31(m，3H)，7.24(s，2H)，6.99(d，2H，J＝9.0Hz)，5.17(s，2H)；LCMS(m/z)：467(MH +)。
I-193:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0935] 1H?NMR(DMSO?d 6，300MHz)：δ9.45(s，1H)，9.27(s，1H)，8.56(d，2H，J＝5.7Hz)，8.06(d，2H，J＝3.6Hz)，7.93(d，1H，J＝7.2Hz)，7.68(d，2H，J＝8.7Hz)，7.42(d，1H，J＝6.0Hz)，7.28(m，4H)，6.98(d，2H，J＝8.7Hz)，5.18(s，2H)；LCMS(m/z)：467(MH +)。
I-194:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(4-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0936] 1H NMR (DMSO d 6, 300MHz): δ 9.33 (s, 1H), 9.23 (s, 1H), 8.56 (d, 2H, J=4.8Hz), 8.07 (d, 1H, J=1.8Hz), 8.02 (d, 1H, J=3.9Hz), 7.86 (dd, 1H, J=2.4 and 8.2Hz), 7.68 (d, 2H, J=9.3Hz), 7.42 (d, 2H, J=5.4Hz), 7.22 (s, 2H), 7.11 (d, 1H, J=8.4Hz), 6.97 (d, 2H, J=9.3Hz), 5.18 (s, 2H), 2.48 (s, 3H); LCMS (m/z): 481 (MH +).
III-72:N2-[4-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[4-(4-pyridylmethyl) phenyl]-2, the 4-pyrimidinediamine
[0937] 1H?NMR(DMSO?d 6，300MHz)：δ9.63(s，1H)，9.43(s，1H)，8.45(d，2H，J＝6.0Hz)，8.13(d，1H，J＝3.6Hz)，7.82(d，2H，J＝8.7Hz)，7.67(d，2H，J＝8.4Hz)，7.57(d，2H，J＝8.7Hz)，7.23(t，4H，J＝9.3Hz)，7.18(br?s，1H)，3.96(s，2H)，2.71(t，2H，J＝6.0Hz)，2.37(q，6H，J＝6.9Hz)，0.84(t，6H，J＝6.5Hz)；LCMS(m/z)：550(MH +)。
I-187:N2-[3-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[3-(3-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0938] 1H NMR (DMSO d 6, 300MHz): δ 9.54 (s, 1H), 9.37 (s, 1H), 8.65 (d, 1H, J=1.8Hz), 8.52 (dd, 1H, J=1.5 and 4.8Hz), 8.13 (d, 1H, J=3.6Hz), 8.05 (d, 1H, J=1.2Hz), 8.02 (m, 1H), 7.84 (m, 1H), 7.47 (m, 2H), and 7.43-7.34 (m, 2H), 7.31 (br s, 1H), 7.24 (m, 2H), 6.74 (dd, 1H, J=2.4 and 7.9Hz), 5.12 (s, 2H), 2.78 (br s, 2H), 2.35 (q, 6H, J=7.2Hz), 0.84 (t, 6H, J=6.9Hz); LCMS (m/z): 566 (MH +).
I-163:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0939] 1H?NMR(DMSO?d 6，300MHz)：δ9.57(s，1H)，9.34(s，1H)，8.57(d，1H，J＝4.5Hz)，8.09(d，1H，J＝3.6Hz)，7.84(d，1H，J＝7.5Hz)，7.79(d，2H，J＝8.7Hz)，7.61(t，4H，J＝6.6Hz)，7.52(d，1H，J＝7.8Hz)，7.33(t，1H，J＝8.7Hz)，7.13(s，2H)，7.02(d，2H，J＝9.0Hz)，5.18(s，2H)；LCMS(m/z)：467(MH +)。
I-164:N2-(3-amino-sulfonyl pyridin-4-yl)-5-fluoro-N4-[4-(2-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0940] 1H?NMR(DMSO?d 6，300MHz)：δ9.29(s，1H)，9.28(s，1H)，8.69(d，1H，J＝7.5Hz)，8.56(m，1H)，8.45(d，1H，J＝3.3Hz)，8.36(s，1H)，7.83(m，1H)，7.58(d，2H，J＝9.0Hz)，7.52(d，1H，J＝8.1Hz)，7.34(m，1H)，7.06(d，2H，J＝9.0Hz)，6.91(d，1H，J＝7.8Hz)，5.18(s，2H)；LCMS(m/z)：468(MH +)。
I-165:N2-[4-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[4-(2-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0941]LCMS(m/z)：566(MH +)。
I-166:N2-[3-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[4-(2-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0942] 1H?NMR(DMSO?d 6，300MHz)：δ9.45(s，1H)，9.28(s，1H)，8.56(d，1H，J＝4.5Hz)，8.14(s，1H)，8.05(m，2H)，7.98(d，1H，J＝8.4Hz)，7.82(m，1H)，7.67(d，2H，J＝9.0Hz)，7.51(d，1H，J＝7.8Hz)，7.33(t，2H，J＝7.8Hz)，7.25(d，1H，J＝7.8Hz)，6.99(d，2H，J＝8.7Hz)，5.17(s，2H)，2.79(t，2H，J＝7.5Hz)，2.38(q，6H，J＝6.9Hz)，0.85(t，6H，J＝7.2Hz)；LCMS(m/z)：566(MH +)。
I-195:5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-5-fluoro-N4-[4-(4-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0943] 1H?NMR(DMSO?d 6，300MHz)：δ9.35(s，1H)，9.25(s，1H)，8.56(d，2H，J＝4.5Hz)，8.05(d，1H，J＝2.4Hz)，7.99(s，1H)，7.92(d，1H，J＝7.8Hz)，7.68(d，2H，J＝8.7Hz)，7.43(d，2H，J＝5.1Hz)，7.33(q，1H，J＝4.8Hz)，7.15(d，1H，J＝7.8Hz)，6.98(d，2H，J＝7.8Hz)，5.18(s，2H)，2.45(s，3H)，2.41(d，3H，J＝4.2Hz)；LCMS(m/z)：495(MH +)。
III-81:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(1-imidazolyl methyl) phenyl]-2, the 4-pyrimidinediamine
[0944] 1H?NMR(DMSO?d 6，300MHz)：δ9.49(s，1H)，9.42(s，1H)，8.11(m，3H)，7.93(m，1H)，7.77(d，3H，J＝8.4Hz)，7.25(m，6H)，6.89(s，1H)，5.14(s，2H)；LCMS(m/z)：440(MH +)。
III-82:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(1-imidazolyl methyl) phenyl]-2, the 4-pyrimidinediamine
[0945] 1H NMR (DMSO d 6, 300MHz): δ 9.38 (s, 2H), 8.14 (s, 1H), 8.08 (s, 2H), 7.86 (dd, 1H, J=1.8 and 8.2Hz), 7.78 (s, 1H), 7.74 (d, 2H, J=4.5Hz), 7.20 (m, 4H), 7.11 (d, 1H, J=8.1Hz), 6.89 (d, 1H, J=0.9Hz), 5.14 (s, 2H), 2.49 (s, 3H); LCMS (m/z): 454 (MH +).
IX-33:5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-5-fluoro-N4-[4-(4-thiomorpholine generation) carbonyl phenyl]-2, the 4-pyrimidinediamine
[0946] 1H?NMR(DMSO?d 6，300MHz)：δ9.52(s，1H)，9.47(s，1H)，8.14(d，1H，J＝3.9Hz)，8.05(d，1H，J＝2.1Hz)，7.92(m，3H)，7.34(m，3H)，7.23(d，1H，J＝8.1Hz)，3.72(br?s，4H)，2.64(br?s，4H)，2.47(s，3H)，2.41(d，3H，J＝4.8Hz)；LCMS(m/z)：517(MH +)。
IX-34:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-thio-morpholinyl) carbonyl phenyl]-2, the 4-pyrimidinediamine
[0947] 1H?NMR(DMSO?d 6，300MHz)：δ9.59(s，1H)，9.57(s，1H)，8.17(d，1H，J＝3.3Hz)，8.12(s，1H)，7.91(d，3H，J＝8.4Hz)，7.37(m，4H)，7.28(s，2H)，3.73(brs，4H)，2.65(br?s，4H)；LCMS(m/z)：489(MH +)。
IX-35:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(4-thio-morpholinyl) carbonyl phenyl]-2, the 4-pyrimidinediamine
[0948] 1H NMR (DMSO d 6, 300MHz): δ 9.53 (s, 1H), 9.48 (s, 1H), 8.13 (t, 2H, J=2.1Hz), 7.92 (d, 2H, J=8.4Hz), 7.87 (dd, 1H, J=2.4 and 8.2Hz), 7.35 (d, 2H, J=8.7Hz), 7.25 (s, 2H), 7.20 (d, 1H, J=8.1Hz), 3.73 (br s, 4H), 2.65 (br s, 4H), 2.46 (s, 3H); LCMS (m/z): 489 (MH +).
IX-23:N4-[4-(1-ethanoyl-4-piperazinyl) carbonyl phenyl]-N2-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0949] 1H?NMR(DMSO?d 6，300MHz)：δ9.58(s，2H)，8.17(d，1H，J＝3.6Hz)，8.13(s，1H)，7.91(m，3H)，7.38(m，5H)，7.25(br?s，1H)，3.72(br?s，4H)，2.48(br?s，8H)，2.02(s，3H)；LCMS(m/z)：514(MH +)。
IX-24:N4-[4-(1-ethanoyl-4-piperazinyl) carbonyl phenyl]-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0950] 1H?NMR(DMSO?d 6，300MHz)：δ9.54(s，1H)，9.48(s，1H)，8.14(d，2H，J＝3.0Hz)，7.93(d，2H，J＝8.1Hz)，7.87(d，1H，J＝7.8Hz)，7.38(d，2H，J＝7.8Hz)，7.25(s，2H)，7.19(d，1H，J＝8.4Hz)，3.49(br?s，8H)，2.50(s，3H)，2.05(s，3H)；LCMS(m/z)：528(MH +)。
IX-25:N4-[4-(1-ethanoyl-4-piperazinyl) carbonyl phenyl]-5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-2, the 4-pyrimidinediamine
[0951] 1H?NMR(DMSO?d 6，300MHz)：δ9.55(s，1H)，9.48(s，1H)，8.15(d，1H，J＝3.3Hz)，8.05(s，1H)，7.92(d，3H，J＝8.1Hz)，7.38(d，2H，J＝8.4Hz)，7.35(q，1H，J＝5.4Hz)，7.23(d，1H，J＝8.1Hz)，3.49(br?s，8H)，2.47(s，3H)，2.41(d，3H，J＝4.8Hz)，2.02(s，3H)；LCMS(m/z)：542(MH +)。
IX-29:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(1-methylsulfonyl-4-piperazinyl) carbonyl phenyl]-2, the 4-pyrimidinediamine
[0952] 1H?NMR(DMSO?d 6，300MHz)：δ9.60(s，2H)，8.18(d，1H，J＝3.6Hz)，8.15(s，1H)，7.93(m，3H)，7.38(m，4H)，7.28(s，2H)，3.60(br?s，4H)，3.17(br?s，4H)，2.90(s，3H)，2.91(s，3H)；LCMS(m/z)：550(MH +)。
IX-30:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(1-methylsulfonyl-4-piperazinyl) carbonyl phenyl]-2, the 4-pyrimidinediamine
[0953] 1H NMR (DMSO d 6, 300MHz): δ 9.55 (s, 1H), 9.48 (s, 1H), 8.13 (m, 2H), 7.94 (d, 2H, J=9.0Hz), (7.85 dd, 1H, J=2.4 and 8.5Hz), 7.38 (d, 1H, J=8.7Hz), 7.24 (s, 2H), 7.20 (d, 1H, J=8.4Hz), 3.61 (br s, 4H), 3.17 (br s, 4H), 2.90 (s, 3H), 2.50 (s, 3H); LCMS (m/z): 564 (MH +).
IX-31:5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-5-fluoro-N4-[4-(1-methylsulfonyl-4-piperazinyl) carbonyl phenyl]-2, the 4-pyrimidinediamine
[0954] 1H?NMR(DMSO?d 6，300MHz)：δ9.56(s，1H)，9.49(s，1H)，8.16(d，1H，J＝3.3Hz)，8.05(d，1H，J＝2.1Hz)，7.92(m，1H)，7.39(d，2H，J＝8.4Hz)，7.34(q，1H，J＝5.1Hz)，7.23(d，1H，J＝8.1Hz)，3.61(br?s，4H)，3.17(br?s，4H)，2.90(s，3H)，2.41(d，3H，J＝4.2Hz)；LCMS(m/z)：578(MH +)。
III-83:5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-5-fluoro-N4-[4-(1-imidazolyl methyl) phenyl]-2, the 4-pyrimidinediamine
[0955] 1H NMR (DMSO d 6, 300MHz): δ 9.41 (s, 2H), 8.09 (d, 1H, J=3.3Hz), 8.00 (d, 1H, J=2.1Hz), 7.92 (dd, 1H, J=2.4 and 8.5Hz), 7.75 (d, 3H, J=8.1Hz), 7.32 (q, 1H, J=4.5Hz), 7.22 (d, 3H, J=8.7Hz), 7.13 (d, 1H, J=8.4Hz), 6.94 (br s, 1H), 5.15 (s, 2H), 2.46 (s, 3H), 2.41 (d, 3H, J=4.5Hz); LCMS (m/z): 468 (MH +).
IX-37:N2-(3-amino-sulfonyl phenyl)-N4-[4-(1,1-dioxo-4-thio-morpholinyl) carbonyl phenyl]-5-fluoro-2, the 4-pyrimidinediamine
[0956] 1H?NMR(DMSO?d 6，300MHz)：δ9.61(s，1H)，9.59(s，1H)，8.18(d，1H，J＝3.3Hz)，8.13(s，1H)，7.92(d，3H，J＝8.7Hz)，7.45(d，2H，J＝8.4Hz)，7.39(m，2H)，7.28(s，2H)，3.89(br?s，4H)，3.26(br?s，4H)；LCMS(m/z)：521(MH +)。
IX-38:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[4-(1,1-dioxo-4-thio-morpholinyl) carbonyl phenyl]-5-fluoro-2, the 4-pyrimidinediamine
[0957] 1H?NMR(DMSO?d 6，300MHz)：δ9.54(s，1H)，9.48(s，1H)，8.14(m，2H)，7.94(d，2H，J＝8.1Hz)，7.85(d，1H，J＝8.5Hz)，7.44(d，2H，J＝7.8Hz)，7.24(s，2H)，7.20(d，1H，J＝8.1Hz)，3.88(br?s，4H)，3.25(br?s，4H)，2.50(s，3H)；LCMS(m/z)：535(MH +)。
IX-39:N4-[4-(1,1-dioxo-4-thio-morpholinyl) carbonyl phenyl]-5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-2, the 4-pyrimidinediamine
[0958] 1H?NMR(DMSO?d 6，300MHz)：δ9.55(s，1H)，9.49(s，1H)，8.15(d，1H，J＝3.9Hz)，8.05(d，1H，J＝2.1Hz)，7.93(m，3H)，7.75(d，3H，J＝8.1Hz)，7.44(d，2H，J＝8.4Hz)，7.34(q，1H，J＝5.2Hz)，7.24(d，1H，J＝8.1Hz)，3.88(br?s，4H)，3.26(br?s，4H)，2.47(s，3H)，2.41(d，3H，J＝4.5Hz)；LCMS(m/z)：549(MH +)。
II-16:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(4-pyridyl oxygen base) phenyl]-2, the 4-pyrimidinediamine
[0959] 1H?NMR(DMSO?d 6，300MHz)：δ9.56(s，1H)，9.48(s，1H)，8.14(d，2H，J＝2.4Hz)，8.00(d，2H，J＝8.7Hz)，7.93(d，2H，J＝8.1Hz)，7.83(d，1H，J＝8.1Hz)，7.46(d，2H，J＝8.7Hz)，7.23(d，3H，J＝7.2Hz)，6.22(d，2H，J＝7.5Hz)，2.48(s，3H)；LCMS(m/z)：467(MH +)。
II-17:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-pyridyl oxygen base) phenyl]-2, the 4-pyrimidinediamine
[0960] 1H?NMR(DMSO?d 6，300MHz)：δ9.59(s，2H)，8.17(d，1H，J＝3.3Hz)，8.13(s，1H)，7.99(d，2H，J＝8.7Hz)，7.94(d，2H，J＝7.8Hz)，7.88(d，1H，J＝8.1Hz)，7.45(m，2H)，7.37(m，1H)，7.27(s，2H)，6.22(d，2H，J＝7.5Hz))；LCMS(m/z)：453(MH +)。
II-18:5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-5-fluoro-N4-[4-(4-pyridyl oxygen base) phenyl]-2, the 4-pyrimidinediamine
[0961] 1H?NMR(DMSO?d 6，300MHz)：δ9.58(s，1H)，9.49(s，1H)，8.15(d，1H，J＝3.9Hz)，8.05-7.88(m，6H)，7.46(d，2H，J＝8.7Hz)，7.34(q，1H，J＝5.1Hz)，7.26(d，1H，J＝8.7Hz)，6.22(d，2H，J＝7.8Hz)，2.47(s，3H)，2.41(d，3H，J＝4.8Hz)；LCMS(m/z)：481(MH +)。
IX-36:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-thio-morpholinyl) carbonyl phenyl]-2, the 4-pyrimidinediamine
[0962] 1H?NMR(DMSO?d 6，300MHz)：δ9.68(s，1H)，9.61(s，1H)，8.20(d，1H，J＝3.6Hz)，7.86(d，2H，J＝8.7Hz)，7.81(d，2H，J＝9.0Hz)，7.63(d，2H，J＝8.7Hz)，7.37(d，2H，J＝8.1Hz)，7.12(s，2H)，3.74(br?s，4H)，2.65(br?s，4H)；LCMS(m/z)：489(MH +)。
IX-32:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(1-methylsulfonyl-4-piperazinyl) carbonyl phenyl]-2, the 4-pyrimidinediamine
[0963] 1H?NMR(DMSO?d 6，300MHz)：δ9.69(s，1H)，9.64(s，1H)，8.20(d，1H，J＝3.6Hz)，7.90(d，2H，J＝8.7Hz)，7.82(d，2H，J＝9.0Hz)，7.65(d，2H，J＝9.0Hz)，7.41(d，2H，J＝8.4Hz)，7.13(s，2H)，3.61(br?s，4H)，3.17(br?s，4H)，2.91(s，3H)；LCMS(m/z)：550(MH +)。
IX-40:N2-(4-amino-sulfonyl phenyl)-N4-[4-(1,1-dioxo-4-thio-morpholinyl) carbonyl phenyl]-5-fluoro-2, the 4-pyrimidinediamine
[0964] 1H?NMR(DMSO?d 6，300MHz)：δ9.67(s，1H)，9.66(s，1H)，8.18(d，1H，J＝3.5Hz)，7.92(d，2H，J＝9.0Hz)，7.80(d，2H，J＝8.2Hz)，7.66(d，2H，J＝8.7Hz)，7.43(d，2H，J＝9.0Hz)，7.13(s，2H)，3.63(br?s，4H)，3.15(br?s，4H)；LCMS(m/z)：521(MH +)。
IX-26:N4-[4-(1-ethanoyl-4-piperazinyl) carbonyl phenyl]-N2-(4-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[0965] 1H?NMR(DMSO?d 6，300MHz)：δ9.69(s，1H)，9.65(s，1H)，8.19(d，1H，J＝3.6Hz)，7.87(d，2H，J＝8.1Hz)，7.82(d，2H，J＝9.0Hz)，7.63(d，2H，J＝8.7Hz)，7.41(d，2H，J＝8.4Hz)，7.13(s，2H)，3.49(br?s，8H)，2.02(s，3H)；LCMS(m/z)：514(MH +)。
I-167:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[(4-((pyridine-2-yl) methoxyl group)-3-aminomethyl phenyl)]-2, the 4-pyrimidinediamine
[0966] 1H?NMR(DMSO?d 6，300MHz)：δ9.44(s，1H)，9.19(s，1H)，8.56(d，1H，J＝3.9Hz)，8.05(d，1H，J＝3.6Hz)，8.02(s，1H)，7.98(m，1H)，7.84(t，1H，J＝7.5Hz)，7.51(m，3H)，7.30(m，5H)，6.92(d，2H，J＝7.8Hz)，5.19(s，2H)，2.25(s，3H)；LCMS(m/z)：481(MH +)。
I-168:N2-(3-amino-4-methyl sulphonyl phenyl)-5-fluoro-N4-[(4-((pyridine-2-yl) methoxyl group)-3-aminomethyl phenyl)]-2, the 4-pyrimidinediamine
[0967] 1H?NMR(DMSO?d 6，300MHz)：δ9.33(s，1H)，9.15(s，1H)，8.57(d，1H，J＝4.5Hz)，8.05(s，1H)，8.02(d，1H，J＝3.6Hz)，7.89(m，1H)，7.82(d，1H，J＝7.5Hz)，7.52(m，3H)，7.33(m，1H)，7.22(s，2H)，7.11(d，1H，J＝8.1Hz)，6.93(d，1H，J＝9.6Hz)，5.19(s，2H)，2.49(s，3H)，2.25(s，3H)；LCMS(m/z)：495(MH +)。
III-73:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-pyridylmethyl) phenyl]-2,4-pyrimidinediamine hydrochloride
[0968] with N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-pyridylmethyl) phenyl]-2; (III-70 50mg) is dissolved in methyl alcohol (10mL) to the 4-pyrimidinediamine, adds 4N HCl and (is dissolved in diox; 63.5 μ L), with reaction mixture stirring at room 1 hour and concentrating under reduced pressure.Use the hexane wash solid at last and under high vacuum thorough drying, the productive rate of gained HCl salt is quantitative. 1H?NMR(DMSO?d 6，300MHz)：δ9.92(s，1H)，9.82(s，1H)，8.81(d，2H，J＝5.4Hz)，8.20(d，1H，J＝4.5Hz)，7.98(s，1H)，7.93(d，1H，J＝5.4Hz)，7.87(d，2H，J＝7.8Hz)，7.72(d，2H，J＝8.7Hz)，7.42-7.28(m，5H)，4.26(s，2H)；LCMS(m/z)：451(MH +)。
[0969] following three kinds of compounds prepare according to mode similar to the above.
III-129:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-pyridylmethyl) phenyl]-2,4-pyrimidinediamine mesylate
[0970] 1H?NMR(DMSO?d 6，300MHz)：δ9.61(s，1H)，9.55(s，1H)，8.79(d，2H，J＝6.0Hz)，8.15(s，1H)，8.04(s，1H)，7.90(br?s，3H)，7.76(d，2H，J＝7.5Hz)，7.36-7.26(m，6H)，4.23(s，2H)，2.31(s，3H)；LCMS(m/z)：451(MH +)。
III-128:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-pyridylmethyl) phenyl]-2,4-pyrimidinediamine tosilate
[0971] 1H?NMR(DMSO?d 6，300MHz)：δ9.55(s，1H)，9.47(s，1H)，8.77(d，2H，J＝5.7Hz)，8.13(d，1H，J＝3.6Hz)，8.06(s，1H)，7.88(m，3H)，7.77(d，2H，J＝8.7Hz)，7.45(d，2H，J＝7.8Hz)，7.34(d，2H，J＝5.7Hz)，7.25(m，3H)，7.08(d，2H，J＝8.1Hz)，4.22(s，2H)，2.27(s，3H)；LCMS(m/z)：451(MH +)。
I-196:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-4-[(2-pyridyl) methylene radical oxygen base phenyl]-2,4-pyrimidinediamine hydrochloride
[0972] 1H?NMR(DMSO?d 6，300MHz)：δ9.98(s，1H)，9.88(s，1H)，8.69(d，1H，J＝4.8Hz)，8.18(d，1H，J＝3.9Hz)，8.10(t，1H，J＝8.4Hz)，7.92(s，1H)，7.85(d，1H，J＝7.8Hz)，7.73(d，1H，J＝7.8Hz)，7.61(m，3H)，7.38(m，4H)，7.03(d，2H，J＝9.0Hz)，5.29(s，2H)；LCMS(m/z)：467(MH +)。
Embodiment 34
III-80: preparation N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(1-epoxy-4-pyridylmethyl) phenyl]-2, the 4-pyrimidinediamine
[0973] with 30% H 2O 2The aqueous solution (23 μ L) is handled N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-pyridylmethyl) phenyl among the THF (15mL)]-2,4-pyrimidinediamine (50mg) and methyl rhenium trioxide (VII) mixture (5mg).Stir and add 30%H after 24 hours 2O 2The aqueous solution (23 μ L) also stirred 24 hours.Reaction mixture is by diatomite filtration, with methanol wash filter bed and concentrated.Resistates obtains 10 milligrams of required products by the HPLC purifying. 1H?NMR(DMSOd 6，300MHz)：δ9.47(s，1H)，9.35(s，1H)，8.10(m，4H)，7.92(m，1H)，7.73(d，2H，J＝8.4Hz)，7.32-7.18(m，8H)，3.91(s，2H)；LCMS(m/z)：467(MH +)。
Embodiment 35
Figure A20068002053302851
[0974] with N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2; 4-pyrimidinediamine (I-230; 0.627mg; 1.33mmol), 4-brooethyl-5-methyl isophthalic acid; 3-dioxole-2-ketone (0.283mg, 1.33mmol) and anhydrous K 2CO 3(0.202g, 1.33mmol) the mixture stirring at room in DMF (5mL) is 3 days.Reaction mixture is poured in the water (50mL), with solid filtering and thorough drying.By the HPLC purifying so that required product I-247 (14mg) and I-248 (14mg) to be provided.
The I-247:N2-{3-[(N-5-methyl isophthalic acid, 3-dioxole-2-ketone-4-yl) methylene radical] the amino-sulfonyl phenyl }-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0975] 1H NMR (DMSO d 6, 300MHz): δ 9.49 (s, 1H), 9.29 (s, 1H), 8.22 (s, 1H), 8.08 (d, 2H, J=3.9Hz), 7.93 (m, 1H), 7.69 (d, 2H, J=9.3Hz), 7.33 (t, 1 hour, J=7.8Hz), 7.24 (d, 1H, J=8.4Hz), 6.98 (d, 2H, J=9.0Hz), 6.32 (s, 1H), 5.12 (s, 2H), 3.87 (d, 2H, J=5.1Hz), 2.40 (s, 3H), 1.94 (s, 3H); LCMS (m/z): 583 (MH +).
I-248:N2-{3-[N-N-two-[(5-methyl isophthalic acid, 3-dioxole-2-ketone-4-yl) methylene radical]] the amino-sulfonyl phenyl }-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0976] 1H NMR (DMSO d 6, 300MHz): δ 9.48 (s, 1H), 9.32 (s, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 8.08 (d, 1H, J=3.3Hz), 8.03 (d, 1H, J=9.6Hz), 7.81 (d, 2H, J=9.0Hz), 7.39 (t, 1 hour, J=8.1Hz), 7.29 (d, 1H, J=7.8Hz), 6.99 (d, 2H, J=9.0Hz), 6.32 (s, 1H), 5.73 (s, 1H), 5.12 (s, 2H), 4.25 (s, 3H), 2.40 (s, 3H), 2.04 (s, 5H); LCMS (m/z): 695 (MH +).
[0977] following compound is according to preparing with embodiment 35 similar modes or by method described here or those of skill in the art's currently known methods.
I-249:N2-{3-[N-N-two-[(the 5-tertiary butyl-1,3-dioxole-2-ketone-4-yl) methylene radical]] the amino-sulfonyl phenyl }-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0978] 1H NMR (DMSO d 6, 300MHz): δ 9.48 (s, 1H), 9.31 (s, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 8.07 (d, 1H, J=3.9Hz), 7.93 (d, 1H, J=8.7Hz), 7.66 (d, 2H, J=9.0Hz), 7.36 (t, 1 hour, J=7.8Hz), 7.21 (d, 1H, J=7.8Hz), 6.98 (d, 2H, J=8.7Hz), 6.32 (s, 1H), 5.12 (s, 2H), 4.39 (s, 4H), 2.40 (s, 3H), 1.20 (s, 18H); LCMS (m/z): 779 (MH +).
The I-250:N2-{3-[(N-5-tertiary butyl-1,3-dioxole-2-ketone-4-yl) methylene radical] the amino-sulfonyl phenyl }-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0979] 1H NMR (DMSO d 6, 300MHz): δ 9.47 (s, 1H), 9.28 (s, 1H), 8.29 (t, 1H, J=6.0Hz), 8.12 (s, 1H), 8.07 (d, 1H, J=3.9Hz), 7.92 (m, 1H), 7.68 (d, 2H, J=9.0Hz), 7.34 (t, 1 hours, J=7.8Hz), 7.25 (d, 1H, J=8.1Hz), 6.98 (d, 2H, J=9.0Hz), 6.32 (s, 1H), 5.12 (s, 2H), 3.93 (d, 2H, J=6.0Hz), 2.40 (s, 3H), 1.11 (s, 9H); LCMS (m/z): 625 (MH +).
The I-257:N2-{3-[(N-5-methyl isophthalic acid, 3-dioxole-2-ketone-4-yl) methylene radical] the amino-sulfonyl phenyl }-5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[0980] 1H NMR (DMSO d 6, 300MHz): δ 9.49 (s, 1H), 9.32 (s, 1H), 8.38 (s, 1H), 8.22 (s, 1H), 8.08 (d, 2H, J=2.1Hz), 7.94 (d, 1H, J=7.8Hz), 7.70 (d, 2H, J=8.1Hz), 7.35 (t, 1 hour, J=7.8Hz), 7.25 (m, 1H), 7.01 (d, 2H, J=8.4Hz), 5.46 (s, 2H), 3.87 (s, 2H), 2.36 (s, 3H), 1.94 (s, 3H); LCMS (m/z): 584 (MH +).
III-17:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(2-cyano ethyl)-3-fluorophenyl]-2, the 4-pyrimidinediamine
[0981] 1H?NMR(DMSO-d 6)：δ9.51(s，2H)，8.11(s，2H)，7.92-7.89(d，J＝8.4Hz，1H)，7.87-7.82(d，J＝12.9Hz，1H)，7.60-7.58(d，J＝8.4Hz，1H)，7.32-7.19(m，4H)，7.09(s，1H)，3.29(s，3H)，2.88-2.86(bd，J＝6Hz，2H)，2.82-2.80(bd，J＝5.7Hz，2H)，LCMS：445.01(MH +)。
III-18:N2-(3-amino-sulfonyl phenyl)-N4-[4-(2-cyano ethyl)-3-fluorophenyl]-5-fluoro-2, the 4-pyrimidinediamine
[0982] 1H?NMR(DMSO-d 6)：δ9.62(s，1H)，9.55(s，1H)，8.16-8.15(d，J＝3.9Hz，1H)8.10(s，1H)，7.98-7.96(d，J＝6.9Hz，1H)，7.87-7.83(dd，J＝12.9Hz，1H)，7.61-7.58(dd，J＝8.4Hz，1H)，7.43-7.23(m，5H)，2.93-2.77(m，4H)，LCMS：430.98(MH +)。
III-19:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[4-(2-cyano ethyl)-3-aminomethyl phenyl]-5-fluoro-2, the 4-pyrimidinediamine
[0983] 1H?NMR(DMSO-d 6)：δ9.39(s，1H)，9.24(s，1H)，8.06-8.05(d，J＝3.9Hz，1H)，7.95-7.91(dd，J＝8.7Hz，1H)，7.63-7.59(dd，J＝8.1Hz，1H)，7.55(s，1H)，7.21(s，2H)，7.14(s，1H)，2.86-2.83(t，2H)，2.79-2.74(t，2H)，LCMS：441.49(MH +)。
III-20:N2-(3-amino-sulfonyl phenyl)-N4-[4-(2-cyano ethyl)-3-aminomethyl phenyl]-5-fluoro-2, the 4-pyrimidinediamine
[0984] 1H?NMR(DMSO-d 6)：δ9.50(s，1H)，9.28(s，1H)，8.10(bs，1H)，8.04(bs，1H)，7.60(d，1H)，7.55(s，1H)，7.25(s，1H)，7.15(s，1H)，6.98(s，2H)，2.86(m，2H)，2.79(s，2H)，2.29(s，3H)，LCMS：427.45(MH +)。
III-21:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[3-chloro-4-(2-cyano ethyl) phenyl]-5-fluoro-2, the 4-pyrimidinediamine
[0985] 1H?NMR(DMSO-d 6)：δ9.49(s，1H)，9.47(s，1H)，8.13-8.12(d，J＝3.6Hz，1H)，8.06-8.06(d，J＝2.1Hz，1H)，7.92-7.90(dd，J＝8.4Hz，1H)，7.88-7.88(d，J＝2.1Hz，1H)，7.85-7.82(dd，J＝8.4Hz，1H)，7.37-7.34(d，J＝8.4Hz，1H)，7.23(s，2H)，7.19(s，1H)，3.00-2.95(t，2H)，3.84-2.80(t，2H)，2.48(s，3H)，LCMS：460.94(MH +)。
III-22:N2-(3-amino-sulfonyl phenyl)-N4-[3-chloro-4-(2-cyano ethyl) phenyl]-5-fluoro-2, the 4-pyrimidinediamine
[0986] 1H?NMR(DMSO-d 6)：δ9.60(s，1H)，9.50(s，1H)，8.16-8.15(d，J＝3.3Hz，1H)，8.05，(s，1H)，8.00-7.97(d，J＝9Hz，1H)，7.89-7.88(d，J＝2.1Hz，1H)，7.85-7.82(d，J＝8.1Hz，1H)，7.44-7.38(t，1H)，7.37(s，1H)，7.34(s，2H)，7.32(s，1H)，3.00-2.95(t，2H)，2.84-2.79(t，2H)，LCMS：446.93(MH +)。
VII-1:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[(2S, 4R)-1-(2-cyano group ethanoyl)-2-methoxycarbonyl tetramethyleneimine-4-yl)-5-fluoro-2, the 4-pyrimidinediamine
[0987] 1H?NMR(DMSO-d 6)：δ9.34(s，1H)，8.41-8.40(d，J＝2.1Hz，1H)，7.92-7.90(d，J＝3.9Hz，1H)，7.76-7.73(d，J＝6.3Hz，1H)，7.67-7.63(dd，J＝7.8Hz，1H)，7.20(s，2H)，7.17(s，1H)，4.73(bs，1H)，4.53-4.47(t，1H)，4.03(bs，2H)，3.91-3.85(m，1H)，3.65(s，1H)，3.55-3.51(d，J＝10.8Hz，1H)，2.43-2.36(m，1H)，2.20-2.15(m，1H)，LCMS：492.20(MH +)。
VII-2:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[(2S, 4S)-1-(2-cyano group ethanoyl)-2-methoxycarbonyl tetramethyleneimine-4-yl]-5-fluoro-2, the 4-pyrimidinediamine
[0988] 1H?NMR(DMSO-d 6)：δ9.37(s，1H)，8.69(s，1H)，7.93-7.92(d，J＝3.3Hz，1H)，7.59-7.56(d，J＝7.5Hz，1H)，7.46-7.43(dd，J＝8.4Hz，1H)，7.19(s，1H)，7.17(s，2H)，4.84-4.82(m，1H)，4.39-4.33(t，1H)，3.94-3.89(t，1H)，3.64(s，3H)，3.44-3.38(t，1H)，2.63-2.59(m，1H)，2.07-2.00(m，1H)，LCMS：492.79(MH +)。
VII-77:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(quinoline-8-yl)-2, the 4-pyrimidinediamine
[0989] 1H?NMR(DMSO-d 6)：δ9.71(s，1H)，9.66(s，1H)，9.00-8.98(d，J＝7.2Hz，1H)，8.94-8.93(d，J＝3.6Hz，1H)，8.45-8.42(d，J＝8.1Hz，1H)，8.25-8.24(d，J＝3.0Hz，1H)，8.21-8.21(d，J＝2.1Hz，1H)，7.91-7.87dd，J＝7.8Hz，1H)，7.68-7.67(d，J＝3.9Hz，1H)，7.66(s，2H)，7.28(s，2H)，2.53(s，3H)，LCMS：425.68(MH +)。
VII-78:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(quinoline-8-yl)-2, the 4-pyrimidinediamine
[0990] 1H?NMR(DMSO-d 6)：δ9.78(s，1H)，9.74-9.74(d，J＝2.7Hz，1H)，9.00-8.97(dd，J＝6.9Hz，1H)，8.95-8.93(dd，J＝3.9Hz，1H)，8.46-8.42(dd，J＝8.4Hz，1H)，8.28-8.27(d，J＝3.3Hz，1H)，8.23(s，1H)，7.93-7.91(d，J＝8.1Hz，1H)，7.68-7.63(m，3H)，7.49-7.38(m，2H)，7.303(s，1H)，LCMS：411.60(MH+)。
VII-79:N2-(3-amino-sulfonyl-4-fluorophenyl)-5-fluoro-N4-(quinoline-8-yl)-2, the 4-pyrimidinediamine
[0991] 1H?NMR(DMSO-d 6)：δ9.73(s，2H)，8.96(s，1H)，8.94-8.94(d，J＝2.4Hz，1H)，8.45-8.43(d，J＝6.9Hz，1H)，8.26-8.25(d，J＝3.0Hz，1H)，8.19-8.16(dd，J＝6Hz，1H)，7.99-7.94(m，1H)，7.68-7.63(m，3H)，7.59(s，2H)，7.37-7.31(t，1H)，LCMS：429.40(MH +)。
VII-69:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(quinoline-6-yl)-2, the 4-pyrimidinediamine
[0992] 1H?NMR(DMSO-d 6)：δ9.69(s，1H)，9.48(s，1H)，8.76-8.74(dd，J＝4.2Hz，1H)，8.61-8.61(d，J＝2.1Hz，1H)，8.21-8.19(d，J＝7.2Hz，1H)，8.16-8.15(d，J＝3.6Hz，1H)，8.12-8.11(d，J＝2.4Hz，1H)，8.10-8.06(dd，J＝9.0Hz，1H)，7.95-7.92(d，J＝9.3Hz，1H)，7.94-7.91(d，J＝8.4Hz，1H)，7.50-7.46(m，1H)，7.25(s，2H)，7.17-7.14(d，J＝8.4Hz，1H)，LCMS：425(MH +)。
VII-70:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(quinoline-6-yl)-2, the 4-pyrimidinediamine
[0993] 1H?NMR(DMSO-d 6)：δ9.96(s，1H)，9.68(s，1H)，8.95-8.94(d，J＝4.2Hz，1H)，8.82(s，1H)，8.61-8.59(d，J＝7.5Hz，1H)，8.28-8.24(m，2H)，8.12-8.07(m，2H)，7.99-7.96(m，1H)，7.78-7.75(m，1H)，7.40-7.38(m，2H)，7.28(s，2H)，LCMS：411.11(MH +)。
VII-57:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(thionaphthene-5-yl)-5-fluoro-2, the 4-pyrimidinediamine
[0994] 1H?NMR(DMSO-d 6)：δ9.44(s，1H)，9.40(s，1H)，8.41-8.40(s，1H)，8.09(s，1H)，8.08(s，1H)，7.93(s，1H)，7.90(s，1H)，7.76-7.74(d，J＝5.4Hz，1H)，7.72-7.68(d，J＝6.6Hz，1H)，7.37-7.35(d，J＝5.4Hz，1H)，7.23(s，2H)，7.13-7.10(d，J＝8.4Hz，1H)，LCMS：430.37(MH +)。
VII-58:N2-(3-amino-sulfonyl phenyl)-N4-(thionaphthene-5-yl)-5-fluoro-2, the 4-pyrimidinediamine
[0995] 1H?NMR(DMSO-d 6)：δ9.51(s，1H)，9.48(s，1H)，8.40(s，1H)，8.13-8.12(d，J＝3.6Hz，1H)，8.06(s，1H)，7.94(m，1H)，7.94-7.91(d，J＝9Hz，1H)，7.76-7.74(d，J＝5.7Hz，1H)，7.72-7.68(dd，J＝2.4Hz，1H)，7.38-7.36(d，J＝5.7Hz，1H)，7.33-7.32(m，2H)，7.25(s，2H)，LCMS：416.39(MH +)。
VII-71:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(2-toluquinoline-6-yl)-2, the 4-pyrimidinediamine
[0996] 1H?NMR(DMSO-d 6)：δ9.62(s，1H)，9.47(s，1H)，8.55(s，1H)，8.15-8.13(d，J＝3.6Hz，1H)，8.10(s，2H)，8.05-8.01(dd，J＝9.3Hz，1H)，7.95-7.91(dd，J＝8.1Hz，1H)，7.85-7.82(d，J＝9.3Hz，1H)，7.38-7.36(d，J＝8.4Hz，1H)，7.25(s，2H)，7.17-7.14(d，J＝8.4Hz，1H)，2.62(s，3H)，2.51(s，3H)，LCMS：439.41(MH +)。
VII-72:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(2-toluquinoline-6-yl)-2, the 4-pyrimidinediamine
[0997] 1H?NMR(DMSO-d 6)：δ9.55(s，1H)，8.55(s，1H)，8.16-8.16(d，J＝3.3Hz，1H)，8.13(s，1H)，8.10-8.08(d，J＝4.5Hz，1H)，8.04(bs，1H)，8.01(bs，1H)，7.85-7.82(d，J＝8.7Hz，1H)，7.38-7.33(m，3H)，2.62(s，3H)，LCMS：425.57(MH +)。
VII-65:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(quinoline-3-yl)-2, the 4-pyrimidinediamine
[0998] 1H?NMR(DMSO-d 6)：δ9.47(s，1H)，9.19(s，1H)，8.86(s，1H)，8.15-8.12(m，2H)，7.92-7.84(m，4H)，7.61-7.52(m，2H)，7.17-7.14(d，J＝8.1Hz，1H)，2.42(s，3H)，LCMS：425.79(MH +)。
VII-66:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(quinoline-3-yl)-2, the 4-pyrimidinediamine
[0999] 1H?NMR(DMSO-d 6)：δ9.46(s，1H)，9.14(s，1H)，8.80(s，1H)，8.12-8.08(m，2H)，7.95-7.84(m，4H)，7.59-7.53(m，3H)，7.34-7.32(m，3H)，LCMS：411.44(MH +)。
VII-67:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(quinoline-5-yl)-2, the 4-pyrimidinediamine
[1000] 1H?NMR(DMSO-d 6)：δ9.15(s，1H)，8.89-8.87(d，J＝3.3Hz，1H)，8.34-8.31(d，J＝8.4Hz，1H)，8.08-8.07(d，J＝3.6Hz，1H)，7.96-7.93(d，J＝8.7Hz，1H)，7.88(s，1H)，7.81-7.75(t，1H)，7.66-7.64(d，J＝6.9Hz，1H)，7.50-7.46(m，2H)，7.36(s，1H)，7.34(s，1H)，6.70-6.68(d，J＝8.1Hz，1H)，2.38(s，3H)，LCMS：425.71(MH +)。
VII-68:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(quinoline-5-yl)-2, the 4-pyrimidinediamine
[1001] 1H?NMR(DMSO-d 6)：δ9.15(s，1H)，8.85(s，1H)，8.40-8.38(d，J＝7.8Hz，1H)，8.00(s，1H)，7.87-7.83(m，2H)，7.77-7.67(m，2H)，7.53-7.50(d，J＝7.8Hz，1H)，7.47-7.42(m，2H)，7.17-7.14(d，J＝7.5Hz，1H)，6.95-6.90(t，1H)，LCMS：411.58(MH +)。
VII-80:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(2-toluquinoline-8-yl)-2, the 4-pyrimidinediamine
[1002] 1H?NMR(DMSO-d 6)：δ9.81(s，1H)，9.71(s，1H)，8.91(s，1H)，8.34-8.31(d，J＝8.4Hz，1H)，8.24-8.23(d，J＝3.3Hz，1H)，8.17(s，1H)，7.87-7.85(d，J＝6.9Hz，1H)，7.63-7.51(m，3H)，7.27-7.24(m，3H)，2.73(s，3H)，2.53(s，3H)，LCMS：439.16(MH +)。
VII-81:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(2-toluquinoline-8-yl)-2, the 4-pyrimidinediamine
[1003] 1H?NMR(DMSO-d 6)：δ9.84(s，1H)，9.81(s，1H)，8.87(s，1H)，8.35-8.33(d，J＝8.4Hz，1H)，8.28-8.27(d，J＝3.3Hz，1H)，8.18(s，1H)，7.90-7.88(m，1H)，7.65-7.62(m，1H)，7.58-7.53(m，2H)，7.45-7.39(m，2H)，7.30(s，2H)，2.74(s，3H)，LCMS：425.06(MH +)。
VII-64:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(quinoline-2-yl)-2, the 4-pyrimidinediamine
[1004] 1H?NMR(DMSO-d 6)：δ9.59(s，1H)，8.31(s，1H)，8.22-8.21(d，J＝3.3Hz，1H)，8.10(s，1H)，8.00-7.97(dd，J＝8.1Hz，1H)，7.96-7.89(d，J＝8.1Hz，1H)，7.81-7.78(d，J＝8.1Hz，1H)，7.71-7.65(t，1H)，7.48-7.43(t，1H)，7.25(s，2H)，7.19-7.16(d，J＝8.4Hz，1H)，7.09(s，1H)，2.54(s，3H)，LCMS：425.87(MH +)。
III-13:N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-[4-(2-cyano ethyl) phenyl]-5-fluoro-2, the 4-pyrimidinediamine
[1005] 1H?NMR(DMSO-d 6)：δ10.52(s，1H)，8.25-8.24(d，J＝2.7Hz，1H)，8.10-8.09(d，J＝3.9Hz，1H)，8.03-7.99(dd，J＝8.7Hz，1H)，7.75-7.73(d，J＝8.4Hz，2H)，7.40-7.37(d，J＝8.7Hz，1H)，7.26-7.23(d，J＝8.4Hz，2H)，2.85-2.78(m，4H)，LCMS：447.45(MH +)。
III-11:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(4-cyano group ethylidene phenyl)-5-methyl-2, the 4-pyrimidinediamine
[1006] 1H?NMR(DMSO-d 6)：δ9.17(s，1H)，8.22(s，1H)，8.07-8.07(d，J＝2.1Hz，1H)，7.96-7.92(dd，J＝8.4Hz，1H)，7.86(s，1H)，7.69-7.66(d，J＝8.4Hz，2H)，7.23-7.20(d，J＝8.7Hz，2H)，7.16-7.11(m，2H)，2.85-2.80(m，4H)，2.10(s，3H)，LCMS：424.01(MH +)。
III-12:N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-[4-(2-cyano ethyl) phenyl]-5-methyl-2, the 4-pyrimidinediamine
[1007] 1H?NMR(DMSO-d 6)：δ9.45(s，1H)，9.41(s，1H)，8.30-8.25(m，2H)，8.09-8.05(d，J＝8.7Hz，1H)，7.88(s，1H)，7.67-7.64(d，J＝8.4Hz，2H)，7.42(s，2H)，7.37-7.34(d，J＝8.7Hz，2H)，7.25-7.22(d，J＝8.4Hz，2H)，2.88-2.79(m，4H)，2.11(s，3H)，LCMS：443.51(MH+)。
VI-103:N4-[4 (2-cyano ethyl)-3-aminomethyl phenyl]-5-fluoro-N2-(4-methyl-3-propionyl amino-sulfonyl phenyl)-2, the 4-pyrimidinediamine
[1008] 1H?NMR(DMSO-d 6)：
Figure A20068002053302901
9.40(s，1H)，9.23(s，1H)，8.10-8.03(m，2H)，8.00-7.69(d，J＝8.4Hz，1H)，7.62-7.59(d，J＝8.1Hz，1H)，7.56(s，1H)，7.17-7.12(t，2H)，6.66-6.64(d，J＝5.1Hz，2H)，2.85-2.83(m，2H)，2.78-2.75(m，2H)，2.45(s，3H)，2.27(s，3H)，2.16-2.11(q，2H)，0.90-0.85(t，3H)，LCMS：497.50(MH +)。
VI-104:N4-[4-(2-cyano ethyl)-3-aminomethyl phenyl]-5-fluoro-N2-(4-methyl-3-propionyl amino-sulfonyl phenyl)-2,4-pyrimidinediamine sodium salt
[1009] 1H?NMR(DMSO-d 6)：
Figure A20068002053302902
9.18(s，1H)，9.15(s，1H)，8.03-8.02(d，J＝3.6Hz，1H)，7.81(s，1H)，7.78(s，1H)，7.64-7.62(d.J＝8.1Hz，1H)，7.60(s，1H)，7.16-7.13(d，J＝8.4Hz，1H)，6.96-6.93(d，J＝7.8Hz，1H)，2.85-2.83(m，2H)，2.78-2.76(m，2H)，2.41(s，1H)，2.28(s，1H)，1.94-1.87(q，2H)，0.87-0.82(t，3H)，LCMS：497.44(MH +)。
V11-39:5-amino-N2-(3-amino-sulfonyl phenyl)-N4-(2, and 2-dimethyl-3-oxo-4H-benzo [1,4] oxazine-6-yl)-2, the 4-pyrimidinediamine
[1010] 1H NMR (DMSO-d 6): δ 10.55 (s, 1H), 8.86 (s, 1H), 8.21 (s, 1H), 8.07 (s, 1H), 7.95 (d, 1H, J=8.0Hz), 7.61 (d, 1H, J=1.3Hz), 7.39 (dd, 1H, J=1.3 and 8.8Hz), 7.30-7.21 (m, 5H), 6.87 (d, 1H, J=8.8Hz), 1.39 (s, 6H).LCMS: retention time: 3.51 minutes. Purity: 99%; MS (m/e): 456 (MH +).
VII-22:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[1-(3-methoxy-propyl) indazole quinoline-5-yl]-2, the 4-pyrimidinediamine
[1011] 1H?NMR(DMSO-d 6)：δ9.48(s，1H)，9.41(s，1H)，8.20(s，1H)，8.10(d，1H，J＝3.8Hz)，8.05(s，1H)，7.99(s，1H)，7.99-7.96(m，1H)，7.64(d，1H，J＝9.1Hz)，7.58(d，1H，J＝9.1Hz)，7.31-7.25(app?m，4H)，4.42(t，2H，J＝6.7Hz)，3.32(s，3H)，3.23(t，2H，J＝6.7Hz)，2.04(qt，2H，J＝6.7Hz)。LCMS: retention time: 4.59 minutes. Purity: 99%; MS (m/e): 472 (MH +).
VII-23:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[1-(2-methoxy ethyl) indazole quinoline-5-yl]-2, the 4-pyrimidinediamine
[1012] 1H?NMR(DMSO-d 6)：δ9.47(s，1H)，9.40(s，1H)，8.16(s，1H)，8.10(d，1H，J＝3.5Hz)，8.05(s，1H)，7.99-7.95(m，2H)，7.65(d，1H，J＝9.8Hz)，7.60(d，1H，J＝8.8Hz)，7.33-7.25(m，4H)，4.54(t，2H，J＝5.3Hz)，3.75(t，2H，J＝5.3Hz)，s，3H)，3.30(s，3H)。LCMS: retention time: 4.31 minutes. Purity: 99%; MS (m/e): 458 (MH +).
I-1:N2-(4-amino-sulfonyl phenyl)-N4-(3-cyano group methoxyl group-4,5-Dimethoxyphenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1013] 1H NMR (DMSO-d 6): δ 8.16 (d, 1H, J=2.2Hz), 7.77 (d, 2H, J=8.3Hz), 7.60 (d, 2H, J=8.3Hz), 7.24 (m, 1H), 7.15 (m, 1H), 5.10 (s, 2H), 3.82 (s, 3H), 3.66 (s, 3H); LCMS: purity 90%; MS (m/e): 475 (MH +).
I-2:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3-cyano group methoxyl group-4,5-Dimethoxyphenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1014] 1H NMR (DMSO-d 6): δ 8.10 (m, 2H), 7.89 (dd, 1H, J=2.1 and J=5.6Hz), 7.25 (m, 1H), 7.15 (m, 2H), 5.12 (s, 2H), 3.74 (s, 3H), 3.68 (s, 3H), 2.48 (s, 3H); LCMS: purity 99%; MS (m/e): 489 (MH +).
V-4: racemize N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[2-methyl-3-oxo-4-(4-methoxy-benzyl)-benzo [1,4] oxazine-6-yl]-2, the 4-pyrimidinediamine
[1015] purity 90%; MS (m/e): 565 (MH +).
V-5: racemize N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[2-methyl-3-oxo-4-(4-methoxy-benzyl)-benzo [1,4] oxazine-6-yl]-2, the 4-pyrimidinediamine
[1016] purity 90%; MS (m/e): 565 (MH +).
V-6:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-(3-oxo-4-cyano methyl-benzo [1,4] oxazine-6-yl]-2,4-pyrimidinediamine
[1017] 1H NMR (DMSO-d 6): δ 8.20 (d, 1H, J=3.9Hz), 7.74 (d, 2H, J=8.4Hz), 7.63 (d, 2H, J=8.4Hz), 7.53 (m, 2H), 7.07 (m, 1H), 5.00 (s, 2H), 4.77 (s, 2H); Purity 92%; MS (m/e): 470 (MH +).
V-7:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(3-oxo-4-cyano methyl-benzo [1,4] oxazine-6-yl]-2,4-pyrimidinediamine
[1018] 1H NMR (DMSO-d 6): δ 8.18 (d, 1H, J=3.3Hz), 8.05 (s, 1H), 7.82 (s, 1H), 7.54 (m, 2H), 7.38 (m, 2H), 4.99 (s, 2H), 4.76 (s, 2H); Purity 90%; MS (m/e): 470 (MH +).
VII-11:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(2,2,4-trimethylammonium-1,1,3-trioxy--benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine
[1019] 1H NMR (DMSO-d 6): δ 8.28 (d, 1H, 3.3Hz), 8.13 (s, 1H), 7.98 (m, 4H), 7.89 (m, 1H), 7.80 (m, 1H), 7.77 (m, 1H), 7.40 (m, 2H), 3.34 (s, 3H), 1.43 (s, 6H); Purity 91%; MS (m/e): 521 (MH +).
VII-12:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-(2,2,4-trimethylammonium-1,1,3-trioxy--benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine
[1020] purity 90%; MS (m/e): 521 (MH +).
V-11:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-(3-oxo-4-cyano methyl-benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine
[1021] 1H NMR (DMSO-d 6): δ 8.21 (d, 1H, J=3.2Hz), 7.80 (m, 3H), 7.64 (m, 2H), 7.42 (m, 1H), 7.13 (s, 1H), 5.00 (s, 2H), 3.66 (s, 2H); Purity 93%; MS (m/e): 486 (MH +).
V-12:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(3-oxo-4-cyano methyl-benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine
[1022] 1H NMR (DMSO-d 6): δ 8.18 (d, 1H, J=3.4Hz), 8.14 (s, 1H), 7.88 (m, 1H), 7.80 (m, 1H), 7.38 (m, 3H) 7.27 (s, 1H), 4.99 (s, 2H), 3.65 (s, 2H); Purity 93%; MS (m/e): 486 (MH +).
V-8:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-oxo-4-cyano methyl-benzo [1,4] oxazine-6-yl]-2, the 4-pyrimidinediamine
[1023] 1H NMR (DMSO-d 6): δ 8.11 (m, 2H), 7.80 (m, 1H), 7.61 (m, 2H), 7.18 (s, 1H), 7.02 (d, 1H, J=8.4Hz), 5.00 (s, 2H), 4.75 (s, 2H), 3.54 (s, 3H); Purity 95%; MS (m/e): 484 (MH +).
V-13:N2-(3-amino-sulfonyl 4-aminomethyl phenyl)-5-fluoro-N4-(3-oxo-4-cyano methyl-benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine
[1024] 1H NMR (DMSO-d 6): δ 8.17 (d, 1H, J=3.4Hz), 8.11 (s, 1H), 7.64 (m, 2H), 7.27 (m, 1H), 7.19 (m, 2H), 4.96 (s, 2H), 4.75 (s, 2H), 3.65 (s, 3H); Purity 95%; MS (m/e): 500 (MH +).
VII-46:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-(2,2,4-trimethylammonium-1,1,3-trioxy--benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine
[1025] purity 90%; MS (m/e): 514 (MH +).
VII-47:N2-(4-amino-sulfonyl phenyl)-N4-cyano methyl-5-fluoro-N4-[3-oxo-4-methyl-benzo [1,4] thiazine-6-yl]-2, the 4-pyrimidinediamine
[1026] 1H NMR (DMSO-d 6): δ 8.21 (d, 1H, J=4.8Hz), 7.88 (d, 2H, J=8.7Hz), 7.69 (d, 2H, J=8.7Hz), 7.46 (d, 1H, J=7.2Hz), 7.33 (bs, 1H), 7.04 (m, 1H), 5.00 (s, 2H), 3.56 (s, 2H), 3.31 (s, 3H); Purity 99%; MS (m/e): 500 (MH +).
V-9:(R/S)-and N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[2-methyl-3-oxo-4-(4-methoxy-benzyl)-benzo [1,4] thiazine-6-yl]-2, the 4-pyrimidinediamine
[1027] 1H NMR (DMSO-d 6): δ 8.10 (d, 1H, J=2.2Hz), 7.82 (m, 1H), 7.63 (m, 2H), 7.16 (m, 3H), 7.04 (d, 2H, J=8.1Hz), 6.78 (d, 2H, J=8.1Hz), 5.00 (m, 2H), 3.76 (q, 1H, J=6.6Hz), 3.63 (s, 3H), 3.34 (s, 3H), 1.36 (d, 3H, J=6.6Hz); Purity 90%; MS (m/e): 595 (MH +).
V-10:(R/S)-and N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[2-methyl-3-oxo-4-(4-methoxy-benzyl)-benzo [1,4] thiazine-6-yl]-2, the 4-pyrimidinediamine
[1028] 1H NMR (DMSO-d 6): δ 8.15 (d, 1H, J=3.6Hz), 7.78 (d, 2H, J=8.4Hz), 7.65 (m, 2H), 7.52 (bs, 1H), 7.34 (d, 1H, J=8.4Hz), 7.13 (s, 1H), 7.07 (d, 2H, J=8.4Hz), 6.79 (d, 2H, J=8.4Hz), 5.06 (s, 2H), 3.79 (q, 1H, J=6.9Hz), 3.64 (s, 3H), 1.38 (d, 3H, J=6.9Hz); Purity 99%; MS (m/e): 581 (MH +).
V-2:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-oxo-4-(2-pyridylmethyl)-benzo [1,4] oxazine-6-yl]-2, the 4-pyrimidinediamine
[1029] purity 90%; MS (m/e): 536 (MH +).
V-3:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-oxo-4-(2-pyridylmethyl)-benzo [1,4] oxazine-6-yl]-2, the 4-pyrimidinediamine
[1030] purity 90%; MS (m/e): 522 (MH +).
VII-36:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(3-oxo-4-cyano methyl-benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine
[1031](LCMS(m/z)：445(MH +)。
VII-44:N2-(3-amino-sulfonyl-4-methyl-phenyl)-5-fluoro-N4-(3-oxo-4H-benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine
[1032]LCMS(m/z)：461(MH +)。
VII-45:N2-(3-amino-sulfonyl-4-methyl-phenyl)-5-fluoro-N4-(3-oxo-4H-benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine
[1033]LCMS(m/z)：475(MH +)。
I-268:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-(4-[3-methyl isophthalic acid, 2,4-oxadiazole-5-yl] methylene radical oxygen base phenyl)-2, the 4-pyrimidinediamine
[1034] 1H NMR (DMSO-d 6): d 9.58 (s, 1H), 9.37 (s, 1H), 7.79 (d, 2H, J=8.7Hz), 7.86 (d, 2H, J=8.7Hz), 7.62 (d, 2H, J=8.7Hz), 7.12 (s, 2H), 7.03 (d, 2H, J=8.7Hz), 5.47 (s, 2H), 2.36 (s, 3H); LCMS: purity: 100%; MS (m/e): 472.4 (MH+).
I-271:N2-(5-N, N-diethylamino alkylsulfonyl-2-p-methoxy-phenyl)-5-fluoro-N4-(4-[3-methyl isophthalic acid, 2,4-oxadiazole-5-yl] methylene radical oxygen base phenyl)-2, the 4-pyrimidinediamine
[1035] LCMS: purity: 91.7%; MS (m/e): 558.5 (MH+).
I-272:5-fluoro-N4-(4-[3-methyl isophthalic acid, 2,4-oxadiazole-5-yl] methylene radical oxygen base phenyl)-N2-(5-piperdine sulfonyl phenyl)-2, the 4-pyrimidinediamine
[1036] LCMS: purity: 100%; MS (m/e): 558.5 (MH+).
VII-48:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-(4-methyl-3-oxo-benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine
[1037] LCMS: purity: 96.5%; MS (m/e): 461.4 (MH+).
VII-49:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(4-methyl-3-oxo-benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine
[1038] LCMS: purity: 97.4%; MS (m/e): 461.4 (MH+).
VII-40:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-(4-methyl-3-oxo-benzo [1,4] oxazine-6-yl)-2, the 4-pyrimidinediamine
[1039] LCMS: purity: 97.1%; MS (m/e): 445.1 (MH+).
VII-41:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(4-methyl-3-oxo-benzo [1,4] oxazine-6-yl)-2, the 4-pyrimidinediamine
[1040] LCMS: purity: 97.1%; MS (m/e): 445.1 (MH+).
VII-50:5-fluoro-N4-(4-methyl-3-oxo-benzo [1,4] thiazine-6-yl)-N2-(3-piperidino-(1-position only) alkylsulfonyl phenyl)-2, the 4-pyrimidinediamine
[1041] LCMS: purity: 100%; MS (m/e): 529.4 (MH+).
VII-54:N2-(3-amino-sulfonyl phenyl)-N4-(2-aminocarboxyl cumarone-5-yl)-5-fluoro-2, the 4-pyrimidinediamine
[1042] LCMS: purity: 84.5%; MS (m/e): 443.4 (MH+).
IX-5:N2-(3-amino-sulfonyl phenyl)-N4-(1-cyano group methylene radical indoles-5-yl)-5-fluoro-2, the 4-pyrimidinediamine
[1043] LCMS: purity: 92.6%; MS (m/e): 438.3 (MH+).
VII-59:N2-(4-amino-sulfonyl phenyl)-N4-(4-N-tert-butoxycarbonyl amino-3,4-dihydro-2H-1-chromene-6-yl)-5-fluoro-2, the 4-pyrimidinediamine
[1044] LCMS: purity: 97.7%; MS (m/e): 473.4 (MH+).
IX-6:N2-(4-amino-sulfonyl phenyl)-N4-(1-cyano group methylene radical indoles-5-yl)-5-fluoro-2, the 4-pyrimidinediamine
[1045] LCMS: purity: 100%; MS (m/e): 438.4 (MH+).
IX-7:N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(1-cyano group methylene radical indoles-5-yl)-5-fluoro-2, the 4-pyrimidinediamine
[1046] LCMS: purity: 100%; MS (m/e): 452.4 (MH+).
IX-8:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(1-cyano group methylene radical indoles-5-yl)-5-fluoro-2, the 4-pyrimidinediamine
[1047] LCMS: purity: 100%; MS (m/e): 472.4 (MH+).
Embodiment 36
Figure A20068002053302941
V-18:N-2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[2,2-dimethyl-3-oxo-4H-pyrido [1,4] oxazine-7-yl]-5-fluoro-2,4-pyrimidinediamine
[1048] with the N4-[2 among the MeOH (2mL), 2-dimethyl-3-oxo-4H-pyrido [1,4] oxazine-7-yl]-2-chloro-5-fluoro-4-PYRIMITHAMINE (40mg, 0.123mmol), 4-methyl-amino-benzene-3-sulphonamide (25.5mg, 0.148mmol) and the heterogeneous mixture of trifluoroacetic acid (50 μ L) the sealing reaction tube in 100 ℃ the heating 24 hours.The gained reaction mixture is used 1-3%2N NH by purification by silica gel column chromatography 3The CH of/MeOH 2Cl 2Eluant solution is to provide 20.0 milligrams (34%) required N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[2,2-dimethyl-3-oxo-4H-pyrido [1,4] oxazine-7-yl]-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d 6): δ 11.08 (s, 1H), 9.46 (s, 1H), 8.12 (d, 1H, J=3.6Hz), 8.07 (d, 1H, J=2.1Hz), 7.88 (m, 1H), 7.64 (d, 1H, J=8.4Hz), 7.38 (d, 1H, J=10.2Hz), 7.24 (s, 2H), 7.16 (d, 1H, J=8.1Hz), 2.49 (s, 3H), 1.43 (s, 6H): LCMS: purity: 97%; MS (m/e): 475 (MH +).
Embodiment 37
VII-30:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-methyl-N4-(3-oxo-benzo [1,4] oxazine-6-yl)-2, the 4-pyrimidinediamine
[1049] with 250 milligrams of 6-amino-3-oxo-4H-benzo [1,4] oxazine and 460 milligram 2, mixture stirred overnight at room temperature in 15mL methyl alcohol of 4-two chloro-5-methylpyrimidines reduces solvent volume by rotary evaporation.Solution is filtered, and filtrate water dilutes and neutralizes with sodium bicarbonate.Precipitation is collected by suction filtration, wash with water and on funnel dry with produce 75 milligrams of (20%) required product 2-chloro-5-methyl-N4-oxo-benzos [1,4] oxazine-6-yl)-the 4-PYRIMITHAMINE. 1H NMR (DMSO-d 6): δ 7.98 (s, 1H), 7.08 (m, 2H), 6.91 (d, 1H J=6Hz), 4.54 (s, 2H), 2.11 (s, 3H) purity 97%; MS (m/e) 291 (MH +).
[1050] with 2-chloro-5-methyl-N4-oxo-benzo [1,4] oxazine-6-yl)-4-PYRIMITHAMINE (25mg), 3-amino-sulfonyl-4-monomethylaniline (40mg) and iPrOH: TFA (4: 1; V/v) heterogeneous mixture heated in tube sealing 24 hours.Gained reaction mixture dilute with water leaches with 2N HCl acidifying and with the gained solid.Solid is added methyl alcohol: water, with sodium bicarbonate aqueous solution neutralization and by filtering separation gained solid to obtain N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-methyl-N4-(3-oxo-benzo [1,4] oxazine-6-yl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d 6): δ 7.86 (s, 1H), 7.80 (s, 1H), 7.77 (m, 1H), 7.31 (bs, 2H), 7.12 (m, 2H), 6.95 (m, 1H), 4.58 (s, 2H), 2.11 (s, 3H); Purity 99%; MS (m/e): 441 (MH +).
Embodiment 38
Figure A20068002053302961
III-27:N2-(4-amino-sulfonyl phenyl)-N4-(4-cyano group ethylidene phenyl)-5-methyl-2,4-pyrimidinediamine and prodrug thereof
Under [1051] 0 ℃ of nitrogen, at toluene solution (1mol L-1,40mL, 40mmol) the middle mixture that adds toluene (20mL) and tetrahydrofuran (THF) (20ml) of triphenylphosphine.Dropwise add then iodomethyl cyanide (2.8mL, 38.7mmol) and vigorous stirring.Remove ice bath and with mixture stirring at room 40 hours again.Mixture is filtered, solid with toluene wash and from the acetonitrile recrystallization to obtain (cyano methyl) trimethylammonium iodate phosphorus of 8 gram white solid.LCMS：243.03(M +)。
[1052] (2.5g, (1g is 6.53mmol) with (cyano methyl) trimethylammonium iodate phosphorus (4g, mixture 16.32mmol) 19.58mmol) to add 4-oil of mirbane methyl alcohol with propionitrile (32mL), diisopropyl ethyl amine.Mixture was heated 24 hours at 97 ℃.In mixture, add entry (1mL) and dense HCl (5mL).(3 * 100mL) extract product with ethyl acetate.Dried over sodium sulfate is used in organic layer salt water washing, concentrates to obtain dark brown solid.Crude product is by hurried column chromatography (ethyl acetate: 3-(4-nitrophenyl) propionitrile of purifying to obtain 740 milligrams of light orange solid state hexane 1: 1). 1H?NMR(DMSO-d 6)：δ8.20-8.17(dd，J＝8.7Hz，2H)，7.59-7.56(d，J＝9.0Hz，2H)，3.06-3.01(m，2H)。
[1053] (740mg 4.2mmol) is dissolved in methyl alcohol (100mL), adds 10%Pd/C and mixture is descended room temperature vibration 30 minutes at hydrogen (50psi) with 3-(4-nitrophenyl) propionitrile.Mixture is used the 20mL methanol wash by diatomite filtration.Obtaining thick material, this material is by hurried column chromatography (ethyl acetate: hexane 1: 1) be further purified 3-(4-aminophenyl) propionitrile to produce 520 milligrams of faint yellow oilies with the organic solvent concentrating under reduced pressure that merges. 1H?NMR(DMSO-d 6)：δ6.91-6.88(d，J＝9.0Hz，2H)，6.49-6.46(d，J＝9.0Hz，2H)，4.92(s，2H)，2.66(s，4H)。
[1054] with 3-(4-aminophenyl) propionitrile (152mg 1.0mmol) is dissolved in Virahol (2mL), adds 2 in solution, 4-two chloro-5-methylpyrimidines (300mg, 1.8mmol).Mixture was stirred 48 hours.All solvents are removed in decompression, add saturated sodium bicarbonate, the water layer ethyl acetate extraction.The acetic acid ethyl ester extract dried over sodium sulfate is filtered, and concentrating under reduced pressure is to obtain crude product.Should thick material by column chromatography (ethyl acetate: hexane, 1: 1-3: 1) be further purified 2-chloro-N4-(4-cyano group ethylidene phenyl)-5-methyl-4-PYRIMITHAMINE to obtain 70 milligrams of colorless oil.wH?NMR(DMSO-d 6)：δ8.80(s，1H)，8.00(s，1H)，7.55-7.52(d，J8.Hz，2H)，7.271-7.244(d，J＝8.1Hz，2H)，2.85-2.80(m，4H)，2.15(s，3H)；LCMS：275.28(MH +)。
[1055] (70mg 0.25mmol) is dissolved in Virahol (2mL) with 2-chloro-N4-(4-cyano group ethylidene phenyl)-5-methyl-4-PYRIMITHAMINE.(70mg, 0.4mmol), mixture was 100 ℃ of heating 48 hours to add trifluoroacetic acid (2) and 4-amino-sulfonyl aniline in solution.Removal of solvent under reduced pressure adds saturated sodium bicarbonate solution and uses ethyl acetate extraction.The organic layer dried over sodium sulfate is filtered and is concentrated to obtain crude product.Crude product is respectively with methylene dichloride and ultrasonic N2-(4-amino-sulfonyl phenyl)-N4-(4-cyano group ethylidene the phenyl)-5-methyl-2 to obtain 120 milligrams of Off-white solid shapes of acetone, 4-pyrimidinediamine. 1H?NMR(DMSO-d 6)：δ8.39(s，1H)，8.35(s，1H)，8.10(s，1H)，7.91(s，1H)，7.81-7.78(d，J＝8.7Hz，2H)，7.63-7.60(d，J＝8.4Hz，2H)，7.57-7.55(d，J＝8.7Hz，2H)，7.26-7.23(d，J＝8.4Hz，2H)，7.07(s，2H)，2.88-2.81(m，4H)，2.11(s，3H)；LCMS：409.01(MH +)。
[1056] at N2-(4-amino-sulfonyl phenyl)-N4-(4-cyano group ethylidene phenyl)-5-methyl-2; 4-pyrimidinediamine (70mg, 0.17mmol) middle THF (2mL), DMAP (10mg, 0.5 equivalent), the triethylamine (0.028mL of adding; 1.2 equivalent) and propionic anhydride (0.024mL, 1.1 equivalents).With the mixture shaken overnight, all solvents are removed in decompression.The resistates dichloromethane extraction, organic layer washes with water, drying, and prodrug N4-(4-cyano group ethylidene the phenyl)-5-methyl-N2-(4-propionyl amino-sulfonyl phenyl)-2 of concentrating under reduced pressure to obtain 20mg Off-white solid shape, 4-pyrimidinediamine. 1H?NMR(DMSO-d 6)：δ11.79(s，1H)，9.55(s，1H)，8.39(s，1H)，7.92(s，1H)，7.84-7.81(d，J＝7.8Hz，2H)，7.65-7.62(d，J＝8.7Hz，2H)，7.61-7.59(d，J＝7.5Hz，2H)，7.27-7.24(d，J＝7.5Hz，2H)，2.86-2.82(m，4H)，2.21-2.13(q，2H)，2.12(s，3H)，0.90-0.85(t，2H)；LCMS：465.02(MH +)。
[1057] with N4-(4-cyano group ethylidene phenyl)-5-methyl-N2-(4-propionyl amino-sulfonyl phenyl)-2, (20mg 0.04mmol) is dissolved in acetonitrile and water to the 4-pyrimidinediamine, dropwise adds 1N NaOH.With solution freeze-drying 48 hours sodium salt with the prodrug III-27 that obtains the faint yellow solid shape. 1H?NMR(DMSO-d 6)：δ9.07(s，1H)，8.24(s，1H)，7.87(s，1H)，7.65-7.63(d，J＝6.6Hz，2H)，7.60-7.57(d，J＝7.2Hz，2H)，7.50-7.48(d，J＝7.2Hz，2H)，7.24-7.22(d，J＝6.9Hz，2H)，2.87-2.81(m，4H)，2.10(s，3H)，1.89-1.86(q，2H)，0.87-0.82(t，3H)；LCMS：465.02(MH +)。
Embodiment 39
I-179:N2-(3-amino-sulfonyl phenyl)-5-methyl-N4-[4-(2-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[1058] in the exsiccant reaction flask, add the 4-nitrophenols (3.858g, 27.75mmol), anhydrous K 2CO 3(8.29g, 60mmol) and acetone (250mL).In this uneven mixture, add 2-pyridylmethyl bromine hydrobromide (7.0g, 27.75mmol) and refluxed 24 hours.200mL acetone is removed in decompression from the gained reaction mixture.The gained resistates is used frozen water (1 liter) dilution then, and the solid of separating out is leached, wash with water and thorough drying to obtain the 2-[(4-nitro-phenoxy) methyl] pyridine (6.05g, 95% productive rate). 1H?NMR(CDCl 3)：δ8.61(d，1H，J＝4.8Hz)，8.19(d，2H，J＝9.0Hz)，7.72(m，2H)，7.46(d，1H，J＝7.8Hz)，7.25(m，1H)，7.05(d，2H，J＝9.3Hz)，5.28(s，2H)；LCMS(m/z)：231(MH +)。
[1059] with the 2-[(4-nitro-phenoxy) methyl] (2.30g 10mmol) is dissolved in ethanol (160mL) and water (40mL) to pyridine.In said mixture, add NH 4Cl (5.30g) also is heated to 70-80 ℃.Vigorous stirring limit in limit adds iron powder (5.50g) in batches in this reaction mixture, continues to stir 2 hours.Reaction mixture is washed filter bed by the Celite pad filtered while hot and with MeOH.Filtrate is concentrated, and dilute with water is used CH 2Cl 2(3 * 75mL) extractions, dry and concentrated) methyl so that the 2-[(4-amino-benzene oxygen of brown solid shape to be provided] pyridine (1.735g), its productive rate is 86%. 1H?NMR(CDCl 3)：δ8.56(m，1H)，7.67(m，1H)，7.49(d，1H，J＝7.8Hz)，7.18(m，1H)，6.80(d，2H，J＝8.7Hz)，6.62(d，2H，J＝8.7Hz)，5.12(s，2H)，3.43(br?s，2H)；LCMS(m/z)：201(MH +)。
[1060] with the 2-[(4-amino-benzene oxygen) methyl] pyridine (0.794g, 3.97mmol) and 2.4-two chloro-5-picolines (0.65g, mixture 3.97mmol) stirring at room 48 hours in the mixture of methyl alcohol (49mL) and water (16mL).The reaction mixture concentrating under reduced pressure to remove MeOH (30mL), is used frozen water (200mL) dilution then.The gained mixture was left standstill 1 hour, isolated solid is leached, wash with water also dry so that 2-chloro-5-methyl-N-[4-(2-pyridyl) methylene radical oxygen base phenyl to be provided]-4-PYRIMITHAMINE (1.21g, 93% productive rate). 1H NMR (DMSO-d 6): δ 8.60 (s, 1H), 8.56 (d, 1H, J=4.8Hz), 7.94 (d, 1H, J=0.9Hz), 7.81 (m, 1H), 7.52 (s, 1H), 7.48 (d, 2H, J=9.3Hz), 7.31 (dd, 1H, J=4.8 and 7.5Hz), 7.02 (d, 2H, J=9.0Hz), 5.17 (s, 2H), 2.14 (s, 3H); LCMS (m/z): 327 (MH +).
[1061] with 2-chloro-5-methyl-N-[4-(2-pyridyl) methylene radical oxygen base phenyl]-4-PYRIMITHAMINE (1.21g) is dissolved in MeOH (65mL), dropwise add 4N HCl and (be dissolved in diox, 2.12mL), stirring at room 1 hour, removal of solvent under reduced pressure is also finally dry so that provide hydrochloride with quantitative yield under high vacuum, and this material can be directly used in following step.
[1062] make 2-chloro-5-methyl-N-[4-(2-pyridyl) methylene radical oxygen base phenyl]-4-PYRIMITHAMINE hydrochloride (54mg, 0.149mmol), the 3-aminobenzene sulfonamide (25.6mg, 0.149mmol) and the mixture of i-PrOH (2mL) the sealing reaction tube in 100 ℃ the reaction 24 hours.[silicagel column is used CH to product by column chromatography 2Cl 2: 2M NH 3MeOH solution (4-5%)] purifying to be to provide N2-(3-amino-sulfonyl phenyl)-5-methyl-N4-[4-(2-pyridyl) methylene radical oxygen base phenyl]-2,4-pyrimidinediamine (I-179; 55.4mg), its productive rate is 80%. 1H NMR (DMSO-d 6): δ 9.23 (s, 1H), 8.57 (d, 1H, J=4.5Hz), 8.21 (s, 1H), 8.00 (m, 2H), 7.84 (s, 1H), 7.81 (dd, 1H, J=1.8 and 7.8Hz), 7.58 (d, 2H, J=8.7Hz), 7.52 (d, 1H, J=8.1Hz), 7.33 (dd, 1H, J=5.1 and 6.9Hz), 7.22 (m, 4H), 6.98 (d, 2H, J=8.7Hz), 5.17 (s, 2H), 2.08 (s, 3H); LCMS (m/z): 463 (MH +).
[1063] following compound is according to preparing with the similar mode of I-179.
I-180:5-methyl-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-[4-(2-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[1064] 1H?NMR(DMSO-d 6)：δ9.12(s，1H)，8.56(d，1H，J＝3.6Hz)，8.17(s，1H)，7.97(m，2H)，7.82(m，2H)，7.59(d，2H，J＝8.7Hz)，7.51(d，1H，J＝7.8Hz)，7.31(m，2H)，7.09(d，1H，J＝9.0Hz)，6.98(d，2H，J＝9.0Hz)，5.17(s，2H)，2.43(s，3H)，2.41(d，3H，J＝4.8Hz)，2.08(s，3H)；LCMS(m/z)：491(MH +)。
I-181:N2-(4-amino-sulfonyl phenyl)-5-methyl-N4-[4-(2-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine:
[1065] 1H NMR (DMSO-d 6): δ 9.35 (s, 1H), 8.57 (d, 1H, J=4.5Hz), 8.30 (s, 1H), 7.86-7.76 (m, 4H), 7.53 (m, 5H), 7.33 (dd, 1H, J=4.8 and 6.7Hz), 7.09 (s, 2H), 7.02 (d, 2H, J=8.7Hz), 5.18 (s, 2H), 2.09 (s, 3H); LCMS (m/z): 463 (MH +).
Embodiment 40
Figure A20068002053303001
VI-53:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(Propargyl oxygen base) phenyl]-2,4-pyrimidinediamine and prodrug thereof
[1066] with the 4-nitrophenols (1.00g, 7.19mmol), (80wt% is dissolved in toluene to propargyl bromide; 0.788mL, 7.09mmol) and K 2CO 3(1.08g 7.84mmol) stirred 18 hours in 60 ℃ in acetone (16.0mL).Reaction mixture is cooled to room temperature and water (200mL) dilution.Isolate 4-(the Propargyl oxygen base) oil of mirbane (1.12g) of white solid by suction filtration. 1H?NMR(CDCl 3)：δ8.22(d，J＝9.0Hz，2H)，7.05(d，J＝9.0Hz，2H)，4.80(d，J＝2.4Hz，2H)，2.59(t，J＝2.4Hz，1H)。
[1067] with 4-(Propargyl oxygen base) oil of mirbane (0.910g, 5.13mmol), iron (1.42g, 25.3mmol) and NH 4Cl (0.719g, 12.8mmol) EtOH/ water (1: 1,55mL) in 70 ℃ of vigorous stirring 15 minutes.Reaction mixture is passed through diatomite heat filtering and vacuum concentration.Resistates is suspended in the dichloromethane solution of 10%2N ammonia methyl alcohol, ultrasonic, and pass through diatomite filtration.Concentrate and obtain brown buttery 4-(Propargyl oxygen base) aniline, this material need not to be further purified just and can use.Usually, isolating Propargyl oxygen base aniline is unsettled, therefore need use immediately after filtering for the second time. 1H?NMR(CDCl 3)：δ6.82(d，J＝8.7Hz，2H)，6.64(d，J＝8.7Hz，2H)，4.61(d，J＝2.4Hz，2H)，2.50(t，J＝2.4Hz，1H)。
[1068] (0.750g, 5.10mmol) with 2, (1.27g, 0.760mmol) (4: 1,35mL) middle stirring at room was 18 hours at MeOH/ water for 4-two chloro-5-fluorine pyrimidines with rough 4-(Propargyl oxygen base) aniline.Reaction mixture washs with EtOAc (200mL) dilution and with 1N HCl (50mL) and salt solution (50mL).With organic layer drying (MgSO 4), filter and vacuum concentration.Resistates by column chromatography (silica gel, hexane are to EtOAc: hexane (1: 10)) purifying is to provide 2-chloro-5-fluoro-N4-[4-(the Propargyl oxygen base) phenyl of light brown solid state]-4-PYRIMITHAMINE (0.514g). 1H NMR (CDCl 3): δ 8.03 (d, J=2.7Hz, 1H), 7.53 (d, J=8.7Hz, 2H), 7.02 (d, J=8.7Hz, 2H), 6.86 (s, 1H), 4.71 (d, J=2.4Hz, 2H), 2.55 (t, J=2.4Hz, 1H); LCMS: purity: 99%; MS (m/e): 279 (MH +).
[1069] with 2-chloro-5-fluoro-N4-[4-(Propargyl oxygen base) phenyl]-4-PYRIMITHAMINE (0.514g; 1.85mmol), 3-(amino-sulfonyl)-4-monomethylaniline (0.689g; 3.70mmol) and trifluoroacetic acid (0.186mL 2.41mmol) mixes in tube sealing with iPrOH (6.0mL) and is incorporated in 100 ℃ of heating 3 hours.Reaction mixture is cooled to room temperature and uses 1N HCl (80mL) dilution.Isolate N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(the Propargyl oxygen base) phenyl of white solid by suction filtration]-2,4-pyrimidinediamine (VI-53) is (0.703g). 1H NMR (DMSO-d 6): δ 10.08 (bs, 2H), 8.19 (d, J=4.5Hz, 1H), 7.89 (s, 1H), 7.74 (dd, J=2.4 and 8.4Hz, 1H), 7.58 (d, J=8.7Hz, 2H), 7.32 (bs, 2H), 7.23 (d, J=8.4Hz, 1H), 6.97 (d, J=8.4Hz, 2H), 4.79 (d, J=2.1Hz, 2H), 3.59-3.55 (m, 1H), 2.53 (s, 3H); LCMS: purity: 97%; MS (m/e): 428 (MH +).
[1070] with N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(Propargyl oxygen base) phenyl]-2; 4-pyrimidinediamine (0.200g; 0.467mmol), (0.118mL 0.847mmol) stirs in THF (6.0mL) for DMAP (40mg, 0.33mmol)) and triethylamine.In solution, dropwise add propionic anhydride (0.180mL, 1.40mmol).With the reaction mixture stirred overnight at room temperature.Solution with ethyl acetate (50mL) dilution and water (5 * 25mL) and salt solution (10mL) wash.With organic layer drying (MgSO 4), filter and evaporation.Resistates is suspended in ethyl acetate (25mL), ultrasonic and prodrug 5-fluoro-N2-(4-methyl-3-propionyl amino-sulfonyl phenyl)-N4-[4-(the Propargyl oxygen base) phenyl of filtration to obtain VI-53]-2,4-pyrimidinediamine (VI-56; 0.20g). 1H NMR (DMSO-d 6): δ 12.01 (s, 1H), 9.44 (s, 1H), 9.26 (s, 1H), 8.16 (d, J=2.4Hz, 1H), 8.06 (dd, J=0.3 and 3.3Hz, 1H), 8.00 (dd, J=2.1 and 7.8Hz, 1H), 7.69 (d, J=8.7Hz, 2H), 7.19 (d, J=8.4Hz, 1H), 6.95 (d, J=8.7Hz, 2H), 4.77 (d, J=2.1Hz, 2H), 3.56 (t, J=2.1Hz, 1H), 2.49 (s, 3H), 2.24 (q, J=7.2Hz, 2H), 0.89 (t, J=7.2Hz, 3H); LCMS: purity: 98%; MS (m/e): 484 (MH +).
[1071] under ice bath cooling with 5-fluoro-N2-(4-methyl-3-propionyl amino-sulfonyl phenyl)-N4-[4-(Propargyl oxygen base) phenyl]-2, (0.125g 0.258mmol) is suspended in acetonitrile (1.5mL) and water (1.5mL) to the 4-pyrimidinediamine.Dropwise add the 1N NaOH aqueous solution (0.260mL).Stirred reaction mixture filters and the sodium salt (separately be expressed as VI-62) of freeze-drying to obtain prodrug VI-56 by glass wool up to its clarification that becomes. 1H NMR (DMSO-d 6): δ 9.17 (bs, 2H), 8.01 (d, J=3.6Hz, 1H), 7.89 (s, 1H), 7.78-7.69 (m, 3H), 6.99-6.92 (m, 3H), 4.76 (d, J=2.1Hz, 1H), 2.43 (s, 3H), 1.95 (q, J=7.2Hz, 2H), 0.86 (t, J=7.2Hz, 3H); LCMS: purity: 98%; MS (m/e): 484 (MH+).
[1072] following compound is according to preparing with embodiment 40 similar modes or by method described here or those of skill in the art's currently known methods.
VII-31:N2-(4-amino-sulfonyl phenyl)-5-methyl-N4-(3-oxo-benzo [1,4] oxazine-6-yl)-2, the 4-pyrimidinediamine
[1073] 1H NMR (DMSO-d 6): δ 7.93 (s, 1H), 7.60 (m, 4H), 7.24 (bs, 2H), 7.08 (m, 1H), 7.02 (m, 1H) 7.27 (s, 1H), 4.61 (s, 2H), 2.14 (s, 3H); Purity 99%; MS (m/e): 427 (MH +).
VII-33:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-methyl-N4-(4-methyl-3-oxo-benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine
[1074] 1H NMR (DMSO-d 6): δ 7.91 (s, 1H), 7.80 (s, 1H), 7.66 (m, 1H), 7.48 (s, 1H), 7.35 (m, 2H), 7.12 (m, 1H), 3.52 (s, 2H), 3.11 (s, 3H), 2.16 (s, 3H); Purity 95%; MS (m/e): 471 (MH +).
VII-34:N2-(4-amino-sulfonyl phenyl)-5-methyl-N4-(4-methyl-3-oxo-benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine
[1075] 1H NMR (DMSO-d 6) :): δ 7.96 (s, 1H), 7.64 (m, 4H), 7.46 (s, 1H), 7.40 (s, 2H), 7.18 (s, 2H), 3.53 (s, 2H), 3.26 (s, 3H), 2.16 (s, 3H); Purity 90%; MS (m/e): 457 (MH+).
VII-32:N2-(3-amino-sulfonyl phenyl)-5-methyl-N4-(3-oxo-benzo [1,4] oxazine-6-yl)-2, the 4-pyrimidinediamine
[1076] 1H NMR (DMSO-d 6): δ 7.91 (s, 1H), 7.82 (m, 1H), 7.65 (s, 1H), 7.51 (m, 1H), 7.36 (m, 3H), 7.04 (s, 1H), 6.98 (m, 1H), 4.60 (s, 2H), 2.14 (s, 3H); Purity 96%; MS (m/e): 427 (MH +).
VII-35:N2-(3-amino-sulfonyl phenyl)-5-methyl-N4-(4-methyl-3-oxo-benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine
[1077] 1H NMR (DMSO-d 6): δ 7.95 (s, 1H), 7.73 (m, 2H), 7.38 (m, 7H), 3.52 (s, 2H), 3.16 (s, 3H), 2.17 (s, 3H); Purity 90%; MS (m/e): 456 (MH +).
VI-63:N2-[3-amino-sulfonyl-4-(2-propyl group) phenyl]-5-fluoro-N4-[4-(Propargyl oxygen base) phenyl]-2, the 4-pyrimidinediamine
[1078] 1H NMR (DMSO-d 6): δ 10.40-9.84 (m, 2H), 8.15 (d, J=4.8Hz, 1H), 7.89 (s, 1H), 7.77 (dd, J=1.8 and 8.1Hz, 1H), 7.61 (d, J=8.7Hz, 2H), 7.43 (d, J=8.7Hz, 1H), 7.39 (s, 2H), 6.95 (d, J=9.0Hz, 2H), 4.77 (d, J=1.8Hz, 2H), 3.77 (q, J=6.9Hz, 1H), 3.56 (t, J=1.8Hz, 1H), 1.20 (d, J=6.9Hz, 6H); LCMS: purity: 98%; MS (m/e): 456 (MH +).
VI-64:N4-{4-[2-(dimethylamino ketonic oxygen base) ethyl] phenyl }-5-fluoro-N2-(3-propionyl amino-sulfonyl phenyl)-2, the 4-pyrimidinediamine
[1079] 1H NMR (DMSO-d 6): δ 11.95 (s, 1H), 9.58 (s, 1H), 9.36 (s, 1H), 8.20 (s, 1H), 8.12-8.04 (m, 2H), 7.71 (d, J=8.4Hz, 2H), and 7.42-7.36 (m, 3H), 7.20 (d, J=8.4Hz, 2H), 4.15 (t, J=6.3Hz, 2H), 2.85 (t, J=7.2Hz, 2H), 2.79 (s, 6H), 2.22 (q, J=7.5Hz, 2H), 0.89 (t, J=7.5Hz, 3H); LCMS: purity: 97%; MS (m/e): 531 (MH +).
VI-65:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(Propargyl amino) phenyl]-2, the 4-pyrimidinediamine
[1080] 1H NMR (DMSO-d 6): δ 9.27 (s, 1H), 9.02 (s, 1H), 8.08 (s, 1H), 7.96 (d, J=3.0Hz, 1H), 7.92 (d, J=8.1Hz, 1H), 7.47 (d, J=8.4Hz, 2H), 7.19 (s, 2H), 7.13 (d, J=9.0Hz, 1H), 6.63 (d, J=8.7Hz, 2H), 5.85 (t, J=6.0Hz, 1H), 3.85 (s, 2H), 3.06-3.04 (m, 1H), 2.48 (s, 3H); LCMS: purity: 98%; MS (m/e): 427 (MH +).
VI-66:N4-{4-[2-(dimethylamino ketonic oxygen base) ethyl] phenyl }-5-fluoro-N2-(3-propionyl amino-sulfonyl phenyl)-2,4-pyrimidinediamine sodium salt
[1081] 1H NMR (DMSO-d 6): δ 9.27 (s, 1H), 9.25 (s, 1H), 8.06 (d, J=3.9Hz, 1H), 7.86-7.82 (m, 2H), 7.74 (d, J=8.4Hz, 2H), 7.27-7.11 (m, 4H), 4.14 (t, J=6.6Hz, 2H), 2.84 (t, J=6.6Hz, 2H), 2.79 (s, 6H), 1.91 (q, J=7.5Hz, 2H), 0.85 (t, J=7.5Hz, 3H); LCMS: purity: 97%.
VI-67:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-{4-[two (Propargyl) amino] phenyl }-5-fluoro-2, the 4-pyrimidinediamine
[1082] 1H NMR (DMSO-d 6): δ 9.34 (s, 1H), 9.17 (s, 1H), 8.09 (d, J=2.1Hz, 1H), 8.01 (d, J=3.6Hz, 1H), 7.91 (dd, J=2.1Hz, 1H), 7.63 (d, J=8.7Hz, 2H), 7.22 (s, 2H), 7.16 (d, J=8.7Hz, 1H), 6.91 (d, J=9.3Hz, 2H), 4.11 (d, J=2.12Hz, 4H), 3.17 (t, J=2.1Hz, 2H), 2.50 (s, 3H); LCMS: purity: 98%; MS (m/e): 465 (MH +).
VI-68:5-fluoro-N2-(4-methyl-3-methylamino alkylsulfonyl phenyl)-N4-[4-(Propargyl oxygen base) phenyl]-2, the 4-pyrimidinediamine
[1083] 1H NMR (DMSO-d 6): δ 9.75 (s, 2H), 8.13 (d, J=3.9Hz, 1H), 7.93-7.89 (m, 1H), 7.84 (dd, J=2.4 and 8.4Hz, 1H), 7.63 (d, J=9.0Hz, 2H), and 7.41-7.34 (m, 1H), 7.24 (d, J=8.1Hz, 1H), 6.96 (d, J=9.0Hz, 2H), 4.78 (d, J=2.4Hz, 2H), 3.57 (t, J=2.4Hz, 1H), 2.49 (s, 3H), 2.40 (d, J=4.8Hz, 3H); LCMS: purity: 96%; MS (m/e): 443 (MH +).
VI-69:5-fluoro-N2-{[4-methyl-3-((1-methyl piperidine-4-yl) amino-sulfonyl)] phenyl }-N4-[4-(Propargyl oxygen base) phenyl]-2, the 4-pyrimidinediamine
[1084] 1H NMR (DMSO-d 6): δ 9.34 (s, 1H), 9.25 (s, 1H), 8.09-8.06 (m, 1H), 8.03 (d, J=3.9Hz, 1H), 7.96-7.87 (m, 1H), 7.69 (d, J=9.0Hz, 2H), 7.67-7.63 (m, 1H), 7.18 (d, J=8.4Hz, 1H), 6.94 (d, J=9.0Hz, 2H), 4.77 (d, J=2.1Hz, 2H), 3.58-3.55 (m, 1H), 3.00-2.86 (m, 1H), 2.80-2.70 (m, 2H), 2.49 (s, 3H), 2.20 (s, 3H), 2.13-2.99 (m, 2H), 1.66-1.40 (m, 4H); LCMS: purity: 96%; MS (m/e): 526 (MH +).
VI-70:N2-[3-amino-sulfonyl-4-(1-methylpiperazine-4-yl) phenyl]-5-fluoro-N4-[4-(Propargyl oxygen base) phenyl]-2, the 4-pyrimidinediamine
[1085] 1H NMR (DMSO-d 6): δ 9.38 (s, 1H), 9.25 (s, 1H), 8.09 (d, J=2.1Hz, 1H), 8.04 (d, J=3.6Hz, 1H), 7.93 (dd, J=2.4 and 8.7Hz, 1H), 7.69 (d, J=8.7Hz, 2H), 7.41 (d, J=8.7Hz, 1H), 6.96 (d, J=9.0Hz, 2H), 6.84 (s, 2H), 4.77 (d, J=2.1Hz, 2H), 3.55 (t, J=2.1Hz, 1H), 2.94-2.86 (m, 4H), 2.53-2.44 (m, 4H), 2.25 (s, 3H); LCMS: purity: 93%; MS (m/e): 512 (MH +).
VI-71:N4-{4-[2-(amino carbonyl amino) ethyl] phenyl }-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1086] 1H NMR (DMSO-d 6): δ 9.37 (s, 1H), 9.27 (s, 1H), 8.12-8.09 (m, 1H), and 8.07-8.03 (m, 1H), 7.92-7.87 (m, 1H), 7.72 (d, J=7.8Hz, 2H), 7.21 (s, 2H), 7.19-7.11 (m, 3H), 5.91-5.85 (m, 1H), 5.40 (s, 2H), and 3.21-3.16 (m, 2H), 2.65 (t, J=7.5Hz, 2H), 2.48 (s, 3H); LCMS: purity: 87%; MS (m/e): 461 (MH +).
VI-72:N4-{4-[2-(amino carbonyl amino) ethyl] phenyl }-N2-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1087] 1H NMR (DMSO-d 6): δ 9.50 (s, 1H), 9.34 (s, 1H), 8.12-8.06 (m, 2H), and 7.98-7.94 (m, 1H), 7.71 (d, J=8.1Hz, 2H), and 7.39-7.32 (m, 2H), 7.25 (s, 2H), 7.15 (d ,=8.4Hz, 2H), 5.89 (s, 1H), 3.24-3.16 (m, 2H), 2.65 (t, J=6.6Hz, 2H); LCMS: purity: 92%; MS (m/e): 447 (MH +).
VI-73:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-{4-[(Propargyl oxygen base) carbonylamino methyl] phenyl }-2, the 4-pyrimidinediamine
[1088] 1H NMR (DMSO-d 6): δ 9.72 (bs, 2H), 8.13 (d, J=4.2Hz, 1H), 8.00 (s, 1H), 7.93-7.86 (m, 1H), 7.82 (dd, J=2.1 and 8.1Hz, 1H), 7.68 (d, J=8.4Hz, 2H), 7.27 (s, 2H), 7.23-7.16 (m, 3H), 4.63 (d, J=2.1Hz, 2H), 4.16 (d, J=5.7Hz, 2H), 3.48 (t, J=2.4Hz, 1H), 2.42 (s, 3H); LCMS: purity: 95%; MS (m/e): 486 (MH +).
VI-74:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-{4-[(Propargyl oxygen base) carbonylamino methyl] phenyl }-2, the 4-pyrimidinediamine
[1089] 1H NMR (DMSO-d 6): δ 9.73 (s, 1H), 9.66 (s, 1H), 8.15 (d, J=4.2Hz, 1H), 8.02 (s, 1H), 7.95-7.87 (m, 2H), 7.69 (d, J=8.4Hz, 2H), 7.41-7.36 (m, 2H), 7.29 (s, 2H), 7.21 (d, J=8.4Hz, 2H), 4.63 (d, J=2.1Hz, 2H), 4.16 (d, J=5.7Hz, 2H), 3.48 (t, J=2.1Hz, 2H); LCMS: purity: 97%; MS (m/e): 471 (MH +).
IX-1:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[1-(propine-3-yl) indoles-5-yl]-2, the 4-pyrimidinediamine
[1090] 1H NMR (DMSO-d 6): δ 10.00 (s, 1H), 9.88 (s, 1H), 8.14 (d, J=4.5Hz, 1H), 7.88-7.78 (m, 3H), 7.50 (d, J=8.7Hz, 1H), 7.41 (d, J=2.7Hz, 1H), 7.38 (dd, J=1.8 and 9.0Hz, 1H), 7.29 (s, 2H), 7.09 (d, J=8.7Hz, 1H), 6.43 (d, J=3.0Hz, 1H), 5.09 (d, J=2.7Hz, 2H), 3.42 (t, J=2.7Hz, 1H), 2.51 (s, 3H); LCMS: purity: 98%; MS (m/e): 451 (MH +).
IX-2:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[1-(propine-3-yl) indoles-5-yl]-2, the 4-pyrimidinediamine
[1091] 1H NMR (DMSO-d 6): δ 10.03 (bs, 2H), 8.18 (d, J=4.5Hz, 1H), 7.97-7.92 (m, 1H), 7.87-7.82 (m, 2H), 7.51 (d, J=8.7Hz, 1H), 7.42-7.36 (m, 3H), and 7.32-7.26 (m, 3H), 6.44 (d, J=3.3Hz, 1H), 5.10 (d, J=2.4Hz, 2H), 3.43 (t, J=2.4Hz, 2H); LCMS: purity: 97%; MS (m/e): 437 (MH +).
VI-75:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(Propargyl amino-sulfonyl) phenyl]-2, the 4-pyrimidinediamine
[1092] 1H NMR (DMSO-d 6): δ 9.84 (s, 1H), 9.70 (s, 1H), 8.23 (d, J=3.6Hz, 1H), 8.14-8.06 (m, 3H), 8.02 (t, J=6.0Hz, 1H), 7.97-7.92 (m, 1H), 7.72 (d, J=8.7Hz, 2H), 7.47-7.37 (m, 2H), 7.30 (s, 2H), 3.67 (dd, J=2.4 and 5.7Hz, 2H), 3.07 (t, J=2.4Hz, 1H); LCMS: purity: 96%; MS (m/e): 478 (MH +).
VI-76:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(Propargyl amino-sulfonyl) phenyl]-2, the 4-pyrimidinediamine
[1093] 1H NMR (DMSO-d 6): δ 9.86 (s, 1H), 9.64 (s, 1H), 8.21 (d, J=3.9Hz, 1H), 8.13-8.08 (m, 2H), 8.06-8.00 (m, 2H), 7.87 (dd, J=2.4 and 8.4Hz, 1H), 7.70 (d, J=8.7Hz, 2H), 7.28 (s, 2H), 7.23 (d, J=8.4Hz, 1H), 3.67 (dd, J=2.4 and 6.0Hz, 2H), 3.07 (t, J=2.7Hz, 1H), 2.52 (s, 3H); LCMS: purity: 96%; MS (m/e): 492 (MH +).
VI-77:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(Propargyl amino-sulfonyl) phenyl]-2, the 4-pyrimidinediamine
[1094] 1H NMR (DMSO-d 6): δ 9.89 (s, 1H), 9.81 (s, 1H), 8.26 (d, J=3.3Hz, 1H), 8.10-8.03 (m, 3H), 7.84 (d, J=9.0,2H), 7.73 (d, J=9.0Hz, 2H), 7.68 (d, J=9.0Hz, 2H), 7.17 (s, 2H), 3.68 (dd, J=2.7 and 5.7Hz, 2H), 3.06 (t, J=2.7Hz, 1H); LCMS: purity: 96MS (m/e): 477 (MH +).
VI-78:5-fluoro-N2-[3-(Propargyl amino-sulfonyl) phenyl]-N4-[4-(Propargyl oxygen base) phenyl]-2, the 4-pyrimidinediamine
[1095] 1H NMR (DMSO-d 6): δ 9.76 (s, 1H), 9.66 (s, 1H), 8.14 (d, J=4.2Hz, 1H), 8.07 (t, J=6.3Hz, 1H), 7.99-7.94 (m, 2H), 7.64 (d, J=9.0Hz, 2H), 7.45-7.32 (m, 2H), 6.96 (d, J=9.0Hz, 2H), 4.78 (d, J=1.8Hz, 2H), 3.67-3.63 (m, 2H), 3.62-3.56 (m, 1H); LCMS: purity: 96%; MS (m/e): 452 (MH +).
IX-3:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[1-(propine-3-yl) indoles-6-yl]-2, the 4-pyrimidinediamine
[1096] 1H NMR (DMSO-d 6): δ 9.90 (s, 1H), 9.74 (s, 1H), 8.13 (d, J=4.2Hz, 1H), 7.96 (s, 1H), 7.86-7.79 (m, 2H), 7.52 (d, J=8.1Hz, 1H), 7.40-7.36 (m, 2H), 7.27 (s, 2H), 7.07 (d, J=8.1Hz, 1H), 6.45 (d, J=3.0Hz, 1H), 5.01 (d, J=2.4Hz, 1H), 3.38 (t, J=2.4Hz, 1H), 2.49 (s, 3H); LCMS: purity: 91%; MS (m/e): 451 (MH +).
IX-4:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[1-(propine-3-yl) indoles-6-yl]-2, the 4-pyrimidinediamine
[1097] 1H NMR (DMSO-d 6): δ 9.70-9.58 (m, 2H), 8.12 (d, J=3.9Hz, 1H), 8.02 (s, 1H), 7.95 (d, J=7.8Hz, 1H), 7.85 (s, 1H), 7.52 (d, J=9.0Hz, 1H), 7.42-7.25 (m, 6H), 6.44 (d, J=2.7Hz, 1H), 5.03 (s, 2H), 3.38 (m, 1H); LCMS: purity: 92%; MS (m/e): 437 (MH +).
VI-79:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-(Propargyl amino-sulfonyl) phenyl]-2, the 4-pyrimidinediamine
[1098] 1H NMR (DMSO-d 6): δ 9.92 (s, 1H), 9.64 (s, 1H), 8.32 (d, J=7.5Hz, 1H), 8.19 (d, J=3.9Hz, 1H), 8.14 (d, J=6.0Hz, 1H), and 8.06-8.03 (m, 1H), 8.00-7.97 (m, 1H), 7.81 (dd, J=2.1 and 8.4Hz, 1H), 7.57-7.46 (m, 2H), 7.27 (s, 2H), 7.22 (d, J=8.7Hz, 1H), 3.69 (dd, J=2.4 and 5.7Hz, 2H), 3.06 (t, J=2.7Hz, 1H), 2.44 (s, 3H); LCMS: purity: 96%; MS (m/e): 492 (MH +).
VI-80:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[3-(Propargyl amino-sulfonyl) phenyl]-2, the 4-pyrimidinediamine
[1099] 1H NMR (DMSO-d 6): δ 9.77 (s, 1H), 9.63 (s, 1H), 8.33-8.27 (m, 1H), 8.21 (d, J=3.6Hz, 1H), 8.15 (t, J=6.3Hz, 1H), 7.99-7.96 (m, 1H), 7.79 (d, J=8.7Hz, 2H), 7.64 (d, J=9.0Hz, 2H), 7.59-7.48 (m, 2H), 7.12 (s, 2H), 3.71 (dd, J=2.4 and 5.7Hz, 2H), 3.06 (t, J=2.4Hz, 1H); LCMS: purity: 95%; MS (m/e): 477 (MH +).
VI-81:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[3-(Propargyl amino-sulfonyl) phenyl]-2, the 4-pyrimidinediamine
[1100] 1H NMR (DMSO-d 6): δ 9.80 (s, 1H), 9.60 (s, 1H), 8.39-8.34 (m, 1H), 8.20 (d, J=3.6Hz, 1H), 8.15 (t, J=6.0Hz, 1H), and 8.10-8.06 (m, 1H), 8.02-7.98 (m, 1H), 7.94-7.88 (m, 1H), 7.54 (t, J=8.1Hz, 1H), 7.49-7.34 (m, 3H), 7.28 (s, 2H), 3.70 (dd, J=2.4 and 5.4Hz, 2H), 3.07 (t, J=2.4Hz, 1H); LCMS: purity: 98%; MS (m/e): 477 (MH +).
III-84:N2-[4-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[4-(1-imidazolyl methyl) phenyl]-2, the 4-pyrimidinediamine
[1101] 1H?NMR(DMSO?d 6，300MHz)：δ9.64(s，1H)，9.49(s，1H)，8.15(d，2H，J＝3.6Hz)，7.81(d，2H，J＝8.4Hz)，7.76(s，1H)，7.70(d，2H，J＝8.1Hz)，7.55(d，2H，J＝8.4Hz)，7.25(d，2H，J＝8.4Hz)，7.20(s，1H)，5.17(s，2H)，2.76(t，2H，J＝7.2Hz)，2.42(m，6H)，0.87(t，6H，J＝7.2Hz)；LCMS(m/z)：539(MH +)。
III-76:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-pyridyl) styroyl]-2, the 4-pyrimidinediamine
[1102] 1H?NMR(DMSO?d 6，300MHz)：δ9.48(s，1H)，9.29(s，1H)，8.41(d，2H，J＝5.1Hz)，8.09(d，2H，J＝2.4Hz)，7.95(m，1H)，7.69(d，2H，J＝8.4Hz)，7.34(d，2H，J＝5.1Hz)，7.24(d，4H，J＝6.0Hz)，7.16(d，2H，J＝8.4Hz)，3.30(d，4H，J＝1.2Hz)；LCMS(m/z)：465(MH +)。
III-77:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(4-pyridyl) styroyl]-2, the 4-pyrimidinediamine
[1103] 1H?NMR(DMSO?d 6，300MHz)：δ9.38(s，1H)，9.26(s，1H)，8.41(d，2H，J＝4.5Hz)，8.10(s，1H)，8.05(d，1H，J＝3.3Hz)，7.89(d，1H，J＝8.1Hz)，7.80(d，2H，J＝7.8Hz)，7.23(m，4H)，7.15(m，3H)，3.31(d，4H，J＝1.2Hz)，2.48(s，3H)；LCMS(m/z)：479(MH +)。
III-78:5-fluoro-N2-[3-N-(methyl) amino-sulfonyl-4-aminomethyl phenyl]-N4-[4-(4-pyridyl) styroyl]-2, the 4-pyrimidinediamine
[1104] 1H?NMR(DMSO?d 6，300MHz)：δ9.38(s，1H)，9.27(s，1H)，8.41(d，2H，J＝5.1Hz)，8.07(d，2H，J＝3.9Hz)，8.01(s，1H)，7.93(m，1H)，7.69(d，2H，J＝8.4Hz)，7.32(q，1H，J＝4.8Hz)，7.23(d，2H，J＝5.4Hz)，7.17(t，3H，J＝8.1Hz)，3.30(s，4H)，2.46(s，3H)，2.42(d，3H，J＝4.5Hz)；LCMS(m/z)：493(MH +)。
I-169:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-pyridyl)-3-fluorine methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[1105] 1H?NMR(DMSO?d 6，300MHz)：δ9.56(s，1H)，9.40(s，1H)，8.56(m，1H)，8.11(d，1H，J＝3.9Hz)，8.08(s，1H)，7.95(m，1H)，7.88(m，1H)，7.84(m，2H)，7.52(d，1H，J＝7.5Hz)，7.48(s，1H)，7.35(m，2H)，7.26(s，2H)，7.16(t，1H，J＝9.3Hz)，5.23(s，2H)；LCMS(m/z)：485(MH +)。
I-170:5-fluoro-N2-[3-N-(methyl) amino-sulfonyl-4-aminomethyl phenyl]-N4-[4-(2-pyridyl)-3-methyl methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[1106] 1H?NMR(DMSO?d 6，300MHz)：δ9.32(s，1H)，9.15(s，1H)，8.57(m，1H)，8.03(d，1H，J＝3.9Hz)，7.94(m，2H)，7.83(m，1H)，7.52(m，3H)，7.33(m，2H)，7.14(d，1H，J＝8.7Hz)，6.93(d，1H，J＝9.6Hz)，5.18(s，2H)，2.45(s，3H)，2.41(d，3H，J＝4.2Hz)，2.25(s，3H)；LCMS(m/z)：509(MH +)。
I-171:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-pyridyl)-3-chlorine methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[1107] 1H NMR (DMSO d 6, 300MHz): δ 9.53 (s, 1H), 9.37 (s, 1H), 8.57 (m, 1H), 8.10 (d, 1H, J=3.6Hz), 8.03 (s, 1H), 7.96 (m, 1H), 7.85 (m, 2H), (7.72 dd, 1H, J=2.4 and 9.0Hz), 7.55 (d, 1H, J=8.1Hz), 7.35 (m, 3H), 7.25 (s, 2H), 7.17 (d, 1H, J=9.3Hz), 5.27 (s, 2H); LCMS (m/z): 501 (MH +).
I-172:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(2-pyridyl)-3-fluorine methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[1108] 1H?NMR(DMSO?d 6，300MHz)：δ9.44(s，1H)，9.37(s，1H)，8.56(d，1H，J＝3.9Hz)，8.09(s，1H)，8.07(d，1H，J＝3.6Hz)，7.90-7.81(m，3H)，7.51(t，2H，J＝7.5Hz)，7.34(m，1H)，7.24(s，1H)，7.15(m，2H)，5.23(s，2H)，2.49(s，3H)；LCMS(m/z)：449(MH +)。
I-173:5-fluoro-N2-[3-N-(methyl) amino-sulfonyl-4-aminomethyl phenyl]-N4-[4-(2-pyridyl)-3-fluorine methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[1109] 1H NMR (DMSO d 6, 300MHz): δ 9.48 (s, 1H), 9.38 (s, 1H), 8.57 (m, 1H), 8.08 (d, 1H, J=3.0Hz), 8.01 (s, 1H), (7.95 dd, 1H, J=2.1 and 8.4Hz), 7.83 (m, 2H), 7.51 (t, 2H, J=9.3Hz), 7.35 (m, 2H), 7.19 (d, 1H, J=8.1Hz), 7.14 (d, 1H, J=9.3Hz), 5.23 (s, 2H), 2.46 (s, 3H), 2.41 (d, 1H, J=4.2Hz); LCMS (m/z): 513 (MH +).
I-174:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(2-pyridyl)-3-chlorine methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[1110] 1H?NMR(DMSO?d 6，300MHz)：δ9.42(s，1H)，9.34(s，1H)，8.57(d，1H，J＝3.6Hz)，8.07(m，1H)，7.86(m，3H)，7.73(d，1H，J＝9.0Hz)，7.55(d，1H，J＝7.5Hz)，7.34(t，1H，J＝5.1Hz)，7.24(s，2H)，7.16(d，2H，J＝8.7Hz)，5.26(s，2H)，2.49(s，3H)；LCMS(m/z)：515(MH +)。
IX-54:5-fluoro-N2-[3-N-(methyl) amino-sulfonyl-4-aminomethyl phenyl]-N4-[4-(2-pyridyl)-3-chlorine methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[1111] 1H NMR (DMSO d 6, 300MHz): δ 9.43 (s, 1H), 9.35 (s, 1H), 8.56 (m, 1H), 8.09 (d, 1H, J=3.0Hz), 7.96 (m, 2H), 7.85 (m, 2H), 7.71 (dd, 1H, J=3.0 and 8.8Hz), 7.55 (d, 1H, J=7.8Hz), 7.34 (t, 2H, J=5.1Hz), 7.17 (t, 2H, J=9.0Hz), 5.26 (s, 2H), 2.45 (s, 3H), 2.41 (d, 1H, J=4.8Hz); LCMS (m/z): 529 (MH +).
II-11:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-pyridyl oxygen base) phenyl]-2, the 4-pyrimidinediamine
[1112] 1H?NMR(DMSO?d 6，300MHz)：δ9.57(s，1H)，9.52(s，1H)，8.43(s，1H)，8.39(t，1H，J＝2.1Hz)，8.18(t，2H，J＝3.3Hz)，7.99(d，1H，J＝7.5Hz)，7.93(d，2H，J＝8.7Hz)，7.44(m，4H)，7.32(s，2H)，7.13(d，2H，J＝9.0Hz)；LCMS(m/z)：453(MH +)。
III-85:5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-[4-(1-imidazolyl methyl) phenyl]-2,4-pyrimidinediamine hydrochloride
[1113] 1H?NMR(DMSO?d 6，300MHz)：δ9.79(s，1H)，9.75(s，1H)，9.30(s，1H)，8.18(d，1H，J＝3.0Hz)，7.94(s，1H)，7.86(d，1H，J＝8.1Hz)，7.80(d，3H，J＝8.1Hz)，7.69(s，1H)，7.38(d，3H，J＝8.4Hz)，7.20(d，1H，J＝8.4Hz)，5.40(s，2H)，2.48(s，3H)，2.39(d，3H，J＝4.2Hz)；LCMS(m/z)：468(MH +)。
III-86:5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-[4-(1-imidazolyl methyl) phenyl]-2,4-pyrimidinediamine dihydrochloride
[1114] 1H?NMR(DMSO?d 6，300MHz)：δ9.85(s，1H)，9.81(s，1H)，9.31(s，1H)，8.19(d，1H，J＝4.2Hz)，7.93(s，1H)，7.84(d，1H，J＝8.1Hz)，7.80(d，3H，J＝8.1Hz)，7.69(s，1H)，7.38(d，3H，J＝8.4Hz)，7.20(d，1H，J＝8.4Hz)，5.41(s，2H)，2.48(s，3H)，2.39(d，3H，J＝4.2Hz)；LCMS(m/z)：468(MH +)。
II-12:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(3-pyridyl oxygen base) phenyl]-2, the 4-pyrimidinediamine
[1115] 1H?NMR(DMSO?d 6，300MHz)：δ9.42(s，1H)，9.40(s，1H)，8.32(m，2H)，8.08(d，2H，J＝3.0Hz)，7.86m，2H)，7.39(m，2H)，7.23(s，2H)，7.09(m，4H)，2.36(s，3H)，7.13；LCMS(m/z)：467(MH +)。
II-13:5-fluoro-N2-[3-N-(methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-[4-(3-pyridyl oxygen base) phenyl]-2, the 4-pyrimidinediamine
[1116] 1H NMR (DMSO d 6, 300MHz): δ 9.43 (s, 1H), 9.40 (s, 1H), 8.35 (s, 1H), 8.32 (t, 1H, J=2.4Hz), 8.09 (d, 1H, J=3.6Hz), 8.00 (s, 1H), 7.93 (dd, 1H, J=1.8 and 8.2Hz), 7.84 (d, 2H, J=8.7Hz), 7.39 (m, 2H), 7.33 (q, 1H, J=4.2Hz), 7.18 (d, 1H, J=8.4Hz), 7.06 (d, 2H, J=8.7Hz), 2.44 (s, 3H), 2.40 (d, 3H, J=4.5Hz); LCMS (m/z): 481 (MH +).
III-79:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-pyridyl) styroyl]-2, the 4-pyrimidinediamine
[1117] 1H?NMR(DMSO?d 6，300MHz)：δ9.56(s，1H)，9.37(s，1H)，8.42(d，2H，J＝4.2Hz)，8.11(d，1H，J＝3.6Hz)，7.79(d，2H，J＝8.4Hz)，7.61(t，4H，J＝9.3Hz)，7.24(d，2H，J＝5.1Hz)，7.19(d，4H，J＝8.1Hz)，7.15(s，2H)，3.92(s，4H)；LCMS(m/z)：465(MH +)。
I-175:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-pyridyl)-3-chlorine methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[1118] 1H?NMR(DMSO?d 6，300MHz)：δ9.71(s，1H)，9.51(s，1H)，8.64(d，1H，J＝4.1Hz)，8.20(d，1H，J＝3.6Hz)，7.92(m，2H)，7.85(d，2H，J＝8.7Hz)，7.71(d，2H，J＝9.3Hz)，7.63(d，2H，J＝8.7Hz)，7.41(m，1H)，7.26(d，1H，J＝9.3Hz)，7.19(s，2H)，5.33(s，2H)；LCMS(m/z)：501(MH +)。
I-176:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-pyridyl)-3-methyl methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[1119] 1H?NMR(DMSO?d 6，300MHz)：δ9.63(s，1H)，9.33(s，1H)，8.63(m，1H)，8.15(d，1H，J＝3.9Hz)，7.91(t，1H，J＝7.8Hz)，7.85(d，2H，J＝8.7Hz)，7.66(d，2H，J＝8.4Hz)，7.60(m，2H)，7.42(m，2H)，7.19(s，2H)，7.03(d，1H，J＝8.4Hz)，5.26(s，2H)，2.34(s，3H)；LCMS(m/z)：481(MH +)。
II-14:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-pyridyl oxygen base) phenyl]-2, the 4-pyrimidinediamine
[1120] 1H?NMR(DMSO?d 6，300MHz)：δ9.67(s，1H)，9.58(s，1H)，8.41(d，2H，J＝12.3Hz)，8.21(d，1H，J＝3.3Hz)，7.86(d，4H，J＝6.9Hz)，7.68(d，2H，J＝9.0Hz)，7.48(s，2H)，7.17(m，4H)；LCMS(m/z)：453(MH +)。
III-87:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(1-imidazolyl) styroyl]-2, the 4-pyrimidinediamine
[1121] 1H?NMR(DMSO?d 6，300MHz)：δ9.51(s，1H)，9.32(s，1H)，8.09(d，2H，J＝3.6Hz)，7.94(s，1H)，7.71(d，2H，J＝8.4Hz)，7.48(s，1H)，7.35(m，2H)，7.26(s，2H)，7.14(s，1H)，7.10(d，2H，J＝8.4Hz)，6.83(s，1H)，4.26(t，2H，J＝6.9Hz)，3.06(t，2H，J＝7.2Hz)；LCMS(m/z)：454(MH +)。
III-88:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(1-imidazolyl) styroyl]-2, the 4-pyrimidinediamine
[1122] 1H NMR (DMSO d 6, 300MHz): δ 9.47 (s, 1H), 9.35 (s, 1H), 8.17 (s, 1H), 8.13 (d, 1H, J=3.0Hz), 7.95 (dd, 1H, J=2.1 and 8.1Hz), 7.78 (d, 2H, J=8.1Hz), 7.54 (s, 1H), 7.29 (s, 2H), 7.24 (d, 1H, J=8.1Hz), 7.20 (s, 2H), 7.16 (d, 2H, J=8.4Hz), 6.90 (s, 1H), 4.26 (t, 2H, J=6.9Hz), 3.06 (t, 2H, J=7.2Hz), 2.53 (s, 3H); LCMS (m/z): 468 (MH +).
III-91:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(2-methyl isophthalic acid-imidazolyl methyl) phenyl]-2, the 4-pyrimidinediamine
[1123] 1H NMR (DMSO d 6, 300MHz): δ 9.39 (s, 2H), 8.08 (d, 1H, J=3.0Hz), 7.89 (s, 1H),, 7.87 (dd, 1H, J=2.1 and 8.2Hz), 7.78 (d, 2H, J=8.4Hz), 7.24 (s, 1H), 7.15 (s, 1H), 7.11 (d, 2H, J=8.4Hz), 6.79 (s, 1H), 5.10 (s, 2H), 2.49 (s, 3H), 2.26 (s, 3H); LCMS (m/z): 468 (MH +).
III-89:5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-[4-(1-imidazolyl) styroyl]-2, the 4-pyrimidinediamine
[1124] 1H NMR (DMSO d 6, 300MHz): δ 9.40 (s, 1H), 9.29 (s, 1H), 8.08 (d, 1H, J=3.9Hz), 8.02 (d, 1H, J=2.1Hz), 7.95 (dd, 1H, J=1.8 and 8.4Hz), 7.71 (d, 2H, J=8.4Hz), 7.48 (s, 1H), 7.33 (q, 1H, J=4.5Hz), 7.20 (d, 1H, J=8.4Hz), 7.14 (s, 1H), 7.10 (d, 2H, J=8.4Hz), 6.84 (s, 1H), 4.19 (t, 2H, J=7.2Hz), 3.00 (t, 2H, J=7.2Hz), 2.46 (s, 3H), 2.42 (d, 3H, J=4.8Hz); LCMS (m/z): 482 (MH +).
I-177:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-pyridyl)-3-fluorine methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine
[1125] 1H NMR (DMSO d 6, 300MHz): δ 9.72 (s, 1H), 9.54 (s, 1H), 8.64 (d, 1H, J=4.8Hz), 8.21 (d, 1H, J=3.6Hz), 7.92 (m, 2H), 7.88 (d, 2H, J=8.4Hz), 7.70 (d, 2H, J=8.7Hz), 7.60 (d, 1H, J=8.1Hz), 7.50 (d, 1H, J=8.7Hz), 7.41 (dd, 1H, J=5.1 and 6.7Hz), 7.26 (t, 1H, J=9.3Hz), 7.21 (s, 2H), 5.31 (s, 2H); LCMS (m/z): 485 (MH +).
III-92:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-methyl isophthalic acid-imidazolyl methyl) phenyl]-2, the 4-pyrimidinediamine
[1126] 1H?NMR(DMSO?d 6，300MHz)：δ9.60(s，1H)，9.49(s，1H)，8.13(t，2H，J＝3.6Hz)，7.77(d，1H，J＝9.0Hz)，7.70(d，2H，J＝8.4Hz)，7.55(d，2H，J＝8.7Hz)，7.27(s，2H)，7.15(s，1H)，7.17(s，1H)，7.12(d，2H，J＝8.4Hz)，6.79(s，1H)，5.13(s，2H)，2.24(s，3H)；LCMS(m/z)：454(MH +)。
III-99:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-{4-[1-(1,2, the 4-triazolyl) methyl] phenyl }-2, the 4-pyrimidinediamine
[1127] 1H?NMR(DMSO?d 6，300MHz)：δ9.60(s，1H)，9.49(s，1H)，8.64(s，1H)，8.15(d，1H，J＝3.6Hz)，7.98(s，1H)，7.80(d，2H，J＝8.7Hz)，7.74(d，2H，J＝8.4Hz)，7.62(d，2H，J＝8.7Hz)，7.27(d，2H，J＝8.7Hz)，7.14(s，2H)，5.39(s，2H)；LCMS(m/z)：441(MH +)。
III-95:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-{4-[1-(1,2,3-triazoles base) methyl] phenyl }-2, the 4-pyrimidinediamine
[1128] 1H NMR (DMSO d 6, 300MHz): δ 9.41 (s, 1H), 9.40 (s, 1H), 8.17 (s, 1H), 8.09 (d, 2H, J=3.6Hz), (7.86 dd, 1H, J=2.1 and 8.2Hz), 7.79 (d, 2H, J=8.4Hz), 7.73 (s, 1H), 7.26 (d, 2H, J=8.7Hz), 7.24 (s, 1H), 7.12 (d, 1H, J=8.1Hz), 5.74 (s, 2H), 2.48 (s, 3H); LCMS (m/z): 455 (MH +).
III-96:N2-4-amino-sulfonyl phenyl)-and 5-fluoro-N4-{4-[1-(1,2,3-triazoles base) methyl] phenyl }-2, the 4-pyrimidinediamine
[1129] 1H?NMR(DMSO?d 6，300MHz)：δ9.60(s，1H)，9.51(s，1H)，8.17(d，1H，J＝0.9Hz)，8.15(d，1H，J＝3.6Hz)，7.78(t，3H，J＝5.4Hz)，7.74(s，2H)，7.61(d，2H，J＝8.7Hz)，7.29(d，2H，J＝8.4Hz)，7.15(s，2H)，5.59(s，2H)；LCMS(m/z)：441(MH +)。
III-100:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-{4-[1-(1,2, the 4-triazolyl) methyl] phenyl }-2, the 4-pyrimidinediamine
[1130] 1H?NMR(DMSO?d 6，300MHz)：δ9.50(s，1H)，9.44(s，1H)，8.64(s，1H)，8.63(s，1H)，8.11(d，1H，J＝3.9Hz)，8.09(s，1H)，7.97(s，1H)，7.93(bs?s，1H)，7.78(d，2H，J＝8.4Hz)，7.33(d，2H，J＝4.8Hz)，7.26(d，4H，J＝7.5Hz)，5.37(s，2H)；LCMS(m/z)：441(MH +)。
III-101:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-{4-[1-(1,2, the 4-triazolyl) methyl] phenyl }-2, the 4-pyrimidinediamine
[1131] 1H NMR (DMSO d 6, 300MHz): δ 9.46 (s, 2H), 8.70 (s, 1H), 8.15 (d, 1H, J=3.3Hz), 8.04 (s, 1H), 7.94 (dd, 1H, J=2.4 and 8.4Hz), 7.84 (d, 2H, J=8.4Hz), 7.30 (m, 3H), 7.19 (s, 1H), 7.17 (s, 1H), 5.44 (s, 2H), 2.55 (s, 3H); LCMS (m/z): 455 (MH +).
III-102:5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-{4-[1-(1,2, the 4-triazolyl) methyl] phenyl }-2, the 4-pyrimidinediamine
[1132] 1H NMR (DMSO d 6, 300MHz): δ 9.42 (s, 1H), 9.40 (s, 1H), 8.64 (s, 1H), 8.09 (d, 1H, J=3.6Hz), 8.01 (d, 1H, J=1.8Hz), 7.97 (s, 1H), 7.93 (dd, 1H, J=2.4 and 8.1Hz), 7.77 (d, 2H, J=8.7Hz), 7.34 (q, 1H, J=4.8Hz), 7.24 (d, 2H, J=8.4Hz), 7.15 (d, 1H, J=8.4Hz), 5.38 (s, 2H), 2.46 (s, 3H), 2.41 (d, 3H, J=4.8Hz); LCMS (m/z): 469 (MH +).
VII-60:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(1-methyl sulphonyl) indoline-5-yl]-2, the 4-pyrimidinediamine
[1133] 1H?NMR(DMSO?d 6，300MHz)：δ9.47(s，1H)，9.36(s，1H)，8.09(d，1H，J＝3.3Hz)，8.06(s，1H)，7.95(d，1H，J＝7.8Hz)，7.73(s，1H)，7.59(d，1H，J＝8.4Hz)，7.35(m，2H)，7.25(s，2H)，7.20(d，1H，J＝8.4Hz)，3.94(t，2H，J＝8.7Hz)，3.11(t，2H，J＝8.1Hz)，2.97(s，3H)；LCMS(m/z)：479(MH +)。
VII-61:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(1-methyl sulphonyl) indoline-5-yl]-2, the 4-pyrimidinediamine
[1134] 1H NMR (DMSO d 6, 300MHz): δ 9.35 (s, 1H), 9.31 (s, 1H), 8.06 (m, 2H), 7.87 (dd, 1H, J=2.1 and 8.1Hz), 7.72 (s, 1H), 7.58 (d, 1H, J=10.5Hz), 7.18 (m, 4H), 3.94 (t, 2H, J=8.7Hz), 3.10 (t, 2H, J=8.4Hz), 2.96 (s, 3H), 2.48 (s, 3H); LCMS (m/z): 493 (MH +).
VII-62:5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-[4-(1-methyl sulphonyl) indoline-5-yl]-2, the 4-pyrimidinediamine
[1135] 1H NMR (DMSO d 6, 300MHz): δ 9.36 (s, 1H), 9.33 (s, 1H), 8.07 (d, 1H, J=3.6Hz), 7.99 (d, 1H, J=2.1Hz), 7.93 (dd, 1H, J=2.4 and 8.2Hz), 7.71 (s, 1H), 7.57 (dd, 1H, J=2.1 and 8.7Hz), 7.33 (q, 1H, J=4.8Hz), 7.19 (d, 2H, J=8.4Hz), 3.94 (t, 2H, J=8.7Hz), 3.10 (t, 2H, J=8.4Hz), 2.96 (s, 3H), 2.46 (s, 3H), 2.41 (d, 3H, J=4.8Hz); LCMS (m/z): 507 (MH +).
III-93:5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-[4-(2-methyl isophthalic acid-imidazolyl methyl) phenyl]-2, the 4-pyrimidinediamine
[1136] 1H NMR (DMSO d 6, 300MHz): δ 9.39 (s, 2H), 8.09 (d, 1H, J=3.3Hz), 8.00 (d, 1H, J=2.1Hz), 7.92 (dd, 1H, J=2.4 and 8.1Hz), 7.33 (q, 1H, J=5.1Hz), 7.12 (m, 4H), 6.75 (s, 1H), 5.09 (s, 2H), 2.46 (s, 3H), 2.41 (d, 3H, J=4.5Hz), 2.24 (s, 3H); LCMS (m/z): 482 (MH +).
III-97:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-{4-[1-(1,2,3-triazoles base) methyl] phenyl }-2, the 4-pyrimidinediamine
[1137] 1H?NMR(DMSO?d 6，300MHz)：δ9.58(s，1H)，9.52(s，1H)，8.24(s，1H)，8.18(d，1H，J＝3.6Hz)，8.17(s，1H)，7.98(m，1H)，7.86(d，2H，J＝8.7Hz)，7.80(s，1H)，7.40(d，2H，J＝4.8Hz)，7.33(m，4H)，5.64(s，2H)；LCMS(m/z)：441(MH +)。
III-98:5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-{4-[1-(1,2,3-triazoles base) methyl] phenyl }-2, the 4-pyrimidinediamine
[1138] 1H NMR (DMSO d 6, 300MHz): δ 9.43 (s, 1H), 9.41 (s, 1H), 8.17 (d, 1H, J=0.9Hz), 8.09 (d, 1H, J=3.9Hz), 8.00 (d, 1H, J=2.1Hz), 7.92 (dd, 1H, J=2.4 and 8.1Hz), 7.76 (t, 3H, J=8.7Hz), 7.33 (q, 1H, J=5.1Hz), 7.26 (d, 2H, J=9.0Hz), 7.14 (d, 1H, J=8.4Hz), 5.58 (s, 2H), 2.46 (s, 3H), 2.41 (d, 3H, J=4.8Hz); LCMS (m/z): 469 (MH +).
III-90:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(1-imidazolyl) styroyl]-2, the 4-pyrimidinediamine
[1139] 1H?NMR(DMSO?d 6，300MHz)：δ9.61(s，1H)，9.38(s，1H)，8.13(d，1H，J＝3.9Hz)，7.79(d，2H，J＝8.7Hz)，7.62(t，4H，J＝9.0Hz)，7.51(s，1H)，7.23(s，1H)，7.15(s，1H)，7.12(d，2H，J＝8.4Hz)，6.85(s，1H)，4.21(t，2H，J＝6.9Hz)，3.03(t，2H，J＝6.9Hz)；LCMS(m/z)：454(MH +)。
VII-63:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(1-methyl sulphonyl) indoline-5-yl]-2, the 4-pyrimidinediamine
[1140] 1H?NMR(DMSO?d 6，300MHz)：δ9.57(s，1H)，9.41(s，1H)，8.11(d，1H，J＝3.6Hz)，7.78(d，2H，J＝8.4Hz)，7.68(s，1H)，7.60(d，1H，J＝8.4Hz)，7.50(d，1H，J＝8.4Hz)，7.22(d，1H，J＝9.0Hz)，7.13(s，2H)，3.95(t，2H，J＝5.4Hz)，3.12(t，2H，J＝8.1Hz)，2.97(s，3H)；LCMS(m/z)：479(MH +)。
IV-5:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(1,3-oxazole-5-yl) phenyl]-2, the 4-pyrimidinediamine
[1141] 1H?NMR(DMSO?d 6，300MHz)：δ9.58(s，1H)，9.57(s，1H)，8.39(s，1H)，8.16(d，1H，J＝3.6Hz)，8.13(s，1H)，7.97(d，2H，J＝8.7Hz)，7.93(s，1H)，7.67(d，2H，J＝8.4Hz)，7.59(s，1H)，7.39(m，2H)，7.27(s，2H)；LCMS(m/z)：427(MH +)。
IV-6:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(1,3-oxazole-5-yl) phenyl]-2, the 4-pyrimidinediamine
[1142] 1H NMR (DMSO d 6, 300MHz): δ 9.58 (s, 1H), 9.52 (s, 1H), 8.45 (s, 1H), 8.19 (t, 2H, J=3.9Hz), 8.04 (d, 2H, J=8.4Hz), 7.95 (dd, 1H, J=2.1 and 8.4Hz), 7.72 (d, 2H, J=8.7Hz), 7.65 (s, 1H), 7.30 (s, 2H), 7.27 (d, 1H, J=8.4Hz), 2.57 (s, 3H); LCMS (m/z): 441 (MH +).
IV-1:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[3-(1,3-oxazole-5-yl) phenyl]-2, the 4-pyrimidinediamine
[1143] 1H?NMR(DMSO?d 6，300MHz)：δ9.61(s，1H)，9.59(s，1H)，8.47(s，1H)，8.22(d，1H，J＝3.0Hz)，8.10(d，2H，J＝9.9Hz)，8.04(d，1H，J＝7.8Hz)，7.97(m，1H)，7.70(s，1H)，7.50(d，2H，J＝4.8Hz)，7.31(m，4H)；LCMS(m/z)：427(MH +)。
IV-2:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-(1,3-oxazole-5-yl) phenyl]-2, the 4-pyrimidinediamine
[1144] 1H?NMR(DMSO?d 6，300MHz)：δ9.55(s，1H)，9.50(s，1H)，8.46(s，1H)，8.18(d，1H，J＝3.6Hz)，8.12(d，1H，J＝2.1Hz)，8.09(s，1H)，7.95(m，2H)，7.69(s，1H)，7.49(d，2H，J＝5.1Hz)，7.29(s，2H)，7.06(d，1H，J＝8.1Hz)，2.52(s，3H)；LCMS(m/z)：441(MH +)。
IV-7:5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-[4-(1,3-oxazole-5-yl) phenyl]-2, the 4-pyrimidinediamine
[1145] 1H?NMR(DMSO?d 6，300MHz)：δ9.54(s，1H)，9.48(s，1H)，8.39(s，1H)，8.13(d，1H，J＝3.6Hz)，8.06(d，1H，J＝2.4Hz)，7.97(d，2H，J＝8.7Hz)，7.92(d，1H，J＝2.4Hz)，7.66(d，2H，J＝8.7Hz)，7.59(s，1H)，7.33(q，1H，J＝4.8Hz)，7.24(d，1H，J＝8.4Hz)，2.47(s，3H)，2.42(d，3H，J＝4.8Hz)，；LCMS(m/z)：455(MH +)。
IV-8:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(1,3-oxazole-5-yl) phenyl]-2, the 4-pyrimidinediamine
[1146] 1H?NMR(DMSO?d 6，300MHz)：δ9.65(s，1H)，9.59(s，1H)，8.41(s，1H)，8.18(d，1H，J＝3.6Hz)，7.98(s，1H)，7.81(m，4H)，7.64(s，1H)，7.55(d，2H，J＝9.0Hz)，7.47(m，1H)；LCMS(m/z)：427(MH +)。
IV-3:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[3-(1,3-oxazole-5-yl) phenyl]-2, the 4-pyrimidinediamine
[1147] 1H?NMR(DMSO?d 6，300MHz)：δ9.68(s，1H)，9.62(s，1H)，8.40(s，1H)，8.19(d，1H，J＝3.6Hz)，7.93(d，2H，J＝8.7Hz)，7.83(d，2H，J＝8.7Hz)，7.66(m，5H)，7.13(s，2H)；LCMS(m/z)：427(MH +)。
IV-4:5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-[3-(1,3-oxazole-5-yl) phenyl]-2, the 4-pyrimidinediamine
[1148] 1H?NMR(DMSO?d 6，300MHz)：δ9.51(s，1H)，9.45(s，1H)，8.39(s，1H)，8.14(d，1H，J＝3.6Hz)，8.02(s，1H)，7.97-7.85(m，3H)，7.61(s，1H)，7.43(d，2H，J＝5.1Hz)，7.33(q，1H，J＝4.8Hz)，7.03(d，1H，J＝8.1Hz)，2.41(d，6H，J＝4.8Hz)；LCMS(m/z)：455(MH +)。
II-15:N2-[3,5-two (amino-sulfonyl) phenyl)-5-fluoro-N4-[4-(3-pyridyl oxygen base) phenyl]-2, the 4-pyrimidinediamine
[1149] 1H?NMR(DMSO?d 6，300MHz)：δ9.84(s，1H)，9.52(s，1H)，8.40(d，1H，J＝1.5Hz)，8.34(m，2H)，8.16(t，2H，J＝3.6Hz)，7.93(d，2H，J＝8.7Hz)，7.79(t，1H，J＝1.5Hz)，7.50(s，4H)，7.39(m，2H)，7.06(d，2H，J＝9.0Hz)；LCMS(m/z)：532(MH +)。
III-94:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-methyl isophthalic acid-imidazolyl methyl) phenyl]-2, the 4-pyrimidinediamine
[1150] 1H?NMR(DMSO?d 6，300MHz)：δ9.48(s，1H)，9.41(s，1H)，8.10(t，2H，J＝3.9Hz)，7.92(m，1H)，7.78(d，2H，J＝8.4Hz)，7.33(d，2H，J＝4.8Hz)，7.25(s，2H)，7.11(d，3H，J＝8.4Hz)，6.76(s，1H)，5.09(s，2H)，2.24(s，3H)；LCMS(m/z)：454(MH +)。
I-192:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-pyridyl)-methylene radical thio-phenyl]-2, the 4-pyrimidinediamine
[1151] 1H?NMR(DMSO?d 6，300MHz)：δ9.60(s，1H)，9.49(s，1H)，8.48(s，1H)，8.45(d，1H，J＝4.8Hz)，8.19(d，1H，J＝3.9Hz)，8.16(s，1H)，7.98(m，1H)，7.86(d，2H，J＝9.0Hz)，7.74(d，1H，J＝7.8Hz)，7.42(m，2H)，7.34(m，4H)，7.18(s，2H)，4.26(s，2H)；LCMS(m/z)：483(MH +)。
VI-94:N2-(4-amino-sulfonyl) phenyl-5-fluoro-N4-(4-sulphomethyl carbonyl) phenyl-2, the 4-pyrimidinediamine
[1152] 1H NMR (DMSO-d 6): δ 2.81 (t, J=7.5Hz, 1H), 3.74 (d, J=7.5Hz, 2H), 7.11 (br, 2H), 7.30 (d, J=8.1Hz, 2H), 7.62 (d, J=8.4Hz, 2H), 7.68 (d, J=8.1Hz, 2H), 7.80 (d, J=9.3Hz, 2H), 8.13 (d, J=3.6Hz, 1H), 9.42 (br, 1H), 9.59 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.61; LCMS: purity: 79.54%; MS (m/e): 406.05 (M-28).
VI-95:N2-(3-amino-sulfonyl-4-methyl) phenyl-5-fluoro-N4-(4-sulphomethyl carbonyl) phenyl-2, the 4-pyrimidinediamine
[1153] 1H NMR (DMSO-d 6): δ 2.50 (s, 3H), 2.82 (t, J=7.5Hz, 1H), 3.72 (d, J=7.2Hz, 2H), 7.18 (d, J=8.7Hz, 1H), 7.23 (br, 2H), 7.28 (d, J=8.4Hz, 2H), 7.73 (d, J=8.7Hz, 2H), 7.90 (dd, J=8.4Hz, 1H), 8.07 (d, J=3.9Hz, 1H), 8.11 (d, J=2.1Hz, 1H), 9.33 (br, 1H), 9.40 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.55; LCMS: purity: 98.63%; MS (m/e): 420.06 (M-28).
III-41:N2-(4-amino-sulfonyl) phenyl-N4-(4-cyclopropyl carbonyl amino methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[1154] 1H NMR (DMSO-d 6): δ 0.65-0.72 (m, 4H), 1.61 (m, 1H), 4.26 (d, J=6.3Hz, 2H), 7.12 (br, 2H), 7.22 (d, J=8.4Hz, 2H), 7.62 (d, J=8.7Hz, 2H), 7.70 (d, J=8.1Hz, 2H), 7.81 (d, J=8.7Hz, 2H), 8.13 (d, J=3.9Hz, 1H), 8.54 (t, J=5.7Hz, 1H), 9.42 (br, 1H), 9.58 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.16; LCMS: purity: 98.07%; MS (m/e): 457.29 (MH+).
III-42:N2-(3-amino-sulfonyl) phenyl-N4-(4-cyclopropyl carbonyl amino methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[1155] 1H NMR (DMSO-d 6): δ 0.65-0.72 (m, 4H), 1.60 (m, 1H), 4.24 (d, J=6.0Hz, 2H), 7.20 (d, J=8.7Hz, 2H), 7.26 (br, 2H), 7.35 (m, 2H), 7.71 (d, J=8.4Hz, 2H), 7.94 (dt, J=2.1,6.6Hz, 1H), 8.06 (s, 1H), 8.11 (d, J=3.6Hz, 1H), 8.52 (t, J=6.0Hz, 1H), 9.47 (br, 1H), 9.56 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.79; LCMS: purity: 96.52%; MS (m/e): 457.46 (MH+).
III-43:N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-(4-cyclopropyl carbonyl amino methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[1156] 1H NMR (DMSO-d 6): δ 0.66-0.72 (m, 4H), 1.63 (m, 1H), 2.52 (s, 3H), 4.25 (d, J=5.7Hz, 2H), 7.20 (d, J=8.4Hz, 2H), 7.22 (d, J=2.1Hz, 1H), 7.28 (br, 2H), 7.66 (d, J=8.4Hz, 2H), 7.81 (dd, J=2.4,8.1Hz, 1H), 7.97 (s, 1H), 8.15 (d, J=4.2Hz, 1H), 8.54 (t, J=5.7Hz, 1H), 9.80 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-201.18; LCMS: purity: 99.45%; MS (m/e): 471.57 (MH+).
III-125:N2-(4-amino-sulfonyl) phenyl-N4-[4-(N-carbamyl-N-propyl group) amino methyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine
[1157] 1H NMR (DMSO-d 6): δ 0.91 (t, J=7.5Hz, 3H), 1.65 (q, J=7.5Hz, 2H), 2.84 (m, 2H), 4.11 (s, 2H), 7.14 (br, 2H), 7.47 (d, J=8.7Hz, 2H), 7.66 (d, J=8.7Hz, 2H), 7.81 (d, J=8.7Hz, 2H), 7.87 (d, J=8.4Hz, 2H), 8.19 (d, J=3.6Hz, 1H), 8.87 (br, 2H), 9.55 (br, 1H), 9.67 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.11; LCMS: purity: 100%; MS (m/e): 431.45 (M-42).
III-126:N2-(3-amino-sulfonyl) phenyl-N4-[4-(N-carbamyl-N-propyl group) amino methyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine
[1158] 1H NMR (DMSO-d 6): δ 0.91 (t, J=7.2Hz, 3H), 1.65 (q, J=7.5Hz, 2H), 2.84 (m, 2H), 4.09 (s, 2H), 7.28 (br, 2H), 7.36 (t, J=7.8Hz, 1H), 7.41 (d, J=8.7Hz, 1H), 7.46 (d, J=7.8Hz, 2H), 7.90 (d, J=8.1Hz, 2H), 7.95 (d, J=8.4Hz, 1H), 8.09 (s, 1H), 8.16 (dd, J=1.2,3.6Hz, 1H), 8.94 (br, 2H), 9.50 (br, 1H), 9.58 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.56; LCMS: purity: 98.40%; MS (m/e): 431.15 (M-42).
III-127:N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-[4-(N-carbamyl-N-propyl group) amino methyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine
[1159] 1H NMR (DMSO-d 6): δ 0.90 (t, J=7.2Hz, 3H), 1.66 (q, J=7.5Hz, 2H), 2.52 (s, 3H), 2.82 (m, 2H), 4.09 (s, 2H), 7.24 (d, J=8.7Hz, 1H), 7.27 (br, 2H), 7.47 (d, J=8.7Hz, 2H), 7.87 (d, J=8.7Hz, 3H), 8.04 (s, 1H), 8.16 (d, J=3.6Hz, 1H), 9.02 (br, 2H), 9.65 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-201.58; LCMS: purity: 96.79%; MS (m/e): 445.20 (M-42).
III-35:N2-(4-amino-sulfonyl) phenyl-N4-(4-ethyl carbonylamino methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[1160] 1H NMR (DMSO-d 6): δ 1.03 (t, J=7.5Hz, 3H), 2.15 (q, J=7.5Hz, 2H), 4.24 (d, J=6.3Hz, 2H), 7.13 (br, 2H), 7.21 (d, J=8.4Hz, 2H), 7.61 (d, J=8.7Hz, 2H), 7.67 (d, J=8.7Hz, 2H), 7.80 (d, J=8.1Hz, 2H), 8.13 (d, J=3.6Hz, 1H), 8.26 (t, J=6.3Hz, 1H), 9.41 (br, 1H), 9.58 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.68; LCMS: purity: 84.18%; MS (m/e): 445.55 (MH+).
III-36:N2-(3-amino-sulfonyl) phenyl-N4-(4-ethyl carbonylamino methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[1161] 1H NMR (DMSO-d 6): δ 1.03 (t, J=7.5Hz, 3H), 2.14 (q, J=7.5Hz, 2H), 4.22 (d, J=6.0Hz, 2H), 7.19 (d, J=8.4Hz, 2H), 7.25 (br, 2H), 7.34 (m, 2H), 7.72 (d, J=8.4Hz, 2H), 7.95 (dt, J=2.1,7.8Hz, 1H), 8.09 (s, 1H), 8.10 (d, J=3.6Hz, 1H), 8.23 (t, J=6.0Hz, 1H), 9.36 (br, 1H), 9.49 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.05; LCMS: purity: 90.32%; MS (m/e): 445.17 (MH+).
III-37:N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-(4-ethyl carbonylamino methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[1162] 1H NMR (DMSO-d 6): δ 1.03 (t, J=7.5Hz, 3H), 2.14 (q, J=7.5Hz, 2H), 2.49 (s, 3H), 4.22 (d, J=6.3Hz, 2H), 7.16 (d, J=8.4Hz, 1H), 7.18 (d, J=8.7Hz, 2H), 7.22 (br, 2H), 7.72 (d, J=8.4Hz, 2H), 7.89 (dd, J=2.1,7.8Hz, 1H), 8.06 (d, J=3.6Hz, 1H), 8.09 (d, J=2.1Hz, 1H), 8.23 (t, J=6.0Hz, 1H), 9.32 (br, 1H), 9.38 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.60; LCMS: purity: 88.90%; MS (m/e): 459.62 (MH+).
III-113:N4-(3-amino carbonyl amino methyl) phenyl-N2-(4-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[1163] 1H NMR (DMSO-d 6): δ 4.18 (s, 2H), 6.49 (br, 1H), 7.02 (d, J=7.5Hz, 1H), 7.14 (br, 2H), 7.30 (t, J=7.8Hz, 1H), 7.59 (br, 2H), 7.63 (d, J=9.3Hz, 2H), 7.77 (d, J=9.0Hz, 2H), 8.18 (d, J=3.9Hz, 1H), 9.70 (br, 1H), 9.77 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-200.91; LCMS: purity: 89.57%; MS (m/e): 432.18 (MH+).
III-114:N4-(3-amino carbonyl amino methyl) phenyl-N2-(3-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[1164] 1H NMR (DMSO-d 6): δ 4.16 (s, 2H), 6.47 (br, 1H), 6.98 (d, J=7.5Hz, 1H), 7.28 (m, 3H), 7.40 (m, 2H), 7.63 (m, 2H), 7.92 (m, 1H), 7.99 (s, 1H), 8.17 (d, J=4.2Hz, 1H), 9.78 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-200.79; LCMS: purity: 97.93%; MS (m/e): 432.14 (MH+).
III-115:N4-(3-amino carbonyl amino methyl) phenyl-N2-(3-amino-sulfonyl-4-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[1165] 1H NMR (DMSO-d 6): δ 2.49 (s, 3H), 4.17 (d, J=6.6Hz, 2H), 5.53 (br, 2H), 6.43 (t, 1H), 6.94 (d, J=7.8Hz, 1H), 7.23 (m, 4H), 7.68 (m, 2H), 7.90 (dd, J=6.0Hz, 1H), 8.07 (d, J=3.6Hz, 1H), 8.11 (d, 1H), 9.34 (br, 1H), 9.36 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.31; LCMS: purity: 86.53%; MS (m/e): 446.55 (MH+).
III-38:N2-(4-amino-sulfonyl) phenyl-N4-(3-cyclopropyl carbonyl amino methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[1166] 1H NMR (DMSO-d 6): δ 0.64-0.70 (m, 4H), 1.61 (m, 1H), 4.28 (d, J=6.0Hz, 2H), 7.02 (d, J=6.9Hz, 1H), 7.13 (br, 2H), 7.31 (t, J=7.8Hz, 1H), 7.60 (d, J=8.1Hz, 2H), 7.64 (m, 2H), 7.77 (d, J=8.7Hz, 2H), 8.18 (d, J=3.9Hz, 1H), 8.57 (t, J=6.0Hz, 1H), 9.69 (br, 1H), 9.73 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-200.90; LCMS: purity: 98.26%; MS (m/e): 457.49 (MH+).
III-39:N2-(3-amino-sulfonyl) phenyl-N4-(3-cyclopropyl carbonyl amino methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[1167] 1H NMR (DMSO-d 6): δ 0.64-0.71 (m, 4H), 1.61 (m, 1H), 4.27 (d, J=5.7Hz, 2H), 6.97 (d, J=7.2Hz, 1H), 7.29 (m, 3H), 7.38 (m, 2H), 7.64 (s, 1H), 7.70 (d, J=9.0Hz, 1H), 7.93 (d, J=6.9Hz, 1H), 8.01 (s, 1H), 8.16 (d, J=3.9Hz, 1H), 8.55 (t, J=6.0Hz, 1H), 9.67 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-200.98; LCMS: purity: 93.15%; MS (m/e): 457.13 (MH+).
III-40:N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-(3-cyclopropyl carbonyl amino methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[1168] 1H NMR (DMSO-d 6): δ 0.64-0.70 (m, 4H), 1.61 (m, 1H), 2.48 (s, 3H), 4.26 (d, J=5.7Hz, 2H), 6.98 (d, J=8.1Hz, 1H), 7.26 (m, 4H), 7.62 (s, 1H), 7.68 (d, J=8.4Hz, 1H), 7.84 (d, J=8.4Hz, 1H), 8.01 (s, 1H), 8.13 (d, J=4.2Hz, 1H), 8.54 (t, 1H), 9.60 (br, 1H), 9.70 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.36; LCMS: purity: 98.87%; MS (m/e): 471.61 (MH+).
III-122:N2-(4-amino-sulfonyl) phenyl-N4-[4-(2-ethylamino carbonylamino) ethyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine
[1169] 1H NMR (DMSO-d 6): δ 0.97 (t, J=7.2Hz, 3H), 2.67 (t, J=7.2Hz, 2H), 2.98 (q, J=7.2Hz, 2H), 3.22 (t, J=7.8Hz, 2H), 7.16 (br, 2H), 7.17 (d, J=8.4Hz, 2H), 7.62 (d, J=9.0Hz, 2H), 7.64 (d, J=8.7Hz, 2H), 7.78 (d, J=9.3Hz, 2H), 8.14 (d, J=3.9Hz, 1H), 9.50 (br, 1H), 9.67 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.40; LCMS: purity: 98.96%; MS (m/e): 474.56 (MH+).
III-123:N2-(3-amino-sulfonyl) phenyl-N4-[4-(2-ethylamino carbonylamino) ethyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine
[1170] 1H NMR (DMSO-d 6): δ 0.97 (t, J=7.2Hz, 3H), 2.64 (t, J=7.2Hz, 2H), 2.98 (t, J=6.0Hz, 2H), 3.16 (m, 2H), 7.14 (d, J=8.1Hz, 2H), 7.25 (br, 2H), 7.36 (m, 2H), 7.71 (d, J=8.1Hz, 2H), 7.95 (d, J=6.6Hz, 1H), 8.09 (d, J=3.3Hz, 2H), 9.32 (br, 1H), 9.49 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.04; LCMS: purity: 96.25%; MS (m/e): 474.55 (MH+).
III-124:N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-[4-(2-ethylamino carbonylamino) ethyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine
[1171] 1H NMR (DMSO-d 6): δ 0.96 (t, J=7.2Hz, 3H), 2.51 (s, 3H), 2.64 (t, J=7.2Hz, 2H), 2.98 (q, J=7.2Hz, 2H), 3.20 (t, J=7.5Hz, 2H), 7.15 (d, J=8.1Hz, 2H), 7.20 (d, J=8.4Hz, 1H), 7.26 (br, 2H), 7.66 (d, J=8.1Hz, 2H), 7.82 (d, J=8.1Hz, 1H), 8.01 (s, 1H), 8.12 (d, J=4.2Hz, 1H), 9.67 (br, 2H); 19F NMR (282MHz, DMSO-d 6): δ-201.42; LCMS: purity: 90.25%; MS (m/e): 488.16 (MH+).
III-116:N2-(4-amino-sulfonyl) phenyl-N4-(3-ethylamino carbonylamino methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[1172] 1H NMR (DMSO-d 6): δ 0.97 (t, J=7.2Hz, 3H), 3.01 (p, J=6.6Hz, 2H), 4.20 (d, J=6.0Hz, 2H), 5.90 (t, J=5.4Hz, 1H), 6.31 (t, J=6.0Hz, 1H), 6.98 (d, J=8.1Hz, 1H), 7.12 (br, 2H), 7.28 (t, J=7.5Hz, 1H), 7.63 (d, J=8.7Hz, 4H), 7.80 (d, J=8.7Hz, 2H), 8.14 (d, J=3.6Hz, 1H), 9.47 (br, 1H), 9.58 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.50; LCMS: purity: 84.70%; MS (m/e): 460.19 (MH+).
III-117:N2-(3-amino-sulfonyl) phenyl-N4-(3-ethylamino carbonylamino methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[1173] 1H NMR (DMSO-d 6): δ 0.97 (t, J=7.2Hz, 3H), 3.02 (q, J=7.2Hz, 2H), 4.18 (s, 2H), 6.32 (br, 1H), 6.96 (d, J=7.5Hz, 1H), 7.29 (m, 3H), 7.39 (m, 2H), 7.65 (m, 2H), 7.93 (d, J=6.9Hz, 1H), 8.02 (s, 1H), 8.16 (d, J=4.2Hz, 1H), 9.70 (br, 2H); 19FNMR (282MHz, DMSO-d 6): δ-200.97; LCMS: purity: 94.77%; MS (m/e): 460.13 (MH+).
III-118:N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-(3-ethylamino carbonylamino methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine
[1174] 1H NMR (DMSO-d 6): δ 0.98 (t, J=7.2Hz, 3H), 2.50 (s, 3H), 3.02 (p, J=6.6Hz, 2H), 4.19 (d, J=6.0Hz, 2H), 5.86 (t, J=5.7Hz, 1H), 6.26 (t, J=5.7Hz, 1H), 6.93 (d, J=7.8Hz, 1H), 7.18 (d, J=8.4Hz, 1H), 7.22 (br, 2H), 7.26 (d, J=7.8Hz, 1H), 7.69 (m, 2H), 7.90 (dd, J=2.7,8.7Hz, 1H), 8.07 (d, J=3.6Hz, 1H), 8.11 (d, J=2.1Hz, 1H), 9.33 (br, 1H), 9.34 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.30; LCMS: purity: 98.09%; MS (m/e): 474.15 (MH+).
VII-13:N2-(4-amino-sulfonyl) phenyl-N4-[(N-ethylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-5-fluoro-2, the 4-pyrimidinediamine
[1175] 1H NMR (DMSO-d 6): δ 1.22 (t, J=7.5Hz, 3H), 2.86 (t, 2H), 3.13 (q, J=7.5Hz, 2H), 3.50 (t, J=6.0Hz, 2H), 4.40 (s, 2H), 7.13 (br, 2H), 7.15 (m, 1H), 7.57 (m, 2H), 7.61 (d, J=8.7Hz, 2H), 7.78 (d, J=8.7Hz, 2H), 8.14 (d, J=3.3Hz, 1H), 9.40 (br, 1H), 9.61 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.54; LCMS: purity: 94.58%; MS (m/e): 507.37 (MH+).
VII-14:N2-(3-amino-sulfonyl) phenyl-N4-[(N-ethylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-5-fluoro-2, the 4-pyrimidinediamine
[1176] 1H NMR (DMSO-d 6): δ 1.22 (t, J=7.2Hz, 3H), 2.86 (t, 2H), 3.13 (q, J=7.5Hz, 2H), 3.49 (t, 2H), 4.38 (s, 2H), 7.12 (d, J=9.0Hz, 1H), 7.26 (br, 2H), 7.36 (d, J=8.7Hz, 1H), 7.60 (m, 2H), 7.96 (d, 1H), 8.05 (s, 1H), 8.10 (d, J=3.9Hz, 1H), 9.34 (br, 1H), 9.50 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-201.96; LCMS: purity: 82.10%; MS (m/e): 507.37 (MH+).
VII-15:N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-[(N-ethylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-5-fluoro-2, the 4-pyrimidinediamine
[1177] 1H NMR (DMSO-d 6): δ 1.22 (t, J=7.2Hz, 3H), 2.85 (t, 2H), 3.13 (q, J=7.2Hz, 2H), 3.50 (t, J=5.7Hz, 2H), 4.38 (s, 2H), 7.12 (d, J=8.1Hz, 1H), 7.16 (d, J=8.7Hz, 1H), 7.24 (br, 2H), 7.59 (m, 2H), 7.89 (d, J=8.1Hz, 1H), 8.07 (m, 2H), 9.30 (br, 1H), 9.39 (br, 1H); 19F NMR (282MHz, DMSO-d 6): δ-202.55; LCMS: purity: 97.17%; MS (m/e): 521.14 (MH+).
III-23:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(4-cyano group ethylidene-2-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1178] 1H?NMR(DMSO-d 6)：δ9.198(s，1H)，8.984(s，1H)，8.015(bs，2H)，7.722-7.695(d，J＝8.1Hz，1H)，7.259(s，1H)，7.179(s，2H)，7.126(s，1H)，7.098(s，1H)，6.965-6.938(d，J＝8.1Hz，1H)，2.865-2.792(m，4H)，2.438(s，3H)，2.171(s，3H)，LCMS：441.11(MH+)。
III-24:N2-(3-amino-sulfonyl phenyl)-N4-(4-cyano group ethylidene-2-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1179] 1H?NMR(DMSO-d 6)：δ9.315(s，1H)，9.047(s，1H)，8.061-8.049(d，J＝3.6Hz，2H)，7.985(s，1H)，7.805-7.778(d，J＝8.1Hz，1H)，7.259-7.106(m，6H)，2.866-2.816(m，4H)，2.173(s，3H)，LCMS：427.38(MH+)。
III-25:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(4-cyano group ethylidene-3-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1180] 1H?NMR(DMSO-d 6)：δ9.395(s，1H)，8.089(s，2H)，7.920-7.891(d，J＝8.7Hz，1H)，7.503-7.476(d，J＝8.1Hz，1H)，7.315(s，1H)，7.175-7.124(t，3H)，3.742(s，3H)，2.811-2.727(m，4H)，LCMS：457.07(MH+)。
III-26:N2-(3-amino-sulfonyl phenyl)-N4-(4-cyano group ethylidene-2-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1181] 1H?NMR(DMSO-d 6)：δ9.512(s，1H)，9.400(bs，1H)，8.123-8.090(t，2H)，7.988-7.963(d，J＝7.5Hz，1H)，7.500-7.472(d，J＝8.4Hz，1H)，7.370-7.249(m，4H)，7.160-7.132(d，J＝8.4Hz，1H)，3.753(s，3H)，2.812-2.708(m，4H)，LCMS：443.08(MH+)。
IX-46:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(5-methoxycarbonyl-thiophene-2-yl)-2, the 4-pyrimidinediamine
[1182] 1H?NMR(DMSO-d 6)：δ11.120(s，1H)，9.541(s，1H)，8.194-8.183(d，J＝3.3Hz，1H)，8.139(s，1H)，7.618-7.604(d，J＝4.2Hz，1H)，7.261-7.234(m，3H)，6.996-6.983(d，J＝3.9Hz，1H)，3.773(s，3H)，2.527(s，3H)，LCMS：438.36(MH+)。
IX-47:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(5-methoxycarbonyl-thiophene-2-yl)-2, the 4-pyrimidinediamine
[1183] 1H?NMR(DMSO-d 6)：δ11.158(s，1H)，9.642(s，1H)，8.228-8.218(d，J＝3Hz，1H)，8.128(s，1H)，8.020-7.996(d，J＝7.2Hz，1H)，7.452-7.413(m，2H)，7.279(s，2H)，7.004-6.992(d，J＝3.6Hz，1H)，3.773(s，3H)，LCMS：424.32(MH+)。
IX-48:N2-(3-amino-sulfonyl-4-fluorophenyl)-5-fluoro-N4-(5-methoxycarbonyl-thiophene-2-yl)-2, the 4-pyrimidinediamine
[1184] 1H?NMR(DMSO-d 6)：δ11.20(bs，1H)，9.332(s，1H)，8.075-8.057(d，J＝5.4Hz，3H)，7.573-7.559(d，J＝4.2Hz，3H)，7.304-7.244(t，1H)，6.789(s，1H)，3.740(s，3H)，LCMS：442.26(MH+)。
IX-49:N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-(5-methoxycarbonyl-thiophene-2-yl)-2, the 4-pyrimidinediamine
[1185] 1H?NMR(DMSO-d 6)：δ11.166(s，1H)，9.437(s，1H)，8.053(s，1H)，7.930-7.901(d，J＝8.7Hz，2H)，7.692-7.664(d，J＝8.4Hz，2H)，7.591(s，1H)，7.113(s，2H)，6.808(s，1H)，3.757(s，3H)，LCMS：423.97(MH+)。
III-28:N4-(3-chloro-4-cyano group ethylidene-phenyl)-5-fluoro-N2-(4-methyl-3-propionyl amino-sulfonyl phenyl)-2, the 4-pyrimidinediamine
[1186] 1H?NMR(DMSO-d 6)：δ12.029(s，1H)，9.586(s，1H)，9.509(s，1H)，8.149-7.137(m，2H)，8.041-8.012(d，J＝8.7Hz，1H)，7.873(s，1H)，7.849-7.821(d，J＝8.4Hz，1H)，7.371-7.343(d，J＝8.4Hz，1H)，7.252-7.225(d，J＝8.1Hz，1H)，2.996-2.952(t，2H)，2.843-2.797(t，2H)，2.273-2.199(q，2H)，0.906-0.857(t，3H)，LCMS：517.38(MH+)。
III-29:N4-(3-chloro-4-cyano group ethylidene-phenyl)-5-fluoro-N2-(4-methyl-3-propionyl amino-sulfonyl phenyl)-2,4-pyrimidinediamine sodium salt
[1187] 1H?NMR(DMSO-d 6)：δ9.395(s，1H)，9.306(s，1H)，8.097-8.085(d，J＝3.6Hz，1H)，7.922-7.875(m，2H)，7.840(s，1H)，7.780-7.754(d，J＝7.8Hz，1H)，7.375-7.347(d，J＝8.4Hz，1H)，6.997-6.970(d，J＝8.1Hz，1H)，2.991-2.945(t，2H)，2.837-2.788(t，2H)，2.421(s，3H)，1.938-1.863(q，2H)，0.873-0.824(t，3H)，LCMS：514.83(MH+)。
VII-73:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(2-hydroxy-4-methyl quinoline-6-yl)-2, the 4-pyrimidinediamine
[1188] 1H?NMR(DMSO-d 6)：δ11.527(s，1H)，9.460(s，1H)，9.356(s，1H)，8.077(s，2H)，8.030-8.010(d，J＝6.0Hz，1H)，7.889(s，1H)，7.850(s，1H)，7.297-7.268(d，J＝8.7Hz，1H)，7.219(s，2H)，7.076-7.048(d，J＝8.4Hz，1H)，6.382(s，1H)，3.146(s，3H)，2.339(s，2H)，2.076(s，1H)，LCMS：454.92(MH+)。
VII-74:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(2-hydroxy-4-methyl quinoline-6-yl)-2, the 4-pyrimidinediamine
[1189] 1H?NMR(DMSO-d 6)：δ11.531(s，1H)，9.502(s，1H)，9.468(s，1H)，8.117-7.900(m，3H)，7.303-7.243(m，3H)，3.150(s，3H)，2.352(s，2H)，2.074(s，1H)，LCMS：440.94(MH+)。
III-30:N4-(4-cyano group ethylidene-3-trifluoromethyl)-5-fluoro-N2-(4-methyl-3-amino-sulfonyl phenyl)-2, the 4-pyrimidinediamine
[1190] 1H?NMR(DMSO-d 6)：δ9.647(s，1H)，9.506(s，1H)，8.345-8.319(d，J＝7.8Hz，1H)，8.152-8.141(d，J＝3.3Hz，1H)，8.065(s，1H)，7.941(s，1H)，7.891-7.864(d，J＝8.1Hz，1H)，7.541-7.513(d，J＝8.4Hz，1H)，7.244(s，2H)，7.193-7.166(d，J＝8.1Hz，1H)，3.044-2.998(t，2H)，2.883-2.836(t，2H)，LCMS：495.62(MH+)。
III-31:N4-(4-cyano group ethylidene-3-trifluoromethyl)-5-fluoro-N2-(3-amino-sulfonyl phenyl)-2, the 4-pyrimidinediamine
[1191] 1H?NMR(DMSO-d 6)：δ9.603(s，1H)，8.341-8.313(d，J＝8.4Hz，1H)，8.175-8.164(d，J＝3.3Hz，1H)，8.059(s，1H)，7.948(s，2H)，7.546-7.517(d，J＝8.7Hz，1H)，7.385-7.348(m，2H)，3.044-2.996(t，2H)，2.882-2.834(t，2H)，LCMS：481.55(MH+)。
III-47:N4-[4-(the amino carboxyl ethylidene of 2-) phenyl]-5-fluoro-N2-(4-methyl-3-amino-sulfonyl phenyl)-2, the 4-pyrimidinediamine
[1192] 1H?NMR(DMSO-d 6)：δ9.374(s，1H)，9.258(s，1H)，8.115(s，1H)，8.056-8.044(d，J＝3.6Hz，1H)，7.909-7.881(d，J＝8.4Hz，1H)，7.699-7.670(d，J＝8.7Hz，2H)，7.269-7.128(m，6H)，6.740(s，1H)，2.799-2.748(t，2H)，2.370-2.319(t，2H)，LCMS：445.11(MH+)。
III-48:N4-[4-(the amino carboxyl ethylidene of 2-) phenyl]-N2-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1193] 1H?NMR(DMSO-d 6)：δ9.486(s，1H)，9.301(s，1H)，8.094(bs，2H)，7.969-7.942(d，J＝8.1Hz，2H)，7.374-7.341(m，2H)，7.248(bs，3H)，7.164-7.137(d，J＝8.1Hz，2H)，6.743(s，1H)，2.800-2.750(t，2H)，2.370-2.321(t，2H)，LCMS：431.10(MH+)。
III-49:N4-[4-(the amino carboxyl ethylidene of 2-) phenyl]-N2-(4-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1194] 1H?NMR(DMSO-d 6)：δ9.594(s，1H)，9.372(s，1H)，8.125-8.112(d，J＝3.9Hz，1H)，7.818(s，1H)，7.788(s，1H)，7.627-7.591(m，4H)，7.283(s，1H)，7.191-7.163(d，J＝8.4Hz，2H)，6.735(s，1H)，2.821-2.773(t，2H)，2.391-2.342(t，2H)，LCMS：431.05(MH+)。
VII-21:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[3, the 4-dihydro-(1H)-quinoline-2-one--6-yl]-5-fluoro-2, the 4-pyrimidinediamine
[1195] 1H?NMR(DMSO-d 6)：δ9.981(s，1H)，9.306(s，1H)，8.042-8.017(m，2H)，7.898-7.869(d，J＝8.7Hz，1H)，7.565-7.515(m，2H)，7.148-7.120(d，J＝8.4Hz，2H)，6.817-6.789(d，J＝8.4Hz，2H)，2.863-2.814(t，2H)，LCMS：443.05(MH+)。
VII-75:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(2-N, N '-dimethyl amine-quinoline-6-yl)-5-fluoro-2, the 4-pyrimidinediamine
[1196] 1H?NMR(DMSO-d 6)：δ9.393(s，2H)，8.270(s，1H)，8.081(bs，2H)，7.944-7.903(m，2H)，7.789-7.781(d，J＝2.4Hz，1H)，7.508-7.478(d，J＝9Hz，1H)，7.124-7.065(m，3H)，3.146(s，6H)，LCMS：467.99(MH+)。
VII-76:N2-(3-amino-sulfonyl phenyl)-N4-(2-N, N '-dimethyl amine-quinoline-6-yl)-5-fluoro-2, the 4-pyrimidinediamine
[1197] 1H?NMR(DMSO-d 6)：δ9.518(s，1H)，9.446(s，1H)，8.266(s，1H)，8.118-8.017(m，3H)，7.953-7.921(d，J＝9.6Hz，1H)，7.82-7.76(m，2H)，7.516-7.485(d，J＝9.3Hz，1H)7.331(s，2H)，7.265(s，2H)，7.099-7.068(d，J＝9.3Hz，1H)，3.147(s，6H)。
III-51:N2-(3-amino-sulfonyl phenyl)-N4-[(1-ethyl pyrazolyl-5-aminocarboxyl methylene radical) phenyl]-5-fluoro-2, the 4-pyrimidinediamine
[1198] 1H NMR (DMSO-d 6): δ 9.50 (s, 1H), 9.38 (s, 1H), 8.10 (s, 2H), 7.93 (bs, 2H), 7.75 (d, 2H, J=8.4Hz), 7.50 (s, 1H), 7.36 (m, 5H), 6.15 (s, 1H), 3.98 (d, 2H, J=7.8Hz), 3.66 (s, 2H), 1.24 (s, 3H): LCMS: purity: 99%; MS (m/e): 511 (MH +).
III-52:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-N4-[(1-ethyl pyrazolyl-5-aminocarboxyl methylene radical) phenyl]-5-fluoro-2, the 4-pyrimidinediamine
[1199] 1H NMR (DMSO-d 6): δ 9.39 (s, 1H), 9.34 (s, 1H), 8.10 (d, 2H, J=10.8Hz), 7.93 (d, 2H), 7.75 (d, 2H, J=7.8Hz), 7.29 (m, 4H), 6.15 (s, 1H), 3.98 (d, 2H, J=6.9Hz), 3.66 (s, 2H), 2.45 (s, 3H), 1.26 (t, 3H, J=6.3Hz): LCMS: purity: 87%; MS (m/e): 525 (MH +).
III-50:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N-4-[4 (1-methylpyrazole base-3-aminocarboxyl methylene radical) phenyl]-2, the 4-pyrimidinediamine
[1200] 1H NMR (DMSO-d 6): δ 8.09 (s, 2H), 7.96 (d, 1H, J=6.6Hz), 7.69 (d, 2H, J=8.1Hz), 7.49 (s, 1H), 7.31 (m, 4H), 6.39 (s, 1H), 3.72 (s, 3H), 3.56 (s, 2H): LCMS: purity: 92%; MS (m/e): 497 (MH +).
IV-12:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-(N-methylamino alkylsulfonyl) phenyl]-2, the 4-pyrimidinediamine
[1201] 1H NMR (DMSO-d 6): δ 8.40 (d, 1H, J=7.8Hz), 8.15 (d, 1H, J=3.6Hz), 8.09 (s, 1H), 7.96 (s, 1H), 7.84 (m, 1H), 7.55 (t, 1H, J=7.8Hz), 7.44 (d, 2H), 7.21 (m, 3H), 2.45 (s, 3H), 2.43 (s, 3H): LCMS: purity: 99%; MS (m/e): 467 (MH +).
IV-9:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[3-(N, N-dimethylamino alkylsulfonyl) phenyl]-2, the 4-pyrimidinediamine
[1202] 1H NMR (DMSO-d 6): δ 9.75 (s, 1H), 9.57 (s, 1H), 8.56 (bs, 1H), 8.19 (s, 1H, J=2.7Hz), 8.10 (s, 1H), 7.89 (m, 2H), 7.62 (m, 3H), 7.38 (s, 3H), 7.27 (s, 1H), 2.62 (s, 6H): LCMS: purity: 98%; MS (m/e): 467 (MH +).
IV-10:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-(N, N-dimethylamino alkylsulfonyl) phenyl]-2, the 4-pyrimidinediamine
[1203] 1H NMR (DMSO-d 6): δ 9.71 (s, 1H), 9.46 (s, 1H), 8.59 (d, 1H, J=8.4Hz), 8.16 (d, 1H, J=3.6Hz), 8.11 (d, 1H, J=2.4Hz), 7.85 (m, 2H), 7.58 (t, 1H, J=8.1Hz), 7.39 (d, 1H, 8.7Hz), 7.21 (m, 3H), 2.62 (s, 6H), 2.48 (s, 3H): LCMS: purity: 99%; MS (m/e): 481 (MH +).
IV-11:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[3-(N-methylamino alkylsulfonyl) phenyl]-2, the 4-pyrimidinediamine
[1204] 1H NMR (DMSO-d 6): δ 9.73 (s, 1H), 9.53 (σ, 1H), 8.40 (d, 1H, J=8.7Hz), 8.19 (s, 1H), 8.09 (s, 1H), 7.96 (m, 2H), 7.56 (m, 1H), 7.40 (m, 4H), 7.27 (s, 2H), 2.43 (s, 3H): LCMS: purity: 99%; MS (m/e): 453 (MH +).
VI-34:N2-(3-amino-sulfonyl-4-methoxyl group-5-aminomethyl phenyl)-5-fluoro-N4-(4-trifluoromethyl)-2, the 4-pyrimidinediamine
[1205] 1H NMR (DMSO-d 6): δ 9.53 (s, 1H), 9.36 (s, 1H), 8.13 (d, 1H, J=3.6Hz), 7.90 (d, 2H, J=9Hz), 7.80 (s, 2H), 7.30 (d, 2H, J=8.7Hz), 7.03 (s, 2H), 3.76 (s, 3H), 2.21 (s, 3H); LCMS: purity: 92%; MS (m/e): 488 (MH +).
VI-35:N2-(3-amino-sulfonyl phenyl)-N4-(4-tert-butyl-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1206] 1H NMR (DMSO-d 6): δ 9.47 (s, 1H), 9.32 (s, 1H), 8.09 (m, 2H), 7.94 (bd, 1H, J=6.9Hz), 7.69 (d, 2H, J=9Hz), 7.33 (m, 4H), 7.25 (s, 2H), 1.28 (s, 9H); LCMS: purity: 98%; MS (m/e): 416 (MH +)
VI-36:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(4-tert-butyl-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1207] 1H NMR (DMSO-d 6): δ 9.35 (s, 1H), 9.28 (s, 1H), 8.11 (bs, 1H), 8.04 (d, 1H, J=3.3Hz), 7.86 (bdd, 1H, J=8.1Hz), 7.67 (d, 2H, J=8.4Hz), 7.33 (d, 2H, J=8.4Hz), 7.21 (bs, 2H), 7.12 (m, 1H), 2.38 (s, 3H), 1.22 (s, 9H); LCMS: purity: 99%; MS (m/e): 430 (MH +).
VI-37:N2-(3-amino-sulfonyl-4-methoxyl group-5-aminomethyl phenyl)-N4-(4-tert-butyl-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1208] 1H NMR (DMSO-d 6): δ 8.28 (bs, 2H), 8.05 (d, 1H, J=3.9Hz), 7.86 (d, 1H, J=2.4Hz), 7.75 (bd, 1H), 7.64 (d, 2H, J=8.7Hz), 7.33 (d, 2H, J=8.7Hz), 7.01 (s, 2H), 3.75 (s, 3H), 3.31 (s, 3H), 1.27 (s, 9H); LCMS: purity: 96%; MS (m/e): 460 (MH +).
VI-38:N2-(3-amino-sulfonyl phenyl)-N4-(4-chloro-3-trifluoromethyl)-5-fluoro-2, the 4-pyrimidinediamine
[1209] 1H NMR (DMSO-d 6): δ 9.78 (s, 1H), 8.36 (bdd, 1H, J=9Hz), 8.21 (bd, 1H, J=2.1Hz), 8.10 (d, 1H, J=2.1Hz), 8.07 (s, 1H), 7.89 (bd, 1H, J=6.9Hz), 7.62 (d, 1H, J=9.3Hz), 7.38 (m, 2H), 7.27 (m, 2H); LCMS: purity: 99%; MS (m/e): 463 (MH +).
VI-39:N2-(3-amino-sulfonyl-4-methyl-phenyl)-N4-(4-chloro-3-trifluoromethyl)-5-fluoro-2, the 4-pyrimidinediamine
[1210] 1H NMR (DMSO-d 6): δ 9.74 (s, 1H), 9.51 (s, 1H), 8.38 (bd, 1H, J=8.7Hz), 8.17 (d, 1H, J=2.4Hz), 8.10 (s, 1H), 8.08 (s, 1H), 7.83 (d, 1H, J=8.1Hz), 7.61 (d, 1H, J=8.7Hz), 7.25 (s, 2H), 7.18 (d, 1H, J=8.1Hz), 7.09 (s, 1H), 2.50 (s, 3H); LCMS: purity: 96%; MS (m/e): 477 (MH +).
VI-40:N2-(3-amino-sulfonyl-4-methoxyl group-5-aminomethyl phenyl)-N4-(4-chloro-3-trifluoromethyl-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1211] 1H NMR (DMSO-d 6): δ 9.74 (s, 1H), 9.42 (s, 1H), 8.38 (bd, 1H, J=9Hz), 8.17 (d, 1H, J=1.8Hz), 8.08 (s, 1H), 7.81 (s, 1H), 7.75 (s, 1H), 7.61 (d, 1H, J=9Hz), 7.04 (s, 2H), 3.77 (s, 3H), 2.21 (s, 1H); LCMS: purity: 93%; MS (m/e): 507 (MH +).
VI-41:N2-(3-amino-sulfonyl-4-chloro-phenyl-)-5-fluoro-N4-(4-trifluorophenyl)-2, the 4-pyrimidinediamine
[1212] LCMS: purity: 96%; MS (m/e): 463 (MH +).
VI-42:N2-(3-amino-sulfonyl-4-chloro-phenyl-)-5-fluoro-N4-(4-Trifluoromethoxyphen-l)-2, the 4-pyrimidinediamine
[1213] 1H NMR (DMSO-d 6): δ 9.66 (s, 1H), 9.60 (s, 1H), 8.27 (d, 1H, J=1.8Hz), 8.15 (bdd, 1H, J=2.7Hz), 8.00 (bdd, 1H, J=1.5 and 9.0Hz), 7.91 (d, 2H, J=8.1Hz), 7.47 (s, 2H), 7.41 (d, 1H, J=8.7Hz), 7.32 (d, 2H, J=8.7Hz); LCMS: purity: 95%; MS (m/e): 478 (M +).
IX-21:N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(2-cyano group cumarone-5-yl)-5-fluoro-2, the 4-pyrimidinediamine
[1214] LCMS: purity: 91%; MS (m/e): 460 (MH +).
VI-43:N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(4-tert-butyl-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1215] 1H NMR (DMSO-d 6): δ 9.57 (s, 1H), 9.35 (s, 1H), 8.27 (d, 1H, J=2.7Hz), 8.09 (d, 1H, J=3.6Hz), 8.00 (dd, 1H, J=2.7 and 8.7Hz), 7.66 (d, 2H, J=8.4Hz), 7.44 (s, 2H), 7.36 (m, 3H), 1.22 (s, 9H); LCMS: purity: 94%; MS (m/e): 451 (MH +).
VI-44:N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(3-chloro-4-trifluoromethyl-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1216] LCMS: purity: 87%; MS (m/e): 497 (MH +).
III-62:N2-(3-amino-sulfonyl phenyl)-N4-(4-benzyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1217] 1H NMR (DMSO-d 6): δ 9.53 (s, 1H), 9.36 (s, 1H), 8.10 (d, 1H, J=2.7Hz), 8.02 (bs, 1H), 7.96 (bs, 1H), 7.83 (d, 1H, J=1.8Hz), 7.69 (bdd, 1H, J=9.3Hz), 7.47-7.31 (m, 9H), 7.26 (s, 1H), 7.18 (d, 1H, J=9Hz); LCMS: purity: 96%; MS (m/e): 450 (M +).
III-63:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(4-benzyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1218] 1H NMR (DMSO-d 6): δ 9.42 (s, 1H), 9.33 (s, 1H), 8.05 (m, 2H), 7.87 (m, 2H), 7.70 (bd, 1H, J=8.7Hz), 7.46-7.14 (m, 10H), 5.19 (s, 2H), 2.45 (s, 3H); LCMS: purity: 99%; MS (m/e): 465 (MH +).
III-64:N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(4-benzyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1219] 1H NMR (DMSO-d 6): δ 9.65 (s, 1H), 9.40 (s, 1H), 8.22 (d, 1H, J=2.1Hz), 8.10 (d, 1H, J=3.6Hz), (8.02 dd, 1H, J=2.7 and 9Hz), 7.81 (d, 1H, J=2.4Hz), 7.70 (dd, 1H, J=2.7 and 9Hz), 7.39 (m, 8H), 7.19 (d, 2H, J=9Hz), 5.20 (s, 2H); LCMS: purity: 99%; MS (m/e): 485 (MH +).
III-65:N2-(3-amino-sulfonyl-4-methoxyl group-5-aminomethyl phenyl)-N4-(4-benzyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1220] 1H NMR (DMSO-d 6): δ 9.37 (s, 2H), 8.08 (bs, 1H), 7.77 (m, 2H), 7.71 (bd, 1H, J=8.7Hz), 7.37 (m, 5H), 7.18 (m, 2H), 7.03 (s, 2H), 5.18 (s, 2H), 3.75 (s, 3H), 2.16 (s, 3H); LCMS: purity: 94%; MS (m/e): 495 (MH +).
VI-45:N2-(3-amino-sulfonyl-4-isopropyl phenyl)-N4-(3-chloro-4-methoxyl group-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1221] 1H NMR (DMSO-d 6): δ 10.25 (s, 2H), 8.25 (d, 1H, J=8.4Hz), 7.79 (m, 2H), 7.74 (d, 1H, J=1.8Hz), 7.57) dd, 1H, J=1.8 and 8.7Hz), 7.45 (m, 3H), 7.12 (d, 1H, J=8.7Hz), 3.83 (s, 3H), 3.77 (m, 1H), 1.19 (d, 6H, J=6.9Hz); LCMS: purity: 95%; MS (m/e): 467 (MH +).
RIX-22:N2-(3-amino-sulfonyl-4-isopropyl phenyl)-N4-(2-cyano group cumarone-5-yl)-5-fluoro-2, the 4-pyrimidinediamine
[1222] 1H NMR (DMSO-d 6): δ 9.53 (s, 1H), 9.41 (s, 1H), 8.29 (d, 1H, J=1.8Hz), 8.10 (d, 1H, J=3.6Hz), 8.03 (d, 1H, J=2.4Hz), 8.01 (d, 1H), 7.90 (d, 1H), 7.87 (d, 1H, J=2.1Hz), 7.70 (d, 1H, J=8.7Hz), 7.32 (m, 3H), 3.75 (m, 1H), 1.20 (d, 6H, J=6.6Hz); LCMS: purity: 95%; MS (m/e): 467 (MH +).
I-8:N2-(3-amino-sulfonyl-4-isopropyl phenyl)-N4-(4-cyano group methylene radical oxygen base phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1223] 1H NMR (DMSO-d 6): δ 9.71 (bs, 2H), 8.11 (d, 1H, J=4.2Hz), 7.95 (d, 1H, J=2.1Hz), 7.82 (dd, 1H, J=2.1 and 8.4Hz), 7.71 (d, 2H, J=8.7Hz), 7.40 (d, 1H, J=8.4Hz), 7.36 (s, 2H), 7.03 (d, 2H, J=9.3Hz), 5.25 (s, 2H), 3.75 (m, 1H), 1.19 (d, 6H, J=6.9Hz); LCMS: purity: 99%; MS (m/e): 457 (MH +).
N4-(4-amino-sulfonyl methylene radical phenyl)-N2-(3-amino-sulfonyl-4-methyl-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1224] 1H NMR (DMSO-d 6): δ 9.43 (s, 1H), 9.41 (s, 1H), 8.09 (m, 2H), 7.92 (dd, 1H, J=2.4 and 8.4Hz), 7.82 (d, 2H, J=8.4Hz), 7.29 (d, 2H, J=8.4Hz), 7.22 (s, 2H), 7.19 (d, 1H, J=7.2Hz), 6.80 (s, 2H), 4.23 (s, 2H), 2.21 (s, 3H); LCMS: purity: 99%; MS (m/e): 468 (MH +).
VI-46:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(4-trifluoromethyl methylene radical oxygen base phenyl)-2, the 4-pyrimidinediamine
[1225] 1H NMR (DMSO-d 6): δ 10.26 (bs, 2H), 8.24 (d, 1H, J=8.1Hz), 7.87 (s, 1H), 7.70 (bd, 1H, J=8.1Hz), 7.60 (d, 2H, J=9Hz), 7.34 (bs, 2H), 7.25 (d, 1H, J=8.1Hz), 7.04 (d, 2H, J=9Hz), 4.75 (q, 2H, J=8.7Hz); LCMS: purity: 98%; MS (m/e): 472 (MH +).
VI-47:N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(4-trifluoromethyl methylene radical oxygen base phenyl)-2, the 4-pyrimidinediamine
[1226] 1H NMR (DMSO-d 6): δ 10.20 (s, 1H), 10.09 (s, 1H), 8.23 (d, 1H, J=4.8Hz), 7.89 (s, 1H), 7.84 (m, 1H), 7.62 (d, 2H, J=8.7Hz), 7.45 (m, 2H), 7.34 (bs, 2H), 7.03 (d, 2H, J=8.7Hz), 4.75 (q, 2H, J=9Hz); LCMS: purity: 98%; MS (m/e): 458 (MH +).
VI-48:N2-(3-amino-sulfonyl-4-chloro-phenyl-)-5-fluoro-N4-(4-trifluoromethyl methylene radical oxygen base phenyl)-2, the 4-pyrimidinediamine
[1227] 1H NMR (DMSO-d 6): δ 10.23 (s, 1H), 10.03 (s, 1H), 8.23 (d, 1H, J=4.5Hz), 8.10 (d, 1H, J=2.1Hz), (7.87 dd, 1H, J=2.4 and 9Hz), 7.62 (d, 2H, J=8.7Hz), 7.54 (bs, 2H), 7.47 (d, 1H, J=9Hz), 7.05 (d, 2H, J=8.7Hz), 4.75 (q, 2H, J=6Hz); LCMS: purity: 98%; MS (m/e): 492 (M +).
V-16:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(2-cyano group ethylidene-thionaphthene-5-yl)-5-fluoro-2, the 4-pyrimidinediamine
[1228] 1H?NMR(DMSO-d 6)：δ9.423(s，2H)，8.305(s，1H)，8.096-8.070(m，2H)，7.938-7.903(d，J＝8.4Hz，1H)，7.846-7.818(d，J＝8.4Hz，1H)，7.670-7.634(d，J＝8.7Hz，1H)，7.233-7.217(m，3H)，7.154-7.127(d，J＝8.1Hz，1H)，3.238-3.192(t，2H)，2.974-2.928(t，3H)，2.065(s，3H)，LCMS：482.90(MH+)。
IX-45:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[(4R)-1-(2-cyano group ethanoyl)-tetramethyleneimine-4-yl)-and 5-fluoro-2, the 4-pyrimidinediamine
[1229] 1H?NMR(DMSO-d 6)：δ9.324(s，1H)，8.540(s，1H)，7.904-7.891(d，J＝3.9Hz，1H)，7.670-7.650(d，J＝6Hz，1H)，7.579-7.557(d，J＝6.6Hz，1H)，7.185(s，1H)，7.158(s，1H)，4.673(bs，1H)，3.705(bs，1H)，3.552-3.457(m，2H)，3.371-3.355(m，1H)，2.186(bs，1H)，2.032-1.979(m，1H)，LCMS：434.42(MH+)。
VI-113:N2, N4-pair-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1230] 1H NMR (DMSO-d 6): δ 9.75 (s, 1H), 9.52 (s, 1H), 8.20 (m, 2H), 8.11 (d, 2H, J=7.2Hz), 7.94 (d, 1H, J=8.1Hz), 7.52 (m, 2H), 7.41 (m, 4H), 7.27 (s, 2H): LCMS: purity: 94%; MS (m/e): 440 (MH +).
VI-114:N2, N4-pair-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1231] 1H NMR (DMSO-d 6): δ 9.61 (s, 1H), 9.33 (s, 1H), 8.23 (d, 2H, J=2.1Hz), 8.11 (d, 2H, J=1.8Hz), 8.02 (m, 1H), 7.88 (m, 1H), 7.40 (s, 2H), 7.31 (d, 1H, J=8.4Hz), 7.24 (s, 2H), 7.21 (d, 1H, J=8.4Hz), 2.55 (s, 6H): LCMS: purity: 89%; MS (m/e): 468 (MH +).
VI-115:N2, N4-pair-(3-amino-sulfonyl-4-chloro-phenyl-)-5-fluoro-2, the 4-pyrimidinediamine
[1232] 1H NMR (DMSO-d 6): δ 9.86 (s, 1H), 9.64 (s, 1H), 8.34 (d, 1H, J=2.7Hz), 8.28 (d, 1H, J=3.0Hz), 8.24 (d, 1H, J=2.7Hz), 8.20 (d, 1H, J=3.6Hz), 8.01 (m, 1H), 7.63 (s, 1H), 7.57 (d, 1H, J=8.7Hz), 7.49 (s, 1H), 7.46 (s, 1H): LCMS: purity: 91%; MS (m/e): 508 (MH +).
IX-17:N2-[3-amino-sulfonyl-4-(4-methylpiperazine-1-yl) phenyl]-N4-(3-cyano group methylene radical-1H-indoles-6-yl)-5-fluoro-2, the 4-pyrimidinediamine
[1233] LCMS: purity: 94%; MS (m/e): 537 (MH +).
IX-18:N2-[3-amino-sulfonyl-4-(4-methylpiperazine-1-yl) phenyl]-N4-(3-cyano group methylene radical-1H-indoles-7-yl)-5-fluoro-2, the 4-pyrimidinediamine
[1234] LCMS: purity: 96%; MS (m/e): 537 (MH +).
VI-116:N2-[3-amino-sulfonyl-4-(4-methylpiperazine-1-yl) phenyl]-N4-(3-chloro-4-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
[1235] LCMS: purity: 92%; MS (m/e): 523 (MH +).
IX-19:N4-(3-cyano group methylene radical-1H-draws diindyl-5-yl)-5-fluoro-N2-[3-(1-methyl-4-amino piperidine) alkylsulfonyl-4-aminomethyl phenyl]-2, the 4-pyrimidinediamine
[1236] LCMS: purity: 97%; MS (m/e): 549 (MH +).
I-78:N2-(3-amino-sulfonyl phenyl)-N4-[4-(N-cyano group ethanoyl) aminophenyl]-5-fluoro-2, the 4-pyrimidinediamine.
[1237] 1H NMR (DMSO-d 6): δ 8.10 (s, 2H), 7.95 (s, 1H), 7.80 (s, 2H), 7.55 (s, 2H), 7.34 (s, 1H), 7.26 (s, 1H), 3.88 (s, 2H): LCMS: purity: 96%; MS (m/e): 442 (MH +).
I-79:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[4-(N-cyano group ethanoyl) aminophenyl]-5-fluoro-2, the 4-pyrimidinediamine
[1238] 1H NMR (DMSO-d 6): δ 8.11 (s, 1H), 8.06 (s, 1H), 7.78 (d, 1H, J=8.7Hz), 7.50 (d, 2H, J=8.7Hz), 7.17 (m, 3H), 3.88 (s, 2H): LCMS: purity: 91%; MS (m/e): 456 (MH +).
I-80:N2-(3-amino-sulfonyl phenyl)-5-fluorine N4-[3-methyl-4-(N-cyano group ethanoyl) aminophenyl]-2, the 4-pyrimidinediamine
[1239] 1H NMR (DMSO-d 6): δ 8.11 (d, 1H, J=3.6Hz), 8.03 (s, 1H), 7.98 (d, 1H, J=6.6Hz), 7.58 (s, 2H), 7.35 (d, 2H, J=9.0Hz), 7.26 (s, 1H), 3.91 (s, 2H), 2.19 (s, 3H): LCMS: purity: 92%; MS (m/e): 456 (MH +).
I-81:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluorine N4-[3-methyl 4-(N-cyano group ethanoyl) aminophenyl]-2, the 4-pyrimidinediamine
[1240] 1H NMR (DMSO-d 6): δ 8.07 (s, 1H), 7.89 (s, 1H), 7.60 (s, 1H), 7.23 (m, 5H), 3.90 (s, 2H), 2.49 (s, 3H), 2.18 (s, 3H): LCMS: purity: 98%; MS (m/e): 470 (MH +).
I-82:N2-(3-amino-sulfonyl phenyl)-N4-[3-chloro-4-(N-cyano group ethanoyl) aminophenyl]-5-fluoro-2, the 4-pyrimidinediamine
[1241] 1H NMR (DMSO-d 6): δ 8.17 (d, 1H, J=3.6Hz), 8.06 (s, 1H), 7.96 (d, 1H, J=5.4Hz), 7.85 (d, 1H, J=8.7Hz)), 7.59 (s, 1H), 7.40 (s, 1H), 7.36 (d, 1H, J=8.1Hz), 7.26 (s, 1H), 3.97 (s, 2H): LCMS: purity: 97%; MS (m/e): 476 (MH +).
I-83:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[3-chloro-4-(N-cyano group ethanoyl) aminophenyl]-5-fluoro-2, the 4-pyrimidinediamine
[1242] 1H NMR (DMSO-d 6): δ 8.13 (d, 1H, J=3.3), 7.89 (d, 1H, J=2.1) 7.85 (m, 1H), 7.59 (d, 1H, J=9.0Hz), 7.21 (m, 2H), 3.97 (s, 2H), 2.49s, 3H): LCMS: purity: 90%; MS (m/e): 490 (MH +).
I-84:N2-(3-amino-sulfonyl phenyl)-5-fluorine N4-[3-methoxyl group-4-(N-cyano group ethanoyl) aminophenyl]-2, the 4-pyrimidinediamine
[1243] 1H NMR (DMSO-d 6): δ 9.55 (s, 1H) .50 (s, 1H), 9.39 (s, 1H), 8.11 (s, and 1H) 7.98 (d, 1H, J=7.2Hz), 7.81 (d, 1H, J=8.4Hz), 7.53 (d, 1H, J=9.3Hz), 7.41 (s, 1H), 7.34 (s, 2H), 7.25 (s, 1H), 3.96 (s, 2H), 3.78 (s, 3H): LCMS: purity: 93%; MS (m/e): 472 (MH +).
I-85:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluorine N4-[3-methoxyl group-4-(N-cyano group ethanoyl) aminophenyl]-2, the 4-pyrimidinediamine
[1244] 1H NMR (DMSO-d 6): δ 9.55 (s, 1H), 9.39 (s, 1H), 9.35 (s, 1H), 8.08 (t, 3H, J=2.4) 7.92 (d, 1H, J=8.1Hz), 7.81 (d, 1H, J=8.7Hz), 7.53 (d, 1H, J=9.6Hz), 7.41 (s, 1H), 7.23 (s, 2H), 7.17 (d, 1H, J=7.8Hz), 3.96 (s, 2H), 3.77 (s, 3H), 2.49 (s, 3H): LCMS: purity: 93%; MS (m/e): 486 (MH +).
I-86:N2-(3-amino-sulfonyl phenyl)-N4-[4-(N-cyano group ethanoyl-N-methyl) aminophenyl]-5-fluoro-2, the 4-pyrimidinediamine
[1245] 1H NMR (DMSO-d 6): δ 8.17 (d, 1H, J=3.6Hz)), 8.13 (s, 1H), 7.92 (t, 3H, J=8.1Hz), 7.40 (m, 4H), 3.59 (s, 2H), 3.17 (s, 3H): LCMS: purity: 96%; MS (m/e): 457 (MH +).
I-87:N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[4-(N-cyano group ethanoyl-N-methyl) aminophenyl]-5-fluoro-2, the 4-pyrimidinediamine
[1246] 1H NMR (DMSO-d 6): δ 8.12 (s, 2H), 7.94 (d, 2H, J=8.7Hz), 7.86 (d, 1H, J=6.0Hz), 7.31 (d, 2H, J=9.0Hz), 7.28 (d, 3H, J=8.4Hz), 3.60 (s, 2H), 3.17 (s, 3H), 2.49 (s, 3H): LCMS: purity: 93%; MS (m/e): 471 (MH +).
Embodiment 41
Detect the test of the Ramos B clone of IL-4 stimulation
[1247] the B cell that is stimulated by cytokine interleukin element-4 (IL-4) can activate the JAK/Stat approach by the kinases JAK-1 and the JAK-3 of phosphorylation JAK family, and this can make transcription factor Stat-6 by phosphorylation and activation again.The gene that the Stat-6 that is activated raises is low affinity IgE acceptor, CD23.Be the influence of research inhibitor to the JAK family kinase, personnel selection IL-4 stimulates people Ramos B cell.
[1248] Ramos B clone is available from ATCC (ATCC catalog number (Cat.No.) CRL-1596).Method according to the ATCC announcement, with cell cultures in containing 10% heat-inactivated fetal bovine serum (FBS) ((the JRH Biosciences of JRH Biology Science Co., Ltd, Inc), Lenexa, Kansas, catalog number (Cat.No.) 12106-500M) the RPMI 1640 (cell growth medium technology (Cellgro of company limited, MediaTech, Inc.), Herndon, VA, catalog number (Cat.No.) 10-040-CM).With 3.5 * 10 5Density keep cell.Experiment is preceding with Ramos B cell dilution to 3.5 * 10 5Cell/mL is in logarithmic phase to guarantee them.
[1249] cell is got rid of down and is suspended in the RPMI that contains 5% serum.In each hole of 96 hole tissue culture plate, use 5 * 10 4Individual cell.With cell and compound or DMSO (Sigma-Aldrich, St.Louis, MO, catalog number (Cat.No.) D2650) vehicle Control pre-cultivation 1 hour in 37 ℃ incubator.Be the IL-4 (Peprotech company (PeprotechInc.), RockyHill, NJ, catalog number (Cat.No.) 200-04) irritation cell 20-24 hour of 50 units/mL then with ultimate density.Then cell is got rid of down, dye and pass through facs analysis with anti--CD23-PE (BD drugmaker (BD Pharmingen), San Diego, CA, catalog number (Cat.No.) 555711).Use BD LSR I fluidic cell instrument system to detect available from the shellfish enlightening biotechnology company (BectonDickinson Biosciences) of San Jose.The IC that calculates based on this test-results 50Be provided in Table X II.
Embodiment 42
The primary human T cell proliferation test that stimulated by IL-2
[1250] breed at external response cytokine interleukin element-2 (IL-2) with preactivated elementary human T-cell derived from peripheral blood and with TXi Baoshouti and CD28 stimulation.This proliferative response is depended on can phosphorylation and the JAK-1 of activating transcription factor Stat-5 and the activation of JAK-3 Tyrosylprotein kinase.
[1251] the elementary T cell of people is prepared as follows.Whole blood is available from the healthy volunteer, mixed with PBS with 1: 1, be stacked in Ficoll Hypaque (the husky Pharma Biotech of liking to be beautiful (Amersham PharmaciaBiotech), Piscataway, NJ, catalog number (Cat.No.) 17-1440-03) making the ratio of blood/PBS and ficoll is 2: 1, and in centrifugal 30 minutes of 4 ℃ of 1750rpm.Reclaim serum: the lymphocyte on the ficoll interface is also with 5 volume PBS washed twice.Cell is resuspended in contains 40U/mL reorganization IL2 (R﹠amp; D system (R and D Systems), Minneapolis, MN, catalog number (Cat.No.) 202-IL (20 μ g)) Yssel substratum (the lucky Buddhist nun biological product company (Gemini Bio-products) of being confused, Woodland, CA, catalog number (Cat.No.) 400-103) and be inoculated into 1 μ g/mL anti--CD3 (BD drugmaker (BD Pharmingen), San Diego, CA, catalog number (Cat.No.) 555336) and 5 μ g/mL anti--flask of CD28 (immunological technique company (Immunotech), Beckman Coulter of Brea California, catalog number (Cat.No.) IM1376) precoating in.With elementary T cytositimulation 3-4 days, transfer in the new flask then and be maintained at the RPMI that contains 10%FBS and 40U/mLIL-2.
[1252] elementary T cell with the PBS washed twice removing IL-2, and with 2 * 10 6Cell/mL is resuspended in the Yssel substratum.In each hole of the flat culture plate of 96 hole black, add the cell suspending liquid that 50 μ L contain 80U/mL IL-2.Last dull and stereotyped row do not add not stimulated control of IL-2 conduct.Compound begins with 3 times extent of dilution serial dilution in methyl-sulphoxide (DMSO, 99.7% is pure, detects Sigma-Aldrich, St.Louis, MO, catalog number (Cat.No.) D2650 through cell cultures) from 5mM, then to be diluted in the Yssel substratum at 1: 250.In each hole, add 50 μ L 2X compounds in duplicate and each hole was bred 72 hours at 37 ℃.
[1253] use CellTiter-Glo
Figure A20068002053303291
Propagation is measured in photogenic cell viability test (Promega), and this test can be determined the number of viable cell in the culture according to the amount of the ATP (as the sign of metabolic activity cell) that exists.Matrix is melted and reply room temperature.Cell Titer-Glo reagent and mixing diluents are added 100 μ L together afterwards in each hole.Flat board is mixed 2 minutes inducing cracking on the rail mounted vibrator, and cultivate 10 minutes so that signal-balanced in room temperature again.Use that (Shelton, Wallac Victor2 1420 multiple labeling counters CT) detect available from Perkinelmer Inc. (Perkin Elmer).The IC that calculates based on this test-results 50Be provided in Table X II.
Embodiment 43
A549 epithelial cell line with IFN γ stimulation
[1254] the A549 pulmonary epithelial cells responds various different stimulated and raises the surface expression of ICAM-1 (CD54).Therefore, but express as of the influence of reading assessing compound with ICAM-1 unlike signal pathway in the same cell type.Thereby IFN γ activates the JAK/Stat approach and raises ICAM-1.In this embodiment, estimated the rise of the ICAM-1 that IFN γ causes.
[1255] A549 lung epithelial cancerous cell line is derived from American Type Culture Collection.With being added with 10% foetal calf serum, the F12K substratum of 100I.U. penicillin and 100ng/mL Streptomycin sulphate (substratum technology company limited (Mediatech Inc.), Lenexa, KS, catalog number (Cat.No.) 10-025-CV) (complete F12k substratum) carries out routine and cultivates.Cell is at 5%CO 2, cultivate in 37 ℃ the wet environment.Be used for washing the A549 cell and carrying out the floating cell of trypsinized (substratum technology company limited (Mediatech Inc.), catalog number (Cat.No.) 25-052-CI) with PBS before the test.With also centrifugal in the complete F12K substratum with sedimentation cell with the trypsinase cell suspending liquid.With cell mass with 2.0 * 10 5The concentration of/mL is resuspended in complete F12K substratum.With every hole 20,000 cells, cumulative volume 100 μ L with cell inoculation in flat tissue culture plate and spend the night so that it is adherent.
Pyrimidinediamine test compounds or DMSO (contrast) (Sigma-Aldrich, St.Louis, MO, catalog number (Cat.No.) D2650) that 4-replaces cultivated 1 hour together in advance with A549 cell and 2 in [1256] the 2nd days.Use IFN γ (75ng/mL) (Peprotech company (Peprotech Inc.), Rocky Hill, NJ, catalog number (Cat.No.) 300-02) irritation cell then and cultivated 24 hours.The final dosage range of test compounds is the F12K substratum 30 μ M-14nM that per 200 μ L contain 5%FBS, 0.3%DMSO.
Remove cell culture medium in the time of [1257] the 3rd days also with 200 μ L PBS (phosphate-buffered saline) washed cells.Trypsinized is carried out with isolated cell in each hole, add the complete F12K substratum of 200 μ L then and neutralize.Dyeed 20 minutes at 4 ℃ with cell precipitation and with APC link coupled mouse anti human ICAM-1 (CD54) (BD drugmaker (BD Pharmingen), San Diego, CA, catalog number (Cat.No.) 559771) antibody.Express with ice-cold FACS damping fluid (PBS+2%FBS) washed cell and by flow cytometry surface ICAM-1.Use BD LSR I fluidic cell instrument system to detect available from the shellfish enlightening biotechnology company (Becton Dickinson Biosciences) of San Jose.To incident carry out gate (gated) with obtain viable cell distribute (live scatter) and computational geometry mean number (Becton-Dickinson CellQuest software, 3.3 editions, FranklinLakes, NJ).Geometric mean and compound concentration are drawn to generate dose response curve.The IC that calculates based on this test-results 50Be provided in Table X II.
Embodiment 44
U937 IFN γ ICAM1 FACS test
[1258] the U937 person monocytic cell responds various different stimulated and raises the surface expression of ICAM-1 (CD54).Therefore, but express as of the influence of reading assessing compound with ICAM-1 unlike signal pathway in the same cell type.Thereby IFN γ activates the JAK/Stat approach and raises ICAM-1.In this embodiment, estimated the rise of the ICAM-1 that IFN γ causes.
[1259] the U937 human monocyte cell line is available from the ATCC of Rockville Maryland, and catalog number (Cat.No.) is CRL-1593.2, and is incubated at the RPM1-1640 substratum that contains 10% (v/v) FCS.Make the U937 cell grow in 10%RPMI.Then with the concentration of 100,000 cells/160 μ L with cell inoculation in the flat flat board in 96 holes.Following then dilution test compounds: the 10mM test compounds to be to be diluted in DMSO (3 μ L 10mM test compounds are dissolved in 12 μ L DMSO) at 1: 5, then with 1: 3 with the test compounds serial dilution in DMSO (6 μ L test compounds serial dilutions in 12 μ L DMSO to obtain 3 times of diluents).Then 4 μ L test compounds are transferred among the 76 μ L 10%RPMI with obtain 10X solution (100 μ M test compounds, 5%DMSO).Control wells is diluted in 76 μ L 10%RPMI with 4 μ L DMSO.
[1260] 8 points (since 8 kinds of 3 times of weaker concns of 10 μ l) are carried out the test of two multiple holes, wherein 4 holes only contain DMSO (control wells) under incentive condition, and have under 4 Kong Zaifei incentive conditions and only contain DMSO.
[1261] (Beckman Coulter of Brea California) mixes, and the compound that 20 μ L are diluted is transferred to the 96 hole flat boards that every hole contains 160 μ L cells then, and then twice of low speed mixing with compound and the multimek of dilution with 2X.Then with cell and compound at 37 ℃, 5%CO 2Pre-down the cultivation 30 minutes.
[1262] prepare the people IFN γ solution of 100ng/mL to obtain 10X stimulation mixture with 10%RPMI.Stimulate mixture irritation cell and compound so that ultimate density is 10ng/mL IFN γ, 10 μ M test compounds and 0.5%DMSO with 20 μ L IFN γ then.Cell is at 37 ℃, 5%CO 2Condition under keep to stimulate 18-24 hour.
[1263] cell transfer is dyeed to 96 hole circle base plates, in dyeing course, remain on ice.Cell 4 ℃ with centrifugal 5 minutes of 1000rpm to get rid of cell down, abandoning supernatant.Remove and add per 100 μ L FACS damping fluids after the supernatant liquor and add 1 μ L APC link coupled mouse anti human ICAM-1 antibody.Cell is then dark culturing on ice 30 minutes.Add after cultivating 150 μ L FACS damping fluids and 4 ℃ with 1000rpm centrifugal 5 minutes, remove supernatant liquor then.Add 200 μ L FACS damping fluid re-suspended cells after removing supernatant liquor.After suspending with cell 4 ℃ with 1000rpm centrifugal 5 minutes.Remove supernatant liquor then and again cell is resuspended in 150 μ L FACS damping fluids.
[1264] use BD LSR I fluidic cell instrument system to detect available from the shellfish enlightening biotechnology company (Becton Dickinson Biosciences) of San Jose.To viable cell carry out gate with obtain or cell distribution and measure ICAM-APC geometric mean (Becton-Dickinson CellQuest software, 3.3 editions, Franklin Lakes, NJ).Analyzing viable cell per-cent and ICAM-1 expresses.With the known control compound of activity test compounds is carried out parallel test.The EC of control compound 50Be generally 40-100nM.The IC that calculates based on this test-results 50Be provided in Table X II.
Table X II
Compound Embodiment 41 Embodiment 42 Embodiment 43 Embodiment 44
I-1 0.36551 9.89222 18.4509 35.3335
I-2 0.53194
I-3 0.10738 0.98708 9999
I-4 0.04905 0.17843 4.85721
I-5 1.64619 29.901
I-6 0.52212 20.9805 9999
I-7 0.12002 0.50172
I-8 0.0587 0.1743 9999 0.41
I-9 0.23306 0.48494 15.6334 0.78723
I-10 0.02551 0.09568 6.54622 0.26124
I-11 0.02333 0.03929 17.6237 0.3294
I-12 0.03694 0.05968 3.19514 0.22195
I-13 0.00627 0.00505 1.34069 0.0435
I-14 0.01296 0.01149 0.61167 0.04176
I-15 0.30896 1.18318 4.96519
I-16 0.12424 0.4356 7777
I-17 0.0487 0.04318 2.34513 0.36534
I-18 0.28251 1.48925 8888 2505.23
I-19 0.50856 1.04177 24.8675 10.0825
I-20 0.03672 0.06619 6.53867 0.33882
I-21 0.09302 0.25767 22.7159 0.8223
I-22 0.23636 0.94439 14.3679 4.43304
I-23 0.03013 0.08823 9999 0.45476
I-24 0.05422 0.29639 9999 1.04466
I-25 0.05582 1.6129 25.3098 8888
I-26 0.03781 0.40073 4.23449 0.42446
I-27 0.06186 0.91443 3.48033 0.53438
I-28 0.06454 0.5598 7777 1.89233
I-29 0.1196 0.50183
I-30 5.43333 3.57085
I-31 4.62505
I-32 0.16136 2.78095 5.49713 1.96749
I-33 0.0965 0.1705 8888 0.89708
I-34 0.06229 0.80566 7777 1.05493
I-35 0.04696 1.1331 8.58425 1.82151
I-36 8.80466 9999
I-37 0.49851 3.68499 5.73717
I-38 6.44228
I-39 0.84081 9.32297
I-40 0.30838 31.0382 3345.23
I-41 0.03738 10.15
I-42 0.02408 8888
I-43 0.01826 0.18317 36.6502 0.77073
I-44 0.05316 0.34166 9999 5.06833
I-45 0.1036 0.83377 17.0422 3.63512
I-46 0.11322 0.40872 9999 0.75129
I-47 0.12011 0.55068 0.75908
I-48 1.40357
I-49 2.31794 5.55983
Compound Embodiment 41 Embodiment 42 Embodiment 43 Embodiment 44
I-50 0.37337 25.1264
I-51 0.26268 2.11715 32.1941
I-52 0.15228 5.30087 9999 68.6571
I-53 0.23595 12.2055
I-54 0.27682 7.15982
I-55 9999
I-56 0.10355 0.2618 4.97271 0.42424
I-57 0.02161 0.05314 9999 0.13971
I-58 0.00505 0.01925 0.73026 0.06599
I-59 0.00655 0.02487 0.94741 0.05766
I-60 0.10288 2.17439 7.89243 0.84765
I-61 0.04586 0.12299 8888 0.42748
I-62 0.10056 0.37599 3.52859 0.73487
I-63 0.16924 1.31421 34.3138 0.69103
I-64 0.11281 1.87772 5.16607 1.15237
I-65 0.09651 0.04731 8888 0.31629
I-66 0.10306 0.28704 9999 0.68933
I-67 0.03322 0.15663 4.61611 0.23869
I-68 0.18704 0.48243 4.96049 0.91274
I-69 0.11784 1.02837 5.64408 5000.08
I-70 0.06138 0.57305 3.43038 0.384
I-71 0.06178 0.13591 3.26769 0.32803
I-72 0.05239 0.30295 3.30881 0.57377
I-73 0.11976 0.7281 5.55843 1.06264
I-74 0.24475 1.49815 10.7945 1.75731
I-75 0.19865 3.3 7777 3.1
I-76 0.10102 0.19585 5.13601 1.12224
I-77 0.14716 1.61795
I-78 0.6349 1.2051
I-79 0.4606 1.0611
I-80 0.3649 0.4697
I-81 0.3597 0.9566
I-82 0.2439 1.3819
I-83 0.158 1.7561 14.9
I-84 1.4005
I-85 0.7913
I-86 0.9162
I-87 1.0381
I-88 1.07518
I-89 5.49992 9999
I-90 0.40109 2.19063 6.16341
I-91 2.03142
I-92 0.16624 0.54302 9999 15.59
I-93 0.26489 1.17393 23.774 11.0701
I-94 0.34492 0.56287 5.66845
I-95 0.11825 0.32508 9999 6.3
I-96 0.13177 0.77151 40.8692 3.30063
I-97 0.21244 0.86883 31.0729 27.4081
I-98 0.29451 37.2587 10.9783
Compound Embodiment 41 Embodiment 42 Embodiment 43 Embodiment 44
I-99 0.06863 0.14752 9999 3.77549
I-100 0.38027 9999 6670.09
I-101 0.32832 51.1576 36.6028
I-102 0.21893 0.21079 43.7663 15.5943
I-103 1.24843 9999
I-104 1.42542 9999
I-105 1.1675 9999
I-106 2.95316
I-107 1.51103
I-108 0.14545 0.14758 9999 3.97385
I-109 0.30527 0.20336 25.9633 9.93933
I-110 0.35788 0.25307 20.584 3.92933
I-111 0.89035 9999
I-112 2.36464 9999
I-113 0.16466 1.6854 9999 13.5121
I-114 0.44754 6.70638 9999 9999
I-115 0.79259 7777
I-116 0.27394 0.97166 9999 4455.33
I-117 0.35266 0.30095 36.4268 14.5685
I-118 0.292 0.55723 2.42563
I-119 0.21095 2.43898 9.67128 11.8985
I-120 0.20071 0.27964 19.9754 4.45634
I-121 0.18382 0.63384 14.5419 2.98512
I-122 0.29151 3.5 9999 15.6681
I-123 0.15927 0.22497 12.8283 2.2221
I-124 0.10241 0.34199 10.373 1.33026
I-125 0.53802
I-126 0.35476 0.60989 7.20132
I-127 0.2333 0.50965 2.5105
I-128 0.87135
I-129 0.61228
I-130 0.60114 1.73251
I-131 0.26226 3.78086 2.99277
I-132 0.35129 0.46431 2.71959
I-133 0.23656 1.34872 9999
I-134 0.17762 0.50998 9999 3.23999
I-135 0.11208 0.10418 3.24251 1.82933
I-136 0.13205 0.19642 8.11382 1.64002
I-137 0.38672 1.09918 9999 29.5795
I-138 0.4607 0.22286 91.4861 9.46799
I-139 0.37466 0.24038 11.5578 3.26019
I-140 0.38751
I-141 0.1625 0.66903 15.6032
I-142 0.15485 0.85438 9999
I-143 1.19256
I-144 1.00541
I-145 0.54156 0.3493
I-146 0.36436 7777 9999
I-147 0.07985 0.17442 7777 9999
I-148 0.06117 0.24003 9999 9999
Compound Embodiment 41 Embodiment 42 Embodiment 43 Embodiment 44
I-149 0.1613 0.19724 14.7293
I-150 0.06569 0.06806 7777 10.5387
I-151 0.06185 0.07829 9999 8888
I-152 0.30174 1.5412
I-153 0.11405 0.33375 9999
I-154 0.27631 0.9925 9999
I-155 0.11775 0.09932 9999 65.0584
I-156 0.06549 0.14151 9999 2.62254
I-157 0.24574 1.8906 9999
I-158 0.2967 0.44535 1.38012
I-159 0.33805 0.53944 1.63449
I-160 0.13042 0.2484 0.92282
I-161 0.31398 2.41123
I-162 0.05105 0.13566 9999 0.59381
I-163 0.17656 0.4391 1.40511
I-164 9999
I-165 0.24517 0.44644 1.63555
I-166 0.61646
I-167 0.14175 7777
I-168 0.15437 1.17511 9999
I-169 0.0546 0.1373 8888
I-170 0.4507
I-171 0.11717 0.41497
I-172 0.04734 0.2771 38.674 1.09663
I-173 0.11513 0.907 9999 15.5343
I-174 0.11681 1.23383 8888
I-175 0.14696 3.0806 9999
I-176 0.25875 1.69038
I-177 8888 0.5
I-178 0.0235 0.0293 0.11756
I-179 0.02427 0.01178 0.11711
I-180 0.0624 0.02868 0.4558
I-181 0.01301
I-182 0.18961 1.12876 8888
I-183 0.24913 1.83159 2.27747
I-184 0.48571 2.57372 6.62465
I-185 0.29773 9999
I-186 0.18828 1.08437 3.53394
I-187 2.91228
I-188 0.0427 0.0642 15.0825 0.50022
I-189 0.13708 0.14331 6.74171 0.50811
I-190 0.14533 0.24207 9.30992 1.5006
I-191 0.13487 0.29228 0.79644
I-192 0.13748 0.15499 0.97787
I-193 0.03822 0.05562 9999
I-194 0.02858 0.09935 5.02722
I-195 0.08263 0.12705 9999 9999
I-196 0.12446 0.13926 9999 0.75397
I-197 0.13477 0.32885 1.2782
I-198 0.10154 0.46016 9999 0.80536
I-199 0.23967 3.02692 2.68752
Compound Embodiment 41 Embodiment 42 Embodiment 43 Embodiment 44
I-200 9999
I-201 9999
I-202 3.075
I-203 0.26472 0.68359 5.77164 3.1332
I-204 0.25571 1.6463 3.92821
I-205 0.31543 1.8632 9.4856 3341.09
I-206 0.72572
I-207 8888
I-208 1.39961
I-209 0.58003 4.46766 2.96679 9999
I-210 0.86614
I-211 1.05253
I-212 0.75778
I-213 11.4811
I-214 0.14442 1.32831 1.30455
I-215 0.97626
I-216 0.20482 0.49337 1.56836
I-217 0.02498 0.21692 36.591 0.4785
I-218 0.07262 0.11588 3.26785 0.43399
I-219 0.03162 0.12305 7.16246 0.58776
I-220 0.12138 1.06662 7777 8888
I-221 0.34372 2.68161 4.43571
I-222 0.03308 0.58244 9999 0.84
I-223 0.08803 0.62525 9.08836 1.20989
I-224 0.03615 0.19417 11.324 0.4936
I-225 0.69987
I-226 0.49797
I-227 1.48242
I-228 3.80514
I-229 3.75639
I-230 0.08426 0.06925 10.477 0.46548
I-231 0.09468 0.29003 9999 8.40421
I-232 1.42979
I-233 0.14834 0.37693 9999 1.74874
I-234 0.10247 1.00762 8.15676 2.01923
I-235 0.17818 0.4695 9999 2.55555
I-236 1.98037
I-237 0.14699 2.04005 9999 3.57746
I-238 0.16477 0.45567 9999 1.12717
I-239 0.23965 9999 7.05758
I-240 0.20499 5.25922 8888
I-241 0.26564 0.44243 2.87423
I-242 0.52009
I-243 0.91747
I-244 0.28501 1.40668 14.7078 3.11959
I-245 0.20153 1.74332 16.6871 4.1888
I-246 0.10624 0.18232 8.87569 0.87257
I-247 0.225 0.1187 11.115 1.0767
I-248 0.38838 0.13774 2.65851
I-249 0.51223 11.0003
I-250 0.67255
Compound Embodiment 41 Embodiment 42 Embodiment 43 Embodiment 44
I-251 0.16719 0.15516 34.8518 1.09204
I-252 0.0906 0.55777 74.2104 2.46619
I-253 0.12662 2.56423
I-254 0.15452 1.91498 8.95614 1.82459
I-255 0.25614 2.86397 39.3342 5.52062
I-256 0.28206 38.2034 9999 15.9307
I-257 0.14527 0.10222 3.07682 0.95888
I-258 0.02798 0.05539 9999 0.3241
I-259 0.02793 0.06575 7.50745 0.3147
I-260 0.09477 0.22271 8.44012 0.98515
I-261 5031.28
I-262 0.07832 0.16396 3.67509 1.04486
I-263 0.12368 0.06443 0.66548
I-264 0.59917 14.9995
I-265 0.04232 0.0397 4.08382 0.41479
I-266 0.08513 0.20071 9999 0.824
I-267 0.32828 2.01965 5.06578
I-268 0.06074 0.13983 5.0785 0.21895
I-269 0.91657
I-270 0.77962
I-271 9999
I-272 0.78775
I-273 0.47773 0.19296 12.8791 5.10428
I-274 1.17189
I-275 0.22313 0.57744 9999 1.9
I-276 0.13508 0.10582 8.0902 0.8217
I-277 0.15065 0.09153 6.91127 1.47355
I-278 0.19343 0.41215 11.0338 2.26901
I-279 0.12274 0.16744 9999 0.9178
I-280 0.14472 0.9783 1.45628
I-281 0.09321 0.09036 9999 0.97459
I-282 0.33926 0.69745 3.10495
I-283 0.51821 0.3617 2.94063
I-284 0.13587 0.42105 1.54787
I-285 0.13257 0.31358 1.485
II-1 0.18176 1.13989 8.32597
II-2 0.24439 1.51926 4.59317
II-3 0.08404 0.91766 11.921 6.50431
II-4 0.31643 2.37109 3.51083
II-5 2.20619
II-6 0.11067 1.2178 6.38785
II-7 0.14372 0.52156 1.62567
II-8 0.03878 0.56414 9999
II-9 0.23159 1.31747 2.7171
II-10 0.36923 0.8756 1.39632
II-11 0.10669 0.19762 0.91162
II-12 0.05626 0.40891 5.52004 1.19102
II-13 0.32334
II-14 0.04685 0.57852
II-15 0.98189 1.10065
II-16 18.3048 3.71528
Compound Embodiment 41 Embodiment 42 Embodiment 43 Embodiment 44
II-17 21.2024 8.20964
II-18 2.04279 3.30797
II-19 0.39546 8888 9999
II-20 0.42846 0.96892 11.5294
II-21 0.69755 1.76163 41.7481
II-22 0.85847 7.48812
III-1 0.15102 0.54475 1.11685
III-2 0.22374 3.43534 6.71592
III-3 0.53624
III-4 0.01872 0.17102 8.36734 1.71666
III-5 4.9773 9999
III-6 0.78109 30.674
III-7 0.0851 0.19544 12.3228 1.08953
III-8 0.13823 0.92083 14.4636 2.2522
III-9 0.21457 1.80396 23.6063 6.98319
III-10 0.22461 0.92188 9999 3.52348
III-11 0.0642 0.04604 2.24405 0.16825
III-12 0.07001 0.10746 3.51838 0.32092
III-13 0.2953 0.70092
III-14 0.13985 0.05263 3.60147 0.58483
III-15 0.07596 0.10691 4.65521 0.55294
III-16 0.2733 0.34222 7.23576 1.79675
III-17 0.05674 0.1974 0.78205
III-18 0.03659 0.13567 0.54387
III-19 0.07229 0.17392 21.8899 0.05559
III-20 0.04299 0.76298 6.63588 3.33323
III-21 0.0303 0.11378 0.33867
III-22 0.04545 0.07611 8888 0.44428
III-23 0.39727
III-24 0.25751 1.62056
III-25 0.27162 1.25963
III-26 0.16196 0.58276
III-27 0.05834 0.11898 7777 0.25737
III-28 3.74795 17.4221
III-29 3.63333 12.3622 9999
III-30 0.06455 0.31911 9999
III-31 0.09536 0.32762 1.70465
III-32 4.40366 3.31651 9999
III-33 1.68071 0.85213
III-34 0.47276 0.38085
III-35 1.0814
III-36 0.3944 0.3819
III-37 0.2997 0.834
III-38 0.1976 1.127
III-39 0.1171 0.1297 4.15 1.435
III-40 0.1341 0.2286 1.116
III-41 1.0134
III-42 0.2936 0.6406
III-43 0.2705 0.8975
III-44 1.43012
III-45 0.29277 0.38431
Compound Embodiment 41 Embodiment 42 Embodiment 43 Embodiment 44
III-46 0.21144 1.05234
III-47 0.21084 0.36642 9999
III-48 0.20373 0.21773 9999
III-49 0.17801
III-50 0.30572 1.96867
III-51 1.00749
III-52 0.18299 1.20459
III-53 0.0977 0.28629 1.13155
III-54 0.13522 0.13989 9999 1.59326
III-55 0.14436 0.97312
III-56 0.19581 0.49929
III-57 0.05356 0.16996 55.5368 0.83776
III-58 0.15671 1.25684
III-59 0.14965 0.45792
III-60 0.13462 0.17751 25.5295 1.01469
III-61 0.25873 1.08295
III-62 0.1715 0.699
III-63 0.3153 1.8768
III-64 0.4473 5.9565
III-65 0.209 0.9359
III-66 0.14152 1.15034 0.96668
III-67 0.34745 3.05467
III-68 3.23069
III-69 3.31825
III-70 0.06446 0.16921 9999 1.64984
III-71 0.09785 0.36848 8.25586 1.70255
III-72 1.95167
III-73 0.13087 0.43435
III-74 0.09524 0.17541 9999 0.93514
III-75 0.16969 0.22009 10.0944 1.77125
III-76 0.1042 0.1348 0.447
III-77 0.1774 0.2095 0.681
III-78 0.2754 0.2041 7777 22.9
III-79 0.16853 0.96749
III-80 3.15582 0.84435
III-81 0.18003 0.20392 48.3461 3.42825
III-82 0.12695 0.15998 24.1674 2.27381
III-83 0.09874 0.09622 9999 1.35976
III-84 0.4428 1.8956
III-85 0.07272 0.12242 9999 3.62044
III-86 0.0976 0.09394 9999 6.44528
III-87 0.14099 0.14172 76.2393 2.94666
III-88 0.14065 0.16557 10.6231 2.03999
III-89 0.11498
III-90 0.35751 0.46822 2.6323
III-91 0.14274 0.46742
III-92 0.32272 1.89757
III-93 0.17308 0.81891
III-94 0.16161 0.71606
III-95 0.1494 0.37003 29.7109
III-96 3.32588 2.18995
Compound Embodiment 41 Embodiment 42 Embodiment 43 Embodiment 44
III-97 0.27887 1.02568
III-98 0.11654 0.45747
III-99 1.03465 2.17142
III-100 0.16233 0.19656 1.9107
III-101 0.2401 0.4464
III-102 0.30171 0.48559
III-103 0.23001 1.05998 2.42638
III-104 0.24173 1.19132 2.1621
III-105 1.27754
III-106 0.04277 0.07508 5.89649 0.49188
III-107 0.21914 0.5404 1.52384
III-108 0.18343 1.21503 1.50897
III-109 0.14312 0.25198 0.53111
III-110 0.24698 0.99788 13.5631
III-111 0.32121 0.92557 5.34359
III-112 2.47605
III-113 1.0305 0.345
III-114 2.6833
III-115 1.6524
III-116 0.19663 3.94714 7777
III-117 0.39696
III-118 0.62434 2.29421
III-119 1.29867
III-120 0.65536 0.5542
III-121 0.57495 1.0202
III-122 0.53873
III-123 0.17252 1.38789
III-124 0.29523
III-125 0.8356
III-126 0.1972 0.4701
III-127 0.1982 0.6123
III-128 0.14513 0.13942 28.0649 1.43941
III-129 0.17355 0.1799 31.2977 1.187
IV-1 0.07356 0.28652 0.27169
IV-2 0.08002 0.36242 0.70488
IV-3 0.09325
IV-4 0.15095 0.3032 2.42396
IV-5 0.09767 0.11589 16.0697 0.50367
IV-6 0.10292 0.13159 0.88048
IV-7 0.11241 0.20304 1.23784
IV-8 0.16592 0.62672
IV-9 0.19023 1
IV-10 0.13472 0.71395
IV-11 0.3672
IV-12 0.25666 1.21823
V-1 2.00456 9.77279 9999
V-2 1.17796
V-3 0.66409 13.7306
V-4 0.10843 1.53933 9.24355
V-5 0.69624
V-6 0.02185 0.07083 7777 0.57206
Compound Embodiment 41 Embodiment 42 Embodiment 43 Embodiment 44
V-7 0.05877 0.12703 5.00173 0.82053
V-8 0.02908 0.22532 5.20729 0.61971
V-9 1.11064
V-10 0.26102 8.26777 2.69871
V-11 0.0698 0.79519 8888 1.41593
V-12 0.18817 0.95693 54.0071 3.03787
V-13 0.05289 0.46847 6.86738 1.19717
V-14 0.19711 2.59168 6.84803
V-15 0.17289 9.30756 8888
V-16 8.3722
VI-1 0.20474
VI-2 0.08925 3.57169 9999
VI-3 0.20565 8.79279 9999 9999
VI-4 0.02107 0.2312 9999 9999
VI-5 0.04047 0.71837 8888 1.3851
VI-6 0.03747 1.44938 14.9708 7.70441
VI-7 0.76592
VI-8 2.28135
VI-9 0.05327 0.94453 9.95895 14.5216
VI-10 0.22022 2.39519 24.9026 9999
VI-11 0.25923 4.61735 47.0634 7.13718
VI-12 0.14575 1.3099 9999 8888
VI-13 0.09654 1.34867 8.2263 1.3926
VI-14 0.41325 7777 9.26616
VI-15 0.045 0.46887 0.76722
VI-16 0.25935 3.91458 8888
VI-17 0.04344 0.2436 6.42231 0.45391
VI-18 0.25733 4.36513 6.06278
VI-19 1.02551
VI-20 0.72602
VI-21 11.321
VI-22 0.66268
VI-23 0.59672
VI-24 8.61565
VI-25 9.91092
VI-26 0.04444 0.0289 1.70264 0.257
VI-27 0.07613 3.7609 0.5446
VI-28 0.75443
VI-29 0.04982 0.36201 8888
VI-30 0.01324 0.1702 9999
VI-31 18.2541
VI-32 0.33323 1.65819
VI-33 0.27207 0.66049
VI-34 0.1567 0.8386
VI-35 0.1583 1.2589
VI-36 0.3743 4.4975
VI-37 0.0692 1.0785 12.4
VI-38 0.4143 2.0675
VI-39 0.401 3.139
VI-40 0.2883 1.2369
Compound Embodiment 41 Embodiment 42 Embodiment 43 Embodiment 44
VI-41 0.3425 6.2401
VI-42 0.4515 6.1678
VI-43 0.7393 6.1404
VI-44 0.4293 7.3093
VI-45 0.1081 1.3279 10.53
VI-46 0.1435 1.2558
VI-47 0.0828 0.2589 9999 0.596
VI-48 0.3153 2.2429
VI-49 0.26786 1.26457 2.09896
VI-50 0.21701 0.94365 1.87806
VI-51 0.15225 0.54688 9999 2.13363
VI-52 0.16844 0.16223 5.91841 1.73898
VI-53 0.05631 0.18115 11.3381 0.56491
VI-54 0.14667 0.96651 31.0319 1.61592
VI-55 0.12204 0.62467 1.36955
VI-56 9.6557
VI-57 0.20172 1.18287
VI-58 0.16427 0.72381 9999
VI-59 0.07598 0.33972 4.98157
VI-60 0.08692 0.18673 3.84551 0.40964
VI-61 0.09897 0.18455 3.11335 0.36684
VI-62 3.9717
VI-63 0.15987 0.36325 1.74329
VI-64 5.80304
VI-65 0.09062 0.20944 4.12861 0.9643
VI-66 6.0949
VI-67 0.14725 0.7175
VI-68 0.1016 0.74156 26.8087 1.80963
VI-69 0.19376 1.34478 18.7049
VI-70 0.07056 0.31112 8888 0.65688
VI-71 1.07371
VI-72 0.45477
VI-73 0.25111 2.01413
VI-74 0.09458 0.34829 9999 3.85373
VI-75 0.90444 0.92854
VI-76 0.54911 0.78345
VI-77 9999 43.2745
VI-78 0.16137
VI-79 0.096
VI-80 0.3601
VI-81 3.1748
VI-82 0.21184 1.63499 8888
VI-83 0.11255 0.29326 7.29592 0.53506
VI-84 0.13247 0.51438 4.58337
VI-85 0.12862 0.76235 24.7027
VI-86 0.1531 0.17808 4.43831 0.48745
VI-87 0.5411 1.24269
VI-88 0.21559 1.18558 24.6776
VI-89 0.13188 0.17139 5.75508 2.04395
VI-90 1.075 3.9664
VI-91 0.22118 1.23424 9999
Compound Embodiment 41 Embodiment 42 Embodiment 43 Embodiment 44
VI-92 0.0835 0.10732 12.9834 1.1583
VI-93 0.10988 0.5602
VI-94 0.9442
VI-95 1.0032
VI-96 0.80335
VI-97 3.00715
VI-98 0.13555 0.9859 9999 9999
VI-99 0.06845 0.6166 9999 9999
VI-100 0.32107 0.07427 9.1817 4.89859
VI-101 0.91914
VI-102 0.18285 0.13496 14.7259 2.7967
VI-103 3.07902
VI-104 1.98452
VI-105 10.2998
VI-106 0.06219 1.19886 9999 9999
VI-107 0.15912 0.07409 8888 0.85644
VI-108 9999
VI-109 0.13553 2.86926 7777 9999
VI-110 0.08364 0.34532 9999 5.46321
VI-111 0.31375 1.09272 3.43245
VI-112 0.15223 0.77009 1.25566
VI-113 0.6995
VI-114 0.2095 2.2419 9999 33.19
VI-115 0.8899
VI-116 0.0311 0.1742 8.101 0.673
VII-1 6.653
VII-2 36.2228
VII-3 14.0844 16.5455
VII-4 2.49292 9999
VII-5 4.12527
VII-6 0.10208 1.99812 23.4363 3.6535
VII-7 0.50186 3.91608 9999
VII-8 0.39911 8.63335 7777 7777
VII-9 0.24627 2.71965 17.0751 5.34695
VII-10 0.86258
VII-11 0.60232
VII-12 0.60208 6.68655 31.7728
VII-13 0.13967 0.38047 7777 1.28577
VII-14 0.10259 0.17683 9.92695 0.87716
VII-15 0.06662 0.12058 13.1417 0.56816
VII-16 0.27544 1.07422 24.3537
VII-17 0.35301 2.09765 6.96416
VII-18 0.22688 0.83852 1.29055
VII-19 0.08753 0.51424 12.53 1.25627
VII-20 0.28603 0.69758
VII-21 0.54792
VII-22 0.1114 0.1276 9999 0.84875
VII-23 0.12929 0.16124 61.259 0.59644
VII-24 0.62303
VII-25 0.21695
Compound Embodiment 41 Embodiment 42 Embodiment 43 Embodiment 44
VII-26 0.54544 1.20006 9.26107
VII-27 0.41342 2.05177 6.2489
VII-28 0.0367 0.70906 16.5843 8888
VII-29 0.0476 1.46279 30.5071 38.4779
VII-30 0.0358 0.02682 8.91572 0.70135
VII-31 0.12467 0.17419 9999 7.27828
VII-32 0.1071 0.0321 8888 2.057
VII-33 0.02891 0.01839
VII-34 0.04504 0.02248
VII-35 0.0448 0.0461 8888 0.245
VII-36 0.02945 0.11909 82.8107 1.08605
VII-37 0.02814
VII-38 0.06234 0.41674
VII-39 0.77157 0.91901
VII-40 0.23602 6.48486 9999
VII-41 0.04694 0.26426 9999 9999
VII-42 0.6688 7.28447 45.547
VII-43 0.60291 9999
VII-44 0.03299 0.54552 9.12322 1.22643
VII-45 0.04385 0.28169 4.03246 0.47741
VII-46 0.96115
VII-47 2.67352
VII-48 0.03083 0.3365 9999 0.66
VII-49 0.03778 0.05493 3.06481 0.57652
VII-50 0.34963 0.85602 4.41963 5.0643
VII-51 0.54109 1.79232 9999
VII-52 47.0815
VII-53 0.16792 0.48379 5.46124
VII-54 0.29487 0.59608 64.6261
VII-55 0.18411 0.59857 1.66866
VII-56 0.18495 1.28469 1.92946
VII-57 0.10717 0.8182 10.6982 0.73524
VII-58 0.13577 0.26518 1.09844
VII-59 0.83147 2.98692
VII-60 0.06501 0.15195 2.60397 0.56965
VII-61 3333.23 0.14031 2.69156 0.35591
VII-62 0.10412 0.14422 9999 0.49561
VII-63 0.23311 0.30064 6.02744
VII-64 0.36258 3.8097
VII-65 0.38533 3.05525
VII-66 0.36866 2.87032
VII-67 0.31467 0.76791
VII-68 0.81157 1.30092
VII-69 0.07673 0.69583 7.50321 0.98982
VII-70 0.06542 0.37513 6.47721 2.76015
VII-71 0.14944 0.56875 5.47023
VII-72 0.08484 0.41516 9.93038 1.18433
VII-73 6.08963 4444.5
VII-74 4.56128 8888
Compound Embodiment 41 Embodiment 42 Embodiment 43 Embodiment 44
VII-75 0.54401
VII-76 0.67316
VII-77 0.12407 1.78366 3.53562
VII-78 0.08583 0.6825 9999 8888
VII-79 0.20627 3.20167 7777
VII-80 2.03294
VII-81 3.07323
VII-82 0.3126 1.07552 8888
VII-83 0.0775 0.93655 9999
VIII-1 1.58839
VIII-2 0.1777 0.40901 8.54969
VIII-3 0.15335 1.84224 10.0847
IX-1 0.08928 0.58079 4.88106 1.13251
IX-2 0.0795 0.28213 8888 1.76728
IX-3 0.11457
IX-4 0.12037
IX-5 0.02962 0.07382 6.09872 1.84617
IX-6 0.08403 0.53531 36.7836 8888
IX-7 0.10867 0.7509 9999 4.73418
IX-8 0.04643 0.12398 5.24218 0.54254
IX-9 8.87638 5016.37
IX-10 6.40728
IX-11 0.1146 0.21538 7777 2.23698
IX-12 0.09731 0.11725 7777 3.47525
IX-13 0.13847 0.43042 30.2755 1.84616
IX-14 0.05744 0.65645 3.37992 1.08814
IX-15 0.21708 0.15678 7777 5.36404
IX-16 0.20966 0.22281 7777 2.50539
IX-17 0.1084 0.8151 21.95 1.98
IX-18 0.1684 2.4 55.18 6.659
IX-19 0.1179 1.5963 3.368
IX-20 0.12232 1.79208 2.89558
IX-21 0.2709 2.7359
IX-22 0.2953 1.59
IX-23 9.57788
IX-24 6.33149 38.3916
IX-25 6.3071
IX-26 9999
IX-27 1.37969 7.62931
IX-28 1.66076 10.0529
IX-29 3.45769
IX-30 1.93529 6.79992
IX-31 1.4025
IX-32 9999 9999
IX-33 0.52102
IX-34 0.58245 0.57557 3.95135
IX-35 0.45471 0.8665 9999 2.09598
IX-36 1.03601 9999
IX-37 3.70466
Compound Embodiment 41 Embodiment 42 Embodiment 43 Embodiment 44
IX-38 2.31392
IX-39 1.39641
IX-40 9999 9999
IX-41 0.13318 6.25787 9999
IX-42 0.29236 2.17331 9999
IX-43 0.52347 2.80149
IX-44 0.22324 0.78907 8.16963 2.93981
IX-45 3.615
IX-46 0.07388 1.38897 7777
IX-47 0.22282 2.38854
IX-48 0.25834 2.62415 9.56437
IX-49 0.0965 61.8954 9999
IX-50 0.17891 9999
IX-51 0.23983 9999
IX-52 0.11677
IX-53 0.24002
IX-54 0.17434 2.47371 9999
X-1 8.24549
X-2 1.84451
X-3 0.34839 1.09444 4.97666 1.3837

Claims (44)

1. the compound of formula I:
Figure A20068002053300021
Its solvate, prodrug or pharmacy acceptable salt; Wherein:
X is selected from: the alkynyl of the thiazolinyl of the amino of the alkoxyl group of the alkyl of alkyl, replacement, alkoxyl group, replacement, amino, replacement, carboxyl, carboxylic acid ester groups, cyano group, halogen, nitro, thiazolinyl, replacement, alkynyl and replacement;
R is selected from: the cycloalkyl of the alkynyl of the thiazolinyl of the alkyl of hydrogen, alkyl, replacement, thiazolinyl, replacement, alkynyl, replacement, cycloalkyl and replacement;
Ring A is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl group and heterocycle, and wherein encircling A is not indyl or benzimidazolyl-;
Y is selected from: key ,-NR 7-,-C (O) NR 7-,-NR 7C (O)-,-NR 7C (O) O-,-OC (O) NR 7-,-NR 7C (O) NR 7-, oxygen and sulphur, wherein R 7Independent is the alkyl of hydrogen, alkyl or replacement;
Alk is key or straight or branched alkylidene group, wherein R then when alk and Y respectively do for oneself key 1By a covalent bonds in the ring A;
R 1Be selected from: heterocycle, acyl group, aminoacyl oxygen base and the amino carbonyl amino of the heteroaryl of the aryl of cyano group, acyl amino, aminoacyl, aryl, replacement, carboxyl, carboxylic acid ester groups, carboxylic acid ester groups oxygen base, heteroaryl, replacement, heterocycle, replacement; Perhaps
R 1-alk-Y-is R 10-C (O)-S-alk-C (O)-, wherein alk in the literary composition definition and R 10It is the alkyl of alkyl or replacement; Perhaps
R 1-alk-Y-is R 11R 12NS (O) 2-, R wherein 11And R 12Independent is the alkyl of alkyl or replacement;
P is 0,1,2 or 3 when ring A is monocycle, and perhaps p is 0,1,2,3,4 or 5 when ring A comprises a plurality of ring;
Each R 2Independently be selected from: the heterocyclyloxy base of the heterocycle of the heteroaryloxy of the heteroaryl of the cycloalkyloxy of the cycloalkyl of the aryloxy of the aryl of the amino of the alkoxyl group of the alkyl of alkyl, replacement, alkoxyl group, replacement, amino, replacement, aryl, replacement, aryloxy, replacement, cyano group, cycloalkyl, replacement, cycloalkyloxy, replacement, heteroaryl, replacement, heteroaryloxy, replacement, heterocycle, replacement, heterocyclyloxy base, replacement, aminoacyl, aminoacyl oxygen base, carboxyl, carboxylic acid ester groups, carbonate group, nitro and halogen, two R on the perhaps same carbon atom 2The formation oxo (=O);
Z 1, Z 2And Z 3Independent separately is carbon or nitrogen, if Z wherein 1Be then Z of nitrogen 2And Z 3Be carbon, if Z 2Be then Z of nitrogen 1And Z 3Be carbon, and if Z 3Be then Z of nitrogen 1And Z 2Be carbon, if Z wherein 1, Z 2Or Z 3Be then SO of nitrogen 2R 4R 5Debond is in nitrogen;
Q is 0,1,2 or 3;
Each R 3Independently be selected from: the heterocycle of the cycloalkyl of the alkoxyl group of the alkyl of hydrogen, alkyl, replacement, alkoxyl group, replacement, cycloalkyl or replacement, halogen, heterocycle and replacement;
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement, acyl group and M +, M wherein +Be to be selected from K +, Na +, Li +Or +N (R 6) 4The metal counter ion, R wherein 6Be hydrogen or alkyl, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4Or R 5Be to be selected from Ca 2+, Mg 2+ or Ba 2+The divalence counter ion, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms; Perhaps
When q is 1,2 or 3, R 5Can with a R who is incorporated into its alpha position 3Group forms together suc as formula the condensed ring shown in the II:
Wherein W is selected from: C 1-C 3The C of alkylidene group, replacement 1-C 3Alkylidene group, C 2-C 3The C of alkenylene and replacement 2-C 3Alkenylene, wherein one or more carbon atoms have been selected from oxygen, sulphur, S (O), S (O) 2, C (O) or NR 8Part replace R wherein 8Be selected from hydrogen or alkyl, perhaps R 8It is the key that participates in forming unsaturated-N=C＜site;
Prerequisite is:
When alk is key and Y when being key, R 1Not cyano group, carboxyl, carboxylic acid ester groups or amino carbonyl amino;
When alk is-CH 2-, Y is an oxygen, R 1When being phenyl, ring A is not a cycloalkyl;
When alk is that key, Y are key and ring A when being phenyl, R 1Not the heterocycle or the aminoacyl oxygen base of heterocycle, replacement;
As Y or R 1-alk-Y-formation is connected to ring A's-NR 7C (O) O-or-NR 7C (O) NR 7-when directly connecting, R 7Be hydrogen; With
When Y is-C (O) NR 7-,-NR 7C (O)-,-OC (O) NR 7-,-NR 7C (O) O-or-NR 7C (O) NR 7-and alk when being key, R 1Not acyl group, acyl amino, aminoacyl or amino carbonyl amino.
2. compound as claimed in claim 1, wherein:
Y is an oxygen;
R is a hydrogen;
Z 1, Z 2And Z 3The carbon of respectively doing for oneself;
Each R 2Independently be selected from: alkyl, the alkyl that replaces, alkoxyl group, the alkoxyl group that replaces, amino, the amino that replaces, aryl, the aryl that replaces, aryloxy, the aryloxy that replaces, cyano group, cycloalkyl, the cycloalkyl that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryl, the heteroaryl that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocycle, the heterocycle that replaces, the heterocyclyloxy base, the heterocyclyloxy base that replaces, aminoacyl, aminoacyl oxygen base, carboxyl, carboxylic acid ester groups, carbonate group, nitro and halogen; With
SO 2NR 4R 5With position between the amino at 2 places of pyrimidine becomes.
3. compound as claimed in claim 2, wherein:
X is a fluorine; With
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement and acyl group; Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms.
4. compound as claimed in claim 3, wherein, ring A is a phenyl.
5. the compound shown in the formula IIA as claimed in claim 2:
Figure A20068002053300041
Wherein q-1 is 0,1 or 2.
6. compound as claimed in claim 5, wherein, ring A is a phenyl.
7. compound as claimed in claim 1, wherein:
Y is an oxygen;
R is a hydrogen;
X is a fluorine;
Z 1, Z 2And Z 3The carbon of respectively doing for oneself;
Each R 2Independently be selected from: alkyl, the alkyl that replaces, alkoxyl group, the alkoxyl group that replaces, amino, the amino that replaces, aryl, the aryl that replaces, aryloxy, the aryloxy that replaces, cyano group, cycloalkyl, the cycloalkyl that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryl, the heteroaryl that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocycle, the heterocycle that replaces, the heterocyclyloxy base, the heterocyclyloxy base that replaces, aminoacyl, aminoacyl oxygen base, carboxyl, carboxylic acid ester groups, carbonate group, nitro and halogen; With
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement and acyl group; Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms;
SO 2NR 4R 5Become contraposition with the amino at 2 places of pyrimidine.
8. compound as claimed in claim 7, wherein, ring A is a phenyl.
9. the compound of formula III:
Its solvate, prodrug or pharmacy acceptable salt; Wherein:
X is selected from: the alkynyl of the thiazolinyl of the amino of the alkoxyl group of the alkyl of alkyl, replacement, alkoxyl group, replacement, amino, replacement, carboxyl, carboxylic acid ester groups, cyano group, halogen, nitro, thiazolinyl, replacement, alkynyl and replacement;
R is selected from: the cycloalkyl of the alkynyl of the thiazolinyl of the alkyl of hydrogen, alkyl, replacement, thiazolinyl, replacement, alkynyl, replacement, cycloalkyl and replacement;
Ring A is selected from: aryl, heteroaryl, cycloalkyl, cycloalkenyl group and heterocycle, and wherein encircling A is not indyl or benzimidazolyl-;
P is 0,1,2 or 3;
Each R 2Independently be selected from: alkyl, the alkyl that replaces, alkoxyl group, the alkoxyl group that replaces, amino, the amino that replaces, aryl, the aryl that replaces, aryloxy, the aryloxy that replaces, cyano group, cycloalkyl, the cycloalkyl that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryl, the heteroaryl that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocycle, the heterocycle that replaces, the heterocyclyloxy base, the heterocyclyloxy base that replaces, aminoacyl, aminoacyl oxygen base, carboxyl, carboxylic acid ester groups, carbonate group, alkylsulfonyl, oxo, nitro and halogen;
Z 1, Z 2And Z 3Independent separately is carbon or nitrogen, if Z wherein 1Be then Z of nitrogen 2And Z 3Be carbon, if Z 2Be then Z of nitrogen 1And Z 3Be carbon, and if Z 3Be then Z of nitrogen 1And Z 2Be carbon, if Z wherein 1, Z 2Or Z 3Be then SO of nitrogen 2R 4R 5Debond is in nitrogen;
Q is 0,1,2 or 3;
Each R 3Independently be selected from: the heterocycle of the cycloalkyl of the alkoxyl group of the alkyl of hydrogen, alkyl, replacement, alkoxyl group, replacement, cycloalkyl or replacement, halogen, heterocycle and replacement;
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement, acyl group and M +, M wherein +Be to be selected from K +, Na +, Li +Or +N (R 6) 4The metal counter ion, R wherein 6Be hydrogen or alkyl, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4Or R 5Be to be selected from Ca 2+, Mg 2+ or Ba 2+The divalence counter ion, and SO 2NR 4R 5Nitrogen be N -Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms; Perhaps
When q is 1,2 or 3, R 5Can with a R who is incorporated into its alpha position 3Group forms together suc as formula the condensed ring shown in the IV:
Figure A20068002053300061
Wherein W is selected from: C 1-C 3The C of alkylidene group, replacement 1-C 3Alkylidene group, C 2-C 3The C of alkenylene and replacement 2-C 3Alkenylene, wherein one or more carbon atoms have been selected from oxygen, sulphur, S (O), S (O) 2, C (O) or NR 8Part replace R wherein 8Be selected from hydrogen or alkyl, perhaps R 8It is the key that participates in forming unsaturated-N=C＜site;
Prerequisite is:
If p=0, then X is not a bromine;
If ring A is a cycloalkyl, then X is not a bromine;
If p=2 and each R 2Be methoxyl group, halogen, trihalogenmethyl or three halogen methoxyl group, then R 4And R 5Not a hydrogen and a methyl;
If p=2 and R 2Be fluorine and methyl, then R is not the thiazolinyl that replaces; With
If ring A is a phenyl, p=1 and R 2Be chlorine, R then 4And R 5Not a hydrogen and a methyl.
10. compound as claimed in claim 9, wherein:
R is a hydrogen;
Z 1, Z 2And Z 3The carbon of respectively doing for oneself;
Each R 2Independently be selected from: alkyl, the alkyl that replaces, alkoxyl group, the alkoxyl group that replaces, amino, the amino that replaces, aryl, the aryl that replaces, aryloxy, the aryloxy that replaces, cyano group, cycloalkyl, the cycloalkyl that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryl, the heteroaryl that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocycle, the heterocycle that replaces, the heterocyclyloxy base, the heterocyclyloxy base that replaces, aminoacyl, aminoacyl oxygen base, carboxyl, carboxylic acid ester groups, carbonate group, nitro and halogen; With
SO 2NR 4R 5With position between the amino at 2 places of pyrimidine becomes.
11. compound as claimed in claim 10, wherein:
X is fluorine or methyl; With
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement and acyl group; Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms.
12. compound 1 as claimed in claim 1, wherein encircling A is phenyl.
13. the compound shown in the formula IVA as claimed in claim 10:
Figure A20068002053300071
Wherein q-1 is 0,1 or 2.
14. compound 3 as claimed in claim 1, wherein encircling A is phenyl.
15. compound as claimed in claim 9, wherein:
R is a hydrogen;
Z 1, Z 2And Z 3The carbon of respectively doing for oneself;
Each R 2Independently be selected from: alkyl, the alkyl that replaces, alkoxyl group, the alkoxyl group that replaces, amino, the amino that replaces, aryl, the aryl that replaces, aryloxy, the aryloxy that replaces, cyano group, cycloalkyl, the cycloalkyl that replaces, cycloalkyloxy, the cycloalkyloxy that replaces, heteroaryl, the heteroaryl that replaces, heteroaryloxy, the heteroaryloxy that replaces, heterocycle, the heterocycle that replaces, the heterocyclyloxy base, the heterocyclyloxy base that replaces, aminoacyl, aminoacyl oxygen base, carboxyl, carboxylic acid ester groups, carbonate group, nitro and halogen; With
SO 2NR 4R 5Become contraposition with the amino at 2 places of pyrimidine.
16. compound as claimed in claim 15, wherein:
X is fluorine or methyl; With
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement and acyl group; Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms.
17. compound as claimed in claim 16, wherein encircling A is phenyl.
18. the compound shown in the formula V as claimed in claim 9:
Figure A20068002053300072
Wherein:
R 4And R 5Independently be selected from: the alkyl of hydrogen, alkyl, replacement and acyl group; Perhaps
R 4And R 5Form the heterocyclic group of heterocycle or replacement with institute's bonded nitrogen-atoms;
R 7Be selected from: the alkyl of hydrogen, alkyl or replacement; With
V is selected from: C 1-C 3The C of alkylidene group, replacement 1-C 3Alkylidene group, C 2-C 3The C of alkenylene and replacement 2-C 3Alkenylene, wherein one or more carbon atoms have been selected from oxygen, sulphur, S (O), S (O) 2Or NR 8Heteroatoms replace R wherein 8Be selected from hydrogen or alkyl, perhaps R 8It is the key that participates in forming unsaturated-N=C＜site.
19. compound 8 as claimed in claim 1, wherein:
X is fluorine or methyl;
R is a hydrogen;
Z 1, Z 2And Z 3The carbon of respectively doing for oneself; With
SO 2NR 4R 5With position between the amino at 2 places of pyrimidine becomes.
20. compound 8 as claimed in claim 1, wherein:
X is fluorine or methyl;
R is a hydrogen;
Z 1, Z 2And Z 3The carbon of respectively doing for oneself; With
SO 2NR 4R 5Become contraposition with the amino at 2 places of pyrimidine.
21. be selected from down the compound of group:
I-1 N2-(4-amino-sulfonyl phenyl)-N4-(3-cyano group methoxyl group-4,5-Dimethoxyphenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-2 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3-cyano group methoxyl group-4,5-Dimethoxyphenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-3 N2-(4-amino-sulfonyl) phenyl-N4-(3-cyano group methoxyl group) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-4 N2-(3-amino-sulfonyl) phenyl-N4-(3-cyano group methoxyl group) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-5 N4-(3-cyano group methoxyl group) phenyl-5-fluoro-N2-[3-(4-methylpiperazine-1-yl) alkylsulfonyl] phenyl-2, the 4-pyrimidinediamine;
I-6 N4-(3-cyano group methoxyl group) phenyl-5-fluoro-N2-[4-(4-methylpiperazine-1-yl) alkylsulfonyl] phenyl-2, the 4-pyrimidinediamine;
I-7 N2-(4-amino-sulfonyl-3-methoxyl group) phenyl-N4-(3-cyano group methoxyl group) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-8 N2-(3-amino-sulfonyl-4-isopropyl phenyl)-N4-(4-cyano group methylene radical oxygen base phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-9 N2-[3-amino-sulfonyl-4-(4-methylpiperazine-1-yl) phenyl]-5-fluoro-N4-(4-cyano group methylene radical oxygen base phenyl)-2, the 4-pyrimidinediamine;
I-10 N2-[3-amino-sulfonyl-4-(4-methylpiperazine-1-yl) phenyl]-5-fluoro-N4-(4-cyano group methylene radical oxygen base-3-fluorophenyl)-2, the 4-pyrimidinediamine;
I-11 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(4-cyano group methylene radical oxygen base-3-fluorophenyl)-2, the 4-pyrimidinediamine;
I-12 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(4-cyano group methylene radical oxygen base-3-fluorophenyl)-2, the 4-pyrimidinediamine;
I-13 N2-(3-amino-sulfonyl phenyl)-5-bromo-N4-(4-cyano group methylene radical oxygen base phenyl)-2, the 4-pyrimidinediamine;
I-14 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-bromo-N4-(4-cyano group methylene radical oxygen base phenyl)-2, the 4-pyrimidinediamine;
I-15 N2-(3-amino-sulfonyl phenyl)-N4-(4-cyano group methylene radical oxygen base phenyl)-5-trimethyl silyl acetylene-2, the 4-pyrimidinediamine;
I-16 N2-(4-amino-sulfonyl) phenyl-N4-(4-cyano group methoxyl group) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-17 N2-(3-amino-sulfonyl) phenyl-N4-(4-cyano group methoxyl group) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-18 N4-(4-cyano group methoxyl group) phenyl-5-fluoro-N2-[4-(4-methylpiperazine-1-yl) alkylsulfonyl] phenyl-2, the 4-pyrimidinediamine;
I-19 N4-(4-cyano group methoxyl group) phenyl-5-fluoro-N2-[3-(4-methylpiperazine-1-yl) alkylsulfonyl] phenyl-2, the 4-pyrimidinediamine;
I-20 N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-(4-cyano group methoxyl group) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-21 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(4-cyano group methoxyl group) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-22 N2-(4-amino-sulfonyl) phenyl-N4-(4-cyano group methoxyl group-3-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-23 N2-(3-amino-sulfonyl) phenyl-N4-(4-cyano group methoxyl group-3-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-24 N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-(4-cyano group methoxyl group-3-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-25 N2-(4-amino-sulfonyl) phenyl-N4-(4-cyano group methoxyl group-3,5-dimethyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-26 N2-(3-amino-sulfonyl) phenyl-N4-(4-cyano group methoxyl group-3,5-dimethyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-27 N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-(4-cyano group methoxyl group-3,5-dimethyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-28 N2-(4-amino-sulfonyl-3-p-methoxy-phenyl)-N4-(4-cyano group methoxyl group) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-29 N2-(4-amino-sulfonyl-3-methoxyl group) phenyl-N4-(4-cyano group methoxyl group-3-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-30 N4-(4-cyano group methylene radical oxygen base) phenyl-5-fluoro-N2-(4-methyl-3-propionyl amino-sulfonyl) phenyl-2,4-pyrimidinediamine (68);
I-31 N4-(4-cyano group methylene radical oxygen base) phenyl-5-fluoro-N2-(4-methyl-3-propionyl amino-sulfonyl) phenyl-2,4-pyrimidinediamine sodium salt (69);
I-32 N2-(4-amino-sulfonyl-3-methoxyl group) phenyl-N4-(4-cyano group methoxyl group-3,5-dimethyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-33 N2-(3-amino-sulfonyl-4-fluorine) phenyl-N4-(4-cyano group methoxyl group) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-34 N2-(3-amino-sulfonyl-4-fluorine) phenyl-N4-(4-cyano group methoxyl group-3-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-35 N2-(3-amino-sulfonyl-4-fluorine) phenyl-N4-(4-cyano group methoxyl group-3,5-dimethyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-36 N2-(3-acetylamino alkylsulfonyl-4-methyl) phenyl-N4-(4-cyano group methylene radical oxygen base) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-37 N4-(4-cyano group methylene radical oxygen base) phenyl-5-fluoro-N2-(3-isobutyryl amino-sulfonyl-4-methyl) phenyl-2, the 4-pyrimidinediamine;
I-38 N2-(3-acetylamino alkylsulfonyl-4-methyl) phenyl-N4-(4-cyano group methylene radical oxygen base) phenyl-5-fluoro-2,4-pyrimidinediamine sodium salt;
I-39 N4-(4-cyano group methylene radical oxygen base) phenyl-5-fluoro-N2-(3-isobutyryl amino-sulfonyl-4-methyl) phenyl-2,4-pyrimidinediamine sodium salt;
I-40 N4-(4-cyano group methoxyl group-3,5-3,5-dimethylphenyl)-5-fluoro-N2-[4-(4-methylpiperazine-1-yl) alkylsulfonyl phenyl]-2, the 4-pyrimidinediamine;
I-41 N2-(4-amino-sulfonyl phenyl)-N4-(3-chloro-4-cyano group p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-42 N2-(3-amino-sulfonyl phenyl)-N4-(3-chloro-4-cyano group p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-43 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3-chloro-4-cyano group p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-44 N2-(4-amino-sulfonyl phenyl)-N4-(4-cyano group methoxyl group-3-fluorophenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-45 N2-(4-amino-sulfonyl phenyl)-N4-(4-cyano group methoxyl group-3-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-46 N2-(3-amino-sulfonyl phenyl)-N4-(4-cyano group methoxyl group-3-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-47 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(4-cyano group methoxyl group-3-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-48 N4-(4-cyano group methoxyl group-3-fluorophenyl)-5-fluoro-N2-(4-methyl-3-propionyl amino-sulfonyl phenyl)-2, the 4-pyrimidinediamine;
I-49 N4-(4-cyano group methoxyl group-3-fluorophenyl)-5-fluoro-N2-(4-methyl-3-propionyl amino-sulfonyl phenyl)-2,4-pyrimidinediamine sodium salt;
I-50 N2-(3-amino-sulfonyl phenyl)-N4-(4-cyano group methoxyl group-3-hydroxymethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-51 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(4-cyano group methoxyl group-3-hydroxymethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-52 N2-(4-amino-sulfonyl phenyl)-N4-[4-cyano group methoxyl group-3-(1-cyano methyl pyrazole-3-yl) phenyl]-5-fluoro-2, the 4-pyrimidinediamine;
I-53 N2-(3-amino-sulfonyl phenyl)-N4-[4-cyano group methoxyl group-3-(1-cyano methyl pyrazole-3-yl) phenyl]-5-fluoro-2, the 4-pyrimidinediamine;
I-54 N2-(3-amino-sulfonyl-4-aminomethyl phenyl]-N4-[4-cyano group methoxyl group-3-(1-cyano methyl pyrazole-3-yl) phenyl]-5-fluoro-2, the 4-pyrimidinediamine;
I-55 N2-(3-amino-sulfonyl pyridin-4-yl)-N4-(4-cyano group p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-56 N2-(3-amino-sulfonyl-4-p-methoxy-phenyl)-N4-(4-cyano group p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-57 N2-(4-amino-sulfonyl phenyl)-N4-(4-cyano group p-methoxy-phenyl-5)-methyl-2, the 4-pyrimidinediamine;
I-58 N2-(3-amino-sulfonyl phenyl)-N4-(4-cyano group p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine;
I-59 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(4-cyano group p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine;
I-60 racemize N2-(4-amino-sulfonyl) phenyl-N4-[4-(1-cyano group) oxyethyl group-3-methyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-61 racemize N2-(3-amino-sulfonyl) phenyl-N4-[4-(1-cyano group) oxyethyl group-3-methyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-62 racemize N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-[4-(1-cyano group) oxyethyl group-3-methyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-63 racemize N2-(4-amino-sulfonyl) phenyl-N4-[4-(1-cyano group) oxyethyl group-3, the 5-dimethyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-64 racemize N2-(4-amino-sulfonyl-3-methoxyl group) phenyl-N4-[4-(1-cyano group) oxyethyl group-3-methyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-65 racemize N2-(3-amino-sulfonyl) phenyl-N4-[4-(1-cyano group) oxyethyl group] phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-66 racemize N2-(4-amino-sulfonyl) phenyl-N4-[4-(1-cyano group) oxyethyl group] phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-67 racemize N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-[4-(1-cyano group) oxyethyl group] phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-68 racemize N2-(3-amino-sulfonyl-4-fluorine) phenyl-N4-[4-(1-cyano group) oxyethyl group] phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-69 racemize N2-(3-amino-sulfonyl-4-fluorine) phenyl-N4-[4-(1-cyano group) oxyethyl group-3-methyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-70 racemize N2-(4-amino-sulfonyl-3-methoxyl group) phenyl-N4-[4-(1-cyano group) oxyethyl group] phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-71 racemize N2-(3-amino-sulfonyl) phenyl-N4-[4-(1-cyano group) oxyethyl group-3, the 5-dimethyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-72 racemize N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-[4-(1-cyano group) oxyethyl group-3, the 5-dimethyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-73 N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-[4-(1-cyano group-1-methyl) oxyethyl group] phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-74 N2-(3-amino-sulfonyl-4-fluorine) phenyl-N4-[4-(1-cyano group-1-methyl) oxyethyl group] phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-75 N2-(4-amino-sulfonyl) phenyl-N4-[4-(1-cyano group-1-methyl) oxyethyl group] phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-76 N2-(3-amino-sulfonyl) phenyl-N4-[4-(1-cyano group-1-methyl) oxyethyl group] phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-77 N2-(4-amino-sulfonyl-3-methoxyl group) phenyl-N4-[4-(1-cyano group-1-methyl) oxyethyl group] phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-78 N2-(3-amino-sulfonyl phenyl)-N4-[4-(N-cyano group ethanoyl) aminophenyl]-5-fluoro-2, the 4-pyrimidinediamine.
I-79 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[4-(N-cyano group ethanoyl) aminophenyl]-5-fluoro-2, the 4-pyrimidinediamine;
I-80 N2-(3-amino-sulfonyl phenyl)-5-fluorine N4-[3-methyl-4-(N-cyano group ethanoyl) aminophenyl]-2, the 4-pyrimidinediamine;
I-81 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluorine N4-[3-methyl 4-(N-cyano group ethanoyl) aminophenyl]-2, the 4-pyrimidinediamine;
I-82 N2-(3-amino-sulfonyl phenyl)-N4-[3-chloro-4-(N-cyano group ethanoyl) aminophenyl]-5-fluoro-2, the 4-pyrimidinediamine;
I-83 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[3-chloro-4-(N-cyano group ethanoyl) aminophenyl]-5-fluoro-2, the 4-pyrimidinediamine;
I-84 N2-(3-amino-sulfonyl phenyl)-5-fluorine N4-[3-methoxyl group-4-(N-cyano group ethanoyl) aminophenyl]-2, the 4-pyrimidinediamine;
I-85 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluorine N4-[3-methoxyl group-4-(N-cyano group ethanoyl) aminophenyl]-2, the 4-pyrimidinediamine;
I-86 N2-(3-amino-sulfonyl phenyl)-N4-[4-(N-cyano group ethanoyl-N-methyl) aminophenyl]-5-fluoro-2, the 4-pyrimidinediamine;
I-87 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[4-(N-cyano group ethanoyl-N-methyl) aminophenyl]-5-fluoro-2, the 4-pyrimidinediamine;
I-88 N4-(3-aminocarboxyl methoxyl group) phenyl-N2-(3-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-89 N4-(3-aminocarboxyl methoxyl group) phenyl-5-fluoro-N2-[3-(4-methylpiperazine-1-yl) alkylsulfonyl] phenyl-2, the 4-pyrimidinediamine;
I-90 N4-(3-aminocarboxyl methoxyl group) phenyl-N2-(3-amino-sulfonyl-4-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-91 N4-(3-aminocarboxyl methoxyl group) phenyl-N2-(4-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-92 N4-(4-aminocarboxyl methoxyl group-3-methyl) phenyl-N2-(3-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-93 N4-(4-aminocarboxyl methoxyl group-3,5-dimethyl) phenyl-N2-(3-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-94 N4-(4-aminocarboxyl methoxyl group) phenyl-N2-(3-amino-sulfonyl-4-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-95 N4-(4-aminocarboxyl methoxyl group-3-methyl) phenyl-N2-(3-amino-sulfonyl-4-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-96 N4-(4-aminocarboxyl methoxyl group-3,5-dimethyl) phenyl-N2-(3-amino-sulfonyl-4-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-97 N4-(4-aminocarboxyl methoxyl group-3-chloro-phenyl-)-N2-(4-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-98 N4-(4-aminocarboxyl methoxyl group-3-chloro-phenyl-)-N2-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-99 N4-(4-aminocarboxyl methoxyl group-3-chloro-phenyl-)-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-100 N4-(4-aminocarboxyl methoxyl group-3-fluorophenyl)-N2-(4-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-101 N4-(4-aminocarboxyl methoxyl group-3-fluorophenyl)-N2-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-102 N4-(4-aminocarboxyl methoxyl group-3-fluorophenyl)-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-103 N4-(4-aminocarboxyl methoxyl group-3-p-methoxy-phenyl)-N2-(4-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-104 N4-(4-aminocarboxyl methoxyl group-3-p-methoxy-phenyl)-N2-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-105 N4-(4-aminocarboxyl methoxyl group-3-p-methoxy-phenyl)-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-106 N4-(4-aminocarboxyl methoxyl group-3-hydroxymethyl phenyl)-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-107 N4-(4-aminocarboxyl methoxyl group-3-hydroxymethyl phenyl]-N2-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-108 N4-(4-aminocarboxyl p-methoxy-phenyl)-N2-(4-amino-sulfonyl phenyl)-5-methyl-2, the 4-pyrimidinediamine;
I-109 N4-(4-aminocarboxyl p-methoxy-phenyl)-N2-(3-amino-sulfonyl phenyl)-5-methyl-2, the 4-pyrimidinediamine;
I-110 N4-(4-aminocarboxyl p-methoxy-phenyl)-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-methyl-2, the 4-pyrimidinediamine;
I-111 N4-(4-aminocarboxyl methoxyl group) phenyl-N2-(3-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-112 N4-(4-aminocarboxyl methoxyl group) phenyl-5-fluoro-N2-[3-(4-methylpiperazine-1-yl) alkylsulfonyl] phenyl-2, the 4-pyrimidinediamine;
I-113 N4-(4-aminocarboxyl methoxyl group-3-methyl) phenyl-N2-(4-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-114 N4-(4-aminocarboxyl methoxyl group-3,5-dimethyl) phenyl-N2-(4-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-115 N4-(4-aminocarboxyl methoxyl group) phenyl-N2-(4-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-116 racemize N4-[4-(1-aminocarboxyl) oxyethyl group] phenyl-N2-(4-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-117 racemize N4-[4-(1-aminocarboxyl) oxyethyl group] phenyl-N2-(3-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-118 N4-[4-(1-aminocarboxyl) oxyethyl group] phenyl-N2-(3-amino-sulfonyl-4-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-119 racemize N4-[4-(1-aminocarboxyl) oxyethyl group-3-methyl] phenyl-N2-(4-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-120 racemize N4-[4-(1-aminocarboxyl) oxyethyl group-3-methyl] phenyl-N2-(3-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-121 racemize N4-[4-(1-aminocarboxyl) oxyethyl group-3-methyl] phenyl-N2-(3-amino-sulfonyl-4-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-122 racemize N4-[4-(1-aminocarboxyl) oxyethyl group-3, the 5-dimethyl] phenyl-N2-(4-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-123 racemize N4-[4-(1-aminocarboxyl) oxyethyl group-3, the 5-dimethyl] phenyl-N2-(3-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-124 racemize N4-[4-(1-aminocarboxyl) oxyethyl group-3, the 5-dimethyl] phenyl-N2-(3-amino-sulfonyl-4-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-125 N4-[4-(1-aminocarboxyl-1-methyl) oxyethyl group] phenyl-N2-(4-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-126 N4-[4-(1-aminocarboxyl-1-methyl) oxyethyl group] phenyl-N2-(3-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-127 N4-[4-(1-aminocarboxyl-1-methyl) oxyethyl group] phenyl-N2-(3-amino-sulfonyl-4-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
I-128 N2-(4-amino-sulfonyl phenyl)-N4-(4-dimethylamino carbonyl p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-129 N2-(3-amino-sulfonyl phenyl)-N4-(4-dimethylamino carbonyl p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-130 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(4-dimethylamino carbonyl p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-131 N2-(4-amino-sulfonyl phenyl)-N4-(3-chloro-4-dimethylamino carbonyl p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-132 N2-(3-amino-sulfonyl phenyl)-N4-(3-chloro-4-dimethylamino carbonyl p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-133 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3-chloro-4-dimethylamino carbonyl p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-134 N2-(4-amino-sulfonyl phenyl)-N4-(3-chloro-4-dimethylamino carbonyl p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine;
I-135 N2-(3-amino-sulfonyl phenyl)-N4-(3-chloro-4-dimethylamino carbonyl p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine;
I-136 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3-chloro-4-dimethylamino carbonyl p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine;
I-137 N2-(4-amino-sulfonyl phenyl)-N4-(4-dimethylamino carbonyl methoxyl group-3-fluorophenyl)-5-methyl-2, the 4-pyrimidinediamine;
I-138 N2-(3-amino-sulfonyl phenyl)-N4-(4-dimethylamino carbonyl methoxyl group-3-fluorophenyl)-5-methyl-2, the 4-pyrimidinediamine;
I-139 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(4-dimethylamino carbonyl methoxyl group-3-fluorophenyl)-5-methyl-2, the 4-pyrimidinediamine;
I-140 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(3-chloro-4-dimethylamino carbonyl p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-141 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(3-chloro-4-dimethylamino carbonyl p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine;
I-142 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(4-dimethylamino carbonyl methoxyl group-3-fluorophenyl)-5-methyl-2, the 4-pyrimidinediamine;
I-143 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-(4-methylamino carbonyl p-methoxy-phenyl)-2, the 4-pyrimidinediamine;
I-144 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(4-methylamino carbonyl p-methoxy-phenyl)-2, the 4-pyrimidinediamine;
I-145 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(4-methylamino carbonyl p-methoxy-phenyl)-2, the 4-pyrimidinediamine;
I-146 N2-(4-amino-sulfonyl phenyl)-N4-(3-chloro-4-methylamino carbonyl p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-147 N2-(3-amino-sulfonyl phenyl)-N4-(3-chloro-4-methylamino carbonyl p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-148 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3-chloro-4-methylamino carbonyl p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-149 N2-(4-amino-sulfonyl phenyl)-N4-(3-chloro-4-methylamino carbonyl p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine;
I-150 N2-(3-amino-sulfonyl phenyl)-N4-(3-chloro-4-methylamino carbonyl p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine;
I-151 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3-chloro-4-methylamino carbonyl p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine;
I-152 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(3-chloro-4-methylamino carbonyl p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-153 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(3-chloro-4-methylamino carbonyl p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine;
I-154 N2-(4-amino-sulfonyl phenyl)-N4-(3-fluoro-4-methylamino carbonyl p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine;
I-155 N2-(3-amino-sulfonyl phenyl)-N4-(3-fluoro-4-methylamino carbonyl p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine;
I-156 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3-fluoro-4-methylamino carbonyl p-methoxy-phenyl)-5-methyl-2, the 4-pyrimidinediamine;
I-157 N4-(4-allyl amino carbonyl p-methoxy-phenyl)-N2-(4-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-158 N4-(4-allyl amino carbonyl p-methoxy-phenyl)-N2-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-159 N4-(4-allyl amino carbonyl p-methoxy-phenyl)-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
I-160 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(2-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-161 5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-5-fluoro-N4-[4-(2-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-162 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-163 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-164 N2-(3-amino-sulfonyl pyridin-4-yl)-5-fluoro-N4-[4-(2-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-165 N2-[4-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[4-(2-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-166 N2-[3-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[4-(2-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-167 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[(4-((pyridine-2-yl) methoxyl group)-3-aminomethyl phenyl)]-2, the 4-pyrimidinediamine;
I-168 N2-(3-amino-4-methyl sulphonyl phenyl)-5-fluoro-N4-[(4-((pyridine-2-yl) methoxyl group)-3-aminomethyl phenyl)]-2, the 4-pyrimidinediamine;
I-169 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-pyridyl)-3-fluorine methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-170 5-fluoro-N2-[3-N-(methyl) amino-sulfonyl-4-aminomethyl phenyl]-N4-[4-(2-pyridyl)-3-methyl methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-171 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-pyridyl)-3-chlorine methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-172 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(2-pyridyl)-3-fluorine methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-173 5-fluoro-N2-[3-N-(methyl) amino-sulfonyl-4-aminomethyl phenyl]-N4-[4-(2-pyridyl)-3-fluorine methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-174 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(2-pyridyl)-3-chlorine methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-175 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-pyridyl)-3-chlorine methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-176 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-pyridyl)-3-methyl methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-177 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-pyridyl)-3-fluorine methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-178 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(3-pyridyl methoxyl group) phenyl]-2, the 4-pyrimidinediamine;
I-179 N2-(3-amino-sulfonyl phenyl)-5-methyl-N4-[4-(2-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-180 5-methyl-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-[4-(2-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-181 N2-(4-amino-sulfonyl phenyl)-5-methyl-N4-[4-(2-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-182 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[3-(3-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-183 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-(3-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-184 5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-5-fluoro-N4-[3-(3-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-185 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[3-(3-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-186 N2-[4-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[3-(3-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-187 N2-[3-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[3-(3-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-188 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-189 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(3-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-190 5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-5-fluoro-N4-[4-(3-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-191 N2-[4-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[4-(3-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-192 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-pyridyl)-methylene radical thio-phenyl]-2, the 4-pyrimidinediamine;
I-193 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-194 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(4-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-195 5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-5-fluoro-N4-[4-(4-pyridyl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-196 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-4-[(2-pyridyl) methylene radical oxygen base phenyl]-2,4-pyrimidinediamine hydrochloride;
I-197 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(the 3-methyl-(1H)-pyrazoles-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-198 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[4-(1, the 3-dimethyl-(1H)-and pyrazoles-5-yl) methylene radical oxygen base phenyl]-5-fluoro-2, the 4-pyrimidinediamine;
I-199 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[4-(1-benzyl-3-methyl-(1H)-pyrazoles-5-yl) methylene radical oxygen base phenyl]-5-fluoro-2, the 4-pyrimidinediamine;
I-200 N2-(3-amino-sulfonyl-4-fluorophenyl)-5-fluoro-N4-[4-(2,4-dihydro-3-oxo-1,2,4-triazole-5-yl) methylene radical oxygen base phenyl]-2,4-pyrimidinediamine (76);
I-201 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2,4-dihydro-3-oxo-1,2,4-triazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-202 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(2,4-dihydro-3-oxo-1,2,4-triazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-203 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-methyl-3-(2-morpholino ethyl oxygen base) phenyl]-2, the 4-pyrimidinediamine;
I-204 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-methyl-3-(2-morpholino ethyl oxygen base) phenyl] 2, the 4-pyrimidinediamine;
I-205 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-morpholino ethyl oxygen base) phenyl)-2, the 4-pyrimidinediamine;
I-206 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-morpholino ethyl oxygen base) phenyl-2, the 4-pyrimidinediamine;
I-207 5-fluoro-N2-(3-morpholino alkylsulfonyl phenyl)-N4-[4-(2-morpholino ethyl oxygen base) phenyl]-2, the 4-pyrimidinediamine;
I-208 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-methyl-3-(2-morpholino carbonyl methylene radical oxygen base) phenyl]-2, the 4-pyrimidinediamine;
I-209 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-methyl-3-(2-morpholino carbonyl methylene radical oxygen base) phenyl]-2, the 4-pyrimidinediamine;
I-210 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-morpholine-4-base-2-oxo-oxyethyl group) phenyl]-2, the 4-pyrimidinediamine;
I-211 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-morpholine-4-base-2-oxo-oxyethyl group) phenyl]-2, the 4-pyrimidinediamine;
I-212 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(2-morpholine-4-base-2-oxo-oxyethyl group) phenyl]-2, the 4-pyrimidinediamine;
I-213 5-fluoro-N4-(4-methoxycarbonyl p-methoxy-phenyl)-N2-(4-methyl-3-propionyl amino-sulfonyl phenyl)-2, the 4-pyrimidinediamine;
I-214 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[3-(the different azoles of 5-methyl-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-215 5-fluoro-N2-[3-(N-methoxycarbonyl methylene radical) amino-sulfonyl phenyl]-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-216 N2-(3-amino-sulfonyl-5-chloro-4-aminomethyl phenyl)-5-fluoro-N4-[3-methyl-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-217 N2-(3-amino-sulfonyl-4-fluoro-5-aminomethyl phenyl)-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-218 N2-(3-amino-sulfonyl-4-chloro-5-aminomethyl phenyl)-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-219 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-220 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-221 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[3-chloro-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-5-fluoro-2, the 4-pyrimidinediamine;
I-222 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-fluoro-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-223 N2-(3-amino-sulfonyl-5-chloro-4-aminomethyl phenyl)-5-fluoro-N4-[3-fluoro-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-224 N2-(3-amino-sulfonyl-4-fluoro-5-aminomethyl phenyl)-5-fluoro-N4-[3-fluoro-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-225 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-methyl-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-226 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-fluoro-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-N4-methyl-2, the 4-pyrimidinediamine;
I-227 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-methoxycarbonyl methyl-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-228 5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-N2-(4-methyl-3-propionyl amino-sulfonyl phenyl)-2, the 4-pyrimidinediamine;
I-229 5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-N2-(4-methyl-3-(2-methylpropionyl) amino-sulfonyl phenyl)-2, the 4-pyrimidinediamine;
I-230 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine (59, X=H);
I-231 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-232 N2-(3-kharophen alkylsulfonyl phenyl)-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-233 N2-(3-amino-sulfonyl-4-fluorophenyl)-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-234 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-methyl-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-235 5-fluoro-N2-[3-(N-methyl) amino-sulfonyl-4-aminomethyl phenyl]-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-236 5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-N2-(3-N-propionamido) alkylsulfonyl phenyl)]-2, the 4-pyrimidinediamine;
I-237 N2-(3-amino-sulfonyl-4-fluorophenyl)-5-fluoro-N4-[3 methyl-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-238 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[3-methyl-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-239 5-fluoro-N2-[3-N-(methyl) amino-sulfonyl-4-aminomethyl phenyl]-N4-[3-methyl-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-240 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[3 methyl-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-241 N2-[3-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-242 5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-N2-(3-N-propionamido) alkylsulfonyl phenyl)]-2,4-pyrimidinediamine sodium salt;
I-243 N2-(3-kharophen alkylsulfonyl phenyl)-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2,4-pyrimidinediamine sodium salt;
I-244 N2-[3-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[3-methyl-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-245 N2-[4-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[3-methyl-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-246 N2-[4-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-247 N2-{3-[(N-5-methyl isophthalic acid, 3-dioxole-2-ketone-4-yl) methylene radical] the amino-sulfonyl phenyl }-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-248 N2-{3-[N-N-two-[(5-methyl isophthalic acid, 3-dioxole-2-ketone-4-yl) methylene radical]] the amino-sulfonyl phenyl }-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-249 N2-{3-[N-N-two-[(the 5-tertiary butyl-1,3-dioxole-2-ketone-4-yl) methylene radical]] the amino-sulfonyl phenyl }-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
The I-250 N2-{3-[(N-5-tertiary butyl-1,3-dioxole-2-ketone-4-yl) methylene radical] the amino-sulfonyl phenyl }-5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-251 N2-[3-amino-sulfonyl-4-(4-methylpiperazine-1-yl) phenyl]-5-fluoro-N4-[2-fluoro-4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-252 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[3-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2,4-pyrimidinediamine (60);
I-253 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[3-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-254 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-255 5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-[3-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-256 N2-[4-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[3-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-257 N2-{3-[(N-5-methyl isophthalic acid, 3-dioxole-2-ketone-4-yl) methylene radical] the amino-sulfonyl phenyl }-5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-258 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-259 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-260 5-fluoro-N2-[3-N-(methyl) amino-sulfonyl-4-aminomethyl phenyl)-and N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-261 N2-[3-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[3-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-262 5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-3-yl) methylene radical oxygen base phenyl]-the N2-[(3-N-propionamido) the alkylsulfonyl phenyl)]-2, the 4-pyrimidinediamine;
I-263 N2-[4-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-264 5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-3-yl) methylene radical oxygen base phenyl]-the N2-[(3-N-propionamido) the alkylsulfonyl phenyl)]-2, the 4-pyrimidinediamine;
I-265 N2-(3-amino-sulfonyl-4-chloro-5-aminomethyl phenyl)-5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-266 N2-(3-amino-sulfonyl-4-fluorophenyl)-5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-267 N2-(3-amino-sulfonyl-4-fluorophenyl)-5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) ethylidene phenyl]-2, the 4-pyrimidinediamine;
I-268 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-(4-[3-methyl isophthalic acid, 2,4-oxadiazole-5-yl] methylene radical oxygen base phenyl)-2, the 4-pyrimidinediamine;
I-269 5-fluoro-N2-(4-N-methylamino alkylsulfonyl)-3-p-methoxy-phenyl-N4-(4-trifluoromethoxy-3-chloro-phenyl-)-2, the 4-pyrimidinediamine;
I-270 5-fluoro-N4-(3-hydroxy phenyl)-N2-(4-N-methylamino alkylsulfonyl)-3-p-methoxy-phenyl]-2, the 4-pyrimidinediamine;
I-271 N2-(5-N, N-diethylamino alkylsulfonyl-2-p-methoxy-phenyl)-5-fluoro-N4-(4-[3-methyl isophthalic acid, 2,4-oxadiazole-5-yl] methylene radical oxygen base phenyl)-2, the 4-pyrimidinediamine;
I-272 5-fluoro-N4-(4-[3-methyl isophthalic acid, 2,4-oxadiazole-5-yl] methylene radical oxygen base phenyl)-N2-(5-piperdine sulfonyl phenyl)-2, the 4-pyrimidinediamine;
I-273 5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-3-yl) methylene radical oxygen base phenyl]-the N2-[(3-N-propionamido) the alkylsulfonyl phenyl)]-2,4-pyrimidinediamine sodium salt;
I-274 5-fluoro-N4-[4-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl) methoxyl group] phenyl-N2-[3-(4-methylpiperazine-1-yl) alkylsulfonyl] phenyl-2, the 4-pyrimidinediamine;
I-275 N2-(4-amino-sulfonyl) phenyl-5-fluoro-N4-[4-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl) methoxyl group] phenyl-2, the 4-pyrimidinediamine;
I-276 N2-(3-amino-sulfonyl) phenyl-5-fluoro-N4-[4-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl) methoxyl group] phenyl-2, the 4-pyrimidinediamine;
I-277 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) methylene radical oxygen base phenyl]-2,4-pyrimidinediamine (71);
I-278 N2-(3-amino-sulfonyl-4-fluorophenyl)-5-fluoro-N4-[4-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-279 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) p-methoxy-phenyl]-2, the 4-pyrimidinediamine;
I-280 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(2-methylthiazol-4-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-281 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-methylthiazol-4-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-282 5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-[4-(2-methylthiazol-4-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-283 N2-[3-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[4-(2-methylthiazol-4-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-284 N2-[4-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[4-(2-methylthiazol-4-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
I-285 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-methylthiazol-4-yl) methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
II-1 racemize N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-{3-[(1-methyl piperidine-3-yl) oxygen base] phenyl }-2, the 4-pyrimidinediamine;
II-2 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-{3-[(1-methyl piperidine-4-yl) oxygen base] phenyl }-2, the 4-pyrimidinediamine;
II-3 racemize N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-{3-chloro-4-[(1-methyl piperidine-3-yl) oxygen base] phenyl }-5-fluoro-2, the 4-pyrimidinediamine;
II-4 racemize N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-{4-[(1-methyl piperidine-3-yl) oxygen base] phenyl }-2, the 4-pyrimidinediamine;
II-5 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-{3-methyl-4-[(1-methyl piperidine-4-yl) oxygen base] phenyl }-2, the 4-pyrimidinediamine;
II-6 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-{4-[(1-methyl piperidine-4-yl) oxygen base]-the 3-trifluoromethyl }-2, the 4-pyrimidinediamine;
II-7 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-{4-[(1-methyl piperidine-4-yl) oxygen base] phenyl }-2, the 4-pyrimidinediamine;
II-8 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-{3-chloro-4-[(1-methyl piperidine-4-yl) oxygen base] phenyl }-2, the 4-pyrimidinediamine;
II-9 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(N-methylpyrrolidin-3-base oxygen base phenyl)-2, the 4-pyrimidinediamine;
II-10 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(N-methylpyrrolidin-3-base oxygen base phenyl)-2, the 4-pyrimidinediamine;
II-11 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-pyridyl oxygen base) phenyl]-2, the 4-pyrimidinediamine;
II-12 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(3-pyridyl oxygen base) phenyl]-2, the 4-pyrimidinediamine;
II-13 5-fluoro-N2-[3-N-(methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-[4-(3-pyridyl oxygen base) phenyl]-2, the 4-pyrimidinediamine;
II-14 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-pyridyl oxygen base) phenyl]-2, the 4-pyrimidinediamine;
II-15 N2-[3,5-two (amino-sulfonyl) phenyl)-5-fluoro-N4-[4-(3-pyridyl oxygen base) phenyl]-2, the 4-pyrimidinediamine;
II-16 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(4-pyridyl oxygen base) phenyl]-2, the 4-pyrimidinediamine;
II-17 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-pyridyl oxygen base) phenyl]-2, the 4-pyrimidinediamine;
II-18 5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-5-fluoro-N4-[4-(4-pyridyl oxygen base) phenyl]-2, the 4-pyrimidinediamine;
II-19 N2-(3-aminocarboxyl-5-aminomethyl phenyl)-5-fluoro-N2-[4-(1-methylpyrazole-3-yl) amido phenyl)-2, the 4-pyrimidinediamine;
II-20 N2-(3-aminocarboxyl-5-aminomethyl phenyl)-5-fluoro-N2-[4-(1-ethyl pyrazoles-5-yl) amido phenyl)-2, the 4-pyrimidinediamine;
II-21 N2-(3-aminocarboxyl-5-aminomethyl phenyl)-5-fluoro-N2-[4-(1-methylpyrazole-5-yl) amido phenyl)-2, the 4-pyrimidinediamine;
II-22 N2-(3-aminocarboxyl-5-aminomethyl phenyl)-5-fluoro-N2-[4-(1H-pyrazoles-5-yl) amido phenyl)-2, the 4-pyrimidinediamine;
III-1 5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-5-fluoro-N4-(4-cyano methyl phenyl)-2, the 4-pyrimidinediamine;
III-2 N2-[4-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-(4-cyano methyl phenyl)-2, the 4-pyrimidinediamine;
III-3 N2-(4-amino-sulfonyl) phenyl-N4-(4-cyano methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-4 N2-(3-amino-sulfonyl) phenyl-N4-(4-cyano methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-5 N4-(4-cyano methyl) phenyl-5-fluoro-N2-[3-(4-methylpiperazine-1-yl) alkylsulfonyl] phenyl-2, the 4-pyrimidinediamine;
III-6 N4-(4-cyano methyl) phenyl-5-fluoro-N2-[4-(4-methylpiperazine-1-yl) alkylsulfonyl] phenyl-2, the 4-pyrimidinediamine;
III-7 N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-(4-cyano methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-8 N2-(3-amino-sulfonyl-4-chlorine) phenyl-N4-(4-cyano methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-9 N2-(4-amino-sulfonyl-3-methoxyl group) phenyl-N4-(4-cyano methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-10 N2-(3-amino-sulfonyl-4-fluorine) phenyl-N4-(4-cyano methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-11 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(4-cyano group ethylidene phenyl)-5-methyl-2, the 4-pyrimidinediamine;
III-12 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-[4-(2-cyano ethyl) phenyl]-5-methyl-2, the 4-pyrimidinediamine;
III-13 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-[4-(2-cyano ethyl) phenyl]-5-fluoro-2, the 4-pyrimidinediamine;
III-14 N2-(3-amino-sulfonyl phenyl)-N4-[4-(cyano group ethylidene) phenyl]-5-fluoro-2, the 4-pyrimidinediamine;
III-15 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[4-(cyano group ethylidene) phenyl]-5-fluoro-2, the 4-pyrimidinediamine;
III-16 N2-(3-amino-sulfonyl-4-fluorophenyl)-N4-[4-(cyano group ethylidene) phenyl]-5-fluoro-2, the 4-pyrimidinediamine;
III-17 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(2-cyano ethyl)-3-fluorophenyl]-2, the 4-pyrimidinediamine;
III-18 N2-(3-amino-sulfonyl phenyl)-N4-[4-(2-cyano ethyl)-3-fluorophenyl]-5-fluoro-2, the 4-pyrimidinediamine;
III-19 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[4-(2-cyano ethyl)-3-aminomethyl phenyl]-5-fluoro-2, the 4-pyrimidinediamine;
III-20 N2-(3-amino-sulfonyl phenyl)-N4-[4-(2-cyano ethyl)-3-aminomethyl phenyl]-5-fluoro-2, the 4-pyrimidinediamine;
III-21 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[3-chloro-4-(2-cyano ethyl) phenyl]-5-fluoro-2, the 4-pyrimidinediamine;
III-22 N2-(3-amino-sulfonyl phenyl)-N4-[3-chloro-4-(2-cyano ethyl) phenyl]-5-fluoro-2, the 4-pyrimidinediamine;
III-23 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(4-cyano group ethylidene-2-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
III-24 N2-(3-amino-sulfonyl phenyl)-N4-(4-cyano group ethylidene-2-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
III-25 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(4-cyano group ethylidene-3-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine
III-26 N2-(3-amino-sulfonyl phenyl)-N4-(4-cyano group ethylidene-2-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
III-27 N2-(4-amino-sulfonyl phenyl)-N4-(4-cyano group ethylidene phenyl)-5-methyl-2,4-pyrimidinediamine and prodrug thereof
III-28 N4-(3-chloro-4-cyano group ethylidene-phenyl)-5-fluoro-N2-(4-methyl-3-propionyl amino-sulfonyl phenyl)-2, the 4-pyrimidinediamine
III-29 N4-(3-chloro-4-cyano group ethylidene-phenyl)-5-fluoro-N2-(4-methyl-3-propionyl amino-sulfonyl phenyl)-2,4-pyrimidinediamine sodium salt
III-30 N4-(4-cyano group ethylidene-3-trifluoromethyl)-5-fluoro-N2-(4-methyl-3-amino-sulfonyl phenyl)-2, the 4-pyrimidinediamine
III-31 N4-(4-cyano group ethylidene-3-trifluoromethyl)-5-fluoro-N2-(3-amino-sulfonyl phenyl)-2, the 4-pyrimidinediamine
III-32 N4-(4-amino carbonyl amino aminomethyl phenyl)-N2-(4-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
III-33 N4-(4-amino carbonyl amino aminomethyl phenyl)-N2-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
III-34 N4-(4-amino carbonyl amino aminomethyl phenyl)-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
III-35 N2-(4-amino-sulfonyl) phenyl-N4-(4-ethyl carbonylamino methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-36 N2-(3-amino-sulfonyl) phenyl-N4-(4-ethyl carbonylamino methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-37 N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-(4-ethyl carbonylamino methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-38 N2-(4-amino-sulfonyl) phenyl-N4-(3-cyclopropyl carbonyl amino methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-39 N2-(3-amino-sulfonyl) phenyl-N4-(3-cyclopropyl carbonyl amino methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-40 N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-(3-cyclopropyl carbonyl amino methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-41 N2-(4-amino-sulfonyl) phenyl-N4-(4-cyclopropyl carbonyl amino methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-42 N2-(3-amino-sulfonyl) phenyl-N4-(4-cyclopropyl carbonyl amino methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-43 N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-(4-cyclopropyl carbonyl amino methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-44 N4-(4-propenyl amido aminomethyl phenyl)-N2-(4-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
III-45 N4-(4-propenyl amido aminomethyl phenyl)-N2-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
III-46 N4-(4-propenyl amido aminomethyl phenyl)-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
III-47 N4-[4-(the amino carboxyl ethylidene of 2-) phenyl]-5-fluoro-N2-(4-methyl-3-amino-sulfonyl phenyl)-2, the 4-pyrimidinediamine;
III-48 N4-[4-(the amino carboxyl ethylidene of 2-) phenyl]-N2-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
III-49 N4-[4-(the amino carboxyl ethylidene of 2-) phenyl]-N2-(4-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine
III-50 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N-4-[4 (1-methylpyrazole base-3-aminocarboxyl methylene radical) phenyl]-2, the 4-pyrimidinediamine;
III-51 N2-(3-amino-sulfonyl phenyl)-N4-[(1-ethyl pyrazolyl-5-aminocarboxyl methylene radical) phenyl]-5-fluoro-2, the 4-pyrimidinediamine;
III-52 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-N4-[(1-ethyl pyrazolyl-5-aminocarboxyl methylene radical) phenyl]-5-fluoro-2, the 4-pyrimidinediamine;
III-53 N4-{4-[2-(aminocarboxyl oxygen base) ethyl] phenyl }-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
III-54 N4-{4-[2-(aminocarboxyl oxygen base) ethyl] phenyl }-N2-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
III-55 N4-{4-[2-(aminocarboxyl oxygen base) ethyl] phenyl }-N2-(3-amino-sulfonyl-4-chloro-phenyl-)-5-fluoro-2, the 4-pyrimidinediamine;
III-56 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-{4-[2-(dimethylamino ketonic oxygen base) ethyl] phenyl }-5-fluoro-2, the 4-pyrimidinediamine;
III-57 N2-(3-amino-sulfonyl phenyl)-N4-{4-[2-(dimethylamino ketonic oxygen base) ethyl] phenyl }-5-fluoro-2, the 4-pyrimidinediamine;
III-58 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-{4-[2-(dimethylamino ketonic oxygen base) ethyl] phenyl }-5-fluoro-2, the 4-pyrimidinediamine;
III-59 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-{4-[2-(methylamino ketonic oxygen base) ethyl] phenyl }-2, the 4-pyrimidinediamine;
III-60 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-{4-[2-(methylamino ketonic oxygen base) ethyl] phenyl }-2, the 4-pyrimidinediamine;
III-61 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-5-fluoro-N4-{4-[2-(methylamino ketonic oxygen base) ethyl] phenyl }-2, the 4-pyrimidinediamine;
III-62 N2-(3-amino-sulfonyl phenyl)-N4-(4-benzyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
III-63 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(4-benzyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
III-64 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(4-benzyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
III-65 N2-(3-amino-sulfonyl-4-methoxyl group-5-aminomethyl phenyl)-N4-(4-benzyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
III-66 N2-(3-amino-sulfonyl-4-p-methoxy-phenyl)-5-fluoro-N4-[4-(4-pyridylmethyl) phenyl]-2, the 4-pyrimidinediamine;
III-67 N2-[4-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[4-(4-pyridylmethyl) phenyl]-2, the 4-pyrimidinediamine;
III-68 5-fluoro-N4-[4-(4-pyridylmethyl) phenyl]-the N2-[(3-N-propionamido) the alkylsulfonyl phenyl)]-2, the 4-pyrimidinediamine;
III-69 5-fluoro-N4-[4-(4-pyridylmethyl) phenyl]-the N2-[(3-N-propionamido) the alkylsulfonyl phenyl)]-2,4-pyrimidinediamine sodium salt;
III-70 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-pyridylmethyl) phenyl]-2, the 4-pyrimidinediamine;
III-71 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-pyridylmethyl) phenyl]-2, the 4-pyrimidinediamine;
III-72 N2-[4-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[4-(4-pyridylmethyl) phenyl]-2, the 4-pyrimidinediamine;
III-73 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-pyridylmethyl) phenyl]-2,4-pyrimidinediamine hydrochloride;
III-74 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(4-pyridylmethyl) phenyl]-2, the 4-pyrimidinediamine;
III-75 5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-5-fluoro-N4-[4-(4-pyridylmethyl) phenyl]-2, the 4-pyrimidinediamine;
III-76 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-pyridyl) styroyl]-2, the 4-pyrimidinediamine;
III-77 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(4-pyridyl) styroyl]-2, the 4-pyrimidinediamine;
III-78 5-fluoro-N2-[3-N-(methyl) amino-sulfonyl-4-aminomethyl phenyl]-N4-[4-(4-pyridyl) styroyl]-2, the 4-pyrimidinediamine;
III-79 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-pyridyl) styroyl]-2, the 4-pyrimidinediamine;
III-80 prepares N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(1-epoxy-4-pyridylmethyl) phenyl]-2, the 4-pyrimidinediamine;
III-81 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(1-imidazolyl methyl) phenyl]-2, the 4-pyrimidinediamine;
III-82 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(1-imidazolyl methyl) phenyl]-2, the 4-pyrimidinediamine;
III-83 5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-5-fluoro-N4-[4-(1-imidazolyl methyl) phenyl]-2, the 4-pyrimidinediamine;
III-84 N2-[4-(2-N, N-diethylamino ethyl) amino-sulfonyl phenyl)-and 5-fluoro-N4-[4-(1-imidazolyl methyl) phenyl]-2, the 4-pyrimidinediamine;
III-85 5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-[4-(1-imidazolyl methyl) phenyl]-2,4-pyrimidinediamine hydrochloride
III-86 5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-[4-(1-imidazolyl methyl) phenyl]-2,4-pyrimidinediamine dihydrochloride
III-87 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(1-imidazolyl) styroyl]-2, the 4-pyrimidinediamine;
III-88 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(1-imidazolyl) styroyl]-2, the 4-pyrimidinediamine;
III-89 5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-[4-(1-imidazolyl) styroyl]-2, the 4-pyrimidinediamine;
III-90 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(1-imidazolyl) styroyl]-2, the 4-pyrimidinediamine;
III-91 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(2-methyl isophthalic acid-imidazolyl methyl) phenyl]-2, the 4-pyrimidinediamine;
III-92 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-methyl isophthalic acid-imidazolyl methyl) phenyl]-2, the 4-pyrimidinediamine;
III-93 5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-[4-(2-methyl isophthalic acid-imidazolyl methyl) phenyl]-2, the 4-pyrimidinediamine;
III-94 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(2-methyl isophthalic acid-imidazolyl methyl) phenyl]-2, the 4-pyrimidinediamine;
III-95 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-{4-[1-(1,2,3-triazoles base) methyl] phenyl }-2, the 4-pyrimidinediamine;
III-96 N2-4-amino-sulfonyl phenyl)-and 5-fluoro-N4-{4-[1-(1,2,3-triazoles base) methyl] phenyl }-2, the 4-pyrimidinediamine;
III-97 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-{4-[1-(1,2,3-triazoles base) methyl] phenyl }-2, the 4-pyrimidinediamine;
III-98 5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-{4-[1-(1,2,3-triazoles base) methyl] phenyl }-2, the 4-pyrimidinediamine;
III-99 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-{4-[1-(1,2, the 4-triazolyl) methyl] phenyl }-2, the 4-pyrimidinediamine;
III-100 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-{4-[1-(1,2, the 4-triazolyl) methyl] phenyl }-2, the 4-pyrimidinediamine;
III-101 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-{4-[1-(1,2, the 4-triazolyl) methyl] phenyl }-2, the 4-pyrimidinediamine;
III-1025-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-{4-[1-(1,2, the 4-triazolyl) methyl] phenyl }-2, the 4-pyrimidinediamine;
III-103 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(4-N-morpholino methylene radical phenyl)-2, the 4-pyrimidinediamine;
III-104 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(4-N-morpholino methylene radical phenyl)-2, the 4-pyrimidinediamine;
III-105 N2-(3-amino-sulfonyl-4-methylene radical oxygen base phenyl)-5-fluoro-N4-(4-N-morpholino methylene radical phenyl)-2, the 4-pyrimidinediamine;
III-106 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl) ethylidene phenyl]-2, the 4-pyrimidinediamine;
III-107 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(the 4-thiomorpholine is for the methylene radical phenyl)-2, the 4-pyrimidinediamine;
III-108 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(the 4-thiomorpholine is for the methylene radical phenyl)-2, the 4-pyrimidinediamine;
III-109 N2-(3-amino-sulfonyl-4-p-methoxy-phenyl)-5-fluoro-N4-(the 4-thiomorpholine is for the methylene radical phenyl)-2, the 4-pyrimidinediamine;
III-110 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-{4-[(1,1-dioxo thiomorpholine-4-base-) methyl] phenyl-2, the 4-pyrimidinediamine;
III-111 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-{4-[(1,1-dioxo thiomorpholine-4-base-) methyl] phenyl-2, the 4-pyrimidinediamine;
III-112 N2-(3-amino-sulfonyl-4-methyl oxygen base phenyl)-5-fluoro-N4-{4-[(1,1-dioxo thiomorpholine-4-base-) methyl] phenyl-2, the 4-pyrimidinediamine;
III-113 N4-(3-amino carbonyl amino methyl) phenyl-N2-(4-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-114 N4-(3-amino carbonyl amino methyl) phenyl-N2-(3-amino-sulfonyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-115 N4-(3-amino carbonyl amino methyl) phenyl-N2-(3-amino-sulfonyl-4-methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-116 N2-(4-amino-sulfonyl) phenyl-N4-(3-ethylamino carbonylamino methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-117 N2-(3-amino-sulfonyl) phenyl-N4-(3-ethylamino carbonylamino methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-118 N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-(3-ethylamino carbonylamino methyl) phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-119 N2-(4-amino-sulfonyl phenyl)-N4-(4-ethylamino carbonylamino aminomethyl phenyl]-5-fluoro-2, the 4-pyrimidinediamine;
III-120 N2-(3-amino-sulfonyl phenyl]-N4-(4-ethylamino carbonylamino aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
III-121 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(4-ethylamino carbonylamino aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
III-122 N2-(4-amino-sulfonyl) phenyl-N4-[4-(2-ethylamino carbonylamino) ethyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-123 N2-(3-amino-sulfonyl) phenyl-N4-[4-(2-ethylamino carbonylamino) ethyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-124 N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-[4-(2-ethylamino carbonylamino) ethyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-125 N2-(4-amino-sulfonyl) phenyl-N4-[4-(N-carbamyl-N-propyl group) amino methyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-126 N2-(3-amino-sulfonyl) phenyl-N4-[4-(N-carbamyl-N-propyl group) amino methyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-127 N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-[4-(N-carbamyl-N-propyl group) amino methyl] phenyl-5-fluoro-2, the 4-pyrimidinediamine;
III-128 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-pyridylmethyl) phenyl]-2,4-pyrimidinediamine tosilate;
III-129 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-pyridylmethyl) phenyl]-2,4-pyrimidinediamine mesylate;
IV-1 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[3-(1,3-oxazole-5-yl) phenyl]-2, the 4-pyrimidinediamine;
IV-2 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-(1,3-oxazole-5-yl) phenyl]-2, the 4-pyrimidinediamine;
IV-3 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[3-(1,3-oxazole-5-yl) phenyl]-2, the 4-pyrimidinediamine;
IV-4 5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-[3-(1,3-oxazole-5-yl) phenyl]-2, the 4-pyrimidinediamine;
IV-5 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(1,3-oxazole-5-yl) phenyl]-2, the 4-pyrimidinediamine;
IV-6 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(1,3-oxazole-5-yl) phenyl]-2, the 4-pyrimidinediamine;
IV-7 5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-[4-(1,3-oxazole-5-yl) phenyl]-2, the 4-pyrimidinediamine;
IV-8 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(1,3-oxazole-5-yl) phenyl]-2, the 4-pyrimidinediamine;
IV-9 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[3-(N, N-dimethylamino alkylsulfonyl) phenyl]-2, the 4-pyrimidinediamine;
IV-10 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-(N, N-dimethylamino alkylsulfonyl) phenyl]-2, the 4-pyrimidinediamine;
IV-11 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[3-(N-methylamino alkylsulfonyl) phenyl]-2, the 4-pyrimidinediamine;
IV-12 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-(N-methylamino alkylsulfonyl) phenyl]-2, the 4-pyrimidinediamine;
V-1 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[2-(5-methyl-isoxazole-3-yl) methylene radical oxygen yl pyridines-5-yl]-2, the 4-pyrimidinediamine;
V-2 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-oxo-4-(2-pyridylmethyl)-benzo [1,4] oxazine-6-yl]-2, the 4-pyrimidinediamine;
V-3 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-oxo-4-(2-pyridylmethyl)-benzo [1,4] oxazine-6-yl]-2, the 4-pyrimidinediamine;
V-4 racemize N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[2-methyl-3-oxo-4-(4-methoxy-benzyl)-benzo [1,4] oxazine-6-yl]-2, the 4-pyrimidinediamine;
V-5 racemize N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[2-methyl-3-oxo-4-(4-methoxy-benzyl)-benzo [1,4] oxazine-6-yl]-2, the 4-pyrimidinediamine;
V-6 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-(3-oxo-4-cyano methyl-benzo [1,4] oxazine-6-yl]-2,4-pyrimidinediamine;
V-7 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(3-oxo-4-cyano methyl-benzo [1,4] oxazine-6-yl]-2,4-pyrimidinediamine;
V-8 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-oxo-4-cyano methyl-benzo [1,4] oxazine-6-yl]-2, the 4-pyrimidinediamine;
V-9 (R/S)-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[2-methyl-3-oxo-4-(4-methoxy-benzyl)-benzo [1,4] thiazine-6-yl]-2, the 4-pyrimidinediamine;
V-10 (R/S)-N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[2-methyl-3-oxo-4-(4-methoxy-benzyl)-benzo [1,4] thiazine-6-yl]-2, the 4-pyrimidinediamine;
V-11 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-(3-oxo-4-cyano methyl-benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine;
V-12 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(3-oxo-4-cyano methyl-benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine;
V-13 N2-(3-amino-sulfonyl 4-aminomethyl phenyl)-5-fluoro-N4-(3-oxo-4-cyano methyl-benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine;
V-14 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[2,2-dimethyl-3-oxo-4-cyano methyl-5-pyrido [1,4] oxazine-7-yl]-5-fluoro-2,4-pyrimidinediamine;
V-15 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-[2,2-dimethyl-3-oxo-4-cyano methyl-5-pyrido [1,4] oxazine-7-yl]-5-fluoro-2,4-pyrimidinediamine;
V-16 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(2-cyano group ethylidene-thionaphthene-5-yl)-5-fluoro-2, the 4-pyrimidinediamine
V-17 N-2-(3-amino-sulfonyl phenyl)-N4-[2,2-dimethyl-3-oxo-4H-pyrido [1,4] oxazine-7-yl]-5-fluoro-2,4-pyrimidinediamine;
V-18 N-2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[2,2-dimethyl-3-oxo-4H-pyrido [1,4] oxazine-7-yl]-5-fluoro-2,4-pyrimidinediamine;
V-19 (4R)-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(1-cyano group methylene radical carbonyl-4-methyl piperidine-3-yl)-5-fluoro-2; the 4-pyrimidinediamine) or (4S)-and N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(1-cyano group methylene radical carbonyl-4-methyl piperidine-3-yl)-5-fluoro-2, the 4-pyrimidinediamine)
VIII-1 5-fluoro-N4-[4-(5-methyl-isoxazole-3-yl) methylene radical oxygen base phenyl]-N2-(sugar-6-yl)-2, the 4-pyrimidinediamine; With
VIII-2 N4-(3-chloro-4-cyano group methylene radical oxygen base phenyl)-5-fluoro-N2-(5-methyl-2H-1,1-dioxy-1,2,4-benzothiadiazine-7-yl)-2, the 4-pyrimidinediamine.
22. be selected from down the compound of group:
VI-1 5-fluoro-N4-(3-hydroxy phenyl)-N2-[4-(N-methyl) amino-sulfonyl-3-p-methoxy-phenyl]-2, the 4-pyrimidinediamine;
VI-2 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(3-chloro-4-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-3 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(3, the 4-dichlorophenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-4 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3-chloro-4-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-5 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(4-chloro-3-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-6 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3, the 4-dichlorophenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-7 N4-(3-chloro-4-p-methoxy-phenyl)-5-fluoro-N2-[3-(N-methoxycarbonyl methylene radical) amino-sulfonyl phenyl]-2, the 4-pyrimidinediamine;
VI-8 N4-(3, the 4-dichlorophenyl)-5-fluoro-N2-[3-(N-methoxycarbonyl methylene radical) amino-sulfonyl phenyl]-2, the 4-pyrimidinediamine;
VI-9 N4-(3-chloro-4-p-methoxy-phenyl)-5-fluoro-N2-[3-(4-methyl piperidine-1-yl) amino-sulfonyl phenyl]-2, the 4-pyrimidinediamine;
VI-10 N4-(3, the 4-dichlorophenyl)-5-fluoro-N2-[3-(4-methyl piperidine-1-yl) amino-sulfonyl phenyl]-2, the 4-pyrimidinediamine;
VI-11 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(4-chloro-3-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-12 N2-[3-(N-ethanoyl) amino-sulfonyl-4-chloro-phenyl-]-N4-(3-chloro-4-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-13 N2-(3-amino-sulfonyl-5-chloro-4-aminomethyl phenyl)-N4-(3-chloro-4-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-14 N2-(3-amino-sulfonyl-5-chloro-4-aminomethyl phenyl)-N4-(3-chloro-4-Trifluoromethoxyphen-l)-5-fluoro-2, the 4-pyrimidinediamine;
VI-15 N2-(3-amino-sulfonyl-4-fluoro-5-aminomethyl phenyl)-N4-(3-chloro-4-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-16 N2-(3-amino-sulfonyl-4-fluoro-5-aminomethyl phenyl)-N4-(3-chloro-4-Trifluoromethoxyphen-l)-5-fluoro-2, the 4-pyrimidinediamine;
VI-17 N2-(3-amino-sulfonyl-4-chloro-5-aminomethyl phenyl)-N4-(3-chloro-4-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-18 N2-(3-amino-sulfonyl-4-chloro-5-aminomethyl phenyl)-N4-(3-chloro-4-Trifluoromethoxyphen-l)-5-fluoro-2, the 4-pyrimidinediamine;
VI-19 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3-chloro-4-p-methoxy-phenyl)-5-fluoro-N4-methyl-2, the 4-pyrimidinediamine;
VI-20 N2-(3-amino-sulfonyl-4-fluoro-5-aminomethyl phenyl)-N4-(3-chloro-4-p-methoxy-phenyl)-5-fluoro-N4-methyl-2, the 4-pyrimidinediamine;
VI-21 N2-(3-amino-sulfonyl-4-chloro-5-aminomethyl phenyl)-N4-(3-chloro-4-p-methoxy-phenyl)-5-fluoro-N4-methyl-2, the 4-pyrimidinediamine;
VI-22 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3-chloro-4-p-methoxy-phenyl)-5-fluoro-N4-propyl group-2, the 4-pyrimidinediamine;
VI-23 N2-(3-amino-sulfonyl-4-fluoro-5-aminomethyl phenyl)-N4-(3-chloro-4-p-methoxy-phenyl)-5-fluoro-N4-propyl group-2, the 4-pyrimidinediamine;
VI-24 N2-(3-amino-sulfonyl phenyl)-5-carbonyl oxyethyl group?-N4-(N-carbonyl oxyethyl group? methylene radical-N-3-chloro-4-p-methoxy-phenyl)-2, the 4-pyrimidinediamine;
VI-25 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-carbonyl oxyethyl group-N4-(N-carbonyl oxyethyl group methylene radical-N-3-chloro-4-p-methoxy-phenyl)-2, the 4-pyrimidinediamine;
VI-26 N2-(3-amino-sulfonyl phenyl)-5-bromo-N4-(3-chloro-4-p-methoxy-phenyl)-2, the 4-pyrimidinediamine;
VI-27 2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-bromo-N4-(3-chloro-4-p-methoxy-phenyl)-2, the 4-pyrimidinediamine;
VI-28 N2-(3-amino-sulfonyl phenyl)-N4-(3-chloro-4-p-methoxy-phenyl)-5-trimethyl silyl acetylene-2, the 4-pyrimidinediamine;
VI-29 N2-(3-amino-sulfonyl-4-p-methoxy-phenyl)-N4-(3-chloro-4-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-30 N2-(3-amino-sulfonyl-4-methoxyl group-5-aminomethyl phenyl)-N4-(3-chloro-4-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-31 N2-(3-amino-sulfonyl pyridin-4-yl)-N4-(3-chloro-4-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-32 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(4-Trifluoromethoxyphen-l)-2, the 4-pyrimidinediamine;
VI-33 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(4-Trifluoromethoxyphen-l)-2, the 4-pyrimidinediamine;
VI-34 N2-(3-amino-sulfonyl-4-methoxyl group-5-aminomethyl phenyl)-5-fluoro-N4-(4-trifluoromethyl)-2, the 4-pyrimidinediamine;
VI-35 N2-(3-amino-sulfonyl phenyl)-N4-(4-tert-butyl-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-36 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(4-tert-butyl-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-37 N2-(3-amino-sulfonyl-4-methoxyl group-5-aminomethyl phenyl)-N4-(4-tert-butyl-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-38 N2-(3-amino-sulfonyl phenyl)-N4-(4-chloro-3-trifluoromethyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-39 N2-(3-amino-sulfonyl-4-methyl-phenyl)-N4-(4-chloro-3-trifluoromethyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-40 N2-(3-amino-sulfonyl-4-methoxyl group-5-aminomethyl phenyl)-N4-(4-chloro-3-trifluoromethyl-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-41 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-5-fluoro-N4-(4-trifluorophenyl)-2, the 4-pyrimidinediamine;
VI-42 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-5-fluoro-N4-(4-Trifluoromethoxyphen-l)-2, the 4-pyrimidinediamine;
VI-43 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(4-tert-butyl-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-44 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(3-chloro-4-trifluoromethyl-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-45 N2-(3-amino-sulfonyl-4-isopropyl phenyl)-N4-(3-chloro-4-methoxyl group-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-46 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(4-trifluoromethyl methylene radical oxygen base phenyl)-2, the 4-pyrimidinediamine;
VI-47 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(4-trifluoromethyl methylene radical oxygen base phenyl)-2, the 4-pyrimidinediamine;
VI-48 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-5-fluoro-N4-(4-trifluoromethyl methylene radical oxygen base phenyl)-2, the 4-pyrimidinediamine;
VI-49 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-(methylamino ketonic oxygen ylmethyl) phenyl]-2, the 4-pyrimidinediamine;
VI-50 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(4-trifluoromethyl)-2, the 4-pyrimidinediamine;
VI-51 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(4-trifluoromethyl)-2, the 4-pyrimidinediamine;
VI-52 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(4-hydroxymethyl phenyl)-2, the 4-pyrimidinediamine;
VI-53 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(Propargyl oxygen base) phenyl]-2, the 4-pyrimidinediamine;
VI-54 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(4-ethenylphenyl)-2, the 4-pyrimidinediamine;
VI-55 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-5-fluoro-N4-[4-(Propargyl oxygen base) phenyl]-2, the 4-pyrimidinediamine;
VI-56 5-fluoro-N2-(4-methyl-3-propionyl amino-sulfonyl phenyl)-N4-[4-(Propargyl oxygen base) phenyl]-2, the 4-pyrimidinediamine;
VI-57 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-(Propargyl oxygen base) phenyl]-2, the 4-pyrimidinediamine;
VI-58 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-methyl-4-(Propargyl oxygen base) phenyl]-2, the 4-pyrimidinediamine;
VI-59 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[3-chloro-4-(Propargyl oxygen base) phenyl]-5-fluoro-2, the 4-pyrimidinediamine;
VI-60 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-fluoro-4-(Propargyl oxygen base) phenyl]-2, the 4-pyrimidinediamine;
VI-61 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[4-(fourth-2-alkynyloxy base) phenyl]-5-fluoro-2, the 4-pyrimidinediamine;
VI-62 N2-[3-propionyl amino-sulfonyl-4-aminomethyl phenyl]-5-fluoro-N4-[4-(Propargyl oxygen base) phenyl]-2, the 4-pyrimidinediamine;
VI-63 N2-[3-amino-sulfonyl-4-(2-propyl group) phenyl]-5-fluoro-N4-[4-(Propargyl oxygen base) phenyl]-2, the 4-pyrimidinediamine;
VI-64 N4-{4-[2-(dimethylamino ketonic oxygen base) ethyl] phenyl }-5-fluoro-N2-(3-propionyl amino-sulfonyl phenyl)-2, the 4-pyrimidinediamine;
VI-65 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(Propargyl amino) phenyl]-2, the 4-pyrimidinediamine;
VI-66 N4-{4-[2-(dimethylamino ketonic oxygen base) ethyl] phenyl }-5-fluoro-N2-(3-propionyl amino-sulfonyl phenyl)-2,4-pyrimidinediamine sodium salt
VI-67 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-{4-[two (Propargyl) amino] phenyl }-5-fluoro-2, the 4-pyrimidinediamine;
VI-68 5-fluoro-N2-(4-methyl-3-methylamino alkylsulfonyl phenyl)-N4-[4-(Propargyl oxygen base) phenyl]-2, the 4-pyrimidinediamine;
VI-69 5-fluoro-N2-{[4-methyl-3-((1-methyl piperidine-4-yl) amino-sulfonyl)] phenyl }-N4-[4-(Propargyl oxygen base) phenyl]-2, the 4-pyrimidinediamine;
VI-70 N2-[3-amino-sulfonyl-4-(1-methylpiperazine-4-yl) phenyl]-5-fluoro-N4-[4-(Propargyl oxygen base) phenyl]-2, the 4-pyrimidinediamine;
VI-71 N4-{4-[2-(amino carbonyl amino) ethyl] phenyl }-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-72 N4-{4-[2-(amino carbonyl amino) ethyl] phenyl }-N2-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-73 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-{4-[(Propargyl oxygen base) carbonylamino methyl] phenyl }-2, the 4-pyrimidinediamine;
VI-74 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-{4-[(Propargyl oxygen base) carbonylamino methyl] phenyl }-2, the 4-pyrimidinediamine;
VI-75 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(Propargyl amino-sulfonyl) phenyl]-2, the 4-pyrimidinediamine;
VI-76 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(Propargyl amino-sulfonyl) phenyl]-2, the 4-pyrimidinediamine;
VI-77 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(Propargyl amino-sulfonyl) phenyl]-2, the 4-pyrimidinediamine;
VI-78 5-fluoro-N2-[3-(Propargyl amino-sulfonyl) phenyl]-N4-[4-(Propargyl oxygen base) phenyl]-2, the 4-pyrimidinediamine;
VI-79 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[3-(Propargyl amino-sulfonyl) phenyl]-2, the 4-pyrimidinediamine;
VI-80 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[3-(Propargyl amino-sulfonyl) phenyl]-2, the 4-pyrimidinediamine;
VI-81 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[3-(Propargyl amino-sulfonyl) phenyl]-2, the 4-pyrimidinediamine;
VI-82 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-fluoropropyl) phenyl]-2, the 4-pyrimidinediamine;
VI-83 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-fluoropropyl) phenyl]-2, the 4-pyrimidinediamine;
VI-84 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(3-fluoropropyl) phenyl]-2, the 4-pyrimidinediamine;
VI-85 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-hydroxypropyl) phenyl]-2, the 4-pyrimidinediamine;
VI-86 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-hydroxypropyl) phenyl]-2, the 4-pyrimidinediamine;
VI-87 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(3-hydroxypropyl) phenyl]-2, the 4-pyrimidinediamine;
VI-88 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-hydroxybutyl) phenyl]-2, the 4-pyrimidinediamine;
VI-89 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-hydroxybutyl) phenyl]-2, the 4-pyrimidinediamine;
VI-90 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(4-hydroxybutyl) phenyl]-2, the 4-pyrimidinediamine;
VI-91 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-fluorine butyl) phenyl]-2, the 4-pyrimidinediamine;
VI-92 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-fluorine butyl) phenyl]-2, the 4-pyrimidinediamine;
VI-93 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(4-fluorine butyl) phenyl]-2, the 4-pyrimidinediamine;
VI-94 N2-(4-amino-sulfonyl) phenyl-5-fluoro-N4-(4-sulphomethyl carbonyl) phenyl-2, the 4-pyrimidinediamine;
VI-95 N2-(3-amino-sulfonyl-4-methyl) phenyl-5-fluoro-N4-(4-sulphomethyl carbonyl) phenyl-2, the 4-pyrimidinediamine;
VI-96 N2-(3-butyl amino-sulfonyl phenyl)-N4-(3-cyano group-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-97 N2-(3-butyl amino-sulfonyl phenyl)-N4-(3-chloro-4-fluorophenyl) 5-fluoro-2, the 4-pyrimidinediamine;
VI-98 N2-(3-amino-sulfonyl phenyl)-N4-(3-cyano group-4-fluorophenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-99 N2-(3-amino-sulfonyl phenyl)-N4-(3-cyano group-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-100 N2-(3-amino-sulfonyl-4-fluorophenyl)-5-fluoro-N4-(4-hydroxy phenyl)-2, the 4-pyrimidinediamine;
VI-101 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(4-hydroxy phenyl)-2, the 4-pyrimidinediamine;
VI-102 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-hydroxy phenyl]-2, the 4-pyrimidinediamine;
VI-103 N4-[4 (2-cyano ethyl)-3-aminomethyl phenyl]-5-fluoro-N2-(4-methyl-3-propionyl amino-sulfonyl phenyl)-2, the 4-pyrimidinediamine;
VI-104 N4-[4-(2-cyano ethyl)-3-aminomethyl phenyl]-5-fluoro-N2-(4-methyl-3-propionyl amino-sulfonyl phenyl)-2,4-pyrimidinediamine sodium salt;
VI-105 N4-(3, the 4-dichlorophenyl)-N4-methyl-5-fluoro-N2-[3-(N, N-diethyl) amino-sulfonyl-4-p-methoxy-phenyl]-2, the 4-pyrimidinediamine;
VI-106 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-(4-methoxyl group-3-chloro-phenyl-]-2, the 4-pyrimidinediamine;
VI-107 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(4-methoxyl group-3-chloro-phenyl-]-2, the 4-pyrimidinediamine;
VI-108 N4-(3-chloro-4-p-methoxy-phenyl)-N2-(3-N, N-diethylamino alkylsulfonyl-4-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-109 N2-(4-amino-sulfonyl phenyl)-N4-(3, the 4-dichlorophenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-110 N2-(3-amino-sulfonyl phenyl)-N4-(3, the 4-dichlorophenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-111 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-5-fluoro-N4-[4-(2-methoxyl group ethyleneoxy group) phenyl]-2, the 4-pyrimidinediamine;
VI-112 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(2-methoxyl group ethyleneoxy group) phenyl]-2, the 4-pyrimidinediamine;
VI-113 N2, N4-pair-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-114 N2, N4-pair-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VI-115 N2, N4-pair-(3-amino-sulfonyl-4-chloro-phenyl-)-5-fluoro-2, the 4-pyrimidinediamine;
VI-116 N2-[3-amino-sulfonyl-4-(4-methylpiperazine-1-yl) phenyl]-N4-(3-chloro-4-p-methoxy-phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
VII-1 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[(2S, 4R)-1-(2-cyano group ethanoyl)-2-methoxycarbonyl tetramethyleneimine-4-yl)-5-fluoro-2, the 4-pyrimidinediamine;
VII-2 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[(2S, 4S)-1-(2-cyano group ethanoyl)-2-methoxycarbonyl tetramethyleneimine-4-yl]-5-fluoro-2, the 4-pyrimidinediamine;
VII-3 racemize N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(1-benzyl-4-methyl piperidine-3-yl)-5-fluoro-2, the 4-pyrimidinediamine;
VII-4 racemize N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(4-methyl piperidine-3-yl)-2, the 4-pyrimidinediamine;
VII-5 racemize N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(1-cyano group methylene radical carbonyl-4-methyl piperidine-3-yl)-5-fluoro-2, the 4-pyrimidinediamine;
VII-6 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(2-methoxypyridine-5-yl)-2, the 4-pyrimidinediamine;
VII-7 N2-(3-amino-sulfonyl phenyl)-N4-(2-amino-3-Methoxy Pyridine-6-yl)-5-fluoro-2, the 4-pyrimidinediamine;
VII-8 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(2-amino-3-Methoxy Pyridine-6-yl)-5-fluoro-2, the 4-pyrimidinediamine;
VII-9 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[2-amino-3-Methoxy Pyridine-6-yl]-5-fluoro-2,4-pyrimidinediamine (66);
VII-10 N4-(2-amino-3-Methoxy Pyridine-6-yl)-N2-[3-(ethoxy carbonyl methylene radical) amino-sulfonyl phenyl)-and 5-fluoro-2, the 4-pyrimidinediamine;
VII-11 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(2,2,4-trimethylammonium-1,1,3-trioxy--benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine;
VII-12 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-(2,2,4-trimethylammonium-1,1,3-trioxy--benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine;
VII-13 N2-(4-amino-sulfonyl) phenyl-N4-[(N-ethylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-5-fluoro-2, the 4-pyrimidinediamine
VII-14 N2-(3-amino-sulfonyl) phenyl-N4-[(N-ethylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-5-fluoro-2, the 4-pyrimidinediamine
VII-15 N2-(3-amino-sulfonyl-4-methyl) phenyl-N4-[(N-ethylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-5-fluoro-2, the 4-pyrimidinediamine
VII-16 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-2, the 4-pyrimidinediamine;
VII-17 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[2-(methylamino carbonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl]-2, the 4-pyrimidinediamine;
VII-18 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[2-(dimethylamino carbonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl]-2, the 4-pyrimidinediamine;
VII-19 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[1-(methylamino carbonyl)-1,2,3,4-tetrahydroquinoline-6-yl]-2, the 4-pyrimidinediamine;
VII-20 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[1-(methylamino carbonyl)-1,2,3,4-tetrahydroquinoline-6-yl]-2, the 4-pyrimidinediamine;
VII-21 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[3, the 4-dihydro-(1H)-quinoline-2-one--6-yl]-5-fluoro-2, the 4-pyrimidinediamine
VII-22 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[1-(3-methoxy-propyl) indazole quinoline-5-yl]-2, the 4-pyrimidinediamine;
VII-23 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[1-(2-methoxy ethyl) indazole quinoline-5-yl]-2, the 4-pyrimidinediamine;
VII-24 N4-(3,4-ethylenedioxy phenyl)-5-fluoro-N2-[4-(tetramethyleneimine-1-base alkylsulfonyl) phenyl]-2, the 4-pyrimidinediamine;
VII-25 N4-(3,4-ethylenedioxy phenyl)-5-fluoro-N2-[4-(N-methyl) amino-sulfonyl-3-p-methoxy-phenyl]-2, the 4-pyrimidinediamine;
VII-26 racemize N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[2-(N, N-dimethylamino carbonyl)-2,3-Dihydrobenzofuranes-5-yl]-5-fluoro-2, the 4-pyrimidinediamine;
VII-27 racemize N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-[2-(N, N-dimethylamino carbonyl)-2,3-Dihydrobenzofuranes-5-yl]-5-fluoro-2, the 4-pyrimidinediamine;
VII-28 N2-(3-amino-sulfonyl phenyl)-N4-(chroman-4-amine-6-yl)-5-fluoro-2, the 4-pyrimidinediamine;
VII-29 N2-(4-amino-sulfonyl phenyl)-N4-(chroman-4-amine-6-yl)-5-fluoro-2, the 4-pyrimidinediamine;
VII-30 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-methyl-N4-(3-oxo-benzo [1,4] oxazine-6-yl)-2, the 4-pyrimidinediamine;
VII-31 N2-(4-amino-sulfonyl phenyl)-5-methyl-N4-(3-oxo-benzo [1,4] oxazine-6-yl)-2, the 4-pyrimidinediamine;
VII-32 N2-(3-amino-sulfonyl phenyl)-5-methyl-N4-(3-oxo-benzo [1,4] oxazine-6-yl)-2, the 4-pyrimidinediamine;
VII-33 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-methyl-N4-(4-methyl-3-oxo-benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine;
VII-34 N2-(4-amino-sulfonyl phenyl)-5-methyl-N4-(4-methyl-3-oxo-benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine;
VII-35 N2-(3-amino-sulfonyl phenyl)-5-methyl-N4-(4-methyl-3-oxo-benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine;
VII-36 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(3-oxo-4-cyano methyl-benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine;
VII-37 N4-(2,2-dimethyl-3-oxo-4H-benzo [1,4] oxazine-6-yl)-5-fluoro-N2-[4-(N-methyl) amino-sulfonyl-3-p-methoxy-phenyl]-2, the 4-pyrimidinediamine;
VII-38 N2-(3-amino-sulfonyl-4-methoxyl group-5-aminomethyl phenyl)-N4-(2,2-two fluoro-4H-benzo [1,4] oxazine-3-ketone-6-yls)-5-fluoro-2, the 4-pyrimidinediamine;
VII-39 5-amino-N2-(3-amino-sulfonyl phenyl)-N4-(2, and 2-dimethyl-3-oxo-4H-benzo [1,4] oxazine-6-yl)-2, the 4-pyrimidinediamine;
VII-40 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-(4-methyl-3-oxo-benzo [1,4] oxazine-6-yl)-2, the 4-pyrimidinediamine;
VII-41 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(4-methyl-3-oxo-benzo [1,4] oxazine-6-yl)-2, the 4-pyrimidinediamine;
VII-42 N2-(3-amino-sulfonyl phenyl)-N4-[2,2,4-trimethylammonium-3-oxo-5-pyrido [1,4] oxazine-7-yl]-5-fluoro-2,4-pyrimidinediamine;
VII-43 N2-(4-amino-sulfonyl phenyl)-N4-[2,2,4-trimethylammonium-3-oxo-5-pyrido [1,4] oxazine-5-yl]-5-fluoro-2,4-pyrimidinediamine;
VII-44 N2-(3-amino-sulfonyl-4-methyl-phenyl)-5-fluoro-N4-(3-oxo-4H-benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine;
VII-45 N2-(3-amino-sulfonyl-4-methyl-phenyl)-5-fluoro-N4-(3-oxo-4H-benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine;
VII-46 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-(2,2,4-trimethylammonium-1,1,3-trioxy--benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine;
VII-47 N2-(4-amino-sulfonyl phenyl)-N4-cyano methyl-5-fluoro-N4-[3-oxo-4-methyl-benzo [1,4] thiazine-6-yl]-2, the 4-pyrimidinediamine;
VII-48 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-(4-methyl-3-oxo-benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine;
VII-49 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(4-methyl-3-oxo-benzo [1,4] thiazine-6-yl)-2, the 4-pyrimidinediamine;
VII-50 5-fluoro-N4-(4-methyl-3-oxo-benzo [1,4] thiazine-6-yl)-N2-(3-piperidino-(1-position only) alkylsulfonyl phenyl)-2, the 4-pyrimidinediamine;
VII-51 N2-(3-amino-sulfonyl phenyl)-N4-[2,2-dimethyl-3-oxo-4H-5-pyrido [1,4] oxazine-7-yl]-5-fluoro-2,4-pyrimidinediamine;
VII-52 N2-(4-amino-sulfonyl phenyl)-N4-[2,2-dimethyl-3-oxo-4H-5-pyrido [1,4] oxazine-7-yl]-5-fluoro-2,4-pyrimidinediamine;
VII-53 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(2-cyano group cumarone-5-yl)-5-fluoro-2, the 4-pyrimidinediamine;
VII-54 N2-(3-amino-sulfonyl phenyl)-N4-(2-aminocarboxyl cumarone-5-yl)-5-fluoro-2, the 4-pyrimidinediamine;
VII-55 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-pyridylmethyl) benzo [1,4] oxazine-7-yl]-2, the 4-pyrimidinediamine;
VII-56 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(3-pyridylmethyl) benzo [1,4] oxazine-7-yl]-2, the 4-pyrimidinediamine;
VII-57 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(thionaphthene-5-yl)-5-fluoro-2, the 4-pyrimidinediamine;
VII-58 N2-(3-amino-sulfonyl phenyl)-N4-(thionaphthene-5-yl)-5-fluoro-2, the 4-pyrimidinediamine;
VII-59 N2-(4-amino-sulfonyl phenyl)-N4-(4-N-tert-butoxycarbonyl amino-3,4-dihydro-2H-1-chromene-6-yl)-5-fluoro-2, the 4-pyrimidinediamine;
VII-60 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(1-methyl sulphonyl) indoline-5-yl]-2, the 4-pyrimidinediamine;
VII-61 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(1-methyl sulphonyl) indoline-5-yl]-2, the 4-pyrimidinediamine;
VII-62 5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-N4-[4-(1-methyl sulphonyl) indoline-5-yl]-2, the 4-pyrimidinediamine;
VII-63 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(1-methyl sulphonyl) indoline-5-yl]-2, the 4-pyrimidinediamine;
VII-64 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(quinoline-2-yl)-2, the 4-pyrimidinediamine;
VII-65 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(quinoline-3-yl)-2, the 4-pyrimidinediamine;
VII-66 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(quinoline-3-yl)-2, the 4-pyrimidinediamine;
VII-67 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(quinoline-5-yl)-2, the 4-pyrimidinediamine;
VII-68 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(quinoline-5-yl)-2, the 4-pyrimidinediamine;
VII-69 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(quinoline-6-yl)-2, the 4-pyrimidinediamine;
VII-70 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(quinoline-6-yl)-2, the 4-pyrimidinediamine;
VII-71 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(2-toluquinoline-6-yl)-2, the 4-pyrimidinediamine;
VII-72 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(2-toluquinoline-6-yl)-2, the 4-pyrimidinediamine;
VII-73 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(2-hydroxy-4-methyl quinoline-6-yl)-2, the 4-pyrimidinediamine
VII-74 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(2-hydroxy-4-methyl quinoline-6-yl)-2, the 4-pyrimidinediamine
VII-75 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(2-N, N '-dimethyl amine-quinoline-6-yl)-5-fluoro-2, the 4-pyrimidinediamine
VII-76 N2-(3-amino-sulfonyl phenyl)-N4-(2-N, N '-dimethyl amine-quinoline-6-yl)-5-fluoro-2, the 4-pyrimidinediamine
VII-77 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(quinoline-8-yl)-2, the 4-pyrimidinediamine;
VII-78 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(quinoline-8-yl)-2, the 4-pyrimidinediamine;
VII-79 N2-(3-amino-sulfonyl-4-fluorophenyl)-5-fluoro-N4-(quinoline-8-yl)-2, the 4-pyrimidinediamine;
VII-80 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(2-toluquinoline-8-yl)-2, the 4-pyrimidinediamine;
VII-81 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(2-toluquinoline-8-yl)-2, the 4-pyrimidinediamine;
VII-82 (1R, 2R, 3S, 4S) N4-(3-aminocarboxyl two ring [2.2.1] heptan-5-alkene-2-yl)-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2,4-pyrimidinediamine;
VII-83 (1R, 2R, 3S, 4S) N2-(3-amino-sulfonyl-4-methoxyl group-5-aminomethyl phenyl)-N4-(3-aminocarboxyl two ring [2.2.1] heptan-5-alkene-2-yl)-5-fluoro-2,4-pyrimidinediamine; With
VIII-3 N4-(3-chloro-4-p-methoxy-phenyl)-5-fluoro-N2-(5-methyl-2H-1,1-dioxo-1,2,4-benzothiadiazine-7-yl)-2, the 4-pyrimidinediamine.
23. be selected from down the compound of group:
IX-1 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[1-(propine-3-yl) indoles-5-yl]-2, the 4-pyrimidinediamine;
IX-2 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[1-(propine-3-yl) indoles-5-yl]-2, the 4-pyrimidinediamine;
IX-3 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[1-(propine-3-yl) indoles-6-yl]-2, the 4-pyrimidinediamine;
IX-4 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[1-(propine-3-yl) indoles-6-yl]-2, the 4-pyrimidinediamine;
IX-5 N2-(3-amino-sulfonyl phenyl)-N4-(1-cyano group methylene radical indoles-5-yl)-5-fluoro-2, the 4-pyrimidinediamine;
IX-6 N2-(4-amino-sulfonyl phenyl)-N4-(1-cyano group methylene radical indoles-5-yl)-5-fluoro-2, the 4-pyrimidinediamine;
IX-7 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(1-cyano group methylene radical indoles-5-yl)-5-fluoro-2, the 4-pyrimidinediamine;
IX-8 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(1-cyano group methylene radical indoles-5-yl)-5-fluoro-2, the 4-pyrimidinediamine;
IX-9 N4-[3-(aminocarboxyl)-1H-indoles-6-yl]-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
IX-10 N4-[3-(aminocarboxyl)-1H-indoles-6-yl]-N2-(3-amino-sulfonyl-4-chloro-phenyl-)-5-fluoro-2, the 4-pyrimidinediamine;
IX-11 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3-cyano methyl-1H-indoles-6-yl)-5-fluoro-2, the 4-pyrimidinediamine;
IX-12 N2-(3-amino-sulfonyl phenyl)-N4-(3-cyano methyl-1H-indoles-6-yl)-5-fluoro-2, the 4-pyrimidinediamine;
IX-13 N2-(3-amino-sulfonyl phenyl)-N4-(3-cyano methyl-1H-indoles-5-yl)-5-fluoro-2, the 4-pyrimidinediamine;
IX-14 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3-cyano methyl-1H-indoles-5-yl)-5-fluoro-2, the 4-pyrimidinediamine;
IX-15 N2-(3-amino-sulfonyl phenyl)-N4-(3-cyano methyl-1H-indoles-7-yl)-5-fluoro-2, the 4-pyrimidinediamine;
IX-16 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3-cyano methyl-1H-indoles-7-yl)-5-fluoro-2, the 4-pyrimidinediamine;
IX-17 N2-[3-amino-sulfonyl-4-(4-methylpiperazine-1-yl) phenyl]-N4-(3-cyano group methylene radical-1H-indoles-6-yl)-5-fluoro-2, the 4-pyrimidinediamine;
IX-18 N2-[3-amino-sulfonyl-4-(4-methylpiperazine-1-yl) phenyl]-N4-(3-cyano group methylene radical-1H-indoles-7-yl)-5-fluoro-2, the 4-pyrimidinediamine;
IX-19 N4-(3-cyano group methylene radical-1H-indoles-5-yl)-5-fluoro-N2-[3-(1-methyl-4-amino piperidine) alkylsulfonyl-4-aminomethyl phenyl]-2, the 4-pyrimidinediamine;
IX-20 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-(3-cyano methyl-1-methyl-indoles-5-yl)-5-fluoro-2, the 4-pyrimidinediamine;
IX-21 N2-(3-amino-sulfonyl-4-chloro-phenyl-)-N4-(2-cyano group cumarone-5-yl)-5-fluoro-2, the 4-pyrimidinediamine;
IX-22 N2-(3-amino-sulfonyl-4-isopropyl phenyl)-N4-(2-cyano group cumarone-5-yl)-5-fluoro-2, the 4-pyrimidinediamine;
IX-23 N4-[4-(1-ethanoyl-4-piperazinyl) carbonyl phenyl]-N2-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
IX-24 N4-[4-(1-ethanoyl-4-piperazinyl) carbonyl phenyl]-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
IX-25 N4-[4-(1-ethanoyl-4-piperazinyl) carbonyl phenyl]-5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-2, the 4-pyrimidinediamine;
IX-26 N4-[4-(1-ethanoyl-4-piperazinyl) carbonyl phenyl]-N2-(4-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
IX-27 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(4-methylpiperazine-1-base carbonyl) phenyl]-2, the 4-pyrimidinediamine;
IX-28 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-methylpiperazine-1-base carbonyl) phenyl]-2, the 4-pyrimidinediamine;
IX-29 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(1-methylsulfonyl-4-piperazinyl) carbonyl phenyl]-2, the 4-pyrimidinediamine;
IX-30 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(1-methylsulfonyl-4-piperazinyl) carbonyl phenyl]-2, the 4-pyrimidinediamine;
IX-31 5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-5-fluoro-N4-[4-(1-methylsulfonyl-4-piperazinyl) carbonyl phenyl]-2, the 4-pyrimidinediamine;
IX-32 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(1-methylsulfonyl-4-piperazinyl) carbonyl phenyl]-2, the 4-pyrimidinediamine;
IX-33 5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-5-fluoro-N4-[4-(4-thiomorpholine generation) carbonyl phenyl]-2, the 4-pyrimidinediamine;
IX-34 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-thio-morpholinyl) carbonyl phenyl]-2, the 4-pyrimidinediamine;
IX-35 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-[4-(4-thio-morpholinyl) carbonyl phenyl]-2, the 4-pyrimidinediamine;
IX-36 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-[4-(4-thio-morpholinyl) carbonyl phenyl]-2, the 4-pyrimidinediamine;
IX-37 N2-(3-amino-sulfonyl phenyl)-N4-[4-(1,1-dioxo-4-thio-morpholinyl) carbonyl phenyl]-5-fluoro-2, the 4-pyrimidinediamine;
IX-38 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[4-(1,1-dioxo-4-thio-morpholinyl) carbonyl phenyl]-5-fluoro-2, the 4-pyrimidinediamine;
IX-39 N4-[4-(1,1-dioxo-4-thio-morpholinyl) carbonyl phenyl]-5-fluoro-N2-[3-(N-methylamino alkylsulfonyl)-4-aminomethyl phenyl]-2, the 4-pyrimidinediamine;
IX-40 N2-(4-amino-sulfonyl phenyl)-N4-[4-(1,1-dioxo-4-thio-morpholinyl) carbonyl phenyl]-5-fluoro-2, the 4-pyrimidinediamine;
IX-41 N4-(4-ethanoyl sulphomethyl carbonyl phenyl)-N2-(4-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
IX-42 N4-(4-ethanoyl sulphomethyl carbonyl phenyl)-N2-(3-amino-sulfonyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
IX-43 N4-(4-ethanoyl sulphomethyl carbonyl phenyl)-N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
IX-44 N2-(4-amino-sulfonyl phenyl)-N4-[3,5-dimethyl-4-(4-methylpiperazine-1-yl] phenyl)-5-fluoro-2, the 4-pyrimidinediamine;
IX-45 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-N4-[(4R)-1-(2-cyano group ethanoyl)-tetramethyleneimine-4-yl)-and 5-fluoro-2, the 4-pyrimidinediamine
IX-46 N2-(3-amino-sulfonyl-4-aminomethyl phenyl)-5-fluoro-N4-(5-methoxycarbonyl-thiophene-2-yl)-2, the 4-pyrimidinediamine
IX-47 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(5-methoxycarbonyl-thiophene-2-yl)-2, the 4-pyrimidinediamine
IX-48 N2-(3-amino-sulfonyl-4-fluorophenyl)-5-fluoro-N4-(5-methoxycarbonyl-thiophene-2-yl)-2, the 4-pyrimidinediamine
IX-49 N2-(4-amino-sulfonyl phenyl)-5-fluoro-N4-(5-methoxycarbonyl-thiophene-2-yl)-2, the 4-pyrimidinediamine
IX-50 N4-(3, the 4-Dimethoxyphenyl)-5-fluoro-N2-[4-(N-methyl) amino-sulfonyl-3-p-methoxy-phenyl]-2, the 4-pyrimidinediamine;
IX-51 N4-(3, the 5-Dimethoxyphenyl)-5-fluoro-N2-[4-(N-methyl) amino-sulfonyl-3-p-methoxy-phenyl]-2, the 4-pyrimidinediamine;
IX-52 N4-(4-chloro-3-trifluoromethyl)-5-fluoro-N2-[4-(N-methyl) amino-sulfonyl-3-p-methoxy-phenyl]-2, the 4-pyrimidinediamine;
IX-53 N4-(3-chloro-4-Trifluoromethoxyphen-l)-5-fluoro-N2-[4-(N-methyl) amino-sulfonyl-3-p-methoxy-phenyl]-2, the 4-pyrimidinediamine;
IX-54 5-fluoro-N2-[3-N-(methyl) amino-sulfonyl-4-aminomethyl phenyl]-N4-[4-(2-pyridyl)-3-chlorine methylene radical oxygen base phenyl]-2, the 4-pyrimidinediamine;
X-1 6-carbonyl methoxyl group-N4-(3, the 4-dichlorophenyl)-N2-(3-N, N-diethylamino alkylsulfonyl-6-p-methoxy-phenyl)-2, the 4-pyrimidinediamine;
X-2 6-carbonyl methoxyl group-(3-N, N-diethylamino alkylsulfonyl-6-p-methoxy-phenyl)-N4-[3-oxo-benzo [1,4] oxazine-6-yl]-2, the 4-pyrimidinediamine;
X-3 N2-(3-amino-sulfonyl phenyl)-5-fluoro-N4-(2 methyl indole-6-methylene)-2, the 4-pyrimidinediamine.
24. one kind is suppressed the active method of jak kinase, described method comprises makes jak kinase contact with the compound that suppresses the active significant quantity of jak kinase, and wherein said compound is selected from: the described compound of claim A1, the described compound of claim 9, the described compound of claim 21, the described compound of claim 22, the described compound of claim 23 and CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3.
25. one kind is suppressed the active method of jak kinase, described method is included in the compound of the active significant quantity of the external JAK3 of making kinases contact inhibition jak kinase, and wherein said compound is selected from: the described compound of claim 1, the described compound of claim 9, the described compound of claim 21, the described compound of claim 22, the described compound of claim 23 and CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3.
26. method for the treatment of the cell-mediated autoimmune disorder of T, described method comprises the compound of the described autoimmune disorder significant quantity of the patient treatment of suffering from this autoimmune disorder, and wherein said compound is selected from: the described compound of claim 1, the described compound of claim 9, the described compound of claim 21, the described compound of claim 22, the described compound of claim 23 and CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3.
27. method as claimed in claim 26 is characterized in that, described compound and IC 50The kinase whose compound combination of inhibition Syk that scope is at least 10 μ M gives or auxiliary this compound.
28. a treatment or the method for preventing the allograft rejection in the graft acceptor, described method comprises and gives graft acceptor treatment or prevent the compound of described repulsion significant quantity that wherein said compound is selected from: the described compound of claim 1, the described compound of claim 9, the described compound of claim 21, the described compound of claim 22, the described compound of claim 23 and CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3.
29. method as claimed in claim 28 is characterized in that, described repulsion is an acute cellular rejection.
30. method as claimed in claim 28 is characterized in that, described repulsion is chronic rejection.
31. method as claimed in claim 28 is characterized in that, described repulsion is by HVGR or GVHR mediation.
32. method as claimed in claim 28 is characterized in that, described allograft is selected from kidney, heart, liver or lung.
33. method as claimed in claim 28 is characterized in that, described compound and the combination of another kind of immunosuppressor give or auxiliary another kind of immunosuppressor.
34. method as claimed in claim 33 is characterized in that, described immunosuppressor is selected from: ciclosporin, tacrolimus, sirolimus, IMPDH inhibitor, mycophenolate, mycophenlate mofetil, anti--T cell antibody and OKT3.
35. a treatment or the method for preventing the allergy of IV type, described method comprises and gives object treatment or prevent the compound of described allergy significant quantity that wherein said compound is selected from: the described compound of claim 1, the described compound of claim 9, the described compound of claim 21, the described compound of claim 22, the described compound of claim 23 and CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3.
36. method as claimed in claim 35, this method is actual to be prevention method, and described compound is selected from: the described compound of claim 1, the described compound of claim 9, the described compound of claim 21, the described compound of claim 22, the described compound of claim 23 and CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3.
37. method that suppresses the signal transduction cascade that the JAK3 kinases plays a role therein, described method comprises makes a kind of compound of cells contacting of expressing the acceptor that participates in sort signal cascade amplification, and wherein said compound is selected from: the described compound of claim 1, the described compound of claim 9, the described compound of claim 21, the described compound of claim 22, the described compound of claim 23 and CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3.
38. method for the treatment of or preventing the disease of jak kinase mediation, described method comprises the compound of the disease significant quantity that gives object treatment or the mediation of prevention jak kinase, and wherein said compound is selected from: the described compound of claim 1, the described compound of claim 9, the described compound of claim 21, the described compound of claim 22, the described compound of claim 23 and CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3
39. method as claimed in claim 38, wherein, the disease of described JAK mediation is HVGR or GVHR.
40. method as claimed in claim 38, wherein, the disease of described JAK mediation is acute allograft rejection.
41. method as claimed in claim 38, wherein, the disease of described JAK mediation is chronic allograft rejection.
42. pharmaceutical preparation, described pharmaceutical preparation comprises a kind of compound or its prodrug and at least a pharmaceutically acceptable vehicle, thinner, sanitas or stablizer or their mixture, and described compound is selected from: the described compound of claim 1, the described compound of claim 9, the described compound of claim 21, the described compound of claim 22, the described compound of claim 23 and CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3.
43. medicine box, described medicine box comprises a kind of compound or its prodrug, packing and operation instruction, and described compound is selected from: the described compound of claim 1, the described compound of claim 9, the described compound of claim 21, the described compound of claim 22, the described compound of claim 23 and CAS accession number 845817-97-2, CAS accession number 841290-42-4 and CAS accession number 841290-41-3.
44. a medicine box, described medicine box comprise the described pharmaceutical preparation of claim 43, packing and operation instruction.
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US8809343B2 (en) 2008-12-26 2014-08-19 Fudan University Pyrimidine derivative, preparation method and use thereof
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