CN101370792A - Bi-aryl meta-pyrimidine inhibitors of kinases - Google Patents
Bi-aryl meta-pyrimidine inhibitors of kinases Download PDFInfo
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- CN101370792A CN101370792A CNA2006800499668A CN200680049966A CN101370792A CN 101370792 A CN101370792 A CN 101370792A CN A2006800499668 A CNA2006800499668 A CN A2006800499668A CN 200680049966 A CN200680049966 A CN 200680049966A CN 101370792 A CN101370792 A CN 101370792A
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Abstract
The invention provides biaryl meta-pyrimidine compounds having the general structure (A). The pyrimidine compounds of the invention are capable of inhibiting kinases, such as members of the Jak kinase family, and various other specific receptor and non receptor kinases.
Description
Invention field
The present invention relates to protein tyrosine kinase inhibitor, comprise its pharmaceutically acceptable composition of The compounds of this invention and use said composition to treat the field of the method for various illnesss.The present invention be more particularly directed to the inhibitor of the JAK family of protein tyrosine kinase.
Background of invention
Protein kinase is the enzyme family of specificity residue phosphorylation in the catalytic proteins, and it extensively is categorized into tyrosine and serine/threonine kinase.Because of sudden change, overexpression or inappropriate adjusting, lacking of proper care or taking off the excessive generation of adjusting and somatomedin or cytokine or produce the not enough inappropriate kinase activity that produces relates to numerous disease, comprise, but be not limited to cancer, cardiovascular disorder, anaphylaxis, asthma and other respiratory disease, autoimmune disease, inflammatory diseases, osteopathy, metabolic disease and nerve and neurodegenerative disorders are such as alzheimer's disease.Unsuitable kinase activity causes and relates to and the growth of the above-mentioned cell relevant with relative disease, cytodifferentiation, and survival, apoptosis, mitotic division takes place, and the various biological cells of cell cycle control and cell mobility are replied.
Protein kinase has shown as and has treated the class of enzymes of intervening the target no less important.Especially, in cytokine signaling conduction, play a crucial role (Kisseleva etc., Gene, 2002,285,1 of JAK family cell protein tyrosine kinase enzyme (Jak1, Jak2, Jak3 and Tyk2); .Genome Biology such as Yamaoka 2004,5,253)).Cytokine activates JAK in conjunction with its acceptor the time, make the cytokine receptor phosphorylation then, produces signaling molecule thus, particularly finally causes the signal transducer of genetic expression and the docking site of transcriptional activator (STAT) family.Known a large amount of cytokine activates JAK family.These cytokines comprise IFN family, and (IFN-α s/ β/ω/restriction is plain, IFN-γ, IL-10, IL-19, IL-20, IL-22), gp130 family (IL-6, IL-11, OSM, LIF, CNTF, NNT-1/BSF-3, G-CSF, CT-1, Leptin, IL-12, IL-23), γ C family (IL-2, IL-7, TSLP, IL-9, IL-15, IL-21, IL-4, IL-13), IL-3 family (IL-3, IL-5, GM-CSF), strand family (EPO, GH, PRL, TPO), receptor tyrosine kinase (EGF, PDGF, CSF-1 is HGF) with G-protein linked receptor (AT1).
Up to the present, the treatment potential of JAK inhibitor concentrates on the disease of the various immunity system pathology situations of influence.They include, but are not limited to atopy (allergic asthma, atopic dermatitis, allergic rhinitis), cell-mediated hypersensitivity (allergic contact dermatitis, hypersensitivity pneumonitis), rheumatism (systemic lupus erythematous (SLE), rheumatoid arthritis, adolescent arthritis, this Jaeger logical sequence syndrome, scleroderma, polymyositis, ankylosing spondylitis, arthritic psoriasis), transplant (transplant rejection, graft versus host disease (GVH disease)), virus disease (Epstein-Barr virus, hepatitis B, hepatitis C, HIV, HTLV1, varicella zoster virus, human papillomavirus), cancer (leukemia, lymphoma), cardiovascular disease (cardiac hypertrophy, atherosclerosis and arteriosclerosis), neurodegenerative disease (motor neurone disease), food anaphylaxis, inflammatory bowel, Crohn's disease, skin inflammation and because of the immunosuppression of solid tumor inductive.Major part is up to now attempted the immunosuppressant JAK3 of target and is suppressed, for example the acceptability of organ transplantation and allogeneic (with regard to summary, referring to .Current Opinion inInvestigational Drugs such as Borie, 2003,4 (11), 1297).
Recently, found that the conduction of EPO-JAK2 signal is by way of two great discoveries that act in myelosis's illness and proliferative diabetic retinopathy PDR.At first, JAK2 kinases (V617F) function is obtained, somatocyte (acquired) sudden change is reported to the member in " typical case " myelosis illness, comprise polycythemia vera, the paathogenic factor of thrombocythemia of the special property sent out and myelofibrosis with myeloid metaplasia, and found in patient that described sudden change is (with regard to summary with " atypia " myelosis's illness and myelodysplastic syndrome, referring to Tefferi and Gilliland, Cell Cycle 2005,4 (8), e61; Molecular Interventions such as Pesu 2005,5 (4), 211).In addition, find the composing type phosphorylation of (a) V617FJAK2 sudden change and JAK2 and downstream effect thing thereof and induce relevantly based on the erythropoietin allergy in the experiment of cell that (b) V617F JAK2-inductive cell proliferation signal is by the micromolecular inhibitor inhibition of JAK2; (c) the mouse marrow by the retrovirus transduction that contains V617F JAK2 comprises (incuded) erythrocytosis in transplanting mouse.
In addition, have been found that recently composing type activatory JAK approach has been kept in the sudden change among the EPO-R, cause myeloproliferative diseases (myleoproliferative disorders).
The second, find that EPO is effective angiogenic factor of proliferative diabetic retinopathy PDR, promptly influence the work age bracket vision loss in diabetic patients major cause (for example, referring to Aiello, New England Journal of Medicine, 2005,353 (8), 839; .New England Journal of Medicine 2,005 353 (8), 782 such as Watanabe).
In addition, the discovery from Watanabe research shows: (a) intraocular EPO level and VEGF (angiogenic factor in the another kind of well-known proliferative diabetic retinopathy PDR) in the patient of those proliferative diabetic retinopathy PDies apparently higher than disease those patients in the static or non-diabetic control group; (b) EPO and VEGF level are not closely related; (c) the EPO level than VEGF more significantly with exist proliferative diabetic retinopathy PDR relevant; (d) EPO stimulates retina endothelial cell growth and the conduction of intracellular signal wherein; (e) EPO or VEGF inhibitor reduce the retinal neovascularizationization of hypoxia inducible in the rodent model.
Recently confirmed that the sudden change in the EPO acceptor can also influence the signal conduction that relates to the JAK approach, and this may relate to morbid state, wherein the conduction of JAK signal is important in the cell cycle.
The feature that has another relevant JAK approach restrainer.Confirmed that the JAK approach can be replenished in cell survival and propagation.For example, with regard to regard to the Philadelphia chromosome positive cells that causes chronic myelogenous leukemia (CML), the evidence that exists the Jak approach in the composing type activation, to obtain replenishing.Therefore, use the JAK inhibitor can be applied to CML, wherein confirmed the Philadelphia chromosome Bcr-Abl that hybridizes, keep the constitutive activity of cell thus.
Be more significantly with regard to the resistant mutation that produces based on the BCR-ABL specific inhibitor, with regard to guard the gate with regard to T315I transgenation or any other sudden change, may use the JAK inhibitor of the approach that uses based on the BCR-ABL mutant that uses the Jak approach (as with regard to BCR-ABL (T315I) sudden change).Therefore, the Jak inhibitor can be used for the treatment of and has the patient who known therapies is produced resistance, direct target BCR-ABL wherein, and resistance has been turned out to be at present in all resistances among the patient of existing therapy failure and account for leading (50-90%).
The application of JAK inhibitor can also be applied to other bone marrow disease state, both can be hemopathy, also can be other other diseases state that relates to the morbid state of marrow and directly or indirectly relate to the JAK approach.
Therefore, owing to the therapy deficiency of the disease that can utilize the above-mentioned JAK signal transduction path imbalance of treatment or obtain directly or indirectly replenishing, so there is demand in the compound of researching and developing the inhibitor that is used as kinases, particularly jak kinase.
General introduction
An embodiment provides the compound with structure (A):
Another embodiment provides the method for the treatment illness relevant with generating blood vessel, for the experimenter who has this class treatment to need, this method comprises at least a compound or its pharmacy acceptable salt with structure (A) to experimenter's drug treatment significant quantity that these needs are arranged, hydrate, solvate, polymorphic form, crystal formation, N-oxide compound and each enantiomorph and diastereomer.
Other embodiment provides pharmaceutical composition and goods, comprises at least a compound or its pharmacy acceptable salt with structure (A), hydrate, solvate, crystal formation and each diastereomer.
Describe in detail
A.
Term and definition
Following term and definition are applied among the application, and be generally consistent with the term of recommendation among the International Unionof Pure and Applied Chemistry (IUPAC):
Term " heteroatoms " means any atom of non-carbon, for example, and N, O or S.
Term " aromatics " means because of localization not produces the cyclic conjugated molecular entity with stability, and it is obviously greater than inferring the localization structure, such as the stability of kekule structures.
Term " heterocycle " means when being used to describe aromatic ring and comprises aforesaid at least one each heteroatomic aromatic ring.
Term " heterocycle " is being not used in the ring-type that means non-aromatic group when describing aromatic ring (containing ring) group, and this cyclic group is made of about 14 carbon atoms of 3-and at least one above-mentioned heteroatoms.
Term " heterocycle of replacement " refers to regard to aromatics and non-aromatic structure also has following one or more substituent heterocyclic radical.
Term " alkyl " means the monovalence straight or branched alkyl with about 12 carbon atoms of 1-, methyl for example, and ethyl, just-propyl group, different-propyl group, just-butyl, different-butyl, tert-butyl, just-amyl group (n-pentyl) (just being also referred to as-amyl group (n-amyl)), just-hexyl etc.Term " low alkyl group " means the alkyl with about 6 carbon atoms of 1-.
Term " alkyl of replacement " means also has one or more substituent alkyl, and described substituting group is such as hydroxyl, alkoxyl group, sulfydryl, cycloalkyl; the cycloalkyl that replaces, heterocycle, the heterocycle of replacement, aryl, the aryl of replacement; heteroaryl, the heteroaryl of replacement, aryloxy, the aryloxy of replacement; halogen, cyano group, nitro, amino; amido, aldehyde, acyl group, oxygen base acyl group; carboxyl, alkylsulfonyl, sulphonamide, sulfonyl etc.
Term " alkenyl " means the straight or branched alkyl that has at least one carbon-to-carbon double bond and have about 12 carbon atoms of about 2-, and term " alkenyl of replacement " means and also has one or more above-mentioned substituent alkenyls.
Term " alkynyl " means the straight or branched alkyl that has at least one carbon-to-carbon triple bond and have about 12 carbon atoms of about 2-, and term " alkynyl of replacement " means and also has one or more above-mentioned substituent alkynyls.
Term " aryl " means the aromatic group of about 14 carbon atoms of about 5-, and term " aryl of replacement " means and also has one or more above-mentioned substituent aryl.
Term " heteroaryl " means aromatic ring, wherein constitutes this ring structure by about 14 carbon atoms of about 3-and at least one above-mentioned heteroatoms, and term " heteroaryl of replacement " means and also has one or more above-mentioned substituent heteroaryls.
Term " alkoxyl group " means-O-moieties, and wherein alkyl means as above-mentioned definition and term " alkoxyl group of replacement " and also has one or more above-mentioned substituent alkoxyl groups.
Term " cycloalkyl " means the alkyl with about 8 carbon atoms of the 3-that is arranged as ring, and term " cycloalkyl of replacement " means and also has one or more above-mentioned substituent cycloalkyl.
Term " alkylaryl " means the aryl of alkyl-replacement, and term " alkylaryl of replacement " means and also has one or more above-mentioned substituent alkylaryls.
Term " arylalkyl " means the alkyl of aryl-replacement, and term " arylalkyl of replacement " means and also has one or more above-mentioned substituent arylalkyls.
Term " aromatic yl alkenyl " means the alkenyl of aryl-replacement, and term " aromatic yl alkenyl of replacement " means and also has one or more above-mentioned substituent aromatic yl alkenyls.
Term " aromatic yl polysulfide yl " means the alkynyl of aryl-replacement, and term " aromatic yl polysulfide yl of replacement " means and also has one or more above-mentioned substituent aromatic yl polysulfide yls.
Term " arylidene " means the divalent aromatic radical with about 14 carbon atoms of 5-, and term " arylidene of replacement " means and also has one or more above-mentioned substituent arylidene.
Term " chemistry connects " is defined as the formation chemical entity, and wherein two parts constitute the direct chemical key between them.
Term " kinases " means the catalysis phosphate and adds to any enzyme on the residue of protein; For example, Serine and threonine kinase enzyme catalysis phosphate add on Serine and the threonine residues.
Term " jak kinase " means the enzyme of finding in the cell in the immunity system that participates in causing the cell signaling process that white corpuscle grows.
Term " treatment significant quantity " means the tissue that causes researchist, animal doctor, doctor or other clinicists and seek, system, animal or human's biology or the compound of medical response or the consumption of pharmaceutical composition, for example recovers or keeps blood vessel stable state (vasculostasis) or prevention harm or loss or vasculostasis; Reduce tumor load; Reduce the consumption of sickness rate and/or mortality ratio.
Term " pharmaceutically acceptable " mean carrier, thinner or vehicle must with other component compatibility in the preparation and can be to harmful this fact of its recipient.
Term " compound administration " or " giving drug compound " mean the behavior that the experimenter who has treatment to need is provided compound of the present invention or pharmaceutical composition.
Term " antibody " means polyclone or complete molecule of monoclonal antibody and fragment thereof, such as can be in conjunction with the Fab and the F (ab ＇) of epi-position determiner
2, Fv and SCA fragment.
Term " vasculostasis " means to be kept vascular function effect stable state and produces the normal physiological function effect.
Term " vasculostaticagents " means the promoting agent of seeking to solve the disease situation, in described disease situation, by preventing vasculostasis loss or recovery or keeping vasculostasis and deal carefully with vasculostasis.
B. embodiment of the present invention
The compound that is used for the treatment of various diseases, illness and pathology situation with structure (A) is provided according to one embodiment of the invention:
In structure (A), X can be key, O, C=O, SO
2Or CH
2In any kind and Y can be key or NR
9Or X and Y can be key jointly.In addition, in structure (A), R
1And R
2Can be H, C separately
1-C
6Any kind in replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted heterocycle, replacement or unsubstituted aryl or replacement or the unsubstituted heteroaryl; Or R
1And R
2Can be key jointly; Or R
1And R
2Component part jointly is as (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
9-(CH
2)
mOr (CH
2)
r-O-(CH
2)
mOne of, wherein p, q, r, n, m independently are the integer with value of 0-6 separately.
In addition, in structure (A), R
9Can be H, C
1-C
6Alkyl, C
1-C
6Cycloalkyl, C
1-C
6Branched-chain alkyl, C
1-C
6The alkyl that replaces, C
1-C
6Aminoalkyl group or C
1-C
6One of hydroxyalkyl; G
0Can be N, O, H or (of) one of CH, condition is if G
0Be N, so R
3And R
4Can be H, C separately
1-C
6Alkyl, C
1-C
6Replace or unsubstituted hydroxyalkyl or aminoalkyl group C
1-C
6Replace or unsubstituted branched-chain alkyl, replace or unsubstituted aryl or one of replacement or unsubstituted heteroaryl or R
3And R
4Jointly can component part, such as (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
9-(CH
2)
mOr (CH
2)
r-O-(CH
2)
mOne of.
In structure (A), exist some further to relate to G
0Extra condition.More particularly, if G
0Be N, so R
1And R
9Jointly can component part, such as (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
9-(CH
2)
mOr (CH
2)
r-O-(CH
2)
mOne of; Or R
1And R
4Jointly can component part, such as (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
9-(CH
2)
mOr (CH
2)
r-O-(CH
2)
mOne of; Or R
9And R
4Jointly can component part, such as (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
9-(CH
2)
mOr (CH
2)
r-O-(CH
2)
mOne of; Or R
3And R
4Jointly can component part, such as (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
6-(CH
2)
mOr (CH
2)
r-O-(CH
2)
mOne of.
If G in structure (A)
0Be O, so R
3Can be H, C
1-C
6Alkyl and C
1-C
6Replace or unsubstituted hydroxyalkyl or aminoalkyl group, that replace or unsubstituted branched-chain alkyl, replace or unsubstituted cycloalkyl, the heterocycle of the replacement that connects by carbon or nitrogen, replace or unsubstituted aryl or one of the replacement that connects by carbon or nitrogen or unsubstituted heteroaryl, wherein do not have radicals R
4R
1And R
9Jointly can component part, such as (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
9-(CH
2)
mOr (CH
2)
r-O-(CH
2)
mOne of; Or R
1And R
3Jointly can component part, such as (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
9-(CH
2)
mOr (CH
2)
r-O-(CH
2)
mOne of; Or R
9And R
3Jointly can component part, such as (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
9-(CH
2)
mOr (CH
2)
r-O-(CH
2)
mOne of.
If G in structure (A)
0=CH, R so
3And R
4Can be H, C separately
1-C
6Alkyl, C
1-C
6Replace or unsubstituted hydroxyalkyl or aminoalkyl group C
1-C
6Replace or unsubstituted branched-chain alkyl, replace or unsubstituted aryl, by the C of carbon or nitrogen connection
1-C
6Replace or unsubstituted heterocycle or one of the replacement that connects by carbon or nitrogen or unsubstituted heteroaryl, or R
3And R
4Jointly can component part, such as (CHR
9)
r-(CHR
9)
m-(CHR
9)
p, (CHR
9)
r-S-(CHR
9)
m, (CHR
9)
r-SO-(CHR
9)
m, (CHR
9)
r-SO
2-(CHR
9)
m, (CHR
9)
r-NR
9-(CHR
9)
mOr (CHR
9)
r-O-(CHR
9)
mOne of.
In addition, in structure (A), G can be N or CR
6And each G and G are independently of one another, and extra condition is to be no more than two group G can be N, and extra condition is with regard to each CR
6, each R
6With radicals R
6Independently of one another.
In addition, in structure (A), R
5For methyl and part Q as follows:
In part Q, R
6, R
7, R
8Can be one of following group: H, C separately
1-C
6Replace or unsubstituted alkyl C
1-C
6Replace or unsubstituted alkenyl C
1-C
6Replace or unsubstituted alkynyl C
1-C
6Replace or unsubstituted hydroxyalkyl or aminoalkyl group C
1-C
6Replace or unsubstituted branched-chain alkyl C
1-C
6Replace or unsubstituted cycloalkyl, by the replacement or the unsubstituted aryl of carbon or heteroatoms connection, by replacement or the unsubstituted heteroaryl that carbon or heteroatoms connect, C
1-C
6Alkoxyl group, halogen, CF
3,-OCF
3, CHR
3R
4, SR
3, SOR
3, SO
2R
3, SO
2NR
3R
4, SO
3R
3, POR
3, PO
2R
3, PO
2NR
3R
4, PO
2CR
3R
4, PO
3R
3, NR
3R
4, NO
2, CN, OH, CONR
3R
4, COR
3, COOR
3, N R
3COR
4, NR
3CONR
3R
4, OCONR
3R
4, CSNR
3R
4, CSR
3, NR
3CSNR
3R
4, SCONR
3R
4, SCSNR
3R
4Or SCSNR
3R
4Or any R
6And R
7Or R
7And R
8Or R
6And R
8Can constitute jointly and be independently selected from-HN-CH=CH--HN-N=CH-,-HN-N=N-,-O (CH
2)
nO-,-S (CH
2)
nS-,-N=CH-S-,-CH=N-O-,-CH=N-S-,-N=CH-O-,-C=N-O-,-C=N-O-,-CH=CH-CH=CH-,-N=CH-CH=CH-,-CH=N-CH=CH-,-O-CH=CH and-part of any kind among the S-CH=CH-; Or R
3And R
4Jointly can component part, such as (CHR
9)
r-(CHR
9)
m-(CHR
9)
p, (CHR
9)
r-S-(CHR
9)
m, (CHR
9)
r-SO-(CHR
9)
m, (CHR
9)
r-SO
2-(CHR
9)
m, (CHR
9)
r-NR
9-(CHR
9)
mOr (CHR
9)
r-O-(CHR
9)
mOne of.
In addition, in structure (A), A can be O, NR
3, CR
3R
4, S, SO and SO
2One of; And in part Q, G
1Can be CH, N, NH, any kind and G among S and the O
2Can be CR
7, N, NH, any kind among S and the O, wherein each radicals R
7With each other radicals R
7Keep independent; And if G
1Or G
2Be NH, S or O, Q is 5 yuan of heteroaromatic rings so, it is chosen wantonly with 6 yuan of aromatics or non-aromatic ring and condenses; And if G
1Or G
2Be N, Q is 5 or 6 yuan of aromatic rings so, and it is chosen wantonly with 6 yuan of aromatics or non-aromatic ring and condenses, and extra condition is X or G
0Comprise that at least one comprises with X and be selected from O, the heteroatoms of S and N or G
0Comprise the atom of at least four non--hydrogen, comprise heteroatoms, and R
3And R
4Or R
1And R
9Or R
1And R
4Or R
9And R
4Can constitute aromatics jointly, heteroaromatic, ring-type or heterocycle ring system, if or have non-ring system, have an above heteroatoms so, and if A be NR
3, so any R
6, R
7Or R
8Or its combination comprises the substituting group of at least two non--hydrogen independently, if or A be NR
3, Q constitutes R so
6To R
7Or R
7To R
8Fused rings.
Some example compound that operable structure (A) is described includes, but are not limited to I as follows compound to CLXII:
Another embodiment of the invention provides the compound that is used for the treatment of various diseases, illness and pathology situation with general structure (Z):
B-C (Z)
General structure (Z) comprises part B and the C that two kinds of chemistry connect.Part B in the general structure (Z) comprises any part that is selected from down group:
C in said structure (Z) part comprises any part that is selected from following group:
Compound of the present invention or its pharmacy acceptable salt, hydrate, solvate, crystal formation and each diastereomer and method are used for the treatment of various illnesss uniting separately or with other promoting agent (for example following chemotherapeutics or protein therapeutic agent) when giving, comprise, but be not limited to: for example, myelosis's illness, proliferative diabetic retinopathy PDR and other and the relevant illness of generation blood vessel, the cancer that comprises solid tumor and other type, illness in eye, inflammation, psoriatic and virus infection.Treatable cancer types includes, but are not limited to digestion/gastrointestinal cancer, colorectal carcinoma, liver cancer, skin carcinoma, mammary cancer, ovarian cancer, prostate cancer, lymphoma, leukemia (comprising acute myeloid leukaemia and chronic myelogenous leukemia), kidney, lung cancer, muscle cancer, osteocarcinoma, bladder cancer or the cancer of the brain.
Some example of treatable disease and illness comprises that also ocular neovascular forms (ocular neovasculariaztion), infantile hemangioma; The organ anoxic, blood vessel hyperplasia, organ graft repels, lupus, multiple sclerosis, rheumatoid arthritis, psoriatic, type 1 diabetes and the complication that causes because of diabetes, inflammatory diseases, acute pancreatitis, chronic pancreatitis, asthma, anaphylaxis, adult respiratory distress syndrome, cardiovascular disorder, hepatopathy, other hemopathy, asthma, rhinitis, atopic dermatitis, autoimmune thyroid disease (autoimmune thryroid disorders), ulcerative colitis, Crohn's disease, metastatic melanoma, Kaposi sarcoma, multiple myeloma, the illness relevant with cytokine and other autoimmune disease comprise glomerulonephritis, scleroderma, chronic thyroiditis, Graves disease, autoimmunity gastritis, autoimmune hemolytic, the autoimmunity neutropenia, thrombocytopenia, atopy (for example allergic asthma, atopic dermatitis or allergic rhinitis), chronic active hepatitis, myasthenia gravis (myastheniagraivs), multiple sclerosis (multiple scleroiss), inflammatory bowel, graft versus host disease (GVH disease), neurodegenerative disease comprises motor neurone disease, alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington Chorea, cerebral ischemia disease or the neurodegenerative disease that causes because of wound, apoplexy, L-glutamic acid neurotoxic (gluatamateneurtoxicity) or hypoxemia; Ischemia/reperfusion injury in the apoplexy, myocardial ischemia (myocardial ischemica), renal ischaemia, heart attack, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ anoxic and platelet aggregation.
The example of treatable some extra disease and illness also comprises cell-mediated hypersensitivity (allergic contact dermatitis, hypersensitivity pneumonitis), rheumatism (systemic lupus erythematous (SLE) for example, rheumatoid arthritis, adolescent arthritis, this Jaeger logical sequence syndrome, scleroderma, polymyositis, ankylosing spondylitis, arthritic psoriasis), virus disease (Epstein-Barr virus, hepatitis B, hepatitis C, HIV, HTLV1, varicella zoster virus, human papillomavirus), food anaphylaxis, skin inflammation and because of the immunosuppression of solid tumor inductive.
Embodiment of the present invention also provide the article of manufacture that can comprise the pharmaceutical composition that comprises in wrapping material and the wrapping material.These wrapping material can comprise and show that pharmaceutical composition can be used for the treatment of the label of one or more above-mentioned definite illnesss.
Described pharmaceutical composition comprises compound of the present invention.Except that compound of the present invention, described medicine can also comprise other therapeutical agent, and for example, can be by the medicated premix type (vehicle for example that uses commonly used solid or liquid vehicle or thinner and be suitable for required administering mode, tackiness agent, sanitas, stablizer, correctives etc.), prepare according to the field of pharmaceutical preparations technique known.
Therefore, the present invention provides the pharmaceutical composition that comprises therapeutical agent and The compounds of this invention in one embodiment.The concentration that exists of described compound can effectively be treated, for example cancer or treat above-mentioned another kind of disease or illness.
Compound of the present invention can be mixed with therapeutic composition as the form of natural or salt.Pharmaceutically acceptable non-toxic salts comprises the salt (being formed by free carboxy or other anionic group) of alkali addition, they can be derived from mineral alkali, such as, sodium for example, potassium, ammonium, the oxyhydroxide of calcium or iron and such as Isopropylamine, Trimethylamine 99,2-ethylamino-ethanol, Histidine, this class organic bases such as PROCAINE HCL, PHARMA GRADE.This class salt can also form the salt of sour addition with any free cations group, and general and mineral acid, such as, hydrochloric acid for example, sulfuric acid or phosphoric acid or organic acid, such as acetate, citric acid, right-toluenesulphonic acids, methylsulfonic acid, oxalic acid, tartrate, formation such as amygdalic acid.
Salt of the present invention can comprise by using all example hydrochloric acids, Hydrogen bromide, and hydroiodic acid HI, sulfuric acid, this class mineral acid such as phosphoric acid makes the amine salt of amino protonated formation.Salt of the present invention can also comprise by using such as right-toluenesulphonic acids, acetate, and this class appropriate organic such as methylsulfonic acid makes the amine salt of amino protonated formation.Concern be used to implement additional excipients of the present invention for those skilled in the art available those, for example, at American Pharmacopeia United States Pharmacopeia Vol.XXII and NF Vol.XVII, U.S.Pharmacopeia Convention, Inc., Rockville, those that find among the MD (1989) are incorporated herein by reference the associated viscera of these documents.In addition, the present invention includes the polymorphic form of The compounds of this invention.
Mode administration pharmaceutical composition of the present invention that can be by any appropriate, for example, by oral, such as with tablet, capsule, particle or form of powder; Pass through the hypogloeeis; By sucking; By non-enteron aisle, subcutaneous such as passing through, intravenously, intramuscular, sheath interior or intracisternal injection or infusion techniques (for example as sterile injectable water or non-aqueous solution or suspension); By nose, such as spraying by sucking; By the part, such as form with creme or ointment; Or by rectum, such as form with suppository; To comprise the unit dosage of avirulent pharmaceutically acceptable vehicle or thinner.For example, can be to be suitable for quick-release or to prolong the form administration compound of the present invention that discharges.Can be by using the suitable pharmaceutical composition that comprises The compounds of this invention, or discharge speech and can pass through using appts with regard to prolonging, realize quick-release or prolongation release such as hypodermic implant or osmotic pump.Can also be with liposome form administration compound of the present invention.
Remove primates, outside the people, can also be according to various other Mammalss of method treatment of the present invention.For example, can treat Mammals, include, but are not limited to ox, sheep, goat, horse, dog, cat, cavy, rat or other ox, sheep, horse, dog, cat, rodent or muroid.Yet this method can also be implemented in other kind, such as birds (for example chicken).
Can will be used for separately or make unit dosage expediently with the pharmaceutical composition of the compound of this embodiment of other therapeutical agent Combined Preparation, and can the well-known any method preparation of pharmacy field technician.All methods include mixes active ingredient with the carrier that constitutes one or more auxiliary components.Generally speaking, pharmaceutical compositions through the following steps: all even closely mixed active component and liquid vehicle or fine powder solid carrier or both, and then if desired, make product be configured as required preparation.In this pharmaceutical composition, comprise the active target compound that is enough to lysis or situation are produced the consumption of required effect.The pharmaceutical composition that comprises active ingredient can for example, be tablet for being suitable for the form of oral application, tablet, lozenge, water or oil suspension, but dispersed powders or particle, emulsion, hard or soft capsule or syrup or elixir.
Can specify the composition of oral application according to known any method preparation in the pharmaceutical compositions field, and this based composition can comprise one or more and be selected from sweeting agent, correctives, the reagent of tinting material and sanitas is so that provide pharmaceutically exquisite and agreeable to the taste preparation.Tablet comprises active ingredient and is suitable for preparing the mixture of the pharmaceutically acceptable vehicle of nontoxicity of tablet.These vehicle can for, for example, inert diluent, such as lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulate and disintegrating agent, for example, W-Gum or alginic acid; Tackiness agent, starch for example, gelatin or gum arabic, and lubricant, for example Magnesium Stearate, stearic acid or talcum powder.Tablet can be for dressing not, maybe can give their dressings so that delay disintegration and absorption in gi tract by known technology, and be provided at the continuous action of longer-term limit thus.For example, can use the time-delay material, such as glyceryl monostearate or distearin.Can also give their dressings so that be formed for the osmotic therapeutic tablets of controlled release.
The preparation that is used for oral application can also be made hard gelatin capsule, wherein with active ingredient and inert solid diluent, for example, lime carbonate, calcium phosphate or kaolin mix, or make soft gelatin capsule, wherein with active ingredient and water or oily medium, for example peanut oil, whiteruss or mixed with olive oil.
Aqueous suspension comprises active substance and the excipient mixture that is suitable for preparing aqueous suspension.This class vehicle is a suspension agent, Xylo-Mucine for example, methylcellulose gum, Vltra tears, sodiun alginate, polyvinylpyrrolidone, Tragacanth and Sudan Gum-arabic; Dispersion or wetting agent can be naturally occurring phosphatide, the condensation product of Yelkin TTS or alkylene oxide and lipid acid for example, the condensation product of polyoxyethylene stearic acid ester or oxyethane and long chain aliphatic alcohol for example, heptadecaethylene oxycetanol for example, or oxyethane and derived from the condensation product of the partial ester of lipid acid and hexitol, such as octadecanoic acid ester of polyethylene glycol, or oxyethane and derived from the condensation product of lipid acid or hexitol acid anhydrides, for example polyethylene dehydrated sorbitol mono-fatty acid ester.In addition as solubilizing agent polyoxyethylene glycol for example usefully.Aqueous suspension can also comprise: one or more sanitass, and for example ethyl p-hydroxybenzoate or P-hydroxybenzoic acid n-propyl, one or more tinting materials, one or more correctivess and one or more sweeting agents are such as sucrose or asccharin.
Can for example be peanut oil by active ingredient is suspended in vegetables oil, sweet oil, sesame oil or Oleum Cocois or mineral oil are such as the suspension that makes up oil in the whiteruss.This oil suspension can comprise thickening material, for example beeswax, paraffinum durum or hexadecanol.Can add sweeting agent, such as aforesaid those and correctives, so that agreeable to the taste oral preparations is provided.Can pass through to add antioxidant, anticorrosion such as xitix to these compositions.
But be adapted to pass through interpolation water and prepare the dispersed powders of aqueous suspension and the mixture that particle provides active ingredient and dispersion or wetting agent, suspension agent and one or more sanitass.Suitable dispersion or wetting agent and suspension agent described with above-mentioned those be the typical case.Can also there be extra vehicle, for example sweeting agent, correctives and tinting material.
Can use sweeting agent, for example glycerine, propylene glycol, sorbyl alcohol or agent of sucrose obtain syrup and elixir.This class preparation can also comprise negative catalyst, sanitas and correctives and tinting material.
Pharmaceutical composition can be the form of sterile injectable water or oil suspension.Can use those above-mentioned suitable dispersions or wetting agent and suspension agent to prepare this suspension according to known field.Sterile injectable preparation can also be sterile injectable solution or the suspension in non-enteron aisle acceptable diluent or solvent or cosolvent or complexing agent or dispersion agent or vehicle or its combination, for example 1, the 3-butyleneglycol, polyethylene glycols, polypropylene glycols, ethanol or other alcohol, polyvidone, the TWEEN tensio-active agent of various trade marks, sodium lauryl sulphate, Sodium desoxycholate, N,N-DIMETHYLACETAMIDE, the polysorbate class, poloxamer, cyclodextrin, lipid and vehicle, such as inorganic salt (for example sodium-chlor), buffer reagent (for example Trisodium Citrate, sodium phosphate) and sugar (for example sucrose and glucose).In vehicle and the solvent water is arranged operable acceptance, glucose solution, Ringer's solution and isotonic sodium chlorrde solution.In addition, usually aseptic fixed oil is used as solvent or suspension medium.For this purpose, can use the fixed oil of any trade mark, comprise synthetic monoglyceride or di-glycerides.In addition, lipid acid is applied to prepare injection such as oleic acid.
According to the illness of being treated, can prepare and by whole body or these pharmaceutical compositions of topical.The technology that is used to prepare with administration can find in latest edition " Remington ＇ sPharmaceutical Sciences " (Mack Publishing Co, Easton Pa.).Suitable for can comprising, for example oral or stride mucosa delivery; And non-enteron aisle sends, and comprises intramuscular, and is subcutaneous, in the marrow, and in the sheath, in the ventricle, intravenously, intraperitoneal or intranasal administration.With regard to injection, pharmaceutical composition of the present invention can be mixed with the aqueous solution, preferably at the physiological compatibility damping fluid, such as at Hanks solution, the aqueous solution in Ringer's solution or the physiological buffer salt solution.With regard to tissue or cell administration, will be suitable for being used for preparation through the permeate agent of particular barrier.This class permeate agent is generally well known in the art.The pharmaceutical preparation that is used for parenterai administration comprises the aqueous solution of the active compound of water-soluble form.In addition, the suspension of active compound can be prepared into suitable oily injection suspension.Proper fat-soluble solvent or vehicle comprise: fatty oil, and such as sesame oil, or Acrawax, such as ethyl oleate or triglyceride or liposome.Moisture injection suspension can comprise the material that increases this suspension viscosity, such as Xylo-Mucine, and sorbyl alcohol or dextran.The optional reagent that can also comprise suitable stablizer or increase the compound dissolution degree of this suspension is so that prepare highly enriched solution.
Can also be to be used for the suppository form administration compound of the present invention of rectal administration.Can prepare these compositions by hybrid medicine and suitable nonirritant excipient, described vehicle is a solid at normal temperatures, and is liquid under rectal temperature, and fusing and discharge medicine in rectum thus.This class material is theobroma oil and polyethylene glycols.
With regard to topical application, use the creme that comprises The compounds of this invention, ointment, jelly, (with regard to the application's purpose, topical application should comprise mouth wash shua and gargarism) such as solution or suspensions.
In one embodiment, to experimenter's administration compound of the present invention and the antiphlogiston that has this class treatment to need, antihistaminic, chemotherapeutics, immunomodulator, treatment antibody or kinases inhibitor, for example tyrosine kinase inhibitor.Although need not to be restricted, chemotherapeutics comprises antimetabolite, and such as methotrexate, the DNA linking agent is such as cis-platinum/carboplatin; Alkylating agent is such as canbusil; The topoisomerase I inhibitor is such as gengshengmeisu; The microtubule inhibitor is such as safe plain (taxol (paclitaxol)) etc.Other chemotherapeutics comprises, for example, and vinca alkaloids, mitomycin-class microbiotic, bleomycin-class microbiotic, antifol, colchicine, demecoline, Etoposide, Taxan, anthracycline antibiotics, Dx, daunorubicin, carminomycin, epirubicin, idarubicin, mitoxantrone (mithoxanthrone), 4-dimethoxy-daunomycin, 11-deoxidation daunorubicin, 13-deoxidation daunorubicin, Zorubicin-14-benzoate, Zorubicin-14-octylate, Zorubicin-14-naphthylacetic acid salt, amsacrine, carmustine, endoxan, cytosine arabinoside, Etoposide, lovastatin, melphalan, Hycamtin (topetecan), oxaliplatin (oxalaplatin), Chlorambucil, methotrexate (methtrexate), lomustine, Tioguanine, asparaginase, vinealeucoblastine(VLB), vindesine, tamoxifen or mustargen.Although need not to be restricted, treat antibody and comprise and be oriented to the proteic antibody of HER2, such as Herceptin; Be oriented to the antibody of somatomedin or growth factor receptors, cut down the OSI-774 of pearl monoclonal antibody and targeting epidermal growth factor such as the shellfish of target vascular therapy endothelial cell growth factor (ECGF); The antibody of target integrin receptor is such as Vitaxin (being also referred to as MEDI-522) etc.The anticarcinogen type that is applicable to the present composition and method comprises, but be not limited to: 1) alkaloid, comprise microtubule inhibitor (vincristine(VCR) for example, vinealeucoblastine(VLB) and vindesine etc.), microtubule stabilizer (for example taxol [safe plain] and docetaxel, taxotere etc.) and the chromatin depressant of functions, comprise topoisomerase enzyme inhibitor, such as the promoting agent (for example camptothecine and irinotecan (Isirinotecan) [CPT-11] etc.) of epipodophyllotoxin (for example Etoposide [VP-16] and teniposide [VM-26] etc.) and target topoisomerase I; 2) covalency DNA-wedding agent [alkylating agent], comprise mustargen (mustargen for example, Chlorambucil, endoxan, ifosfamide and busulfan [Myelosan] etc.), nitrosoureas (for example carmustine, lomustine and semustine etc.) and other alkylating agent (Dacarbazine for example, methylol melamine, plug is for group and Mitocycin etc.); 3) non-covalent DNA-wedding agent [antitumor antibiotics], comprise nucleic acid inhibitor (for example dactinomycin [dactinomycin] etc.), anthracene nucleus class (daunorubicin [daunomycin and zhengdingmeisu] for example, Dx [Zorubicin] and idarubicin [darubicin] etc.), amerantrone class (anthracycline antibiotics analogue for example, such as, [mitoxantrone] etc.), bleomycin (bleomycin) etc. and Plicamycin (Plicamycin) etc.; 4) antimetabolite, comprise antifol (methotrexate for example, Folex and methotrexate sodium etc.), purine antimetabolite (Ismipur [6-MP for example, mercaptopurine], 6-Tioguanine [6-TG], azathioprine, acyclovir, ganciclovir, chlorine Desoxyadenosine, 2-chlorodeoxyadenosine [CdA] and 2 ＇-deoxidation coformycin [pentostatin] etc.), pyrimidine antagonist (for example fluorine miazines [for example 5 FU 5 fluorouracil (Adrucil), floxuridine (FdUrd) (floxuridine)] etc.) and cytosine(Cyt) arabinose nucleosides (for example Cytosar [ara-C] and fludarabine etc.); 5) enzyme comprises the altheine enzyme; 6) hormone comprises glucocorticosteroid, such as, antiestrogen (for example tamoxifen etc.), non-steroid antiandrogen (for example flutamide etc.) and aromatase inhibitor (for example Anastrozole [Arimidex] etc.); 7) platinic compound (for example cis-platinum and carboplatin etc.); 8) and anticarcinogen, the monoclonal antibody that toxin and/or radionuclide are puted together etc.; 9) biological response modifier (for example Interferon, rabbit [IFN-. α for example. etc.] and interleukin-[for example IL-2 etc.] etc.); 10) adoptive immunotherapy; 11) hemopoieticgrowth factor; 12) promoting agent of inducing tumor cell differentiation (for example all-trans retinoic acid etc.); 13) gene therapy technology; 14) antisense therapy technology; 15) tumor vaccine; 16) be oriented to the therapy (for example Batimistat etc.) of metastatic tumor; With 17) angiogenesis inhibitor.
Pharmaceutical composition of the present invention and method may further include other therapeutical active compound that often is applied to treat above-mentioned pathology situation described herein.The example of other therapeutical agent comprises as follows: cyclosporine (for example ciclosporin A); CTLA4-Ig; Antibody, such as ICAM-3, anti--the IL-2 acceptor (anti--Tac), anti--CD45RB, anti--CD2, anti--CD3 (OKT-3), anti--CD4, anti--CD80, anti--CD86; Blocking-up CD40 and the interactional promoting agent of gp39, such as CD40 and/or gp39 are had specific antibody (being CD154), fusion rotein (CD40Ig and CD8gp39) by CD40 and gp39 structure, NF-κ B depressant of functions, such as nuclear transposition inhibitor, such as Gusperimus (DSG); Cholesteral biosynthesis inhibitor is such as HMG CoA reductase inhibitor (lovastatin and Simvastatin); Nonsteroid anti-inflammatory drugs (NSAIDs) is such as Ibuprofen BP/EP and cyclooxygenase inhibitors, such as rofecoxib; Steroid is such as prednisone or dexamethasone; Gold compound; Antiproliferative agents, such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil, cytotoxic drug is such as azathioprine and endoxan; The TNF-a inhibitor is such as tenidap; Anti-TNF antibody or soluble TNF acceptor and rapamycin (sirolimus or Lei Paming) or derivatives thereof.
Can comprise the protein therapeutic agent with other promoting agent of The compounds of this invention Combined Preparation, such as cytokine, immunomodulator and antibody.Term " cytokine " used herein " comprise chemokine, interleukin-, lymphokine, monokine, G CFS and receptor associated protein(RAP) and function fragment thereof.Term ＂ function fragment ＂ used herein means has biological function or active polypeptide or the peptide of identifying by the functional examination method of determining.
Cytokine comprises endothelial mononuclear cell activating polypeptide II (EMAP-II), granulocyte-macrophage-CSF (GM-CSF), granulocyte-CSF (G-CSF), scavenger cell-CSF (M-CSF), IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-12 and IL-13, Interferon, rabbit etc. and with cell or cell mechanism in particular biological, form or phenotypic alternation are relevant.
When with other therapeutical agent and compound coupling of the present invention, for example, can use them with the consumption described in the Physician Desk Reference (PDR), otherwise just determine by those skilled in the art.
In the treatment or prevention of the illness that relates to cell proliferation, suitable dosage level can be with it with list or multidose administration generally in the about 1000mg/1kg weight in patients of about 0.01-/sky.For example, this dosage level can be at the about 250mg/kg/ of about 0.01-days; Narrower is at the about 100mg/kg/ of about 0.5-days.Suitable dosage level can be at the about 250mg/kg/ of about 0.01-days, the about 100mg/kg/ of about 0.05-days or the about 50mg/kg/ of about 0.1-days or about 1.0mg/kg/ days.For example, in this scope, dosage can be at the about 0.5mg/kg/ of about 0.05-days or the about 5mg/kg/ of about 0.5-days or the about 50mg/kg/ of about 5-days.With regard to oral administration, composition made to comprise about 1.0-about 1, the 000mg active ingredient, for example, about 1.0, about 5.0, about 10.0, about 15.0, about 20.0, about 25.0, about 50.0, about 75.0, about 100.0, about 150.0, about 200.0, about 250.0, about 300.0, about 400.0, about 500.0, about 600.0, about 750.0, about 800.0, about 900.0 and about 1, the tablet form of 000.0mg active ingredient is so that adjust this dosage according to the patient's who is treated symptom.Can be with 1-4 time/day, such as once or twice/day scheme give drug compound.Not medicine-feeding period can be arranged, carry out another kind of dosage regimen subsequently.
Yet, be appreciated that the concrete dosage level and the dosage frequency at any particular patient can change, and depend on various factors, the activity that comprises used particular compound, the metabolic stability of this compound and effect time limit, age, body weight, the general health situation, sex, meals, administering mode and time, discharge rate, drug regimen, the seriousness and the ongoing therapy of host of the concrete state of an illness.
Compound of the present invention can be used separately or with the treatment antibody (or its treatment fragment) of significant quantity, chemotherapeutics or immunotoxicity agent coupling are so that the treatment tumour.The illustrative example that can be used for the chemotherapeutics of this purpose comprises Dx, docetaxel or safe plain.Further should understand the present invention includes and comprise The compounds of this invention, include, but are not limited to vasculostaticagents, such as tyrosine, the conjoint therapy of Serine or threonine kinase enzyme inhibitors and any chemotherapeutics or treatment antibody.
C. embodiment
It is for further illustration advantages and features of the invention that the following example is provided, but is not to specify them to be used for limiting scope of the present invention.
Embodiment 1. general methods
General method
All experiments are all carried out down and in the ar gas environment at anhydrous condition (being dry solvent), but as described, in handling the air sensitive material, use the oven drying instrument and use standard technique.Saturated sodium bicarbonate (NaHCO
3) and the aqueous solution of sodium-chlor (salt solution).Use MerckKieselgel 60 F
254Plate carries out analysis mode thin-layer chromatography (TLC), and by UV-light and/or aubepine, potassium permanganate or the colour developing of phospho-molybdic acid dipping.WatersSymmetryShield has been installed in use
TMGilson 215 liquid processors of RP18 7 μ m (40 x 100mm) Prep-Pak post carry out the reversed-phase HPLC chromatogram.Moving phase is made up of the standard acetonitrile (ACN) and the DI Water that have added 0.1% TFA separately.Carry out purifying with 40mL/ minute flow velocity.NMR spectrum: record under 500MHz
1The H NMR (Nuclear Magnetic Resonance) spectrum.Provide data as follows: chemical shift, multiplicity (s=is unimodal, and d=is bimodal, the t=triplet, and the q=quartet, the qn=quintet, bimodal during dd=is bimodal, the m=multiplet, br s=is wide unimodal), coupling constant (J/Hz) and integration.Coupling constant is directly taken from spectrum and not calibration.Low resolution mass spectrum: use electrospray (ES+) ionization.The protonated parent ion (M+H) or the fragment of extra best best have been put to the proof.Unless otherwise stated, otherwise analyze gradient and form by 10% ACN-100% ACN in water in 5 minutes.
Embodiment 2. N
4
-(4-methoxyl group-phenyl)-pyrimidine-2,4-diamines (intermediate 1)
(0.30g, 2.3mmol) (0.30g, mixture 2.4mmol) are suspended in the acetate (10mL) and at 100 ℃ and heated 2 hours down with 4-methoxyl group-phenyl amine with 4-chloro-pyrimidine-2-base amine.This mixture is cooled to room temperature and under reduced pressure removes acetate.Resistates water-soluble (20mL) and use 7M NaOH solution are neutralized to pH～7.With EtOAc (30mL) extraction gained solution and separation organic layer.With salt water washing organic layer, use MgSO
4Drying and filtration.Concentrated filtrate and obtain title intermediate 1 (0.23g, 45%) with fast silica gel chromatogram method purifying crude product (hexane is to EtOAc) is white solid in a vacuum.
1H?NMR(500MHz，DMSO-d
6):3.69(s，3H)，5.84(d，J＝5.8Hz，1H)，6.79(d，J＝9.1Hz，2H)，7.63(d，J＝9.1Hz，2H)，7.78(d，J＝5.8Hz，1H)，8.65(s，1H)；MS(ESI+):m/z?217(M+H)
+。
Embodiment 3. N
4
-(4-methoxyl group-phenyl)-N
2
-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-benzene
Base]-pyrimidine-2,4-diamines (Compound I)
For synthetic compound I, use above-mentioned intermediate 1 and intermediate 2.Intermediate 2 as follows, 1-[2-(4-bromo-phenoxy group)-ethyl]-tetramethyleneimine is the use that is purchased and conduct is generally acknowledged.
With intermediate 1 (74mg, 0.34mmol), intermediate 2 (0.10g, 0.37mmol), Pd (OAc)
2(5mg, 0.022mmol), Xantphos (26mg, 0.05mmol) and potassium tert.-butoxide (80mg, 0.71mmol) Zai diox/DMF (3/1; Suspension 4mL) is sealed in the microwave reaction pipe and at 160 ℃ and uses microwave irradiation 15 minutes down.After being cooled to room temperature, removing lid and filter the gained mixture and with the solid of DCM washing and filtering.Concentrated filtrate and obtain title compound I (tfa salt of 20mg, 11%) by HPLC purifying resistates is brown solid.
1H?NMR(500MHz，DMSO-d
6):1.80-1.95(m，2H)，1.95-2.10(m，2H)，3.05-3.20(m，2H)，3.55-3.65(m，4H)，3.77(s，3H)，4.29(t，J＝4.9Hz，2H)，6.30(d，J＝6.8Hz，1H)，6.96(d，J＝8.3Hz，2H)，6.98(d，J＝8.3Hz，2H)，7.41(d，J＝8.8Hz，2H)，7.55(d，J＝8.8Hz，2H)，7.89(d，J＝6.2Hz，1H)，9.87(brs，1H)，10.22(br?s，1H)，10.44(br?s，1H)；MS(ESI+):m/z?406(M+H)
+。
Embodiment 4. 4-[4-(4-methoxyl group-phenyl amino)-pyrimidine-2--amino]-N-(2-pyrroles
Alkane-1-base-ethyl)-benzsulfamide (Compound I I)
For synthetic compound II, use intermediate 1 above-mentioned and intermediate 3.The intermediate 3 of formula as follows, 4-bromo-N-(2-tetramethyleneimine-1-base-ethyl)-benzsulfamide uses known synthetic technology synthetic by 4-bromophenyl SULPHURYL CHLORIDE and 2-amino-ethyl tetramethyleneimine.
With above-mentioned intermediate 1 (70mg, 0.32mmol), intermediate 3 (0.12g, 0.36mmol), Pd (OAc)
2(5mg, 0.022mmol), Xantphos (26mg, 0.05mmol) and potassium tert.-butoxide (80mg, 0.71mmol) Zai diox/DMF (3/1; Suspension 4mL) is sealed in the microwave reaction pipe and at 160 ℃ and uses microwave irradiation 15 minutes down.After being cooled to room temperature, removing lid and filter the gained mixture and with the solid of DCM washing and filtering.Concentrated filtrate and obtain title compound II (tfa salt of 0.16g, 85%) by HPLC purifying resistates is white solid.
1H?NMR(500MHz，DMSO-d
6):1.80-1.95(m，2H)，1.95-2.05(m，2H)，2.95-3.05(m，4H)，3.23(q，J＝5.8Hz，2H)，3.50-3.60(m，2H)，3.79(s，3H)，6.41(d，J＝6.8Hz，1H)，6.99(d，J＝8.9Hz，2H)，7.43(d，J＝8.9Hz，2H)，7.71(d，J＝8.6Hz，2H)，7.85-7.95(m，2H)，7.96(t，J＝6.1Hz，1H)，8.02(d，J＝6.2Hz，1H)，9.64(br?s，1H)，10.21(br?s，1H)，10.71(br?s，1H)；MS(ESI+):m/z?469(M+H)
+。
Embodiment 5. 4-[4-(4-hydroxyl-phenyl amino)-pyrimidine-2--amino]-N-(2-tetramethyleneimine
-1-base-ethyl)-benzsulfamide (compound III)
(50mg 0.09mmol) adds BBr in the solution in DCM (6mL) to above-claimed cpd II at room temperature
3(0.1mL) and with this mixture at room temperature stirred 2.5 hours.Use saturated NaHCO
3Solution makes the reaction quencher, extracts this mixture up to pH～7 and with EtOAc (30mL).Separate organic layer and use the salt water washing, use MgSO
4Drying and filtration.Concentrated filtrate and the gained solid is dissolved in minimum EtOAc again.Adding hexane to solid is separated out and title compound III filters, and for white solid (25mg, 64%), need not to be further purified.
1H?NMR(500MHz，DMSO-d
6):1.55-1.65(m，4H)，2.30-2.40(m，4H)，2.43(t，J＝7.0Hz，2H)，2.82(t，J＝6.6Hz，2H)，6.20(d，J＝5.8Hz，1H)，6.70(d，J＝8.8Hz，2H)，7.40(d，J＝8.6Hz，2H)，7.64(d，J＝8.8Hz，2H)，7.92(d，J＝8.4Hz，2H)，8.03(d，J＝5.5Hz，1H)，8.93(s，1H)，9.08(br?s，1H)，9.70(s，1H)；MS(ESI+):m/z?455(M+H)
+。
Embodiment 6. 4-(4-chloro-pyrimidine-2--amino)-N-(2-tetramethyleneimine-1-base-ethyl)-benzene
Sulphonamide (intermediate 4)
With 4-chloro-pyrimidine-2-base amine (1.0g, 7.8mmol), above-mentioned intermediate 3 (2.6g, 7.8mmol), Pd (OAc)
2(90mg, 0.40mmol), Xantphos (0.50g, 0.86mmol) and potassium tert.-butoxide (2.2g, mixture 20mmol) be suspended in the diox (30mL) and under reflux state and ar gas environment in the heating 16 hours.Extract with this mixture impouring water (30mL) and with EtOAc (60mL).Separate organic layer and use the salt water washing, use MgSO
4Drying and filtration.Concentrated filtrate and obtain title intermediate 4 (0.15g, 5%) with fast silica gel chromatogram method purifying crude product (DCM-25% MeOH/DCM) is brown solid in a vacuum.MS(ESI+):m/z382(M+H)
+。
Embodiment 7. 4-[4-(3-methoxyl group-phenyl amino)-pyrimidine-2--amino]-N-(2-pyrroles
Alkane-1-base-ethyl)-benzsulfamide (compound IV)
(0.10g, 0.26mmol) (0.05mL, mixture 0.45mmol) are suspended in acetate (6mL) and heated 1.5 hours down at 100 ℃ with 3-methoxyl group-phenyl amine with above-mentioned intermediate 4.This mixture is cooled to room temperature and under reduced pressure removes acetate.With resistates water-soluble (20mL) and be neutralized to pH～7.With EtOAc (30mL) extraction gained solution and separation organic layer.With salt water washing organic layer, use MgSO
4Drying and filtration.Concentrated filtrate and obtain title compound IV (tfa salt of 55mg, 36%) by HPLC purifying crude product is white solid in a vacuum.
1H?NMR(500MHz，DMSO-d
6):1.80-1.90(m，2H)，1.95-2.05(m，2H)，2.95-3.05(m，4H)，3.24(q，J＝6.0Hz，2H)，3.50-3.60(m，2H)，3.73(s，3H)，6.40(d，J＝6.3Hz，1H)，6.68(d，J＝7.3Hz，1H)，7.18(d，J＝8.2Hz，1H)，7.26(t，J＝8.0Hz，1H)，7.30(s，1H)，7.72(d，J＝8.9Hz，2H)，7.91(t，J＝6.1Hz，1H)，7.95(d，J＝8.7Hz，2H)，8.10(d，J＝6.2Hz，1H)，9.59(brs，1H)，9.87(br?s，1H)，10.38(br?s，1H)；MS(ESI+):m/z?469(M+H)
+。
Embodiment 8. 4-[4-(3-hydroxyl-phenyl amino)-pyrimidine-2--amino]-N-(2-tetramethyleneimine
-1-base-ethyl)-benzsulfamide (compound V)
(30mg 0.05mmol) adds BBr in the solution in DCM (6mL) to above-claimed cpd IV at room temperature
3(0.1mL) and with this mixture at room temperature stirred 2.5 hours.Use saturated NaHCO
3Solution makes the reaction quencher, extracts this mixture up to pH～7 and with EtOAc (30mL).Separate organic layer and use the salt water washing, use dry MgSO
4And filter.Concentrated filtrate and obtain title compound V (tfa salt of 13mg, 46%) by HPLC purifying resistates is pale solid.
1H?NMR(500MHz，DMSO-d
6):1.80-1.90(m，2H)，1.95-2.05(m，2H)，2.95-3.05(m，4H)，3.20-3.30(m，2H)，6.39(d，J＝6.3Hz，1H)，6.53(d，J＝7.2Hz，1H)，7.01(d，J＝9.2Hz，1H)，7.09(s，1H)，7.14(t，J＝8.1Hz，1H)，7.73(d，J＝8.8Hz，2H)，7.90(t，J＝6.2Hz，1H)，7.97(d，J＝8.8Hz，2H)，8.08(d，J＝6.4Hz，1H)，9.48(br?s，1H)，9.57(br?s，1H)，9.86(br?s，1H)，10.41(br?s，1H)；MS(ESI+):m/z?455(M+H)
+。
Embodiment 9. benzos [1,3] dioxole-5-base-(2-chloro-5-methyl-pyrimidine-4-
Base)-amine (intermediate 5)
With 2-chloro-5-methyl-pyrimidine-4-base amine (0.30g, 2.1mmol), 5-bromo-benzo [1,3] dioxole (0.45g, 2.2mmol), Pd (OAc)
2(30mg, 0.13mmol), Xantphos (0.15g, 0.26mmol) and potassium tert.-butoxide (0.45g, mixture 4.0mmol) be suspended in diox (15mL) or and under reflux state and ar gas environment in the heating 16 hours.This reaction mixture is cooled to room temperature and dilutes with DCM (20mL).Filter this mixture and concentrated filtrate in a vacuum.Obtain title intermediate 5 (0.10g, 18%) by flash chromatography on silica gel method purifying resistates (hexane to 50% EtOAc/ hexane), be white solid.MS(ESI+):m/z?264(M+H)
+。
Embodiment 10. N
4
-benzo [1,3] dioxole-5-base-5-methyl-N
2
-[4-(2-
Tetramethyleneimine-1-base-oxyethyl group)-phenyl]-pyrimidine-2,4-diamines (compound VI)
For synthetic compound VI, use intermediate 5 above-mentioned and intermediates 6.The intermediate 6 of synthetic formula as follows in two steps, 4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl amine:, reduce subsequently and obtain anils at first by using the 2-chloroethyl pyrrolidine to make the alkylation of 4-nitrophenols.
Generally well-known synthetic technology is used for synthetic intermediate 6.With above-mentioned intermediate 5 (90mg, 0.34mmol), intermediate 6 (95mg, 0.46mmol), Pd
2(dba)
3(20mg, 0.02mmol), Xantphos (30mg, 0.05mmol) and cesium carbonate (0.30g, mixture 0.9mmol) be suspended in the diox (10mL) and under reflux state and ar gas environment in the heating 20 hours.This reaction mixture is cooled to room temperature and dilutes with DCM (20mL).Filter this mixture and concentrated filtrate in a vacuum.Obtain title compound VI (tfa salt of 40mg, 21%) by HPLC purifying resistates, be brown solid.
1H?NMR(500MHz，DMSO-d
6):1.85-1.95(m，2H)，1.95-2.05(m，2H)，2.13(s，3H)，3.10-3.20(m，2H)，4.26(t，J＝5.0Hz，2H)，6.07(s，2H)，6.90-7.00(m，4H)，7.19(s，1H)，7.37(d，J＝9.0Hz，2H)，7.84(s，1H)，9.60(br?s，1H)，9.89(br?s，1H)，10.32(br?s，1H)；MS(ESI+):m/z?434(M+H)
+。
Embodiment 11. (4-chloro-3-methoxyl group-phenyl)-(2-chloro-5-methyl-pyrimidine-4-yl)-amine (in
Mesosome 7)
With 2-chloro-5-methyl-pyrimidine-4-base amine (0.50g, 3.5mmol), 4-bromo-1-chloro-2-methoxyl group-benzene (0.65mL, 4.8mmol), Pd
2(dba)
3(0.17g, 0.19mmol), Xantphos (0.22g, 0.38mmol) and cesium carbonate (2.3g, mixture 7.1mmol) be suspended in diox (20mL) and under reflux state and ar gas environment in the heating 5 hours.This reaction mixture is cooled to room temperature and dilutes with DCM (30mL).Filter this mixture and concentrated filtrate in a vacuum.Obtain title intermediate 7 (0.55g, 55%) by fast silica gel chromatogram method purifying resistates (hexane to 40% EtOAc/ hexane), be yellow solid.
1H?NMR(500MHz，DMSO-d
6):2.18(s，3H)，3.85(s，3H)，7.35(dd，J＝8.6Hz，J＝2.3Hz，1H)，7.39(d，J＝8.7Hz，1H)，7.56(d，J＝2.3Hz，1H)，8.09(d，J＝0.9Hz，1H)，8.91(s，1H)；MS(ESI+):m/z?284(M+H)
+。
Embodiment 12. (4-chloro-3-methoxyl group-phenyl)-(2-chloro-5-methyl-pyrimidine-4-yl)-methyl-
Amine (intermediate 8)
Under 0 ℃ with intermediate 7 (0.50g, 1.8mmol) and sodium hydride (in mineral oil 60%, 0.15g, 3.8mmol) suspension in THF (10mL) stirred in ar gas environment 5 minutes.Under uniform temp, in said mixture, inject methyl-iodide (0.15mL, 2.4mmol).In 15 minutes, gained solution is stirred to room temperature and further restir 17 hours at room temperature from 0 ℃.Water (10mL) makes the reaction quencher and uses EtOAc (30mL) extraction then.Separate organic layer and use the salt water washing, use MgSO
4Drying and filtration.Concentrated filtrate and obtain title intermediate 8 (0.20g, 38%) by fast silica gel chromatogram method purifying resistates (hexane to 20% EtOAc/ hexane) is white solid.MS(ESI+):m/z?298(M+H)
+。
Embodiment 13. N
2
-(4-(2-(tetramethyleneimine-1-yl) oxyethyl group) phenyl)-N
4
-(4-chloro-3-first
Oxygen base phenyl)-N
4
, 5-dimethyl pyrimidine-2,4-diamines (compound VI I)
(0.15g, 0.49mmol) (0.15g, mixture 0.73mmol) are suspended in the acetate (8mL) and at 100 ℃ and heated 17 hours down with intermediate 6 with every kind of aforesaid intermediate 8 of intermediate.This mixture is cooled to room temperature and under reduced pressure removes acetate.Be neutralized to pH～7 with resistates water-soluble (15mL) and with 7M NaOH solution.With EtOAc (30mL) extraction gained solution and separation organic layer.With salt water washing organic layer, use MgSO
4Drying and filtration.Concentrated filtrate and obtain title compound VII (tfa salt of 0.14g, 49%) by HPLC purifying crude product is white solid in a vacuum.
1H?NMR(500MHz，DMSO-d
6):1.85-1.95(m，2H)，2.00-2.10(m，2H)，3.08-3.18(m，2H)，3.46(s，3H)，3.55-3.65(m，4H)，3.85(s，3H)，4.27(t，J＝5.0Hz，2H)，6.86(d，J＝7.4Hz，1H)，7.01(d，J＝9.0Hz，2H)，7.15(s，1H)，7.46(d，J＝8.4Hz，1H)，7.58(d，J＝8.9Hz，2H)，7.83(s，1H)，9.85(br?s，1H)，10.04(br?s，1H)，10.32(br?s，1H)；MS(ESI+):m/z?468(M+H)
+。
Embodiment 14. (2-chloro-5-methyl-pyrimidine-4-yl)-(4-chloro-phenyl)-amine (intermediate 9)
With 2-chloro-5-methyl-pyrimidine-4-base amine (0.30g, 2.1mmol), 1-bromo-4-chloro-benzene (0.60g, 3.1mmol), Pd
2(dba)
3(95mg, 0.10mmol), Xantphos (0.12g, 0.20mmol) and cesium carbonate (1.3g, mixture 4.0mmol) be suspended in the diox (20mL) and under reflux state and ar gas environment in the heating 4 hours.This reaction mixture is cooled to room temperature and dilutes with DCM (20mL).Filter this mixture and concentrated filtrate in a vacuum.Obtain title intermediate 9 (0.15g, 28%) by fast silica gel chromatogram method purifying resistates (hexane is to the 30%EtOAc/ hexane), be faint yellow solid.MS(ESI+):m/z?254(M+H)
+。
Embodiment 15. N
4
-(4-chloro-phenyl)-5-methyl-N
2
-[4-(2-tetramethyleneimine-1-base-ethoxy
Base)-phenyl]-pyrimidine-2,4-diamines (compound VIII)
With above-mentioned intermediate 9 (0.15g, 0.60mmol) and 6 (0.20g, mixture 0.97mmol) are suspended in acetate (8mL) or and 100 ℃ of down heating 6 hours.This mixture is cooled to room temperature and under reduced pressure removes acetate.Be neutralized to pH～7 with resistates water-soluble (15mL) and with 7M NaOH solution.Filter the gained brown solid and further obtain title compound VIII (tfa salt of 38mg, 12%), be brown oil by the HPLC purifying.
1H?NMR(500MHz，DMSO-d
6):1.80-1.95(m，2H)，2.00-2.10(m，2H)，2.15(s，3H)，3.10-3.20(m，2H)，3.55-3.65(m，4H)，3.77(s，3H)，4.28(t，J＝5.0Hz，2H)，6.95(d，J＝9.0Hz，2H)，7.38(d，J＝8.9Hz，2H)，7.42(d，J＝8.9Hz，2H)，7.62(d，J＝8.8Hz，2H)，7.90(s，1H)，9.48(br?s，1H)，9.84(br?s，1H)，10.10(br?s，1H)；MS(ESI+):m/z?424(M+H)
+。
Embodiment 16. 2-(4-amino-phenoxy group)-ethanol (intermediate 10)
Give 2-(4-nitro-phenoxy group)-ethanol (2.1g, 12mmol) applying argon gas and add Pd/C (10%wt) then in the solution in MeOH (30mL).In indoor vacuum, this mixture is vacuumized and from the hydrogen air bag, fill hydrogen again.Repeat this circulation and this mixture was at room temperature stirred 2 hours.Inhomogeneous reaction mixture is filtered by C salt pad, with the MeOH washing and be concentrated in a vacuum and obtain title intermediate 10 (1.8g, 99%), be brown solid.MS(ESI+):m/z?154(M+H)
+。
Embodiment 17. 2-{4-[4-(4-chloro-3-methoxyl group-phenyl amino)-5-methyl-pyrimidine-2-
Base is amino]-phenoxy group }-ethanol (Compound I X)
With above-mentioned intermediate 7 (50mg, 0.17mmol), 10 (40mg, 0.26mmol), Pd
2(dba)
2(8mg, 0.01mmol), Xantphos (10mg, 0.02mmol) and cesium carbonate (0.13g, 0.40mmol) the suspension in the Zai diox (3mL) be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 15 minutes.After being cooled to room temperature, removing lid and filter the gained mixture and with the solid of DCM washing and filtering.Concentrated filtrate and obtain title compound IX (14mg, 21%) by fast silica gel chromatogram method purifying resistates (hexane is to EtOAc) is the light brown solid.
1H?NMR(500MHz，DMSO-d
6):2.10(s，3H)，3.69(t，J＝5.3Hz，2H)，3.75(s，3H)，3.92(t，J＝5.1Hz，2H)，4.83(t，J＝5.6Hz，1H)，6.78(d，J＝9.0Hz，2H)，7.29(d，J＝8.5Hz，1H)，7.43(dd，J＝8.6Hz，J＝2.2Hz，1H)，7.48(d，J＝2.3Hz，1H)，7.52(d，J＝9.0Hz，2H)，7.88(s，1H)，8.31(s，1H)，8.80(s，1H)；MS(ESI+):m/z?401(M+H)
+。
Embodiment 18. 5-methyl-N
2
-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-pyrimidine
-2,4-diamines (intermediate 11)
(0.13g, 0.87mmol) (0.30g, mixture 1.5mmol) are suspended in the acetate (8mL) and at 100 ℃ and heated 2 hours down with above-mentioned intermediate 6 with 2-chloro-5-methyl-pyrimidine-4-base amine.This mixture is cooled to room temperature and under reduced pressure removes acetate.Be neutralized to pH～7 with resistates water-soluble (15mL) and with 7M NaOH solution.Filter gained solid (30mg) and wash with ether.With EtOAc (30mL) extraction filtrate and separation organic layer.With salt water washing organic layer, use MgSO
4Drying and filtration.Concentrated filtrate and the solid of getting back (0.2g) merge itself and first solid and obtain title intermediate 11 (0.23g, 85%), are the light brown solid.
1H?NMR(500MHz，DMSO-d
6):1.65-1.70(m，4H)，1.89(s，3H)，2.74(t，J＝6.0Hz，2H)，3.98(t，J＝6.1Hz，2H)，6.30(s，2H)，6.78(d，J＝9.1Hz，2H)，7.62(d，J＝9.1Hz，2H)，7.64(s，1H)，8.50(s，1H)；MS(ESI+):m/z?314(M+H)
+。
Embodiment 19. 5-methyl-N
4
-phenyl-N
2
-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-benzene
Base]-pyrimidine-2,4-diamines (compounds X)
With above-mentioned intermediate 11 (25mg, 0.08mmol), bromobenzene (0.05mL, 0.50mmol), Pd
2(dba)
2(5mg, 0.006mmol), Xantphos (10mg, 0.02mmol) and cesium carbonate (70mg, 0.21mmol) the suspension in the Zai diox (3mL) be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 15 minutes.After being cooled to room temperature, removing lid and filter the gained mixture and with the solid of DCM washing and filtering.Concentrated filtrate and obtain title compound X (10mg, 32%) by fast silica gel chromatogram method purifying resistates (DCM-30% MeOH/DCM) is the light brown solid.
1H?NMR(500MHz，DMSO-d
6):1.65-1.72(m，4H)，2.10(s，3H)，2.48-2.58(m，4H)，2.75-2.82(m，2H)，4.00(t，J＝5.9Hz，2H)，6.77(d，J＝9.0Hz，2H)，7.04(t，J＝7.3Hz，1H)，7.32(t，J＝7.9Hz，2H)，7.54(d，J＝9.0Hz，2H)，7.71(d，J＝7.8Hz，2H)，7.84(s，1H)，8.20(s，1H)，8.76(s，1H)；MS(ESI+):m/z?390(M+H)
+。
Embodiment 20. (4-chloro-3-fluoro-phenyl)-(2-chloro-5-methyl-pyrimidine-4-yl)-amine (intermediate
12)
With 2-chloro-5-methyl-pyrimidine-4-base amine (0.50g, 3.5mmol), 4-bromo-1-chloro-2-fluoro-benzene (1.0g, 4.8mmol), Pd
2(dba)
3(0.16g, 0.17mmol), Xantphos (0.20g, 0.34mmol) and cesium carbonate (2.3g, mixture 7.0mmol) be suspended in diox (25mL) and under reflux state and ar gas environment in the heating 15 hours.This reaction mixture is cooled to room temperature and dilutes with DCM (30mL).Filter this mixture and concentrated filtrate in a vacuum.Obtain title intermediate 12 (0.75g, 80%) by fast silica gel chromatogram method purifying resistates (hexane is to the 40%EtOAc/ hexane), be pale solid.MS(ESI+):m/z?272(M+H)
+。
Embodiment 21. N
4
-(4-chloro-3-fluoro-phenyl)-5-methyl-N
2
-[4-(2-tetramethyleneimine-1-base-
Oxyethyl group)-phenyl]-pyrimidine-2,4-diamines (compounds X I)
With above-mentioned intermediate 12 (0.20g, 0.74mmol) and 6 (0.20g, mixture 0.97mmol) are suspended in the acetate (8mL) and 100 ℃ of heating 6 hours down.This mixture is cooled to room temperature and under reduced pressure removes acetate.Be neutralized to pH～7 with resistates water-soluble (15mL) and with 7M NaOH solution.With EtOAc (30mL) extraction gained solution and separation organic layer.With salt water washing organic layer, use MgSO
4Drying and filtration.Concentrated filtrate and obtain title compound XI (90mg, 28%) with fast silica gel chromatogram method purifying crude product (DCM-30% MeOH/DCM) is white solid in a vacuum.
1H?NMR(500MHz，DMSO-d
6):1.65-1.71(m，4H)，2.10(s，3H)，2.45-2.55(m，4H)，2.77(t，J＝6.0Hz，2H)，4.01(t，J＝6.0Hz，2H)，6.82(d，J＝9.0Hz，2H)，7.44(t，J＝8.8Hz，1H)，7.50(d，J＝9.0Hz，2H)，7.55(dd，J＝8.9Hz，J＝2.0Hz，1H)，7.91(s，1H)，8.07(dd，J＝12.5Hz，J＝2.0Hz，1H)，8.43(s，1H)，8.90(s，1H)；MS(ESI+):m/z?442(M+H)
+。
Embodiment 22. N
4
-(4-chloro-3-methoxyl group-phenyl)-5-methyl-N
2
-(4-morpholine-4-Ji Jia
Base-phenyl)-and pyrimidine-2,4-diamines (compounds X II)
With above-mentioned intermediate 7 (50mg, 0.17mmol), 4-morpholine-4-ylmethyl-phenyl amine (50mg, 0.26mmol), Pd
2(dba)
2(8mg, 0.009mmol), Xantphos (10mg, 0.02mmol) and cesium carbonate (0.13g, 0.40mmol) the suspension in the Zai diox (3mL) be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 15 minutes.After being cooled to room temperature, removing lid and filter the gained mixture and with the solid of DCM washing and filtering.Concentrated filtrate and obtain title compound XII (tfa salt of 40mg, 43%) by HPLC purifying resistates is faint yellow solid.
1H?NMR(500MHz，DMSO-d
6):2.16(s，3H)，3.05-3.15(m，2H)，3.10-3.20(m，2H)，3.60-3.70(m，2H)，3.90-4.00(m，2H)，4.28(s，2H)，4.01(t，J＝6.0Hz，2H)，7.25-7.35(m，3H)，7.35-7.41(m，2H)，7.65(d，J＝8.3Hz，2H)，7.98(s，1H)，9.10(br?s，1H)，9.86(br?s，1H)，9.95(br?s，1H)；MS(ESI+):m/z440(M+H)
+。
Embodiment 23. benzos [b] thiophene-5-base-(2-chloro-5-methyl-pyrimidine-4-yl)-amine (centre
Body 13)
With 2-chloro-5-methyl-pyrimidine-4-base amine (0.30g, 2.1mmol), 5-bromo-benzo [b] thiophene (0.6g, 2.8mmol), Pd
2(dba)
3(95mg, 0.10mmol), Xantphos (0.12g, 0.20mmol) and cesium carbonate (1.3g, mixture 4.0mmol) be suspended in the diox (25mL) and under reflux state and ar gas environment in the heating 3 hours.This reaction mixture is cooled to room temperature and dilutes with DCM (30mL).Filter this mixture and concentrated filtrate in a vacuum.Obtain title intermediate 13 (0.23g, 40%) by fast silica gel chromatogram method purifying resistates (hexane is to the 30%EtOAc/ hexane), be white solid.MS(ESI+):m/z?276(M+H)
+。
Embodiment 24. N
4
-benzo [b] thiophene-5-base-5-methyl-N
2
-[4-(2-tetramethyleneimine-1-base-
Oxyethyl group)-phenyl]-pyrimidine-2,4-diamines (compounds X III)
With above-mentioned intermediate 13 (0.23g, 0.83mmol) and 6 (0.35g, mixture 1.7mmol) are suspended in the acetate (8mL) and 100 ℃ of heating 1 day down.This mixture is cooled to room temperature and under reduced pressure removes acetate.Be neutralized to pH～7 with resistates water-soluble (15mL) and with 7M NaOH solution.With EtOAc (30mL) extraction gained solution and separation organic layer.With salt water washing organic layer, use MgSO
4Drying and filtration.Concentrated filtrate and obtain title compound XIII (0.13g, 35%) with fast silica gel chromatogram method purifying crude product (DCM-15% MeOH/DCM) is white solid in a vacuum.
1H?NMR(500MHz，DMSO-d
6):1.65-1.75(m，4H)，2.12(s，3H)，2.50-2.62(m，4H)，2.75-2.85(m，2H)，3.99(t，J＝5.9Hz，2H)，6.70(d，J＝9.0Hz，2H)，7.36(d，J＝5.4Hz，1H)，7.51(d，J＝9.1Hz，2H)，7.61(dd，J＝8.7Hz，J＝2.0Hz，1H)，7.74(d，J＝5.4Hz，1H)，7.85(d，J＝0.8Hz，1H)，7.92(d，J＝8.6Hz，1H)，8.29(d，J＝1.7Hz，1H)，8.34(s，1H)，8.76(s，1H)；MS(ESI+):m/z?446(M+H)
+。
Embodiment 25. benzos [b] thiene-3-yl--(2-chloro-5-methyl-pyrimidine-4-yl)-amine (centre
Body 14)
With 2-chloro-5-methyl-pyrimidine-4-base amine (0.30g, 2.1mmol), 3-bromo-benzo [b] thiophene (0.6g, 2.8mmol), Pd
2(dba)
3(95mg, 0.10mmol), Xantphos (0.12g, 0.20mmol) and cesium carbonate (1.3g, mixture 4.0mmol) be suspended in the diox (25mL) and under reflux state and ar gas environment in the heating 3 hours.This reaction mixture is cooled to room temperature and dilutes with DCM (30mL).Filter this mixture and concentrated filtrate in a vacuum.Obtain title intermediate 14 (65mg, 11%) by fast silica gel chromatogram method purifying resistates (hexane is to the 30%EtOAc/ hexane), be yellow solid.MS(ESI+):m/z?276(M+H)
+。
Embodiment 26. N
4
-benzo [b] thiene-3-yl--5-methyl-N
2
-[4-(2-tetramethyleneimine-1-base-
Oxyethyl group)-phenyl]-pyrimidine-2,4-diamines (compounds X IV)
With above-mentioned intermediate 14 (50mg, 0.18mmol) and 6 (0.10g, mixture 0.48mmol) are suspended in the acetate (8mL) and 100 ℃ of heating 15 hours down.This mixture is cooled to room temperature and under reduced pressure removes acetate.Be neutralized to pH～7 with resistates water-soluble (10mL) and with 7M NaOH solution.With EtOAc (20mL) extraction gained solution and separation organic layer.With salt water washing organic layer, use MgSO
4Drying and filtration.Concentrated filtrate and obtain title compound XIV (10mg, 13%) with fast silica gel chromatogram method purifying crude product (DCM-15% MeOH/DCM) is pale solid in a vacuum.
1H?NMR(500MHz，DMSO-d
6):1.70-1.80(m，4H)，2.19(s，3H)，2.65-2.80(m，4H)，2.85-3.00(m，2H)，3.98-4.03(m，2H)，6.63(d，J＝8.8Hz，2H)，7.37(d，J＝8.6Hz，2H)，7.38-7.45(m，2H)，7.79-7.83(m，1H)，7.87(s，1H)，7.90-8.03(m，1H)，8.33(s，1H)，8.78(s，1H)；MS(ESI+):m/z446(M+H)
+。
Embodiment 27. (2-chloro-5-methyl-pyrimidine-4-yl)-(3-chloro-phenyl)-amine (intermediate 15)
With 2-chloro-5-methyl-pyrimidine-4-base amine (0.30g, 2.1mmol), 1-bromo-3-chloro-benzene (0.60g, 3.1mmol), Pd
2(dba)
3(95mg, 0.10mmol), Xantphos (0.12g, 0.20mmol) and cesium carbonate (1.3g, mixture 4.0mmol) be suspended in the diox (20mL) and under reflux state and ar gas environment in the heating 4 hours.This reaction mixture is cooled to room temperature and dilutes with DCM (20mL).Filter this mixture and concentrated filtrate in a vacuum.Obtain title intermediate 15 (0.30g, 56%) by fast silica gel chromatogram method purifying resistates (hexane is to the 40%EtOAc/ hexane), be faint yellow solid.MS(ESI+):m/z?254(M+H)
+。
Embodiment 28. N
4
-(3-chloro-phenyl)-5-methyl-N
2
-[4-(2-tetramethyleneimine-1-base-ethoxy
Base)-phenyl]-pyrimidine-2,4-diamines (compounds X V)
With above-mentioned intermediate 15 (0.15g, 0.59mmol) and 6 (0.25g, mixture 1.2mmol) are suspended in the acetate (8mL) and 100 ℃ of heating 21 hours down.This mixture is cooled to room temperature and under reduced pressure removes acetate.Be neutralized to pH～7 with resistates water-soluble (15mL) and with 7M NaOH solution.With EtOAc (30mL) extraction gained solution and separation organic layer.With salt water washing organic layer, use MgSO
4Drying and filtration.Concentrated filtrate and obtain title compound XV (60mg, 24%) with fast silica gel chromatogram method purifying crude product (DCM-10% MeOH/DCM) is white solid in a vacuum.
1H?NMR(500MHz，DMSO-d
6):1.65-1.72(m，4H)，2.10(s，3H)，2.50-2.60(m，4H)，2.78-2.83(m，2H)，4.01(t，J＝5.9Hz，2H)，6.81(d，J＝9.1Hz，2H)，7.05-7.08(m，1H)，7.32(t，J＝8.1Hz，1H)，7.52(d，J＝9.0Hz，2H)，7.71(d，J＝8.3Hz，1H)，7.85(t，J＝2.1Hz，1H)，7.89(d，J＝0.7Hz，1H)，8.33(s，1H)，8.86(s，1H)；MS(ESI+):m/z?424(M+H)
+。
Embodiment 29. 3-bromo-N-methyl-benzamide (intermediate 16)
Vigorous stirring 3-bromo-Benzoyl chloride (2.93g, 13.3mmol, 1eq) solution in 30mL THF and with the methylamine of 2.0M in THF (15mL, 29.4mmol 2.2eq) handle.Observe white precipitate and should react stirring 20 minutes.Should react the washing of impouring ethyl acetate (100mL) and water (2 x 150mL) and salt solution (1 x 150mL) then.Go out organic phase and use dried over sodium sulfate from the aqueous phase sedimentation, filter and evaporation and obtain title intermediate 16, be white powder (2.29g, productive rate 82%).
Embodiment 30. 3-(2-chloro-5-methyl-pyrimidine-4-base is amino)-N-methyl-benzamide (in
Mesosome 17)
In exsiccant 50mL round-bottomed flask, merge 2-chloro-5-methyl-pyrimidine-4-base amine (0.3g, 2.09mmol, 1 equivalent), 3-bromo-N-methyl-benzamide (0.489g, 2.29mmol, 1.1 equivalents), cesium carbonate (2.04g, 6.27mmol, 3 equivalents), 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (0.242g, 0.418mmol, 0.2 equivalent) and three (dibenzalacetones), two palladiums (0.191g, 0.209mmol, 0.1 equivalent).The agent of Yong diox (20mL) diluting reaction, applying argon gas and assembling reflux exchanger.This reaction is heated to backflow 16 hours.Change this reaction over to centrifuge tube then, rotation sedimentation, decantation and evaporation.Dilute the gained yellow solid and it is adsorbed on the silica gel with DCM.Carry out chromatogram (50% in hexane ethyl acetate-100% ethyl acetate gradient) and obtain title intermediate 17, be pale yellow powder (0.25g, productive rate 43%).MS (ESI+): 277.01 (M+H), r.t.=1.92 minute.
Embodiment 31. N-methyl-3-{5-methyl-2-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-benzene
Base is amino]-pyrimidine-4-base is amino }-benzamide tfa salt (compounds X VI)
The above-mentioned intermediate 17 of merging in the 15ml microwave container (0.068g, 0.246mmol, 1eq), 4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl amine (0.061g, 0.296mmol, 1.2eq), cesium carbonate (0.241g, 0.74mmol, 3 equivalents), 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (0.029g, 0.05mmol, 0.2 equivalent) and three (dibenzalacetones), two palladiums (0.023g, 0.025mmol, 0.1 equivalent).Use microwave 15 minutes down with 7ml diox diluting reaction agent and at 160 ℃ then.Rotate the precipitation reaction container then, decantation and be evaporated to dried.Carry out the HPLC purifying and obtain the tfa salt (0.084g, 76%) of title product XVI.MS (ESI+): 447.20 (M+H), r.t.=1.53 minute.
1H?NMR(DMSO-d
6):δ1.87-1.91(m，2H)，2.02-2.06(m，2H)，2.16(s，3H)，2.79(d，J＝4.6Hz，3H)，3.11-3.15(m，2H)，3.57-3.61(m，5H)，4.23(t，J＝5.0Hz，3H)，6.84(d，J＝8.8Hz，2H)，7.34(d，J＝8.9Hz，2H)，7.47(t，J＝7.9Hz，1H)，7.68-7.70(m，2H)，7.93(s，1H)，8.00(s，1H)，8.46-8.47(m，1H)，9.80(bs，1H)，9.93(bs，1H)10.41(bs，1H)。
Embodiment 32. N
4
-(4-chloro-3-methoxyl group-phenyl)-5-methyl-N
2
-[4-(2-tetramethyleneimine-1-
Base-oxyethyl group)-phenyl]-pyrimidine-2,4-diamines tfa salt (compounds X VII)
The above-mentioned intermediate 7 of merging in the 15ml microwave container (0.083g, 0.293mmol, 1eq), 4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl amine (0.073g, 0.352mmol, 1.2eq), cesium carbonate (0.287g, 0.879mmol, 3 equivalents), 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (0.034g, 0.059mmol, 0.2 equivalent) and three (dibenzalacetones), two palladiums (0.027g, 0.029mmol, 0.1 equivalent).Use microwave 15 minutes down with 7ml diox diluting reaction agent and at 160 ℃ then.Rotate the precipitation reaction container then, decantation and be evaporated to dried.Carry out the HPLC purifying and obtain the tfa salt (0.1g, 75%) of title product XVII.MS (ESI+): 454.13 (M+H), r.t.=1.82 minute.
1H?NMR(DMSO-d
6):δ1.87-1.90(m，2H)，2.02-2.05(m，2H)，2.15(s，3H)，3.11-3.14(m，2H)，3.58-3.61(m，5H)，3.70(s，3H)，4.26(t，J＝5.0Hz，3H)，6.91(d，J＝8.9Hz，2H)，7.23(m，1H)，7.34-7.4(m，4H)，7.93(s，1H)，9.63(bs，1H)，9.96(bs，1H)10.40(bs，1H)。
Embodiment 33. N-(2-chloro-5-methyl-pyrimidine-4-yl)-N ', N '-dimethyl-benzene-1,3-
Diamines (intermediate 18)
In the 30ml microwave container, merge 2-chloro-5-methyl-pyrimidine-4-base amine (0.343g, 2.38mmol, 1 equivalent), (3-bromo-phenyl)-dimethyl-amine (0.524g, 2.62mmol, 1.1 equivalents), cesium carbonate (2.3g, 7.15mmol, 3 equivalents), 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (0.276g, 0.476mmol, 0.2 equivalent) and three (dibenzalacetones), two palladiums (0.218g, 0.238mmol, 0.1 equivalent).Use microwave 25 minutes down with 12ml diox diluting reaction agent and at 160 ℃ then.Rotate the precipitation reaction container then, decantation and be evaporated to dried.Dilute the gained solid and it is adsorbed on the silica gel with DCM.Carry out chromatogram (0% in DCM the methyl alcohol gradient of methyl alcohol-25% in DCM) and obtain title intermediate 18, be orange solids (0.184g, productive rate 29%).MS (ESI+): 263.02 (M+H), r.t.=1.72 minute.
Embodiment 34. N
4
-(3-dimethylamino-phenyl)-5-methyl-N
2
-[4-(2-tetramethyleneimine-1-
Base-oxyethyl group)-phenyl]-pyrimidine-2,4-diamines tfa salt (compounds X VIII)
The above-mentioned intermediate 18 of merging in the 15ml microwave container (0.092g, 0.35mmol, 1eq), 4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl amine (0.087g, 0.42mmol, 1.2eq), cesium carbonate (0.343g, 1.05mmol, 3 equivalents), 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (0.041g, 0.0702mmol, 0.2 equivalent) and three (dibenzalacetones), two palladiums (0.032g, 0.035mmol, 0.1 equivalent).Use microwave 15 minutes down with 7ml diox diluting reaction agent and at 160 ℃ then.Rotate the precipitation reaction container then, decantation and be evaporated to dried.Carry out the HPLC purifying and obtain the tfa salt (0.035g, 23%) of title compound XVIII.MS (ESI+): 433.21 (M+H), r.t.=1.52 minute.
1H?NMR(DMSO-d
6):δ?1.87-1.90(m，2H)，2.03-2.06(m，2H)，2.15(s，3H)，2.87(s，6H)，3.12-3.15(m，2H)，3.57-3.60(m，4H)，3.70(s，3H)，4.25(t，J＝5.0Hz，3H)，6.34(dd，J＝8.4Hz，J＝2.3Hz，1H)，6.82-6.90(m，4H)，7.20(t，J＝8.0Hz，1H)，7.39(d，J＝9.1Hz，2H)，7.85(s，1H)，9.63(bs，1H)，9.90(bs，1H)10.39(bs，1H)。
Embodiment 35. (2-chloro-5-methyl-pyrimidine-4-yl)-(3,4-two chloro-phenyl)-amine (intermediate
19)
In the 30ml microwave container, merge 2-chloro-5-methyl-pyrimidine-4-base amine (0.408g, 2.83mmol, 1 equivalent), 4-bromo-1,2-two chloro-benzene (0.704g, 3.12mmol, 1.1 equivalent), cesium carbonate (2.8g, 8.49mmol, 3 equivalents), 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (0.328g, 0.57mmol, 0.2 equivalent) and three (dibenzalacetone) two palladium (0.26g, 0.283mmol, 0.1 equivalent).Use microwave 25 minutes down with 12ml diox diluting reaction agent and at 160 ℃ then.Rotate the precipitation reaction container then, decantation and be evaporated to dried.Dilute the gained solid and it is adsorbed on the silica gel with DCM.Carry out chromatogram (15% in hexane the ethyl acetate gradient of ethyl acetate-80% in hexane) and obtain title intermediate 19, be pale yellow powder (0.366g, 45% productive rate).MS (ESI+): 287.97 (M+H), r.t.=3.12 minute
Embodiment 36. N
4
-(3,4-two chloro-phenyl)-5-methyl-N
2
-[4-(2-tetramethyleneimine-1-base-second
The oxygen base)-phenyl]-pyrimidine-2,4-diamines tfa salt (compounds X IX)
The above-mentioned intermediate 19 of merging in the 15ml microwave container (0.09g, 0.313mmol, 1eq), 4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl amine (0.078g, 0.376mmol, 1.2eq), cesium carbonate (0.307g, 0.941mmol, 3 equivalents), 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (0.036g, 0.063mmol, 0.2 equivalent) and three (dibenzalacetones), two palladiums (0.029g, 0.0314mmol, 0.1 equivalent).Use microwave 15 minutes down with 7ml diox diluting reaction agent and at 160 ℃ then.Rotate the precipitation reaction container then, decantation and be evaporated to dried.Carry out the HPLC purifying and obtain the tfa salt (0.056g, 39%) of title compound XIX.MS (ESI+): 458.1 (M+H), r.t.=1.93 minute.
1H?NMR(DMSO-d
6):δ?1.87-1.91(m，2H)，2.03-2.06(m，2H)，2.14(s，3H)，3.12-3.15(m，3H)，3.57-3.60(m，4H)，4.26(t，J＝5.0Hz，2H)，6.97(d，J＝9.0Hz，1H)，7.40(d，J＝9Hz，2H)，7.60(s，2H)，7.97(d，J＝15.35Hz，2H)，9.46(bs，1H)，9.89(bs，1H)10.17(bs，1H)。
Embodiment 37. 4-{3-[4-(4-chloro-3-methoxyl group-phenyl amino)-5-methyl-pyrimidine-2-
Base is amino]-benzyl }-piperazine-1-t-butyl formate (intermediate 20)
Merging (4-chloro-3-methoxyl group-phenyl)-(2-chloro-5-methyl-pyrimidine-4-yl)-amine in the 15ml microwave container (0.092g, 0.325mmol, 1eq), 4-(3-amino-benzyl)-piperazine-1-t-butyl formate (0.114g, 0.39mmol, 1.2eq), cesium carbonate (0.318g, 0.975mmol, 3 equivalents), 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (0.038g, 0.065mmol, 0.2 equivalent) and three (dibenzalacetones), two palladiums (0.03g, 0.0325mmol, 0.1 equivalent).Use microwave irradiation 15 minutes down with 7ml diox diluting reaction agent and at 160 ℃ then.Rotate the precipitation reaction container then, decantation and be evaporated to dried.Carry out the HPLC purifying and obtain the tfa salt (0.075g, 43%) of intermediate 20.MS (ESI+): 539.32 (M+H), r.t.=2.09 minute.
Embodiment 38. N
4
-(4-chloro-3-methoxyl group-phenyl)-5-methyl-N
2
-(3-piperazine-1-Ji Jia
Base-phenyl)-and pyrimidine-2,4-diamines tfa salt (compounds X X)
Handle above-mentioned intermediate 20 (0.075g, 0.14mmol, 1eq) stirred solution in DCM (6ml) with TFA (2ml).After 2 hours, evaporation reaction solvent and the gained resistates ground with ether and obtain title compound XX is white water absorbability solid, tfa salt (0.05g, 82%).MS (ESI+): 439.13 (M+H), r.t.=1.67 minute.
1H?NMR(DMSO-d
6):δ?2.17(s，3H)，2.89(bs，4H)，3.2(bs，4H)，3.68(s，3H)，3.82(bs，3H)，7.16-7.20(m，2H)，7.28(t，J-7.7Hz，1H)，7.33(d，J＝2.3Hz，1H)，7.39(s，1H)，7.42(d，J＝8.5Hz，1H)，7.49-7.51(m，1H)，7.98(s，1H)，8.87(bs，1H)，9.79(bs，1H)10.57(bs，1H)。
Embodiment 39. 2-(4-(2-(tetramethyleneimine-1-yl) oxyethyl group) phenyl amino)-4-aminopyrimidine
-5-nitrile (intermediate 21)
To 2,4-di-amino-pyrimidine-5-nitrile (135mg, 1.00mmol) 1, add in the solution in the 4-diox (20mL) 1-(2-(4-bromine phenoxy group) ethyl) tetramethyleneimine (270mg, 1.0mmol), Cs
2CO
3(1.3g, 4.0mmol), Pd
2(dba)
3(92mg, 0.1mmol) with 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (Xant Phos, 174mg, 0.3mmol).This mixture was heated 4 hours under reflux state and in the Ar environment.Filter out solid and with salt solution (1 x 100mL) wash filtrate.Separate organic solution and drying (Na
2SO
4).Remove and desolvate, pass through solid collected by filtration to obtaining 5mL and adding hexane (50mL).Obtain title intermediate 21 (32mg, 10%) by HPLC purifying crude product.
Embodiment 40. 4-(2,4-two chloro-5-p-methoxy-phenyl amino)-2-(4-(2-(tetramethyleneimine-1-
Base) pyrimidine-5-nitrile (compounds X XI) phenyl-amino oxyethyl group))
To above-mentioned intermediate 21 (32mg 0.1mmol) 1, adds 1-bromo-2 in the solution in the 4-diox (10mL), 4-two chloro-5-anisoles (28mg, 0.11mmol), Cs
2CO
3(97mg, 0.3mmol), Pd
2(dba)
3(7mg, 0.0074mmol) with 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (Xant Phos, 13mg, 0.022mmol).This mixture was heated 4 hours under reflux state and in the Ar environment.Filter out solid and with salt solution (1 x 50mL) wash filtrate.Separate organic solution and drying (Na
2SO
4).Remove in a vacuum and desolvate.By chromatography purification crude product (SiO
2/ CH
2Cl
2, CH then
2Cl
2: MeOH:NH
3.H
2O=100:10:1) and obtain title compound XXI (35mg, 67%).
1H?NMR(500MHz，DMSO-d
6):1.88-1.90(m，2H)；2.00-2.03(m，2H)；3.07-3.11(m，2H)；3.54-3.56(m，4H)；3.81(s，3H)；4.25(br，2H)；6.68(br，2H)；7.32(br，2H)；7.33(s，1H)；7.75(s，1H)；8.50(s，1H)；9.73(br，1H)；9.94(br，1H)；10.60(br，1H)。MS(EI):499.0。
Embodiment 41. 2-(3-(2-(tetramethyleneimine-1-yl) oxyethyl group) phenyl amino)-4-aminopyrimidine
-5-nitrile (intermediate 22)
To 2,4-di-amino-pyrimidine-5-nitrile (145mg, 1.07mmol) 1, add in the solution in the 4-diox (20mL) 1-(2-(3-bromine phenoxy group) ethyl) tetramethyleneimine (290mg, 1.07mmol), Cs
2CO
3(1.43g, 4.4mmol), Pd
2(dba)
3(92mg, 0.1mmol) with 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (Xant Phos, 174mg, 0.3mmol).This mixture was heated 4 hours under reflux state and in the Ar environment.Filter out solid and with salt solution (1 x 100mL) wash filtrate.Separate organic solution and drying (Na
2SO
4).Remove and desolvate, pass through solid collected by filtration to obtaining 5mL and adding hexane (50mL).By HPLC purifying crude product and obtain title intermediate 22 (55mg, 16%).
Embodiment 42. 4-(2,4-two chloro-5-p-methoxy-phenyl amino)-2-(3-(2-(tetramethyleneimine-1-
Base) pyrimidine-5-nitrile (compounds X XII) phenyl-amino oxyethyl group))
To above-mentioned intermediate 22 (50mg 0.15mmol) 1, adds 1-bromo-2 in the solution in the 4-diox (10mL), 4-two chloro-5-anisoles (44mg, 0.17mmol), Cs
2CO
3(200mg, 0.62mmol), Pd
2(dba)
3(14mg, 0.015mmol) with 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (Xant Phos, 27mg, 0.05mmol).This mixture was heated 4 hours under reflux state and in the Ar environment.Filter out solid and with salt solution (1 x 50mL) wash filtrate.Separate organic solution and drying (Na
2SO
4).Remove in a vacuum and desolvate.By HPLC purifying crude product and obtain title compound XXII (6mg, 8%).
1H?NMR(500MHz，DMSO-d
6):1.87-1.89(m，2H)；1.90-2.03(m，2H)；3.04-3.08(m，2H)；3.52-3.56(m，4H)；3.80(s，3H)；4.23(br，2H)；6.62(d，J＝6.4Hz，2H)；6.97(br，1H)；7.14(br，2H)；7.34(s，1H)；7.74(s，1H)；8.54(s，1H)；9.70(br，1H)；9.95(br，1H)；10.83(br，1H)。MS(EI):499.0。
Embodiment 43. 2-chloro-N-(2,4-two chloro-5-p-methoxy-phenyls)-5-methylpyrimidine-4-amine
(intermediate 23)
To 2-chloro-5-methylpyrimidine-4-amine (44.8mg 0.31mmol) 1, adds 1-bromo-2 in the solution in the 4-diox (20mL), 4-two chloro-5-anisoles (96mg, 0.37mmol), Cs
2CO
3(408mg, 1.25mmol), Pd
2(dba)
3(37mg, 0.04mmol) with 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (Xant Phos, 70mg, 0.12mmol).This mixture was heated 4 hours under reflux state and in the Ar environment.Filter out solid and with salt solution (1 x 100mL) wash filtrate.Separate organic solution and drying (Na
2SO
4).Remove in a vacuum and desolvate.Be not used for next step reaction with crude product is purified.
Embodiment 44. N
2
-(3-(2-(tetramethyleneimine-1-yl) oxyethyl group) phenyl)-N
-(2, the 4-dichloro
-5-p-methoxy-phenyl)-and 5-methylpyrimidine-2,4-diamines (compounds X XIII)
To above-mentioned intermediate 23 1, add in the solution in the 4-diox (10mL) 3-(2-(tetramethyleneimine-1-yl) oxyethyl group) aniline (77.3mg, 0.38mmol), Cs
2CO
3(488mg, 1.25mmol), Pd
2(dba)
3(28mg, 0.03mmol) with 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (Xant Phos, 53mg, 0.09mmol).This mixture was heated 4 hours under reflux state and in the Ar environment.Filter out solid and with salt solution (1 x 50mL) wash filtrate.Separate organic solution and drying (Na
2SO
4).Remove in a vacuum and desolvate.By the HPLC purifying with crude product and obtain title compound XXIII (25mg, 15%).
1H?NMR(500MHz，DMSO-d
6):1.87-1.89(m，2H)；1.90-2.03(m，2H)；2.18(s，3H)；3.04-3.08(m，2H)；3.52-3.56(m，4H)；3.80(s，3H)；4.24(t，J＝5.0Hz，2H)；6.71(d，J＝7.65Hz，1H)；6.91(s，1H)；6.96(d，J＝8.5Hz，1H)；7.02(t，J＝8.2Hz，1H)；7.37(s，1H)；7.83(s，1H)；8.02(s，1H)；10.09(br，1H)；10.66(br，1H)；10.82(br，1H)。MS(EI):488.2。
Embodiment 45. 2-chloro-N-(3-p-methoxy-phenyl)-5-methylpyrimidine-4-amine (intermediate 24)
To 2-chloro-5-methylpyrimidine-4-amine (320mg, 2.23mmol) 1, add in the solution in the 4-diox (40mL) 1-bromo-3-anisole (458.5mg, 2.45mmol), Cs
2CO
3(2.9g, 8.9mmol), Pd
2(dba)
3(201mg, 0.22mmol) with 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (Xant Phos, 382mg, 0.66mmol).This mixture was heated 4 hours under reflux state and in the Ar environment.Filter out solid and with salt solution (1 x 100mL) wash filtrate.Separate organic solution and drying (Na
2SO
4).Remove and desolvate, pass through solid collected by filtration to obtaining 5mL and adding hexane (100mL).Crude product title intermediate 24 (500mg, 90%) is used for next step reaction without being further purified.
Embodiment 46. N
2
-(4-(2-(tetramethyleneimine-1-yl) oxyethyl group) phenyl)-N
4
-(3-anisole
Base)-and 5-methyl-pyrimidine-2,4-diamines (compounds X XIV)
To above-mentioned intermediate 24 (240mg, 0.96mmol) 1, add in the solution in the 4-diox (20mL) 4-(2-(tetramethyleneimine-1-yl) oxyethyl group) aniline (200mg, 0.96mmol), Cs
2CO
3(1.3mg, 4.0mmol), Pd
2(dba)
3(82mg, 0.09mmol) with 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (Xant Phos, 156mg, 0.27mmol).This mixture was heated 4 hours under reflux state and in the Ar environment.Filter out solid and with salt solution (1x50mL) wash filtrate.Separate organic solution and drying (Na
2SO
4).Remove in a vacuum and desolvate.By the HPLC purifying with crude product and obtain title compound XXIV (85mg, 20%).
1H?NMR(500MHz，DMSO-d
6):1.89-1.91(m，2H)；1.98-2.05(m，2H)；2.16(s，3H)；3.07-3.12(m，2H)；3.52-3.56(m，4H)；3.73(s，3H)；4.33(t，J＝4.5Hz，2H)；6.83-6.85(m，1H)；6.91(d，J＝8.8Hz，2H)；7.17(s，1H)；7.34(d，J＝8.8Hz，2H)；7.41(t，J＝7.7Hz，1H)；7.56(d，J＝7.7Hz，1H)；7.89(s，1H)；9.75(s，1H)；10.51(s，1H)；10.96(br，1H)。MS(EI):420.2。
Embodiment 47. 3-(2-(4-(2-(tetramethyleneimine-1-yl) oxyethyl group) phenyl amino)-5-methyl
Pyrimidine-4-base is amino)-phenol (compounds X XV)
(50mg is 0.1mmol) at anhydrous CH to above-mentioned compounds X XIV
2Cl
2Add 1.0M in the solution (10mL) at CH
2Cl
2In BBr
3(0.3mL, 0.3mmol).At room temperature this mixture was stirred 3 hours.Add saturated NaHCO
3(20mL) and separate organic layer.Use CH
2Cl
2(3 x 10mL) aqueous phase extracted.Dry organic solution (the Na that merges
2SO
4).By the HPLC purified product and obtain title compound XXV (17mg, 35%), be yellow solid.
1HNMR(500MHz，DMSO-d
6):1.89(br，2H)；2.00(br，2H)；2.14(s，3H)；3.09(br，2H)；3.42(br，4H)；4.33(br，2H)；6.72(d，J＝7.1Hz，1H)；6.91(d，J＝8.4Hz，2H)；6.96(d，J＝7.6Hz，1H)；7.00(s，1H)；7.18(t，J＝8.0Hz，1H)；7.38(d，J＝8.6Hz，2H)；7.88(s，1H)；9.70(s，1H)；9.74(s，1H)；10.55(s，1H)；11.09(br，1H)。MS(EI):406.2。
Embodiment 48. 2-chloro-5-methyl-N-(3-nitrophenyl) pyrimidine-4-amine (intermediate 25)
To 2-chloro-5-methylpyrimidine-4-amine (232mg, 1.61mmol) 1, add in the solution in the 4-diox (40mL) 1-bromo-3-oil of mirbane (359mg, 1.78mmol), Cs
2CO
3(2.1g, 6.4mmol), Pd
2(dba)
3(146mg, 0.16mmol) with 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (Xant Phos, 278mg, 0.48mmol).This mixture was heated 4 hours under reflux state and in the Ar environment.Filter out solid and with salt solution (1 x 100mL) wash filtrate.Separate organic solution and drying (Na
2SO
4).Remove and desolvate, pass through solid collected by filtration to obtaining 5mL and adding hexane (100mL).Crude product title intermediate 25 is used for next step reaction without being further purified.
Embodiment 49. N
2
-(4-(2-(tetramethyleneimine-1-yl) oxyethyl group) phenyl)-5-methyl-N
4
-(3-
Nitrophenyl) pyrimidine-2,4-diamines (compounds X XVI)
To above-mentioned intermediate 25 1, add in the solution in the 4-diox (40mL) 4-(2-(tetramethyleneimine-1-yl) oxyethyl group) aniline (367mg, 1.78mmol), Cs
2CO
3(2.1g, 6.4mmol), Pd
2(dba)
3(146mg, 0.16mmol) with 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (Xant Phos, 218mg, 0.48mmol).This mixture was heated 4 hours under reflux state and in the Ar environment.Filter out solid and with salt solution (1 x 50mL) wash filtrate.Separate organic solution and drying (Na
2SO
4).Remove in a vacuum and desolvate.By the HPLC purifying with crude product and obtain title compound XXVI (51mg, 7%).
1H?NMR(500MHz，DMSO-d
6):1.89-1.92(m，2H)；1.98-2.05(m，2H)；2.21(s，3H)；3.10-3.12(m，2H)；3.52-3.57(m，4H)；4.33(t，J＝4.8Hz，2H)；6.90(d，J＝8.9Hz，2H)；7.32(d，J＝8.9Hz，2H)；7.67(t，J＝8.2Hz，1H)；7.99(s，1H)；7.56(dd，J＝8.4Hz，J＝1.8Hz，1H)；8.09(d，J＝7.4Hz，1H)；8.45(s，1H)；10.14(s，1H)；10.60(s，1H)；11.17(br，1H)。MS(EI):435.2。
Embodiment 50. 4-(2-chloro-5-methylpyrimidine-4-base is amino)-2-benzyl chloride nitrile (intermediate 26)
To 2-chloro-5-methylpyrimidine-4-amine (144mg, 1.0mmol) 1, add in the solution in the 4-diox (20mL) 4-bromo-2-benzyl chloride nitrile (217mg, 1.0mmol), Cs
2CO
3(1.3g, 4.0mmol), Pd
2(dba)
3(91mg, 0.1mmol) with 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (Xant Phos, 173mg, 0.3mmol).This mixture was heated 4 hours under reflux state and in the Ar environment.Filter out solid and with salt solution (1 x 100mL) wash filtrate.Separate organic solution and drying (Na
2SO
4).Remove and desolvate, pass through solid collected by filtration to obtaining 5mL and adding hexane (100mL).Crude product title intermediate 26 is used for next step reaction without being further purified.
Embodiment 51. 4-(2-(4-(2-(tetramethyleneimine-1-yl) oxyethyl group) phenyl amino)-5-methyl
Pyrimidine-4-base is amino)-2-benzyl chloride nitrile (compounds X XVII)
To above-mentioned intermediate 26 (140mg, 0.5mmol) 1, add in the solution in the 4-diox (20mL) 4-(2-(tetramethyleneimine-1-yl) oxyethyl group) aniline (113mg, 0.55mmol), Cs
2CO
3(660mg, 2.0mmol), Pd
2(dba)
3(46mg, 0.05mmol) with 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (Xant Phos, 87mg, 0.15mmol).This mixture was heated 4 hours under reflux state and in the Ar environment.Filter out solid and with salt solution (1 x 50mL) wash filtrate.Separate organic solution and drying (Na
2SO
4).Remove in a vacuum and desolvate.With crude product and obtain title compound XXVII (11.5mg, 5%), be yellow solid by the HPLC purifying.
1H?NMR(500MHz，DMSO-d
6):1.89-1.92(m，2H)；1.98-2.05(m，2H)；2.20(s，3H)；3.08-3.13(m，2H)；3.56-3.59(m，4H)；4.36(t，J＝4.9Hz，2H)；7.03(d，J＝9.0Hz，2H)；7.40(d，J＝9.0Hz，2H)；7.87(br，1H)；7.92(d，J＝8.6Hz，1H)；8.03(s，1H)；8.16(s，1H)；9.82(br，1H)；10.37(br，1H)；10.90(br，1H)。MS(EI):449.1。
Embodiment 52. N
2
-(4-(2-(tetramethyleneimine-1-yl) oxyethyl group) phenyl)-5-methyl-N
4
-to first
Phenyl pyrimidine-2,4-diamines (compounds X XVIII)
To above-mentioned intermediate 11 (50mg, 0.16mmol) 1, add in the solution in the 4-diox (20mL) 1-bromo-4-methylbenzene (28mg, 0.16mmol), Cs
2CO
3(210mg, 0.64mmol), Pd
2(dba)
3(10mg, 0.01mmol) with 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (Xant Phos, 18mg, 0.03mmol).This mixture was heated 4 hours under reflux state and in the Ar environment.Filter out solid.Remove in a vacuum and desolvate.With crude product and obtain title compound XXVIII (15.7mg, 6%), be yellow solid by the HPLC purifying.
1H?NMR(500MHz，DMSO-d
6):1.85-1.89(m，2H)；1.96-2.01(m，2H)；2.12(s，3H)；2.31(s，3H)；3.04-3.08(m，2H)；3.51-3.55(m，4H)；4.32(br，2H)；6.89(br，2H)；7.18(br，2H)；7.31(br，2H)；7.41(br，2H)；7.84(s，1H)；9.71(s，1H)；10.46(s，1H)；11.13(br，1H)。MS(EI):404.2。
Embodiment 53. N
2
-(4-(2-(tetramethyleneimine-1-yl) oxyethyl group) phenyl)-N
4
-(4-chloro-3-first
The base phenyl)-and 5-methylpyrimidine-2,4-diamines (compounds X XIX)
To above-mentioned intermediate 11 (80mg, 0.25mmol) 1, add in the solution in the 4-diox (20mL) 4-bromo-1-chloro-2-methylbenzene (63mg, 0.30mmol), Cs
2CO
3(326mg, 1.0mmol), Pd
2(dba)
3(18mg, 0.02mmol) with 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (Xant Phos, 36mg, 0.06mmol).This mixture was heated 4 hours under reflux state and in the Ar environment.Filter out solid.Remove in a vacuum and desolvate.With crude product and obtain title compound XXIX (17.5mg, 15%), be yellow solid by the HPLC purifying.
1H?NMR(500MHz，DMSO-d
6):1.85-1.89(m，2H)；1.96-2.01(m，2H)；2.12(s，3H)；2.25(s，3H)；3.04-3.08(m，2H)；3.51-3.55(m，4H)；4.32(br，2H)；6.91(br，2H)；7.04(br，1H)；7.31(br，1H)；7.41(br，2H)；7.58(s，1H)；7.89(br，1H)；9.75(s，1H)；10.54(s，1H)；11.13(br，1H)。MS(EI):438.1。
Embodiment 54. N-(4-(2-(tetramethyleneimine-1-yl) oxyethyl group) phenyl)-4-benzyl-5-methyl
Pyrimidine-2-amine (compounds X XX)
To 4-benzyl-2-chloropyrimide (286mg, 1.4mmol) 1, add in the solution in the 4-diox (20mL) 4-(2-(tetramethyleneimine-1-yl) oxyethyl group) aniline (288mg, 1.4mmol), Cs
2CO
3(1.82g, 5.6mmol), Pd
2(dba)
3(92mg, 0.1mmol) with 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (Xant Phos, 173mg, 0.3mmol).This mixture was heated 4 hours under reflux state and in the Ar environment.Filter out solid.Remove in a vacuum and desolvate.With crude product and obtain title compound XXX (42mg, 10%), be yellow solid by the HPLC purifying.
1H?NMR(500MHz，DMSO-d
6):1.89(br，2H)；2.00(br，2H)；3.09(br，2H)；3.54(br，4H)；4.31(br，2H)；6.71(d，J＝5.0Hz，1H)；6.93(d，J＝8.8Hz，2H)；7.24(m，1H)；7.32(m，4H)；7.62(d，J＝8.8Hz，2H)；8.32(d，J＝5.0Hz，1H)；9.66(s，1H)；10.92(br，1H)。MS(EI):375.2。
Embodiment 55. 4-((1H-indoles-4-yl) methyl)-N-(4-(2-(tetramethyleneimine-1-yl) ethoxy
Base) phenyl)-5-methylpyrimidine-2-amine (compounds X XXI)
To above-mentioned intermediate 11 (460mg, 1.46mmol) 1, add in the solution in the 4-diox (20mL) 4-bromo-1H-indoles (288mg, 1.46mmol), Cs
2CO
3(1.95g, 6.0mmol), Pd
2(dba)
3(128mg, 0.14mmol) with 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (Xant Phos, 243mg, 0.42mmol).With this mixture under reflux state and the Ar environment in heated overnight.Filter out solid.Remove in a vacuum and desolvate.By HPLC purifying crude product and obtain title compound XXXI (66mg, 10%), be yellow solid.
1H?NMR(500MHz，DMSO-d
6):1.87(br，2H)；1.98-2.05(m，2H)；2.21(s，3H)；3.15(br，2H)；3.52(br，2H)；3.69(br，2H)；4.24(br，2H)；6.33(s，1H)；6.60(br，2H)；6.82(br，1H)；6.92(br，1H)；7.02(br，2H)；7.16(br，1H)；7.26(br，1H)；7.43(m，1H)；7.88(m，1H)；10.11(s，1H)；11.40(s，1H)。MS(EI):429.1。
Embodiment 56. 2-chloro-5-methyl-N-(naphthalene-1-yl) pyrimidines-4-amine (intermediate 27)
To 2-chloro-5-methylpyrimidine-4-amine (144mg, 1.0mmol) 1, add in the solution in the 4-diox (40mL) the 1-bromonaphthalene (227mg, 1.1mmol), Cs
2CO
3(1.3g, 4.0mmol), Pd
2(dba)
3(91mg, 0.1mmol) with 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (Xant Phos, 183mg, 0.3mmol).This mixture was heated 4 hours under reflux state and in the Ar environment.Filter out solid and with salt solution (1 x 100mL) wash filtrate.Separate organic solution and drying (Na
2SO
4).Remove and desolvate, pass through solid collected by filtration to obtaining 5mL and adding hexane (100mL).Crude product title intermediate 27 is used for next step reaction without being further purified.
Embodiment 57. N-(4-(2-(tetramethyleneimine-1-yl) oxyethyl group) phenyl)-5-methyl-4-(naphthalene
-1-yl) pyrimidine-2-amine (compounds X XXII)
To above-mentioned intermediate 27 (235mg, 0.87mmol) 1, add in the solution in the 4-diox (20mL) 4-(2-(tetramethyleneimine-1-yl) oxyethyl group) aniline (183mg, 0.87mmol), Cs
2CO
3(1.3g, 4.0mmol), Pd
2(dba)
3(46mg, 0.05mmol) with 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (Xant Phos, 87mg, 0.15mmol).This mixture was heated 4 hours under reflux state and in the Ar environment.Filter out solid and with salt solution (1 x 50mL) wash filtrate.Separate organic solution and drying (Na
2SO
4).Remove in a vacuum and desolvate.With crude product and obtain title compound XXXII (89mg, 21%), be yellow solid by the HPLC purifying.
1H?NMR(500MHz，DMSO-d
6):1.88-1.90(m，2H)；1.97-2.03(m，2H)；2.30(s，3H)；3.03-3.08(m，2H)；3.50-3.53(m，4H)；4.21(t，J＝4.9Hz，2H)；6.50(d，J＝7.2Hz，2H)；6.82(d，J＝8.6Hz，2H)；7.54(d，J＝7.8Hz，2H)；7.57-7.61(m，1H)；7.63(t，J＝7.4Hz，1H)；7.89(d，J＝8.3Hz，2H)；7.95(s，1H)；8.02(d，J＝8.3Hz，1H)；8.08(d，J＝7.7Hz，1H)；10.37(s，1H)；10.43(s，1H)；10.93(br，1H)。MS(EI):440.1。
Embodiment 58. 1-(2-chloro-5-methylpyrimidine-4-yl) isoquinoline 99.9 (intermediate 28)
To 2-chloro-5-methylpyrimidine-4-amine (144mg, 1.0mmol) 1, add in the solution in the 4-diox (40mL) 1-chlorine isoquinoline 99.9 (164mg, 1.0mmol), Cs
2CO
3(1.3g, 4.0mmol), Pd
2(dba)
3(91mg, 0.1mmol) with 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (Xant Phos, 183mg, 0.3mmol).This mixture was heated 4 hours under reflux state and in the Ar environment.Filter out solid and with salt solution (1 x 100mL) wash filtrate.Separate organic solution and drying (Na
2SO
4).Remove and desolvate, pass through solid collected by filtration to obtaining 5mL and adding hexane (100mL).Crude product title intermediate 28 is used for next step reaction without being further purified.
Embodiment 59. N-(4-(2-(tetramethyleneimine-1-yl) oxyethyl group) phenyl)-4-(isoquinoline 99.9-1-
Base)-5-methylpyrimidine-2-amine (compounds X XXIII)
To above-mentioned intermediate 28 (90mg, 0.33mmol) 1, add in the solution in the 4-diox (20mL) 4-(2-(tetramethyleneimine-1-yl) oxyethyl group) aniline (76mg, 0.37mmol), Cs
2CO
3(391mg, 1.2mmol), Pd
2(dba)
3(28mg, 0.03mmol) with 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (Xant Phos, 52mg, 0.09mmol).This mixture was heated 4 hours under reflux state and in the Ar environment.Filter out solid and with salt solution (1 x 50mL) wash filtrate.Separate organic solution and drying (Na
2SO
4).Remove in a vacuum and desolvate.With crude product and obtain title compound XXXIII (21mg, 15%), be yellow solid by the HPLC purifying.
1H?NMR(500MHz，DMSO-d
6):1.64-1.70(m，6H)；2.23(s，3H)；2.78(t，J＝5.9Hz，2H)；4.04(t，J＝5.9Hz，2H)；6.38(d，J＝7.2Hz，1H)；6.93(d，J＝9.0Hz，2H)；6.97(d，J＝7.2Hz，1H)；7.45(br，1H)；7.57(d，J＝8.8Hz，1H)；7.58-7.62(m，1H)；7.70-7.78(m，2H)；8.04(s，1H)；8.75(d，J＝8.1Hz，1H)；9.06(s，1H)；9.19(s，1H)。MS(EI):441.2。
Embodiment 60. N
2
-(4-(2-(tetramethyleneimine-1-yl) oxyethyl group) phenyl)-N
4
-(3-(fluoroform
Base) phenyl)-and 5-methylpyrimidine-2,4-diamines (compounds X XXIV)
With 2-chloro-5-methyl-pyrimidine-4-base amine (143mg, 1.0mmol), 1-bromo-3-(trifluoromethyl) benzene (225mg, 1.0mmol), Pd
2(dba)
3(9.0mg, 0.01mmol), Xantphos (12mg, 0.02mmol) and cesium carbonate (650mg, mixture 2.0mmol) be suspended in the diox (15mL) and under reflux state and ar gas environment in the heating 15 hours.This reaction mixture is cooled to room temperature and dilutes with DCM (30mL).Filter this mixture and concentrated filtrate in a vacuum.Use HPLC purifying resistates and obtain N
4-(3-(trifluoromethyl) phenyl)-5-methylpyrimidine-2, the 4-diamines is pale solid (192mg, 67%).MS(ESI+):m/z?288(M+H)
+。With N
4-(3-(trifluoromethyl) phenyl)-5-methylpyrimidine-2,4-diamines (28.7mg, 0.1mmol) and 4-(2-(tetramethyleneimine-1-yl) oxyethyl group) aniline (22mg, mixture 0.12mmol) are dissolved in acetate (5mL) and heated 10 minutes down and in the microwave at 150 ℃.This mixture is cooled to room temperature and under reduced pressure removes acetate.Obtain title compound XXXIV by HPLC purifying resistates, be brown solid (16mg, 35%).
1H?NMR(500MHz，DMSO-d
6):1.65-1.71(m，4H)，2.11(s，3H)，2.45-2.55(m，4H)，2.74(t，J＝6.0Hz，2H)，3.98(t，J＝6.0Hz，2H)，6.76(d，J＝9.0Hz，2H)，7.35(d，J＝5.1Hz，1H)，7.45-7.57(m，3H)，7.9-7.97(m，2H)，8.20(d，J＝7.6Hz，1H)，8.41(s，1H)，8.85(s，1H)，m/z?458(M+H)
+。
Embodiment 61. 2-chloro-N-(4-(trifluoromethyl) phenyl)-5-methylpyrimidine-4-amine (intermediate
29)
With 2-chloro-5-methylpyrimidine-4-amine (159 μ L, 1.2mmol), 1-bromo-4-(trifluoromethyl) benzene (150mg, 1.0mmol), potassium tert.-butoxide (224mg, 2.0mmol), Xantphos (120mg, 0.2mmol) and acid chloride (26mg, suspension 0.1mmol) are sealed in the microwave reaction pipe and and 160 ℃ of irradiations 15 minutes down.This mixture is cooled to room temperature, uses DCM to cross filter solid so that flushing and under reduced pressure concentrated this solution.Obtain title intermediate 29 (128.7mg, 43%) by fast silica gel chromatogram method purifying resistates (hexane is to EtOAc), be white solid.MS(ESI+):m/z?288(M+H)
+。
Embodiment 62. N
2
-(4-(2-(tetramethyleneimine-1-yl) oxyethyl group) phenyl)-N
4
-(4-(fluoroform
Base) phenyl)-and 5-methylpyrimidine-2,4-diamines (compounds X XXV)
With above-mentioned intermediate 29 (128mg, 0.5mmol) and 6 (212mg, mixture 1.0mmol) are suspended in the acetate (5mL) and 75 ℃ of heating 18 hours down.This mixture is cooled to room temperature and under reduced pressure removes acetate.Use saturated NaHCO
3The aqueous solution (50mL) alkalization resistates and extract with DCM (2x50mL).Concentrate organic layer in a vacuum and pass through anti-phase C18 flash chromatography (water-CH
3CN, 0.1% TFA) the purifying crude product.Use saturated NaHCO
3Extract with moisture fraction and with EtOAc in the aqueous solution.Concentrate organic layer in a vacuum and resistates is dissolved in DCM.Be added in HCl in the diox and ether and filter the gained solid and obtain the hydrochloride (166mg, 70%) of title compound XXXV, be gray solid.
1H?NMR(500MHz，DMSO-d
6):1.80-1.95(m，2H)，1.95-2.10(m，2H)，2.19(s，3H)，3.05-3.20(m，2H)，3.55-3.65(m，6H)，4.33(t，J＝4.7Hz，2H)，6.97(d，J＝8.7Hz，2H)，7.34(d，J＝8.8Hz，2H)，7.73(d，J＝8.5Hz，2H)，7.83(d，J＝8.0Hz，2H)，7.94(s，1H)，9.92(br?s，1H)，10.44(br?s，1H)，10.85(br?s，1H)；MS(ESI+):m/z?458.5(M+H)
+。
Embodiment 63. benzos [1,3] dioxole-4-base-(2-chloro-5-methyl-pyrimidine
-4-yl)-amine (intermediate 30)
With 2-chloro-5-methyl-pyrimidine-4-base amine (1.4g, 9.7mmol), 4-bromo-benzo [1,3] dioxole (2.0g, 10mmol), Pd
2(dba)
3(0.80g, 0.87mmol), Xantphos (1.0g, 1.7mmol) and cesium carbonate (6.3g, mixture 19mmol) be suspended in the diox (40mL) and under reflux state and ar gas environment in the heating 5 hours.This reaction mixture is cooled to room temperature and dilutes with DCM (30mL).Filter this mixture and concentrated filtrate in a vacuum.Obtain title compound (1.0g, 39%) by fast silica gel chromatogram method purifying resistates (hexane-50% EtOAc/ hexane), be white solid.
1HNMR(500MHz，DMSO-d
6):δ?2.13(s，3H)，5.99(s，2H)，6.80-6.90(m，3H)，8.01(s，1H)，8.92(s，1H)。MS(ES+):m/z?264(M+H)
+。
Embodiment 64. N
4
-benzo [1,3] dioxole-4-base-5-methyl-N
2
-[4-(2-
Tetramethyleneimine-1-base-oxyethyl group)-phenyl]-pyrimidine-2,4-diamines (compounds X XXVI)
With intermediate 30 (0.25g, 0.95mmol) and 4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl amine (0.40g, 1.9mmol) mixture in acetate (15mL) is 100 ℃ of down heating 20 hours.This mixture is cooled to room temperature and under reduced pressure removes acetate.Be neutralized to pH～7 with resistates water-soluble (20mL) and with 10% NaOH solution.With EtOAc (2 x 30mL) extraction gained solution and separation organic layer.With salt water washing organic layer, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and obtain title compound (0.14g, 34%) with fast silica gel chromatogram method purifying crude product (DCM-20% MeOH/DCM) is white solid in a vacuum.
1H?NMR(500MHz，DMSO-d
6):δ?1.65-1.75(m，4H)，2.06(s，3H)，2.55-2.65(m，4H)，2.78-2.88(m，2H)，3.98(t，J＝5.8Hz，2H)，5.89(s，2H)，6.65(d，J＝9.0Hz，2H)，6.79-6.84(m，2H)，6.89(dd，J＝7.7，1.7Hz，1H)，7.45(d，J＝9.1Hz，2H)，7.81(s，1H)，8.23(s，1H)，8.73(s，1H)。MS(ES+):m/z434(M+H)
+。
Embodiment 65. N
4
-benzo [1,3] dioxole-4-base-5-methyl-N
2
-[4-(4-
Methyl-piperazine-1-yl)-phenyl]-pyrimidine-2,4-diamines (compounds X XXVII)
With intermediate 30 (0.10g, 0.38mmol) and 4-(4-methyl-piperazine-1-yl)-phenyl amine (0.12g, 0.51mmol) mixture in acetate (3mL) be sealed in the microwave reaction pipe and at 150 ℃ down with microwave irradiations 15 minutes.After being cooled to room temperature, removing lid and concentrate this mixture.Neutralize this mixture to solid precipitation with resistates water-soluble (20mL) and with 10% NaOH solution.Cross filter solid and obtain title compound (22mg, 14%) by flash chromatography on silica gel method purifying (DCM-15% MeOH/DCM) then, be the incarnadine solid.
1H?NMR(500MHz，DMSO-d
6):δ?2.06(s，3H)，2.21(s，3H)，2.44(t，J＝4.8Hz，4H)，2.97(t，J＝4.9Hz，4H)，5.89(s，2H)，6.67(d，J＝9.1Hz，2H)，6.80-6.86(m，2H)，6.91(dd，J＝7.6，1.7Hz，1H)，7.41(d，J＝9.0Hz，2H)，7.79(s，1H)，8.17(s，1H)，8.63(s，1H)。MS(ES+):m/z?419(M+H)
+。
Embodiment 66. (4-chloro-3-methoxyl group-phenyl)-(2-chloro-5-methyl-pyrimidine-4-yl)-amine (in
Mesosome 31)
With 2-chloro-5-methyl-pyrimidine-4-base amine (0.50g, 3.5mmol), 4-bromo-1-chloro-2-methoxyl group-benzene (0.65mL, 4.8mmol), Pd
2(dba)
3(0.17g, 0.19mmol), Xantphos (0.22g, 0.38mmol) and cesium carbonate (2.3g, mixture 7.1mmol) be suspended in the diox (20mL) and under reflux state and ar gas environment in the heating 5 hours.This reaction mixture is cooled to room temperature and dilutes with DCM (30mL).Filter this mixture and concentrated filtrate in a vacuum.Obtain title compound (0.55g, 55%) by fast silica gel chromatogram method purifying resistates (hexane-40% EtOAc/ hexane), be yellow solid.
1H?NMR(500MHz，DMSO-d
6):δ?2.18(s，3H)，3.85(s，3H)，7.35(dd，J＝8.6，2.3Hz，1H)，7.39(d，J＝8.7Hz，1H)，7.56(d，J＝2.3Hz，1H)，8.09(d，J＝0.9Hz，1H)，8.91(s，1H)。MS(ES+):m/z?284(M+H)
+。
Embodiment 67. N
4
-(4-chloro-3-methoxyl group-phenyl)-5-methyl-N
2
-(4-pyrazol-1-yl first
Base-phenyl)-and pyrimidine-2,4-diamines (compounds X XXVIII)
With intermediate 31 (0.20g, 0.70mmol), 4-pyrazol-1-yl methyl-phenyl amine (0.14g, 0.81mmol), Pd
2(dba)
3(40mg, 0.044mmol), Xantphos (50mg, 0.086mmol) and cesium carbonate (0.50g, 1.5mmol) Zai diox/DMF (3/1,4mL) suspension in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 20 minutes.After being cooled to room temperature, removing lid and filter the gained mixture and with the solid of DCM washing and filtering.Concentrated filtrate and by HPLC purifying resistates.Merge cut and the saturated NaHCO of impouring
3Solution (40mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and the gained solid is dissolved in minimum EtOAc and adds hexane to solid precipitation.After the filtration, obtain title compound, be pale solid (0.13g, 44%).
1H?NMR(500MHz，DMSO-d
6):δ?2.11(s，3H)，3.74(s，3H)，5.22(s，2H)，6.25(t，J＝2.1Hz，1H)，7.08(d，J＝8.6Hz，2H)，7.27(d，J＝9.3Hz，1H)，7.40-7.45(m，3H)，7.60(d，J＝8.6Hz，2H)，7.75(d，J＝1.8Hz，1H)，7.91(s，1H)，8.36(s，1H)，9.04(s，1H)
MS(ES+):m/z?421(M+H)
+。
Embodiment 68. 5-methyl-N
2
-[4-(4-methyl-piperazine-1-yl)-phenyl]-pyrimidine-2,4-two
Amine (intermediate 32)
With 2-chloro-5-methyl-pyrimidine-4-base amine (1.0g, 6.9mmol) and 4-(4-methyl-piperazine-1-yl)-phenyl amine (1.5mL, 7.8mmol) mixture in acetate (15mL) heated 2.5 hours down at 100 ℃.This mixture is cooled to room temperature and under reduced pressure removes acetate.With resistates water-soluble (20mL) and with 10% NaOH solution this mixture that neutralizes, up to solid precipitation.After filtering and washing with water, obtain the title mixture, be gray solid (1.3g, 63%).
1H?NMR(500MHz，DMSO-d
6):δ?1.88(s，3H)，2.21(s，3H)，2.21(s，3H)，2.44(t，J＝4.8Hz，4H)，3.00(t，J＝4.8Hz，4H)，6.27(s，2H)，6.79(d，J＝9.0Hz，2H)，7.57(d，J＝9.0Hz，2H)，7.63(s，1H)，8.42(s，1H)。MS(ES+):m/z?299(M+H)
+。
Embodiment 69. N
4
-(4-chloro-3-methoxyl group-phenyl)-5-methyl-N
2
-[4-(4-methyl-piperazine
-1-yl)-phenyl]-pyrimidine-2,4-diamines (compounds X XXIX)
With intermediate 32 (0.30g, 1.0mmol), 4-bromo-1-chloro-2-methoxyl group-benzene (0.20mL, 1.5mmol), Pd
2(dba)
3(50mg, 0.055mmol), Xantphos (65mg, 0.11mmol) and cesium carbonate (0.70g, 2.1mmol) Zai diox/DMF (3/1,8mL) suspension in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 20 minutes.After being cooled to room temperature, removing lid and filter the gained mixture and with the solid of DCM washing and filtering.Concentrated filtrate and by HPLC purifying resistates.Merge fraction and the saturated NaHCO of impouring
3Solution (40mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and the EtOAc/ hexanes mixtures (1/5,30mL) in grinding residues.After filtration, obtain title compound, be pale solid (0.20g, 46%).
1H?NMR(500MHz，DMSO-d
6):δ?2.09(s，3H)，2.21(s，3H)，2.45(t，J＝4.9Hz，4H)，3.02(t，J＝4.9Hz，4H)，3.73(s，3H)，6.79(d，J＝9.1Hz，2H)，7.27(d，J＝8.6Hz，1H)，7.42-7.47(m，3H)，7.49(d，J＝2.3Hz，1H)，7.86(s，1H)，8.28(s，1H)，8.72(s，1H)。MS(ES+):m/z?439(M+H)
+。
Embodiment 70. N
4
-(4-chloro-3-methoxyl group-phenyl)-5-methyl-N
2
-(4-morpholine-4-base-benzene
Base)-and pyrimidine-2,4-diamines (compounds X L)
(0.10g, 0.35mmol) (80mg, 0.45mmol) mixture in acetate (3mL) is sealed in the microwave reaction pipe and at 160 ℃ and uses microwave irradiation 20 minutes down with 4-morpholine-4-base-phenyl amine with intermediate 31.After being cooled to room temperature, removing lid and concentrate this mixture.With resistates water-soluble (20mL) and with 10% NaOH solution this mixture that neutralizes, up to solid precipitation.Cross filter solid and obtain title compound (55mg, 37%) by flash chromatography on silica gel method purifying (DCM-10% MeOH/DCM) then, be the light brown solid.
1H?NMR(500MHz，DMSO-d
6):δ?2.10(s，3H)，3.00(t，J＝4.8Hz，4H)，3.71-3.76(m，7H)，6.80(d，J＝9.0Hz，2H)，7.28(d，J＝8.6Hz，1H)，7.45(dd，J＝8.7，2.2Hz，1H)，7.47-7.50(m，3H)，7.87(s，1H)，8.29(s，1H)，8.75(s，1H)。MS(ES+):m/z426(M+H)
+。
Embodiment 71. N
4
-(4-chloro-3-methoxyl group-phenyl)-5-methyl-N
2
-(4-pyrazol-1-yl-benzene
Base)-and pyrimidine-2,4-diamines (compounds X LI)
(90mg, 0.32mmol) (70mg, 0.44mmol) mixture in acetate (3mL) is sealed in the microwave reaction pipe and at 160 ℃ and uses microwave irradiation 20 minutes down with 4-pyrazol-1-yl-phenyl amine with intermediate 31.After being cooled to room temperature, removing lid and concentrate this mixture.With resistates water-soluble (20mL) and with 10% NaOH solution this mixture that neutralizes, up to solid precipitation.Cross filter solid and pass through the HPLC purifying then.Merge the fraction of calibration and concentrate then and obtain title compound (tfa salt of 40mg, 24%), be white solid.
1H?NMR(500MHz，DMSO-d
6):δ?2.17(s，3H)，3.75(s，3H)，6.54(t，J＝1.9Hz，1H)，7.30(d，J＝6.6Hz，1H)，7.39(d，J＝2.1Hz，1H)，7.40(d，J＝8.6Hz，1H)，7.59(d，J＝8.9Hz，2H)，7.71(d，J＝8.9Hz，2H)，7.73(d，J＝1.6Hz，1H)，7.93(s，1H)，8.41(d，J＝2.5Hz，1H)，9.41(s，1H)，10.05(s，1H)。MS(ES+):m/z?407(M+H)
+。
Embodiment 72. N
4
-(4-chloro-3-methoxyl group-phenyl)-5-methyl-N
2
-(4-piperidines-1-base-benzene
Base)-and pyrimidine-2,4-diamines (XLII)
(0.11g, 0.39mmol) (90mg, 0.51mmol) mixture in acetate (3mL) is sealed in the microwave reaction pipe and at 160 ℃ and uses microwave irradiation 20 minutes down with 4-piperidines-1-base-phenyl amine with intermediate 31.After being cooled to room temperature, removing lid and concentrate this mixture.With resistates water-soluble (20mL) and with 10% NaOH solution this mixture that neutralizes, up to solid precipitation.Cross filter solid and obtain title compound (10mg, 6%) by flash chromatography on silica gel method purifying (hexane-70% EtOAc/ hexane) then, be the light brown solid.
1H?NMR(500MHz，DMSO-d
6):δ?1.48-1.53(m，2H)，1.59-1.65(m，4H)，2.09(s，3H)，3.00(t，J＝5.4Hz，4H)，3.73(s，3H)，6.78(d，J＝9.0Hz，2H)，7.27(d，J＝8.7Hz，1H)，7.40-7.47(m，3H)，7.50(d，J＝2.2Hz，1H)，7.86(s，1H)，8.28(s，1H)，8.71(s，1H)。MS(ES+):m/z?424(M+H)
+。
Embodiment 73. N
4
-(4-chloro-3-methoxyl group-phenyl)-5-methyl-N
2
-[4-(4-methyl-piperazine
-1-ylmethyl)-phenyl]-pyrimidine-2,4-diamines (XLIII)
With intermediate 31 (50mg, 0.18mmol), 4-(4-methyl-piperazine-1-ylmethyl)-phenyl amine (50mg, 0.24mmol), Pd
2(dba)
3(10mg, 0.011mmol), Xantphos (13mg, 0.022mmol) and cesium carbonate (0.12g, 0.37mmol) Zai diox/DMF (3/1,4mL) suspension in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 15 minutes.After being cooled to room temperature, removing lid and filter the gained mixture and with the solid of DCM washing and filtering.Concentrated filtrate and obtain title compound (35mg, 44%) by fast silica gel chromatogram method purifying resistates (DCM-10% MeOH/DCM) is pale solid.
1H?NMR(500MHz，DMSO-d
6):δ?2.11(s，3H)，2.15(s，3H)，2.20-2.45(m，8H)，3.35(s，2H)，3.75(s，3H)，7.07(d，J＝8.5Hz，2H)，7.28(d，J＝8.5Hz，1H)，7.44(dd，J＝8.7，2.3Hz，1H)，7.47(d，J＝2.3Hz，1H)，7.57(d，J＝8.5Hz，2H)，7.91(s，1H)，8.36(s，1H)，8.98(s，1H)。MS(ES+):m/z453(M+H)
+.
Embodiment 74. N
4
-(4-chloro-3-methoxyl group-phenyl)-5-methyl-N
2
-(4-piperazine-1-base-
Phenyl)-and pyrimidine-2,4-diamines (compounds X LIV)
With intermediate 31 (0.20g, 0.70mmol) and 4-(4-amino-phenyl)-piperazine-1-t-butyl formate (0.22g, 0.79mmol) mixture in acetate (4mL) be sealed in the microwave reaction pipe and at 150 ℃ down with microwave irradiations 15 minutes.After being cooled to room temperature, remove lid and concentrated filtrate.Fraction and the saturated NaHCO of impouring by HPLC purifying resistates and merging calibration
3Solution (40mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4And dry and filtration.Concentrated filtrate and the gained solid is dissolved in minimum EtOAc and adds hexane until solid precipitation.After filtration, obtain the title mixture, be pale solid (0.10g, 33%).
1H?NMR(500MHz，DMSO-d
6):δ?2.10(s，3H)，3.16(s，8H)，3.73(s，3H)，6.83(d，J＝9.0Hz，2H)，7.29(d，J＝8.8Hz，1H)，7.44(dd，J＝8.7，2.1Hz，1H)，7.49-7.52(m，3H)，7.88(s，1H)，8.32(s，1H)，8.81(s，1H)
MS(ES+):m/z?425(M+H)
+。
The embodiment 75. N-tertiary butyl-3-{5-methyl-2-[4-(4-methyl-piperazine-1-yl)-phenyl
Amino]-pyrimidine-4-base is amino }-benzsulfamide (compounds X LV)
With intermediate 32 (0.30g, 1.0mmol), the 3-bromo-N-tertiary butyl-benzsulfamide (0.35g, 1.2mmol), Pd
2(dba)
3(60mg, 0.066mmol), Xantphos (70mg, 0.12mmol) and cesium carbonate (0.70g, 2.1mmol) Zai diox/DMF (3/1,8mL) suspension in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 20 minutes.After being cooled to room temperature, removing lid and filter the gained mixture and with the solid of DCM washing and filtering.Concentrated filtrate and by HPLC purifying resistates.Merge fraction and the saturated NaHCO of impouring
3Solution (40mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and the mixture of EtOAc/ hexane (1/7,40mL) in grinding residues.After filtration, obtain title compound, be pale solid (0.30g, 59%).
1H?NMR(500MHz，DMSO-d
6):δ?1.12(s，9H)，2.11(s，3H)，2.22(s，3H)，2.45(t，J＝4.7Hz，4H)，3.02(t，J＝4.8Hz，4H)，6.81(d，J＝9.1Hz，2H)，7.45-7.52(m，4H)，7.56(s，1H)，7.89(s，1H)，8.10-8.16(m，2H)，8.51(s，1H)，8.70(s，1H)
MS(ES+):m/z?510(M+H)
+。
The embodiment 76. N-tertiary butyl-3-(2-chloro-5-methyl-pyrimidine-4-base is amino)-benzsulfamide
(intermediate 33)
With 2-chloro-5-methyl-pyrimidine-4-base amine (0.4g, 2.8mmol), the 3-bromo-N-tertiary butyl-benzsulfamide (1.0g, 3.4mmol), Pd
2(dba)
3(0.17g, 0.19mmol), Xantphos (0.2g, 3.5mmol) and cesium carbonate (2.0g, mixture 6.1mmol) be suspended in the diox (25mL) and under reflux state and ar gas environment in the heating 3 hours.This reaction mixture is cooled to room temperature and dilutes with DCM (30mL).Filter this mixture and concentrated filtrate in a vacuum.Resistates is dissolved in EtOAc and adds hexane, up to solid precipitation.After filtration, obtain title compound (1.2g, 98%), be the light brown solid.It not purifiedly is used for next step.MS(ES+):m/z?355(M+H)
+。
The embodiment 77. N-tertiary butyl-3-[5-methyl-2-(4-morpholine-4-ylmethyl-phenyl amino)-
Pyrimidine-4-base is amino]-benzsulfamide (compounds X LVI)
With intermediate 33 (0.50g, 1.4mmol), 4-morpholine-4-ylmethyl-phenyl amine (0.35g, 1.8mmol), Pd
2(dba)
3(0.10g, 0.11mmol), Xantphos (0.12g, 0.21mmol) and cesium carbonate (1.0g, mixture 3.1mmol) be suspended in the diox (25mL) and under reflux state and ar gas environment in the heating 3 hours.With this reaction mixture be cooled to room temperature and with the dilution DCM (30mL).Filter this mixture and concentrated filtrate in a vacuum.Fraction and the saturated NaHCO of impouring by HPLC purifying resistates and merging calibration
3Solution (50mL).With the water layer of EtOAc (2 x 50mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and the gained solid is dissolved in minimum EtOAc and adds hexane is up to solid precipitation.After filtration, obtain title compound, be pale solid (0.23g, 31%).
1H?NMR(500MHz，DMSO-d
6):δ?1.12(s，9H)，2.13(s，3H)，2.28-2.34(m，4H)，3.35(s，2H)，3.55(t，J＝4.8Hz，4H)，7.10(d，J＝8.5Hz，2H)，7.45-7.52(m，2H)，7.57(s，1H)，7.59(d，J＝8.5Hz，2H)，7.94(s，1H)，8.10(s，1H)，8.13-8.16(m，1H)，8.58(s，1H)，8.95(s，1H)。MS(ES+):m/z511(M+H)
+。
The embodiment 78. N-tertiary butyl-3-{5-methyl-2-[4-(4-oxygen base-morpholine-4-ylmethyl)-
Phenyl amino]-pyrimidine-4-base is amino }-benzsulfamide (compounds X LVII)
With above-claimed cpd XLVI (30mg, 0.06mmol) and 3-chlorine peroxybenzoic acid (77%, 14mg, 0.06mmol) solution in chloroform (30mL) at room temperature stirred 1 hour.Except that desolvating and passing through silica gel purification gained mixture, use 20% CH by rotary evaporation
3OH/CHCl
3For elutriant obtains title compound, be pale solid (15mg, 48%).
1H?NMR(500MHz，DMSO-d
6):δ?1.12(s，9H)，2.14(s，3H)，2.71(d，J＝10.9Hz，2H)，3.63(d，J＝9.9Hz，2H)，4.08(t，J＝11.6Hz，2H)，4.28(s，2H)，7.38(d，J＝8.5Hz，2H)，7.50(d，J＝5.0Hz，2H)，7.61(s，1H)，7.66(d，J＝8.5Hz，2H)，7.96(s，1H)，8.13(m，2H)，8.63(s，1H)，9.13(s，1H)。MS(ES+):m/z?527(M+H)
+。
The embodiment 79. N-tertiary butyl-3-[5-methyl-2-(4-pyrazol-1-yl-phenyl amino)-pyrimidine
-4-base is amino]-benzsulfamide (compounds X LVIII)
(0.10g, 0.28mmol) (50mg, the mixture of mixture 0.31mmol) in acetate (3mL) are sealed in the microwave reaction pipe and at 130 ℃ and use microwave irradiation 15 minutes down with 4-pyrazol-1-yl-phenyl amine with intermediate 33.After being cooled to room temperature, remove lid and concentrated filtrate.Be neutralized to solid precipitation with resistates water-soluble (20mL) and with 10% NaOH solution.Filter brown solid and pass through the HPLC purifying then.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and the gained solid is dissolved in minimum EtOAc and adds hexane is up to solid precipitation.After filtration, obtain title compound, be white solid (15mg, 11%).
1H?NMR(500MHz，DMSO-d
6):δ?1.12(s，9H)，2.15(s，3H)，6.49(t，J＝2.2Hz，1H)，7.50-7.55(m，2H)，7.58(s，1H)，7.62(d，J＝9.1Hz，2H)，7.68(d，J＝1.3Hz，1H)，7.77(d，J＝9.1Hz，2H)，7.96(s，1H)，8.11(s，1H)，8.13-8.16(m，1H)，8.33(d，J＝2.5Hz，1H)，8.64(s，1H)，9.17(s，1H)。MS(ES+):m/z?478(M+H)
+。
The embodiment 80. N-tertiary butyl-3-[5-methyl-2-(6-piperazine-1-base-pyridin-3-yl ammonia
Base)-pyrimidine-4-base is amino]-benzsulfamide (compounds X LIX)
With intermediate 33 (0.10g, 0.28mmol) and 4-(5-amino-pyridine-2-yl)-piperazine-1-t-butyl formate (90mg, 0.32mmol) mixture in acetate (3mL) be sealed in the microwave reaction pipe and at 130 ℃ down with microwave irradiations 15 minutes.After being cooled to room temperature, remove lid and concentrated filtrate.Resistates is dissolved in DCM (5mL) and adds 30%TFA/DCM (6mL).This mixture was at room temperature stirred 1 hour, concentrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and the gained solid is dissolved in minimum EtOAc and adds hexane is up to solid precipitation.After filtration, obtain title compound, be white solid (10mg, 7%).
1H?NMR(500MHz，DMSO-d
6):δ?1.12(s，9H)，2.11(s，3H)，2.83(t，J＝5.0Hz，4H)，3.28-3.33(m，4H)，6.73(d，J＝9.1Hz，1H)，7.40-7.49(m，2H)，7.57(s，1H)，7.86(dd，J＝9.1，2.7Hz，1H)，7.88(s，1H)，8.10-8.16(m，2H)，8.28(d，J＝2.5Hz，1H)，8.53(s，1H)，8.72(s，1H)。MS(ES+):m/z?497(M+H)
+。
The embodiment 81. N-tertiary butyl-3-[5-methyl-2-(4-pyrazol-1-yl methyl-phenyl amino)-
Pyrimidine-4-base is amino]-benzsulfamide (compound L)
(0.10g, 0.28mmol) (50mg, 0.29mmol) mixture in acetate (3mL) is sealed in the microwave reaction pipe and at 130 ℃ and uses microwave irradiation 15 minutes down with 4-pyrazol-1-yl methyl-phenyl amine with intermediate 33.After being cooled to room temperature, remove lid and concentrated filtrate.Fraction and the saturated NaHCO of impouring by HPLC purifying resistates and merging calibration
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and the gained solid is dissolved in minimum EtOAc and adds hexane is up to solid precipitation.Filter the back and obtain title compound, be white solid (12mg, 9%).
1H?NMR(500MHz，DMSO-d
6):δ?1.12(s，9H)，2.13(s，3H)，5.21(s，2H)，6.24(t，J＝1.9Hz，1H)，7.08(d，J＝8.5Hz，2H)，7.27-7.50(m，3H)，7.56(s，1H)，7.60(d，J＝8.4Hz，2H)，7.75(d，J＝2.1Hz，1H)，7.94(s，1H)，8.14(d，J＝7.9Hz，1H)，8.59(s，1H)，9.01(s，1H)。MS(ES+):m/z?492(M+H)
+。
Embodiment 82. 5-methyl-N
2
-[3-(piperidines-1-alkylsulfonyl)-phenyl]-pyrimidine-2, the 4-diamines
(intermediate 34)
With 2-chloro-5-methyl-pyrimidine-4-base amine (0.25g, 1.74mmol) and 3-(piperidines-1-alkylsulfonyl)-phenyl amine (0.50g, 2.1mmol) mixture in acetate (4mL) is sealed in the microwave reaction pipe in and at 130 ℃ of usefulness microwave irradiations 15 minutes down.After being cooled to room temperature, removing lid and concentrate this mixture.With resistates water-soluble (20mL) and with 10% NaOH solution pH is adjusted to～9.With EtOAc (2 x 30mL) extraction gained solution and separation organic layer.With the organic layer that the salt water washing merges, use anhydrous Na
2SO
4Drying and filtration.In a vacuum concentrated filtrate and with crude product (～0.6g) not purifiedly be used for next step.MS(ES+):m/z?348(M+H)
+。
The embodiment 83. N-tertiary butyl-3-{5-methyl-2-[3-(piperidines-1-alkylsulfonyl)-phenylamino
Base]-pyrimidine-4-base is amino }-benzsulfamide (compound L I)
With intermediate 34 (0.10g, 0.29mmol), the 3-bromo-N-tertiary butyl-benzsulfamide (84mg, 0.29mmol), Pd
2(dba)
3(15mg, 0.016mmol), Xantphos (20mg, 0.035mmol) and cesium carbonate (0.18g, 0.55mmol) Zai diox/DMF (3/1,4mL) suspension in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 15 minutes.After being cooled to room temperature, removing lid and filter the gained mixture and with the solid of DCM washing and filtering.Concentrated filtrate and by HPLC purifying resistates.Merge fraction and the saturated NaHCO of impouring
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and resistates is dissolved in minimum EtOAc and adds hexane is up to solid precipitation.Filter the back and obtain title compound, be white solid (20mg, 12%).
1H?NMR(500MHz，DMSO-d
6):δ?1.12(s，9H)，1.30-1.40(m，2H)，1.50-1.56(m，4H)，2.16(s，3H)，2.88(t，J＝5.3Hz，4H)，7.17(d，J＝7.8Hz，1H)，7.43(t，J＝8.0Hz，1H)，7.59-7.60(m，2H)，7.58(s，1H)，8.13(s，1H)，7.16(dd，J＝7.9，1.9Hz，1H)，8.18-8.22(m，1H)，8.67(s，1H)，9.37(s，1H)。MS(ES+):m/z?559(M+H)
+。
The embodiment 84. N-tertiary butyl-3-{5-methyl-2-[4-(4-methyl-piperazine-1-ylmethyl)-
Phenyl amino]-pyrimidine-4-base is amino }-benzsulfamide (compound L II)
With intermediate 33 (0.10g, 0.28mmol), 4-(4-methyl-piperazine-1-ylmethyl)-phenyl amine (65mg, 0.32mmol), Pd
2(dba)
3(20mg, 0.022mmol), Xantphos (25mg, 0.043mmol) and cesium carbonate (0.18g, 0.55mmol) Zai diox/DMF (3/1,4mL) suspension in be sealed in the microwave reaction pipe and at 170 ℃ down with microwave irradiations 15 minutes.After being cooled to room temperature, removing lid and filter the gained mixture and with the solid of DCM washing and filtering.Concentrated filtrate and by HPLC purifying resistates.Merge fraction and the saturated NaHCO of impouring
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and resistates is dissolved in minimum EtOAc and adds hexane is up to solid precipitation.Filter the back and obtain title compound, be white solid (53mg, 36%).
1H?NMR(500MHz，DMSO-d
6):δ?1.12(s，9H)，2.13(s，3H)，2.15(s，3H)，2.20-2.45(m，4H)，3.25-3.40(m，6H)，7.08(d，J＝8.6Hz，2H)，7.45-7.52(m，2H)，7.56(s，1H)，7.57(d，J＝8.6Hz，2H)，7.94(s，1H)，8.09(s，1H)，8.13-8.16(m，1H)，8.58(s，1H)，8.94(s，1H)。MS(ES+):m/z?524(M+H)
+。
The embodiment 85. N-tertiary butyl-3-[5-methyl-2-(4-piperazine-1-base-3-trifluoromethyl-benzene
Base is amino)-pyrimidine-4-base is amino]-benzsulfamide (compound L III)
With intermediate 33 (0.10g, 0.28mmol), 4-(4-amino-2-trifluoromethyl-phenyl)-piperazine-1-t-butyl formate (0.1g, 0.29mmol), Pd
2(dba)
3(20mg, 0.022mmol), Xantphos (25mg, 0.043mmol) and cesium carbonate (0.18g, 0.55mmol) Zai diox/DMF (3/1,4mL) mixture in be sealed in the microwave reaction pipe and at 170 ℃ down with microwave irradiations 15 minutes.After being cooled to room temperature, removing lid and filter the gained mixture.Solid and concentrated filtrate with the DCM washing and filtering.Resistates is dissolved in DCM (5mL) and adds 50% TFA/DCM (6mL).This mixture was at room temperature stirred 2 hours, concentrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and the gained solid is dissolved in minimum EtOAc and adds hexane is up to solid precipitation.Filter the back and obtain title compound, be white solid (42mg, 26%).
1H?NMR(500MHz，DMSO-d
6):δ?1.12(s，9H)，2.14(s，3H)，2.70-2.75(m，4H)，2.80-2.85(m，4H)，7.36(d，J＝8.5Hz，2H)，7.45-7.52(m，2H)，7.55(s，1H)，7.90-8.00(m，3H)，8.07(s，1H)，8.15(d，J＝7.6Hz，1H)，8.63(s，1H)，9.22(s，1H)
MS(ES+):m/z?564(M+H)
+。
Embodiment 86. 3-{2-[4-(4-ethanoyl-piperazine-1-yl)-3-trifluoromethyl-phenylamino
Base]-5-methyl-pyrimidine-4-base is amino }-the N-tertiary butyl-benzsulfamide (compound L IV)
With intermediate 33 (0.10g, 0.28mmol), 1-[4-(4-amino-2-trifluoromethyl-phenyl)-piperazine-1-yl]-ethyl ketone (0.1g, 0.35mmol), Pd
2(dba)
3(15mg, 0.016mmol), Xantphos (20mg, 0.035mmol) and cesium carbonate (0.20g, 0.61mmol) Zai diox/DMF (3/1,4mL) mixture in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 15 minutes.After being cooled to room temperature, removing lid and filter the gained mixture.With the solid of DCM washing and filtering and concentrated filtrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With the water layer of EtOAc (2x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and the gained solid is dissolved in minimum EtOAc and adds hexane is up to solid precipitation.Filter the back and obtain title compound, be white solid (64mg, 38%).
1H?NMR(500MHz，DMSO-d
6):δ?1.12(s，9H)，2.04(3，H)，2.14(s，3H)，2.73(t，J＝4.9Hz，2H)，2.79(t，J＝4.7Hz，2H)，3.50-3.60(m，4H)，7.40(d，J＝8.7Hz，2H)，7.45-7.52(m，2H)，7.56(s，1H)，7.90-8.00(m，3H)，8.07(s，1H)，8.14(d，J＝7.2Hz，1H)，8.64(s，1H)，9.26(s，1H)。MS(ES+):m/z606(M+H)
+。
Embodiment 87. 5-methyl-N
2
-[3-(4-methyl-piperazine-1-alkylsulfonyl)-phenyl]-pyrimidine
-2,4-diamines (intermediate 35)
With 2-chloro-5-methyl-pyrimidine-4-base amine (0.25g; 1.74mmol) and 3-(4-methyl-piperazine-1-alkylsulfonyl)-phenyl amine (0.50g, 2.0mmol) mixture in acetate (4mL) be sealed in the microwave reaction pipe and at 130 ℃ down with microwave irradiations 15 minutes.After being cooled to room temperature, removing lid and concentrate this mixture.With resistates water-soluble (20mL) and with 10% NaOH solution pH is adjusted to～9.With EtOAc (2 x 30mL) extraction gained solution and separation organic layer.With the organic layer that the salt water washing merges, use anhydrous Na
2SO
4Drying and filtration.In a vacuum concentrated filtrate and with crude product (～0.42g) be used for next step without being further purified.MS(ES+):m/z?363(M+H)
+。
The embodiment 88. N-tertiary butyl-3-{5-methyl-2-[3-(4-methyl-piperazine-1-alkylsulfonyl)-
Phenyl amino]-pyrimidine-4-base is amino }-benzsulfamide (compound L V)
With intermediate 35 (0.10g, 0.28mmol), the 3-bromo-N-tertiary butyl-benzsulfamide (80mg, 0.27mmol), Pd
2(dba)
3(15mg, 0.016mmol), Xantphos (20mg, 0.035mmol) and cesium carbonate (0.18g, 0.55mmol) Zai diox/DMF (3/1,4mL) suspension in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 15 minutes.After being cooled to room temperature, removing lid and filter the gained mixture and with the solid of DCM washing and filtering.Concentrated filtrate and by HPLC purifying resistates.Merge fraction and the saturated NaHCO of impouring
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and resistates is dissolved in minimum EtOAc and adds hexane is up to solid precipitation.Filter the back and obtain title compound, be white solid (10mg, 6%).
1H?NMR(500MHz，DMSO-d
6):δ?1.12(s，9H)，2.13(s，3H)，2.16(s，3H)，2.33-2.40(m，4H)，2.85-2.94(m，4H)，7.18(d，J＝8.1Hz，1H)，7.44(t，J＝8.0Hz，1H)，7.49-7.54(m，2H)，7.58(s，1H)，8.00-8.03(m，2H)，8.13(s，1H)，8.15(dd，J＝8.6，1.6Hz，1H)，8.18-8.23(m，1H)，8.66(s，1H)，9.38(s，1H)。MS(ES+):m/z?574(M+H)
+。
The embodiment 89. N-tertiary butyl-3-[5-methyl-2-(4-piperazine-1-ylmethyl-phenyl amino)-
Pyrimidine-4-base is amino]-benzsulfamide (compound L VI)
With intermediate 33 (0.10g, 0.28mmol), 4-(4-amino-benzyl)-piperazine-1-t-butyl formate (0.1g, 0.34mmol), Pd
2(dba)
3(15mg, 0.016mmol), Xantphos (20mg, 0.035mmol) and cesium carbonate (0.20g, 0.61mmol) Zai diox/DMF (3/1, mixture 4mL) be sealed in the microwave reaction pipe and at 170 ℃ down with microwave irradiations 15 minutes.After being cooled to room temperature, removing lid and filter the gained mixture.Solid and concentrated filtrate with the DCM washing and filtering. resistates is dissolved in DCM (6mL) and adds TFA (3mL).This mixture was at room temperature stirred 1 hour, concentrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and with the gained solid hexane/EtOAc (10/1, grind in 55mL).Filter the back and obtain title compound, be white solid (32mg, 22%).
1H?NMR(500MHz，DMSO-d
6):δ?1.12(s，9H)，2.13(s，3H)，2.30-2.40(m，4H)，2.85(t，J＝4.7Hz，4H)，3.38(s，2H)，7.09(d，J＝8.5Hz，2H)，7.45-7.52(m，2H)，7.56(s，1H)，7.59(d，J＝8.5Hz，2H)，7.94(s，1H)，8.10(s，1H)，8.13-8.16(m，1H)，8.59(s，1H)，8.96(s，1H)。MS(ES+):m/z510(M+H)
+。
The embodiment 90. N-tertiary butyl-3-{5-methyl-2-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-
Phenyl amino]-pyrimidine-4-base is amino }-benzsulfamide (compound L VII)
With intermediate 33 (0.10g, 0.28mmol) and 4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl amine (0.10g, 0.49mmol) mixture in acetate (3mL) be sealed in the microwave reaction pipe and at 150 ℃ down with microwave irradiations 20 minutes.After being cooled to room temperature, remove lid and concentrated filtrate.Fraction and the saturated NaHCO of impouring by HPLC purifying resistates and merging calibration
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and the gained solid is dissolved in minimum EtOAc and adds hexane is up to solid precipitation.Filter the back and obtain title compound, be white solid (40mg, 27%).
1H?NMR(500MHz，DMSO-d
6):δ?1.12(s，9H)，1.65-1.70(m，4H)，2.12(s，3H)，2.45-2.55(m，4H)，2.76(t，J＝5.8Hz，2H)，3.99(t，J＝6.0Hz，2H)，6.79(d，J＝9.0Hz，2H)，7.46-7.53(m，4H)，7.56(s，1H)，7.90(s，1H)，8.10-8.15(m，2H)，8.53(s，1H)，8.77(s，1H)。MS(ES+):m/z?525(M+H)
+。
Embodiment 91. 3-{5-methyl-2-[4-(4-methyl-piperazine-1-yl)-phenyl amino]-pyrimidine
-4-base is amino }-benzsulfamide (compound L VIII)
With intermediate 32 (0.10g, 0.33mmol), 3-bromo-benzsulfamide (0.10g, 0.42mmol), Pd
2(dba)
3(20mg, 0.022mmol), Xantphos (25mg, 0.043mmol) and cesium carbonate (0.25g, 0.77mmol) the suspension in the Zai diox (3mL) be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 15 minutes.After being cooled to room temperature, removing lid and filter the gained mixture and with the solid of DCM washing and filtering.Concentrated filtrate and by HPLC purifying resistates.Merge fraction and the saturated NaHCO of impouring
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and obtain title compound is gray solid (10mg, 7%).
1H?NMR(500MHz，DMSO-d
6):δ?2.10(s，3H)，2.22(s，3H)，2.44(t，J＝4.9Hz，4H)，3.03(t，J＝4.9Hz，4H)，6.81(d，J＝9.0Hz，2H)，7.34(s，2H)，7.45-7.50(m，4H)，7.89(s，1H)，8.06(s，1H)，8.13-8.18(m，1H)，8.54(s，1H)，8.70(s，1H)。MS(ES+):m/z?454(M+H)
+。
Embodiment 92. N-methyl-3-{5-methyl-2-[4-(4-methyl-piperazine-1-yl)-phenylamino
Base]-pyrimidine-4-base is amino }-benzsulfamide (compound L IX)
With intermediate 32 (0.10g, 0.33mmol), 3-bromo-N-methyl-benzsulfamide (0.11g, 0.44mmol), Pd
2(dba)
3(20mg, 0.022mmol), Xantphos (25mg, 0.043mmol) and cesium carbonate (0.25g, 0.77mmol) Zai diox/DMF (3/1,4mL) suspension in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 20 minutes.After being cooled to room temperature, removing lid and filter the gained mixture and with the solid of DCM washing and filtering.Concentrated filtrate and by HPLC purifying resistates.Merge fraction and the saturated NaHCO of impouring
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and with resistates at DCM/Et
2The mixture of O (1/5,30mL) the middle grinding.Filter the back and obtain title compound, be light brown solid (65mg, 42%).
1H?NMR(500MHz，DMSO-d
6):δ?2.11(s，3H)，2.23(s，3H)，2.44(d，J＝5.0Hz，3H)，2.45-2.50(m，4H)，3.03(t，J＝4.9Hz，4H)，6.81(d，J＝9.1Hz，2H)，7.40-7.43(m，2H)，7.46(d，J＝9.1Hz，2H)，7.52(t，J＝8.0Hz，1H)，7.89(s，1H)，7.94(t，J＝1.8Hz，1H)，8.29(br?d，J＝8.3Hz，1H)，8.56(s，1H)，8.72(s，1H)。MS(ES+):m/z?468(M+H)
+。
Embodiment 93. N, N-dimethyl-3-{5-methyl-2-[4-(4-methyl-piperazine-1-yl)-benzene
Base is amino]-pyrimidine-4-base is amino }-benzsulfamide (compound L X)
With intermediate 32 (0.13g, 0.43mmol), 3-bromo-N, N-dimethyl-benzsulfamide (0.14g, 0.53mmol), Pd
2(dba)
3(25mg, 0.027mmol), Xantphos (30mg, 0.052mmol) and cesium carbonate (0.33g, 1.0mmol) Zai diox/DMF (3/1,4mL) suspension in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 20 minutes.After being cooled to room temperature, removing lid and filter the gained mixture and with the solid of DCM washing and filtering.Concentrated filtrate and by HPLC purifying resistates.Merge fraction and the saturated NaHCO of impouring
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and with resistates the mixture of EtOAc/ hexane (1/5, grind in 30mL).Filter the back and obtain title compound, be pale solid (60mg, 29%).
1H?NMR(500MHz，DMSO-d
6):δ?2.17(s，3H)，2.23(s，3H)，2.44(d，J＝5.0Hz，3H)，2.45-2.50(m，4H)，2.63(s，6H)，3.03(t，J＝4.9Hz，4H)，6.81(d，J＝9.1Hz，2H)，7.36(d，J＝8.0Hz，1H)，7.45(d，J＝9.1Hz，2H)，7.54(t，J＝8.0Hz，1H)，7.84(t，J＝1.9Hz，1H)，7.90(s，1H)，8.46(br?d，J＝7.8Hz，1H)，8.57(s，1H)，8.74(s，1H)。MS(ES+):m/z?482(M+H)
+。
Embodiment 94. N-sec.-propyl-3-{5-methyl-2-[4-(4-methyl-piperazine-1-yl)-phenyl
Amino]-pyrimidine-4-base is amino }-benzsulfamide (compound L XI)
With intermediate 32 (0.10g, 0.33mmol), 3-bromo-N-sec.-propyl-benzsulfamide (0.11g, 0.39mmol), Pd
2(dba)
3(20mg, 0.022mmol), Xantphos (25mg, 0.043mmol) and cesium carbonate (0.25g, 0.77mmol) Zai diox/DMF (3/1,4mL) suspension in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 20 minutes.After being cooled to room temperature, removing lid and filter the gained mixture and with the solid of DCM washing and filtering.Concentrated filtrate and by HPLC purifying resistates.Merge fraction and the saturated NaHCO of impouring
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and with resistates the mixture of EtOAc/ hexane (1/10, grind in 33mL).Filter the back and obtain title compound, be pale solid (47mg, 29%).
1H?NMR(500MHz，DMSO-d
6):δ?0.98(d，J＝6.6Hz，6H)，2.11(s，3H)，2.24(s，3H)，2.45-2.50(m，4H)，3.03(t，J＝4.8Hz，4H)，3.20-3.27(m，1H)，6.80(d，J＝9.0Hz，2H)，7.40-7.52(m，4H)，7.59(d，J＝7.1Hz，1H)，7.89(s，1H)，8.21(br?d，J＝7.9Hz，1H)，8.53(s，1H)，8.71(s，1H)。MS(ES+):m/z?496(M+H)
+。
Embodiment 95. N
4
-(3-methylsulfonyl-4-methyl-phenyl)-5-methyl-N
2
-[4-(the 4-methyl-
Piperazine-1-yl)-phenyl]-pyrimidine-2,4-diamines (compound L XII)
With intermediate 32 (0.10g, 0.33mmol), 4-bromo-2-methylsulfonyl-1-methyl-benzene (0.10g, 0.40mmol), Pd
2(dba)
3(20mg, 0.022mmol), Xantphos (25mg, 0.043mmol) and cesium carbonate (0.25g, 0.77mmol) Zai diox/DMF (3/1,4mL) suspension in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 15 minutes.After being cooled to room temperature, removing lid and filter the gained mixture and with the solid of DCM washing and filtering.Concentrated filtrate and by HPLC purifying resistates.Merge fraction and the saturated NaHCO of impouring
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and with resistates the mixture of EtOAc/ hexane (1/5, grind in 30mL).Filter the back and obtain title compound, be light brown solid (41mg, 27%).
1H?NMR(500MHz，DMSO-d
6):δ?2.09(s，3H)，2.22(s，3H)，2.45(t，J＝4.7Hz，4H)，2.61(s，3H)，3.03(t，J＝4.9Hz，4H)，3.20(s，3H)，6.80(d，J＝9.1Hz，2H)，7.35(d，J＝8.5Hz，1H)，7.44(d，J＝9.0Hz，2H)，7.87(s，1H)，8.05(d，J＝2.4Hz，1H)，8.21(br?d，J＝7.0Hz，1H)，8.55(s，1H)，8.71(s，1H)。MS(ES+):m/z?467(M+H)
+。
Embodiment 96. N-cyclohexyl-3-{5-methyl-2-[4-(4-methyl-piperazine-1-yl)-phenyl
Amino]-pyrimidine-4-base is amino }-benzsulfamide (compound L XIII)
With intermediate 32 (0.10g, 0.33mmol), 3-bromo-N-cyclohexyl-benzsulfamide (0.13g, 0.41mmol), Pd
2(dba)
3(20mg, 0.022mmol), Xantphos (25mg, 0.043mmol) and cesium carbonate (0.25g, 0.77mmol) Zai diox/DMF (3/1,4mL) suspension in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 15 minutes.After being cooled to room temperature, removing lid and filter the gained mixture and with the solid of DCM washing and filtering.Concentrated filtrate and by HPLC purifying resistates.Merge fraction and the saturated NaHCO of impouring
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and with resistates the mixture of EtOAc/ hexane (1/10, grind in 33mL).Filter the back and obtain title compound, be pale solid (45mg, 25%).
1H?NMR(500MHz，DMSO-d
6):δ?1.07-1.17(m，6H)，1.53-1.63(m，4H)，2.11(s，3H)，2.22(s，3H)，2.45(t，J＝4.7Hz，4H)，2.90-3.00(m，1H)，3.02(t，J＝4.8Hz，4H)，6.80(d，J＝9.1Hz，2H)，7.43-7.53(m，4H)，7.65(d，J＝7.3Hz，1H)，7.89(s，1H)，8.05(s，1H)，8.18(brd，J＝7.7Hz，1H)，8.52(s，1H)，8.71(s，1H)。MS(ES+):m/z?536(M+H)
+。
Embodiment 97. N, N-diethyl-3-{5-methyl-2-[4-(4-methyl-piperazine-1-yl)-benzene
Base is amino]-pyrimidine-4-base is amino }-benzsulfamide (compound L XIV)
With intermediate 32 (0.10g, 0.33mmol), 3-bromo-N, N-diethyl-benzsulfamide (0.12g, 0.41mmol), Pd
2(dba)
3(20mg, 0.022mmol), Xantphos (25mg, 0.043mmol) and cesium carbonate (0.25g, 0.77mmol) Zai diox/DMF (3/1,4mL) suspension in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 15 minutes.After being cooled to room temperature, removing lid and filter the gained mixture and with the solid of DCM washing and filtering.Concentrated filtrate and by HPLC purifying resistates.Merge fraction and the saturated NaHCO of impouring
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and with resistates the mixture of EtOAc/ hexane (1/10, grind in 33mL).Filter the back and obtain title compound, be pale solid (45mg, 27%).
1H?NMR(500MHz，DMSO-d
6):δ?1.06(t，J＝7.1Hz，6H)，2.11(s，3H)，2.22(s，3H)，2.44(t，J＝4.7Hz，4H)，3.03(t，J＝4.8Hz，4H)，3.16(q，J＝7.1Hz，4H)，6.80(d，J＝9.1Hz，2H)，7.39(d，J＝8.1Hz，1H)，7.45(d，J＝9.0Hz，2H)，7.50(t，J＝8.1Hz，1H)，7.89(t，J＝1.9Hz，1H)，7.89(s，1H)，8.39(br?d，J＝7.9Hz，1H)，8.53(s，1H)，8.74(s，1H)。MS(ES+):m/z?510(M+H)
+。
Embodiment 98. 5-methyl-N
2
-[4-(4-methyl-piperazine-1-yl)-phenyl]-N
4
-[3-(morpholine
-4-alkylsulfonyl)-phenyl]-pyrimidine-2,4-diamines (compound L XV)
With intermediate 32 (0.10g, 0.33mmol), 4-(3-bromo-benzenesulfonyl)-morpholine (0.12g, 0.39mmol), Pd
2(dba)
3(20mg, 0.022mmol), Xantphos (25mg, 0.043mmol) and cesium carbonate (0.25g, 0.77mmol) Zai diox/DMF (3/1,4mL) suspension in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 15 minutes.After being cooled to room temperature, removing lid and filter the gained mixture and with the solid of DCM washing and filtering.Concentrated filtrate and by HPLC purifying resistates.Merge fraction and the saturated NaHCO of impouring
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and with resistates the mixture of EtOAc/ hexane (1/10, grind in 33mL).Filter the back and obtain title compound, be incarnadine solid (90mg, 52%).
1H?NMR(500MHz，DMSO-d
6):δ?2.12(s，3H)，2.22(s，3H)，2.45(t，J＝4.8Hz，4H)，2.89(t，J＝4.6Hz，4H)，3.03(t，J＝4.8Hz，4H)，3.64(t，J＝4.7Hz，4H)，6.81(d，J＝9.1Hz，2H)，7.35(d，J＝8.1Hz，1H)，7.45(d，J＝9.0Hz，2H)，7.56(t，J＝8.1Hz，1H)，7.84(t，J＝1.9Hz，1H)，7.91(s，1H)，8.47(br?d，J＝8.4Hz，1H)，8.59(s，1H)，8.75(s，1H)。MS(ES+):m/z?524(M+H)
+。
Embodiment 99. 3-{5-methyl-2-[4-(4-methyl-piperazine-1-yl)-phenyl amino]-pyrimidine
-4-base is amino }-ethyl benzoate (intermediate 36)
With intermediate 32 (0.10g, 0.33mmol), 3-bromo-ethyl benzoate (0.07mL, 0.44mmol), Pd
2(dba)
3(20mg, 0.022mmol), Xantphos (25mg, 0.043mmol) and cesium carbonate (0.25g, 0.77mmol) the suspension in the Zai diox (3mL) be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 15 minutes.After being cooled to room temperature, removing lid and filter the gained mixture and with the solid of DCM washing and filtering.Concentrated filtrate and obtain title compound (0.10g, 68%) by fast silica gel chromatogram method purifying resistates (DCM-10% MeOH/DCM).MS(ES+):m/z?447(M+H)
+。
Embodiment 100.3-{5-methyl-2-[4-(4-methyl-piperazine-1-yl)-phenyl amino]-phonetic
Pyridine-4-base is amino }-benzamide (compound L XVI)
(0.10g is 0.22mmol) at dense NH with intermediate 36
4Mixture among the OH is sealed in the reaction tubes and at 50 ℃ and heated 3 days down.Extract with this mixture impouring water (15mL) and with EtOAc (2 x 30mL).With the organic layer that the salt water washing merges, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With EtOAc (2 x 30mL) aqueous layer extracted and with the organic layer that the salt water washing merges, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and with resistates the mixture of EtOAc/ hexane (1/10, grind in 33mL).Filter the back and obtain title compound, be white solid (10mg, 11%).
1H?NMR(500MHz，DMSO-d
6):δ?2.10(s，3H)，2.22(s，3H)，2.40-2.50(m，4H)，2.95-3.05(m，4H)，6.75(d，J＝9.1Hz，2H)，7.30-7.40(m，2H)，7.45(d，J＝9.1Hz，2H)，7.53-7.58(m，1H)，7.85(s，1H)，7.90(brs，2H)，8.03(s，1H)，8.37(s，1H)，8.71(s，1H)。MS(ES+):m/z?418(M+H)
+。
Embodiment 101. 2-methyl-3-{5-methyl-2-[4-(4-methyl-piperazine-1-yl)-phenylamino
Base]-pyrimidine-4-base is amino }-ethyl benzoate (compound L XVII)
With intermediate 32 (0.10g, 0.33mmol), 3-bromo-2-methyl-ethyl benzoate (0.10mL, 0.41mmol), Pd
2(dba)
3(20mg, 0.022mmol), Xantphos (25mg, 0.043mmol) and cesium carbonate (0.25g, 0.77mmol) the suspension in the Zai diox (3mL) be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 20 minutes.After being cooled to room temperature, removing lid and filter the gained mixture and with the solid of DCM washing and filtering.Concentrated filtrate and obtain title compound (0.14g, 92%) by fast silica gel chromatogram method purifying resistates (30%MeOH and 1% TEA of DCM-in DCM) is light brown oily thing.
1H?NMR(500MHz，DMSO-d
6):δ?1.32(t，J＝7.1Hz，3H)，2.10(s，3H)，2.21(s，3H)，2.32(s，3H)，2.40-2.45(m，4H)，2.94(t，J＝4.8Hz，4H)，4.30(q，J＝7.1Hz，2H)，6.57(d，J＝9.1Hz，2H)，7.25(d，J＝8.9Hz，2H)，7.35(t，J＝7.8Hz，1H)，7.48(dd，J＝7.9，1.0Hz，1H)，7.70(dd，J＝7.8，1.1Hz，1H)，7.78(s，1H)，8.23(s，1H)，8.58(s，1H)。MS(ES+):m/z461(M+H)
+。
Embodiment 102. 2-methyl-3-{5-methyl-2-[4-(4-methyl-piperazine-1-yl)-phenylamino
Base]-pyrimidine-4-base is amino }-benzamide (compound L XVIII)
In ar gas environment to 100 ℃ of following above-claimed cpd LXVII (0.10g, 0.22mmol) and methane amide (0.05mL, 1.3mmol) add in the mixture in DMF (5mL) NaOMe (0.10g, 0.46mmol).This mixture stirred 2 hours under uniform temp and restir 15 hours at room temperature then.Extract with this mixture impouring water (15mL) and with EtOAc (2 x 15mL).With the organic layer that the salt water washing merges, use dry anhydrous Na
2SO
4And filter.Concentrated filtrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With EtOAc (2 x 30mL) aqueous layer extracted and with the organic layer that the salt water washing merges, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and with resistates the EtOAc/ hexane (1/5, grind in mixture 30mL).Filter the back and obtain title compound, be white solid (20mg, 21%).
1H?NMR(500MHz，DMSO-d
6):δ?2.09(s，3H)，2.21(s，3H)，2.23(s，3H)，2.40-2.45(m，4H)，2.97(t，J＝4.8Hz，4H)，6.69(d，J＝9.1Hz，2H)，7.24-7.28(m，2H)，7.35(d，J＝9.0Hz，2H)，7.39-7.43(m，2H)，7.69(s，1H)，7.78(s，1H)，8.01(s，1H)，8.53(s，1H)。MS(ES+):m/z?432(M+H)
+。
Embodiment 103. (2-chloro-5-methyl-pyrimidine-4-yl)-(4-chloro-3-trifluoromethyl-phenyl)-amine
(intermediate 37)
With 2-chloro-5-methyl-pyrimidine-4-base amine (0.30g, 2.1mmol), 4-bromo-1-chloro-2-trifluoromethyl-benzene (0.40mL, 2.7mmol), Pd
2(dba)
3(0.10g, 0.11mmol), Xantphos (0.13g, 0.22mmol) and cesium carbonate (1.5g, 4.6mmol) Zai diox/DMF (6/1,7mL) mixture in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 15 minutes.After being cooled to room temperature, removing lid and filter the gained mixture and with the solid of DCM washing and filtering.Concentrated filtrate and obtain title compound (0.65g, 96%) by fast silica gel chromatogram method purifying resistates (hexane-50% EtOAc/ hexane) is white solid.MS(ES+):m/z?322(M+H)
+。
Embodiment 104. N
4
-(4-chloro-3-trifluoromethyl-phenyl)-5-methyl-N
2
-[4-(piperidines-4-
Base oxygen base)-phenyl]-pyrimidine-2,4-diamines (compound L XIX)
With intermediate 37 (0.10g, 0.31mmol) and 4-(4-amino-phenoxy group)-piperidines-1-t-butyl formate (0.12g, 0.41mmol) mixture in acetate (3mL) be sealed in the microwave reaction pipe and at 150 ℃ down with microwave irradiations 15 minutes.After being cooled to room temperature, removing lid and concentrate this mixture.Be neutralized to solid precipitation with resistates water-soluble (20mL) and with 10% NaOH solution.Filter the gained solid and pass through the HPLC purifying.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With EtOAc (2 x 30mL) aqueous layer extracted and with the organic layer that the salt water washing merges, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and obtain title compound is white solid (30mg, 20%).
1H?NMR(500MHz，DMSO-d
6):δ?1.69-1.77(m，2H)，2.00-2.04(m，2H)，2.11(s，3H)，2.90-3.00(m，2H)，3.10-3.20(m，2H)，4.40-4.48(m，1H)，6.84(d，J＝9.0Hz，2H)，7.49(d，J＝9.0Hz，2H)，7.58(d，J＝8.8Hz，1H)，7.94(s，1H)，8.12(d，J＝2.6Hz，1H)，8.21(br?d，J＝8.2Hz，1H)，8.64(s，1H)，8.93(s，1H)。MS(ES+):m/z?478(M+H)
+。
Embodiment 105. 5-methyl-N
2
-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-pyrimidine
-2,4-diamines (intermediate 38)
With 2-chloro-5-methyl-pyrimidine-4-base amine (0.50g, 3.5mmol) and 4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl amine (1.1g, 5.3mmol) mixture in acetate (8mL) be sealed in the microwave reaction pipe and at 150 ℃ down with microwave irradiations 15 minutes.After being cooled to room temperature, removing lid and concentrate this mixture.Be neutralized to pH～10 with resistates water-soluble (30mL) and with 10%NaOH solution.With the organic layer that EtOAc (2 x 30mL) extracts the gained water layer and merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and obtain title compound is gray solid (0.80g, 73%).It not purifiedly is used for next step.MS(ES+):m/z?314(M+H)
+。
Embodiment 106.3-{5-methyl-2-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenylamino
Base]-pyrimidine-4-base is amino }-benzsulfamide (compound L XX)
With intermediate 38 (0.10g, 0.32mmol), 3-bromo-benzsulfamide (0.10g, 0.42mmol), Pd
2(dba)
3(20mg, 0.022mmol), Xantphos (25mg, 0.043mmol) and cesium carbonate (0.20g, 0.61mmol) Zai diox/DMF (3/1,4mL) mixture in be sealed in the microwave reaction pipe and at 170 ℃ down with microwave irradiations 25 minutes.After being cooled to room temperature, removing lid and filter the gained mixture and with the solid of DCM washing and filtering.Concentrated filtrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With EtOAc (2 x 30mL) aqueous layer extracted and with the organic layer that the salt water washing merges, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and with solid the EtOAc/ hexanes mixtures (1/10, grind in 33mL).Filter the back and obtain title compound, be white solid (1mg, 7%).
1H?NMR(500MHz，DMSO-d
6):δ?1.65-1.72(m，4H)，2.11(s，3H)，2.49-2.52(m，4H)，2.75-2.80(m，2H)，4.00(t，J＝5.9Hz，2H)，6.80(d，J＝9.0Hz，2H)，7.34(s，2H)，7.45-7.50(m，2H)，7.52(d，J＝9.0Hz，2H)，7.90(s，1H)，8.05(s，1H)，8.10-8.15(m，1H)，8.57(s，1H)，8.77(s，1H)。MS(ES+):m/z469(M+H)
+。
Embodiment 107. 5-methyl-N
2
-(4-morpholine-4-ylmethyl-phenyl)-pyrimidine-2, the 4-diamines
(intermediate 39)
(0.40g, 2.8mmol) (0.60g, 3.1mmol) mixture in acetate (15mL) heated 17 hours down at 70 ℃ with 4-morpholine-4-ylmethyl-phenyl amine with 2-chloro-5-methyl-pyrimidine-4-base amine.After being cooled to room temperature, concentrate this mixture.Be neutralized to pH～10 with resistates water-soluble (30mL) and with 10% NaOH solution.With the organic layer that EtOAc (2 x 30mL) extracts the gained water layer and merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and obtain title compound is brown syrup shape thing (0.70g, 83%).It is used for next step without being further purified.MS(ES+):m/z?300(M+H)
+
Embodiment 108
N
4
-(1H-indoles-4-yl)-5-methyl-N
2
-(4-morpholine-4-ylmethyl-phenyl)-
Pyrimidine-2,4-diamines (compound L XXI)
With intermediate 39 (0.40g, 1.3mmol), 4-bromo-1-triisopropyl silyl-1H-indoles (0.50g, 1.4mmol), Pd
2(dba)
3(0.10g, 0.11mmol), Xantphos (0.12g, 0.21mmol) and cesium carbonate (0.90g, mixture 2.8mmol) be suspended in the diox (20mL) and under reflux state and ar gas environment in the heating 4 hours.This reaction mixture is cooled to room temperature and dilutes with DCM (30mL).Filter this mixture and concentrated filtrate in a vacuum.(hexane-EtOAc) obtain the precursor that TIPS protects is yellow oil by fast silica gel chromatogram method purifying resistates.
Precursor (50mg, 0.088mmol) the middle TBAF (0.5mL, 1M in THF) that adds to the above-mentioned TIPS protection in THF (5mL).This mixture at room temperature stirred 1 hour and impouring water (20mL) then.With EtOAc (2 x 20mL) aqueous layer extracted and with the organic layer that the salt water washing merges, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With EtOAc (2 x 30mL) aqueous layer extracted and with the organic layer that the salt water washing merges, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and solid is dissolved in minimum EtOAc and adds hexane then is up to solid precipitation.Filter the back and obtain title compound, be light brown solid (6mg, overall yield 1%).
1H?NMR(500MHz，DMSO-d
6):δ?2.17(s，3H)，2.25-2.30(m，4H)，3.29(s，2H)，3.54(t，J＝4.5Hz，4H)，6.40(t，J＝2.2Hz，1H)，6.89(d，J＝8.5Hz，2H)，7.09(t，J＝7.8Hz，1H)，7.25(d，J＝8.0Hz，1H)，7.27(t，J＝2.8Hz，1H)，7.30(d，J＝7.5Hz，1H)，7.43(d，J＝8.5Hz，2H)，7.85(s，1H)，8.14(s，1H)，8.77(s，1H)，11.10(s，1H)。MS(ES+):m/z?415(M+H)
+。
Embodiment 109. 4-[4-(4-amino-5-methyl-pyrimidine-2--amino)-benzyl]-piperazine
-1-t-butyl formate (intermediate 40)
With 2-chloro-5-methyl-pyrimidine-4-base amine (0.35g, 2.4mmol) and 4-(4-amino-benzyl)-piperazine-1-t-butyl formate (0.80g, 2.8mmol) mixture in acetate (20mL) heated 1 day down at 70 ℃.After being cooled to room temperature, concentrate this mixture.Be neutralized to pH～10 with resistates water-soluble (30mL) and with 10% NaOH solution.With the organic layer that EtOAc (2 x 30mL) extracts the gained water layer and merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and not purified title compound is used for next step.MS(ES+):m/z?399(M+H)
+。
Embodiment 110. N
4
-(1H-indoles-4-yl)-5-methyl-N
2
-(4-piperazine-1-ylmethyl-benzene
Base)-and pyrimidine-2,4-diamines (compound L XXII)
With intermediate 40 (0.78g, 2.0mmol), 4-bromo-1-triisopropyl silyl-1H-indoles (0.70g, 2.0mmol), Pd
2(dba)
3(0.15g, 0.16mmol), Xantphos (0.19g, 0.32mmol) and cesium carbonate (1.3g, mixture 4.0mmol) be suspended in the diox (20mL) and under reflux state and ar gas environment in the heating 4.5 hours.This reaction mixture is cooled to room temperature, filters and with the solid of DCM (30mL) washing and filtering.Concentrated filtrate and obtain the precursor of TIPS protection by fast silica gel chromatogram method purifying resistates (hexane-30%EtOAc/ hexane).
Precursor (0.10g, 0.15mmol) adding TFA (2mL) to the above-mentioned TIPS protection in DCM (8mL).This mixture was at room temperature stirred 2 hours and concentrate then.Fraction and the saturated NaHCO of impouring by HPLC purifying resistates and merging calibration
3Solution (30mL).With EtOAc (2 x 30mL) aqueous layer extracted and with the organic layer that the salt water washing merges, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and with solid the mixture of EtOAc/ hexane (1/5, grind in 30mL).After filtration, obtain title compound, be white solid (25mg, overall yield 3%).
1H?NMR(500MHz，DMSO-d
6):δ?2.17(s，3H)，2.20-2.30(m，4H)，2.73(t，J＝4.6Hz，4H)，3.28(s，2H)，6.41(t，J＝2.2Hz，1H)，6.89(d，J＝8.5Hz，2H)，7.09(t，J＝7.8Hz，1H)，7.24(d，J＝8.3Hz，1H)，7.27(t，J＝2.8Hz，1H)，7.31(d，J＝7.5Hz，1H)，7.44(d，J＝8.5Hz，2H)，7.85(s，1H)，8.13(s，1H)，8.77(s，1H)，11.10(s，1H)
MS(ES+):m/z?414(M+H)
+。
Embodiment 111. 5-methyl-N
4
-(7-Methyl-1H-indole-4-yl)-N
2
-(4-(4-methyl piperazine
Piperazine-1-yl) pyrimidine-2 phenyl), 4-diamines (compound L XXIII)
With intermediate 32 (674mg, 2.25mmol), 4-bromo-7-Methyl-1H-indole (522mg, 2.48mmol), Pd
2(dba)
3(182mg, 0.2mmol), Xantphos (360mg, 0.6mmol) and cesium carbonate (2.6g, mixture 8mmol) be suspended in the diox (50mL) and under reflux state and ar gas environment in the heating 20 hours.Filter this mixture and concentrated filtrate in a vacuum.Obtain title compound (136mgHCl salt, 13%) by HPLC purifying resistates, be white solid.
1H?NMR(500MHz，DMSO-d
6):δ?2.21(s，3H)，2.55(s，3H)，2.80(d，J＝4.6Hz，3H)，3.00-3.05(m，2H)，3.10-3.16(m，2H)，3.45-3.48(m，2H)，3.64-3.66(m，2H)，6.33-6.34(m，1H)，6.63(br，2H)，6.92-6.97(m，4H)，7.35(t，J＝2.7Hz，1H)，7.83(s，1H)，10.04(s，1H)，10.24(s，1H)，11.08(brs，1H)，11.34(s，1H)，12.12(br?s，1H)。MS(ES+):m/z?428(M+H)
+。
Embodiment 112. N
4
-(7-chloro-1H-indoles-4-yl)-5-methyl-N
2
-(4-(4-methylpiperazine
-1-yl) pyrimidine-2 phenyl), 4-diamines (compound L XXIV)
With intermediate 32 (298mg, 1.0mmol), 4-bromo-7-chloro-1H-indoles (231mg, 1.04mmol), Pd
2(dba)
3(92mg, 0.1mmol), Xantphos (180mg, 0.3mmol) and cesium carbonate (1.3g, mixture 4mmol) be suspended in the diox (50mL) and under reflux state and ar gas environment in the heating 20 hours.Filter this mixture and concentrated filtrate in a vacuum.Obtain title compound (251mg HCl salt, 51%) by HPLC purifying resistates, be white solid.
1H?NMR(500MHz，DMSO-d
6):δ?2.21(s，3H)，2.80(d，J＝4.6Hz，3H)，3.01-3.05(m，2H)，3.08-3.13(m，2H)，3.46-3.48(m，2H)，3.65-3.67(m，2H)，6.46-6.47(m，1H)，6.64(brs，1H)，6.93(d，J＝8.9Hz，2H)，7.05(d，J＝8.1Hz，2H)，7.25(d，J＝8.0Hz，2H)，7.43-7.44(m，1H)，7.87(s，1H)，10.13(s，1H)，10.27(s，1H)，11.00(br?s，1H)，11.70(s，1H)，12.23(br?s，H)。MS(ES+):m/z?448(M+H)
+。
Embodiment 113. N
2
-(4-(2-(tetramethyleneimine-1-yl) oxyethyl group) phenyl)-5-methyl-N
4
-(7-
Methyl-1H-indole-4-yl) pyrimidine-2,4-diamines (compound L XXV)
With intermediate 38 (410mg, 1.3mmol), 4-bromo-7-Methyl-1H-indole (275mg, 1.3mmol), Pd
2(dba)
3(92mg, 0.1mmol), Xantphos (180mg, 0.3mmol) and cesium carbonate (1.3g, mixture 4mmol) be suspended in the diox (50mL) and under reflux state and ar gas environment in the heating 20 hours.Filter this mixture and concentrated filtrate in a vacuum.Obtain title compound (92mgHCl salt, 15%) by HPLC purifying resistates, be white solid.
1H?NMR(500MHz，DMSO-d
6):δ?1.88-1.90(m，2H)，1.93-2.02(m，2H)，2.21(s，3H)，2.55(s，3H)，3.06-3.10(m，2H)，3.51-3.54(m，4H)，4.26(t，J＝4.9Hz，2H)，6.33-6.34(m，1H)，6.61(br?d，2H)，6.93-6.95(m，2H)，7.03(d，J＝8.9Hz，2H)，7.34(t，J＝2.8Hz，1H)，7.85(s，1H)，10.07(s，1H)，10.33(s，1H)，10.91(br?s，1H)，11.34(s，1H)，12.15(br?s，H)。MS(ES+):m/z?443(M+H)
+。
Embodiment 114. N
2
-(4-(2-(tetramethyleneimine-1-yl) oxyethyl group) phenyl)-5-methyl-N
4
-(7-
Chloro-1H-indoles-4-yl) pyrimidine-2,4-diamines (compound L XXVI)
With intermediate 38 (270mg, 0.86mmol), 4-bromo-7-chloro-1H-indoles (198mg, 0.86mmol), Pd
2(dba)
3(72mg, 0.08mmol), Xantphos (140mg, 0.24mmol) and cesium carbonate (1.3g, mixture 4mmol) be suspended in the diox (50mL) and under reflux state and ar gas environment in the heating 20 hours.Filter this mixture and concentrated filtrate in a vacuum.Obtain title compound (33mg HCl salt, 8%) by HPLC purifying resistates, be white solid.
1H?NMR(500MHz，DMSO-d
6):δ?1.88-1.90(m，2H)，1.93-2.02(m，2H)，2.22(s，3H)，3.06-3.10(m，2H)，3.51-3.54(m，4H)，4.27(t，J＝4.9Hz，2H)，6.46-6.47(m，1H)，6.63(br?d，2H)，6.95(d，J＝8.2Hz，2H)，7.06(d，J＝8.0Hz，1H)，7.25(d，J＝8.0Hz，1H)，7.43(t，J＝2.8Hz，1H)，7.90(s，1H)，10.13(s，1H)，10.40(s，1H)，10.94(br?s，1H)，11.70(s，1H)，12.33(br?s，H)。MS(ES+):m/z?463(M+H)
+。
Embodiment 115. N
2
-(4-(2-(tetramethyleneimine-1-yl) oxyethyl group) phenyl)-5-methyl-N
4
-(7-
Fluoro-1H-indoles-4-yl) pyrimidine-2,4-diamines (compound L XXVII)
With intermediate 38 (413mg, 1.3mmol), 4-bromo-7-fluoro-1H-indoles (310mg, 1.45mmol), Pd
2(dba)
3(92mg, 0.1mmol), Xantphos (180mg, 0.3mmol) and cesium carbonate (1.3g, mixture 4mmol) be suspended in the diox (50mL) and under reflux state and ar gas environment in the heating 20 hours.Filter this mixture and concentrated filtrate in a vacuum.Obtain title compound (10mg HCl salt, 1.5%) by HPLC purifying resistates, be brown solid.
1H?NMR(500MHz，DMSO-d
6):δ?1.88-1.90(m，2H)，1.93-2.02(m，2H)，2.21(s，3H)，3.06-3.10(m，2H)，3.51-3.56(m，4H)，4.26(t，J＝4.9Hz，2H)，6.42-6.43(m，1H)，6.63(brd，2H)，6.95-7.04(m，3H)，7.35(d，J＝8.9Hz，1H)，7.42(t，J＝2.8Hz，1H)，7.89(s，1H)，10.08(s，1H)，10.41(s，1H)，10.90(br?s，1H)，11.85(s，1H)，12.33(br?s，H)。MS(ES+):m/z?447(M+H)
+。
Embodiment 116. N
4
-(3-tert-butyl-phenyl)-5-methyl-N
2
-(4-(4-methylpiperazine-1-yl)
Phenyl) pyrimidine-2,4-diamines (compound L XXVIII)
With intermediate 32 (298mg, 1.0mmol), the 1-tertiary butyl-3-bromobenzene (256mg, 1.2mmol), Pd
2(dba)
3(92mg, 0.1mmol), Xantphos (180mg, 0.3mmol) and cesium carbonate (1.3g, mixture 4mmol) be suspended in the diox (50mL) and under reflux state and ar gas environment in the heating 20 hours.Filter this mixture and concentrated filtrate in a vacuum.Obtain title compound (27mg HCl salt, 6%) by HPLC purifying resistates, be white solid.
1H?NMR(500MHz，DMSO-d
6):δ?1.25(s，9H)，2.16(s，3H)，2.80(d，J＝4.6Hz，3H)，3.04-3.16(m，4H)，3.47-3.49(m，2H)，3.65-3.67(m，2H)，6.90(d，J＝8.9Hz，2H)，7.26(d，J＝9.0Hz，2H)，7.28-7.35(m，2H)，7.45(t，J＝1.8Hz，1H)，7.50(d，J＝7.8Hz，1H)，7.86(s，1H)，9.70(s，1H)，10.37(s，1H)，11.01(br?s，1H)，12.34(br?s，H)。MS(ES+):m/z?431(M+H)
+。
Embodiment 117. N-(3-tert-butyl-phenyl)-2-chloro-5-methylpyrimidine-4-amine (intermediate 41)
With 2-chloro-5-methylpyrimidine-4-amine (670mg, 4.7mmol), the 1-tertiary butyl-3-bromobenzene (1.5g, 7mmol), Pd
2(dba)
3(366mg, 0.4mmol), Xantphos (695mg, 1.2mmol) and cesium carbonate (6.2g, mixture 19mmol) be suspended in the diox (150mL) and under reflux state and ar gas environment in the heating 20 hours.Filter this mixture and concentrated filtrate in a vacuum.Resistates is dissolved in EtOAc (10mL) and adds hexane (100mL).Obtain thick title compound (1.2g, 99%) by solid collected by filtration and with hexane wash, be yellow solid.
Embodiment 118. N
4
-(3-tert-butyl-phenyl)-5-methyl-N
2
-(4-(piperidin-4-yl oxygen base) benzene
Base) pyrimidine-2,4-diamines (compound L XXIX)
With intermediate 41 (740mg, 2.68mmol) and 4-(4-amino-benzene oxygen) piperidines-1-t-butyl formate (500mg, mixture 1.71mmol) are suspended in the acetate (10mL) and 100 ℃ of heating 4 hours down.This mixture is cooled to room temperature and under reduced pressure removes acetate.With resistates water-soluble (20mL) and be neutralized to pH～7.With EtOAc (30mL) extraction gained solution and separation organic layer.With salt water washing organic layer, use MgSO
4Drying and filtration.Concentrated filtrate and obtain title compound (276mg HCl salt, 35%) by HPLC purifying crude product is yellow solid in a vacuum.
1H?NMR(500MHz，DMSO-d
6):δ?1.22(s，9H)，1.77-1.81(m，2H)，2.03-2.07(m，2H)，2.14(s，3H)，3.00-3.04(m，2H)，3.18(br?s，2H)，4.56-4.57(m，1H)，6.86(d，J＝8.9Hz，2H)，7.26-7.31(m，4H)，7.40(s，1H)，7.44(d，J＝7.5Hz，1H)，7.84(s，1H)，8.93(br?s，1H)，8.99(br?s，1H)，9.67(s，1H)，10.31(s，1H)。MS(ES+):m/z?432(M+H)
+。
Embodiment 119.4-(4-(4-amino-5-methylpyrimidine-2-base is amino) phenoxy group) piperidines-1-
T-butyl formate (intermediate 42)
(540mg, 3.7mmol), (1.1g, mixture 3.7mmol) are suspended in the acetate (20mL) and at 70 ℃ and heated 1 hour down 4-(4-amino-benzene oxygen) piperidines-1-t-butyl formate with 2-chloro-5-methylpyrimidine-4-amine.This mixture is cooled to room temperature and under reduced pressure removes acetate.With resistates water-soluble (20mL) and be neutralized to pH～7.With EtOAc (30mL) extraction gained solution and separation organic layer.With salt water washing organic layer, use MgSO
4Drying and filtration.Concentrated filtrate and obtain title compound (1.4g, 95%) is yellow solid in a vacuum.
Embodiment 120. N
4
-(1H-indazole-4-yl)-5-methyl-N
2
-(4-(piperidin-4-yl oxygen base) benzene
Base) pyrimidine-2,4-diamines (compound L XXX)
With intermediate 42 (480mg, 1.2mmol), 4-bromo-1H-indazole (236mg, 1.2mmol), Pd
2(dba)
3(92mg, 0.1mmol), Xantphos (180mg, 0.3mmol) and cesium carbonate (1.3g, mixture 4mmol) be suspended in the diox (50mL) and under reflux state and ar gas environment in the heating 20 hours.Filter this mixture and concentrated filtrate in a vacuum.Obtain title compound (4mg HCl salt, 1.2%) by HPLC purifying resistates, be yellow solid.
1HNMR(500MHz，DMSO-d
6):δ?1.75-1.80(m，2H)，2.02-2.07(m，2H)，2.24(s，3H)，3.05-3.09(m，2H)，3.17-3.21(m，2H)，4.52(br?s，1H)，6.63(d，J＝8.6Hz，2H)，7.01(d，J＝8.6Hz，2H)，7.14(d，J＝7.3Hz，2H)，7.38-7.44(m，2H)，7.62(d，J＝8.9Hz，2H)，7.92(s，1H)，8.02(s，1H)，9.00(br?s，1H)，9.04(br?s，1H)，10.20(s，1H)，10.33(s，1H)。MS(ES+):m/z?416(M+H)
+。
Embodiment 121. 4-{3-[4-(4-chloro-3-methoxyl group-phenyl amino)-5-methyl-pyrimidine-2-
Base is amino]-benzyl }-piperazine-1-t-butyl formate (intermediate 43)
With intermediate 31 (0.092g, 0.33mmol), 4-(3-amino-benzyl)-piperazine-1-t-butyl formate (0.11g, 0.39mmol), Pd
2(dba)
3(0.03g, 0.033mmol), Xantphos (0.038g, 0.065mmol) and cesium carbonate (0.32g, mixture 0.98mmol) be suspended in the diox (5mL) and at 160 ℃ down with microwave irradiations 15 minutes.This reaction mixture is cooled to room temperature and centrifugal settling.Decantation should reaction and concentrated in a vacuum organic phase.Obtain title compound (0.075g, 43%) by HPLC purifying resistates, be brown solid.
Embodiment 122. N
4
-(4-chloro-3-methoxyl group-phenyl)-5-methyl-N
2
-(3-piperazine-1-Ji Jia
Base-phenyl)-and pyrimidine-2,4-diamines (compound L XXXI)
Handle intermediate 43 (0.075g, 0.14mmol) solution in DCM (8mL) with TFA (2mL).Stir after 2 hours, remove and to desolvate and the gained resistates ground with ether and obtain white hygroscopic powder (0.05g, 82%).
1H?NMR(500MHz，DMSO-d
6):δ?2.17(s，3H)，2.89(br?s，4H)，3.2(br?s，4H)，3.68(s，4H)，3.82(br?s，3H)，7.16-7.19(m，2H)，7.28(t，J＝7.9Hz，1H)，7.33(d，J＝2.3Hz，1H)，7.39(s，1H)，7.43(d，J＝8.5Hz，1H)，7.49(d，8.6Hz，1H)，7.98(s，1H)，8.8(br?s，2H)，9.78(br?s，1H)，10.57(br?s，1H)。MS(ES+):m/z?439(M+H)
+。
Embodiment 123. N
4
-(4-chloro-3-methoxyl group-phenyl)-5-methyl-N
2
-[4-(piperidin-4-yl
The oxygen base)-phenyl]-pyrimidine-2,4-diamines (compound L XXXII)
With intermediate 31 (0.66g, 2.3mmol) and 4-(4-amino-phenoxy group)-piperidines-1-t-butyl formate (0.88mg, 3.0mmol) mixture in acetate (15mL) at 160 ℃ down with microwave irradiations 15 minutes.This mixture is cooled to room temperature and under reduced pressure removes acetate.Be neutralized to solid precipitation with resistates water-soluble (20mL) and with 10% NaOH solution.Filter, carry out column chromatography subsequently and obtain title compound, be light brown solid (0.51g, 50%).
1H?NMR(500MHz，DMSO-d
6):δ?1.37-1.44(m，2H)，1.86-1.89(m，2H)，2.09(s，3H)，2.50-2.56(m，2H)，2.91-2.95(m，2H)，3.16(s，3H)，3.32(br?s，3H)，3.72(s，3H)，4.09(brs，1H)，4.21-4.26(m，1H)，6.77(d，J＝9Hz，2H)，7.27(d，J＝8.5Hz，1H)，7.40-7.42(m，1H)，7.46-7.49(m，3H)，7.87(s，1H)，8.31(s，1H)，8.78(s，1H)。MS(ES+):m/z440(M+H)
+。
Embodiment 124. 4-{3-[4-(4-chloro-3-methoxyl group-phenyl amino)-5-methyl-pyrimidine-2-
Base is amino]-phenyl }-piperazine-1-t-butyl formate (intermediate 44)
With intermediate 31 (0.13g, 0.46mmol) and 4-(3-amino-phenyl)-piperazine-1-t-butyl formate (0.19mg, 0.68mmol) mixture in acetate (8mL) is 80 ℃ of down heating 15 hours.This mixture is cooled to room temperature and under reduced pressure removes acetate.With resistates water-soluble (20mL) and with 10% NaOH solution this mixture that neutralizes.Use ethyl acetate extraction then, with the salt water washing and be evaporated to and obtain the oily resistates.Carry out column chromatography and obtain title compound, be white solid (0.12g, 48%).
Embodiment 125. N
4
-(4-chloro-3-methoxyl group-phenyl)-5-methyl-N
2
-(3-piperazine-1-base-
Phenyl)-and pyrimidine-2,4-diamines (compound L XXXIII)
Handle intermediate 44 (0.11g, 0.21mmol) solution in DCM (8mL) with TFA (1mL).After stirring 3 hours, remove and desolvate and the gained resistates is dissolved in ethyl acetate and washs with 10% sodium hydrogen carbonate solution.Use the dried over sodium sulfate organic phase then, filter and be evaporated to and obtain white powder.With it with DCM (5mL) dilution and with the HCl (0.5mL) of 4M Zai diox processing.At once obtain the HCL salt of title compound except that desolvating, be white solid (0.06g, 67%).
1H?NMR(500MHz，DMSO-d
6):δ?2.18(s，3H)，3.12(brs，4H)，3.22(brs，4H)，3.65(s，3H)，6.80(d，J＝8.1Hz，1H)，6.95(s，2H)，7.14(t，J＝8.2Hz，1H)，7.23(d，J＝7.0Hz，1H)，7.37-7.40(m，2H)，7.95(s，1H)，9.33(br?s，2H)，9.88(s，1H)，10.62(s，1H)。MS(ES+):m/z?425(M+H)
+。
Embodiment 126. 2-[4-(3-bromo-phenyl)-piperidines-1-yl]-ethanol (intermediate 45)
With DMF (20mL) dilution 4-(3-bromo-phenyl)-piperidines (1.2g, 4.8mmol) and ethylene bromohyrin (0.72mL is 10mmol) and with salt of wormwood (2.7g, 20mmol) processing.They were stirred 18 hours at ambient temperature, be poured over waterborne then and use ethyl acetate extraction.Use salt water washing organic phase then, use dried over sodium sulfate, filter and be evaporated to and obtain clarifying oily matter (0.6g, 44%).
Embodiment 127. 2-[4-(3-{5-methyl-2-[4-(4-methyl-piperazine-1-yl)-phenylamino
Base]-pyrimidine-4-base is amino }-phenyl)-piperidines-1-yl]-ethanol (compound L XXXIV)
With intermediate 32 (0.11g, 0.38mmol), intermediate 45 (0.21g, 0.75mmol), Pd
2(dba)
3(0.034g, 0.037mmol), Xantphos (0.043g, 0.075mmol) and cesium carbonate (0.37g, mixture 1.1mmol) be suspended in the diox (10mL) and at 160 ℃ down with microwave irradiations 15 minutes.This reaction mixture is cooled to room temperature and centrifugal settling.Decantation should reaction and concentrated in a vacuum organic phase.Obtain title compound (0.075g, 43%) by HPLC purifying resistates, be purple solid (0.02g, 11%).
1H?NMR(500MHz，DMSO-d
6):δ?1.60-1.67(m，2H)，1.73(d，J＝11.3Hz，2H)，2.02-2.07(m，2H)，2.08(s，3H)，2.21(s，3H)，2.39-2.45(m，7H)，2.95(d，J＝11.4Hz，2H)，3.00(t，J＝4.66Hz，4H)，3.50(t，J＝6.44Hz，2H)，6.76(d，J＝9Hz，2H)，6.92(d，J＝8.5Hz，1H)，7.22(t，J＝7.8Hz，1H)，7.45-7.49(m，3H)，7.66(d，J＝7.7Hz，1H)，7.82(s，1H)，8.09(s，1H)，8.67(s，1H)。MS(ES+):m/z?502(M+H)
+。
Embodiment 128. 4-(3-bromo-benzenesulfonyl amino)-piperidines-1-t-butyl formate (intermediate
46)
Merge 3-bromo-benzene sulfonyl chloride (2.2g, 8.7mmol) and 4-amino-piperadine-1-t-butyl formate (2g, 10mmol) and with DCM (50mL) and TEA (3.6mL 26mmol) dilutes.After 16 hours, will react the impouring separating funnel and wash with water.Use salt water washing organic phase then, use dried over sodium sulfate, filter and be evaporated to and obtain clarifying oily matter, it solidifies (3.6g, 98%) when stablizing.
Embodiment 129. 4-(3-{5-methyl-2-[4-(4-methyl-piperazine-1-yl)-phenyl amino]-
Pyrimidine-4-base is amino }-benzenesulfonyl amino)-piperidines-1-t-butyl formate (intermediate 47)
With intermediate 32 (0.15g, 0.518mmol), intermediate 46 (0.28g, 0.67mmol), Pd
2(dba)
3(0.024g, 0.026mmol), Xantphos (0.03g, 0.052mmol) and cesium carbonate (0.34g, mixture 1mmol) be suspended in the diox (10mL) and at 160 ℃ down with microwave irradiations 15 minutes.This reaction mixture is cooled to room temperature and centrifugal settling.In this reaction of decantation on ice.Dry gained precipitation and directly carry out deprotection steps (0.2g).
Embodiment 130. 3-{5-methyl-2-[4-(4-methyl-piperazine-1-yl)-phenyl amino]-phonetic
Pyridine-4-base is amino }-N-piperidin-4-yl-benzsulfamide (compound L XXXV)
With DCM (10mL) diluted intermediate 47 (0.2g, 0.32mmol and handle with TFA (0.3mL).After 3 hours, remove reaction solvent and pass through HPLC purifying gained resistates (0.01g, 6%).
1H?NMR(500MHz，DMSO-d
6):δ?1.30-1.35(m，2H)，1.56-1.58(m，2H)，1.98(s，2H)，2.11(s，3H)，2.21(s，3H)，2.43-2.45(m，4H)，2.84-2.87(m，2H)，3.02(t，J＝4.6Hz，2H)，6.80(d，J＝9Hz，2H)，7.45-7.51(m，4H)，7.78(br?s，1H)，7.88(s，1H)，8.05(s，1H)，8.20(d，J＝7.6Hz，1H)，8.53(s，1H)，8.71(s，1H)。MS(ES+):m/z537(M+H)
+。
Embodiment 131. N
4
-(4-(trifluoromethyl)-3-aminomethyl phenyl)-5-methyl-N
2
-(4-(4-first
Base piperazine-1-yl) pyrimidine-2 phenyl), 4-diamine hydrochloride (compound L XXXVI)
With argon gas give intermediate 32 (0.12g, 0.40mmol), 1-bromo-3-(trifluoromethyl)-2-methylbenzene (0.14g, 0.59mmol), Pd
2(dba)
3(37mg, 0.04mmol), Xantphos (47mg, 0.08mmol) and cesium carbonate (0.39g, 1.20mmol) the suspension in the Zai diox (20mL) degassing is 2 minutes, in vitro refluxes in sealing then and spends the night.After being cooled to room temperature, except that desolvating and passing through silica gel purification gained mixture, use 10% CH by rotary evaporation
3OH/CHCl
3Obtain title compound as elutriant, be white solid.White mass is dissolved in CHCl
3(30mL) and the HCl in 2M Zai diox be ground to pH1.Remove by rotary evaporation and to desolvate and make solid recrystallization (25mg, 13%) from acetone.
1H?NMR(500MHz，DMSO-d
6):δ?2.20(s，3H)，2.26(s，3H)，2.77(d，J＝4.5Hz，3H)，3.00-3.20(m，4H)，3.45(d，J＝11.6Hz，2H)，3.63(d，J＝12.2Hz，2H)，6.71(d，J＝8.1Hz，2H)，7.05(d，J＝9.0Hz，2H)，7.55(t，J＝7.9Hz，1H)，7.63(d，J＝7.8Hz，1H)，7.77(d，J＝7.77Hz，1H)，7.94(s，1H)，10.13(s，1H)，10.60(s，1H)，11.28(s，1H)。MS(ES+):m/z?457(M+H)
+。
Embodiment 132. 5-methyl-N
2
-(4-(4-methylpiperazine-1-yl) phenyl)-N
4
-(3-(methyl
Alkylsulfonyl) phenyl)-and pyrimidine-2,4-diamines (compound L XXXVII)
With argon gas give intermediate 32 (0.13g, 0.44mmol), 1-bromo-3-(methyl sulphonyl) benzene (0.24g, 1.0mmol), Pd
2(dba)
3(40mg, 0.04mmol), Xantphos (50mg, 0.08mmol) and cesium carbonate (0.43g, 1.32mmol) the suspension in the Zai diox (50mL) degassing is 2 minutes, refluxes then and spends the night.After being cooled to room temperature, except that desolvating and passing through silica gel purification gained mixture, use 30% CH by rotary evaporation
3OH/CHCl
3Obtain title compound as elutriant, be faint yellow solid (35mg, 15%).
1H?NMR(500MHz，DMSO-d
6):δ?2.11(s，3H)，2.23(s，3H)，2.46(brs，4H)，3.03(t，J＝4.4Hz，4H)，3.19(s，3H)，6.81(d，J＝9.0Hz，2H)，7.45(d，J＝8.9Hz，2H)，7.5-7.6(m，2H)，7.91(s，1H)，8.05(s，1H)，8.36(d，J＝6.7Hz，1H)，8.60(s，1H)，8.77(s，1H)。MS(ES+):m/z?453(M+H)
+。
Embodiment 133. 1-bromo-3-(sulfonyl propyl base) benzene (intermediate 48)
To 3-bromobenzene mercaptan (0.50g, 2.6mmol) add in the solution in the Zai diox (50mL) propyl iodide (1.1g, 6.5mmol) and cesium carbonate (2.2g, 6.8mmol) and under refluxing, be stirred to all 3-bromobenzene mercaptan and all react.Use saturated NaHCO
3Solution (25mL) makes the reaction quencher and uses CHCl
3(60mL) extract this mixture.Will be at CHCl
3In product and mCPBA (2.9g 13mmol) is back to all raw materials together and all reacts.To remove excessive mCPBA, use Na with 2M NaOH washing organic layer
2SO
4Drying and filtration.Concentrated filtrate and with silicagel column purifying crude product uses 1:1 hexane/CHCl
3Obtain colorless oil (0.30g in 2-goes on foot, 43%) as elutriant.
1H?NMR(500MHz，DMSO-d
6):0.92(t，J＝7.4Hz，3H)，1.52-1.60(m，2H)，3.35-3.38(m，2H)，7.63(t，J＝8.0Hz，1H)，7.88-7.91(m，1H)，7.95-7.98(m，1H)，8.04(t，J＝1.8Hz，1H)。
Embodiment 134. 5-methyl-N
2
-(4-(4-methylpiperazine-1-yl) phenyl)-N
4
-(3-(propyl group
Alkylsulfonyl) phenyl)-and pyrimidine-2,4-diamine hydrochloride (compound L XXXVIII)
With argon gas give intermediate 32 (0.25g, 0.84mmol), intermediate 48 (0.26g, 1mmol), Pd
2(dba)
3(8mg, 0.01mmol), Xantphos (16mg, 0.03mmol) and cesium carbonate (0.82g, 2.52mmol) the suspension in the Zai diox (50mL) degassing is 2 minutes, refluxes then and spends the night.After being cooled to room temperature, except that desolvating and passing through silica gel purification gained mixture, use 10% CH by rotary evaporation
3OH/CHCl
3Obtain title compound as elutriant.White mass is dissolved in CHCl
3(30mL) and the HCl in 2M Zai diox be ground to pH1.Remove by rotary evaporation and to desolvate and make solid recrystallization (65mg, 15%) from methyl alcohol.
1H?NMR(500MHz，DMSO-d
6):0.90(t，J＝7.4Hz，3H)，1.50-1.60(m，2H)，2.18(s，3H)，2.81(s，3H)，3.00-3.13(m，4H)，3.27(t，J＝7.7Hz，2H)，3.48(d，J＝10.9Hz，2H)，3.75(d，J＝11.4Hz，2H)，6.95(d，J＝8.8Hz，2H)，7.27(d，J＝8.9Hz，2H)，7.64(t，J＝8.0Hz，1H)，7.73(d，J＝7.8Hz，1H)，7.93(s，1H)，8.00(s，1H)，8.07(s，1H)，9.92(s，1H)，10.36(s，1H)，10.99(s，1H)。MS(ES+):m/z?481(M+H)
+。
Embodiment 135. 3-(morpholino methyl) aniline (intermediate 49)
At room temperature (0.1g, (5.9g, 39.02mmol), (3.4g, 39.02mmol), (2.7g is 43mmol) in the solution in methyl alcohol (50mL) for sodium cyanoborohydride for morpholine 0.73mmol) to join the 3-nitrobenzaldehyde with zinc chloride.This solution is heated to backflow 1 hour.After the cooling, water (2mL) makes the reaction quencher, and removes methyl alcohol by rotary evaporation.Crude product is dissolved in 2M NaOH (50mL) and uses CHCl
3Na is used in extraction
2SO
4Drying and filtration.Concentrated filtrate in a vacuum.
At room temperature use Ni and the above-mentioned crude product of hydrazine reduction in methyl alcohol (200mL) in Ruan.By using the TLC monitoring reaction of ethyl acetate.Behind all raw material reactions, remove methyl alcohol by rotary evaporation.By the silica gel purification crude product, use ethyl acetate to obtain white solid (1.5g in 2-goes on foot, 50%) as elutriant.
1H?NMR(500MHz，DMSO-d
6):2.31(s，4H)，3.28(s，2H)，3.56(t，J＝4.6Hz，4H)，4.97(s，2H)，6.40-6.45(m，2H)，6.53(t，J＝1.8Hz，1H)，6.93(t，J＝7.7Hz，1H)。
Embodiment 136 5-methyl-N
2
-(3-(morpholino methyl) phenyl) pyrimidine-2,4-diamines (centre
Body 50)
(0.17g, 1.17mmol) (0.25g, mixture 1.30mmol) are suspended in the acetate (10mL) and at 100 ℃ and heated 2 hours down with intermediate 49 with 2-chloro-5-methylpyrimidine-4-amine.This mixture is cooled to room temperature and under reduced pressure removes acetate.With resistates water-soluble (20mL) and be neutralized to pH～8.Use CHCl
3(100mL) extraction gained solution and separation organic layer.With salt water washing organic layer, use Na
2SO
4Drying and filtration.Concentrated filtrate and by silicagel column purifying crude product uses 10% CH in a vacuum
3OH/EtOAc obtains title compound as elutriant, is oily matter (0.15g, 43%).
1H?NMR(500MHz，DMSO-d
6):1.91(s，3H)，2.35(s，4H)，3.17(s，2H)，3.57(t，J＝4.4Hz，4H)，6.37(s，2H)，6.78(d，J＝7.5Hz，1H)，7.13(t，J＝7.8Hz，1H)，7.59(s，1H)，7.69(s，1H)，7.74(d，J＝9.3Hz，1H)，8.68(s，1H)。
The embodiment 137. N-tertiary butyl-3-[5-methyl-2-(3-morpholine-4-ylmethyl-phenylamino
Base)-pyrimidine-4-base is amino]-benzsulfamide hydrochloride (compound L XXXIX)
With argon gas give intermediate 50 (1.0g, 3.42mmol), the 3-bromo-N-tertiary butyl-benzsulfamide (1.28g, 4.28mmol), Pd
2(dba)
3(30mg, 0.03mmol), Xantphos (40mg, 0.07mmol) and cesium carbonate (3.34g, 10.24mmol) the suspension in the Zai diox (50mL) degassing is 2 minutes, refluxes then and spends the night.After being cooled to room temperature, except that desolvating and passing through silica gel purification gained mixture, use 10%CH by rotary evaporation
3OH/CHCl
3Obtain title compound as elutriant, be white solid.This white solid is dissolved in Re diox (150mL) and the HCl in 2M Zai diox is ground to pH1.Remove by rotary evaporation and to desolvate and make solid recrystallization (0.15g, 8%) from methyl alcohol.
1H?NMR(500MHz，DMSO-d
6):1.08(s，9H)，2.20(s，3H)，3.0-3.2(m，4H)，3.7-4.0(m，4H)，4.23(s，2H)，7.33(t，J＝7.9Hz，1H)，7.38(d，J＝7.7Hz，1H)，7.48(s，1H)，7.55-7.65(m，3H)，7.71(d，J＝7.9Hz，1H)，7.90(d，J＝7.4Hz，1H)，8.01(s，1H)，9.96(br?s，1H)，10.61(br?s，1H)，11.31(br?s，1H)。MS(ES+):m/z?511(M+H)
+。
Embodiment 138. 2-chloro-5-methyl-N-(3, the 5-3,5-dimethylphenyl) pyrimidine-4-amine (intermediates
51)
With 1-bromo-3, and the 5-dimethyl benzene (104 μ L, 0.77mmol), 2-chloro-5-methyl-pyrimidine-4-base amine (104mg, 0.72mmol), Pd (OAC)
2(15mg, 0.07mmol), Xantphos (83mg, 0.14mmol) and potassium tert.-butoxide (159mg, 1.42mmol) the mixture in the Zai diox (8mL) at 160 ℃ down with microwave irradiations 20 minutes.This reaction mixture is cooled to room temperature and filtration, uses DCM and washed with methanol.Concentrated filtrate and use gradient purified by flash chromatography (ethyl acetate of 0-100% in hexane) and obtain title compound is yellow oil (89mg, 50%).MS(ES+):m/z?248(M+H)
+.
Embodiment 139. 5-methyl-N
4
-(3, the 5-3,5-dimethylphenyl)-N
2
-(4-(piperidin-4-yl oxygen base)
Phenyl) pyrimidine-2,4-diamines (compounds X C)
With intermediate 51 (89mg, 0.36mmol) and 4-(4-amino-phenoxy group)-piperidines-1-t-butyl formate (139mg, 0.47mmol) mixture in acetate at room temperature stirred 16 hours, be heated to then 95 ℃ following 2 hours.Concentrate this reaction mixture in a vacuum and pass through the preparation HPLC purifying.Use NaHCO
3(aqueous solution) is alkalize product and extract with ethyl acetate (3x30mL) (10mL).With the organic layer that salt solution (5mL) washing merges, dry (Na
2SO
4) and concentrate.Free alkali is dissolved in MeOH (5mL) and dense HCl (5) and concentrates the HCl salt that obtains title compound after 2 minutes in the vacuum in the presence of DCM and hexane are arranged, be pale solid (63mg, 40%).
1H?NMR(500MHz，DMSO-d
6):δ?1.72-1.83(m，2H)，2.02-2.08(m，2H)，2.14(d，J＝0.6Hz，3H)，2.24(s，6H)，3.04-3.15(m，2H)，3.21-3.31(m，2H)，4.57-4.60(m，1H)，6.85(s，1H)，6.91(d，J＝8.9Hz，2H)，7.20(s，2H)，7.37(d，J＝8.9Hz，2H)，7.85(s，1H)，8.50(br?s，1H)，8.56(br?s，1H)，9.36(br?s，1H)，10.10(br?s，1H)。MS(ES+):m/z?404(M+H)
+。
Embodiment 140. 2-chloro-N-(3, the 5-Dimethoxyphenyl)-5-methylpyrimidine-4-amine (centre
Body 52)
With 1-bromo-3, and the 5-dimethoxy benzene (436mg, 2.01mmol), 2-chloro-5-methyl-pyrimidine-4-base amine (287mg, 2.00mmol), Pd (OAc)
2(44mg, 0.20mmol), Xantphos (237mg, 0.41mmol) and potassium tert.-butoxide (448mg, 3.99mmol) the mixture among Zai diox (15mL) and the DMF (5mL) at 160 ℃ down with microwaves 20 minutes.This reaction mixture is cooled to room temperature and filtration, uses DCM and washed with methanol.Concentrated filtrate and use gradient purified by flash chromatography (ethyl acetate of 0-100% in hexane) and obtain title compound is yellow solid (182mg, 33%).
1H?NMR(500MHz，DMSO-d
6):δ?2.17(s，3H)，3.74(s，6H)，6.27(t，J＝2.2Hz，1H)，6.99(d，J＝2.2Hz，2H)，8.06(s，1H)，8.71(s，1H)。MS(ES+):m/z?280(M+H)
+。
Embodiment 141. N
4
-(3, the 5-Dimethoxyphenyl)-5-methyl-N
2
-(4-(piperidin-4-yl oxygen
Base) pyrimidine-2 phenyl), 4-diamines (compounds X CI)
With intermediate 52 (100mg, 0.36mmol) and 4-(4-amino-phenoxy group)-piperidines-1-t-butyl formate (106mg, 0.36mmol) mixture heating up to 95 in acetate is ℃ following 2 hours.Concentrate this reaction mixture in a vacuum and obtain the tfa salt of title compound, be tawny solid (75mg, 39%) by the preparation HPLC purifying.
1H?NMR(500MHz，DMSO-d
6):δ?1.74-1.83(m，2H)，2.03-2.11(m，2H)，2.15(s，3H)，3.06-3.15(m，2H)，3.21-3.30(m，2H)，3.69(s，6H)，4.57-4.60(m，1H)，6.39(t，J＝2.2Hz，1H)，6.80(d，J＝2.2Hz，2H)，6.89(d，J＝8.9Hz，2H)，7.37(d，J＝9.0Hz，2H)，7.86(s，1H)，8.53(br?s，1H)，8.58(brs，1H)，9.49(br?s，1H)，10.24(br?s，1H)。MS(ES+):m/z436(M+H)
+。
Embodiment 142. 5-methyl-N
2
-(4-(4-methylpiperazine-1-yl) phenyl)-N
4
-(3-(piperidines
-1-yl) pyrimidine-2 phenyl), 4-diamines (compounds X CII)
With 1-(3-bromophenyl) piperidines (91mg, 0.38mmol), intermediate 32 (99mg, 0.33mmol), Pd
2(dba)
3(15mg, 0.02mmol), Xantphos (24mg, 0.04mmol) and cesium carbonate (219mg, 0.67mmol) the mixture in the Zai diox (4mL) at 160 ℃ down with microwaves 15 minutes.This reaction mixture is cooled to room temperature, and vacuum concentration is dissolved in methyl alcohol, and filters, and uses DCM and washed with methanol.Concentrated filtrate and use the preparation HPLC purifying and obtain the tfa salt of title compound is pale solid (14mg, 8%).
1H?NMR(500MHz，DMSO-d
6):δ?1.47-1.53(m，2H)，1.56-1.61(m，4H)，2.07(s，3H)，2.21(s，3H)，2.44(t，J＝4.9Hz，4H)，3.01(t，J＝4.9Hz，4H)，3.08(t，J＝5.4Hz，4H)，6.63(dd，J＝8.2，2.3Hz，1H)，6.76(d，J＝9.0Hz，2H)，7.12(t，J＝8.3Hz，1H)，7.14(s，1H)，7.27(d，J＝7.6Hz，1H)，7.50(d，J＝9.0Hz，2H)，7.81(s，1H)，8.00(s，1H)，8.67(s，1H)。MS(ES+):m/z?458(M+H)
+。
Embodiment 143. N
4
-(3-(1H-pyrroles-1-yl) phenyl)-5-methyl-N
2
-(4-(4-methyl piperazine
Piperazine-1-yl) pyrimidine-2 phenyl), 4-diamines (compounds X CIII)
With 1-(3-bromophenyl)-1H-pyrroles (86mg, 0.39mmol), intermediate 32 (99mg, 0.33mmol), Pd
2(dba)
3(16mg, 0.02mmol), Xantphos (26mg, 0.05mmol) and cesium carbonate (215mg, 0.66mmol) the mixture in the Zai diox (4mL) at 160 ℃ down with microwaves 15 minutes.This reaction mixture is cooled to room temperature, concentrates in a vacuum, be dissolved in methyl alcohol and filtration, use DCM and washed with methanol.Concentrated filtrate and use the preparation HPLC purifying and obtain the tfa salt of title compound is pale solid (32mg, 18%).
1H?NMR(500MHz，DMSO-d
6):δ?2.11(s，3H)，2.21(s，3H)，2.42(t，J＝4.9Hz，4H)，2.95(t，J＝4.9Hz，4H)，6.24(t，J＝2.2Hz，2H)，6.58(d，J＝8.9Hz，2H)，7.23(dd，J＝7.8，1.8Hz，1H)，7.31(t，J＝2.2Hz，2H)，7.37(t，J＝8.1Hz，1H)，7.43(d，J＝9.0Hz，2H)，7.60(d，J＝8.8Hz，1H)，7.86(t，J＝2.2Hz，1H)，7.87(s，1H)，8.30(s，1H)，8.74(s，1H)。MS(ES+):m/z440(M+H)
+。
Embodiment 144. 5-{2-[4-(1-tertbutyloxycarbonyl-piperidin-4-yl oxygen base)-phenylamino
Base]-5-methyl-pyrimidine-4-base is amino }-indoles-1-t-butyl formate (intermediate 53)
With 5-bromo-1H-indoles-1-t-butyl formate (161mg, 0.54mmol), intermediate 42 (202mg, 0.50mmol), Pd
2(dba)
3(29mg, 0.03mmol), Xantphos (36mg, 0.07mmol) and cesium carbonate (321mg, 0.98mmol) the mixture in the Zai diox (5mL) at 160 ℃ down with microwaves 20 minutes.This reaction mixture is cooled to room temperature and filtration, uses the DCM flushing.Concentrated filtrate and use gradient purified by flash chromatography (MeOH of 0-20% in DCM) and obtain title compound is light brown solid (290mg, 94%).MS(ES+):m/z?615(M+H)
+。
Embodiment 145. N
4
-(1H-indoles-5-yl)-5-methyl-N
2
-(4-(piperidin-4-yl oxygen base) benzene
Base) pyrimidine-2,4-diamines (compounds X CIV)
To Acetyl Chloride 98Min. (670 μ L, 9.42mmol) add in the solution in methyl alcohol (22mL) intermediate 53 (290mg, 0.47mmol) and with this reaction mixture be heated to 60 ℃ following 4 hours.Concentrate this reaction mixture in a vacuum and obtain the tfa salt of title compound, be brown solid (6mg, 2%) by the preparation HPLC purifying.
1H?NMR(500MHz，DMSO-d
6):δ?1.70-1.78(m，2H)，1.98-2.07(m，2H)，2.16(s，3H)，3.02-3.11(m，2H)，3.21-3.30(m，2H)，4.44-4.53(m，1H)，6.43(s，1H)，6.75(d，J＝8.2Hz，2H)，7.16(d，J＝8.4Hz，1H)，7.31(d，J＝8.7Hz，2H)，7.40-7.42(m，2H)，7.71(s，1H)，7.78(s，1H)，8.48(br?s，1H)，8.54(br?s，1H)，9.65(br?s，1H)，9.99(br?s，1H)，11.18(s，1H)。MS(ES+):m/z?415(M+H)
+。
Embodiment 146. N4-(4-chloro-3-methoxyl group-phenyl)-5-methyl-N2-(6-piperazine-1-base-
Pyridin-3-yl)-and pyrimidine-2,4-diamines (compounds X CV)
With intermediate 31 (0.10g, 0.35mmol), 4-(5-amino-pyridine-2-yl)-piperazine-1-t-butyl formate (0.10g, 0.36mmol), Pd
2(dba)
3(30mg, 0.033mmol), Xantphos (35mg, 0.06mmol) and cesium carbonate (0.23g, 0.71mmol) Zai diox/DMF (3/1,4mL) mixture in be sealed in the microwave reaction pipe and at 170 ℃ down with microwave irradiations 30 minutes.After being cooled to room temperature, removing lid and filter the gained mixture.Solid and concentrated filtrate with the DCM washing and filtering.(hexane-EtOAc) obtains the precursor of Boc-protection by fast silica gel chromatogram method purifying resistates.In the solution of this precursor in DCM (5mL), add TFA (3mL).This mixture was at room temperature stirred 30 minutes, concentrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and with the gained solid the mixture of hexane/EtOAc (10/1, grind in 55mL).Filter the back and obtain title compound, be white solid (20mg, 13%).
1H?NMR(500MHz，DMSO-d
6):δ?2.09(s，3H)，2.81(t，J＝5.0Hz，4H)，3.29-3.31(m，4H)，3.73(s，3H)，6.70(d，J＝9.1Hz，1H)，7.26(d，J＝8.6Hz，1H)，7.42(d，J＝9.1Hz，1H)，7.49(d，J＝2.2Hz，1H)，7.76(dd，J＝9.1，2.6Hz，1H)，7.86(s，1H)，8.29(s，1H)，8.31(d，J＝2.6Hz，1H)，8.71(s，1H)。MS(ES+):m/z?426(M+H)
+。
Embodiment 147. 4-(4-amino-2-methoxycarbonyl-phenyl)-piperazine-1-t-butyl formate
(intermediate 54)
(1.0g 2.7mmol) adds 10wt%Pd/C (0.1 equivalent wt) in the solution in MeOH (30mL) to 4-(2-methoxycarbonyl-4-nitro-phenyl)-piperazine-1-t-butyl formate in ar gas environment.This mixture vacuumized and and then charge into hydrogen (3 circulations) and at room temperature stirred 2 hours.Inhomogeneous reaction mixture is filtered by C salt pad, with MeOH washing and concentrated in a vacuum.Be not used for next step with thick amino-compound is purified.MS(ES+):m/z?336(M+H)
+。
Embodiment 148. 5-[4-(4-chloro-3-methoxyl group-phenyl amino)-5-methyl-pyrimidine-2-base
Amino]-2-piperazine-1-base-methyl benzoate (compounds X CVI)
With intermediate 31 (0.10g, 0.35mmol), intermediate 54 (0.14g, 0.42mmol), Pd
2(dba)
3(30mg, 0.033mmol), Xantphos (35mg, 0.06mmol) and cesium carbonate (0.23g, mixture 0.71mmol) be suspended in the diox (15mL) and under reflux state and ar gas environment in the heating 2.5 hours.This reaction mixture is cooled to room temperature and dilutes with DCM (30mL).Filter this mixture and concentrated filtrate.Obtain the precursor of Boc-protection by fast silica gel chromatogram method purifying resistates (hexane-60% EtOAc/ hexane).In the solution of this precursor in DCM (5mL), add TFA (2mL).This mixture was at room temperature stirred 1 hour, concentrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and be dissolved in minimum EtOAc then.Add hexane up to solid precipitation.Filter the back and obtain title compound, be white solid (40mg, 24%).
1H?NMR(500MHz，DMSO-d
6):δ?2.11(s，3H)，2.80-2.90(m，8H)，3.73(s，3H)，3.74(s，3H)，6.98(d，J＝8.9Hz，1H)，7.25(d，J＝8.5Hz，1H)，7.40-7.48(m，2H)，7.69(dd，J＝8.9，2.6Hz，1H)，7.90(d，J＝2.6Hz，1H)，7.91(s，1H)，8.36(s，1H)，9.04(s，1H)。MS(ES+):m/z?483(M+H)
+。
Embodiment 149. 5-amino-2-(2-tetramethyleneimine-1-base-oxyethyl group)-methyl benzoate (centre
Body 55)
With 5-amino-2-hydroxy-benzoic acid methyl esters (1.0g, 6.0mmol), 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (1.2g, 7.1mmol) and cesium carbonate (5.0g, 15mmol) suspension in DMF (40mL) is 60 ℃ of down heating 17 hours.This mixture is cooled to room temperature, impouring water (60mL) and extract with EtOAc (2 x 50mL).With the extract that the salt water washing merges, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and obtain title compound (0.2g, 13%) by fast silica gel chromatogram method purifying resistates (DCM-30% MeOH/DCM) is the light brown solid.MS(ES+):m/z?265(M+H)
+。
Embodiment 150. 5-[4-(benzo [1,3] dioxole-4-base is amino)-5-methyl-
Pyrimidine-2--amino]-2-(2-tetramethyleneimine-1-base-oxyethyl group)-methyl benzoate (compound
XCVII)
With intermediate 30 (0.15g, 0.57mmol), intermediate 55 (0.20g, 0.75mmol), Pd
2(dba)
3(50mg, 0.055mmol), Xantphos (60mg, 0.10mmol) and cesium carbonate (0.30g, 0.92mmol) Zai diox/DMF (3/1,4mL) mixture in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 20 minutes.After being cooled to room temperature, removing lid and filter the gained mixture.With the solid of DCM washing and filtering, concentrated filtrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and be dissolved in minimum EtOAc then.Add hexane to solid precipitation.Filter the back and obtain title compound, be pale solid (30mg, 11%).
1H?NMR(500MHz，DMSO-d
6):δ?1.65-1.72(m，4H)，2.07(s，3H)，2.50-2.62(m，4H)，2.75-2.85(m，2H)，3.73(s，3H)，4.02(t，J＝5.8Hz，2H)，5.88(s，2H)，6.78-6.88(m，3H)，6.92(dd，J＝8.0，2.1Hz，1H)，7.75-7.80(m，2H)，7.83(s，1H)，8.22(s，1H)，8.89(s，1H)。MS(ES+):m/z?492(M+H)
+。
The embodiment 151. N-tertiary butyl-3-{5-methyl-2-[4-(piperidin-4-yl oxygen base)-phenylamino
Base]-pyrimidine-4-base is amino }-benzsulfamide (compounds X CVIII)
With intermediate 33 (0.15g, 0.42mmol) and 4-(4-amino-phenoxy group)-piperidines-1-t-butyl formate (0.15g, 0.51mmol) mixture in acetate (3mL) be sealed in the microwave reaction pipe and at 150 ℃ down with microwave irradiations 20 minutes.After being cooled to room temperature, removing lid and concentrate this mixture.With resistates water-soluble (20mL) and with 10% NaOH solution pH is adjusted to solid precipitation.Cross filter solid and pass through the HPLC purifying then.The fraction that merges calibration, the saturated NaHCO of impouring
3Solution (30mL) and extract with EtOAc (2 x 30mL).With the extract that the salt water washing merges, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and be dissolved in minimum EtOAc then.Add hexane to solid precipitation.Filter the back and obtain title compound, be white solid (20mg, 9%).
1H?NMR(500MHz，DMSO-d
6):δ?1.12(s，9H)，1.65-1.73(m，2H)，1.95-2.05(m，2H)，2.12(s，3H)，2.89-2.95(m，2H)，3.10-3.20(m，2H)，4.40-4.45(m，1H)，6.84(d，J＝9.1Hz，2H)，7.45-7.60(m，6H)，7.90(s，1H)，8.10-8.15(m，2H)，8.55(s，1H)，8.81(s，1H)。MS(ES+):m/z?511(M+H)
+。
Embodiment 152. 2-(5-amino-pyridine-2-base oxygen base)-ethanol (intermediate 56)
(5-nitro-pyridine-2-base oxygen base)-(1.0g 5.4mmol) adds 10wt% Pd/C (0.1 equivalent wt) to ethanol in the solution in MeOH (30mL) to 2-in ar gas environment.This mixture vacuumized and and then fill hydrogen (3 circulations) and at room temperature stirred 1 hour.Inhomogeneous reaction mixture is filtered by C salt pad, with MeOH washing and concentrated in a vacuum.Be not used for next step with thick amino-compound is purified.MS(ES+):m/z?155(M+H)
+。
Embodiment 153. 2-{5-[4-(benzo [1,3] dioxole-4-base is amino)-5-first
Base-pyrimidine-2--amino]-pyridine-2-base oxygen base }-ethanol (compounds X CIX)
With intermediate 30 (0.10g, 0.38mmol), intermediate 56 (0.10g, 0.65mmol), Pd
2(dba)
3(30mg, 0.033mmol), Xantphos (35mg, 0.06mmol) and cesium carbonate (0.26g, 0.80mmol) Zai diox/DMF (3/1,4mL) mixture in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 20 minutes.After being cooled to room temperature, removing lid and filter the gained mixture.With the solid of DCM washing and filtering, concentrated filtrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and be dissolved in minimum EtOAc then.Add hexane to solid precipitation.Filter the back and obtain title compound, be pale solid (50mg, 35%).
1H?NMR(500MHz，DMSO-d
6):δ?2.06(s，3H)，3.66(q，J＝5.4Hz，2H)，4.15(t，J＝5.2Hz，2H)，4.77(t，J＝5.5Hz，2H)，5.91(s，2H)，6.52(d，J＝9.0Hz，1H)，6.78-6.90(m，3H)，7.82(s，1H)，7.96(dd，J＝8.9，2.7Hz，1H)，8.22(d，J＝2.6Hz，1H)，8.27(s，1H)，8.84(s，1H)。MS(ES+):m/z?382(M+H)
+。
Embodiment 154. 1-[2-(2-methoxyl group-4-nitro-phenoxy group)-ethyl]-tetramethyleneimine (centre
Body 57)
With 2-methoxyl group-4-nitro-phenolic acid potassium (2.0g, 9.7mmol), 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (2.0g, 12mmol) and cesium carbonate (7.0,22mmol) suspension in DMF (35mL) is 80 ℃ of down heating 16 hours.This mixture is cooled to room temperature, impouring water (60mL) and extract with EtOAc (2 x 50mL).With the extract that the salt water washing merges, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and not purifiedly be used for next step.
MS(ES+):m/z?267(M+H)
+。
Embodiment 155. 3-methoxyl group-4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl amine (intermediate 58)
(1.7g 6.4mmol) adds 10wt% Pd/C (0.1 equivalent wt) in the solution in MeOH (30mL) to intermediate 57 in ar gas environment.This mixture vacuumized and and then fill hydrogen (3 circulations) and at room temperature stirred 1 hour.Inhomogeneous reaction mixture is filtered by C salt pad, with MeOH washing and concentrated in a vacuum.Be not used for next step with thick amino-compound is purified.MS(ES+):m/z?237(M+H)
+。
Embodiment 156. N
4
-benzo [1,3] dioxole-4-base-N
2
-[3-methoxyl group
-4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-5-methyl-pyrimidine-2,4-diamines (compound
C)
With intermediate 30 (0.10g, 0.38mmol), intermediate 58 (0.11g, 0.46mmol), Pd
2(dba)
3(30mg, 0.033mmol), Xantphos (35mg, 0.06mmol) and cesium carbonate (0.25g, 0.77mmol) Zai diox/DMF (3/1,4mL) mixture in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 20 minutes.After being cooled to room temperature, removing lid and filter the gained mixture.With the solid of DCM washing and filtering, concentrated filtrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and be dissolved in minimum EtOAc then.Add hexane to solid precipitation.Filter the back and obtain title compound, be white solid (50mg, 28%).
1H?NMR(500MHz，DMSO-d
6):δ?1.65-1.72(m，4H)，2.06(s，3H)，2.50-2.62(m，4H)，2.75-2.85(m，2H)，3.50(s，3H)，3.94(t，J＝6.1Hz，2H)，5.84(s，2H)，6.67(d，J＝8.8Hz，1H)，6.78(dd，J＝7.8，1.1Hz，1H)，6.83(t，J＝7.9Hz，1H)，6.92(dd，J＝8.1，1.1Hz，1H)，7.14(dd，J＝8.7，2.4Hz，1H)，7.23(d，J＝2.4Hz，1H)，7.83(s，1H)，8.21(s，1H)，8.69(s，1H)。MS(ES+):m/z?464(M+H)
+。
The embodiment 157. N-tertiary butyl-3-[2-(4-imidazoles-1-base-phenyl amino)-5-methyl-phonetic
Pyridine-4-base is amino]-benzsulfamide (Compound C I)
With intermediate 33 (0.40g, 1.1mmol), 4-imidazoles-1-base-phenyl amine (0.20g, 1.3mmol), Pd
2(dba)
3(0.10g, 0.11mmol), Xantphos (0.12g, 0.21mmol) and cesium carbonate (0.80g, 2.5mmol) Zai diox/DMF (3/1,8mL) mixture in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 30 minutes.After being cooled to room temperature, removing lid and filter the gained mixture.With the solid of DCM washing and filtering, concentrated filtrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (40mL).With the water layer of EtOAc (2 x 40mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and be dissolved in minimum EtOAc then.Add hexane to solid precipitation.Filter the back and obtain title compound, be pale solid (0.15g, 28%).
1H?NMR(500MHz，DMSO-d
6):δ?1.12(s，9H)，2.15(s，3H)，7.07(s，1H)，7.43(d，J＝9.0Hz，2H)，7.50-7.60(m，3H)，7.61(s，1H)，7.79(d，J＝9.0Hz，2H)，7.98(s，1H)，8.08-8.13(m，3H)，8.64(s，1H)，9.19(s，1H)。MS(ES+):m/z478(M+H)
+。
The embodiment 158. N-tertiary butyl-3-[2-(4-imidazoles-1-ylmethyl-phenyl amino)-5-methyl
-pyrimidine-4-base is amino]-benzsulfamide (Compound C II)
With intermediate 33 (0.10g, 0.28mmol), 4-imidazoles-1-ylmethyl-phenyl amine (60mg, 0.35mmol), Pd
2(dba)
3(25mg, 0.027mmol), Xantphos (30mg, 0.052mmol) and cesium carbonate (0.20g, 0.61mmol) Zai diox/DMF (3/1,4mL) mixture in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 20 minutes.After being cooled to room temperature, removing lid and filter the gained mixture.With the solid of DCM washing and filtering, concentrated filtrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and be dissolved in minimum EtOAc then.Add hexane to solid precipitation.Filter the back and obtain title compound, be white solid (40mg, 29%).
1H?NMR(500MHz，DMSO-d
6):δ?1.12(s，9H)，2.13(s，3H)，5.07(s，2H)，6.89(s，1H)，7.12(d，J＝8.6Hz，2H)，7.15(s，1H)，7.46(t，J＝7.9Hz，1H)，7.49-7.52(m，1H)，7.56(s，1H)，7.63(d，J＝8.6Hz，2H)，7.72(s，1H)，7.94(s，1H)，8.09(s，1H)，8.14(d，J＝8.1Hz，1H)，8.60(s，1H)，9.02(s，1H)。MS(ES+):m/z?492(M+H)
+。
Embodiment 159. 2-(4-amino-phenoxy group)-ethanol (intermediate 59)
Give 2-(4-nitro-phenoxy group)-ethanol (2.1g, 12mmol) applying argon gas and add 10wt% Pd/C (0.1 equivalent wt) then in the solution in MeOH (30mL).Vacuumize under indoor vacuum, for this mixture and from the hydrogen capsule, fill hydrogen again.Repeat this circulation again and this mixture was at room temperature stirred 2 hours.Inhomogeneous reaction mixture is filtered by C salt pad, with the MeOH washing and concentrate in a vacuum and obtain title compound (1.8g, 99%), be brown solid.MS(ES+):m/z?154(M+H)
+。
The embodiment 160. N-tertiary butyl-3-{2-[4-(2-hydroxyl-oxyethyl group)-phenyl amino]-the 5-first
Base-pyrimidine-4-base is amino }-benzsulfamide (Compound C III)
With intermediate 33 (0.10g, 0.28mmol), intermediate 59 (55mg, 0.36mmol), Pd
2(dba)
3(25mg, 0.027mmol), Xantphos (30mg, 0.052mmol) and cesium carbonate (0.20g, 0.61mmol) Zai diox/DMF (3/1,4mL) mixture in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 20 minutes.After being cooled to room temperature, removing lid and filter the gained mixture.With the solid of DCM washing and filtering, concentrated filtrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and be dissolved in minimum EtOAc then.Add hexane to solid precipitation.Filter the back and obtain title compound, be white solid (15mg, 11%).
1H?NMR(500MHz，DMSO-d
6):δ?1.12(s，9H)，2.12(s，3H)，3.69(q，J＝5.2Hz，2H)，3.91(t，J＝5.1Hz，2H)，4.82(t，J＝5.5Hz，2H)，6.80(d，J＝9.1Hz，2H)，7.45-7.50(m，2H)，7.52(d，J＝9.0Hz，2H)，7.55(s，1H)，7.90(s，1H)，8.08-8.15(m，2H)，8.53(s，1H)，8.77(s，1H)。MS(ES+):m/z472(M+H)
+。
Embodiment 161. N
4
-(4-chloro-3-methoxyl group-phenyl)-5-methyl-N
2
-(4-piperazine-1-Ji Jia
Base-phenyl)-and pyrimidine-2,4-diamines (Compound C IV)
With intermediate 31 (0.10g, 0.35mmol), 4-(4-amino-benzyl)-piperazine-1-t-butyl formate (0.12g, 0.41mmol), Pd
2(dba)
3(30mg, 0.033mmol), Xantphos (35mg, 0.06mmol) and cesium carbonate (0.23g, 0.71mmol) Zai diox/DMF (3/1,4mL) mixture in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 20 minutes.After being cooled to room temperature, removing lid and filter the gained mixture.Solid and concentrated filtrate with the DCM washing and filtering.Obtain the precursor of Boc-protection by fast silica gel chromatogram method purifying resistates (hexane-60% EtOAc/ hexane).In the solution of this precursor in DCM (5mL), add TFA (3mL).This mixture was at room temperature stirred 1 hour, concentrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and be dissolved in minimum EtOAc then.Add hexane to solid precipitation.Filter the back and obtain title compound, be white solid (13mg, 9%).
1H?NMR(500MHz，DMSO-d
6):δ?2.11(s，3H)，2.30-2.40(m，4H)，2.83(t，J＝4.8Hz，4H)，3.37(s，2H)，3.75(s，3H)，7.08(d，J＝8.6Hz，2H)，7.29(d，J＝8.6Hz，1H)，7.43(dd，J＝8.6，2.2Hz，1H)，7.47(d，J＝2.2Hz，1H)，7.59(d，J＝8.6Hz，2H)，7.91(s，1H)，8.37(s，1H)，8.99(s，1H)。MS(ES+):m/z?439(M+H)
+。
The embodiment 162. N-tertiary butyl-3-{5-methyl-2-[4-(2-methyl-imidazoles-1-yl)-phenyl
Amino]-pyrimidine-4-base is amino }-benzsulfamide (Compound C V)
With intermediate 33 (0.10g, 0.28mmol), 4-(2-methyl-imidazoles-1-yl)-phenyl amine (60mg, 0.35mmol), Pd
2(dba)
3(25mg, 0.027mmol), Xantphos (30mg, 0.052mmol) and cesium carbonate (0.20g, 0.61mmol) Zai diox/DMF (3/1,4mL) mixture in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 20 minutes.After being cooled to room temperature, removing lid and filter the gained mixture.With the solid of DCM washing and filtering, concentrated filtrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and be dissolved in minimum EtOAc then.Add hexane to solid precipitation.Filter the back and obtain title compound, be white solid (30mg, 22%).
1H?NMR(500MHz，DMSO-d
6):δ?1.11(s，9H)，2.15(s，3H)，2.24(s，3H)，6.87(d，J＝1.2Hz，1H)，7.18(d，J＝1.3Hz，1H)，7.22(d，J＝8.9Hz，2H)，7.50-7.55(m，2H)，7.56(s，1H)，7.79(d，J＝8.9Hz，2H)，7.98(s，1H)，8.07-8.10(m，2H)，8.65(s，1H)，9.26(s，1H)。MS(ES+):m/z?492(M+H)
+。
The embodiment 163. N-tertiary butyl-3-{5-methyl-2-[4-(2-methyl-imidazoles-1-ylmethyl)-
Phenyl amino]-pyrimidine-4-base is amino }-benzsulfamide (Compound C VI)
With intermediate 33 (0.10g, 0.28mmol), 4-(2-methyl-imidazoles-1-ylmethyl)-phenyl amine (65mg, 0.35mmol), Pd
2(dba)
3(25mg, 0.027mmol), Xantphos (30mg, 0.052mmol) and cesium carbonate (0.20g, 0.61mmol) Zai diox/DMF (3/1,4mL) mixture in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 20 minutes.After being cooled to room temperature, removing lid and filter the gained mixture.With the solid of DCM washing and filtering, concentrated filtrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and be dissolved in minimum EtOAc then.Add hexane to solid precipitation.Filter the back and obtain title compound, be white solid (30mg, 21%).
1H?NMR(500MHz，DMSO-d
6):δ?1.12(s，9H)，2.13(s，3H)，2.24(s，3H)，5.01(s，2H)，6.73(d，J＝1.2Hz，1H)，7.01(d，J＝8.6Hz，2H)，7.07(d，J＝1.1Hz，1H)，7.44(t，J＝7.9Hz，1H)，7.48-7.51(m，1H)，7.56(s，1H)，7.62(d，J＝8.6Hz，2H)，7.94(s，1H)，8.08(s，1H)，8.12(d，J＝8.1Hz，1H)，8.60(s，1H)，9.02(s，1H)。MS(ES+):m/z?506(M+H)
+。
The embodiment 164. N-tertiary butyl-3-[5-methyl-2-(4-pyridin-4-yl methyl-phenylamino
Base)-pyrimidine-4-base is amino]-benzsulfamide (Compound C VII)
With intermediate 33 (0.10g, 0.28mmol), 4-pyridin-4-yl methyl-phenyl amine (65mg, 0.35mmol), Pd
2(dba)
3(25mg, 0.027mmol), Xantphos (30mg, 0.052mmol) and cesium carbonate (0.20g, 0.61mmol) Zai diox/DMF (3/1,4mL) mixture in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 20 minutes.After being cooled to room temperature, removing lid and filter the gained mixture.With the solid of DCM washing and filtering, concentrated filtrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and be dissolved in minimum EtOAc then.Add hexane to solid precipitation.Filter the back and obtain title compound, be white solid (45mg, 32%).
1H?NMR(500MHz，DMSO-d
6):δ?1.11(s，9H)，2.13(s，3H)，3.87(s，2H)，7.07(d，J＝8.6Hz，2H)，7.22(d，J＝6.0Hz，2H)，7.43(t，J＝7.9Hz，1H)，7.47-7.50(m，1H)，7.56(d，J＝6.3Hz，2H)，7.58(s，1H)，7.93(s，1H)，8.09(s，1H)，8.13(d，J＝8.0Hz，1H)，8.44(d，J＝5.8Hz，2H)，8.58(s，1H)，8.94(s，1H)。MS(ES+):m/z?503(M+H)
+。
The embodiment 165. N-tertiary butyl-3-[5-methyl-2-(4-morpholine-4-base-phenyl amino)-phonetic
Pyridine-4-base is amino]-benzsulfamide (Compound C VIII)
With intermediate 33 (0.10g, 0.28mmol), 4-morpholine-4-base-phenyl amine (60mg, 0.34mmol), Pd
2(dba)
3(25mg, 0.027mmol), Xantphos (30mg, 0.052mmol) and cesium carbonate (0.20g, 0.61mmol) Zai diox/DMF (3/1,4mL) mixture in be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 20 minutes.After being cooled to room temperature, removing lid and filter the gained mixture.With the solid of DCM washing and filtering, concentrated filtrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and be dissolved in minimum EtOAc then.Add hexane to solid precipitation.Filter the back and obtain title compound, be gray solid (45mg, 32%).
1H?NMR(500MHz，DMSO-d
6):δ?1.12(s，9H)，2.12(s，3H)，3.00(t，J＝4.8Hz，4H)，3.73(t，J＝4.8Hz，4H)，6.82(d，J＝9.1Hz，2H)，7.45-7.52(m，4H)，7.56(s，1H)，7.89(s，1H)，8.10-8.17(m，2H)，8.52(s，1H)，8.73(s，1H)。MS(ES+):m/z497(M+H)
+。
The embodiment 166. N-tertiary butyl-3-[5-methyl-2-(4-[1,2,4] triazol-1-yl methyl-benzene
Base is amino)-pyrimidine-4-base is amino]-benzsulfamide (Compound C IX)
With intermediate 33 (0.10g, 0.28mmol), 4-[1,2,4] triazol-1-yl methyl-phenyl amine (60mg, 0.34mmol), Pd
2(dba)
3(25mg, 0.027mmol), Xantphos (30mg, 0.052mmol) and cesium carbonate (0.20g, 0.61mmol) the mixture in the Zai diox (4mL) be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 20 minutes.After being cooled to room temperature, removing lid and filter the gained mixture.With the solid of DCM washing and filtering, concentrated filtrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and be dissolved in minimum EtOAc then.Add hexane to solid precipitation.Filter the back and obtain title compound, be white solid (37mg, 27%).
1H?NMR(500MHz，DMSO-d
6):δ?1.17(s，9H)，2.13(s，3H)，5.29(s，2H)，7.14(d，J＝8.6Hz，2H)，7.46(t，J＝7.8Hz，1H)，7.48-7.51(m，1H)，7.56(s，1H)，7.63(d，J＝8.6Hz，2H)，7.94(s，1H)，7.95(s，1H)，8.08(s，1H)，8.13(d，J＝8.0Hz，1H)，8.59(s，1H)，8.60(s，1H)，9.04(s，1H)。MS(ES+):m/z493(M+H)
+。
The embodiment 167. N-tertiary butyl-3-{5-methyl-2-[4-(4-methyl-imidazoles-1-yl)-phenyl
Amino]-pyrimidine-4-base is amino }-benzsulfamide (Compound C X)
With intermediate 33 (0.10g, 0.28mmol), 4-(4-methyl-imidazoles-1-yl)-phenyl amine (60mg, 0.35mmol), Pd
2(dba)
3(25mg, 0.027mmol), Xantphos (30mg, 0.052mmol) and cesium carbonate (0.20g, 0.61mmol) the mixture in the Zai diox (3mL) be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 20 minutes.After being cooled to room temperature, removing lid and filter the gained mixture.With the solid of DCM washing and filtering, concentrated filtrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With EtOAc (2 x 30mL extract the water layer that merges) and with the organic layer that the salt water washing merges, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and be dissolved in minimum EtOAc then.Add hexane to solid precipitation.Filter the back and obtain title compound, be pale solid (20mg, 15%).
1H?NMR(500MHz，DMSO-d
6):δ?1.12(s，9H)，2.15(s，3H)，2.16(s，3H)，7.30(s，1H)，7.38(d，J＝9.0Hz，2H)，7.50-7.56(m，2H)，7.57(s，1H)，7.76(d，J＝9.0Hz，2H)，7.96(s，1H)，7.97(s，1H)，8.09-8.13(m，2H)，8.63(s，1H)，9.16(s，1H)。MS(ES+):m/z?492(M+H)
+。
The embodiment 168. N-tertiary butyl-3-[5-methyl-2-(4-[1,2,4] triazol-1-yl-phenylamino
Base)-pyrimidine-4-base is amino]-benzsulfamide (Compound C XI)
With intermediate 33 (0.10g, 0.28mmol), 4-[1,2,4] triazol-1-yl-phenyl amine (55mg, 0.34mmol), Pd
2(dba)
3(25mg, 0.027mmol), Xantphos (30mg, 0.052mmol) and cesium carbonate (0.20g, 0.61mmol) the mixture of Zai diox (3mL) be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 20 minutes.After being cooled to room temperature, removing lid and filter the gained mixture.With the solid of DCM washing and filtering, concentrated filtrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and be dissolved in minimum EtOAc then.Add hexane to solid precipitation.Filter the back and obtain title compound, be white solid (40mg, 29%).
1H?NMR(500MHz，DMSO-d
6):δ?1.12(s，9H)，2.15(s，3H)，7.50-7.58(m，3H)，7.63(d，J＝9.1Hz，2H)，7.83(d，J＝9.0Hz，2H)，7.99(s，1H)，8.09(s，1H)，8.10-8.15(m，1H)，8.17(s，1H)，8.66(s，1H)，9.12(s，1H)，9.27(s，1H)。MS(ES+):m/z?479(M+H)
+。
The embodiment 169. N-tertiary butyl-3-{5-methyl-2-[3-(1H-tetrazolium-5-yl)-phenylamino
Base]-pyrimidine-4-base is amino }-benzsulfamide (Compound C XII)
With intermediate 33 (0.10g, 0.28mmol), 3-(1H-tetrazolium-5-yl)-phenyl amine (55mg, 0.34mmol), Pd
2(dba)
3(25mg, 0.027mmol), Xantphos (30mg, 0.052mmol) and cesium carbonate (0.20g, 0.61mmol) the mixture in the Zai diox (3mL) be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 20 minutes.After being cooled to room temperature, removing lid and filter the gained mixture.With the solid of DCM washing and filtering, concentrated filtrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and be dissolved in minimum EtOAc then.Add hexane to solid precipitation.Filter the back and obtain title compound, be white solid (15mg, 11%).
1H?NMR(500MHz，DMSO-d
6):δ?1.13(s，9H)，2.15(s，3H)，7.26(t，J＝7.9Hz，1H)，7.38(t，J＝8.0Hz，1H)，7.44(dd，J＝7.9，1.1Hz，1H)，7.50(d，J＝7.6Hz，1H)，7.58(s，1H)，7.79(dd，J＝8.1，1.4Hz，1H)，7.98(s，1H)，8.16(s，1H)，8.22(s，1H)，8.27(d，J＝7.8Hz，1H)，8.57(s，1H)，9.08(s，1H)。MS(ES+):m/z?480(M+H)
+。
Embodiment 170. 4-(1H-tetrazolium-5-yl)-phenyl amine (intermediate 60)
(1.0g 5.2mmol) adds 10wt% Pd/C (0.1 equivalent wt) in the solution in MeOH (30mL) to 5-(4-nitro-phenyl)-1H-tetrazolium in ar gas environment.This mixture is vacuumized, fill hydrogen (3 circulations) again and at room temperature stirred 1.5 hours.Inhomogeneous reaction mixture is filtered by C salt pad, with MeOH washing and concentrated in a vacuum.Be not used for next step with thick amino-compound is purified.MS(ES+):m/z?162(M+H)
+。
The embodiment 171. N-tertiary butyl-3-{5-methyl-2-[4-(1H-tetrazolium-5-yl)-phenylamino
Base]-pyrimidine-4-base is amino }-benzsulfamide (Compound C XIII)
With intermediate 33 (0.10g, 0.28mmol), intermediate 60 (60mg, 0.37mmol), Pd
2(dba)
3(25mg, 0.027mmol), Xantphos (30mg, 0.052mmol) and cesium carbonate (0.20g, 0.61mmol) Zai diox/DMF (3/1; Mixture 4mL) is sealed in the microwave reaction pipe and at 160 ℃ and uses microwave irradiation 20 minutes down.After being cooled to room temperature, removing lid and filter the gained mixture.With the solid of DCM washing and filtering, concentrated filtrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and be dissolved in minimum EtOAc then.Add hexane to solid precipitation.Filter the back and obtain title compound, be white solid (15mg, 11%).
1H?NMR(500MHz，DMSO-d
6):δ?1.13(s，9H)，2.16(s，3H)，7.52-7.56(m，2H)，7.57(s，1H)，7.83(s，4H)，8.01(s，1H)，8.08(s，1H)，8.13-8.19(m，1H)，8.69(s，1H)，9.34(s，1H)。MS(ES+):m/z?480(M+H)
+。
Embodiment 172. 3-{2-[4-(4-ethanoyl-piperazine-1-yl)-phenyl amino]-the 5-methyl-
Pyrimidine-4-base is amino }-the N-tertiary butyl-benzsulfamide (Compound C XIV)
With intermediate 33 (0.10g, 0.28mmol), 1-[4-(4-amino-phenyl)-piperazine-1-yl]-ethyl ketone (80mg, 0.36mmol), Pd
2(dba)
3(25mg, 0.027mmol), Xantphos (30mg, 0.052mmol) and cesium carbonate (0.20g, 0.61mmol) the mixture in the Zai diox (3mL) be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 20 minutes.After being cooled to room temperature, removing lid and filter the gained mixture.With the solid of DCM washing and filtering, concentrated filtrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and be dissolved in minimum EtOAc then.Add hexane to solid precipitation.Filter the back and obtain title compound, be pale solid (55mg, 37%).
1H?NMR(500MHz，DMSO-d
6):δ?1.12(s，9H)，2.04(s，3H)，2.12(s，3H)，2.97(t，J＝5.2Hz，2H)，3.03(t，J＝5.1Hz，2H)，3.57(q，J＝5.4Hz，4H)，6.85(d，J＝9.0Hz，2H)，7.46-7.52(m，4H)，7.56(s，1H)，7.90(s，1H)，8.10-8.17(m，2H)，8.52(s，1H)，8.75(s，1H)。MS(ES+):m/z?538(M+H)
+。
The embodiment 173. N-tertiary butyl-3-{5-methyl-2-[4-(1-morpholine-4-base-ethyl)-phenyl
Amino]-pyrimidine-4-base is amino }-benzsulfamide (Compound C XV)
With intermediate 33 (0.10g, 0.28mmol), 4-(1-morpholine-4-base-ethyl)-phenyl amine (80mg, 0.39mmol), Pd
2(dba)
3(30mg, 0.033mmol), Xantphos (35mg, 0.061mmol) and cesium carbonate (0.26g, 0.80mmol) the mixture in the Zai diox (4mL) be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 20 minutes.After being cooled to room temperature, removing lid and filter the gained mixture.With the solid of DCM washing and filtering, concentrated filtrate and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration
3Solution (30mL).With the water layer of EtOAc (2 x 30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na
2SO
4Drying and filtration.Concentrated filtrate and be dissolved in minimum EtOAc then.Add hexane to solid precipitation.Filter the back and obtain title compound, be white solid (40mg, 27%).
1H?NMR(500MHz，DMSO-d
6):δ?1.12(s，9H)，1.25(d，J＝6.6Hz，3H)，2.13(s，3H)，2.20-2.30(m，2H)，2.30-2.40(m，2H)，3.24(q，J＝6.6Hz，1H)，3.54(t，J＝4.4Hz，4H)，7.10(d，J＝8.5Hz，2H)，7.45-7.52(m，2H)，7.55(s，1H)，7.57(d，J＝8.5Hz，2H)，7.93(s，1H)，8.09(s，1H)，8.15(d，J＝7.7Hz，1H)，8.57(s，1H)，8.92(s，1H)。MS(ES+):m/z?525(M+H)
+。
Embodiment 174. N
4
-(1H-indoles-4-yl)-5-methyl-N
2
-(4-(4-methylpiperazine-1-yl)
Phenyl) pyrimidine-2,4-diamines (Compound C XVI)
With intermediate 32 (270mg, 0.9mmol), 4-bromo-1H-indoles (196mg, 0.9mmol), Pd
2(dba)
3(91mg, 0.09mmol), Xantphos (157mg, 0.27mmol) and cesium carbonate (1.2g, mixture 3.6mmol) be suspended in the diox (100mL) and under reflux state and ar gas environment in the heating 20 hours.Filter this mixture and concentrated filtrate in a vacuum.Obtain title compound (55mg HCl salt, 14%) by HPLC purifying resistates, be white solid.
1H?NMR(500MHz，DMSO-d
6):δ?2.22(s，3H)，2.79(d，J＝4.3Hz，3H)，2.98-3.03(m，2H)，3.08-3.14(m，2H)，3.46-3.48(m，2H)，3.64-3.66(m，2H)，6.35-6.36(m，1H)，6.63(br?d，J＝8.0Hz，1H)，6.98(d，J＝9.1Hz，2H)，7.05(d，J＝7.4Hz，1H)，7.16(t，J＝7.6Hz，1H)，7.36(t，J＝2.8Hz，2H)，7.43(d，J＝8.0Hz，1H)，7.86(s，1H)，10.07(s，1H)，10.27(s，1H)，11.00(br?s，1H)，11.38(s，1H)，12.16(br?s，H)。MS(ES+):m/z414(M+H)
+。
Embodiment 175. 2-chloro-5-methyl-N-(2, the 3-3,5-dimethylphenyl) pyrimidine-4-amine (intermediates
61)
With 2-chloro-5-methylpyrimidine-4-amine (143.6mg, 1mmol), 1-bromo-2, the 3-dimethyl benzene (222mg, 1.2mmol), Pd
2(dba)
3(92mg, 0.1mmol), Xantphos (174mg, 0.3mmol) and cesium carbonate (1.3g, mixture 4mmol) be suspended in the diox (150mL) and under reflux state and ar gas environment in the heating 20 hours.Filter this mixture and concentrated filtrate in a vacuum.Resistates is dissolved in EtOAc (10mL) and adds hexane (100mL).Obtain thick title compound by solid collected by filtration and with hexane wash, be yellow solid.
Embodiment 176. 5-methyl-N
4
-(2, the 3-3,5-dimethylphenyl)-N
2
-(4-(piperidin-4-yl oxygen base)
Phenyl) pyrimidine-2,4-diamines (Compound C XVII)
(292.4mg, mixture 1.0mmol) are suspended in the acetate (10mL) and 100 ℃ of heating 4 hours down with intermediate 61 (1.0mmol) and 4-(4-amino-benzene oxygen) piperidines-1-t-butyl formate.This mixture is cooled to room temperature and under reduced pressure removes acetate.With resistates water-soluble (20mL) and be neutralized to pH～7.With EtOAc (30mL) extraction gained solution and separation organic layer.With salt water washing organic layer, use MgSO
4Drying and filtration.Concentrated filtrate and obtain title compound (105mg HCl salt, 24%) by HPLC purifying crude product is yellow solid in a vacuum.
1H?NMR(500MHz，DMSO-d
6):δ?1.76-1.83(m，2H)，2.03(s，3H)，2.05-2.09(m，2H)，2.17(s，3H)，2.30(s，3H)，3.02-3.05(m，2H)，3.18(br?s，2H)，4.53-4.56(m，1H)，6.72(d，J＝8.5Hz，2H)，7.11-7.14(m，3H)，7.19-7.24(m，2H)，7.87(s，1H)，9.06(br?s，1H)，9.13(br?s，1H)，9.92(s，1H)，10.43(s，1H)。MS(ES+):m/z?404(M+H)
+。
Embodiment 177. N
4
-(4-chloro-3,5-3,5-dimethylphenyl)-5-methyl-N
2
-(4-(4-methyl piperazine
Piperazine-1-yl) pyrimidine-2 phenyl), 4-diamines (Compound C XVIII)
With intermediate 32 (240mg, 0.8mmol), 5-bromo-2-chloro-1, the 3-dimethyl benzene (212mg, 0.96mmol), Pd
2(dba)
3(92mg, 0.1mmol), Xantphos (170mg, 0.3mmol) and cesium carbonate (1.3g, mixture 4mmol) be suspended in the diox (100mL) and under reflux state and ar gas environment in the heating 20 hours.Filter this mixture and concentrated filtrate in a vacuum.Obtain title compound (63mgHCl salt, 17%) by HPLC purifying resistates, be white solid.
1H?NMR(500MHz，DMSO-d
6):δ?2.15(s，3H)，2.17(s，3H)，2.80(d，J＝4.5Hz，3H)，3.06-3.14(m，4H)，3.48-3.52(m，2H)，3.75-3.77(m，2H)，6.93(d，J＝8.9Hz，2H)，7.29(d，J＝8.9Hz，2H)，7.46(s，2H)，7.90(s，1H)，9.65(s，1H)，10.49(s，1H)，11.13(br?s，2H)。MS(ES+):m/z?437(M+H)
+。
Embodiment 178. N
2
-(4-(2-(tetramethyleneimine-1-yl) oxyethyl group) phenyl)-N
4
-(the 3-tertiary butyl
Phenyl)-and 5-methyl-pyrimidine-2,4-diamines (Compound C XIX)
With intermediate 41 (365mg, 1.32mmol) and 4-(2-(tetramethyleneimine-1-yl) oxyethyl group) aniline (410mg 1.98mmol) is suspended in the acetate (20mL) and 100 ℃ of heating 4 hours down.This mixture is cooled to room temperature and under reduced pressure removes acetate.With resistates water-soluble (20mL) and be neutralized to pH～7.With EtOAc (30mL) extraction gained solution and separation organic layer.With salt water washing organic layer, use dry MgSO
4And filter.Concentrated filtrate and obtain title compound (127mg HCl salt, 20%) by HPLC purifying crude product is white solid in a vacuum.
1H?NMR(500MHz，DMSO-d
6):δ?1.89-1.91(m，2H)，1.98-2.02(m，2H)，2.17(s，3H)，3.07-3.12(m，2H)，3.52-3.57(m，4H)，4.32(t，J＝4.8Hz，2H)，6.90(d，J＝8.9Hz，2H)，7.29-7.38(m，4H)，7.43-7.44(m，1H)，7.48(d，J＝7.9Hz，1H)，7.89(s，1H)，9.75(s，1H)，10.51(s，1H)，11.07(br，1H)。MS(ESI+):m/z?446(M+H)
+。
Embodiment 179. N
2
-(4-(2-(tetramethyleneimine-1-yl) oxyethyl group) phenyl)-N
4
-(4-(uncle's 3-fourth
The base phenyl amino)-5-methylpyrimidine-2-yl)-5-methylpyrimidine-2,4-diamines (Compound C XX)
With intermediate 41 (210mg, 0.67mmol), intermediate 38 (185mg, 0.67mmol), Pd
2(dba)
3(55mg, 0.06mmol), Xantphos (104mg, 0.18mmol) and cesium carbonate (782g, mixture 2.4mmol) be suspended in the diox (50mL) and under reflux state and ar gas environment in the heating 20 hours.Filter this mixture and concentrated filtrate in a vacuum.Obtain title compound (94mg HCl salt, 24%) by HPLC purifying resistates, be yellow solid.
1H?NMR(500MHz，DMSO-d
6):δ?1.29(s，9H)，1.84-1.88(m，2H)，1.94-2.01(m，2H)，2.14(s，3H)，2.27(s，3H)，3.06-3.10(m，2H)，3.51-3.56(m，4H)，4.29(t，J＝4.9Hz，2H)，6.97(d，J＝9.1Hz，2H)，7.27(d，J＝8.6Hz，2H)，7.34(t，J＝7.9Hz，2H)，7.57(t，J＝1.9Hz，2H)，7.65(d，J＝9.1Hz，1H)，7.72(d，J＝8.6Hz，2H)，8.15(s，1H)，8.39(s，1H)，9.82(s，1H)，10.21(br?s，1H)，10.68(br?s，1H)，10.93(br?s，1H)。MS(ES+):m/z?553(M+H)
+。
Embodiment 180. 5-methyl-N
2
-[4-(4-methyl-piperazine-1-yl)-phenyl]-N
4
-[3-(piperazine
Pyridine-1-alkylsulfonyl)-phenyl]-pyrimidine-2,4-diamines (Compound C XXI)
With intermediate 32 (150mg, 0.5mmol), 1-(3-bromo-benzenesulfonyl)-piperidines (152mg, 0.5mmol), Pd
2(dba)
3(46mg, 0.05mmol), Xantphos (87mg, 0.15mmol) and cesium carbonate (652mg, mixture 2mmol) be suspended in the diox (20mL) and under reflux state and ar gas environment in the heating 20 hours.Filter this mixture and concentrated filtrate in a vacuum.Obtain title compound (84mgHCl salt, 37%) by HPLC purifying resistates, be white solid.
1H?NMR(500MHz，DMSO-d
6):δ?1.30-1.34(m，2H)，1.50-1.55(m，4H)，2.17(s，3H)，2.81(d，J＝4.5Hz，3H)，2.88(t，J＝5.3Hz，4H)，3.04-3.16(m，4H)，3.47-3.51(m，2H)，3.75-3.77(m，2H)，6.33-6.34(m，1H)，6.95(d，J＝9.0Hz，2H)，7.25(d，J＝9.0Hz，2H)，7.56-7.63(m，2H)，7.83(t，J＝1.7Hz，1H)，7.92(s，1H)，8.05(d，J＝9.3Hz，1H)，9.94(s，1H)，10.38(s，1H)，10.88(br?s，1H)。MS(ES+):m/z?522(M+H)
+。
Embodiment 181. 5-methyl-N
2
-[4-(4-methyl-piperazine-1-yl)-phenyl]-N
4
-[3-(2-
Methyl-piperidines-1-alkylsulfonyl)-phenyl]-pyrimidine-2,4-diamines (Compound C XXII)
With intermediate 32 (161mg, 0.54mmol), 1-(3-bromo-benzenesulfonyl)-2-methyl-piperidines (172mg, 0.54mmol), Pd
2(dba)
3(46mg, 0.05mmol), Xantphos (87mg, 0.15mmol) and cesium carbonate (652mg, mixture 2mmol) be suspended in the diox (20mL) and under reflux state and ar gas environment in the heating 20 hours.Filter this mixture and concentrated filtrate in a vacuum.Obtain title compound (10mg HCl salt, 3%) by HPLC purifying resistates, be white solid.
1H?NMR(500MHz，DMSO-d
6):δ?0.98(d，J＝6.9Hz，3H)，1.15-1.21(m，1H)，1.36-1.40(m，3H)，1.47-1.53(m，2H)，2.18(s，3H)，2.80(d，J＝4.5Hz，3H)，2.94-2.99(m，1H)，3.05-3.16(m，4H)，3.47-3.49(m，2H)，3.59-3.61(m，2H)，3.73-3.76(m，2H)，4.08-4.10(m，1H)，6.93(d，J＝8.9Hz，2H)，7.25(d，J＝8.9Hz，2H)，7.58(t，J＝8.0Hz，1H)，7.65(d，J＝8.0Hz，1H)，7.92(d，J＝7.1Hz，2H)，7.96(br，1H)，9.95(s，1H)，10.45(s，1H)，11.00(br?s，1H)。MS(ES+):m/z?536(M+H)
+。
Embodiment 182. N-cyclopentyl-3-{5-methyl-2-[4-(4-methyl-piperazine-1-yl)-phenyl
Amino]-pyrimidine-4-base is amino }-benzsulfamide (Compound C XXIII)
With intermediate 32 (229mg, 0.78mmol), 3-bromo-N-cyclopentyl-benzsulfamide (280mg, 0.92mmol), Pd
2(dba)
3(92mg, 0.1mmol), Xantphos (180mg, 0.3mmol) and cesium carbonate (1.3g, mixture 4mmol) be suspended in the diox (100mL) and under reflux state and ar gas environment in the heating 20 hours.Filter this mixture and concentrated filtrate in a vacuum.Obtain title compound (130mgHCl salt, 25%) by HPLC purifying resistates, be white solid.
1H?NMR(500MHz，DMSO-d
6):δ?1.27-1.36(m，4H)，1.36-1.58(m，4H)，2.18(s，3H)，2.80(d，J＝4.6Hz，3H)，3.05-3.15(m，4H)，3.36-3.42(m，1H)，3.47-3.49(m，2H)，3.74-3.76(m，2H)，6.94(d，J＝8.7Hz，2H)，7.26(d，J＝8.9Hz，2H)，7.59(t，J＝8.0Hz，1H)，7.68(d，J＝8.0Hz，1H)，7.75(d，J＝7.1Hz，2H)，7.92(br，2H)，7.93(br，1H)，9.96(s，1H)，10.45(s，1H)，11.98(br?s，1H)。MS(ES+):m/z?522(M+H)
+。
Embodiment 183. 5-methyl-N
2
-[4-(4-methyl-piperazine-1-yl)-phenyl]-N
4
-[3-(pyrrole
Cough up alkane-1-alkylsulfonyl) phenyl]-pyrimidine-2,4-diamines (Compound C XXIV)
With intermediate 32 (298mg, 1.0mmol), 1-(3-bromo-benzenesulfonyl)-tetramethyleneimine (360mg, 1.24mmol), Pd
2(dba)
3(92mg, 0.1mmol), Xantphos (180mg, 0.3mmol) and cesium carbonate (1.3g, mixture 4mmol) be suspended in the diox (100mL) and under reflux state and ar gas environment in the heating 20 hours.Filter this mixture and concentrated filtrate in a vacuum.Obtain title compound (200mg HCl salt, 37%) by HPLC purifying resistates, be white solid.
1H?NMR(500MHz，DMSO-d
6):δ?1.61-1.65(m，4H)，2.19(s，3H)，2.80(br，3H)，3.06-3.16(m，10H)，3.74-3.77(br，2H)，6.94(d，J＝9.0Hz，2H)，7.26(d，J＝9.0Hz，2H)，7.60(t，J＝8.0Hz，1H)，7.65(d，J＝8.0Hz，1H)，7.91(t，J＝1.7Hz，1H)，7.93(s，1H)，8.05(d，J＝7.5Hz，1H)，9.95(s，1H)，10.43(s，1H)，11.07(br?s，1H)。MS(ES+):m/z?508(M+H)
+。
Embodiment 184. N
4
-[3-(2,5-dimethyl-tetramethyleneimine-1-alkylsulfonyl)-phenyl]-5-methyl
-N
2
-[4-(4-methyl-piperazine-1-yl)-phenyl]-pyrimidine-2,4-diamines (Compound C XXV)
With intermediate 32 (298mg, 1.0mmol), 1-(3-bromo-benzenesulfonyl)-2,5-dimethyl-tetramethyleneimine (318mg, 1.0mmol), Pd
2(dba)
3(92mg, 0.1mmol), Xantphos (180mg, 0.3mmol) and cesium carbonate (1.3g, mixture 4mmol) be suspended in the diox (100mL) and under reflux state and ar gas environment in the heating 20 hours.Filter this mixture and concentrated filtrate in a vacuum.Obtain title compound (100mg HCl salt, 17%) by HPLC purifying resistates, be white solid.
1H?NMR(500MHz，DMSO-d
6):δ?1.26(s，3H)，1.27(s，3H)，1.45-1.48(m，4H)，2.19(s，3H)，2.80(d，J＝4.6Hz，3H)，3.06-3.15(m，4H)，3.47-3.50(m，2H)，3.60-3.64(m，2H)，3.74-3.76(m，2H)，6.94(d，J＝9.0Hz，2H)，7.25(d，J＝9.0Hz，2H)，7.59(t，J＝8.0Hz，1H)，7.68(d，J＝7.6Hz，1H)，7.93(br，2H)，8.02(br，1H)，9.97(s，1H)，10.47(s，1H)，11.07(br?s，1H)。MS(ES+):m/z?536(M+H)
+。
The embodiment 185. N-tertiary butyl-3-[5-methyl-2-(4-piperazine-1-base-phenyl amino)-phonetic
Pyridine-4-base is amino]-benzsulfamide (Compound C XXVI)
With intermediate 33 (355mg, 1.0mmol), 4-(4-aminophenyl) piperazine-1-t-butyl formate (278mg, 1.0mmol), Pd
2(dba)
3(92mg, 0.1mmol), Xantphos (180mg, 0.3mmol) and cesium carbonate (1.3g, mixture 4mmol) be suspended in the diox (100mL) and under reflux state and ar gas environment in the heating 20 hours.Filter this mixture and concentrated filtrate in a vacuum.Resistates is dissolved in CH
2Cl
2(10mL) and add trifluoroacetic acid (2mL).This mixture was at room temperature stirred 4 hours, after this add 10% NaOH.Separate organic layer and use CH
2Cl
2(10mL x 2) aqueous layer extracted.Dry organic layer (the Na that merges
2SO
4).Remove in a vacuum and desolvate.Obtain title compound (62mg, 12%) by HPLC purifying resistates, be white solid.
1H?NMR(500MHz，DMSO-d
6):δ?1.10(s，9H)，2.18(s，3H)，3.20(br，4H)，3.33(br，4H)，6.94(d，J＝9.0Hz，2H)，7.25(d，J＝9.0Hz，2H)，7.57(t，J＝8.0Hz，1H)，7.63(s，1H)，7.71(d，J＝8.1Hz，1H)，7.87(br，1H)，7.92(br，1H)，7.96(br，1H)，9.30(br，1H)，9.96(s，1H)，10.46(s，1H)。MS(ES+):m/z?496(M+H)
+。
The embodiment 186. N-tertiary butyl-3-(2-{4-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-benzene
Base is amino }-[5-methyl-pyrimidine-4-base is amino]-benzsulfamide (Compound C XXVII)
With above-claimed cpd CXXVI (31mg 0.06mmol) is dissolved in DMF (10mL), add subsequently ethylene bromohyrin (16mg, 0.13mmol) and diisopropylethylamine (33mg, 0.25mmol).This mixture was at room temperature stirred 48 hours.In a vacuum except that desolvating and resistates being dissolved in EtOAc (20mL).Use saturated NaHCO
3With this solution of salt water washing.The dry organic layer that merges and be concentrated into 2mL solution adds Et subsequently
2O (20mL).By centrifugal collection solid and change into its HCl salt (10.7mg, 30%).
1H?NMR(500MHz，DMSO-d
6):δ?1.09(s，9H)，2.17(s，3H)，3.12-3.23(m，4H)，3.56-3.60(m，2H)，3.69-3.74(m，2H)，3.83(br，2H)，4.13(br，2H)，6.94(d，J＝9.0Hz，2H)，7.25(d，J＝9.0Hz，2H)，7.57(t，J＝8.0Hz，1H)，7.63(s，1H)，7.71(d，J＝8.1Hz，1H)，7.87(br，1H)，7.93(br，1H)，7.95(br，1H)，9.98(s，1H)，10.53(s，1H)，10.75(br，1H)。MS(ES+):m/z?540(M+H)
+。
The embodiment 187. N-tertiary butyl-3-[5-methyl-2-(3-piperazine-1-base-phenyl amino)-phonetic
Pyridine-4-base is amino]-benzsulfamide (Compound C XXVIII)
With intermediate 33 (240mg, 0.67mmol), 4-(3-aminophenyl) piperazine-1-t-butyl formate (166mg, 0.6mmol), Pd
2(dba)
3(55mg, 0.06mmol), Xantphos (104mg, 0.18mmol) and cesium carbonate (782mg, mixture 2.4mmol) be suspended in the diox (100mL) and under reflux state and ar gas environment in the heating 20 hours.Filter this mixture and concentrated filtrate in a vacuum.Resistates is dissolved in CH
2Cl
2(10mL) and add trifluoroacetic acid (2mL).This mixture was at room temperature stirred 4 hours, after this add 10% NaOH.Separate organic layer and use CH
2Cl
2(10mL x 2) aqueous layer extracted.Dry organic layer (the Na that merges
2SO
4).Remove in a vacuum and desolvate.Obtain title compound (18mg, 6%) by HPLC purifying resistates, be white solid.
1H?NMR(500MHz，DMSO-d
6):δ?1.10(s，9H)，2.19(s，3H)，3.17(br，4H)，3.27-3.29(m，4H)，6.80(d，J＝8.1Hz，1H)，6.87(br，1H)，6.96(d，J＝8.1Hz，1H)，7.16(t，J＝8.1Hz，1H)，7.53(t，J＝8.3Hz，1H)，7.61(s，1H)，7.70(d，J＝7.8Hz，1H)，7.94(br，3H)，9.19(br，2H)，9.93(s，1H)，10.48(s，1H)。MS(ES+):m/z?496(M+H)
+。
The embodiment 188. N-tertiary butyl-3-(2-{3-[4-(2-hydroxyl-ethyl)-piperazine-1-yl]-benzene
Base is amino }-[5-methyl-pyrimidine-4-base is amino]-benzsulfamide (Compound C XXIX)
With above-claimed cpd CXXVI (12mg 0.024mmol) is dissolved in DMF (10mL), add subsequently ethylene bromohyrin (6.1mg, 0.048mmol) and diisopropylethylamine (12mg, 0.092mmol).This mixture was at room temperature stirred 48 hours.In a vacuum except that desolvating and resistates being dissolved in EtOAc (20mL).Use saturated NaHCO
3With this solution of salt water washing.The dry organic layer that merges and be concentrated into 2mL solution adds Et subsequently
2O (20mL).By centrifugal collection solid and change into its HCl salt (7mg, 51%).
1H?NMR(500MHz，DMSO-d
6):δ?1.09(s，9H)，2.19(s，3H)，3.12-3.22(m，4H)，3.56-3.60(m，2H)，3.69-3.74(m，2H)，3.81(br，2H)，4.12(br，2H)，6.80(br，1H)，6.88(br，1H)，6.96(br，1H)，7.16(br，1H)，7.57(br，1H)，7.60(s，1H)，7.69(d，J＝7.8Hz，1H)，7.94(br，3H)，9.94(s，1H)，10.49(s，1H)。MS(ES+):m/z?540(M+H)
+。
Embodiment 189. N
2
-(4-(1H-pyrazol-1-yl) phenyl)-N
4
-(3-tert-butyl-phenyl)-5-first
Yl pyrimidines-2,4-diamines (Compound C XXX)
With intermediate 41 (580mg, 2.1mmol) and 4-(1H-pyrazol-1-yl) aniline (335mg, mixture 2.1mmol) are suspended in the acetate (10mL) and 100 ℃ of heating 4 hours down.This mixture is cooled to room temperature and under reduced pressure removes acetate.With resistates water-soluble (20mL) and be neutralized to pH～7.With EtOAc (30mL) extraction gained solution and separation organic layer.With salt water washing organic layer, use MgSO
4Drying and filtration.Concentrated filtrate and obtain title compound (31mg, 4%) by HPLC purifying crude product is yellow solid in a vacuum.
1H?NMR(500MHz，DMSO-d
6):δ?1.24(s，9H)，2.18(s，3H)，6.53(t，J＝2.0Hz，1H)，7.33(d，J＝8.0Hz，1H)，7.38(t，J＝7.9Hz，1H)，7.44(s，1H)，7.47(d，J＝8.2Hz，1H)，7.50(d，J＝8.9Hz，2H)，7.67(d，J＝8.9Hz，2H)，7.73(s，1H)，7.95(s，1H)，8.43(d，J＝2.4Hz，1H)，9.81(br?s，1H)，10.67(s，1H)。MS(ES+):m/z?399(M+H)
+。
Embodiment 190. N
4
-(7-chloro-1H-indoles-4-yl)-5-methyl-N
2
-(4-((piperazine-1-yl)
Methyl) phenyl)-and pyrimidine-2,4-diamines (Compound C XXXI)
With intermediate 40 (150mg, 0.37mmol), 4-bromo-7-chloro-1H-indoles (87mg, 0.37mmol), Pd
2(dba)
3(38mg, 0.04mmol), Xantphos (76mg, 0.12mmol) and cesium carbonate (521mg, mixture 1.6mmol) be suspended in the diox (50mL) and under reflux state and ar gas environment in the heating 20 hours.Filter this mixture and concentrated filtrate in a vacuum.Resistates is dissolved in CH
2Cl
2(10mL) and add trifluoroacetic acid (2mL).This mixture was at room temperature stirred 4 hours, after this add 10% NaOH.Separate organic layer and use CH
2Cl
2(10mL x 2) aqueous layer extracted.Dry organic layer (the Na that merges
2SO
4).Remove in a vacuum and desolvate.Obtain title compound (26mg, 15%) by HPLC purifying resistates, be white solid.
1H?NMR(500MHz，DMSO-d
6):δ?2.21(s，3H)，3.30(br，4H)，3.50(br，4H)，4.42(br，2H)，6.91(s，1H)，7.11(d，J＝8.3Hz，1H)，7.40(d，J＝7.5Hz，1H)，7.42(t，J＝2.7Hz，1H)，7.70(br，4H)，8.03(s，1H)，9.87(br，1H)，9.95(s，1H)，10.64(s，1H)，11.64(s，1H)。MS(ES+):m/z?448(M+H)
+。
Embodiment 191. N
4
-(3-tert-butyl-phenyl)-5-methyl-N
2
-(4-(2-methyl isophthalic acid H-imidazoles
-1-yl) phenyl)-and pyrimidine-2,4-diamines (Compound C XXXII)
With intermediate 41 (180mg, 0.65mmol) and 4-(2-methyl isophthalic acid H-imidazoles-1-yl) aniline (113mg, 0.65mmol), Pd
2(dba)
3(55mg, 0.06mmol), Xantphos (104mg, 0.18mmol) and cesium carbonate (782mg, mixture 2.4mmol) be suspended in the diox (100mL) and under reflux state and ar gas environment in the heating 20 hours.Filter this mixture and concentrated filtrate in a vacuum.Obtain title compound (78mg HCl salt, 27%) by HPLC purifying resistates, be white solid.
1H?NMR(500MHz，DMSO-d
6):δ?1.26(s，9H)，2.21(s，3H)，2.50(s，3H)，7.31-7.36(m，1H)，7.40(t，J＝7.8Hz，1H)，7.44(d，J＝8.9Hz，2H)，7.47(d，J＝8.0Hz，2H)，7.65(d，J＝8.9Hz，2H)，7.75(d，J＝2.1Hz，1H)，7.79(d，J＝2.1Hz，2H)，8.03(s，1H)，10.02(s，1H)，11.26(s，1H)。MS(ES+):m/z413(M+H)
+。
Embodiment 192. 4-(4-methyl isophthalic acid H-imidazoles-1-yl) aniline (intermediate 62)
To 1-fluoro-4-oil of mirbane (1.7g, 12mmol) add in the solution in DMF (100mL) 4-methyl isophthalic acid H-imidazoles (0.82g, 10mmol) and K
2CO
3(11g, 80mmol).This mixture was heated 20 hours in ar gas environment and under the reflux state.Filter this mixture and concentrated filtrate in a vacuum.Resistates is dissolved in EtOAc (100mL) and with salt water washing (100mL x 2).Dry organic layer and concentrated.Solid is dissolved in MeOH and with Ar foaming 2 minutes, after this adds 10% Pd-C.Hydrogenation was carried out 4 hours.Remove catalyzer and obtain title compound (1.5g, 87%) except that desolvating in a vacuum, be brown solid.
Embodiment 193. N
4
-(3-tert-butyl-phenyl)-5-methyl-N
2
-(4-(4-methyl isophthalic acid H-imidazoles
-1-yl) pyrimidine-2 phenyl), 4-diamines (Compound C XXXIII)
With intermediate 41 (318mg, 1.15mmol) and intermediate 62 (200mg, 1.15mmol), Pd
2(dba)
3(92mg, 0.1mmol), Xantphos (180mg, 0.3mmol) and cesium carbonate (1.3g, mixture 4mmol) be suspended in the diox (100mL) and under reflux state and ar gas environment in the heating 20 hours.Filter this mixture and concentrated filtrate in a vacuum.Obtain title compound (66mg HCl salt, 20%) by HPLC purifying resistates, be white solid.
1H?NMR(500MHz，DMSO-d
6):δ?1.26(s，9H)，2.19(s，3H)，2.36(s，3H)，7.30(d，J＝7.9Hz，1H)，7.41(d，J＝7.9Hz，1H)，7.44(t，J＝1.8Hz，1H)，7.54(d，J＝7.9Hz，1H)，7.59(d，J＝9.0Hz，2H)，7.68(d，J＝9.0Hz，2H)，7.94(s，1H)，7.99(s，1H)，9.53(d，J＝1.3Hz，1H)，9.72(br?s，1H)，10.81(br?s，1H)。MS(ES+):m/z?413(M+H)
+。
Embodiment 194. 4-(4-aminophenyl) piperidines-1-t-butyl formate (intermediate 63)
To 4-(4-nitrophenyl) piperidines (412mg, 2mmol) add in the solution in CH2Cl2 (100mL) carbonic acid two-tert-butyl ester (480mg, 2.2mmol) and N, N-lutidine-4-amine (50mg, 0.4mmol).This mixture was at room temperature stirred 20 hours.In this mixture, add saturated NaHCO3 (100mL).Separate organic layer and with CH2Cl2 (50mL x2) aqueous layer extracted.The dry organic solution that merges and concentrated in a vacuum.Resistates is dissolved in MeOH and with Ar foaming 2 minutes, after this adds 10% Pd-C.Hydrogenation was carried out 4 hours.Obtain title compound (460mg, 83%) by removing by filter catalyzer and removing to desolvate in a vacuum, be white solid.
Embodiment 195. N
4
-(3-tert-butyl-phenyl)-5-methyl-N
2
-(4-(piperidin-4-yl) phenyl)
Pyrimidine-2,4-diamines (Compound C XXXIV)
(170mg, 0.6mmol) (170mg, mixture 0.6mmol) are suspended in the acetate (10mL) and at 100 ℃ and heated 4 hours down with intermediate 63 with intermediate 41.This mixture is cooled to room temperature and under reduced pressure removes acetate.With resistates water-soluble (20mL) and be neutralized to pH～7.With EtOAc (30mL) extraction gained solution and separation organic layer.With salt water washing organic layer, use MgSO
4Drying and filtration.Concentrated filtrate and obtain title compound (8mg, 3%) by HPLC purifying crude product is white solid in a vacuum.
1H?NMR(500MHz，DMSO-d
6):δ?1.26(s，9H)，1.76-1.88(m，4H)，2.17(s，3H)，2.76-2.81(m，1H)，2.93-3.00(m，2H)，3.36-3.40(m，2H)，7.07(d，J＝8.5Hz，1H)，7.30-7.36(m，4H)，7.44(s，1H)，7.46(d，J＝8.7Hz，1H)，7.91(s，1H)，8.84(brs，1H)，8.92(br?s，1H)，9.73(s，1H)，10.45(s，1H)。MS(ES+):m/z?416(M+H)
+。
Embodiment 196. N
4
-(3-tert-butyl-phenyl)-5-methyl-N
2
-(4-(1-morpholino ethyl) benzene
Base) pyrimidine-2,4-diamines (Compound C XXXV)
With intermediate 41 (276mg, 1.0mmol) and 4-(1-morpholino ethyl) aniline (210mg, 1.0mmol), Pd
2(dba)
3(92mg, 0.1mmol), Xantphos (180mg, 0.3mmol) and cesium carbonate (1.3g, mixture 4mmol) be suspended in the diox (100mL) and under reflux state and ar gas environment in the heating 20 hours.Filter this mixture and concentrated filtrate in a vacuum.Obtain title compound (17mg HCl salt, 4%) by HPLC purifying resistates, be yellow solid.
1H?NMR(500MHz，DMSO-d
6):δ?1.26(s，9H)，1.66(d，J＝6.8Hz，3H)，2.19(s，3H)，2.79(br，2H)，2.92(br，1H)，3.61-3.64(m，2H)，3.77-3.82(m，2H)，3.94-3.99(m，2H)，7.32(d，J＝7.8Hz，1H)，7.42(t，J＝1.9Hz，1H)，7.43(d，J＝7.8Hz，1H)，7.46-7.52(m，5H)，7.97(s，1H)，9.86(s，1H)，10.78(s，1H)，11.72(br?s，1H)。MS(ES+):m/z?446(M+H)
+。
Embodiment 197.5-bromo-2-methyl-benzene sulfonyl chloride (intermediate 64)
(1.99g, 11.61mmol) and with chlorsulfonic acid (1.55mL 23.22mmol) handles the vigorous stirring bromide.In case addition is finished, the red syrup of gained is heated to 60 ℃.Reaction TLC after 10 minutes shows and does not have raw material and make the reaction quencher on ice by being poured over.By washing extraction product with EtOAc (2 x 150mL).Use Na
2SO
4Dry organic phase is filtered and is evaporated to and obtains yellow oil (2.2g, 70%).
Embodiment 198. 5-bromo-2, N-dimethyl-benzsulfamide (intermediate 65)
(2.4mL 4.8mmol) handles intermediate 64 (0.43g, 1.58mmol) the stirring suspension in DCM (5mL) with the methylamine solution of 2.0M in THF.After 16 hours, remove reaction solvent and with EtOAc (150mL) dilution gained resistates and wash with water.Use Na
2SO
4Dry organic phase is filtered and is evaporated to and obtains white solid (0.37g, 89%).
Embodiment 199. 2, N-dimethyl-5-{5-methyl-2-[4-(2-tetramethyleneimine-1-base-ethoxy
Base)-phenyl amino]-pyrimidine-4-base is amino }-benzsulfamide (Compound C XXXVI)
With intermediate 65 (0.14g, 0.52mmol), intermediate 38 (0.14g, 0.43mmol), Pd
2(dba)
3(0.040g, 0.043mmol), Xantphos (0.050g, 0.087mmol) and cesium carbonate (0.43g, mixture 1.3mmol) are suspended in the diox (10mL), be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 15 minutes.This reaction mixture is cooled to room temperature and centrifugal settling.Decantation should reaction and concentrated in a vacuum organic phase.Obtain title compound by HPLC purifying resistates, be white solid (0.052g, 24%).
1H?NMR(500MHz，DMSO-d
6):δ?1.66-1.70(m，4H)，2.08(s，3H)，2.43(d，J＝4.9Hz，3H)，2.5(br?s，4H)，2.78，(t，J＝5.7Hz)，4.00(t，J＝5.9Hz)，6.79(d，J＝9.0Hz，2H)，7.31(d，J＝9.7Hz，1H)，7.42(q，J＝9.8Hz，1H)，7.49(d，J＝9.0Hz，1H)，7.87(s，1H)，7.97(d，J＝2.3Hz，1H)，8.07-8.09(m，1H)，8.49(s，1H)，8.75(s，1H)。MS(ES+):m/z?497(M+H)
+。
The embodiment 200. 5-bromo-N-tertiary butyls-2-methyl-benzsulfamide (intermediate 66)
(1.4mL 13.6mmol) handles intermediate 64 (1.22g, 4.5mmol) the stirring suspension in DCM (25mL) with tert-butylamine.After 16 hours, remove reaction solvent and the gained solid is ground with water.(1.3g, 94%) in a vacuum spends the night solid drying.
The embodiment 201. N-tertiary butyl-5-(2-chloro-5-methyl-pyrimidine-4-base is amino)-2-methyl-
Benzsulfamide (intermediate 67)
With intermediate 66 (0.90g, 2.96mmol), 2-chloro-5-methyl-pyrimidine-4-base amine (0.33g, 2.28mmol), Pd
2(dba)
3(0.21g, 0.23mmol), Xantphos (0.264g, 0.46mmol) and cesium carbonate (2.2g, mixture 6.8mmol) are suspended in the diox (15mL), be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 15 minutes.This reaction mixture is cooled to room temperature and centrifugal settling.Decantation should reaction and concentrated in a vacuum organic phase.Obtain title compound with silicagel column purifying resistates, be white solid (0.12g, 14%).
The embodiment 202 N-tertiary butyl-5-[2-(4-imidazoles-1-base-phenyl amino)-5-methyl-pyrimidine
-4-base is amino]-2-methyl-benzsulfamide (Compound C XXXVII)
With intermediate 67 (0.113g, 0.31mmol), 4-imidazoles-1-base-phenyl amine (0.059g, 0.37mmol), Pd
2(dba)
3(0.028g, 0.03mmol), Xantphos (0.036g, 0.06mmol) and cesium carbonate (0.3g, mixture 0.92mmol) are suspended in the diox (6mL), be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 15 minutes.Decantation should reaction and concentrated in a vacuum organic phase.Obtain title compound by HPLC purifying resistates, be white solid (0.052g, 24%).
1H?NMR(500MHz，DMSO-d
6):δ?1.11(s，9H)，2.13(s，3H)，2.58(s，3H)，7.07(s，1H)，7.34(d，J＝8.5Hz，1H)，7.42(d，J＝8.9Hz，2H)，7.48(s，1H)，7.60(s，1H)，7.78(d，J＝8.9Hz，2H)，7.94(s，1H)，7.98-8.00(m，1H)，8.09(s，1H)，8.12(d，J＝2.3Hz，1H)，8.56(s，1H)，9.16(s，1H)。MS(ES+):m/z492(M+H)
+。
The embodiment 203. N-tertiary butyl-3-{5-methyl-2-[4-(tetramethyleneimine-1-carbonyl)-phenylamino
Base]-pyrimidine-4-base is amino }-benzsulfamide (Compound C XXXVIII)
With intermediate 33 (0.11g, 0.32mmol), (4-amino-phenyl)-tetramethyleneimine-1-base-ketone (0.072g, 0.38mmol), Pd
2(dba)
3(0.029g, 0.032mmol), Xantphos (0.037g, 0.063mmol) and cesium carbonate (0.3g, mixture 0.95mmol) are suspended in the diox (6mL), be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 15 minutes.Decantation should reaction and concentrated in a vacuum organic phase.Obtain title compound by HPLC purifying resistates, be white solid (0.040g, 25%).
1H?NMR(500MHz，DMSO-d
6):δ?1.11(s，9H)，1.8(br?s，4H)，2.14(s，3H)，3.44(t，J＝6.6Hz，4H)，7.38(d，J＝9.0Hz，2H)，7.52-7.54(m，2H)，7.56(s，1H)，7.70(d，J＝9.8Hz，2H)，7.98(s，1H)，8.08-8.10(m，2H)，8.60(br?s，1H)，9.24(s，1H)。MS(ES+):m/z?509(M+H)
+。
The embodiment 204. N-tertiary butyl-3-{5-methyl-2-[4-(morpholine-4-carbonyl)-phenylamino
Base]-pyrimidine-4-base is amino }-benzsulfamide (Compound C XXXIX)
With intermediate 33 (0.13g, 0.37mmol), (4-amino-phenyl)-morpholine-4-base-ketone (0.092g, 0.45mmol), Pd
2(dba)
3(0.034g, 0.037mmol), Xantphos (0.043g, 0.075mmol) and cesium carbonate (0.37g, mixture 1.1mmol) are suspended in the diox (6mL), be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 15 minutes.Decantation should reaction and concentrated in a vacuum organic phase.Obtain title compound by HPLC purifying resistates, be white solid (0.065g, 33%).
1H?NMR(500MHz，DMSO-d
6):δ?1.11(s，9H)，2.14(s，3H)，3.49(br?s，4H)，3.59(br?s，4H)，5.75(s，1H)，7.25(d，J＝9.0Hz，2H)，7.52-7.54(m，2H)，7.56(s，1H)，7.71(d，J＝9.0Hz，2H)，7.98(s，1H)，8.06-8.08(m，2H)，8.65(br?s，1H)，9.26(s，1H)。MS(ES+):m/z?525(M+H)
+。
The embodiment 205. N-tertiary butyl-3-{5-methyl-2-[4-(piperazine-1-carbonyl)-phenylamino
Base]-pyrimidine-4-base is amino }-benzsulfamide (Compound C XL)
With intermediate 33 (0.12g, 0.33mmol), 4-(4-amino-benzoyl)-piperazine-1-t-butyl formate (0.12g, 0.45mmol), Pd
2(dba)
3(0.030g, 0.037mmol), Xantphos (0.038g, 0.075mmol) and cesium carbonate (0.33g, mixture 1.1mmol) are suspended in the diox (6mL), be sealed in the microwave reaction pipe and at 160 ℃ down with microwave irradiations 15 minutes.Decantation should reaction and concentrated in a vacuum organic phase.By silica gel column chromatography purifying resistates (EtOAc of 25%-100% in hexane).Use the TFA solution-treated product of 20mL 20% in DCM then.Remove by rotary evaporation subsequently and desolvate.Obtain title compound by HPLC purifying gained material resistates, be white solid (0.045g, 26%).
1H?NMR(500MHz，DMSO-d
6):δ?1.11(s，9H)，2.14(s，3H)，2.82(br?s，4H)，3.48(br?s，4H)，7.24(d，J＝9.0Hz，2H)，7.51-7.53(m，2H)，7.55(s，1H)，7.71(d，J＝9.0Hz，2H)，7.94(s，1H)，8.06-8.08(m，2H)，8.65(br?s，1H)，9.25(s，1H)。MS(ES+):m/z?524(M+H)
+。
Embodiment 206. 4-(4-(4-(3-p-methoxy-phenyl amino)-5-methylpyrimidine-2-base is amino)
Phenoxy group) piperidines-1-t-butyl formate (intermediate 68)
With 1-bromo-3-anisole (69.5 μ L, 0.56mmol), intermediate 42 (205mg, 0.51mmol), Pd
2(dba)
3(23mg, 0.03mmol), Xantphos (33mg, 0.06mmol) and cesium carbonate (359mg, 1.10mmol) in the microwave of mixture under 160 ℃ in the Zai diox (3mL) irradiation 20 minutes.This reaction mixture is cooled to room temperature, filters and wash filtrate with DCM and MeOH., be light brown solid (215mg, 83%) to the liquid that concentrate to merge and use gradient purified by flash chromatography (ethyl acetate of 0-100% in hexane) and obtain title compound in vacuum.
Embodiment 207. 3-(2-(4-(piperidin-4-yl oxygen base) phenyl amino)-5-methylpyrimidine-4-
Base is amino) phenol (Compound C XLI)
(215mg 0.42mmol) adds BBr in the mixture in DCM (4mL) to intermediate 68
3(120 μ L 1.27mmol) and at room temperature stirred 64 hours.Make reaction quencher and concentrated in a vacuum with MeOH.Obtain the tfa salt (116mg, 56%) of title compound by preparation HPLC purifying resistates and concentrated in a vacuum fraction.This tfa salt is dissolved in MeOH and makes it pass through SPE PL-HCO
3The MP-resin column concentrates in a vacuum, grinds and filters and obtain title compound with ether, is white solid (31mg, the rate of recovery 69%).
1H?NMR(500MHz，DMSO-d
6):δ?1.51-1.60(m，2H)，1.90-1.98(m，2H)，2.07(s，3H)，2.70-2.78(m，2H)，3.02-3.09(m，2H)，4.28-4.36(m，1H)，6.48(dd，J＝8.1，2.2Hz，1H)，6.79(d，J＝9.1Hz，2H)，7.06-7.11(m，2H)，7.16(d，J＝8.5Hz，1H)，7.57(d，J＝9.1Hz，2H)，7.82(s，1H)，8.08(s，1H)，8.73(s，1H)，9.27(brs，1H)。MS(ES+):m/z392(M+H)
+。
Embodiment 208. (2-chloro-5-methyl-pyrimidine-4-yl)-(4-fluoro-3-methoxyl group-phenyl)-amine
(intermediate 69)
With 2-chloro-5-methyl-pyrimidine-4-base amine (1.2g, 8.1mmol), 4-bromo-1-fluoro-2-methoxyl group-benzene (1.8g, 8.9mmol), Pd
2(dba)
3(0.74g, 0.81mmol), Xantphos (0.93g, 1.6mmol) and cesium carbonate (7.88g, mixture 24.2mmol) be suspended in the diox (60mL) and under reflux state and ar gas environment in the heating 5 hours.This reaction mixture is cooled to room temperature and dilutes with DCM (30mL).Filter this mixture and concentrated filtrate in a vacuum.Obtain title compound (0.3g, 14%) by fast silica gel chromatogram method purifying resistates, be light brown solid.
Embodiment 209. N
4
-(4-fluoro-3-methoxyl group-phenyl)-5-methyl-N
2
-[4-(2-tetramethyleneimine
-1-base-oxyethyl group)-phenyl]-pyrimidine-2,4-diamines (Compound C XLII)
With intermediate 69 (0.1g, 0.37mmol) and 4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl amine (0.16g, mixture 0.75mmol) be suspended in the acetate (10mL) and be heated to 110 ℃ following 16 hours.This reaction mixture is cooled to room temperature and concentrated in a vacuum.Obtain title compound (0.03g, 17%) by HPLC purifying resistates, be green solid.
1H?NMR(500MHz，DMSO-d
6):δ?1.88(br?s，2H)，2.0(br?s，2H)，2.15(s，3H)，3.08(br?s，2H)，3.55(br?s，4H)，3.7(s，3H)，4.32(br?s，2H)，6.9(d，J＝7.9Hz，2H)，7.13(br?s，1H)，7.21-7.25(m，1H)，7.32-7.34(m，3H)，7.89(s，1H)，9.78(br?s，1H)，10.48(brs，1H)，10.92(br?s，1H)。MS(ES+):m/z?438(M+H)
+。
Embodiment 210. (2-chloro-pyrimidine-4-yl)-(3-methoxyl group-2-methyl-phenyl)-amine (intermediate
70)
(0.68g, 5mmol) with 2, (0.74g, mixture 5mmol) are suspended in the ethanol (10mL) and at room temperature stirred 20 hours 4-two chloro-pyrimidines with 3-methoxyl group-2-methyl-phenyl amine.Dilute this reaction mixture with DCM (50mL), filter and concentrate in a vacuum.Obtain title compound (0.085g, 7%) by silica gel column chromatography purifying resistates, be yellow solid.
Embodiment 211. N
4
-(3-methoxyl group-2-methyl-phenyl)-N
2
-[4-(2-tetramethyleneimine-1-base-
Oxyethyl group)-phenyl]-pyrimidine-2,4-diamines (Compound C XLIII)
With intermediate 70 (0.08g, 0.32mmol) and 4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl amine (0.13g, mixture 0.64mmol) be suspended in the acetate (10mL) and be heated to 80 ℃ following 16 hours.This reaction mixture is cooled to room temperature and extremely concentrated in vacuum.Obtain title compound (0.03g, 17%) by HPLC purifying resistates, be gray solid.
1H?NMR(500MHz，DMSO-d
6):δ?1.89(br?s，2H)，2.0(br?s，4H)，3.08(br?s，2H)，3.4(br?s，4H)，3.54(br?s，4H)，3.83(s，3H)，4.31(br?s，2H)，6.86(br?s，2H)，6.97(d，J＝8.1Hz，2H)，7.26(t，J＝8.1Hz1H)，7.34(br?s，2H)，7.89(s，1H)，9.73(br?s，1H)，10.62(br?s，2H)，11.01(br?s，1H)。MS(ES+):m/z?420(M+H)
+。
Embodiment 212. 4-(4-acetylamino-benzenesulfonyl)-piperidines-1-t-butyl formate (in
Mesosome 71)
With 4-(4-bromo-benzenesulfonyl)-piperidines-1-t-butyl formate (4g, 9.92mmo), ethanamide (0.88g, 14.9mmol), Pd
2(dba)
3(0.46g, 0.49mmol), Xantphos (0.56g, 0.99mmol) and cesium carbonate (9.7g, mixture 29.8mmol) be suspended in the diox (60mL) and under reflux state and ar gas environment in the heating 4 hours.This reaction mixture is cooled to room temperature and is poured on ice.Collect gained yellow solid and drying by filtering.Obtain title compound by flash chromatography on silica gel method purifying crude product, be light brown solid (3.12g, 82%).
Embodiment 213. 4-(4-amino-benzenesulfonyl)-piperidines-1-t-butyl formate (intermediate 72)
Use 60mL Claisen ' s alkali (to be dissolved in 63mL H
2O is diluted to the 88g KOH of 250mL with MeOH) diluted intermediate 71 (2.6g, suspension 6.7mmol) and be heated to 90 ℃.After 2 hours, make reaction pine for breaking away from, be cooled to room temperature and water (50mL dilution) from adding.Collect gray solid by suction filtration, wash with water and dried overnight (2.2g, 97%).
Embodiment 214. N
4
-(4-chloro-3-methoxyl group-phenyl)-5-methyl-N
2
-[4-(piperidines-4-sulphur
Acyl group)-phenyl]-pyrimidine-2,4-diamines (Compound C XLIV)
With intermediate 31 (0.14g, 0.51mmol), intermediate 72 (0.19g, 0.56mmol), Pd
2(dba)
3(0.046g, 0.051mmol), Xantphos (0.59g, 0.1mmol) and cesium carbonate (0.5g, mixture 1.52mmol) be suspended in the diox (8mL) and at 160 ℃ down with microwaves 15 minutes.This reaction mixture is cooled to room temperature and centrifugal settling.Decantation solvent and evaporation then.Obtain the precursor of the N-protected of title compound by flash chromatography on silica gel method purifying gained resistates.With 20% in DCM these solids of TFA solution-treated and at once the evaporation.Resistates is dissolved in minimum EtOAc and drops in a large amount of excessive ether.Collect gained pale yellow powder and drying (0.16g, 55%) by filtering.
1H?NMR(500MHz，DMSO-d
6):δ?1.61-1.69(m，2H)，1.98-2.01(m，2H)，2.16(s，3H)，2.86(q，J＝12Hz，2H)，3.35(d，J＝12.6Hz，2H)，3.64(tt，J＝11.7Hz，J＝3.8Hz，1H)，3.79(s，3H)，7.34(dd，J＝8.7Hz，J＝2.0Hz，1H)，7.39-7.41(m，2H)，7.6(d，J＝8.9Hz，2H)，7.91(d，J＝8.9Hz，2H)，8.02(s，1H)，8.19-8.21(m，1H)，8.6-8.63(m，1H)，8.89(br?s，1H)。MS(ES+):m/z?488(M+H)
+。
Embodiment 215. (4-chloro-3-methyl-phenyl)-(2-chloro-5-methyl-pyrimidine-4-yl)-amine (in
Mesosome 73)
With 2-chloro-5-methyl-pyrimidine-4-base amine (0.34g, 2.34mmol), 4-bromo-1-chloro-2-methyl-benzene (0.58g, 2.8
Mmol), Pd
2(dba)
3(0.21g, 0.23mmol), Xantphos (0.47g, 0.47mmol) and cesium carbonate (2.3g, mixture 7mmol) are suspended in the diox (9mL), at 160 ℃ down with microwaves 20 minutes.This reaction mixture is cooled to room temperature and centrifugal settling.Decantation solvent and evaporation then.Obtain title compound by fast silica gel chromatogram method purifying gained resistates, be yellow solid (0.24g, 38%).
Embodiment 216. N
4
-(4-chloro-3-methyl-phenyl)-5-methyl-N
2
-[4-(piperidin-4-yl oxygen
Base)-phenyl]-pyrimidine-2,4-diamines (Compound C XLV)
With HOAc (5mL) diluted intermediate 73 (0.071g, 0.27mmol) and 4-(4-amino-phenoxy group)-piperidines-1-t-butyl formate (0.1g, mixture 0.35mmol) and at 150 ℃ down with microwave irradiations 15 minutes.Remove then and desolvate and with HPLC purifying gained resistates.Separate title compound, be white solid (0.025g, 22%).
1H?NMR(500MHz，DMSO-d
6):δ?1.76-1.83(m，2H)，2.05-2.09(m，2H)，2.13(s，3H)，2.27(s，3H)，3.10(br?s，2H)，3.16(br?s，2H)，4.58-4.61(m，1H)，6.93(d，J＝9Hz，2H)，7.34-7.39(m，3H)，7.43-7.45(m，1H)，7.59(s，1H)，7.87(s，1H)，8.51(br?s，1H)，8.55(br?s，1H)，9.38(br?s，1H)，10.0(brs，1H)。MS(ES+):m/z?424(M+H)
+。
Embodiment 217. N-(3-bromo-phenyl)-ethanamide (intermediate 74)
(2.3mL 13.3mmol) handles 3-bromo-phenyl amine (1.04g, solution 6mmol) and be cooled to 0 ℃ with DIEA.By the syringe dripping acetyl chloride (0.47mL, 6.7mmol).Make reacting recovery to room temperature and stirred 1 hour.Be poured over reaction waterborne then and the washing once.The evaporation organic phase is to obtaining light brown solid (1.25g, 98%).
Embodiment 218. N-[3-(2-chloro-5-methyl-pyrimidine-4-base is amino)-phenyl]-ethanamide
(intermediate 75)
With 2-chloro-5-methyl-pyrimidine-4-base amine (0.71g, 4.9mmol), intermediate 74 (1.25g, 5.9mmol), Pd
2(dba)
3(0.45g, 0.49mmol), Xantphos (0.57g, 0.98mmol) and cesium carbonate (4.8g, mixture 14.7mmol) are suspended in the diox (40mL), reflux 18 hours.Then this reaction mixture is cooled to room temperature, filters and evaporating solvent.Obtain title compound by fast silica gel chromatogram method purifying gained resistates, be white solid (0.44,32%).
Embodiment 219. N-(3-{5-methyl-2-[4-(piperidin-4-yl oxygen base)-phenyl amino]-phonetic
Pyridine-4-base is amino }-phenyl)-ethanamide (Compound C XLVI)
With HOAc (5mL) diluted intermediate 75 (0.074g, 0.27mmol) and 4-(4-amino-phenoxy group)-piperidines-1-t-butyl formate (0.1g, mixture 0.35mmol) and at 150 ℃ down with microwave irradiations 15 minutes.Remove then and desolvate and with HPLC purifying gained resistates.Separate title compound, be white solid (0.072g, 62%).
1H?NMR(500MHz，DMSO-d
6):δ?1.74-1.81(m，2H)，2.03-2.07(m，5H)，2.15(s，3H)，3.09(br?s，2H)，3.24(br?s，2H)，4.54-4.57(m，1H)，6.85(d，J＝8.8Hz，2H)，7.22(d，J＝7.7Hz，2H)，7.29-7.39(m，4H)，7.77(s，1H)，7.87(s，1H)，8.55(br?s，1H)，8.60(br?s，1H)，9.67(s，1H)，10.0(br?s，1H)，10.2(br?s，1H)。MS(ES+):m/z?433(M+H)
+。
Embodiment 220. N-(3-bromo-2-methyl-phenyl)-ethanamide (intermediate 76)
(8.4mL 48mmol) handles 3-bromo-2-methyl-phenyl amine (4.1g, solution 21.9mmol) and be cooled to 0 ℃ with DIEA.By the syringe dripping acetyl chloride (1.7mL, 24.1mmol).Make reacting recovery to room temperature and stirred 1 hour.Be poured over reaction waterborne then and the washing once.The evaporation organic phase is to obtaining pale solid.Grind and obtain title compound with hexane, be white solid (4.4g, 89%).
Embodiment 221. N-[3-(2-chloro-5-methyl-pyrimidine-4-base is amino)-2-methyl-phenyl]-
Ethanamide (intermediate 77)
With 2-chloro-5-methyl-pyrimidine-4-base amine (0.86g, 5.9mmol), intermediate 76 (1.6g, 7.1mmol), Pd
2(dba)
3(0.55g, 0.59mmol), Xantphos (0.69g, 1.2mmol) and cesium carbonate (5.8g, mixture 17.8mmol) are suspended in the diox (40mL), reflux 16 hours.Then this reaction mixture is cooled to room temperature, filters and evaporating solvent.Obtain title compound by fast silica gel chromatogram method purifying gained resistates, be white solid (0.56g, 32%).
Embodiment 222. N-(2-methyl-3-{5-methyl-2-[4-(piperidin-4-yl oxygen base)-phenylamino
Base]-pyrimidine-4-base is amino }-phenyl)-ethanamide (Compound C XLVII)
With HOAc (5mL) diluted intermediate 77 (0.15g, 0.5mmol) and 4-(4-amino-phenoxy group)-piperidines-1-t-butyl formate (0.19g, mixture 0.65mmol) and at 150 ℃ down with microwave irradiations 15 minutes.Remove then and desolvate and with HPLC purifying gained resistates.Separate title compound, be white solid (0.091g, 41%).
1H?NMR(500MHz，DMSO-d
6):δ?1.71-1.78(m，2H)，2.02-2.08(m，8H)，2.16(s，3H)，3.09(br?s，2H)，3.24(br?s，2H)，4.50-4.52(m，1H)，6.77(d，J＝8.4Hz，2H)，7.09-7.15(m，3H)，7.27(t，J＝7.9Hz，1H)，7.49(d，J＝8.1Hz，1H)，7.86(s，1H)，8.54(br?s，1H)，8.59(br?s，1H)，9.45(s，1H)，9.84(br?s，1H)，10.34(br?s，1H)。MS(ES+):m/z447(M+H)
+。
Embodiment 223. 5-methyl-N
2
-[4-(4-methyl-piperazine-1-yl)-phenyl]-N
4
-(3-nitro
-phenyl)-and pyrimidine-2,4-diamines (intermediate 78)
With 1-bromo-3-nitro-benzene (0.77g, 3.8mmol), intermediate 32 (0.95g, 3.2mmol), Pd
2(dba)
3(0.29g, 0.32mmol), Xantphos (0.37g, 0.64mmol) and cesium carbonate (3.1g, mixture 9.6mmol) are suspended in diox (40mL), reflux 16 hours.Then this reaction mixture is cooled to room temperature, filters and evaporating solvent.Obtain title compound by flash chromatography on silica gel method purifying gained resistates, be white solid (0.53g, 40%).
Embodiment 224. N
4
-(3-amino-phenyl)-5-methyl-N
2
-[4-(4-methyl-piperazine-1-
Base)-phenyl]-pyrimidine-2,4-diamines (intermediate 79)
With purification for argon intermediate 78 (0.23g, 0.54mmol) slurry in MeOH (25mL) and handle with Pd/C 10%wt. (0.18g).With hydrogen substitution reaction gas and stirred 4 hours.Remove the hydrogen capsule then and make argon gas stream cross reaction, after this filter by C salt.Evaporating solvent is to obtaining light brown solid (0.17g, 83%) then.
Embodiment 225.1-(3-{5-methyl-2-[4-(4-methyl-piperazine-1-yl)-phenyl amino]-
Pyrimidine-4-base is amino }-phenyl)-3-phenyl-urea (Compound C XLVIII)
(0.058mL 0.54mmol) handles intermediate 79 (0.17g, 0.45mmol) suspension in DCM (10mL) and stirring 1 hour with phenylcarbimide.Remove reaction solvent then and obtain title compound, be white solid (0.075g, 33%) by HPLC purifying gained resistates.
1H?NMR(500MHz，DMSO-d
6):δ?2.09(s，3H)，2.15(s，3H)，2.30-2.32(m，4H)，2.92-2.94(m，4H)，6.74(d，J＝8.4Hz，2H)，6.94-6.97(m，1H)，7.19-7.28(m，5H)，7.45(d，J＝8.8Hz，2H)，7.53(d，J＝9.0Hz，2H)，7.73(br?s，1H)，7.83(s，1H)，8.23(s，1H)，8.68(s，1H)，8.74(s，1H)，8.78(s，1H)。MS(ES+):m/z?509(M+H)
+。
Embodiment 226. 1-(3-{5-methyl-2-[4-(4-methyl-piperazine-1-yl)-phenyl amino]-
Pyrimidine-4-base is amino }-phenyl)-3-(3-trifluoromethyl-phenyl)-urea (Compound C XLIX)
(0.043mL 0.31mmol) handles intermediate 79 (0.1g, 0.26mmol) suspension in DCM (8mL) and stirring 1 hour with 1-isocyanate group-3-trifluoromethyl-benzene.Remove reaction solvent then and obtain title compound, be white solid (0.039g, 26%) by HPLC purifying gained resistates.
1H?NMR(500MHz，DMSO-d
6):δ?2.16(s，3H)，2.82(s，3H)，2.86(brs，2H)，3.08(br?s，2H)，3.42(br?s，2H)，3.69(br?s，2H)，6.88(d，J＝8.4Hz，2H)，7.20(br?s，1H)，7.29-7.33(m，5H)，7.52(t，J＝7.9Hz，1H)，7.57(d，J＝8.5Hz，1H)，7.77(s，1H)，7.84(s，1H)，8.09(s，1H)，9.42(s，1H)，9.66(s，1H)，9.71(br?s，1H)，10.1(br?s，1H)。MS(ES+):m/z577(M+H)
+。
Embodiment 227. (2-chloro-5-methyl-pyrimidine-4-yl)-(2-methyl-3-trifluoromethyl-phenyl)-
Amine (intermediate 80)
With 2-chloro-5-methyl-pyrimidine-4-base amine (0.18g, 5.9mmol), 1-bromo-2-methyl-3-trifluoromethyl-benzene (0.33g, 1.4mmol), Pd
2(dba)
3(0.12g, 0.13mmol), Xantphos (0.15g, 0.25mmol) and cesium carbonate (1.23g, mixture 3.8mmol) are suspended in diox (8mL), at 160 ℃ down with microwaves 18 minutes.Centrifugal settling reaction vessel and decantation then, evaporating solvent and obtain title compound by fast silica gel chromatogram method purifying gained resistates is white solid (0.095g, 25%) subsequently.
Embodiment 228. 5-methyl-N
4
-(2-methyl-3-trifluoromethyl-phenyl)-N
2
-[4-(piperidines
-4-base oxygen base)-phenyl]-pyrimidine-2,4-diamines (Compound C L)
With HOAc (5mL) diluted intermediate 80 (0.058g, 0.2mmol) and 4-(4-amino-phenoxy group)-piperidines-1-t-butyl formate (0.073g, mixture 0.25mmol) and at 150 ℃ down with microwaves 15 minutes.Remove then and desolvate and with HPLC purifying gained resistates.Separate title compound, be white solid (0.025g, 30%).
1H?NMR(500MHz，DMSO-d
6):δ?1.71-1.78(m，2H)，2.00-2.04(m，2H)，2.18(s，3H)，2.25(s，3H)，3.08(br?s，2H)，3.22(br?s，2H)，4.50-4.52(m，1H)，6.70(d，J＝8.3Hz，2H)，7.10(d，J＝8.9Hz，2H)，7.54(t，J＝7.8，1H)，7.62(d，J＝7.7Hz，1H)，7.75(d，J＝7.8Hz，1H)，7.91(s，1H)，8.54(br?s，1H)，8.61(br?s，1H)，9.88(s，1H)，10.34(br?s，1H)。MS(ES+):m/z?458(M+H)
+。
Embodiment 229. (3-bromo-phenyl)-tetramethyleneimine-1-base-ketone (intermediate 81)
With 3-bromo-Benzoyl chloride (2.7g, 12mmol) solution in DCM (40mL) be cooled to 0 ℃ and with tetramethyleneimine (3mL 36.8mmol) handles.Make reaction reach room temperature and stirred 4 hours.Be poured over mixture waterborne then and the washing once.Use salt water washing organic phase then, use dried over sodium sulfate, filter and be evaporated to and obtain amber oily thing (3.1g, 100%).
Embodiment 230. [3-(2-chloro-5-methyl-pyrimidine-4-base is amino)-phenyl]-tetramethyleneimine-1-
Base-ketone (intermediate 82)
With 2-chloro-5-methyl-pyrimidine-4-base amine (0.22g, 1.5mmol), intermediate 81 (0.46g, 1.8mmol), Pd
2(dba)
3(0.14g, 0.15mmol), Xantphos (0.17g, 0.3mmol) and cesium carbonate (1.5g, mixture 4.5mmol) are suspended in the diox (8mL), at 160 ℃ down with microwaves 18 minutes.With reaction vessel centrifugal settling and decantation, evaporating solvent obtains title compound by fast silica gel chromatogram method purifying gained resistates subsequently then, is white solid (0.25g, 53%).
Embodiment 231. (3-{5-methyl-2-[4-(piperidin-4-yl oxygen base)-phenyl amino]-pyrimidine-4-
Base is amino }-phenyl)-tetramethyleneimine-1-base-ketone (Compound C LI)
With HOAc (6mL) diluted intermediate 82 (0.1g, 0.32mmol) and 4-(4-amino-phenoxy group)-piperidines-1-t-butyl formate (0.12g, mixture 0.41mmol) and at 150 ℃ down with microwaves 15 minutes.Remove then and desolvate and with HPLC purifying gained resistates.Separate title compound, be white solid (0.005g, 3%).
1H?NMR(500MHz，DMSO-d
6):δ?1.74-1.81(m，4H)，1.83-1.88(m，2H)，2.05-2.09(m，2H)，2.16(s，3H)，2.25(s，3H)，3.25(br?s，2H)，3.34(t，J＝6.5Hz，2H)，3.46(t，J＝6.9Hz，2H)，4.45-4.59(m，1H)，6.91(d，J＝8.8Hz，2H)，7.32(d，J＝8.9Hz，2H)，7.36(d，J＝7.7Hz，1H)，7.43(t，J＝7.8，1H)，7.67(d，J＝7.9Hz，1H)，7.70(s，1H)，7.89(s，1H)，8.50(br?s，1H)，8.56(br?s，1H)，9.64(br?s，1H)，10.21(br?s，1H)。MS(ES+):m/z?473(M+H)
+。
Embodiment 232. 3-bromo-N-sec.-propyl-benzamide (intermediate 83)
With 3-bromo-Benzoyl chloride (0.83g, 3.8mmol) solution in DCM (40mL) be cooled to 0 ℃ and with Isopropylamine (0.96mL 11.32mmol) handles.Make reaction reach room temperature and stirred 24 hours.Be poured over mixture waterborne then and the washing once.Use salt water washing organic phase then, use dried over sodium sulfate, filter and be evaporated to and obtain white solid (0.6g, 66%).
Embodiment 233. N-sec.-propyl-3-{5-methyl-2-[4-(4-methyl-piperazine-1-yl)-phenyl
Amino]-pyrimidine-4-base is amino }-benzamide (Compound C LII)
With intermediate 32 (0.1g, 0.34mmol), intermediate 83 (0.13g, 0.54mmol), Pd
2(dba)
3(0.031g, 0.034mmol), Xantphos (0.039g, 0.067mmol) and cesium carbonate (0.33g, mixture 1mmol) are suspended in the diox (8mL), at 160 ℃ down with microwaves 15 minutes.Centrifugal settling reaction vessel and decantation then, evaporating solvent and obtain title compound by HPLC purifying gained resistates is white solid (0.011g, 7%) subsequently.
1H?NMR(500MHz，DMSO-d
6):δ?1.14(d，J＝6.7Hz，6H)，2.16(s，4H)，2.87(s，4H)，3.10(br?s，2H)，3.51(s，2H)，4.22(m，1H)，6.85(d，J＝8.8Hz，2H)，7.30-7.32(m，2H)，7.45(t，J＝7.8Hz，1H)，7.69-7.70(m，2H)，7.90(s，1H)，7.99(s，1H)，8.24(d，J＝7.7Hz，1H)，9.70(br?s，1H)，9.94(brs，1H)，10.2(br?s，1H)。MS(ES+):m/z?460(M+H)
+。
The embodiment 234. 3-bromo-N-tertiary butyl-benzamide (intermediate 84)
With 3-bromo-Benzoyl chloride (0.83g, 3.8mmol) solution in DCM (10mL) be cooled to 0 ℃ and with tert-butylamine (1.2mL 11.3mmol) handles.Make reaction reach room temperature and stirred 4 hours.Be poured over mixture waterborne then and the washing once.Use salt water washing organic phase then, use dried over sodium sulfate, filter and be evaporated to and obtain amber oily thing (0.9g, 94%).
The embodiment 235. N-tertiary butyl-3-{5-methyl-2-[4-(4-methyl-piperazine-1-yl)-stupid base
Amino]-pyrimidine-4-base is amino }-benzamide (Compound C LIII)
With intermediate 32 (0.1g, 0.34mmol), intermediate 84 (0.1g, 0.4mmol), Pd
2(dba)
3(0.031g, 0.034mmol), Xantphos (0.039g, 0.067mmol) and cesium carbonate (0.33g, mixture 1mmol) are suspended in the diox (8mL), at 160 ℃ down with microwaves 15 minutes.Centrifugal settling reaction vessel and decantation then, evaporating solvent and obtain title compound by HPLC purifying gained resistates is white solid (0.055g, 35%) subsequently.
1H?NMR(500MHz，DMSO-d
6):δ?1.36(s，9H)，2.09(s，3H)，2.21(s，3H)，2.43(t，J＝2.8Hz，4H)，3.00(t，J＝2.8Hz，4H)，6.74(d，J＝9.1Hz，2H)，7.35(t，J＝7.9Hz，1H)，7.44-7.48(m，3H)，7.67(s，1H)，7.85(s，1H)，7.88-7.92(m，2H)，8.36(s，1H)，8.74(s，1H)。MS(ES+):m/z?474(M+H)
+。
Embodiment 236. 5-methyl-N
2
-[4-(4-methyl-piperazine-1-yl)-phenyl]-N
4
-(3-piperidines
-4-base-phenyl)-and pyrimidine-2,4-diamines (Compound C LIV)
With intermediate 32 (0.08g, 0.27mmol), 4-(3-bromo-phenyl)-piperidines (0.084g, 0.35mmol), Pd
2(dba)
3(0.025g, 0.027mmol), Xantphos (0.031g, 0.054mmol) and cesium carbonate (0.26g, mixture 0.81mmol) are suspended in the diox (8mL), at 160 ℃ down with microwaves 15 minutes.Centrifugal settling reaction vessel and decantation then.Evaporating solvent and obtain title compound by HPLC purifying gained resistates is white solid (0.007g, 6%) subsequently.
1H?NMR(500MHz，DMSO-d
6):δ?1.74-1.79(m，3H)，2.09(s，3H)，2.21(s，3H)，2.43(t，J＝2.8Hz，4H)，3.00(t，J＝2.8Hz，4H)，6.76(d，J＝9.1Hz，2H)，6.90(d，J＝7.7Hz，1H)，7.24(t，J＝7.9Hz，1H)，7.47-7.53(m，3H)，7.68(d，J＝8.2Hz，1H)，7.82(s，1H)，8.18(s，1H)，8.67(s，1H)。MS(ES+):m/z458(M+H)
+。
Embodiment 237. 4-(3-{5-methyl-2-[4-(4-methyl-piperazine-1-yl)-phenyl amino]-
Pyrimidine-4-base is amino }-benzenesulfonyl)-piperidines-1-benzyl formate (intermediate 85)
With intermediate 32 (0.17g, 0.58mmol), 4-(3-bromo-benzenesulfonyl)-piperidines-1-benzyl formate (0.28g, 0.64mmol), Pd
2(dba)
3(0.053g, 0.058mmol), Xantphos (0.067g, 0.12mmol) and cesium carbonate (0.57g, mixture 1.74mmol) are suspended in the diox (8mL), at 160 ℃ down with microwaves 15 minutes.Centrifugal settling reaction vessel and at decantation on ice then.Collect yellow solid, dry and without being further purified use (0.4g, 100%).
Embodiment 238. 5-methyl-N
2
-[4-(4-methyl-piperazine-1-yl)-phenyl]-N
4
-[3-(piperazine
Pyridine-4-alkylsulfonyl)-phenyl]-pyrimidine-2,4-diamines (Compound C LV)
With the BBr of 1M in DCM
3(2mL 2mmol) handles intermediate 85 (0.17g, 0.26mmol) stirred solution in DCM (15mL).After 4 hours, make the reaction quencher, remove subsequently and desolvate by slow interpolation MeOH (4mL).Obtain title compound by HPLC purifying resistates, be purple powder (0.008g, 6%).
1H?NMR(500MHz，DMSO-d
6):δ?1.31-1.40(m，2H)，1.75(d，J＝10.8Hz，2H)，2.12(s，3H)，2.21(s，3H)，2.36-2.41(m，2H)，2.44(t，J＝4.9Hz，4H)，2.95(d，J＝12.5Hz，2H)，3.02(t，J＝4.9Hz，4H)，3.24(tt，J＝11.7Hz，J＝3.8Hz，1H)，6.81(d，J＝9.0Hz，2H)，7.44(m，3H)，7.56(t，J＝8.0Hz，1H)，7.90-7.91(m，2H)，8.49(d，J＝7.6Hz，1H)，8.60(s，1H)，8.74(s，1H)。MS(ES+):m/z?522(M+H)
+。
Embodiment 239. 4-(4-(4-(1H-indoles-4-base is amino)-5-methylpyrimidine-2-base is amino)
Phenoxy group) piperidines-1-t-butyl formate (intermediate 86)
With 4-bromo-1H-indoles (41 μ L, 0.33mmol), intermediate 42 (131mg, 0.33mmol), Pd
2(dba)
3(30mg, 0.03mmol), Xantphos (60mg, 0.10mmol) and cesium carbonate (428mg, 1.31mmol) in the microwave of mixture under 160 ℃ in the Zai diox (3mL) irradiation 20 minutes.This reaction mixture is cooled to room temperature and uses the DCM washing and filtering.Concentrated filtrate and obtain title compound by gradient purified by flash chromatography (MeOH of 0-15% in DCM) is white solid (30mg, 17%).
Embodiment 240. N
4
-(1H-indoles-4-yl)-5-methyl-N
2
-(4-(piperidin-4-yl oxygen base) benzene
Base) pyrimidine-2,4-diamines (Compound C LVI)
(27mg, 0.05mmol) mixture in 30% TFA/DCM (1mL) stirred 3 hours with intermediate 86.At this reaction mixture of vacuum concentration and by the preparation HPLC purifying.Concentrate the gained fraction in a vacuum and obtain the tfa salt of title compound, be tawny solid (11mg, 43%).
1H?NMR(500MHz，DMSO-d
6):δ?1.71-1.77(m，2H)，1.98-2.06(m，2H)，2.22(s，3H)，3.03-3.12(m，2H)，3.19-3.27(m，2H)，4.44-4.53(m，1H)，6.34-6.37(m，1H)，6.64(br?d，J＝8.3Hz，2H)，7.08(t，J＝7.2Hz，3H)，7.14(t，J＝7.8Hz，1H)，7.36(t，J＝2.7Hz，1H)，7.39(d，J＝8.1Hz，1H)，7.84(s，1H)，8.48(br?s，1H)，8.55(br?s，1H)，9.85(br?s，1H)，9.98(br?s，1H)，11.27(s，1H)。
Embodiment 241. 2-chloro-N-{2-[4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl amino]-
Pyrimidine-5-yl }-5 (3-trifluoromethyl-benzamido)-benzamide (Compound C LVII)
In ar gas environment with the 3-bromopyridine (379mg, 2.4mmol), 4-amino-2-chloro-5-methylpyrimidine (287mg, 2.0mmol), Pd
2(dba)
3(18mg, 0.02mmol), xantphos (23mg, 0.04mmol) and cesium carbonate (975mg, 3.0mmol) the mixture in the Zai diox (15mL) heated 1 hour under reflux state.Removing desolvates and by HPLC resistates is carried out purifying obtains intermediate 2-chloro-5-methyl-N-(pyridin-3-yl) pyrimidine-4-amine, is yellow solid (252mg, 57%).In order to carry out the Buckwald second time, in ar gas environment with 2-chloro-5-methyl-N-(pyridin-3-yl) pyrimidine-4-amine (80mg, 0.36mmol), 4-(2-(tetramethyleneimine-1-yl) oxyethyl group) aniline (74mg, 0.34mmol), Pd
2(dba)
3(3.2mg, 0.003mmol), xantphos (4.2mg, 0.007mmol) and cesium carbonate (234mg, 0.72mmol) the mixture in the Zai diox (5mL) heated 1 hour under reflux state.Use HPLC that this crude product mixture is carried out purifying and obtained title compound, be light brown solid (28mg, 20%).
1H NMR (500MHz, DMSO-d
6): δ 1.85-1.95 (m, 2H), 2.0-2.09 (m, 2H), 2.18 (s, 3H), 3.09-3.18 (m, 2H), and 3.55-3.65 (m, 4H), 4.27 (dd, J=5.2,4.7Hz, 2H), 6.94 (d, J=8.9Hz, 2H), 7.35 (d, J=8.9Hz, 2H), 7.50 (dd, J=8.2,4.8Hz, 1H), 7.92-7.96 (m, 1H), and 8.08-8.15 (m, 1H), 8.45 (dd, J=4.8,1.4,1H), 8.84,9.75,9.85,10.24 (4br s, each 1H).MS(ES+):m/z?329(M+H)
+。
Embodiment 242. N
2
-(4-(2-(tetramethyleneimine-1-yl) oxyethyl group) phenyl)-5-methyl
-N
4
-(3-(trifluoromethoxy) phenyl) pyrimidine-2,4-diamines (Compound C LVIII)
In ar gas environment with 1-bromo-3-(trifluoromethoxy) benzene (241mg, 1.0mmol), 4-amino-2-chloro-5-methylpyrimidine (143mg, 1.0mmol), Pd
2(dba)
3(9mg, 0.01mmol), xantphos (14mg, 0.02mmol) and cesium carbonate (650mg, 2.0mmol) the mixture in the Zai diox (15mL) heated 10 hours under reflux state.Removing desolvates and by HPLC resistates is carried out purifying obtains intermediate 2-chloro-5-methyl-N-(pyridin-3-yl) pyrimidine-4-amine, is brown solid (260mg, 85%).In ar gas environment with this intermediate (100mg, 0.33mmol) and 4-(2-(tetramethyleneimine-1-yl) oxyethyl group) (67mg, 0.33mmol) mixture in Glacial acetic acid (5mL) heated 3 hours under reflux state aniline.Use HPLC that this crude product mixture is carried out purifying and obtained title compound, be white solid (11mg, 7%).
1H NMR (500MHz, DMSO-d
6): δ 1.65-1.72 (m, 4H), 2.11 (s, 3H), 2.51-2.55 (m, 2H, overlapping with solvent peak), 2.75 (t, J=5.9Hz, 2H), 3.25-3.34 (m, 2H, overlapping with solvent peak), 3.99 (t, J=5.9Hz, 2H), 6.79 (d, J=8.9Hz, 2H), 6.98 (d, J=8.0Hz, 1H), 7.40 (dd, J=7.6,7.4Hz, 1H), 7.50 (d, J=8.9Hz, 2H), 7.76 (br s, 1H), 7.87 (d, J=8.41H), 7.90,8.31,8.41,8.84 (4s, 1H each).MS(ES+):m/z?474(M+H)
+。
Embodiment 243. N
2
-(4-(2-(tetramethyleneimine-1-yl) oxyethyl group) phenyl)-N
4
-(4-chlorine
-3-(trifluoromethyl) phenyl)-and 5-methylpyrimidine-2,4-diamines (Compound C LIX)
In ar gas environment with 4-bromo-1-chloro-2-(trifluoromethyl) benzene (259mg, 1.0mmol), 4-amino-2-chloro-5-methylpyrimidine (143mg, 1.0mmol), Pd
2(dba)
3(9mg, 0.01mmol), xantphos (14mg, 0.02mmol) and cesium carbonate (650mg, 2.0mmol) the mixture in the Zai diox (15mL) heated 10 hours under reflux state.Except that desolvating and obtaining intermediate 2-chloro-N-(4-chloro-3-(trifluoromethyl) phenyl)-5-methylpyrimidine-4-amine, be brown solid (200mg, 62%) by HPLC purifying resistates.With this intermediate (161mg, 0.5mmol) and 4-(2-(tetramethyleneimine-1-yl) oxyethyl group) (103mg, 0.5mmol) mixture in Glacial acetic acid (5mL) heated 3 hours under reflux state aniline.Use HPLC that this crude product mixture is carried out purifying and obtained title compound, be brown solid (75mg, 31%).
1H NMR (500MHz, DMSO-d
6): δ 1.65-1.72 (m, 4H), 2.10 (s, 3H), 2.51-2.55 (m, 4H, overlapping with solvent peak), 2.75 (t, J=6.0Hz, 2H), 4.0 (t, J=5.9Hz, 2H), 6.79 (d, J=8.5Hz, 2H), 7.47 (d, J=9.0Hz, 2H), 7.58 (d, J=9.0Hz, 2H), 7.93 (s, 1H), 8.01 (d, J=2.5Hz, 1H), 8.22 (d, J=8.5Hz, 2H), 8.60,8.88 (2s, 1H each).MS(ES+):m/z?492(M+H)
+。
The kinase whose IC of embodiment 244. Jak2
50
PH-value determination pH
Use is based on luminous kinase assay and the IC that measures compound available from the reorganization JAK2 of Upstate Cell SignalingSolutions
50Value.At room temperature with in the flat 96-of the white hole flat board (Nunc) carry out replicate(determination) with the final volume of 50 μ L.Each hole comprises the 40 μ L damping fluids of being made up of the 40mM Tris damping fluid of pH7.4, comprises 50mM MgCl in the described 40mM Tris damping fluid
2, 800 μ M EGTA, 350 μ M Triton X-100,2mM beta-mercaptoethanol, 100 μ M peptide substrates (PDKtide; Upstate Cell SignalingSolutions) and an amount of JAK2 (75-25ng/ hole), make this be determined in 60 minutes to linear.Make the TargeGen compound at IC by in 2.5 μ L DMSO, adding an amount of compound
50Final concentration in the pH-value determination pH is at 1000-0.01 μ M; The DMSO that is present in each mensuration is constant in 5%.Is that 3 μ M startup is reacted by adding 10 μ LATP to final mensuration concentration.After reaction is carried out 60 minutes, add 50 μ L kinases-Glo reagent (Promega) so that termination reaction.This solution was carried out 10 minutes again so that the luminous reaction maximization.
Use then to luminous intensity and measure Ultra 384 instrument (Tecan) measured value of setting.Also carry out two kinds of control reaction: a kind of reaction does not contain compound, and second kind of reaction neither contains inhibitor, does not contain peptide substrates yet.(Version 4 to use Prism; GraphPad Software) the non-linear curve fitting ability IC that from experimental data, derives
50Value.The result is as shown in table 1.
Table 1. compound of the present invention and to the kinase whose IC value of Jak2
Embodiment 245. selects the effect of compound to measure
HEL, CTLL-2 ﹠amp; Normal people's epidermis inoblast (NHDF) from US mode culture collection center (American Tissue Cu lture Collection Rockville, MD).The BaF/3 cell available from DKFZ Cancer Research Center (Heidel berg, Germany).
Make BaF/3, HEL ﹠amp; The NHDF cell is grown in and has replenished penicillin, Streptomycin sulphate, RPMI 1640 substratum of L-glutaminate and 10% foetal calf serum (FBS) (Gibco BRL, Gaithersburg, MD) in.The CTLL-2 cell is grown in further replenished the 20U/mL recombinant il-2 that (Hoffmann-LaRoche, Nutley is in same medium NJ).The plasmid that comprises people JAK2 encoding sequence available from Invitrogen (Madison, WI).By using site-directed mutagenesis to produce JAK2
V617FcDNA uses two-dimentional sequence verification subsequently so that the V617F sudden change is imported people JAK2 encoding sequence.Subsequently this cDNA subclone is gone into retroviral vector and the BaF/3 cell of transduceing.Select to express JAK2
V617FLasting transduction the BaF/3 cell and keep with 1mg/mlG418.Lentiviruses transduction by using pLenti6-GFP (Invitrogen) is used the GFP transfered cell blasticidin to select and uses FACs to analyze to confirm that GFP expresses subsequently.
Use XTT cell proliferation reagent box, (Roche, Alameda CA) carry out cell proliferating determining according to the explanation of manufacturers.In brief, will carry out bed board among the XLV of about 2.5 * 103 cells according to triplicate 100 μ L RPMI growth medium+various dose in micro titer plate well.After 72 hours, the 20 microlitre XTT of hatching are joined in each hole and with it hatched 4-6 hour.(Molecular Devices, Sunnyvale is CA) in 450nm and the painted first of measuring formation under the 650nm correction by spectrophotometry to use the Vmax spectrophotometer
Product.(San Diego CA) measures the IC50 value, therefore, the concentration (mM) (logarithmically calibrated scale) of OD value on y-axle (linear scale) and x-axle is drawn to use GraphPad Prism 4.0 softwares.Data are carried out the nonlinear regression and fitting analysis and with IC
50PH-value determination pH is for suppressing the concentration of 50% propagation.
Propagation EC50:
HEL-270nM
Baf3:JAK2V617F-297nM
Contrasting data: IL-2-inductive JAK3-dependency propagation-3395nM
Contrasting data: normal people's epidermis inoblast-6487nM
Apoptosis is measured
Will be with 1,3 and 10 μ M XLV at the middle BaF/3-JAK that cultivates of growth medium (RPMI, 10%FBS, 1mg/ml G418 and 10 μ g/ml blasticidins)
V617FCell was handled 24 hours.By after, use DNA separating kit (Puregen, Chino, CA) isolation of genomic DNA from cell precipitation with 5 minutes collecting cells of 890 RCF (relative centrifugal force).Make 5 μ g genomic dnas of every duplicate samples carry out 1.2% agarose gel electrophoresis so that detect genomic DNA fragmentization (dna ladder shape assay method).In contrast, converge rate growth medium (Cambrex, Walkersville, MD) the adhesion normal people epidermis inoblast (NHDF) of Pei Yanging with the XLV processing with 60% as mentioned above.After using ice-cold PBS to wash 2 times, isolation of genomic DNA carries out agarose gel electrophoresis from the NHDF cell.
Immunoblotting
The centrifugal BaF/3-JAK that handles with XLV or vehicle reference substance
V617FCell is with ice-cold PBS washing 2X and the cracking of use RIPA damping fluid.(Pierce, Rockford IL) measure protein concn and make 100 μ g total cell proteins of the every duplicate samples in 1X electrophoresis spike buffer reagent carry out western blot analysis to use the BCA method.Use anti--phosphoric acid-STAT5 (Tyr694/699) (Upstate Biotechnology, Charlottesville VA) surveys western blotting, peels off and re-use anti--STAT5 antibody (CellSignaling Technology subsequently, Danvers MA) surveys.By enhanced chemoluminescence method (Pierce) phosphoric acid-STAT5 or STAT5 protein are manifested.Carry out signal conduction studies in the body in a similar way.In brief, the 11st day of injection cell, by oral to animals administer vehicle or 100mg/kg XLV.After administration, gathered in 7 hours spleen and rapidly the FastPrep machine (Qbiogen, Irvine, CA) in homogenize.Make 100 μ g spleen homogenize things carry out western blot analysis separately.Use anti--phosphoric acid-STAT5 (Tyr694/699) and use anti--STAT5 antibody to survey western blotting and manifest subsequently by the enhanced chemoluminescence method.
The FACs of circulating tumor load analyzes
At injection BaF/3-JAK2
V617FDuring behind the cell suspension the 11st day, from accept vectorial 1 mouse, gather 1mL blood by terminal heart depletion method, in addition, by acquisition method behind the non-lethal socket of the eye from 3 groups of each 10 administrations 10,30 or the mouse of 100mg/kg XLV in gather 0.1mL blood and be collected in jointly in the dosage group.By Ficoll (Sigma-Aldrich, St.Louis, MO) bed course centrifuging (600 RCF and 30 minutes) separating blood monocyte.Make isolated cells carry out facs analysis so that measure the positive BaF/3:JAK2 of GFP
V617FCell per-cent.The result is presented in the following table.
Orally give XLV reduces cyclic J AK2 in the dose-dependently mode
V617FTumor cell number
The circulating tumor model
Express JAK2 for the SCID injected in mice by intravenously
V617FBaF/3 cell with GFP.Behind the infusion beginning in 3 days with shown in oral dose administration XLV and behind infusion, stopped in 20 days.In the time of the 11st day, blood sampling and carry out that FACs analyzes so that measure GFP male circulating cells per-cent from animal in every group.In the parallel research of carrying out, handle animal as mentioned above, but in the time of the 11st day to they administration 100mg/kg single medicine dosage, after 4 hours, put to death animal subsequently and analyze STAT5 phosphorylation in the spleen of expansion of lotus knurl.The result is presented in the following table.
Use data in the circulating tumor model XLV body
*When oral tube feed because of sucking tracheae death
Behind tumor injection the 3rd day the beginning every day 2 oral administrations
Eye contact and efficacy data
Contact data by eye drop administration 0.1% compound:
When the topical of the compound that is mixed with 0.1% dosage in 0.2% tyloxapol/1% HPMC/4% mannitol, the exposure level of measuring in mouse ocular tissue rear portion is presented on two different time points, promptly at 2 hours with at 7 hours.Select the efficacy data of compound as shown in table 2.
Table 2
Concentration (nM) behind the local 0.1% preparation QDX1 that instils of two surveys in the mouse ocular tissue
Change in the eye efficacy study of embodiment 246. in oxygen-inductive retinopathy (OIR) model
Compound XVII
Use mouse oxygen-inductive retinopathy (OIR) model measurement compounds X VII, wherein by make mouse young baby circulation from oxygen level normally to hyperoxia and return to oxygen level then and normally cause retinal neovascularizationization.Begin to change C57BL/6 mouse group over to hyperoxic environment (70% O when being born back the 7th day (P7)
2).After 5 days, make animal groups turn back to normoxic environment (21% O
2), wherein then they were kept 5 days again, they accept the compounds X VII of topical application or suitable vehicle in this process.When this time limit finishes, preparation retina overall fixed thing and with Sugar receptors (BSL I) dyeing of fluorescently-labeled identification mouse endothelium finally obtains digitized video and use image analysis software programanalysis so that quantitative to the area vasculosa by fluorescence microscopy.In once studying, and the animal minimizing 29% that treat than vehicle twice administration every day (bid), 0.1% compounds X VII preparation demonstration area vasculosa (P＜0.05, n=11-15); In research for the second time, observe and reduce 22% (P＜0.02, n=6).The result is summarised in the table 3.
Table 3
Although described the present invention, be appreciated that modification and modification comprise within the spirit and scope of the present invention with reference to the foregoing description.Therefore, the present invention is only limited by following claim.
Claims (103)
1. have the compound of structure (A) or the pharmacy acceptable salt of compound (A), hydrate, solvate, crystal formation, N-oxide compound and each diastereomer:
Wherein:
X is selected from key, O, C=0, SO
2And CH
2Y is selected from key or NR
9Or X and Y are key jointly;
R
1And R
2Be selected from H independently of one another, C
1-C
6Replace or unsubstituted alkyl, replace or unsubstituted cycloalkyl, replace or unsubstituted heterocycle, replace or unsubstituted aryl and replacement or unsubstituted heteroaryl; Or R
1And R
2Common is key; Or R
1And R
2Common formation is selected from (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
9-(CH
2)
m(CH
2)
r-O-(CH
2)
mPart;
P separately, q, r, n, m independently are the integer of value with 0-6,
R
9Be selected from H, C
1-C
6Alkyl, C
1-C
6Cycloalkyl, C
1-C
6Branched-chain alkyl, C
1-C
6The alkyl that replaces, C
1-C
6Aminoalkyl group and C
1-C
6Hydroxyalkyl;
G
0Be selected from N, O, H and CH,
Condition is if G
0Be N, so:
R separately
3And R
4Be independently selected from H, C
1-C
6Alkyl, C
1-C
6Replace or unsubstituted hydroxyalkyl or aminoalkyl group C
1-C
6Replace or unsubstituted branched-chain alkyl, replace or unsubstituted aryl and replacement or unsubstituted heteroaryl, or R
3And R
4Common formation is selected from (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
9-(CH
2)
m(CH
2)
r-O-(CH
2)
mPart;
Extra condition is if G
0Be N, so:
R
1And R
9Common formation is selected from (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
9-(CH
2)
m(CH
2)
r-O-(CH
2)
mPart; Or R
1And R
4Common formation is selected from (CH
2)
m, (CH
2) r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
9-(CH
2)
m(CH
2)
r-O-(CH
2)
mPart; Or R
9And R
4Common formation is selected from (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
9-(CH
2)
m(CH
2)
r-O-(CH
2)
mPart; Or R
3And R
4Common formation is selected from (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
6-(CH
2)
m(CH
2)
r-O-(CH
2)
mPart;
Extra condition is if G
0Be 0, so:
R
3Be selected from H, C
1-C
6Alkyl and C
1-C
6Replace or unsubstituted hydroxyalkyl or aminoalkyl group, replace or unsubstituted branched-chain alkyl, replace or unsubstituted cycloalkyl, the heterocycle of the replacement that connects by carbon or nitrogen, replace or unsubstituted aryl, replacement or unsubstituted heteroaryl by carbon or nitrogen connect wherein do not have radicals R
4R
1And R
9Common formation is selected from (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
9-(CH
2)
m(CH
2)
r-O-(CH
2)
mPart; Or R
1And R
3Common formation is selected from (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
9-(CH
2)
m(CH
2)
r-O-(CH
2)
mPart; Or R
9And R
3Common formation is selected from (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2) m, (CH
2)
r-NR
9-(CH
2)
m(CH
2)
r-O-(CH
2)
mPart;
Extra condition is if G
0=CH, R so
3And R
4Be selected from H independently of one another, C
1-C
6Alkyl, C
1-C
6Replace or unsubstituted hydroxyalkyl or aminoalkyl group C
1-C
6Replace or unsubstituted branched-chain alkyl, replace or unsubstituted aryl, by the C of carbon or nitrogen connection
1-C
6Replace or unsubstituted heterocycle, with replacement that is connected by carbon or nitrogen or unsubstituted heteroaryl, or R
3And R
4Common formation is selected from (CHR
9)
r-(CHR
9)
m-(CHR
9)
p, (CHR
9)
r-S-(CHR
9)
m, (CHR
9)
r-SO-(CHR
9)
m, (CHR
9)
r-SO
2-(CHR
9)
m, (CHR
9)
r-NR
9-(CHR
9)
m(CHR
9)
r-O-(CHR
9)
mPart;
G is N or CR
6And each G and G are independently of one another, and extra condition is to be no more than two G groups can be N, and extra condition is with regard to each CR
6, each R
6With radicals R
6Independently of one another;
R
5Be methyl;
R separately wherein
6, R
7, R
8Be independently selected from H, C
1-C
6Replace or unsubstituted alkyl C
1-C
6Replace or unsubstituted alkenyl C
1-C
6Replace or unsubstituted alkynyl C
1-C
6Replace or unsubstituted hydroxyalkyl or aminoalkyl group C
1-C
6Replace or unsubstituted branched-chain alkyl C
1-C
6Replace or unsubstituted cycloalkyl, by the replacement or the unsubstituted aryl of carbon or heteroatoms connection, by replacement or the unsubstituted heteroaryl that carbon or heteroatoms connect, C
1-C
6Alkoxyl group, halogen, CF
3,-OCF
3, CHR
3R
4, SR
3, SOR
3, SO
2R
3, SO
2NR
3R
4, SO
3R
3, POR
3, PO
2R
3, PO
2NR
3R
4, PO
2CR
3R
4, PO
3R
3, NR
3R
4, NO
2, CN, OH, CONR
3R
4, COR
3, COOR
3, NR
3COR
4, NR
3CONR
3R
4, OCONR
3R
4, CSNR
3R
4, CSR
3, NR
3CSNR
3R
4, SCONR
3R
4, SCSNR
3R
4And SCSNR
3R
4Or any R
6And R
7Or R
7And R
8Or R
6And R
8Common formation is independently selected from-HN-CH=CH--HN-N=CH-,-HN-N=N-,-O (CH
2)
nO-,-S (CH
2)
nS-,-N=CH-S-,-CH=N-O-,-CH=N-S-,-N=CH-O-,-C=N-O-,-C=N-O-,-CH=CH-CH=CH-,-N=CH-CH=CH-,-CH=N-CH=CH-,-O-CH=CH and-part of S-CH=CH-; Or R
3And R
4Common formation is selected from (CHR
9)
r-(CHR
9)
m-(CHR
9)
p, (CHR
9)
r-S-(CHR
9)
m, (CHR
9)
r-SO-(CHR
9)
m, (CHR
9)
r-SO
2-(CHR
9) m, (CHR
9)
r-NR
9-(CHR
9)
m(CHR
9)
r-O-(CHR
9)
mPart;
A is selected from O, NR
3, CR
3R
4, S, SO and SO
2
G
1Be selected from CH, N, NH, S and O;
G
2Be selected from CR
7, N, NH, S and O, wherein each radicals R
7With each extra radicals R
7Independent;
And if G
1Or G
2Be NH, S or O, Q is 5 yuan of heteroaromatic rings so, and it is chosen wantonly with 6 yuan of aromatics or non--aromatic ring and condenses; And if G
1Or G
2Be N, Q is 5 or 6 yuan of aromatic rings so, and it is chosen wantonly with 6 yuan of aromatics or non--aromatic ring and condenses;
Condition is X or G
0Comprise that at least one comprises with X and be selected from O, the heteroatoms of S and N, or G
0Comprise the atom of at least four non--hydrogen, comprise heteroatoms, and R
3And R
4Or R
1And R
9Or R
1And R
4Or R
9And R
4The common aromatics that forms, heteroaromatic, ring or heterocycle system, if or non-ring system exist, have an above heteroatoms so, and if A be NR
3, so any R
6, R
7Or R
8Or its any combination comprises the substituting group of at least two non--hydrogen independently, if or A be NR
3, Q is by R so
6To R
7Or R
7To R
8Constitute fused rings.
2. the compound or its pharmacy acceptable salt that comprise first part that is connected with second part chemistry, hydrate, solvate, crystal formation, N-oxide compound and each diastereomer, wherein said first part is selected from:
With
And wherein said second part is selected from:
3. the described compound of claim 1, wherein this compound is selected from the compound with formula I-CLXII:
With
4. the described compound of claim 1, wherein this compound is
5. the described compound of claim 1, wherein this compound is
6. the described compound of claim 1, wherein this compound is
7. the described compound of claim 1, wherein this compound is selected from:
8. the described compound of claim 1, wherein this compound is selected from:
With
9. the described compound of claim 1, wherein this compound is selected from:
10. the described compound of claim 1, wherein this compound is selected from:
11. the described compound of claim 1, wherein this compound is selected from:
12. the described compound of claim 1, wherein this compound is selected from:
13. the described compound of claim 1, wherein this compound is selected from:
14. the described compound of claim 1, wherein this compound is
15. the described compound of claim 1, wherein this compound is selected from
16. the described compound of claim 1, wherein this compound is selected from:
17. the described compound of claim 1, wherein this compound is
18. the described compound of claim 1, wherein this compound is
19. the described compound of claim 1, wherein this compound is
20. the described compound of claim 1, wherein this compound is
21. the described compound of claim 1, wherein this compound is selected from:
22. the described compound of claim 1, wherein this compound is
23. the described compound of claim 1, wherein this compound is selected from:
24. the described compound of claim 1, wherein this compound is selected from:
25. the described compound of claim 1, wherein this compound is selected from:
26. the described compound of claim 1, wherein this compound is
27. the described compound of claim 1, wherein this compound is selected from:
28. the described compound of claim 1, wherein this compound is
29. the described compound of claim 1, wherein this compound is selected from:
30. the described compound of claim 1, wherein this compound is selected from:
31. the described compound of claim 1, wherein this compound is selected from:
32. the described compound of claim 1, wherein this compound is
33. the described compound of claim 1, wherein this compound is
34. the described compound of claim 1, wherein this compound is selected from:
35. the described compound of claim 1, wherein this compound is
36. the described compound of claim 1, wherein this compound is selected from:
37. the described compound of claim 1, wherein this compound is selected from:
38. the described compound of claim 1, wherein this compound is selected from:
39. the described compound of claim 1, wherein this compound is
40. the described compound of claim 1, wherein this compound is selected from:
41. the described compound of claim 1, wherein this compound is selected from:
42. the described compound of claim 1, wherein this compound is selected from:
43. the described compound of claim 1, wherein this compound is
44. the described compound of claim 1, wherein this compound is
45. the described compound of claim 1, wherein this compound is
46. the described compound of claim 1, wherein this compound is selected from:
47. the described compound of claim 1, wherein this compound is
48. the described compound of claim 1, wherein this compound is
49. the described compound of claim 1, wherein this compound is selected from:
50. the described compound of claim 1, wherein this compound is
51. the described compound of claim 1, wherein this compound is selected from:
With
52. the described compound of claim 1, wherein this compound is
53. the described compound of claim 1, wherein this compound is
54. the described compound of claim 1, wherein this compound is selected from:
With
55. the described compound of claim 1, wherein this compound is selected from:
56. the described compound of claim 1, wherein this compound is
57. the described compound of claim 1, wherein this compound is
58. the described compound of claim 1, wherein this compound is
59. the described compound of claim 1, wherein this compound is
60. the described compound of claim 1, wherein this compound is
61. the described compound of claim 1, wherein this compound is selected from:
62. the described compound of claim 1, wherein this compound is
63. the described compound of claim 1, wherein this compound is selected from:
64. the described compound of claim 1, wherein this compound is
65. the described compound of claim 1, wherein this compound is
66. the described compound of claim 1, wherein this compound is
67. the described compound of claim 1, wherein this compound is selected from:
68. the described compound of claim 1, wherein this compound is
69. the described compound of claim 1, wherein this compound is
70. the described compound of claim 1, wherein this compound is
71. the described compound of claim 1, wherein this compound is
72. the described compound of claim 1, wherein this compound is
73. the described compound of claim 1, wherein this compound is
74. the described compound of claim 1, wherein this compound is
75. the method for the illness that treatment is relevant with generating blood vessel, comprise any one at least a compound or its pharmacy acceptable salt of claim 1-3 of the experimenter that these needs are arranged being treated significant quantity, hydrate, solvate, crystal formation, N-oxide compound and each diastereomer.
76. the described method of claim 75, wherein said illness is myelosis's illness, polycythemia vera, the thrombocythemia of the special property sent out, myelofibrosis with myeloid metaplasia, any other illness relevant with marrow, proliferative diabetic retinopathy PDR, cancer, illness in eye, inflammation, relevant any disease or virus infection take place with blood vessel in psoriatic.
77. the described method of claim 75, wherein said illness are polycythemia vera.
78. the described method of claim 75, wherein said illness are the thrombocythemia of the special property sent out.
79. the described method of claim 75, wherein said illness are the myelofibrosis with myeloid metaplasia.
80. the described method of claim 75, wherein said illness are any illness relevant with marrow.
81. the described method of claim 76, wherein said cancer is selected from digestion/gastrointestinal cancer, colorectal carcinoma, liver cancer, skin carcinoma, mammary cancer, ovarian cancer, prostate cancer, lymphoma, leukemia, kidney, lung cancer, muscle cancer, osteocarcinoma, bladder cancer and the cancer of the brain.
82. the described method of claim 75, wherein said illness are selected from ocular neovascular and form, infantile hemangioma; The organ anoxic, blood vessel hyperplasia, organ graft repels, lupus, multiple sclerosis, rheumatoid arthritis, psoriatic, 1 type or type ii diabetes and the complication that causes because of diabetes, inflammatory diseases, acute pancreatitis, chronic pancreatitis, asthma, anaphylaxis, adult respiratory distress syndrome, cardiovascular disorder, hepatopathy, other hemopathy, asthma, rhinitis, atopy, dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, metastatic melanoma, Kaposi sarcoma, multiple myeloma, the illness relevant and other autoimmune disease with cytokine, glomerulonephritis, scleroderma, chronic thyroiditis, Graves disease, autoimmunity gastritis, autoimmune hemolytic, autoimmunity neutropenia, thrombocytopenia, allergic asthma, atopic dermatitis, allergic rhinitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel, graft versus host disease (GVH disease), neurodegenerative disease, motor neurone disease, alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington Chorea, cerebral ischemia disease or the neurodegenerative disease that causes because of wound, apoplexy, L-glutamic acid neurotoxic or hypoxemia; Ischemia/reperfusion injury in the apoplexy, myocardial ischemia, renal ischaemia, heart attack, cardiac hypertrophy, atherosclerosis and arteriosclerosis, the organ anoxic, platelet aggregation, allergic contact dermatitis, hypersensitivity pneumonitis, systemic lupus erythematous, adolescent arthritis, this Jaeger logical sequence syndrome, scleroderma, polymyositis, ankylosing spondylitis, arthritic psoriasis, Epstein-Barr virus, hepatitis B, hepatitis C, HIV, HTLV1, varicella zoster virus, human papillomavirus, food anaphylaxis, skin inflammation and because of the immunosuppression of solid tumor inductive.
83. the described method of claim 82, wherein said illness are cardiovascular disorder.
84. the described method of claim 82, wherein said illness are hemopathy.
85. the described method of claim 75, wherein said illness are chronic myelogenous leukemia (CML).
86. the described method of claim 85, the present treatment of wherein said chronic myelogenous leukemia opposing.
87. the described method of claim 75, wherein said illness are myelosis's illness.
88. the described method of claim 87, wherein said myelosis illness produces because of kinase mutant.
89. the described method of claim 88, wherein said kinases are the JAK family kinase.
90. the described method of claim 87, wherein said myelosis illness produces because of the acquisition of JAK family kinase by way of function.
91. the described method of claim 87, wherein said myelosis illness is as causing the result that gene or protein merge to produce because of the JAK family kinase by way of the acquisition of function.
92. the described method of claim 75, wherein said illness is relevant with kinases.
93. the described method of claim 92, wherein said kinases are the JAK family kinase.
94. pharmaceutical composition comprises at least a compound any among the claim 1-3 or its N-oxide compound or its pharmacy acceptable salt, hydrate, solvate, crystal formation and Ge Qi diastereomer and pharmaceutically acceptable carrier thereof.
95. goods, comprise wrapping material and be included in the interior pharmaceutical composition of these wrapping material, wherein said wrapping material comprise and show that described pharmaceutical composition can be used for the treatment of the label that generates the blood vessel associated conditions, and this pharmaceutical composition comprises at least a compound any among the claim 1-3 or its N-oxide compound or its pharmacy acceptable salt, hydrate, solvate, crystal formation and each diastereomer.
96. goods, comprise wrapping material and be included in the interior pharmaceutical composition of these wrapping material, wherein said wrapping material comprise and show that described pharmaceutical composition can be used for the treatment of the label of following disease: myelosis's illness, proliferative diabetic retinopathy PDR, cancer, illness in eye, inflammation, psoriatic or virus infection, and wherein said pharmaceutical composition comprises at least a compound any among the claim 1-3 or its N-oxide compound or pharmacy acceptable salt, hydrate, solvate, crystal formation and each diastereomer.
97. the described goods of claim 96, wherein said illness is selected from digestion/gastrointestinal cancer, colorectal carcinoma, liver cancer, skin carcinoma, mammary cancer, ovarian cancer, prostate cancer, lymphoma, leukemia, kidney, lung cancer, muscle cancer, osteocarcinoma, bladder cancer and the cancer of the brain.
98. the method for the illness that treatment is relevant with generating blood vessel, comprise any one at least a compound or its N-oxide compound or pharmacy acceptable salt among the claim 1-3 of experimenter's drug treatment significant quantity that this class treatment needs are arranged, hydrate, solvate, crystal formation and each diastereomer associating antiphlogiston, chemotherapeutics, immunomodulator, treatment antibody or kinases inhibitor.
99. the method for pharmaceutical compositions comprises at least a compound any among the claim 1-3 or its N-oxide compound or its pharmacy acceptable salt, hydrate, solvate, crystal formation salt and each diastereomer and pharmaceutically acceptable carrier combinations.
100. the method for the illness that treatment is relevant with generating blood vessel, comprise any one at least a compound or its N-oxide compound or pharmacy acceptable salt among the claim 1-3 of experimenter's topical treatment significant quantity that this class treatment needs are arranged, hydrate, solvate, crystal formation and each diastereomer.
The described method of claim 100, wherein said administration and antiphlogiston, chemotherapeutics, immunomodulator, treatment antibody or kinases inhibitor carry out together.
Claim 100 or 101 described methods, wherein said illness is an illness in eye.
The described method of claim 102, wherein said topical comprises the administration eye drop.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310043377.0A CN103626742B (en) | 2005-11-01 | 2006-10-26 | Bi-aryl meta-pyrimidine inhibitors of kinases |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US73262905P | 2005-11-01 | 2005-11-01 | |
| US60/732,629 | 2005-11-01 | ||
| US83800306P | 2006-08-15 | 2006-08-15 | |
| US60/838,003 | 2006-08-15 | ||
| PCT/US2006/042044 WO2007053452A1 (en) | 2005-11-01 | 2006-10-26 | Bi-aryl meta-pyrimidine inhibitors of kinases |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201310043377.0A Division CN103626742B (en) | 2005-11-01 | 2006-10-26 | Bi-aryl meta-pyrimidine inhibitors of kinases |
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| CN101370792A true CN101370792A (en) | 2009-02-18 |
| CN101370792B CN101370792B (en) | 2013-03-20 |
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| CN200680049966.8A Active CN101370792B (en) | 2005-11-01 | 2006-10-26 | Bi-aryl meta-pyrimidine inhibitors of kinases |
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|---|---|
| CN (1) | CN101370792B (en) |
| UA (3) | UA99899C2 (en) |
| ZA (1) | ZA200804083B (en) |
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| CN102791131A (en) * | 2010-01-13 | 2012-11-21 | 葛兰素史密斯克莱有限责任公司 | Compounds and methods |
| CN103242240A (en) * | 2012-02-10 | 2013-08-14 | 上海温康化学研发有限公司 | Sulfonamide compound intermediate, salt thereof and preparation method thereof |
| CN103282036A (en) * | 2010-11-07 | 2013-09-04 | 塔格根公司 | Compositions and methods for treating myelofibrosis |
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| GB0004887D0 (en) * | 2000-03-01 | 2000-04-19 | Astrazeneca Uk Ltd | Chemical compounds |
-
2006
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- 2006-10-26 ZA ZA200804083A patent/ZA200804083B/en unknown
- 2006-10-26 UA UAA201203128A patent/UA109412C2/en unknown
- 2006-10-26 UA UAA201203127A patent/UA109411C2/en unknown
- 2006-10-26 CN CN200680049966.8A patent/CN101370792B/en active Active
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Also Published As
| Publication number | Publication date |
|---|---|
| ZA200804083B (en) | 2009-09-30 |
| UA109412C2 (en) | 2015-08-25 |
| UA109411C2 (en) | 2015-08-25 |
| UA99899C2 (en) | 2012-10-25 |
| CN101370792B (en) | 2013-03-20 |
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