CN101370792B - Bi-aryl meta-pyrimidine inhibitors of kinases - Google Patents

Bi-aryl meta-pyrimidine inhibitors of kinases Download PDF

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CN101370792B
CN101370792B CN200680049966.8A CN200680049966A CN101370792B CN 101370792 B CN101370792 B CN 101370792B CN 200680049966 A CN200680049966 A CN 200680049966A CN 101370792 B CN101370792 B CN 101370792B
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CN101370792A (en
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J·J·曹
J·胡德
D·罗赫塞
C·C·梅克
A·麦克菲尔森
G·诺龙哈
V·派特哈克
J·雷尼克
R·M·索尔
曾斌琦
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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

Kinase whose bi-aryl meta-pyrimidine inhibitors
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 above-mentioned Growth of Cells relevant with relative disease, cytodifferentiation, and survival, apoptosis, mitotic division occurs, and the various biological cells of cell cycle control and cell mobility are replied.
Protein kinase has shown as the class of enzymes with Results 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 (Jak1, Jak2, Jak3 and Tyk2); The .Genome Biology such as Yamaoka 2004,5,253)).Cytokine activates JAK in conjunction with its acceptor the time, then make the cytokine receptor phosphorylation, produces thus signaling molecule, 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 (IFN-α s/ β/ω/restriction element, 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, I L-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, HGF) and 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 impact.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 the immunosuppression of inducing because of solid tumor.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, with JAK2 kinases (V617F) gain-of-function, somatocyte (acquired) sudden change is reported to the member in " typical case " myelosis illness, comprise polycythemia vera, the paathogenic factor of idiopathic thrombocythemia and myelofibrosis with myeloid metaplasia, and found in the patient with " atypia " myelosis's illness and myelodysplastic syndrome that described sudden change is (with regard to summary, referring to Tefferi and Gilliland, Cell Cycle 2005,4 (8), e61; The 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) the V617F JAK2-cell proliferation signal of inducing 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 the JAK approach that composing type activates 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, namely affect 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; The .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 neovascularization of hypoxia inducible in the rodent model.
Recently confirmed that the sudden change in the EPO acceptor can also affect 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 cell of the Philadelphia chromosome positive 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 thus the constitutive activity of cell.
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 of the disease that can utilize the above-mentioned JAK signal transduction path imbalance for the treatment of or directly or indirectly be replenished is not enough, 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):
Figure S2006800499668D00041
Another embodiment provides the method for the treatment illness relevant with generating blood vessel, for the experimenter who has this class treatment to need, the 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 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 to comprise aforesaid at least one each heteroatomic aromatic ring when being used for describing 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 to have the monovalence straight or branched alkyl of 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 to have the alkyl of about 6 carbon atoms of 1-.
Term " alkyl of replacement " means also to have 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 also to have 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 also to have 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 also to have one or more above-mentioned substituent aryl.
Term " heteroaryl " means aromatic ring, wherein consist of this ring structure by about 14 carbon atoms of about 3-and at least one above-mentioned heteroatoms, and term " heteroaryl of replacement " means also to have one or more above-mentioned substituent heteroaryls.
Term " alkoxyl group " means-the O-moieties, and wherein alkyl means also to have one or more above-mentioned substituent alkoxyl groups such as above-mentioned definition and term " alkoxyl group of replacement ".
Term " cycloalkyl " means to have the alkyl of about 8 carbon atoms of the 3-that is arranged as ring, and term " cycloalkyl of replacement " means also to have one or more above-mentioned substituent cycloalkyl.
Term " alkylaryl " means the aryl of alkyl-replacement, and term " alkylaryl of replacement " means also to have one or more above-mentioned substituent alkylaryls.
Term " arylalkyl " means the alkyl of aryl-replacement, and term " arylalkyl of replacement " means also to have 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 also to have 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 also to have one or more above-mentioned substituent aromatic yl polysulfide yls.
Term " arylidene " means to have the divalent aromatic radical of about 14 carbon atoms of 5-, and term " arylidene of replacement " means also to have one or more above-mentioned substituent arylidene.
Term " chemistry connects " is defined as the formation chemical entity, and wherein two parts consist of the direct chemical bond 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 to participate in to cause the enzyme found in the cell in the immunity system of the cell signaling process that white corpuscle grows.
Term " treatment significant quantity " means to cause tissue that researchist, animal doctor, doctor or other clinicists 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 preventing damage or loss or vasculostasis; Reduce tumor load; The consumption of reducing sickness rate and/or mortality ratio.
Term " pharmaceutically acceptable " mean carrier, thinner or vehicle must with preparation in other component compatibility and can be to harmful this fact of its recipient.
Term " compound administration " or " giving drug compound " mean the experimenter who has treatment to need is provided the behavior of compound of the present invention or pharmaceutical composition.
Term " antibody " means polyclone or the complete molecule of monoclonal antibody and fragment thereof, and is all if the Fab of associative list position determiner and F (ab ') 2, Fv and SCA fragment.
Term " vasculostasis " means to keep vascular function effect stable state and produces normal physiological function.
Term " vasculostatic agents " means to seek to solve the promoting agent of 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:
Figure S2006800499668D00071
In structure (A), X can be key, O, C=O, SO 2Or CH 2In any number of 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 6Replace or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted heterocycle, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl in any number of; Or R 1And R 2Jointly can be key; Or R 1And R 2Common component part is 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, 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 without 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, 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, 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 independent 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:
Figure S2006800499668D00091
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 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 4Or SCSNR 3R 4Or any R 6And R 7Or R 7And R 8Or R 6And R 8Can jointly consist of 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-any number of part 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 number of and G among S and the O 2Can be CR 7, N, NH, any number of 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 4Jointly can consist of aromatics, heteroaromatic, ring-type or heterocycle ring system, if or have non-ring system, have so an above heteroatoms, and if A be NR 3, so any R 6, R 7Or R 8Or its composition independency ground comprises the substituting group of at least two non--hydrogen, if or A be NR 3, Q consists of 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 to the compound of CLXII:
Figure S2006800499668D00111
Figure S2006800499668D00121
Figure S2006800499668D00131
Figure S2006800499668D00141
Figure S2006800499668D00151
Figure S2006800499668D00161
Figure S2006800499668D00171
Figure S2006800499668D00181
Figure S2006800499668D00201
Figure S2006800499668D00211
Figure S2006800499668D00221
Figure S2006800499668D00231
Figure S2006800499668D00241
Figure S2006800499668D00251
Figure S2006800499668D00261
Figure S2006800499668D00271
Figure S2006800499668D00281
Figure S2006800499668D00291
Figure S2006800499668D00301
Figure S2006800499668D00311
Figure S2006800499668D00331
Figure S2006800499668D00341
Figure S2006800499668D00351
Figure S2006800499668D00361
Figure S2006800499668D00371
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 and is selected from lower group any part:
Figure S2006800499668D00381
Figure S2006800499668D00401
Figure S2006800499668D00411
C in said structure (Z) part comprises and is selected from lower group any part:
Figure S2006800499668D00421
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 illness relevant with generating blood vessel, the cancer that comprises solid tumor and other type, illness in eye, inflammation, psoriatic and virus infection.Treatable type of cancer 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 the immunosuppression of inducing because of solid tumor.
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 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 known technology of field of pharmaceutical preparations.
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 with any free cations group the salt of sour addition, and general and mineral acid, such as, hydrochloric acid for example, sulfuric acid or phosphoric acid or organic acid, such as acetic acid, citric acid, p-toluenesulphonic acids, methylsulfonic acid, oxalic acid, tartrate, the 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 p-toluenesulphonic acids, acetic acid, and the organic acid that this class such as methylsulfonic acid is suitable makes the amine salt of amino protonated formation.Pay close attention to be used for implementing 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, the form of particle or 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 the form with creme or ointment; Or by rectum, such as the 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.
Except 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 the method can also be implemented in other kind, such as birds (for example chicken).
Can will be used for separately or make expediently unit dosage 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 consists of 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 necessary, 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 according to known any method preparation in the pharmaceutical compositions field composition of oral application, and this based composition can comprise one or more and be selected from sweeting agent, correctives, the reagent of tinting material and sanitas is in order to 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 calcium 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 in order to delay disintegration and absorption in gi tract by known technology, and be provided at thus the continuous action of longer-term limit.For example, can use the time-delay material, such as glyceryl monostearate or distearin.Can also give their dressings in order to 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, calcium 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 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, in order to agreeable to the taste oral preparations is provided.Can pass through to add antioxidant, anticorrosion to these compositions such as xitix.
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 take 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 the 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 according to known field, use those above-mentioned suitable dispersions or wetting agent and suspension agent to prepare this suspension.Sterile injectable preparation can also be sterile injectable solution or the suspension in the acceptable thinner of non-enteron aisle 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 fixedly oil is used as solvent or suspension medium.For this purpose, can use the fixedly 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 for the treatment of, can prepare and by whole body or these pharmaceutical compositions of topical.The technology that is used for preparation and administration can find in latest edition " Remington ' sPharmaceutical Sciences " (Mack Publishing Co, Easton Pa.).Suitable for 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 seeing through the permeate agent of particular barrier for preparation.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.Suitable 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 in order to 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 solid at normal temperatures, and is liquid under rectal temperature, and thus fusing and discharge medicine in rectum.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; Microtubule inhibitors is such as PTX (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 the antibody that is oriented to HER2 albumen, such as Herceptin; Be oriented to the antibody of somatomedin or growth factor receptors, such as the Avastin of target vascular therapy endothelial cell growth factor (ECGF) and the OSI-774 of targeting epidermal growth factor; 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 inhibitors (vincristine(VCR) for example, vinealeucoblastine(VLB) and vindesine etc.), microtubule stabilizer (for example taxol [PTX] and docetaxel, taxotere etc.) and the chromatin depressant of functions, comprise topoisomerase enzyme inhibitor, such as the promoting agent (such as camptothecine and irinotecan (Isirinotecan) [CPT-11] etc.) of epipodophyllotoxin (such as 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, phosphinothioylidynetrisaziridine and Mitocycin etc.); 3) non-covalent DNA-wedding agent [antitumor antibiotics], comprise nucleic acid inhibitor (such as dactinomycin [dactinomycin] etc.), anthracycline (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, the chlorine Desoxyadenosine, 2-chlorodeoxyadenosine [CdA] and 2 '-deoxidation coformycin [pentostatin] etc.), pyrimidine antagonist (for example 5-FU class [for example 5 FU 5 fluorouracil (Adrucil), floxuridine (FdUrd) (floxuridine)] etc.) and Ara-C (such as Cytosar [ara-C] and fludarabine etc.); 5) enzyme comprises L-ASP; 6) hormone comprises glucocorticosteroid, such as, antiestrogen (such as tamoxifen etc.), non-steroid antiandrogen (such as flutamide etc.) and aromatase inhibitor (such as Anastrozole [Arimidex] etc.); 7) platinic compound (such as cis-platinum and carboplatin etc.); 8) and anticarcinogen, the monoclonal antibody that toxin and/or radionuclide are puted together etc.; 9) biological response modifier (such as Interferon, rabbit [such as IFN-. α. etc.] and interleukin-[such as IL-2 etc.] etc.); 10) adoptive immunotherapy; 11) hemopoieticgrowth factor; 12) promoting agent of inducing tumor cell differentiation (such as all-trans retinoic acid etc.); 13) gene therapy technology; 14) antisense therapy technology; 15) tumor vaccine; 16) be oriented to the therapy (such as 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 rapammune) 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 used herein " function fragment " means to have 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 be determined 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 in order to adjust this dosage according to the patient's who treats symptom.Can be with 1-4 times/day, such as once or twice/day scheme to drug compound.Not medicine-feeding period can be arranged, carry out subsequently another kind of dosage regimen.
Yet, be appreciated that concrete dosage level and the dosage frequency for 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, 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 PTX.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 and non-designated they be used for limiting scope of the present invention.
Embodiment 1. general methods
General method
All experiments are all carried out under anhydrous condition (being dry solvent) and in the ar gas environment, but as described, in processing the air sensitive material, use oven drying instrument and Application standard technology.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.WatersSymmetry Shield has been installed in use TMGilson 215 liquid processors of RP18 7 μ m (40x100mm) Prep-Pak posts carry out the reversed-phase HPLC chromatogram.Moving phase is comprised of the standard acetonitrile (ACN) and the DI Water that have added separately 0.1%TFA.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.Algorithm: use electrospray (ES+) ionization.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 formed by 10% ACN-100%ACN in water in 5 minutes.
Embodiment 2. N 4 -(4-methoxyl group-phenyl)-pyrimidine-2,4-diamines (intermediate 1)
Figure S2006800499668D00521
The mixture of 4-chloro-pyrimidine-2-base amine (0.30g, 2.3mmol) and 4-methoxyl group-phenyl amine (0.30g, 2.4mmol) is suspended in the acetic acid (10mL) and at 100 ℃ to descend to heat 2 hours.This mixture is cooled to room temperature and under reduced pressure removes acetic acid.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 purification of 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-pyrrolidin-1-yl-oxyethyl group)-benzene Base]-pyrimidine-2,4-diamines (Compound I)
Figure S2006800499668D00522
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.
Figure S2006800499668D00531
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 uses microwave irradiation 15 minutes under 160 ℃.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)
Figure S2006800499668D00532
For synthetic compound II, use intermediate 1 above-mentioned and intermediate 3.The intermediate 3 of formula as follows, 4-bromo-N-(2-pyrrolidin-1-yl-ethyl)-benzsulfamide uses known synthetic technology synthetic by 4-bromophenyl SULPHURYL CHLORIDE and 2-amino-ethyl tetramethyleneimine.
Figure S2006800499668D00533
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 uses microwave irradiation 15 minutes under 160 ℃.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)
Figure S2006800499668D00541
To at room temperature adding BBr in the solution of above-claimed cpd II (50mg, 0.09mmol) in DCM (6mL) 3(0.1mL) and with this mixture at room temperature stirred 2.5 hours.Use saturated NaHCO 3Solution makes the reaction quencher, until pH～7 and extract this mixture 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-pyrrolidin-1-yl-ethyl)-benzene Sulphonamide (intermediate 4)
Figure S2006800499668D00551
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), the mixture of Xantphos (0.50g, 0.86mmol) and potassium tert.-butoxide (2.2g, 20mmol) are suspended in the diox (30mL) and heated 16 hours under reflux state and in the ar gas environment.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 purification of crude product (DCM-25%MeOH/DCM) is brown solid in a vacuum.MS(ESI+)：m/z 382(M+H) +。
Embodiment 7.4-[4-(3-methoxyl group-phenyl amino)-pyrimidine-2--amino]-N-(2-pyrroles Alkane-1-base-ethyl)-benzsulfamide (compound IV)
Figure S2006800499668D00552
The mixture of above-mentioned intermediate 4 (0.10g, 0.26mmol) and 3-methoxyl group-phenyl amine (0.05mL, 0.45mmol) is suspended in acetic acid (6mL) and descends heating 1.5 hours at 100 ℃.This mixture is cooled to room temperature and under reduced pressure removes acetic acid.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 purification of 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)
Figure S2006800499668D00561
To at room temperature adding BBr in the solution of above-claimed cpd IV (30mg, 0.05mmol) in DCM (6mL) 3(0.1mL) and with this mixture at room temperature stirred 2.5 hours.Use saturated NaHCO 3Solution makes the reaction quencher, until pH～7 and extract this mixture 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)
Figure S2006800499668D00562
With 2-chloro-5-methyl-pyrimidine-4-yl amine (0.30g, 2.1mmol), 5-bromo-benzo [1,3] dioxole (0.45g, 2.2mmol), Pd (OAc) 2(30mg, 0.13mmol), the mixture of Xantphos (0.15g, 0.26mmol) and potassium tert.-butoxide (0.45g, 4.0mmol) are suspended in diox (15mL) or and heated 16 hours under reflux state and in the ar gas environment.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 is to the 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- Pyrrolidin-1-yl-oxyethyl group)-phenyl]-pyrimidine-2,4-diamines (compound vi)
Figure S2006800499668D00571
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-pyrrolidin-1-yl-oxyethyl group)-phenyl amine: at first by using the 2-chloroethyl pyrrolidine to make the alkylation of 4-nitrophenols, reduce subsequently and obtain anils.
Figure S2006800499668D00572
Generally well-known synthetic technology is for the synthesis of intermediate 6.With above-mentioned intermediate 5 (90mg, 0.34mmol), intermediate 6 (95mg, 0.46mmol), Pd 2(dba) 3(20mg, 0.02mmol), the mixture of Xantphos (30mg, 0.05mmol) and cesium carbonate (0.30g, 0.9mmol) are suspended in the diox (10mL) and heated 20 hours under reflux state and in the ar gas environment.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(500 MHz，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)
Figure S2006800499668D00581
With 2-chloro-5-methyl-pyrimidine-4-yl 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), the mixture of Xantphos (0.22g, 0.38mmol) and cesium carbonate (2.3g, 7.1mmol) are suspended in diox (20mL) and heated 5 hours under reflux state and in the ar gas environment.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)
Figure S2006800499668D00582
Under 0 ℃, intermediate 7 (0.50g, 1.8mmol) and sodium hydride (in mineral oil 60%, 0.15g, the 3.8mmol) suspension in THF (10mL) was 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 then uses EtOAc (30mL) extraction.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-(pyrrolidin-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)
The mixture of every kind of aforesaid intermediate 8 of intermediate (0.15g, 0.49mmol) and intermediate 6 (0.15g, 0.73mmol) is suspended in the acetic acid (8mL) and at 100 ℃ to descend to heat 17 hours.This mixture is cooled to room temperature and under reduced pressure removes acetic acid.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 purification of 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)
Figure S2006800499668D00592
With 2-chloro-5-methyl-pyrimidine-4-yl amine (0.30g, 2.1mmol), 1-bromo-4-chloro-benzene (0.60g, 3.1mmol), Pd 2(dba) 3(95mg, 0.10mmol), the mixture of Xantphos (0.12g, 0.20mmol) and cesium carbonate (1.3g, 4.0mmol) are suspended in the diox (20mL) and heated 4 hours under reflux state and in the ar gas environment.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-pyrrolidin-1-yl-ethoxy Base)-phenyl]-pyrimidine-2,4-diamines (compound VIII)
The mixture of above-mentioned intermediate 9 (0.15g, 0.60mmol) and 6 (0.20g, 0.97mmol) is suspended in acetic acid (8mL) or and 100 ℃ of lower heating 6 hours.This mixture is cooled to room temperature and under reduced pressure removes acetic acid.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%) by the HPLC purifying, be brown oil.
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)
Figure S2006800499668D00602
Give in 2-(4-nitro-phenoxy group)-solution of ethanol (2.1g, 12mmol) in MeOH (30mL) applying argon gas and then add Pd/C (10%wt).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 the celite 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)
Figure S2006800499668D00611
With above-mentioned intermediate 7 (50mg, 0.17mmol), 10 (40mg, 0.26mmol), Pd 2(dba) 2(8mg, 0.01mmol), (suspension in 0.13g, the 0.40mmol) Zai diox (3mL) is sealed in the microwave reaction pipe and uses microwave irradiation 15 minutes under 160 ℃ for Xantphos (10mg, 0.02mmol) and cesium carbonate.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-pyrrolidin-1-yl-oxyethyl group)-phenyl]-pyrimidine -2,4-diamines (intermediate 11)
Figure S2006800499668D00612
The mixture of 2-chloro-5-methyl-pyrimidine-4-yl amine (0.13g, 0.87mmol) and above-mentioned intermediate 6 (0.30g, 1.5mmol) is suspended in the acetic acid (8mL) and at 100 ℃ to descend to heat 2 hours.This mixture is cooled to room temperature and under reduced pressure removes acetic acid.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-pyrrolidin-1-yl-oxyethyl group)-benzene Base]-pyrimidine-2,4-diamines (compounds X)
Figure S2006800499668D00621
With above-mentioned intermediate 11 (25mg, 0.08mmol), bromobenzene (0.05mL, 0.50mmol), Pd 2(dba) 2(5mg, 0.006mmol), (suspension in 70mg, the 0.21mmol) Zai diox (3mL) is sealed in the microwave reaction pipe and uses microwave irradiation 15 minutes under 160 ℃ for Xantphos (10mg, 0.02mmol) and cesium carbonate.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)
Figure S2006800499668D00631
With 2-chloro-5-methyl-pyrimidine-4-yl amine (0.50g, 3.5mmol), 4-bromo-1-chloro-2-fluoro-benzene (1.0g, 4.8mmol), Pd 2(dba) 3(0.16g, 0.17mmol), the mixture of Xantphos (0.20g, 0.34mmol) and cesium carbonate (2.3g, 7.0mmol) are suspended in diox (25mL) and heated 15 hours under reflux state and in the ar gas environment.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-(the 2-pyrrolidin-1-yl- Oxyethyl group)-phenyl]-pyrimidine-2,4-diamines (compounds X I)
Figure S2006800499668D00632
The mixture of above-mentioned intermediate 12 (0.20g, 0.74mmol) and 6 (0.20g, 0.97mmol) is suspended in the acetic acid (8mL) and at 100 ℃ to descend to heat 6 hours.This mixture is cooled to room temperature and under reduced pressure removes acetic acid.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 purification of 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)
Figure S2006800499668D00641
With above-mentioned intermediate 7 (50mg, 0.17mmol), 4-morpholine-4-ylmethyl-phenyl amine (50mg, 0.26mmol), Pd 2(dba) 2(8mg, 0.009mmol), (suspension in 0.13g, the 0.40mmol) Zai diox (3mL) is sealed in the microwave reaction pipe and uses microwave irradiation 15 minutes under 160 ℃ for Xantphos (10mg, 0.02mmol) and cesium carbonate.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)
Figure S2006800499668D00642
With 2-chloro-5-methyl-pyrimidine-4-yl amine (0.30g, 2.1mmol), 5-bromo-benzo [b] thiophene (0.6g, 2.8mmol), Pd 2(dba) 3(95mg, 0.10mmol), the mixture of Xantphos (0.12g, 0.20mmol) and cesium carbonate (1.3g, 4.0mmol) are suspended in the diox (25mL) and heated 3 hours under reflux state and in the ar gas environment.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-(the 2-pyrrolidin-1-yl- Oxyethyl group)-phenyl]-pyrimidine-2,4-diamines (compounds X III)
Figure S2006800499668D00651
The mixture of above-mentioned intermediate 13 (0.23g, 0.83mmol) and 6 (0.35g, 1.7mmol) is suspended in the acetic acid (8mL) and at 100 ℃ to descend to heat 1 day.This mixture is cooled to room temperature and under reduced pressure removes acetic acid.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 purification of 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)
Figure S2006800499668D00661
With 2-chloro-5-methyl-pyrimidine-4-yl amine (0.30g, 2.1mmol), 3-bromo-benzo [b] thiophene (0.6g, 2.8mmol), Pd 2(dba) 3(95mg, 0.10mmol), the mixture of Xantphos (0.12g, 0.20mmol) and cesium carbonate (1.3g, 4.0mmol) are suspended in the diox (25mL) and heated 3 hours under reflux state and in the ar gas environment.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-(the 2-pyrrolidin-1-yl- Oxyethyl group)-phenyl]-pyrimidine-2,4-diamines (compounds X IV)
Figure S2006800499668D00662
The mixture of above-mentioned intermediate 14 (50mg, 0.18mmol) and 6 (0.10g, 0.48mmol) is suspended in the acetic acid (8mL) and at 100 ℃ to descend to heat 15 hours.This mixture is cooled to room temperature and under reduced pressure removes acetic acid.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 purification of 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)
Figure S2006800499668D00671
With 2-chloro-5-methyl-pyrimidine-4-yl amine (0.30g, 2.1mmol), 1-bromo-3-chloro-benzene (0.60g, 3.1mmol), Pd 2(dba) 3(95mg, 0.10mmol), the mixture of Xantphos (0.12g, 0.20mmol) and cesium carbonate (1.3g, 4.0mmol) are suspended in the diox (20mL) and heated 4 hours under reflux state and in the ar gas environment.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-pyrrolidin-1-yl-ethoxy Base)-phenyl]-pyrimidine-2,4-diamines (compounds X V)
The mixture of above-mentioned intermediate 15 (0.15g, 0.59mmol) and 6 (0.25g, 1.2mmol) is suspended in the acetic acid (8mL) and at 100 ℃ to descend to heat 21 hours.This mixture is cooled to room temperature and under reduced pressure removes acetic acid.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 purification of crude product (DCM-10% MeOH/DCM) is white solid in a vacuum. 1H NMR(500 MHz，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)
Figure S2006800499668D00681
Vigorous stirring 3-bromo-Benzoyl chloride (2.93g, 13.3mmol, 1eq) in 30mL THF solution and process with the methylamine (15mL, 29.4mmol, 2.2eq) of 2.0M in THF.Observe white precipitate and should react stirring 20 minutes.Then should react the washing of impouring ethyl acetate (100mL) and water (2x150mL) and salt solution (1x150mL).
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-yl is amino)-N-methyl-benzamide (in Mesosome 17)
Figure S2006800499668D00682
In the 50mL of drying round-bottomed flask, merge 2-chloro-5-methyl-pyrimidine-4-yl 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), two (diphenylphosphino)-9 of 4,5-, 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.Then change this reaction over to centrifuge tube, 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-pyrrolidin-1-yl-oxyethyl group)-benzene Base is amino]-pyrimidine-4-yl is amino }-benzamide tfa salt (compounds X VI)
Figure S2006800499668D00691
In the 15ml microwave container, merge above-mentioned intermediate 17 (0.068g, 0.246mmol, 1eq), 4-(2-pyrrolidin-1-yl-oxyethyl group)-phenyl amine (0.061g, 0.296mmol, 1.2eq), cesium carbonate (0.241g, 0.74mmol, 3 equivalents), two (diphenylphosphino)-9 of 4,5-, 9-dimethyl xanthene (0.029g, 0.05mmol, 0.2 equivalent) and three (dibenzalacetones), two palladiums (0.023g, 0.025mmol, 0.1 equivalent).Then with 7ml diox diluting reaction agent and 160 ℃ of lower microwave 15 minutes of using.Then rotate the precipitation reaction container, 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)
In the 15ml microwave container, merge above-mentioned intermediate 7 (0.083g, 0.293mmol, 1eq), 4-(2-pyrrolidin-1-yl-oxyethyl group)-phenyl amine (0.073g, 0.352mmol, 1.2eq), cesium carbonate (0.287g, 0.879mmol, 3 equivalents), two (diphenylphosphino)-9 of 4,5-, 9-dimethyl xanthene (0.034g, 0.059mmol, 0.2 equivalent) and three (dibenzalacetones), two palladiums (0.027g, 0.029mmol, 0.1 equivalent).Then with 7ml diox diluting reaction agent and 160 ℃ of lower microwave 15 minutes of using.Then rotate the precipitation reaction container, 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)
Figure S2006800499668D00701
In the 30ml microwave container, merge 2-chloro-5-methyl-pyrimidine-4-yl 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), two (diphenylphosphino)-9 of 4,5-, 9-dimethyl xanthene (0.276g, 0.476mmol, 0.2 equivalent) and three (dibenzalacetones), two palladiums (0.218g, 0.238mmol, 0.1 equivalent).Then with 12ml diox diluting reaction agent and 160 ℃ of lower microwave 25 minutes of using.Then rotate the precipitation reaction container, 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)
Figure S2006800499668D00711
In the 15ml microwave container, merge above-mentioned intermediate 18 (0.092g, 0.35mmol, 1eq), 4-(2-pyrrolidin-1-yl-oxyethyl group)-phenyl amine (0.087g, 0.42mmol, 1.2eq), cesium carbonate (0.343g, 1.05mmol, 3 equivalents), two (diphenylphosphino)-9 of 4,5-, 9-dimethyl xanthene (0.041g, 0.0702mmol, 0.2 equivalent) and three (dibenzalacetones), two palladiums (0.032g, 0.035mmol, 0.1 equivalent).Then with 7ml diox diluting reaction agent and 160 ℃ of lower microwave 15 minutes of using.Then rotate the precipitation reaction container, 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)：δ1.87-1.90(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-yl 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), two (diphenylphosphino)-9 of 4,5-, 9-dimethyl xanthene (0.328g, 0.57mmol, 0.2 equivalent) and three (dibenzalacetone) two palladium (0.26g, 0.283mmol, 0.1 equivalent).Then with 12ml diox diluting reaction agent and 160 ℃ of lower microwave 25 minutes of using.Then rotate the precipitation reaction container, 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-pyrrolidin-1-yl-second The oxygen base)-phenyl]-pyrimidine-2,4-diamines tfa salt (compounds X IX)
Figure S2006800499668D00721
In the 15ml microwave container, merge above-mentioned intermediate 19 (0.09g, 0.313mmol, 1eq), 4-(2-pyrrolidin-1-yl-oxyethyl group)-phenyl amine (0.078g, 0.376mmol, 1.2eq), cesium carbonate (0.307g, 0.941mmol, 3 equivalents), two (diphenylphosphino)-9 of 4,5-, 9-dimethyl xanthene (0.036g, 0.063mmol, 0.2 equivalent) and three (dibenzalacetones), two palladiums (0.029g, 0.0314mmol, 0.1 equivalent).Then with 7ml diox diluting reaction agent and 160 ℃ of lower microwave 15 minutes of using.Then rotate the precipitation reaction container, 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)：δ1.87-1.91(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)
Figure S2006800499668D00722
In the 15ml microwave container, merge (4-chloro-3-methoxyl group-phenyl)-(2-chloro-5-methyl-pyrimidine-4-yl)-amine (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), two (diphenylphosphino)-9 of 4,5-, 9-dimethyl xanthene (0.038g, 0.065mmol, 0.2 equivalent) and three (dibenzalacetones), two palladiums (0.03g, 0.0325mmol, 0.1 equivalent).Then with 7ml diox diluting reaction agent and 160 ℃ of lower microwave irradiation 15 minutes of using.Then rotate the precipitation reaction container, 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)
Figure S2006800499668D00731
Process the stirred solution of above-mentioned intermediate 20 (0.075g, 0.14mmol, 1eq) 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)：δ2.17(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-(pyrrolidin-1-yl) oxyethyl group) phenyl amino)-4-aminopyrimidine -5-nitrile (intermediate 21)
Figure S2006800499668D00732
In the solution of 2,4-di-amino-pyrimidine-5-nitrile (135mg, 1.00mmol) in Isosorbide-5-Nitrae-diox (20mL), add 1-(2-(4-bromine phenoxy group) ethyl) tetramethyleneimine (270mg, 1.0mmol), Cs 2CO 3(1.3g, 4.0mmol), Pd 2(dba) 3Two (diphenylphosphino)-9 of (92mg, 0.1mmol) and 4,5-, 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 (1x100mL) wash filtrate.Separate organic solution and drying (Na 2SO 4).Desolventizing is passed through solid collected by filtration to obtaining 5mL and adding hexane (50mL).Obtain title intermediate 21 (32mg, 10%) by HPLC purification of crude product.
Embodiment 40.4-(2,4-, two chloro-5-p-methoxy-phenyls are amino)-2-(4-(2-(tetramethyleneimine-1- Base) oxyethyl group) phenyl-amino) pyrimidine-5-nitrile (compounds X XI)
Figure S2006800499668D00741
In the solution of above-mentioned intermediate 21 (32mg, 0.1mmol) in Isosorbide-5-Nitrae-diox (10mL), add 1-bromo-2,4-two chloro-5-anisoles (28mg, 0.11mmol), Cs 2CO 3(97mg, 0.3mmol), Pd 2(dba) 3Two (diphenylphosphino)-9 of (7mg, 0.0074mmol) and 4,5-, 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 (1x50mL) wash filtrate.Separate organic solution and drying (Na 2SO 4).In a vacuum desolventizing.By chromatography purification crude product (SiO 2/ CH 2Cl 2, CH then 2Cl 2: MeOH: NH 3H 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-(pyrrolidin-1-yl) oxyethyl group) phenyl amino)-4-aminopyrimidine -5-nitrile (intermediate 22)
Figure S2006800499668D00751
In the solution of 2,4-di-amino-pyrimidine-5-nitrile (145mg, 1.07mmol) in Isosorbide-5-Nitrae-diox (20mL), add 1-(2-(3-bromine phenoxy group) ethyl) tetramethyleneimine (290mg, 1.07mmol), Cs 2CO 3(1.43g, 4.4mmol), Pd 2(dba) 3Two (diphenylphosphino)-9 of (92mg, 0.1mmol) and 4,5-, 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 (1x100mL) wash filtrate.Separate organic solution and drying (Na 2SO 4).Desolventizing is passed through solid collected by filtration to obtaining 5mL and adding hexane (50mL).By HPLC purification of crude product and obtain title intermediate 22 (55mg, 16%).
Embodiment 42.4-(2,4-, two chloro-5-p-methoxy-phenyls are amino)-2-(3-(2-(tetramethyleneimine-1- Base) oxyethyl group) phenyl-amino) pyrimidine-5-nitrile (compounds X XII)
Figure S2006800499668D00752
In the solution of above-mentioned intermediate 22 (50mg, 0.15mmol) in Isosorbide-5-Nitrae-diox (10mL), add 1-bromo-2,4-two chloro-5-anisoles (44mg, 0.17mmol), Cs 2CO 3(200mg, 0.62mmol), Pd 2(dba) 3Two (diphenylphosphino)-9 of (14mg, 0.015mmol) and 4,5-, 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 (1x50mL) wash filtrate.Separate organic solution and drying (Na 2SO 4).In a vacuum desolventizing.By HPLC purification of 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)
Figure S2006800499668D00761
In the 2-chloro-5-methylpyrimidine-solution of 4-amine (44.8mg, 0.31mmol) in Isosorbide-5-Nitrae-diox (20mL), add 1-bromo-2,4-two chloro-5-anisoles (96mg, 0.37mmol), Cs 2CO 3(408mg, 1.25mmol), Pd 2(dba) 3Two (diphenylphosphino)-9 of (37mg, 0.04mmol) and 4,5-, 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 (1x100mL) wash filtrate.Separate organic solution and drying (Na 2SO 4).In a vacuum desolventizing.Crude product is not purified for next step reaction.
Embodiment 44.N 2 -(3-(2-(pyrrolidin-1-yl) oxyethyl group) phenyl)-N 4 -(2,4-dichloro -5-p-methoxy-phenyl)-and 5-methylpyrimidine-2,4-diamines (compounds X XIII)
Figure S2006800499668D00762
In the solution of above-mentioned intermediate 23 in Isosorbide-5-Nitrae-diox (10mL), add 3-(2-(pyrrolidin-1-yl) oxyethyl group) aniline (77.3mg, 0.38mmol), Cs 2CO 3(488mg, 1.25mmol), Pd 2(dba) 3Two (diphenylphosphino)-9 of (28mg, 0.03mmol) and 4,5-, 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 (1x50mL) wash filtrate.Separate organic solution and drying (Na 2SO 4).In a vacuum desolventizing.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)
In the 2-chloro-5-methylpyrimidine-solution of 4-amine (320mg, 2.23mmol) in Isosorbide-5-Nitrae-dioxs (40mL), add 1-bromo-3-anisole (458.5mg, 2.45mmol), Cs 2CO 3(2.9g, 8.9mmol), Pd 2(dba) 3Two (diphenylphosphino)-9 of (201mg, 0.22mmol) and 4,5-, 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 (1x100mL) wash filtrate.Separate organic solution and drying (Na 2SO 4).Desolventizing is passed through solid collected by filtration to obtaining 5mL and adding hexane (100mL).With crude product title intermediate 24 (500mg, 90%) without being further purified for next step reaction.
Embodiment 46.N 2 -(4-(2-(pyrrolidin-1-yl) oxyethyl group) phenyl)-N 4 -(3-anisole Base)-and 5-methyl-pyrimidine-2,4-diamines (compounds X XIV)
Figure S2006800499668D00772
In the solution of above-mentioned intermediate 24 (240mg, 0.96mmol) in Isosorbide-5-Nitrae-diox (20mL), add 4-(2-(pyrrolidin-1-yl) oxyethyl group) aniline (200mg, 0.96mmol), Cs 2CO 3(1.3mg, 4.0mmol), Pd 2(dba) 3Two (diphenylphosphino)-9 of (82mg, 0.09mmol) and 4,5-, 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).In a vacuum desolventizing.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-(pyrrolidin-1-yl) oxyethyl group) phenyl amino)-5-methyl Pyrimidine-4-yl is amino)-phenol (compounds X XV)
Figure S2006800499668D00781
To above-mentioned compounds X XIV (50mg, 0.1mmol) at anhydrous CH 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(3x10mL) 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)
Figure S2006800499668D00791
In the 2-chloro-5-methylpyrimidine-solution of 4-amine (232mg, 1.61mmol) in Isosorbide-5-Nitrae-dioxs (40mL), add 1-bromo-3-oil of mirbane (359mg, 1.78mmol), Cs 2CO 3(2.1g, 6.4mmol), Pd 2(dba) 3Two (diphenylphosphino)-9 of (146mg, 0.16mmol) and 4,5-, 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 (1x100mL) wash filtrate.Separate organic solution and drying (Na 2SO 4).Desolventizing is passed through solid collected by filtration to obtaining 5mL and adding hexane (100mL).With crude product title intermediate 25 without being further purified for next step reaction.
Embodiment 49.N 2 -(4-(2-(pyrrolidin-1-yl) oxyethyl group) phenyl)-5-methyl-N 4 -(3- Nitrophenyl) pyrimidine-2,4-diamines (compounds X XVI)
Figure S2006800499668D00792
In the solution of above-mentioned intermediate 25 in Isosorbide-5-Nitrae-diox (40mL), add 4-(2-(pyrrolidin-1-yl) oxyethyl group) aniline (367mg, 1.78mmol), Cs 2CO 3(2.1g, 6.4mmol), Pd 2(dba) 3Two (diphenylphosphino)-9 of (146mg, 0.16mmol) and 4,5-, 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 (1x50mL) wash filtrate.Separate organic solution and drying (Na 2SO 4).In a vacuum desolventizing.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)
Figure S2006800499668D00801
In the 2-chloro-5-methylpyrimidine-solution of 4-amine (144mg, 1.0mmol) in Isosorbide-5-Nitrae-dioxs (20mL), add 4-bromo-2-benzyl chloride nitrile (217mg, 1.0mmol), Cs 2CO 3(1.3g, 4.0mmol), Pd 2(dba) 3Two (diphenylphosphino)-9 of (91mg, 0.1mmol) and 4,5-, 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 (1x100mL) wash filtrate.Separate organic solution and drying (Na 2SO 4).Desolventizing is passed through solid collected by filtration to obtaining 5mL and adding hexane (100mL).With crude product title intermediate 26 without being further purified for next step reaction.
Embodiment 51.4-(2-(4-(2-(pyrrolidin-1-yl) oxyethyl group) phenyl amino)-5-methyl Pyrimidine-4-yl is amino)-2-benzyl chloride nitrile (compounds X XVII)
Figure S2006800499668D00802
In the solution of above-mentioned intermediate 26 (140mg, 0.5mmol) in Isosorbide-5-Nitrae-diox (20mL), add 4-(2-(pyrrolidin-1-yl) oxyethyl group) aniline (113mg, 0.55mmol), Cs 2CO 3(660mg, 2.0mmol), Pd 2(dba) 3Two (diphenylphosphino)-9 of (46mg, 0.05mmol) and 4,5-, 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 (1x50mL) wash filtrate.Separate organic solution and drying (Na 2SO 4).In a vacuum desolventizing.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-(pyrrolidin-1-yl) oxyethyl group) phenyl)-5-methyl-N 4 -to first Phenyl pyrimidine-2,4-diamines (compounds X XVIII)
In the solution of above-mentioned intermediate 11 (50mg, 0.16mmol) in Isosorbide-5-Nitrae-diox (20mL), add 1-bromo-4-methylbenzene (28mg, 0.16mmol), Cs 2CO 3(210mg, 0.64mmol), Pd 2(dba) 3Two (diphenylphosphino)-9 of (10mg, 0.01mmol) and 4,5-, 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.In a vacuum desolventizing.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-(pyrrolidin-1-yl) oxyethyl group) phenyl)-N 4 -(4-chloro-3-first The base phenyl)-and 5-methylpyrimidine-2,4-diamines (compounds X XIX)
Figure S2006800499668D00821
In the solution of above-mentioned intermediate 11 (80mg, 0.25mmol) in Isosorbide-5-Nitrae-diox (20mL), add 4-bromo-1-chloro-2-methyl benzene (63mg, 0.30mmol), Cs 2CO 3(326mg, 1.0mmol), Pd 2(dba) 3Two (diphenylphosphino)-9 of (18mg, 0.02mmol) and 4,5-, 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.In a vacuum desolventizing.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-(pyrrolidin-1-yl) oxyethyl group) phenyl)-4-benzyl-5-methyl Pyrimidine-2-amine (compounds X XX)
Figure S2006800499668D00822
In the solution of 4-benzyl-2-chloropyrimide (286mg, 1.4mmol) in Isosorbide-5-Nitrae-dioxs (20mL), add 4-(2-(pyrrolidin-1-yl) oxyethyl group) aniline (288mg, 1.4mmol), Cs 2CO 3(1.82g, 5.6mmol), Pd 2(dba) 3Two (diphenylphosphino)-9 of (92mg, 0.1mmol) and 4,5-, 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.In a vacuum desolventizing.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-(pyrrolidin-1-yl) ethoxy Base) phenyl)-5-methylpyrimidine-2-amine (compounds X XXI)
Figure S2006800499668D00831
In the solution of above-mentioned intermediate 11 (460mg, 1.46mmol) in Isosorbide-5-Nitrae-diox (20mL), add 4-bromo-1H-indoles (288mg, 1.46mmol), Cs 2CO 3(1.95g, 6.0mmol), Pd 2(dba) 3Two (diphenylphosphino)-9 of (128mg, 0.14mmol) and 4,5-, 9-dimethyl xanthene (Xant Phos, 243mg, 0.42mmol).With this mixture under reflux state and the Ar environment in heated overnight.Filter out solid.In a vacuum desolventizing.By HPLC purification of 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) pyrimidine-4-amine (intermediate 27)
Figure S2006800499668D00832
In the 2-chloro-5-methylpyrimidine-solution of 4-amine (144mg, 1.0mmol) in Isosorbide-5-Nitrae-dioxs (40mL), add 1-bromonaphthalene (227mg, 1.1mmol), Cs 2CO 3(1.3g, 4.0mmol), Pd 2(dba) 3Two (diphenylphosphino)-9 of (91mg, 0.1mmol) and 4,5-, 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 (1x100mL) wash filtrate.Separate organic solution and drying (Na 2SO 4).Desolventizing is passed through solid collected by filtration to obtaining 5mL and adding hexane (100mL).With crude product title intermediate 27 without being further purified for next step reaction.
Embodiment 57.N-(4-(2-(pyrrolidin-1-yl) oxyethyl group) phenyl)-5-methyl-4-(naphthalene -1-yl) pyrimidine-2-amine (compounds X XXII)
Figure S2006800499668D00841
In the solution of above-mentioned intermediate 27 (235mg, 0.87mmol) in Isosorbide-5-Nitrae-diox (20mL), add 4-(2-(pyrrolidin-1-yl) oxyethyl group) aniline (183mg, 0.87mmol), Cs 2CO 3(1.3g, 4.0mmol), Pd 2(dba) 3Two (diphenylphosphino)-9 of (46mg, 0.05mmol) and 4,5-, 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 (1x50mL) wash filtrate.Separate organic solution and drying (Na 2SO 4).In a vacuum desolventizing.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)
Figure S2006800499668D00851
In the 2-chloro-5-methylpyrimidine-solution of 4-amine (144mg, 1.0mmol) in Isosorbide-5-Nitrae-dioxs (40mL), add 1-chlorine isoquinoline 99.9 (164mg, 1.0mmol), Cs 2CO 3(1.3g, 4.0mmol), Pd 2(dba) 3Two (diphenylphosphino)-9 of (91mg, 0.1mmol) and 4,5-, 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 (1x100mL) wash filtrate.Separate organic solution and drying (Na 2SO 4).Desolventizing is passed through solid collected by filtration to obtaining 5mL and adding hexane (100mL).With crude product title intermediate 28 without being further purified for next step reaction.
Embodiment 59.N-(4-(2-(pyrrolidin-1-yl) oxyethyl group) phenyl)-4-(isoquinoline 99.9-1- Base)-5-methylpyrimidine-2-amine (compounds X XXIII)
Figure S2006800499668D00852
In the solution of above-mentioned intermediate 28 (90mg, 0.33mmol) in Isosorbide-5-Nitrae-diox (20mL), add 4-(2-(pyrrolidin-1-yl) oxyethyl group) aniline (76mg, 0.37mmol), Cs 2CO 3(391mg, 1.2mmol), Pd 2(dba) 3Two (diphenylphosphino)-9 of (28mg, 0.03mmol) and 4,5-, 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 (1x50mL) wash filtrate.Separate organic solution and drying (Na 2SO 4).In a vacuum desolventizing.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-(pyrrolidin-1-yl) oxyethyl group) phenyl)-N 4 -(3-(fluoroform Base) phenyl)-and 5-methylpyrimidine-2,4-diamines (compounds X XXIV)
Figure S2006800499668D00861
With 2-chloro-5-methyl-pyrimidine-4-yl amine (143mg, 1.0mmol), 1-bromo-3-(trifluoromethyl) benzene (225mg, 1.0mmol), Pd 2(dba) 3(9.0mg, 0.01mmol), the mixture of Xantphos (12mg, 0.02mmol) and cesium carbonate (650mg, 2.0mmol) are suspended in the diox (15mL) and heated 15 hours under reflux state and in the ar gas environment.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 the mixture of 4-(2-(pyrrolidin-1-yl) oxyethyl group) aniline (22mg, 0.12mmol) be dissolved in acetic acid (5mL) and in 150 ℃ of lower and microwaves, heated 10 minutes.This mixture is cooled to room temperature and under reduced pressure removes acetic acid.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)
Figure S2006800499668D00871
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 the suspension of acid chloride (26mg, 0.1mmol) be sealed in the microwave reaction pipe and and 160 ℃ of lower irradiations 15 minutes.This mixture is cooled to room temperature, uses DCM to cross filter solid in order to wash and under reduced pressure concentrate 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-(pyrrolidin-1-yl) oxyethyl group) phenyl)-N 4 -(4-(fluoroform Base) phenyl)-and 5-methylpyrimidine-2,4-diamines (compounds X XXV)
Figure S2006800499668D00872
The mixture of above-mentioned intermediate 29 (128mg, 0.5mmol) and 6 (212mg, 1.0mmol) is suspended in the acetic acid (5mL) and at 75 ℃ to descend to heat 18 hours.This mixture is cooled to room temperature and under reduced pressure removes acetic acid.Use saturated NaHCO 3The aqueous solution (50mL) alkalization resistates and extract with DCM (2x50mL).Concentrate in a vacuum organic layer and pass through anti-phase C18 flash chromatography (water-CH 3CN, 0.1%TFA) the purification of crude product.Use saturated NaHCO 3Extract with moisture fraction and with EtOAc in the aqueous solution.Concentrate in a vacuum organic layer 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)
Figure S2006800499668D00881
With 2-chloro-5-methyl-pyrimidine-4-yl amine (1.4g, 9.7mmo l), 4-bromo-benzo [1,3] dioxole (2.0g, 10mmol), Pd 2(dba) 3(0.80g, 0.87mmol), the mixture of Xantphos (1.0g, 1.7mmol) and cesium carbonate (6.3g, 19mmol) are suspended in the diox (40mL) and heated 5 hours under reflux state and in the ar gas environment.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)：δ2.13(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- Pyrrolidin-1-yl-oxyethyl group)-phenyl]-pyrimidine-2,4-diamines (compounds X XXVI)
Intermediate 30 (0.25g, 0.95mmol) and 4-(2-pyrrolidin-1-yl-oxyethyl group)-mixture of phenyl amine (0.40g, 1.9mmol) in acetic acid (15mL) were heated 20 hours under 100 ℃.This mixture is cooled to room temperature and under reduced pressure removes acetic acid.Be neutralized to pH～7 with resistates water-soluble (20mL) and with 10% NaOH solution.With EtOAc (2x30mL) 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 purification of crude product (DCM-20% MeOH/DCM) is white solid in a vacuum.
1H NMR(500MHz，DMSO-d 6)：δ1.65-1.75(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)
Figure S2006800499668D00891
With intermediate 30 (0.10g, 0.38mmol) and 4-(4-methyl-piperazine-1-the yl)-mixture of phenyl amine (0.12g, 0.51mmol) in acetic acid (3mL) is sealed in the microwave reaction pipe and lower to microwave irradiations 15 minutes at 150 ℃.After being cooled to room temperature, remove lid and concentrated this mixture.Neutralize this mixture to solid precipitation with resistates water-soluble (20mL) and with 10%NaOH solution.Cross filter solid and then obtain title compound (22mg, 14%) by flash chromatography on silica gel method purifying (DCM-15% MeOH/DCM), be the incarnadine solid.
1H NMR(500MHz，DMSO-d 6)：δ2.06(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)
Figure S2006800499668D00901
With 2-chloro-5-methyl-pyrimidine-4-yl 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), the mixture of Xantphos (0.22g, 0.38mmol) and cesium carbonate (2.3g, 7.1mmol) are suspended in the diox (20mL) and heated 5 hours under reflux state and in the ar gas environment.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)：δ2.18(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 (3/1, the suspension in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 20 minutes at 160 ℃) Zai diox/DMF.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 (2x30mL) 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)：δ2.11(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)
Figure S2006800499668D00911
2-chloro-5-methyl-pyrimidine-4-yl amine (1.0g, 6.9mmol) and 4-(4-methyl-piperazine-1-the yl)-mixture of phenyl amine (1.5mL, 7.8mmol) in acetic acid (15mL) were heated 2.5 hours under 100 ℃.This mixture is cooled to room temperature and under reduced pressure removes acetic acid.With resistates water-soluble (20mL) and with 10% NaOH solution this mixture that neutralizes, until solid precipitation.After filtering and washing with water, obtain the title mixture, be gray solid (1.3g, 63%).
1H NMR(500 MHz，DMSO-d 6)：δ1.88(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 (3/1, the suspension in 8mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 20 minutes at 160 ℃) Zai diox/DMF.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 (2x30mL) 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)：δ2.09(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)
Figure S2006800499668D00922
Mixture in acetic acid (3mL) is sealed in the microwave reaction pipe and uses microwave irradiation 20 minutes under 160 ℃ with intermediate 31 (0.10g, 0.35mmol) and 4-morpholine-4-base-phenyl amine (80mg, 0.45mmol).After being cooled to room temperature, remove lid and concentrated this mixture.With resistates water-soluble (20mL) and with 10%NaOH solution this mixture that neutralizes, until solid precipitation.Cross filter solid and then obtain title compound (55mg, 37%) by flash chromatography on silica gel method purifying (DCM-10% MeOH/DCM), be the light brown solid.
1H NMR(500MHz，DMSO-d 6)：δ2.10(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)
Figure S2006800499668D00931
Mixture in acetic acid (3mL) is sealed in the microwave reaction pipe and uses microwave irradiation 20 minutes under 160 ℃ with intermediate 31 (90mg, 0.32mmol) and 4-pyrazol-1-yl-phenyl amine (70mg, 0.44mmol).After being cooled to room temperature, remove lid and concentrated this mixture.With resistates water-soluble (20mL) and with 10%NaOH solution this mixture that neutralizes, until solid precipitation.Cross filter solid and then pass through the HPLC purifying.Merge the fraction of calibration and then concentrated and obtain title compound (tfa salt of 40mg, 24%), be white solid.
1H NMR(500MHz，DMSO-d 6)：δ2.17(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-piperidin-1-yl-benzene Base)-and pyrimidine-2,4-diamines (XLII)
Intermediate 31 (0.11g, 0.39mmo l) and the mixture of 4-piperidin-1-yl-phenyl amine (90mg, 0.51mmol) in acetic acid (3mL) be sealed in the microwave reaction pipe and lower to microwave irradiations 20 minutes at 160 ℃.After being cooled to room temperature, remove lid and concentrated this mixture.With resistates water-soluble (20mL) and with 10%NaOH solution this mixture that neutralizes, until solid precipitation.Cross filter solid and then obtain title compound (10mg, 6%) by flash chromatography on silica gel method purifying (hexane-70% EtOAc/ hexane), be the light brown solid.
1H NMR(500MHz，DMSO-d 6)：δ1.48-1.53(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)
Figure S2006800499668D00942
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 (3/1, the suspension in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 15 minutes at 160 ℃) Zai diox/DMF.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)：δ2.11(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)-mixture of piperazine-1-t-butyl formate (0.22g, 0.79mmol) in acetic acid (4mL) is sealed in the microwave reaction pipe and lower to microwave irradiations 15 minutes at 150 ℃.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 (2x30mL) 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)：δ2.10(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-yl is amino }-benzsulfamide (compounds X LV)
Figure S2006800499668D00961
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 (3/1, the suspension in 8mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 20 minutes at 160 ℃) Zai diox/DMF.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 (2x30mL) 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)：δ1.12(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-yl is amino)-benzsulfamide (intermediate 33)
Figure S2006800499668D00962
With 2-chloro-5-methyl-pyrimidine-4-yl amine (0.4g, 2.8mmol), the 3-bromo-N-tertiary butyl-benzsulfamide (1.0g, 3.4mmol), Pd 2(dba) 3(0.17g, 0.19mmol), the mixture of Xantphos (0.2g, 3.5mmol) and cesium carbonate (2.0g, 6.1mmol) are suspended in the diox (25mL) and heated 3 hours under reflux state and in the ar gas environment.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, until solid precipitation.After filtration, obtain title compound (1.2g, 98%), be the light brown solid.It is not purified 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-yl is amino]-benzsulfamide (compounds X LVI)
Figure S2006800499668D00971
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), the mixture of Xantphos (0.12g, 0.21mmol) and cesium carbonate (1.0g, 3.1mmol) are suspended in the diox (25mL) and heated 3 hours under reflux state and in the ar gas environment.
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 (2x50mL) 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 until solid precipitation.After filtration, obtain title compound, be pale solid (0.23g, 31%).
1H NMR(500MHz，DMSO-d 6)：δ1.12(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-yl is amino }-benzsulfamide (compounds X LVII)
Figure S2006800499668D00981
Solution in chloroform (30mL) at room temperature stirred 1 hour with above-claimed cpd XLVI (30mg, 0.06mmol) and 3-chlorine peroxybenzoic acid (77%, 14mg, 0.06mmol).By the rotary evaporation desolventizing and by silica gel purification gained mixture, use 20%CH 3OH/CHCl 3For elutriant obtains title compound, be pale solid (15mg, 48%).
1H NMR(500MHz，DMSO-d 6)：δ1.12(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)
The mixture of mixture in acetic acid (3mL) of intermediate 33 (0.10g, 0.28mmol) and 4-pyrazol-1-yl-phenyl amine (50mg, 0.31mmol) be sealed in the microwave reaction pipe and lower to microwave irradiations 15 minutes at 130 ℃.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 then pass through the HPLC purifying.The fraction and the saturated NaHCO of impouring that merge calibration 3Solution (30mL).With the water layer of EtOAc (2x30mL) 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 until solid precipitation.After filtration, obtain title compound, be white solid (15mg, 11%).
1H NMR(500MHz，DMSO-d 6)：δ1.12(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-yl is amino]-benzsulfamide (compounds X LIX)
Figure S2006800499668D00991
With intermediate 33 (0.10g, 0.28mmol) and 4-(5-amino-pyridine-2-the yl)-mixture of piperazine-1-t-butyl formate (90mg, 0.32mmol) in acetic acid (3mL) is sealed in the microwave reaction pipe and lower to microwave irradiations 15 minutes at 130 ℃.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, concentrated and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration 3Solution (30mL).With the water layer of EtOAc (2x30mL) 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 until solid precipitation.After filtration, obtain title compound, be white solid (10mg, 7%).
1H NMR(500MHz，DMSO-d 6)：δ1.12(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-yl is amino]-benzsulfamide (compound L)
Figure S2006800499668D01001
Mixture in acetic acid (3mL) is sealed in the microwave reaction pipe and uses microwave irradiation 15 minutes under 130 ℃ with intermediate 33 (0.10g, 0.28mmol) and 4-pyrazol-1-yl methyl-phenyl amine (50mg, 0.29mmol).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 (2x30mL) 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 until solid precipitation.Obtain title compound after filtering, be white solid (12mg, 9%).
1H NMR(500MHz，DMSO-d 6)：δ1.12(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)
Figure S2006800499668D01002
With 2-chloro-5-methyl-pyrimidine-4-yl amine (0.25g; 1.74mmol) and 3-(piperidines-1-the alkylsulfonyl)-mixture of phenyl amine (0.50g, 2.1mmol) in acetic acid (4mL) is sealed in the microwave reaction pipe and lower to microwave irradiations 15 minutes at 130 ℃.After being cooled to room temperature, remove lid and concentrated this mixture.With resistates water-soluble (20mL) and with 10%NaOH solution pH is adjusted to～9.With EtOAc (2x30mL) 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 purified 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-yl is amino }-benzsulfamide (compound L I)
Figure S2006800499668D01011
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 (3/1, the suspension in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 15 minutes at 160 ℃) Zai diox/DMF.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 (2x30mL) 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 until solid precipitation.Obtain title compound after filtering, be white solid (20mg, 12%).
1H NMR(500MHz，DMSO-d 6)：δ1.12(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-yl is amino }-benzsulfamide (compound L II)
Figure S2006800499668D01021
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 (3/1, the suspension in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 15 minutes at 170 ℃) Zai diox/DMF.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 (2x30mL) 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 until solid precipitation.Obtain title compound after filtering, be white solid (53mg, 36%).
1H NMR(500MHz，DMSO-d 6)：δ1.12(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-yl is amino]-benzsulfamide (compound L III)
Figure S2006800499668D01022
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 (3/1, the mixture in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 15 minutes at 170 ℃) Zai diox/DMF.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, concentrated and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration 3Solution (30mL).With the water layer of EtOAc (2x30mL) 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 until solid precipitation.Obtain title compound after filtering, be white solid (42mg, 26%).
1H NMR(500MHz，DMSO-d 6)：δ1.12(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-phenyl ammonia Base]-5-methyl-pyrimidine-4-yl is amino }-the N-tertiary butyl-benzsulfamide (compound L IV)
Figure S2006800499668D01031
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 (3/1, the mixture in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 15 minutes at 160 ℃) Zai diox/DMF.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 (2x30mL) 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 until solid precipitation.Obtain title compound after filtering, be white solid (64mg, 38%).
1H NMR(500MHz，DMSO-d 6)：δ1.12(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)
Figure S2006800499668D01041
With 2-chloro-5-methyl-pyrimidine-4-yl amine (0.25g; 1.74mmol) and 3-(4-methyl-piperazine-1-the alkylsulfonyl)-mixture of phenyl amine (0.50g, 2.0mmol) in acetic acid (4mL) is sealed in the microwave reaction pipe and lower to microwave irradiations 15 minutes at 130 ℃.After being cooled to room temperature, remove lid and concentrated this mixture.With resistates water-soluble (20mL) and with 10%NaOH solution pH is adjusted to～9.With EtOAc (2x30mL) 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) without being further purified for next step.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-yl is amino }-benzsulfamide (compound L V)
Figure S2006800499668D01051
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 (3/1, the suspension in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 15 minutes at 160 ℃) Zai diox/DMF.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 (2x30mL) 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 until solid precipitation.Obtain title compound after filtering, be white solid (10mg, 6%).
1H NMR(500MHz，DMSO-d 6)：δ1.12(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-yl is amino]-benzsulfamide (compound L VI)
Figure S2006800499668D01052
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 (3/1, mixture 4mL) is sealed in the microwave reaction pipe and uses microwave irradiation 15 minutes under 170 ℃) Zai diox/DMF.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, concentrated and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration 3Solution (30mL).With the water layer of EtOAc (2x30mL) 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).Obtain title compound after filtering, be white solid (32mg, 22%).
1H NMR(500MHz，DMSO-d 6)：δ1.12(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-pyrrolidin-1-yl-oxyethyl group)- Phenyl amino]-pyrimidine-4-yl is amino }-benzsulfamide (compound L VII)
Figure S2006800499668D01061
With intermediate 33 (0.10g, 0.28mmol) and 4-(2-pyrrolidin-1-yl-oxyethyl group)-mixture of phenyl amine (0.10g, 0.49mmol) in acetic acid (3mL) is sealed in the microwave reaction pipe and lower to microwave irradiations 20 minutes at 150 ℃.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 (2x30mL) 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 until solid precipitation.Obtain title compound after filtering, be white solid (40mg, 27%).
1H NMR(500MHz，DMSO-d 6)：δ1.12(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)
Figure S2006800499668D01071
With intermediate 32 (0.10g, 0.33mmol), 3-bromo-benzsulfamide (0.10g, 0.42mmol), Pd 2(dba) 3(20mg, 0.022mmol), (suspension in 0.25g, the 0.77mmol) Zai diox (3mL) is sealed in the microwave reaction pipe and uses microwave irradiation 15 minutes under 160 ℃ for Xantphos (25mg, 0.043mmol) and cesium carbonate.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 (2x30mL) 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)：δ2.10(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-yl 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 (3/1, the suspension in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 20 minutes at 160 ℃) Zai diox/DMF.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 (2x30mL) 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.Obtain title compound after filtering, be light brown solid (65mg, 42%).
1H NMR(500MHz，DMSO-d 6)：δ2.11(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-yl is amino }-benzsulfamide (compound L X)
Figure S2006800499668D01082
With intermediate 32 (0.13g, 0.43mmo l), 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 (3/1, the suspension in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 20 minutes at 160 ℃) Zai diox/DMF.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 (2x30mL) 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).Obtain title compound after filtering, be pale solid (60mg, 29%).
1H NMR(500MHz，DMSO-d 6)：δ2.17(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-yl is amino }-benzsulfamide (compound L XI)
Figure S2006800499668D01091
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 (3/1, the suspension in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 20 minutes at 160 ℃) Zai diox/DMF.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 (2x30mL) 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).Obtain title compound after filtering, be pale solid (47mg, 29%).
1H NMR(500MHz，DMSO-d 6)：δ0.98(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)
Figure S2006800499668D01101
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 (3/1, the suspension in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 15 minutes at 160 ℃) Zai diox/DMF.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 (2x30mL) 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).Obtain title compound after filtering, be light brown solid (41mg, 27%).
1H NMR(500MHz，DMSO-d 6)：δ2.09(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-yl 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 (3/1, the suspension in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 15 minutes at 160 ℃) Zai diox/DMF.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 (2x30mL) 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).Obtain title compound after filtering, be pale solid (45mg, 25%).
1H NMR(500MHz，DMSO-d 6)：δ1.07-1.17(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(br d，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-yl is amino }-benzsulfamide (compound L XIV)
Figure S2006800499668D01112
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 (3/1, the suspension in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 15 minutes at 160 ℃) Zai diox/DMF.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 (2x30mL) 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).Obtain title compound after filtering, be pale solid (45mg, 27%).
1H NMR(500MHz，DMSO-d 6)：δ1.06(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)
Figure S2006800499668D01121
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 (3/1, the suspension in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 15 minutes at 160 ℃) Zai diox/DMF.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 (2x30mL) 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).Obtain title compound after filtering, be incarnadine solid (90mg, 52%).
1H NMR(500MHz，DMSO-d 6)：δ2.12(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)
Figure S2006800499668D01131
With intermediate 32 (0.10g, 0.33mmol), 3-bromo-ethyl benzoate (0.07mL, 0.44mmol), Pd 2(dba) 3(20mg, 0.022mmol), (suspension in 0.25g, the 0.77mmol) Zai diox (3mL) is sealed in the microwave reaction pipe and uses microwave irradiation 15 minutes under 160 ℃ for Xantphos (25mg, 0.043mmol) and cesium carbonate.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)
Figure S2006800499668D01132
With intermediate 36 (0.10g, 0.22mmol) at dense NH 4Mixture among the OH is sealed in the reaction tubes and under 50 ℃ and heated 3 days.Extract with this mixture impouring water (15mL) and with EtOAc (2x30mL).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 (2x30mL) 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).Obtain title compound after filtering, be white solid (10mg, 11%).
1H NMR(500MHz，DMSO-d 6)：δ2.10(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(br s，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-yl is amino }-ethyl benzoate (compound L XVII)
Figure S2006800499668D01141
With intermediate 32 (0.10g, 0.33mmol), 3-bromo-2-methyl-ethyl benzoate (0.10mL, 0.41mmol), Pd 2(dba) 3(20mg, 0.022mmol), (suspension in 0.25g, the 0.77mmol) Zai diox (3mL) is sealed in the microwave reaction pipe and uses microwave irradiation 20 minutes under 160 ℃ for Xantphos (25mg, 0.043mmol) and cesium carbonate.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 the 1%TEA of DCM-in DCM) is light brown oily thing.
1H NMR(500MHz，DMSO-d 6)：δ1.32(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-yl is amino }-benzamide (compound L XVIII)
Figure S2006800499668D01151
In ar gas environment to adding NaOMe (0.10g, 0.46mmol) at 100 ℃ of lower above-claimed cpd LXVII (0.10g, 0.22mmol) and methane amide (0.05mL, 1.3mmol) in the mixture in DMF (5mL).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 (2x15mL).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 (2x30mL) 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).Obtain title compound after filtering, be white solid (20mg, 21%).
1H NMR(500MHz，DMSO-d 6)：δ2.09(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)
Figure S2006800499668D01161
With 2-chloro-5-methyl-pyrimidine-4-yl amine (0.30g, 2.1mmo l), 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 (6/1, the mixture in 7mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 15 minutes at 160 ℃) Zai diox/DMF.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)
Figure S2006800499668D01162
With intermediate 37 (0.10g, 0.31mmol) and 4-(4-amino-phenoxy group)-mixture of piperidines-1-t-butyl formate (0.12g, 0.41mmol) in acetic acid (3mL) is sealed in the microwave reaction pipe and lower to microwave irradiations 15 minutes at 150 ℃.After being cooled to room temperature, remove lid and concentrated 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 (2x30mL) 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)：δ1.69-1.77(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-pyrrolidin-1-yl-oxyethyl group)-phenyl]-pyrimidine -2,4-diamines (intermediate 38)
Figure S2006800499668D01171
With 2-chloro-5-methyl-pyrimidine-4-yl amine (0.50g, 3.5mmol) and 4-(2-pyrrolidin-1-yl-oxyethyl group)-mixture of phenyl amine (1.1g, 5.3mmol) in acetic acid (8mL) is sealed in the microwave reaction pipe and lower to microwave irradiations 15 minutes at 150 ℃.After being cooled to room temperature, remove lid and concentrated this mixture.Be neutralized to pH～10 with resistates water-soluble (30mL) and with 10%NaOH solution.With the organic layer that EtOAc (2x30mL) 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 is not purified for next step.MS(ES+)：m/z 314(M+H) +。
Embodiment 106.3-{5-methyl-2-[4-(2-pyrrolidin-1-yl-oxyethyl group)-phenylamino Base]-pyrimidine-4-yl is amino }-benzsulfamide (compound L XX)
Figure S2006800499668D01172
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 (3/1, the mixture in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 25 minutes at 170 ℃) Zai diox/DMF.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 (2x30mL) 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).Obtain title compound after filtering, be white solid (11mg, 7%).
1H NMR(500MHz，DMSO-d 6)：δ1.65-1.72(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)
Figure S2006800499668D01181
Mixture in acetic acid (15mL) was 70 ℃ of lower heating 17 hours with 2-chloro-5-methyl-pyrimidine-4-yl amine (0.40g, 2.8mmol) and 4-morpholine-4-ylmethyl-phenyl amine (0.60g, 3.1mmol).After being cooled to room temperature, concentrated this mixture.Be neutralized to pH～10 with resistates water-soluble (30mL) and with 10% NaOH solution.With the organic layer that EtOAc (2x30mL) 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%).With it without being further purified for next step.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)
Figure S2006800499668D01191
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), the mixture of Xantphos (0.12g, 0.21mmol) and cesium carbonate (0.90g, 2.8mmol) are suspended in the diox (20mL) and heated 4 hours under reflux state and in the ar gas environment.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.
In the precursor (50mg, 0.088mmol) of the above-mentioned TIPS protection in THF (5mL), add TBAF (0.5mL, 1M in THF).This mixture at room temperature stirred 1 hour and impouring water (20mL) then.With EtOAc (2x20mL) 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 (2x30mL) 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 then adds hexane is until solid precipitation.Obtain title compound after filtering, be light brown solid (6mg, overall yield 1%).
1H NMR(500MHz，DMSO-d 6)：δ2.17(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)
Figure S2006800499668D01201
2-chloro-5-methyl-pyrimidine-4-yl amine (0.35g, 2.4mmol) and 4-(4-amino-benzyl)-mixture of piperazine-1-t-butyl formate (0.80g, 2.8mmol) in acetic acid (20mL) were heated 1 day under 70 ℃.After being cooled to room temperature, concentrated this mixture.Be neutralized to pH～10 with resistates water-soluble (30mL) and with 10%NaOH solution.With the organic layer that EtOAc (2x30mL) 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)
Figure S2006800499668D01202
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), the mixture of Xantphos (0.19g, 0.32mmol) and cesium carbonate (1.3g, 4.0mmol) are suspended in the diox (20mL) and heated 4.5 hours under reflux state and in the ar gas environment.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) to the above-mentioned TIPS protection in DCM (8mL) adds TFA (2mL).This mixture was at room temperature stirred 2 hours and then concentrate.Fraction and the saturated NaHCO of impouring by HPLC purifying resistates and merging calibration 3Solution (30mL).With EtOAc (2x30mL) 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)：δ2.17(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) phenyl) pyrimidine-2,4-diamines (compound L XXIII)
Figure S2006800499668D01211
With intermediate 32 (674mg, 2.25mmol), 4-bromine-7-methyl-1H-indoles (522mg, 2.48mmol), Pd 2(dba) 3(182mg, 0.2mmol), the mixture of Xantphos (360mg, 0.6mmol) and cesium carbonate (2.6g, 8mmol) are suspended in the diox (50mL) and heated 20 hours under reflux state and in the ar gas environment.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)：δ2.21(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(br s，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) phenyl) pyrimidine-2,4-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), the mixture of Xantphos (180mg, 0.3mmol) and cesium carbonate (1.3g, 4mmol) are suspended in the diox (50mL) and heated 20 hours under reflux state and in the ar gas environment.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)：δ2.21(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(br s，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-(pyrrolidin-1-yl) oxyethyl group) phenyl)-5-methyl-N4-(7- Methyl-1H-indole-4-yl) pyrimidine-2,4-diamines (compound L XXV)
Figure S2006800499668D01222
With intermediate 38 (410mg, 1.3mmol), 4-bromine-7-methyl-1H-indoles (275mg, 1.3mmol), Pd 2(dba) 3(92mg, 0.1mmol), the mixture of Xantphos (180mg, 0.3mmol) and cesium carbonate (1.3g, 4mmol) are suspended in the diox (50mL) and heated 20 hours under reflux state and in the ar gas environment.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)：δ1.88-1.90(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-(pyrrolidin-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), the mixture of Xantphos (140mg, 0.24mmol) and cesium carbonate (1.3g, 4mmol) are suspended in the diox (50mL) and heated 20 hours under reflux state and in the ar gas environment.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)：δ1.88-1.90(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-(pyrrolidin-1-yl) oxyethyl group) phenyl)-5-methyl-N 4 -(7- Fluoro-1H-indoles-4-yl) pyrimidine-2,4-diamines (compound L XXVII)
Figure S2006800499668D01241
With intermediate 38 (413mg, 1.3mmol), 4-bromo-7-fluoro-1H-indoles (310mg, 1.45mmol), Pd 2(dba) 3(92mg, 0.1mmol), the mixture of Xantphos (180mg, 0.3mmol) and cesium carbonate (1.3g, 4mmol) are suspended in the diox (50mL) and heated 20 hours under reflux state and in the ar gas environment.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)：δ1.88-1.90(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(br d，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)
Figure S2006800499668D01251
With intermediate 32 (298mg, 1.0mmol), the 1-tertiary butyl-3-bromobenzene (256mg, 1.2mmol), Pd 2(dba) 3(92mg, 0.1mmol), the mixture of Xantphos (180mg, 0.3mmol) and cesium carbonate (1.3g, 4mmol) are suspended in the diox (50mL) and heated 20 hours under reflux state and in the ar gas environment.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)：δ1.25(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)
Figure S2006800499668D01252
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), the mixture of Xantphos (695mg, 1.2mmol) and cesium carbonate (6.2g, 19mmol) are suspended in the diox (150mL) and heated 20 hours under reflux state and in the ar gas environment.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 the hexane washing, 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)
Figure S2006800499668D01261
The mixture of intermediate 41 (740mg, 2.68mmol) and 4-(4-amino-benzene oxygen) piperidines-1-t-butyl formate (500mg, 1.71mmol) is suspended in the acetic acid (10mL) and at 100 ℃ to descend to heat 4 hours.This mixture is cooled to room temperature and under reduced pressure removes acetic acid.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 purification of crude product is yellow solid in a vacuum.
1H NMR(500MHz，DMSO-d 6)：δ1.22(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)
Figure S2006800499668D01262
With 2-chloro-5-methylpyrimidine-4-amine (540mg, 3.7mmol), the mixture of 4-(4-amino-benzene oxygen) piperidines-1-t-butyl formate (1.1g, 3.7mmol) is suspended in the acetic acid (20mL) and under 70 ℃ and heated 1 hour.This mixture is cooled to room temperature and under reduced pressure removes acetic acid.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)
Figure S2006800499668D01271
With intermediate 42 (480mg, 1.2mmol), 4-bromo-1H-indazole (236mg, 1.2mmol), Pd 2(dba) 3(92mg, 0.1mmol), the mixture of Xantphos (180mg, 0.3mmol) and cesium carbonate (1.3g, 4mmol) are suspended in the diox (50mL) and heated 20 hours under reflux state and in the ar gas environment.Filter this mixture and concentrated filtrate in a vacuum.Obtain title compound (4mg HCl salt, 1.2%) by HPLC purifying resistates, be yellow solid.
1H NMR(500MHz，DMSO-d 6)：δ1.75-1.80(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), the mixture of Xantphos (0.038g, 0.065mmol) and cesium carbonate (0.32g, 0.98mmol) are suspended in the diox (5mL) and use microwave irradiation 15 minutes under 160 ℃.This reaction mixture is cooled to room temperature and centrifugal settling.Decantation is somebody's turn to do reaction and concentrates 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)
Figure S2006800499668D01282
Process the solution of intermediate 43 (0.075g, 0.14mmol) in DCM (8mL) with TFA (2mL).Stir after 2 hours desolventizing and the gained resistates ground with ether and obtain white hygroscopic powder (0.05g, 82%).
1H NMR(500MHz，DMSO-d 6)：δ2.17(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)
Figure S2006800499668D01291
Intermediate 31 (0.66g, 2.3mmol) and 4-(4-amino-phenoxy group)-mixture of piperidines-1-t-butyl formate (0.88mg, 3.0mmol) in acetic acid (15mL) are used microwave irradiation 15 minutes under 160 ℃.This mixture is cooled to room temperature and under reduced pressure removes acetic acid.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)：δ1.37-1.44(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(br s，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)
Figure S2006800499668D01292
Intermediate 31 (0.13g, 0.46mmol) and 4-(3-amino-phenyl)-mixture of piperazine-1-t-butyl formate (0.19mg, 0.68mmol) in acetic acid (8mL) were heated 15 hours under 80 ℃.This mixture is cooled to room temperature and under reduced pressure removes acetic acid.With resistates water-soluble (20mL) and with 10% NaOH solution this mixture that neutralizes.Then use ethyl acetate extraction, 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)
Process the solution of intermediate 44 (0.11g, 0.21mmol) in DCM (8mL) with TFA (1mL).After stirring 3 hours, desolventizing and the gained resistates is dissolved in ethyl acetate and washs with 10% sodium hydrogen carbonate solution.Then use the dried over sodium sulfate organic phase, 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 desolventizing and obtain the HCL salt of title compound is white solid (0.06g, 67%).
1H NMR(500MHz，DMSO-d 6)：δ2.18(s，3H)，3.12(br s，4H)，3.22(br s，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)-piperidin-1-yl]-ethanol (intermediate 45)
Figure S2006800499668D01302
Process with DMF (20mL) dilution 4-(3-bromo-phenyl)-piperidines (1.2g, 4.8mmol) and ethylene bromohyrin (0.72mL, 10mmol) and with salt of wormwood (2.7g, 20mmol).They were stirred 18 hours at ambient temperature, then be poured over waterborne and use ethyl acetate extraction.Then use salt water washing organic phase, 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-yl is amino }-phenyl)-piperidin-1-yl]-ethanol (compound L XXXIV)
Figure S2006800499668D01311
With intermediate 32 (0.11g, 0.38mmol), intermediate 45 (0.21g, 0.75mmol), Pd 2(dba) 3(0.034g, 0.037mmol), the mixture of Xantphos (0.043g, 0.075mmol) and cesium carbonate (0.37g, 1.1mmol) are suspended in the diox (10mL) and use microwave irradiation 15 minutes under 160 ℃.This reaction mixture is cooled to room temperature and centrifugal settling.Decantation is somebody's turn to do reaction and concentrates 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)：δ1.60-1.67(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 is amino)-piperidines-1-t-butyl formate (intermediate 46)
Figure S2006800499668D01312
Merge 3-bromo-benzene sulfonyl chloride (2.2g, 8.7mmol) and 4-amino-piperadine-1-t-butyl formate (2g, 10mmol) and dilute with DCM (50mL) and TEA (3.6mL, 26mmol).After 16 hours, will react the impouring separating funnel and wash with water.Then use salt water washing organic phase, 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-yl is amino }-benzenesulfonyl is amino)-piperidines-1-t-butyl formate (intermediate 47)
Figure S2006800499668D01321
With intermediate 32 (0.15g, 0.518mmol), intermediate 46 (0.28g, 0.67mmol), Pd 2(dba) 3(0.024g, 0.026mmol), the mixture of Xantphos (0.03g, 0.052mmol) and cesium carbonate (0.34g, 1mmol) are suspended in the diox (10mL) and use microwave irradiation 15 minutes under 160 ℃.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)
Figure S2006800499668D01322
With DCM (10mL) diluted intermediate 47 (0.2g, 0.32mmol and process 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)：δ1.30-1.35(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) phenyl) pyrimidine-2,4-diamine hydrochloride (compound L XXXVI)
Figure S2006800499668D01331
With argon gas to intermediate 32 (0.12g, 0.40mmol), 1-bromo-3-(trifluoromethyl)-2-methylbenzene (0.14g, 0.59mmol), Pd 2(dba) 3(37mg, 0.04mmol), (degassed 2 minutes of the suspension in 0.39g, the 1.20mmol) Zai diox (20mL) then in vitro refluxes in sealing and spends the night for Xantphos (47mg, 0.08mmol) and cesium carbonate.After being cooled to room temperature, by the rotary evaporation desolventizing and by silica gel purification gained mixture, use 10%CH 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 pH 1.By the rotary evaporation desolventizing and make solid recrystallization (25mg, 13%) from acetone.
1H NMR(500MHz，DMSO-d 6)：δ2.20(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)
Figure S2006800499668D01332
With argon gas to intermediate 32 (0.13g, 0.44mmol), 1-bromo-3-(methyl sulphonyl) benzene (0.24g, 1.0mmol), Pd 2(dba) 3(40mg, 0.04mmol), (degassed 2 minutes of the suspension in 0.43g, the 1.32mmol) Zai diox (50mL) then refluxes and spends the night for Xantphos (50mg, 0.08mmol) and cesium carbonate.After being cooled to room temperature, by the rotary evaporation desolventizing and by silica gel purification gained mixture, use 30%CH 3OH/CHCl 3Obtain title compound as elutriant, be faint yellow solid (35mg, 15%).
1H NMR(500MHz，DMSO-d 6)：δ2.11(s，3H)，2.23(s，3H)，2.46(br s，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)
Figure S2006800499668D01341
To 3-bromobenzene mercaptan (0.50g, 2.6mmol add propyl iodide (1.1g in the solution in the) Zai diox (50mL), 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) be back to together all raw materials and all react.To remove excessive mCPBA, use Na with 2M NaOH washing organic layer 2SO 4Drying and filtration.Concentrated filtrate and with silicagel column purification of 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 to intermediate 32 (0.25g, 0.84mmol), intermediate 48 (0.26g, 1mmol), Pd 2(dba) 3(8mg, 0.01mmol), (degassed 2 minutes of the suspension in 0.82g, the 2.52mmol) Zai diox (50mL) then refluxes and spends the night for Xantphos (16mg, 0.03mmol) and cesium carbonate.After being cooled to room temperature, by the rotary evaporation desolventizing and by silica gel purification gained mixture, use 10%CH 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 pH 1.By the rotary evaporation desolventizing 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)
Figure S2006800499668D01352
At room temperature zinc chloride (0.1g, 0.73mmol) is joined 3-nitrobenzaldehyde (5.9g, 39.02mmol), morpholine (3.4g, 39.02mmol), in the solution of sodium cyanoborohydride (2.7g, 43mmol) in methyl alcohol (50mL).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)
Figure S2006800499668D01361
The mixture of 2-chloro-5-methylpyrimidine-4-amine (0.17g, 1.17mmol) and intermediate 49 (0.25g, 1.30mmol) is suspended in the acetic acid (10mL) and at 100 ℃ to descend to heat 2 hours.This mixture is cooled to room temperature and under reduced pressure removes acetic acid.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 purification of 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-yl is amino]-benzsulfamide hydrochloride (compound L XXXIX)
Figure S2006800499668D01371
With argon gas to intermediate 50 (1.0g, 3.42mmol), the 3-bromo-N-tertiary butyl-benzsulfamide (1.28g, 4.28mmol), Pd 2(dba) 3(30mg, 0.03mmol), (degassed 2 minutes of the suspension in 3.34g, the 10.24mmol) Zai diox (50mL) then refluxes and spends the night for Xantphos (40mg, 0.07mmol) and cesium carbonate.After being cooled to room temperature, by the rotary evaporation desolventizing and by silica gel purification gained mixture, use 10%CH 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.By the rotary evaporation desolventizing 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-(3,5-3,5-dimethylphenyl) pyrimidine-4-amine (intermediate 51)
Figure S2006800499668D01372
With 1-bromo-3,5-dimethyl benzene (104 μ l, 0.77mmol), 2-chloro-5-methyl-pyrimidine-4-yl amine (104mg, 0.72mmol), Pd (OAC) 2(15mg, 0.07mmol), (mixture in 159mg, the 1.42mmol) Zai diox (8mL) is 160 ℃ of lower microwave irradiation 20 minutes of using for Xantphos (83mg, 0.14mmol) and potassium tert.-butoxide.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 -(3,5-3,5-dimethylphenyl)-N 2 -(4-(piperidin-4-yl oxygen base) Phenyl) pyrimidine-2,4-diamines (compounds X C)
Figure S2006800499668D01381
Intermediate 51 (89mg, 0.36mmol) and 4-(4-amino-phenoxy group)-piperidines-mixture of 1-t-butyl formate (139mg, 0.47mmol) in acetic acid were at room temperature stirred 16 hours, then be heated to 95 ℃ lower 2 hours.Concentrate in a vacuum this reaction mixture 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 concentrated.Free alkali is dissolved in MeOH (5mL) and dense HCl (5) and the concentrated HCl salt that obtains title compound in the vacuum in the presence of DCM and hexane are arranged after 2 minutes, is pale solid (63mg, 40%).
1H NMR(500MHz，DMSO-d 6)：δ1.72-1.83(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-(3,5-Dimethoxyphenyl)-5-methylpyrimidine-4-amine (centre Body 52)
Figure S2006800499668D01391
With 1-bromo-3,5-dimethoxy benzene (436mg, 2.01mmol), 2-chloro-5-methyl-pyrimidine-4-yl amine (287mg, 2.00mmol), Pd (OAc) 2(44mg, 0.20mmol), (mixture among 448mg, 3.99mmol) Zai diox (15mL) and the DMF (5mL) is 160 ℃ of lower microwave 20 minutes of using for Xantphos (237mg, 0.41mmol) and potassium tert.-butoxide.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)：δ2.17(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 -(3,5-Dimethoxyphenyl)-5-methyl-N 2 -(4-(piperidin-4-yl oxygen Base) phenyl) pyrimidine-2,4-diamines (compounds X CI)
Figure S2006800499668D01392
With intermediate 52 (100mg, 0.36mmol) and 4-(4-amino-phenoxy group)-piperidines-mixture heating up to 95 of 1-t-butyl formate (106mg, 0.36mmol) in acetic acid ℃ lower 2 hours.Concentrated this reaction mixture and obtain the tfa salt of title compound by the preparation HPLC purifying is tawny solid (75mg, 39%) in a vacuum.
1H NMR(500MHz，DMSO-d 6)：δ1.74-1.83(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) phenyl) pyrimidine-2,4-diamines (compounds X CII)
Figure S2006800499668D01401
With 1-(3-bromophenyl) piperidines (91mg, 0.38mmol), intermediate 32 (99mg, 0.33mmol), Pd 2(dba) 3(15mg, 0.02mmol), (mixture in 219mg, the 0.67mmol) Zai diox (4mL) is 160 ℃ of lower microwave 15 minutes of using for Xantphos (24mg, 0.04mmol) and cesium carbonate.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)：δ1.47-1.53(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) phenyl) pyrimidine-2,4-diamines (compounds X CIII)
Figure S2006800499668D01411
With 1-(3-bromophenyl)-1H-pyrroles (86mg, 0.39mmol), intermediate 32 (99mg, 0.33mmol), Pd 2(dba) 3(16mg, 0.02mmol), (mixture in 215mg, the 0.66mmol) Zai diox (4mL) is 160 ℃ of lower microwave 15 minutes of using for Xantphos (26mg, 0.05mmol) and cesium carbonate.This reaction mixture is cooled to room temperature, concentrated 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)：δ2.11(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-yl 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), (mixture in 321mg, the 0.98mmol) Zai diox (5mL) is 160 ℃ of lower microwave 20 minutes of using for Xantphos (36mg, 0.07mmol) and cesium carbonate.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)
Add in the solution of Acetyl Chloride 98Min. (670 μ l, 9.42mmol) in methyl alcohol (22mL) intermediate 53 (290mg, 0.47mmol) and with this reaction mixture be heated to 60 ℃ lower 4 hours.Concentrated this reaction mixture and obtain the tfa salt of title compound by the preparation HPLC purifying is brown solid (6mg, 2%) in a vacuum.
1H NMR(500MHz，DMSO-d 6)：δ1.70-1.78(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)
Figure S2006800499668D01422
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 (3/1, the mixture in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 30 minutes at 170 ℃) Zai diox/DMF.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, concentrated and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration 3Solution (30mL).With the water layer of EtOAc (2x30mL) 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).Obtain title compound after filtering, be white solid (20mg, 13%).
1H NMR(500MHz，DMSO-d 6)：δ2.09(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)
Figure S2006800499668D01431
In ar gas environment, in 4-(2-methoxycarbonyl-4-nitro-phenyl)-solution of piperazine-1-t-butyl formate (1.0g, 2.7mmol) in MeOH (30mL), add 10wt%Pd/C (0.1 equivalent wt).This mixture vacuumized and and then be filled with hydrogen (3 circulations) and at room temperature stirred 2 hours.Inhomogeneous reaction mixture is filtered by the celite pad, with MeOH washing and concentrated in a vacuum.Thick amino-compound is not purified for next step.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)
Figure S2006800499668D01441
With intermediate 31 (0.10g, 0.35mmol), intermediate 54 (0.14g, 0.42mmol), Pd 2(dba) 3(30mg, 0.033mmol), the mixture of Xantphos (35mg, 0.06mmol) and cesium carbonate (0.23g, 0.71mmol) are suspended in the diox (15mL) and heated 2.5 hours under reflux state and in the ar gas environment.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, concentrated and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration 3Solution (30mL).With the water layer of EtOAc (2x30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na 2SO 4Drying and filtration.Concentrated filtrate and then be dissolved in minimum EtOAc.Add hexane until solid precipitation.Obtain title compound after filtering, be white solid (40mg, 24%).
1H NMR(500MHz，DMSO-d 6)：δ2.11(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-pyrrolidin-1-yl-oxyethyl group)-methyl benzoate (centre Body 55)
Figure S2006800499668D01451
With 5-amino-2-hydroxy-benzoic acid methyl esters (1.0g, 6.0mmol), 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (1.2g, 7.1mmol) and the suspension of cesium carbonate (5.0g, 15mmol) in DMF (40mL) were 60 ℃ of lower heating 17 hours.This mixture is cooled to room temperature, impouring water (60mL) and extract with EtOAc (2x50mL).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-pyrrolidin-1-yl-oxyethyl group)-methyl benzoate (compound XCVII)
Figure S2006800499668D01452
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 (3/1, the mixture in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 20 minutes at 160 ℃) Zai diox/DMF.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 (2x30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na 2SO 4Drying and filtration.Concentrated filtrate and then be dissolved in minimum EtOAc.Add hexane to solid precipitation.Obtain title compound after filtering, be pale solid (30mg, 11%).
1H NMR(500MHz，DMSO-d 6)：δ1.65-1.72(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-yl is amino }-benzsulfamide (compounds X CVIII)
Figure S2006800499668D01461
With intermediate 33 (0.15g, 0.42mmol) and 4-(4-amino-phenoxy group)-mixture of piperidines-1-t-butyl formate (0.15g, 0.51mmol) in acetic acid (3mL) is sealed in the microwave reaction pipe and lower to microwave irradiations 20 minutes at 150 ℃.After being cooled to room temperature, remove lid and concentrated this mixture.With resistates water-soluble (20mL) and with 10% NaOH solution pH is adjusted to solid precipitation.Cross filter solid and then pass through the HPLC purifying.The fraction that merges calibration, the saturated NaHCO of impouring 3Solution (30mL) and extract with EtOAc (2x30mL).With the extract that the salt water washing merges, use anhydrous Na 2SO 4Drying and filtration.Concentrated filtrate and then be dissolved in minimum EtOAc.Add hexane to solid precipitation.Obtain title compound after filtering, be white solid (20mg, 9%).
1H NMR(500MHz，DMSO-d 6)：δ1.12(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)
Figure S2006800499668D01462
In ar gas environment, in 2-(5-nitro-pyridine-2-base oxygen the base)-solution of ethanol (1.0g, 5.4mmol) in MeOH (30mL), add 10wt%Pd/C (0.1 equivalent wt).This mixture vacuumized and and then fill hydrogen (3 circulations) and at room temperature stirred 1 hour.Inhomogeneous reaction mixture is filtered by the celite pad, with MeOH washing and concentrated in a vacuum.Thick amino-compound is not purified for next step.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)
Figure S2006800499668D01471
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 (3/1, the mixture in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 20 minutes at 160 ℃) Zai diox/DMF.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 (2x30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na 2SO 4Drying and filtration.Concentrated filtrate and then be dissolved in minimum EtOAc.Add hexane to solid precipitation.Obtain title compound after filtering, be pale solid (50mg, 35%).
1H NMR(500MHz，DMSO-d 6)：δ2.06(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)
Figure S2006800499668D01481
With 2-methoxyl group-4-nitro-phenolic acid potassium (2.0g, 9.7mmol), (7.0,22mmol) suspension in DMF (35mL) was 80 ℃ of lower heating 16 hours for 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (2.0g, 12mmol) and cesium carbonate.This mixture is cooled to room temperature, impouring water (60mL) and extract with EtOAc (2x50mL).With the extract that the salt water washing merges, use anhydrous Na 2SO 4Drying and filtration.Concentrated filtrate and not purified for next step.
MS(ES+)：m/z 267(M+H) +。
Embodiment 155.3-methoxyl group-4-(2-pyrrolidin-1-yl-oxyethyl group)-phenyl amine (intermediate 58)
Figure S2006800499668D01482
In ar gas environment, in the solution of intermediate 57 (1.7g, 6.4mmol) in MeOH (30mL), add 10wt%Pd/C (0.1 equivalent wt).This mixture vacuumized and and then fill hydrogen (3 circulations) and at room temperature stirred 1 hour.Inhomogeneous reaction mixture is filtered by the celite pad, with MeOH washing and concentrated in a vacuum.Thick amino-compound is not purified for next step.MS(ES+)：m/z 237(M+H) +。
Embodiment 156.N 4 -benzo [1,3] dioxole-4-base-N 2 -[3-methoxyl group -4-(2-pyrrolidin-1-yl-oxyethyl group)-phenyl]-5-methyl-pyrimidine-2,4-diamines (compound C)
Figure S2006800499668D01483
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 (3/1, the mixture in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 20 minutes at 160 ℃) Zai diox/DMF.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 (2x30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na 2SO 4Drying and filtration.Concentrated filtrate and then be dissolved in minimum EtOAc.Add hexane to solid precipitation.Obtain title compound after filtering, be white solid (50mg, 28%).
1H NMR(500MHz，DMSO-d 6)：δ1.65-1.72(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)
Figure S2006800499668D01491
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 (3/1, the mixture in 8mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 30 minutes at 160 ℃) Zai diox/DMF.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 (2x40mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na 2SO 4Drying and filtration.Concentrated filtrate and then be dissolved in minimum EtOAc.Add hexane to solid precipitation.Obtain title compound after filtering, be pale solid (0.15g, 28%).
1H NMR(500MHz，DMSO-d 6)：δ1.12(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-yl is amino]-benzsulfamide (Compound C II)
Figure S2006800499668D01501
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 (3/1, the mixture in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 20 minutes at 160 ℃) Zai diox/DMF.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 (2x30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na 2SO 4Drying and filtration.Concentrated filtrate and then be dissolved in minimum EtOAc.Add hexane to solid precipitation.Obtain title compound after filtering, be white solid (40mg, 29%).
1H NMR(500MHz，DMSO-d 6)：δ1.12(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)
Figure S2006800499668D01511
Give in 2-(4-nitro-phenoxy group)-solution of ethanol (2.1g, 12mmol) in MeOH (30mL) applying argon gas and then add 10wt%Pd/C (0.1 equivalent wt).Vacuumize under indoor vacuum, for this mixture and from the hydrogen capsule, fill again hydrogen.Repeat again this circulation and this mixture was at room temperature stirred 2 hours.Inhomogeneous reaction mixture is filtered by the celite pad, with MeOH washing and concentrated and obtain title compound (1.8g, 99%) in a vacuum, 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-yl is amino }-benzsulfamide (Compound C III)
Figure S2006800499668D01512
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 (3/1, the mixture in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 20 minutes at 160 ℃) Zai diox/DMF.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 (2x30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na 2SO 4Drying and filtration.Concentrated filtrate and then be dissolved in minimum EtOAc.Add hexane to solid precipitation.Obtain title compound after filtering, be white solid (15mg, 11%).
1H NMR(500MHz，DMSO-d 6)：δ1.12(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)
Figure S2006800499668D01521
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 (3/1, the mixture in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 20 minutes at 160 ℃) Zai diox/DMF.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, concentrated and by HPLC purifying resistates.The fraction and the saturated NaHCO of impouring that merge calibration 3Solution (30mL).With the water layer of EtOAc (2x30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na 2SO 4Drying and filtration.Concentrated filtrate and then be dissolved in minimum EtOAc.Add hexane to solid precipitation.Obtain title compound after filtering, be white solid (13mg, 9%).
1H NMR(500MHz，DMSO-d 6)：δ2.11(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-yl is amino }-benzsulfamide (Compound C V)
Figure S2006800499668D01531
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 (3/1, the mixture in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 20 minutes at 160 ℃) Zai diox/DMF.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 (2x30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na 2SO 4Drying and filtration.Concentrated filtrate and then be dissolved in minimum EtOAc.Add hexane to solid precipitation.Obtain title compound after filtering, be white solid (30mg, 22%).
1H NMR(500MHz，DMSO-d 6)：δ1.11(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-yl 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 (3/1, the mixture in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 20 minutes at 160 ℃) Zai diox/DMF.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 (2x30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na 2SO 4Drying and filtration.Concentrated filtrate and then be dissolved in minimum EtOAc.Add hexane to solid precipitation.Obtain title compound after filtering, be white solid (30mg, 21%).
1H NMR(500MHz，DMSO-d 6)：δ1.12(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-yl is amino]-benzsulfamide (Compound C VII)
Figure S2006800499668D01542
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 (3/1, the mixture in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 20 minutes at 160 ℃) Zai diox/DMF.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 (2x30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na 2SO 4Drying and filtration.Concentrated filtrate and then be dissolved in minimum EtOAc.Add hexane to solid precipitation.Obtain title compound after filtering, be white solid (45mg, 32%).
1H NMR(500MHz，DMSO-d 6)：δ1.11(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 (3/1, the mixture in 4mL) is sealed in the microwave reaction pipe and is lower to microwave irradiations 20 minutes at 160 ℃) Zai diox/DMF.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 (2x30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na 2SO 4Drying and filtration.Concentrated filtrate and then be dissolved in minimum EtOAc.Add hexane to solid precipitation.Obtain title compound after filtering, be gray solid (45mg, 32%).
1H NMR(500MHz，DMSO-d 6)：δ1.12(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-yl is amino]-benzsulfamide (Compound C IX)
Figure S2006800499668D01561
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), (mixture in 0.20g, the 0.61mmol) Zai diox (4mL) is sealed in the microwave reaction pipe and uses microwave irradiation 20 minutes under 160 ℃ for Xantphos (30mg, 0.052mmol) and cesium carbonate.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 (2x30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na 2SO 4Drying and filtration.Concentrated filtrate and then be dissolved in minimum EtOAc.Add hexane to solid precipitation.Obtain title compound after filtering, be white solid (37mg, 27%).
1H NMR(500MHz，DMSO-d 6)：δ1.17(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-yl is amino }-benzsulfamide (Compound C X)
Figure S2006800499668D01571
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), (mixture in 0.20g, the 0.61mmol) Zai diox (3mL) is sealed in the microwave reaction pipe and uses microwave irradiation 20 minutes under 160 ℃ for Xantphos (30mg, 0.052mmol) and cesium carbonate.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 (2x30mL extracts 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 then be dissolved in minimum EtOAc.Add hexane to solid precipitation.Obtain title compound after filtering, be pale solid (20mg, 15%).
1H NMR(500MHz，DMSO-d 6)：δ1.12(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-yl is amino]-benzsulfamide (Compound C XI)
Figure S2006800499668D01572
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), (mixture of 0.20g, 0.61mmol) Zai diox (3mL) is sealed in the microwave reaction pipe and uses microwave irradiation 20 minutes under 160 ℃ for Xantphos (30mg, 0.052mmol) and cesium carbonate.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 (2x30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na 2SO 4Drying and filtration.Concentrated filtrate and then be dissolved in minimum EtOAc.Add hexane to solid precipitation.Obtain title compound after filtering, be white solid (40mg, 29%).
1H NMR(500MHz，DMSO-d 6)：δ1.12(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-TETRAZOLE-5-yl)-phenylamino Base]-pyrimidine-4-yl is amino }-benzsulfamide (Compound C XII)
Figure S2006800499668D01581
With intermediate 33 (0.10g, 0.28mmol), 3-(1H-TETRAZOLE-5-yl)-phenyl amine (55mg, 0.34mmol), Pd 2(dba) 3(25mg, 0.027mmol), (mixture in 0.20g, the 0.61mmol) Zai diox (3mL) is sealed in the microwave reaction pipe and uses microwave irradiation 20 minutes under 160 ℃ for Xantphos (30mg, 0.052mmol) and cesium carbonate.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 (2x30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na 2SO 4Drying and filtration.Concentrated filtrate and then be dissolved in minimum EtOAc.Add hexane to solid precipitation.Obtain title compound after filtering, be white solid (15mg, 11%).
1H NMR(500MHz，DMSO-d 6)：δ1.13(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-TETRAZOLE-5-yl)-phenyl amine (intermediate 60)
In ar gas environment, in 5-(4-nitro-phenyl)-solution of 1H-TETRAZOLE (1.0g, 5.2mmol) in MeOH (30mL), add 10wt%Pd/C (0.1 equivalent wt).This mixture is vacuumized, fill again hydrogen (3 circulations) and at room temperature stirred 1.5 hours.Inhomogeneous reaction mixture is filtered by the celite pad, with MeOH washing and concentrated in a vacuum.Thick amino-compound is not purified for next step.MS(ES+)：m/z 162(M+H) +。
The embodiment 171.N-tertiary butyl-3-{5-methyl-2-[4-(1H-TETRAZOLE-5-yl)-phenylamino Base]-pyrimidine-4-yl 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 uses microwave irradiation 20 minutes under 160 ℃.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 (2x30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na 2SO 4Drying and filtration.Concentrated filtrate and then be dissolved in minimum EtOAc.Add hexane to solid precipitation.Obtain title compound after filtering, be white solid (15mg, 11%).
1H NMR(500MHz，DMSO-d 6)：δ1.13(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-yl 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), (mixture in 0.20g, the 0.61mmol) Zai diox (3mL) is sealed in the microwave reaction pipe and uses microwave irradiation 20 minutes under 160 ℃ for Xantphos (30mg, 0.052mmol) and cesium carbonate.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 (2x30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na 2SO 4Drying and filtration.Concentrated filtrate and then be dissolved in minimum EtOAc.Add hexane to solid precipitation.Obtain title compound after filtering, be pale solid (55mg, 37%).
1H NMR(500MHz，DMSO-d 6)：δ1.12(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-yl is amino }-benzsulfamide (Compound C XV)
Figure S2006800499668D01611
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), (mixture in 0.26g, the 0.80mmol) Zai diox (4mL) is sealed in the microwave reaction pipe and uses microwave irradiation 20 minutes under 160 ℃ for Xantphos (35mg, 0.061mmol) and cesium carbonate.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 (2x30mL) extraction merging and the organic layer that merges with the salt water washing, use anhydrous Na 2SO 4Drying and filtration.Concentrated filtrate and then be dissolved in minimum EtOAc.Add hexane to solid precipitation.Obtain title compound after filtering, be white solid (40mg, 27%).
1H NMR(500MHz，DMSO-d 6)：δ1.12(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)
Figure S2006800499668D01612
With intermediate 32 (270mg, 0.9mmol), 4-bromo-1H-indoles (196mg, 0.9mmol), Pd 2(dba) 3(91mg, 0.09mmol), the mixture of Xantphos (157mg, 0.27mmol) and cesium carbonate (1.2g, 3.6mmol) are suspended in the diox (100mL) and heated 20 hours under reflux state and in the ar gas environment.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)：δ2.22(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-(2,3-3,5-dimethylphenyl) pyrimidine-4-amine (intermediate 61)
Figure S2006800499668D01621
With 2-chloro-5-methylpyrimidine-4-amine (143.6mg, 1mmol), 1-bromo-2,3-dimethyl benzene (222mg, 1.2mmol), Pd 2(dba) 3(92mg, 0.1mmol), the mixture of Xantphos (174mg, 0.3mmol) and cesium carbonate (1.3g, 4mmol) are suspended in the diox (150mL) and heated 20 hours under reflux state and in the ar gas environment.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 the hexane washing, be yellow solid.
Embodiment 176.5-methyl-N 4 -(2,3-3,5-dimethylphenyl)-N 2 -(4-(piperidin-4-yl oxygen base) Phenyl) pyrimidine-2,4-diamines (Compound C XVII)
Figure S2006800499668D01631
The mixture of intermediate 61 (1.0mmol) and 4-(4-amino-benzene oxygen) piperidines-1-t-butyl formate (292.4mg, 1.0mmol) is suspended in the acetic acid (10mL) and at 100 ℃ to descend to heat 4 hours.This mixture is cooled to room temperature and under reduced pressure removes acetic acid.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 purification of crude product is yellow solid in a vacuum.
1H NMR(500MHz，DMSO-d 6)：δ1.76-1.83(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) phenyl) pyrimidine-2,4-diamines (Compound C XVIII)
With intermediate 32 (240mg, 0.8mmol), 5-bromo-2-chloro-1,3-dimethyl benzene (212mg, 0.96mmol), Pd 2(dba) 3(92mg, 0.1mmol), the mixture of Xantphos (170mg, 0.3mmol) and cesium carbonate (1.3g, 4mmol) are suspended in the diox (100mL) and heated 20 hours under reflux state and in the ar gas environment.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)：δ2.15(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-(pyrrolidin-1-yl) oxyethyl group) phenyl)-N 4 -(the 3-tertiary butyl Phenyl)-and 5-methyl-pyrimidine-2,4-diamines (Compound C XIX)
Figure S2006800499668D01641
Intermediate 41 (365mg, 1.32mmol) and 4-(2-(pyrrolidin-1-yl) oxyethyl group) aniline (410mg, 1.98mmol) are suspended in the acetic acid (20mL) and at 100 ℃ to descend to heat 4 hours.This mixture is cooled to room temperature and under reduced pressure removes acetic acid.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 purification of crude product is white solid in a vacuum.
1H NMR(500MHz，DMSO-d 6)：δ1.89-1.91(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-(pyrrolidin-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)
Figure S2006800499668D01651
With intermediate 41 (210mg, 0.67mmol), intermediate 38 (185mg, 0.67mmol), Pd 2(dba) 3(55mg, 0.06mmol), the mixture of Xantphos (104mg, 0.18mmol) and cesium carbonate (782g, 2.4mmol) are suspended in the diox (50mL) and heated 20 hours under reflux state and in the ar gas environment.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)：δ1.29(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)
Figure S2006800499668D01652
With intermediate 32 (150mg, 0.5mmol), 1-(3-bromo-benzenesulfonyl)-piperidines (152mg, 0.5mmol), Pd 2(dba) 3(46mg, 0.05mmol), the mixture of Xantphos (87mg, 0.15mmol) and cesium carbonate (652mg, 2mmol) are suspended in the diox (20mL) and heated 20 hours under reflux state and in the ar gas environment.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)：δ1.30-1.34(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)
Figure S2006800499668D01661
With intermediate 32 (161mg, 0.54mmol), 1-(3-bromo-benzenesulfonyl)-2-methyl-piperidines (172mg, 0.54mmol), Pd 2(dba) 3(46mg, 0.05mmol), the mixture of Xantphos (87mg, 0.15mmol) and cesium carbonate (652mg, 2mmol) are suspended in the diox (20mL) and heated 20 hours under reflux state and in the ar gas environment.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)：δ0.98(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-yl is amino }-benzsulfamide (Compound C XXIII)
Figure S2006800499668D01671
With intermediate 32 (229mg, 0.78mmol), 3-bromo-N-cyclopentyl-benzsulfamide (280mg, 0.92mmol), Pd 2(dba) 3(92mg, 0.1mmol), the mixture of Xantphos (180mg, 0.3mmol) and cesium carbonate (1.3g, 4mmol) are suspended in the diox (100mL) and heated 20 hours under reflux state and in the ar gas environment.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)：δ1.27-1.36(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)
Figure S2006800499668D01681
With intermediate 32 (298mg, 1.0mmol), 1-(3-bromo-benzenesulfonyl)-tetramethyleneimine (360mg, 1.24mmol), Pd 2(dba) 3(92mg, 0.1mmol), the mixture of Xantphos (180mg, 0.3mmol) and cesium carbonate (1.3g, 4mmol) are suspended in the diox (100mL) and heated 20 hours under reflux state and in the ar gas environment.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)：δ1.61-1.65(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)
Figure S2006800499668D01682
With intermediate 32 (298mg, 1.0mmol), 1-(3-bromo-benzenesulfonyl)-2,5-dimethyl-tetramethyleneimine (318mg, 1.0mmol), Pd 2(dba) 3(92mg, 0.1mmol), the mixture of Xantphos (180mg, 0.3mmol) and cesium carbonate (1.3g, 4mmol) are suspended in the diox (100mL) and heated 20 hours under reflux state and in the ar gas environment.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)：δ1.26(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)
Figure S2006800499668D01691
With intermediate 33 (355mg, 1.0mmol), 4-(4-aminophenyl) piperazine-1-t-butyl formate (278mg, 1.0mmol), Pd 2(dba) 3(92mg, 0.1mmol), the mixture of Xantphos (180mg, 0.3mmol) and cesium carbonate (1.3g, 4mmol) are suspended in the diox (100mL) and heated 20 hours under reflux state and in the ar gas environment.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(10mLx2) aqueous layer extracted.Dry organic layer (the Na that merges 2SO 4).In a vacuum desolventizing.Obtain title compound (62mg, 12%) by HPLC purifying resistates, be white solid.
1H NMR(500MHz，DMSO-d 6)：δ1.10(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-yl is amino]-benzsulfamide (Compound C XXVII)
Figure S2006800499668D01701
Above-claimed cpd CXXVI (31mg, 0.06mmol) is dissolved in DMF (10mL), adds subsequently ethylene bromohyrin (16mg, 0.13mmol) and diisopropylethylamine (33mg, 0.25mmol).This mixture was at room temperature stirred 48 hours.In a vacuum desolventizing and resistates is 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)：δ1.09(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)
Figure S2006800499668D01711
With intermediate 33 (240mg, 0.67mmol), 4-(3-aminophenyl) piperazine-1-t-butyl formate (166mg, 0.6mmol), Pd 2(dba) 3(55mg, 0.06mmol), the mixture of Xantphos (104mg, 0.18mmol) and cesium carbonate (782mg, 2.4mmol) are suspended in the diox (100mL) and heated 20 hours under reflux state and in the ar gas environment.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(10mLx2) aqueous layer extracted.Dry organic layer (the Na that merges 2SO 4).In a vacuum desolventizing.Obtain title compound (18mg, 6%) by HPLC purifying resistates, be white solid.
1H NMR(500MHz，DMSO-d 6)：δ1.10(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-yl is amino]-benzsulfamide (Compound C XXIX)
Above-claimed cpd CXXVI (12mg, 0.024mmol) is dissolved in DMF (10mL), adds subsequently ethylene bromohyrin (6.1mg, 0.048mmol) and diisopropylethylamine (12mg, 0.092mmol).This mixture was at room temperature stirred 48 hours.In a vacuum desolventizing and resistates is 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)：δ1.09(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)
The mixture of intermediate 41 (580mg, 2.1mmol) and 4-(1H-pyrazol-1-yl) aniline (335mg, 2.1mmol) is suspended in the acetic acid (10mL) and at 100 ℃ to descend to heat 4 hours.This mixture is cooled to room temperature and under reduced pressure removes acetic acid.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 purification of crude product is yellow solid in a vacuum.
1H NMR(500MHz，DMSO-d 6)：δ1.24(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)
Figure S2006800499668D01731
With intermediate 40 (150mg, 0.37mmol), 4-bromo-7-chloro-1H-indoles (87mg, 0.37mmol), Pd 2(dba) 3(38mg, 0.04mmol), the mixture of Xantphos (76mg, 0.12mmol) and cesium carbonate (521mg, 1.6mmol) are suspended in the diox (50mL) and heated 20 hours under reflux state and in the ar gas environment.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(10mLx2) aqueous layer extracted.Dry organic layer (the Na that merges 2SO 4).In a vacuum desolventizing.Obtain title compound (26mg, 15%) by HPLC purifying resistates, be white solid.
1H NMR(500MHz，DMSO-d 6)：δ2.21(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-1 H-imidazole-1-group) aniline (113mg, 0.65mmol), Pd 2(dba) 3(55mg, 0.06mmol), the mixture of Xantphos (104mg, 0.18mmol) and cesium carbonate (782mg, 2.4mmol) are suspended in the diox (100mL) and heated 20 hours under reflux state and in the ar gas environment.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)：δ1.26(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-1 H-imidazole-1-group) aniline (intermediate 62)
In the solution of 1-fluoro-4-oil of mirbane (1.7g, 12mmol) in DMF (100mL), add 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 (100mLx2).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 in a vacuum desolventizing and obtain title compound (1.5g, 87%), be brown solid.
Embodiment 193.N 4 -(3-tert-butyl-phenyl)-5-methyl-N 2 -(4-(4-methyl isophthalic acid H-imidazoles -1-yl) phenyl) pyrimidine-2,4-diamines (Compound C XXXIII)
With intermediate 41 (318mg, 1.15mmol) and intermediate 62 (200mg, 1.15mmol), Pd 2(dba) 3(92mg, 0.1mmol), the mixture of Xantphos (180mg, 0.3mmol) and cesium carbonate (1.3g, 4mmol) are suspended in the diox (100mL) and heated 20 hours under reflux state and in the ar gas environment.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)：δ1.26(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)
Figure S2006800499668D01751
In the solution of 4-(4-nitrophenyl) piperidines (412mg, 2mmol) in CH2Cl2 (100mL), add 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 (50mLx2) 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.By remove by filter catalyzer and in a vacuum desolventizing obtain title compound (460mg, 83%), 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)
Figure S2006800499668D01761
The mixture of intermediate 41 (170mg, 0.6mmol) and intermediate 63 (170mg, 0.6mmol) is suspended in the acetic acid (10mL) and at 100 ℃ to descend to heat 4 hours.This mixture is cooled to room temperature and under reduced pressure removes acetic acid.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 purification of crude product is white solid in a vacuum.
1H NMR(500MHz，DMSO-d 6)：δ1.26(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), the mixture of Xantphos (180mg, 0.3mmol) and cesium carbonate (1.3g, 4mmol) are suspended in the diox (100mL) and heated 20 hours under reflux state and in the ar gas environment.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)：δ1.26(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)
Figure S2006800499668D01771
Vigorous stirring bromide (1.99g, 11.61mmol) and process with chlorsulfonic acid (1.55mL, 23.22mmol).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 (2x150mL).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)
Figure S2006800499668D01772
Process the stirring suspension of intermediate 64 (0.43g, 1.58mmol) in DCM (5mL) with the methylamine solution (2.4mL, 4.8mmol) 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-pyrrolidin-1-yl-oxyethyl group)-phenyl amino]-pyrimidine-4-yl is amino }-benzsulfamide (Compound C XXXVI)
Figure S2006800499668D01773
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, 1.3mmol) mixture be suspended in the diox (10mL), be sealed in the microwave reaction pipe and lower to microwave irradiations 15 minutes at 160 ℃.This reaction mixture is cooled to room temperature and centrifugal settling.Decantation is somebody's turn to do reaction and concentrates in a vacuum organic phase.Obtain title compound by HPLC purifying resistates, be white solid (0.052g, 24%).
1H NMR(500MHz，DMSO-d 6)：δ1.66-1.70(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 butyl-2-methyl-benzsulfamide (intermediate 66)
Figure S2006800499668D01781
Process the stirring suspension of intermediate 64 (1.22g, 4.5mmol) in DCM (25mL) with tert-butylamine (1.4mL, 13.6mmol).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-yl is amino)-2-methyl- Benzsulfamide (intermediate 67)
With intermediate 66 (0.90g, 2.96mmol), 2-chloro-5-methyl-pyrimidine-4-yl amine (0.33g, 2.28mmol), Pd 2(dba) 3(0.21g, 0.23mmol), Xantphos (0.264g, 0.46mmol) and cesium carbonate (2.2g, 6.8mmol) mixture be suspended in the diox (15mL), be sealed in the microwave reaction pipe and lower to microwave irradiations 15 minutes at 160 ℃.This reaction mixture is cooled to room temperature and centrifugal settling.Decantation is somebody's turn to do reaction and concentrates in a vacuum organic phase.Obtain title compound with silicagel column purifying resistates, be white solid (0.12g, 14%).
The embodiment 202N-tertiary butyl-5-[2-(4-imidazoles-1-base-phenyl amino)-5-methyl-pyrimidine -4-base is amino]-2-methyl-benzsulfamide (Compound C XXXVII)
Figure S2006800499668D01791
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, 0.92mmol) mixture be suspended in the diox (6mL), be sealed in the microwave reaction pipe and lower to microwave irradiations 15 minutes at 160 ℃.Decantation is somebody's turn to do reaction and concentrates in a vacuum organic phase.Obtain title compound by HPLC purifying resistates, be white solid (0.052g, 24%).
1H NMR(500MHz，DMSO-d 6)：δ1.11(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-yl is amino }-benzsulfamide (Compound C XXXVIII)
Figure S2006800499668D01792
With intermediate 33 (0.11g, 0.32mmol), (4-amino-phenyl)-pyrrolidin-1-yl-ketone (0.072g, 0.38mmol), Pd 2(dba) 3(0.029g, 0.032mmol), Xantphos (0.037g, 0.063mmol) and cesium carbonate (0.3g, 0.95mmol) mixture be suspended in the diox (6mL), be sealed in the microwave reaction pipe and lower to microwave irradiations 15 minutes at 160 ℃.Decantation is somebody's turn to do reaction and concentrates in a vacuum organic phase.Obtain title compound by HPLC purifying resistates, be white solid (0.040g, 25%).
1H NMR(500MHz，DMSO-d 6)：δ1.11(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-yl 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, 1.1mmol) mixture be suspended in the diox (6mL), be sealed in the microwave reaction pipe and lower to microwave irradiations 15 minutes at 160 ℃.Decantation is somebody's turn to do reaction and concentrates in a vacuum organic phase.Obtain title compound by HPLC purifying resistates, be white solid (0.065g, 33%).
1H NMR(500MHz，DMSO-d 6)：δ1.11(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-yl is amino }-benzsulfamide (Compound C XL)
Figure S2006800499668D01811
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, 1.1mmol) mixture be suspended in the diox (6mL), be sealed in the microwave reaction pipe and lower to microwave irradiations 15 minutes at 160 ℃.Decantation is somebody's turn to do reaction and concentrates in a vacuum organic phase.By silica gel column chromatography purifying resistates (EtOAc of 25%-100% in hexane).Then use the TFA solution-treated product of 20mL 20% in DCM.Subsequently by the rotary evaporation desolventizing.Obtain title compound by HPLC purifying gained material resistates, be white solid (0.045g, 26%).
1H NMR(500MHz，DMSO-d 6)：δ1.11(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-(the 3-p-methoxy-phenyl is amino)-5-methylpyrimidine-2-base is amino) Phenoxy group) piperidines-1-t-butyl formate (intermediate 68)
Figure S2006800499668D01812
With 1-bromo-3-anisole (69.5 μ L, 0.56mmol), intermediate 42 (205mg, 0.51mmol), Pd 2(dba) 3(23mg, 0.03mmol), (irradiation is 20 minutes in the microwave of mixture under 160 ℃ in 359mg, the 1.10mmol) Zai diox (3mL) for Xantphos (33mg, 0.06mmol) and cesium carbonate.This reaction mixture is cooled to room temperature, filters and wash filtrate with DCM and MeOH., be light brown solid (215mg, 83%) to the concentrated liquid that merges 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)
Figure S2006800499668D01821
In the mixture of intermediate 68 (215mg, 0.42mmol) in DCM (4mL), add BBr 3(120 μ L, 1.27mmol) and at room temperature stirred 64 hours.Make reaction quencher and concentrated in a vacuum with MeOH.By preparation HPLC purifying resistates and in a vacuum concentrated fraction obtain the tfa salt (116mg, 56%) of title compound.This tfa salt is dissolved in MeOH and makes it pass through SPE PL-HCO 3The MP-resin column, concentrated in a vacuum, grind and filter and obtain title compound with ether, be white solid (31mg, the rate of recovery 69%).
1H NMR(500MHz，DMSO-d 6)：δ1.51-1.60(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(br s，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-yl 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), the mixture of Xantphos (0.93g, 1.6mmol) and cesium carbonate (7.88g, 24.2mmol) are suspended in the diox (60mL) and heated 5 hours under reflux state and in the ar gas environment.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)
Be suspended in the mixture of intermediate 69 (0.1g, 0.37mmol) and 4-(2-pyrrolidin-1-yl-oxyethyl group)-phenyl amine (0.16g, 0.75mmol) in the acetic acid (10mL) and be heated to 110 ℃ lower 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)：δ1.88(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)
Figure S2006800499668D01841
Be suspended in the mixture of 3-methoxyl group-2-methyl-phenyl amine (0.68g, 5mmol) and 2,4-, two chloro-pyrimidines (0.74g, 5mmol) in the ethanol (10mL) and at room temperature stirred 20 hours.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-(the 2-pyrrolidin-1-yl- Oxyethyl group)-phenyl]-pyrimidine-2,4-diamines (Compound C XLIII)
Figure S2006800499668D01842
Be suspended in the mixture of intermediate 70 (0.08g, 0.32mmol) and 4-(2-pyrrolidin-1-yl-oxyethyl group)-phenyl amine (0.13g, 0.64mmol) in the acetic acid (10mL) and be heated to 80 ℃ lower 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)：δ1.89(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＝8.1Hz 1H)，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)
Figure S2006800499668D01851
With 4-(4-bromo-benzenesulfonyl)-piperidines-1-t-butyl formate (4g, 9.92mmol), ethanamide (0.88g, 14.9mmol), Pd 2(dba) 3(0.46g, 0.49mmol), the mixture of Xantphos (0.56g, 0.99mmol) and cesium carbonate (9.7g, 29.8mmol) are suspended in the diox (60mL) and heated 4 hours under reflux state and in the ar gas environment.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 purification of crude product, be light brown solid (3.12g, 82%).
Embodiment 213.4-(4-amino-benzenesulfonyl)-piperidines-1-t-butyl formate (intermediate 72)
Figure S2006800499668D01852
Use 60mL Claisen ' s alkali (to be dissolved in 63mL H 2O is diluted to the 88g KOH of 250mL with MeOH) suspension of diluted intermediate 71 (2.6g, 6.7mmol) and be heated to 90 ℃.After 2 hours, make reaction pine for breaking away from from adding, be cooled to room temperature and water (50mL dilution).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)
Figure S2006800499668D01853
With intermediate 31 (0.14g, 0.51mmol), intermediate 72 (0.19g, 0.56mmol), Pd 2(dba) 3(0.046g, 0.051mmol), the mixture of Xantphos (0.59g, 0.1mmol) and cesium carbonate (0.5g, 1.52mmol) are suspended in the diox (8mL) and use microwave 15 minutes under 160 ℃.This reaction mixture is cooled to room temperature and centrifugal settling.Then decantation solvent and evaporation.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)：δ1.61-1.69(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)
Figure S2006800499668D01861
With 2-chloro-5-methyl-pyrimidine-4-yl 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), the mixture of Xantphos (0.47g, 0.47mmol) and cesium carbonate (2.3g, 7mmol) are suspended in the diox (9mL), 160 ℃ of lower microwave 20 minutes of using.This reaction mixture is cooled to room temperature and centrifugal settling.Then decantation solvent and evaporation.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)
Figure S2006800499668D01871
With the mixture of HOAc (5mL) diluted intermediate 73 (0.071g, 0.27mmol) and 4-(4-amino-phenoxy group)-piperidines-1-t-butyl formate (0.1g, 0.35mmol) and 150 ℃ of lower microwave irradiation 15 minutes of using.Then desolventizing and with HPLC purifying gained resistates.Separate title compound, be white solid (0.025g, 22%).
1H NMR(500MHz，DMSO-d 6)：δ1.76-1.83(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)
Figure S2006800499668D01872
Process the solution of 3-bromo-phenyl amine (1.04g, 6mmol) and be cooled to 0 ℃ with DIEA (2.3mL, 13.3mmol).Drip Acetyl Chloride 98Min. (0.47mL, 6.7mmol) by syringe.Make reacting recovery to room temperature and stirred 1 hour.Then be poured over reaction waterborne 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-yl is amino)-phenyl]-ethanamide (intermediate 75)
Figure S2006800499668D01873
With 2-chloro-5-methyl-pyrimidine-4-yl amine (0.71g, 4.9mmol), intermediate 74 (1.25g, 5.9mmol), Pd 2(dba) 3(0.45g, 0.49mmol), the mixture of Xantphos (0.57g, 0.98mmol) and cesium carbonate (4.8g, 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 the mixture of HOAc (5mL) diluted intermediate 75 (0.074g, 0.27mmol) and 4-(4-amino-phenoxy group)-piperidines-1-t-butyl formate (0.1g, 0.35mmol) and 150 ℃ of lower microwave irradiation 15 minutes of using.Then desolventizing and with HPLC purifying gained resistates.Separate title compound, be white solid (0.072g, 62%).
1H NMR(500MHz，DMSO-d 6)：δ1.74-1.81(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)
Figure S2006800499668D01882
Process the solution of 3-bromo-2-methyl-phenyl amine (4.1g, 21.9mmol) and be cooled to 0 ℃ with DIEA (8.4mL, 48mmol).Drip Acetyl Chloride 98Min. (1.7mL, 24.1mmol) by syringe.Make reacting recovery to room temperature and stirred 1 hour.Then be poured over reaction waterborne 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-yl is amino)-2-methyl-phenyl]- Ethanamide (intermediate 77)
Figure S2006800499668D01891
With 2-chloro-5-methyl-pyrimidine-4-yl amine (0.86g, 5.9mmol), intermediate 76 (1.6g, 7.1mmol), Pd 2(dba) 3(0.55g, 0.59mmol), the mixture of Xantphos (0.69g, 1.2mmol) and cesium carbonate (5.8g, 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-yl is amino }-phenyl)-ethanamide (Compound C XLVII)
Figure S2006800499668D01892
With the mixture of HOAc (5mL) diluted intermediate 77 (0.15g, 0.5mmol) and 4-(4-amino-phenoxy group)-piperidines-1-t-butyl formate (0.19g, 0.65mmol) and 150 ℃ of lower microwave irradiation 15 minutes of using.Then desolventizing and with HPLC purifying gained resistates.Separate title compound, be white solid (0.091g, 41%).
1H NMR(500MHz，DMSO-d 6)：δ1.71-1.78(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), the mixture of Xantphos (0.37g, 0.64mmol) and cesium carbonate (3.1g, 9.6mmol) is suspended in diox (40mL), refluxes 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)
Figure S2006800499668D01902
With purification for argon intermediate 78 (0.23g, 0.54mmol) in MeOH (25mL) slurry and process with Pd/C 10%wt. (0.18g).With hydrogen substitution reaction gas and stirred 4 hours.Then remove the hydrogen capsule and make argon gas stream cross reaction, after this filter by celite.Then evaporating solvent is to obtaining light brown solid (0.17g, 83%).
Embodiment 225.1-(3-{5-methyl-2-[4-(4-methyl-piperazine-1-yl)-phenyl amino]- Pyrimidine-4-yl is amino }-phenyl)-3-phenyl-urea (Compound C XLVIII)
Figure S2006800499668D01911
With phenylcarbimide (0.058mL, 0.54mmol) process intermediate 79 (0.17g, 0.45mmol) in DCM (10mL) suspension and stirred 1 hour.Then remove reaction solvent and obtain title compound by HPLC purifying gained resistates, be white solid (0.075g, 33%).
1H NMR(500MHz，DMSO-d 6)：δ2.09(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-yl is amino }-phenyl)-3-(3-trifluoromethyl-phenyl)-urea (Compound C XLIX)
With 1-isocyanate group-3-trifluoromethyl-benzene (0.043mL, 0.31mmol) process intermediate 79 (0.1g, 0.26mmol) in DCM (8mL) suspension and stirred 1 hour.Then remove reaction solvent and obtain title compound by HPLC purifying gained resistates, be white solid (0.039g, 26%).
1H NMR(500MHz，DMSO-d 6)：δ2.16(s，3H)，2.82(s，3H)，2.86(br s，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)
Figure S2006800499668D01921
With 2-chloro-5-methyl-pyrimidine-4-yl amine (0.18g, 5.9mmol), 1-bromo-2-methyl-3-trifluoromethyl-benzene (0.33g, 1.4mmol), Pd 2(dba) 3(0.12g, 0.13mmol), the mixture of Xantphos (0.15g, 0.25mmol) and cesium carbonate (1.23g, 3.8mmol) is suspended in diox (8mL), 160 ℃ of lower microwave 18 minutes of using.Then centrifugal settling reaction vessel and decantation, 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)
Figure S2006800499668D01922
With the mixture of HOAc (5mL) diluted intermediate 80 (0.058g, 0.2mmol) and 4-(4-amino-phenoxy group)-piperidines-1-t-butyl formate (0.073g, 0.25mmol) and 150 ℃ of lower microwave 15 minutes of using.Then desolventizing and with HPLC purifying gained resistates.Separate title compound, be white solid (0.025g, 30%).
1H NMR(500MHz，DMSO-d 6)：δ1.71-1.78(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)-pyrrolidin-1-yl-ketone (intermediate 81)
Figure S2006800499668D01931
The solution of 3-bromo-Benzoyl chloride (2.7g, 12mmol) in DCM (40mL) is cooled to 0 ℃ and process with tetramethyleneimine (3mL, 36.8mmol).Make reaction reach room temperature and stirred 4 hours.Then be poured over mixture waterborne and the washing once.Then use salt water washing organic phase, 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-yl is amino)-phenyl]-tetramethyleneimine-1- Base-ketone (intermediate 82)
Figure S2006800499668D01932
With 2-chloro-5-methyl-pyrimidine-4-yl amine (0.22g, 1.5mmol), intermediate 81 (0.46g, 1.8mmol), Pd 2(dba) 3(0.14g, 0.15mmol), the mixture of Xantphos (0.17g, 0.3mmol) and cesium carbonate (1.5g, 4.5mmol) are suspended in the diox (8mL), 160 ℃ of lower microwave 18 minutes of using.Then with reaction vessel centrifugal settling and decantation, evaporating solvent obtains title compound by fast silica gel chromatogram method purifying gained resistates subsequently, 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)-pyrrolidin-1-yl-ketone (Compound C LI)
Figure S2006800499668D01933
With the mixture of HOAc (6mL) diluted intermediate 82 (0.1g, 0.32mmol) and 4-(4-amino-phenoxy group)-piperidines-1-t-butyl formate (0.12g, 0.41mmol) and 150 ℃ of lower microwave 15 minutes of using.Then desolventizing and with HPLC purifying gained resistates.Separate title compound, be white solid (0.005g, 3%).
1H NMR(500MHz，DMSO-d 6)：δ1.74-1.81(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)
Figure S2006800499668D01941
The solution of 3-bromo-Benzoyl chloride (0.83g, 3.8mmol) in DCM (40mL) is cooled to 0 ℃ and process with Isopropylamine (0.96mL, 11.32mmol).Make reaction reach room temperature and stirred 24 hours.Then be poured over mixture waterborne and the washing once.Then use salt water washing organic phase, 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-yl is amino }-benzamide (Compound C LII)
Figure S2006800499668D01942
With intermediate 32 (0.1g, 0.34mmol), intermediate 83 (0.13g, 0.54mmol), Pd 2(dba) 3(0.031g, 0.034mmol), the mixture of Xantphos (0.039g, 0.067mmol) and cesium carbonate (0.33g, 1mmol) are suspended in the diox (8mL), 160 ℃ of lower microwave 15 minutes of using.Then centrifugal settling reaction vessel and decantation, evaporating solvent and obtain title compound by HPLC purifying gained resistates is white solid (0.011g, 7%) subsequently.
1H NMR(500MHz，DMSO-d 6)：δ1.14(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)
Figure S2006800499668D01951
The solution of 3-bromo-Benzoyl chloride (0.83g, 3.8mmol) in DCM (10mL) is cooled to 0 ℃ and process with tert-butylamine (1.2mL, 11.3mmol).Make reaction reach room temperature and stirred 4 hours.Then be poured over mixture waterborne and the washing once.Then use salt water washing organic phase, 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)-phenyl Amino]-pyrimidine-4-yl is amino }-benzamide (Compound C LIII)
Figure S2006800499668D01952
With intermediate 32 (0.1g, 0.34mmol), intermediate 84 (0.1g, 0.4mmol), Pd 2(dba) 3(0.031g, 0.034mmol), the mixture of Xantphos (0.039g, 0.067mmol) and cesium carbonate (0.33g, 1mmol) are suspended in the diox (8mL), 160 ℃ of lower microwave 15 minutes of using.Then centrifugal settling reaction vessel and decantation, evaporating solvent and obtain title compound by HPLC purifying gained resistates is white solid (0.055g, 35%) subsequently.
1H NMR(500MHz，DMSO-d 6)：δ1.36(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)
Figure S2006800499668D01961
With intermediate 32 (0.08g, 0.27mmol), 4-(3-bromo-phenyl)-piperidines (0.084g, 0.35mmol), Pd 2(dba) 3(0.025g, 0.027mmol), the mixture of Xantphos (0.031g, 0.054mmol) and cesium carbonate (0.26g, 0.81mmol) are suspended in the diox (8mL), 160 ℃ of lower microwave 15 minutes of using.Then centrifugal settling reaction vessel and decantation.Evaporating solvent and obtain title compound by HPLC purifying gained resistates is white solid (0.007g, 6%) subsequently.
1H NMR(500MHz，DMSO-d 6)：δ1.74-1.79(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-yl 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), the mixture of Xantphos (0.067g, 0.12mmol) and cesium carbonate (0.57g, 1.74mmol) are suspended in the diox (8mL), 160 ℃ of lower microwave 15 minutes of using.Then centrifugal settling reaction vessel and at decantation on ice.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)
Figure S2006800499668D01972
With the BBr of 1M in DCM 3(2mL, 2mmol) processes the stirred solution of intermediate 85 (0.17g, 0.26mmol) in DCM (15mL).After 4 hours, make reaction quencher, subsequently desolventizing by slow interpolation MeOH (4mL).Obtain title compound by HPLC purifying resistates, be purple powder (0.008g, 6%).
1H NMR(500MHz，DMSO-d 6)：δ1.31-1.40(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), (irradiation is 20 minutes in the microwave of mixture under 160 ℃ in 428mg, the 1.31mmol) Zai diox (3mL) for Xantphos (60mg, 0.10mmol) and cesium carbonate.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)
Figure S2006800499668D01982
The mixture of intermediate 86 (27mg, 0.05mmol) in 30%TFA/DCM (1mL) stirred 3 hours.At this reaction mixture of vacuum concentration and by the preparation HPLC purifying.Concentrated gained fraction and obtain the tfa salt of title compound is tawny solid (11mg, 43%) in a vacuum.
1H NMR(500MHz，DMSO-d 6)：δ1.71-1.77(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-pyrrolidin-1-yl-oxyethyl group)-phenyl amino]- Pyrimidine-5-yl }-5 (3-trifluoromethyl-benzamido)-benzamide (Compound C LVII)
Figure S2006800499668D01991
In ar gas environment with 3-bromopyridine (379mg, 2.4mmol), 4-amino-2-chloro-5-methylpyrimidine (287mg, 2.0mmol), Pd 2(dba) 3(18mg, 0.02mmol), (mixture in 975mg, the 3.0mmol) Zai diox (15mL) heated 1 hour under reflux state for xantphos (23mg, 0.04mmol) and cesium carbonate.Desolventizing and by HPLC resistates is carried out purifying and obtain 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-(pyrrolidin-1-yl) oxyethyl group) aniline (74mg, 0.34mmol), Pd 2(dba) 3(3.2mg, 0.003mmol), (mixture in 234mg, the 0.72mmol) Zai diox (5mL) heated 1 hour under reflux state for xantphos (4.2mg, 0.007mmol) and cesium carbonate.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), (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), 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-(pyrrolidin-1-yl) oxyethyl group) phenyl)-5-methyl -N 4 -(3-(trifluoromethoxy) phenyl) pyrimidine-2,4-diamines (Compound C LVIII)
Figure S2006800499668D02001
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), (mixture in 650mg, the 2.0mmol) Zai diox (15mL) heated 10 hours under reflux state for xantphos (14mg, 0.02mmol) and cesium carbonate.Desolventizing and by HPLC resistates is carried out purifying and obtain intermediate 2-chloro-5-methyl-N-(pyridin-3-yl) pyrimidine-4-amine is brown solid (260mg, 85%).In ar gas environment, this intermediate (100mg, 0.33mmol) and 4-(2-(pyrrolidin-1-yl) oxyethyl group) mixture of aniline (67mg, 0.33mmol) in Glacial acetic acid (5mL) were heated 3 hours under reflux state.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-(pyrrolidin-1-yl) oxyethyl group) phenyl)-N 4 -(4-chlorine -3-(trifluoromethyl) phenyl)-and 5-methylpyrimidine-2,4-diamines (Compound C LIX)
Figure S2006800499668D02002
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), (mixture in 650mg, the 2.0mmol) Zai diox (15mL) heated 10 hours under reflux state for xantphos (14mg, 0.02mmol) and cesium carbonate.Desolventizing and obtain intermediate 2-chloro-N-(4-chloro-3-(trifluoromethyl) phenyl)-5-methylpyrimidine-4-amine by HPLC purifying resistates is brown solid (200mg, 62%).This intermediate (161mg, 0.5mmol) and 4-(2-(pyrrolidin-1-yl) oxyethyl group) mixture of aniline (103mg, 0.5mmol) in Glacial acetic acid (5mL) were heated 3 hours under reflux state.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 restructuring JAK2 of Upstate Cell SignalingSolutions 50Value.At room temperature with in the flat 96-of white hole dull and stereotyped (Nunc) carry out replicate(determination) with the final volume of 50 μ L.Each hole comprises the 40 μ L damping fluids that the 40mM Tris damping fluid by pH 7.4 forms, and 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 L peptide substrates (PDKtide; Upstate Cell SignalingSolutions) and an amount of JAK2 (75-25ng/ hole), so that this be determined in 60 minutes as linear.Make the TargeGen compound at IC by in 2.5 μ LDMSO, 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%.By add 10 μ LATP to the final concentration of measuring be that 3 μ M start reaction.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.
Then use as 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 the second reaction neither contains inhibitor, does not also contain peptide substrates.(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
Figure S2006800499668D02021
Figure S2006800499668D02041
Figure S2006800499668D02051
Figure S2006800499668D02061
Figure S2006800499668D02071
Figure S2006800499668D02081
Figure S2006800499668D02091
Figure S2006800499668D02101
Figure S2006800499668D02111
Figure S2006800499668D02121
Figure S2006800499668D02131
Figure S2006800499668D02141
Figure S2006800499668D02161
Figure S2006800499668D02171
Figure S2006800499668D02191
Figure S2006800499668D02201
Figure S2006800499668D02211
Figure S2006800499668D02241
Figure S2006800499668D02251
Embodiment 245. selects the effect of compound to measure
HEL, CTLL-2 ﹠amp; Normal people's epidermis inoblast (NHDF) is from US mode culture collection center (American Tissue Culture Collection Rockville, MD).The BaF/3 cell is available from DKFZ Cancer Research Center (Heidelberg, Germany).
Make BaF/3, HEL ﹠amp; The NHDF Growth of Cells is replenishing penicillin, and Streptomycin sulphate is in RPMI 1640 substratum (Gibco BRL, Gaithersburg, MD) of L-glutaminate and 10% foetal calf serum (FBS).Make the CTLL-2 Growth of Cells in the same medium of further having replenished 20U/mL recombinant il-2 (Hoffmann-LaRoche, Nutley, NJ).Comprise the plasmid of people JAK2 encoding sequence available from Invitrogen (Madison, WI).By using site-directed mutagenesis to produce JAK2 V617FCDNA uses two-dimentional sequence verification subsequently in order to the V617F sudden change is imported people JAK2 encoding sequence.Subsequently this cDNA subclone is entered retroviral vector and the BaF/3 cell of transduceing.Select to express JAK2 V617FLasting transduction the BaF/3 cell and keep with 1mg/ml G418.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, carry out cell proliferating determining according to the explanation (Roche, Alameda, CA) 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.Use Vmax spectrophotometer (Molecular Devices, Sunnyvale, CA) at 450nm and the cured product of painted first of under the 650nm correction, measuring formation by spectrophotometry.Use GraphPad Prism 4.0 softwares (San Diego, CA) to measure the IC50 value, therefore, the concentration (mM) (logarithmically calibrated scale) of OD value on y-axle (linear scale) and x-axle is drawn.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
The JAK3-dependency propagation-3395nM that contrasting data: IL-2-induces
Contrasting data: normal people's epidermis inoblast-6487nM
Apoptosis is measured
Will be at the middle BaF/3-JAK that cultivates of growth medium (RPMI, 10%FBS, 1mg/ml G418 and 10 μ g/ml blasticidins) with 1,3 and 10 μ M XLV V617FCell was processed 24 hours.By after with 5 minutes collecting cells of 890RCF (relative centrifugal force), use DNA separating kit (Puregen, Chino, CA) isolation of genomic DNA from cell precipitation.Make 5 μ g genomic dnas of every duplicate samples carry out 1.2% agarose gel electrophoresis in order to detect genomic DNA fragment (dna ladder shape assay method).In contrast, converge the adhesion normal people epidermis inoblast (NHDF) that rate is cultivated at growth medium (Cambrex, Walkersville, MD) 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 processes with XLV or vehicle reference substance V617FCell is with ice-cold PBS washing 2X and the cracking of use RIPA damping fluid.Use BCA method (Pierce, Rockford, IL) mensuration 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.Use anti--phosphoric acid-STAT5 (Tyr694/699) (Upstate Biotechnology, Charlottesville, VA) survey western blotting, peel off subsequently and re-use anti--STAT5 antibody (CellSignaling Technology, Danvers, MA) survey.By the chemoluminescence method (Pierce) that strengthens phosphoric acid-STAT5 or STAT5 protein are manifested.Carry out in a similar way signal conduction studies in the body.In brief, the 11st day of injection cell, by oral to animals administer vehicle or 100mg/kg XLV.After administration, gathered spleen and rapidly homogenize in FastPrep machine (Qbiogen, Irvine, CA) in 7 hours.Make 100 μ g spleen homogenize things carry out separately western blot analysis.Use anti--phosphoric acid-STAT5 (Tyr694/699) and use subsequently anti--STAT5 antibody to survey western blotting and manifest by the chemoluminescence method that strengthens.
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 jointly be collected in the dosage group.By Ficoll (Sigma-Aldrich, St.Louis, MO) bed course centrifuging (600 RCF and 30 minutes) separating blood monocyte.Make the cell of separation carry out facs analysis in order to measure the positive BaF/3:JAK2 of GFP V617FCell per-cent.The result is presented in the following table.
The oral XLV of giving reduces cyclic J AK2 in the dose-dependently mode V617FTumor cell number
Figure S2006800499668D02281
The circulating tumor model
Express JAK2 by intravenously to the SCID injected in mice 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 in order to measure the circulating cells per-cent of the GFP positive from animal in every group.In the parallel research of carrying out, process as mentioned above animal, but in the time of the 11st day to they administration 100mg/kg single medicine dosage, after 4 hours, put to death subsequently animal 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
Figure S2006800499668D02291
*When oral tube feed because of suck tracheae death behind tumor injection the 3rd day 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, namely 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
Figure S2006800499668D02301
Change in the eye efficacy study of embodiment 246. in retinopathy (OIR) model of oxygen-induce Compound XVII
Use retinopathy (OIR) the model measurement compounds X VII of mouse oxygen-induce, wherein by make mouse young baby circulation from oxygen level normally to hyperoxia and then return to oxygen level and normally cause retinal neovascularization.Begin to change C57BL/6 mouse group over to hyperoxic environment (70% O when the 7th day (P7) after be born 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, the whole fixture of preparation retina 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 for the second time research, observe and reduce 22% (P＜0.02, n=6).The result is summarised in the table 3.
Table 3
Figure S2006800499668D02311
Although described the present invention with reference to above-described embodiment, be appreciated that modification and modification comprise within the spirit and scope of the present invention.Therefore, the present invention is only limited by following claim.

Claims (40)

1. the compound or its pharmacy acceptable salt that have structure (A):
Wherein:
X is selected from key, O and CH 2Y is selected from key or NR 9Or X and Y are key jointly;
R 1And R 2Be selected from independently of one another H, C 1-C 6Unsubstituted alkyl, replacement or unsubstituted C 3-C 8Cycloalkyl, replacement or unsubstituted C 3-C 14Heterocycle, replacement or unsubstituted C 5-C 14Aryl and replacement or unsubstituted C 3-C 14Heteroaryl; 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, q, r, n, m independently are the integer with value of 0-6 separately,
R 9Be selected from H, C 1-C 6Alkyl, C 1-C 6Cycloalkyl, C 1-C 6Branched-chain alkyl and C 1-C 6The alkyl that replaces;
G 0Be selected from N, O, H and CH,
Condition is if G 0Be N, so:
R 3And R 4Be selected from independently of one another 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 C 5-C 14Aryl, and replacement or unsubstituted C 3-C 14Heteroaryl, 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 O, so:
R 3Be selected from H, C 1-C 6Alkyl, C 1-C 6Replace or unsubstituted hydroxyalkyl or aminoalkyl group, replace or unsubstituted C 1-C 6Branched-chain alkyl replaces or unsubstituted C 3-C 8Cycloalkyl, the C of the replacement that connects by carbon or nitrogen 3-C 14Heterocycle replaces or unsubstituted C 5-C 14Aryl is by replacement or the unsubstituted C of carbon or nitrogen connection 3-C 14Heteroaryl is wherein without radicals R 4Or 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;
Extra condition is if G 0=CH, so:
R 3And R 4Be selected from independently of one another H, C 1-C 6Alkyl, C 1-C 6Replace or unsubstituted hydroxyalkyl or aminoalkyl group, replace or unsubstituted C 1-C 6Branched-chain alkyl replaces or unsubstituted C 5-C 14Aryl is by replacement or the unsubstituted C of carbon or nitrogen connection 3-C 14Heterocycle is with the replacement or the unsubstituted C that are connected the connection of carbon or nitrogen 3-C 14Heteroaryl, 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 independently is N or CR separately 6, maybe when being incorporated into X, G is C, condition is to be no more than two G groups can be N, and each R 6With radicals R 6Independently of one another;
R 5Be methyl;
Figure FSB00000957780100021
R wherein 6, R 7And R 8Be selected from independently of one another H, replacement or unsubstituted C 1-C 6Alkenyl, replacement or unsubstituted C 1-C 6Alkynyl, C 1-C 6Replace or unsubstituted hydroxyalkyl or aminoalkyl group, replacement or unsubstituted C 1-C 6Cycloalkyl, replacement or unsubstituted C 5-C 14Aryl, the replacement or the unsubstituted C that connect by carbon or heteroatoms 3-C 14Heteroaryl, halogen, CF 3,-OCF 3, SO 2H, SO 2(C 1-C 6Alkyl), SO 2N (C 1-C 6Alkyl) H, SO 2N (C 1-C 6Alkyl) (C 1-C 6Alkyl), SO 2N (C 1-C 6Branched-chain alkyl) H, NH 2, NH (C 1-C 6Alkyl), N (C 1-C 6Alkyl) (C 1-C 6Alkyl), NO 2, CN, CONH 2, CONH (C 1-C 6Alkyl), CON (C 1-C 6Alkyl) (C 1-C 6Alkyl), CO (C 1-C 6Alkyl), COOH, COO-(C 1-C 6Alkyl), NHCO-(C 1-C 6Alkyl) and NHCONH-(C 5-C 14Aryl); Or 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-,-CH=CH-CH=CH-,-N=CH-CH=CH-,-CH=N-CH=CH-,-O-CH=CH and-part of S-CH=CH-;
The heterocycle of the aryl of the alkynyl of the alkyl that wherein replaces, the thiazolinyl of replacement, replacement, the cycloalkyl of replacement, replacement, the heteroaryl of replacement or replacement has and is selected from following one or more substituting groups: hydroxyl, C 1-C 6Alkoxyl group, sulfydryl, C 3-C 8Cycloalkyl, C 3-C 14Heterocycle, C 5-C 14Aryl, halogen, cyano group, nitro, amino, amido, aldehyde, acyl group, oxygen base acyl group, carboxyl, alkylsulfonyl, sulphonamide and sulfonyl;
A is selected from O, NH, N-(C 1-C 6Alkyl), CH 2, S, SO and SO 2
G 1Be selected from CH and N;
G 2Be selected from CR 7And N, wherein each radicals R 7With each extra radicals R 7Independent;
Wherein heterocycle comprises the heteroatoms that at least one is selected from N, O and S at every turn when occurring;
Wherein heteroaryl comprises the heteroatoms that at least one is selected from N, O and S at every turn when occurring;
C wherein 1-C 6Cycloalkyl does not comprise C at every turn when occurring 1Cycloalkyl and C 2Cycloalkyl;
C wherein 1-C 6Branched-chain alkyl does not comprise C at every turn when occurring 1Branched-chain alkyl and C 2Branched-chain alkyl;
C wherein 1-C 6Thiazolinyl does not comprise C at every turn when occurring 1Thiazolinyl;
C wherein 1-C 6Alkynyl does not comprise C at every turn when occurring 1Alkynyl.
2. the compound of claim 1, wherein R 9Be selected from C 1-C 6Aminoalkyl group and C 1-C 6Hydroxyalkyl.
3. the compound of claim 1, wherein X is O.
4. the compound of claim 1, wherein G 0N.
5. the compound of claim 3, wherein G 0N.
6. the compound of claim 5, wherein Y is key, and R 1And R 2Each is H naturally.
7. the compound of claim 6, wherein R 7SO 2NH-(C 1-C 6Branched-chain alkyl), C wherein 1-C 6Branched-chain alkyl does not comprise C 1Branched-chain alkyl and C 2Branched-chain alkyl.
8. the compound of claim 5, wherein 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.
9. the compound of claim 5, wherein R 3And R 4H respectively does for oneself.
10. the compound of claim 4, wherein X is key, and Y is key, and p, q and n respectively do for oneself 0, and R 3And R 4With G 0Common 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.
11. the compound of claim 10, wherein G 1And G 2The CH that respectively does for oneself, and R7 is SO 2NH-(C 1-C 6Branched-chain alkyl), wherein the C1-C6 branched-chain alkyl does not comprise C 1Branched-chain alkyl and C 2Branched-chain alkyl.
12. the compound by following representative: first part that is connected with the second part chemistry, or its pharmacy acceptable salt, wherein said first part is selected from:
Figure FSB00000957780100041
Figure FSB00000957780100051
Figure FSB00000957780100061
And wherein said the second part is selected from:
Figure FSB00000957780100062
13. a compound or its pharmacy acceptable salt, wherein this compound is selected from lower group:
Figure FSB00000957780100072
Figure FSB00000957780100081
Figure FSB00000957780100091
Figure FSB00000957780100101
Figure FSB00000957780100111
Figure FSB00000957780100121
Figure FSB00000957780100131
Figure FSB00000957780100141
Figure FSB00000957780100171
Figure FSB00000957780100181
Figure FSB00000957780100191
Figure FSB00000957780100201
Figure FSB00000957780100211
Figure FSB00000957780100231
14. at least a compound of any one or its pharmacy acceptable salt purposes in the medicine of the illness relevant with the generation blood vessel for the preparation for the treatment of among the claim 1-13.
15. the described purposes of claim 14, wherein said illness are myelosis's illness, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, proliferative diabetic retinopathy PDR, cancer, illness in eye, inflammation, psoriatic or virus infection.
16. the described purposes of claim 15, wherein said illness are polycythemia vera.
17. the described purposes of claim 15, wherein said illness are essential thrombocythemia.
18. the described purposes of claim 15, wherein said illness are the myelofibrosis with myeloid metaplasia.
19. the described purposes of claim 15, wherein said illness are any illness relevant with marrow.
20. the described purposes of claim 15, wherein said cancer are selected from digestion/gastrointestinal cancer, 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.
21. the described purposes of claim 15, wherein said cancer are colorectal carcinoma.
22. the described purposes of claim 15, wherein said illness are chronic myelogenous leukemia.
23. the described purposes of claim 22, the present treatment of wherein said chronic myelogenous leukemia opposing.
24. it is sick that the described purposes of claim 15, wherein said illness are myelosis
Disease.
25. the described purposes of claim 24, wherein said myelosis illness produces because of the acquisition of JAK family kinase by way of function.
26. the described purposes of claim 24, 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.
27. the described purposes of claim 15, wherein said illness is relevant with kinases.
28. the described purposes of claim 27, wherein said kinases are the JAK family kinase.
29. pharmaceutical composition comprises at least a compound or its pharmacy acceptable salt of any one among the claim 1-13 and pharmaceutically acceptable carrier.
30. compound or its pharmacologically acceptable salts by the following formula representative:
Figure FSB00000957780100241
31. compound or its pharmacologically acceptable salts by the following formula representative:
Figure FSB00000957780100242
32. pharmaceutical composition comprises compound and the pharmaceutically acceptable carrier of claim 31.
33. pharmaceutical composition comprises compound and the pharmaceutically acceptable carrier of claim 30.
34. each compound is for the preparation of the purposes in the medicine for the treatment of myelosis illness among the claim 1-13,30 and 31.
35. the purposes of claim 34, wherein said illness are essential thrombocythemia or polycythemia vera.
36. the purposes of each compound in the medicine of the disease that is selected from leukemia, scleroderma or rheumatoid arthritis for the preparation for the treatment of among the claim 1-13,30 and 31.
37. the purposes of claim 36, wherein said disease are leukemia.
38. the purposes of claim 37, wherein said disease are acute myeloid leukaemia.
39. the purposes of claim 37, wherein said disease are chronic myelogenous leukemia.
40. the purposes of claim 39, the present treatment of wherein said chronic myelogenous leukemia opposing.
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