CN1335849A - Pyrrolopyrimidines as protein kinase inhibitors - Google Patents

Pyrrolopyrimidines as protein kinase inhibitors Download PDF

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CN1335849A
CN1335849A CN99813217A CN99813217A CN1335849A CN 1335849 A CN1335849 A CN 1335849A CN 99813217 A CN99813217 A CN 99813217A CN 99813217 A CN99813217 A CN 99813217A CN 1335849 A CN1335849 A CN 1335849A
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pyrrolo
amino
pyrimidin
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G·C·赫斯特
D·克莱德伍德
N·威沙特
K·里特尔
L·D·阿诺德
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Ebert GmbH and Co KG
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Abstract

Chemical compounds having structural formula (I) and physiologically acceptable salts and metabolites thereof, are inhibitors of serine/threonine and tyrosine kinase activity. Several of the kinases, whose activity is inhibited by these chemical compounds, are involved in immunologic, hyperproliferative, or angiogenic processes. Thus, these chemical compounds can ameliorate disease states where angiogenesis or endothelial cell hyperproliferation is a factor. These compounds can be used to treat cancer and hyper proliferative disorders, rheumatoid arthritis, disorders of the immune system, transplant rejections and imflammatory disorders.

Description

Pyrrolopyrimidine as kinases inhibitor
Related application
The U.S. Provisional Application No.60/100832 that the application submitted on September 18th, 1; the U. S. application No.No.60/100833 that on September 18th, 1998 submitted to; the interests of the U. S. application No.No.60/100946 that the U. S. application No.No.60/100834 that submitted on September 18th, 1998 and on September 18th, 1998 submit to, whole Inner of these application reference hold to draw and do this paper reference.
Background of invention
Have at least 400 kinds of enzymes to be confirmed as protein kinase.The phosphorus acylation reaction of these enzyme catalysis target protein substrates.Phosphorus acylation reaction generally is to make phosphate transfer to reaction on the protein substrate from ATP.To transfer to the ad hoc structure above it be tyrosine to phosphate in the target substrate, Serine or threonine residues.Because the target structure that these amino-acid residues are phosphoryls to be shifted, so these protein kinases usually are called as Tyrosylprotein kinase or Serine, threonine kinase.
Protein tyrosine kinase.Protein tyrosine kinase (PTK) is the enzyme of the specific tyrosine residues phosphorylation in the catalysis cell protein.The posttranslational modification of these substrate protein white matters (often being enzyme self) can be used as molecular switch, is used to regulate cell proliferation, activation or differentiation (referring to for example Schlessinger and Ulrich, 1992, neurone 9:383-391).In a lot of diseases, observe unusual or excessive PTK activity; described disease comprises optimum and malignant proliferation disease and the disease (for example autoimmune disease) that is caused by the inappropriate activation of immunity system, the anti-experimenter's disease of allograft rejection and graft.In addition, endothelial cell specific acceptor PTK, as KDR and Tie-2 mediation angiogenesis, therefore the disease that participates in supporting cancer and other to relate to incorrect vascularization (diabetic retinopathy for example, the choroid neovascularity that is caused by the macula degeneration relevant with the age generates psoriasis, sacroiliitis, retinopathy of prematurity, infantile hemangioma) process.
Tyrosylprotein kinase can be acceptor-type (have the extracellular, stride film and cell intracellular domain) or non--receptor type (being intracellular fully).
Receptor tyrosine kinase (RTK).RTK comprises large numbers of varied bioactive transmembrane receptors that have.At present, 19 kinds of different RTK subtribes have been identified at least.Receptor tyrosine kinase (RTK) family comprise to the growth of various kinds of cell type and break up vital acceptor (Yarden and Ullrich, bioid academic year comments, 57:433-478,1988; Ullrich and Schlessinger, cell, 61:243-254,1990).The inherent function of RTK in conjunction with being activated, causes acceptor and a plurality of cell substrate phosphorylation through part, causes a plurality of cell responses (Ullrich ﹠amp then; Schlessinger, cell, 61:203-212,1990).Therefore, the receptor tyrosine kinase Mediated Signal Transduction is interacted initial by the extracellular with the particular growth factor (part), next generally be receptor dimerization, and Inner is at the stimulation and the acceptor transphosphorylation of protein hydroxyphenylaminopropionic acid kinase activity.Take this to produce the binding site of intracellular signal transduction molecule, be convenient to suitable cell response (for example cell fission with a series of, differentiation, metabolism, the variation of extracellular microenvironment) kytoplasm signaling molecule forms mixture, and (example is seen Schlessinger and Ulrich, 1992, neurone 9:1-20).
Protein with SH2 (src homology-2) or Tyrosine O-phosphate combination (PTB) structural domain combines so that signal is transmitted in the cell with activated tyrosine kinase receptor and substrate thereof with high-affinity.These two structural domain identification Tyrosine O-phosphates (Fantl etc., 1992, cell, 69:413-423; Songyang etc., 1994, molecular cytobiology, 14:2777-2785; Songyang etc., 1993, cell, 72:767-778; With Koch etc., 1991, science, 252:668-678; Shoelson, Curr.Opin.Chem.Biol (1997), 1 (2), 227-234; Cowburn, Curr.Opin.Struct.Biol. (1997), 7 (6), 835-838).Identified several and the interior substrate protein white matter of receptor tyrosine kinase (RTK) bonded cell.They can be divided into two big groups: (1) has the substrate of catalyst structure domain; (2) lack this structural domain but can be used as adapter and with the molecule bonded substrate with catalytic activity (Songyang etc., 1993, cell, 72:767-778).Interactional specificity between the SH2 of acceptor or protein and its substrate or the PTB structural domain is by being right after the amino-acid residue decision on every side of phosphorylated tyrosine residue.For example, the binding affinity difference between the aminoacid sequence on SH2 structural domain and the special receptor around the Tyrosine O-phosphate residue relevant with the difference of viewed its substrate phosphorylation distribution plan (Songyang etc., 1993, cell, 72:767-778).Observations shows that the function of each receptor tyrosine kinase is not only determined by the utilizability of its expression pattern and part, also by being determined by the selection of time of special receptor activated downstream signal transduction pathway array and those stimulations and the length of holding time.Therefore, phosphorylation provides important regulating step, can determine the selectivity of the signal pathway collected by specific growth factor receptors and differentiation factor receptors.
It is believed that such as FGFR-1 PDGFR, several receptor tyrosine kinases of TIE-2 and c-Met and vasculogenesis is worked with its bonded somatomedin, but wherein some can promote vasculogenesis (Mustonen and Alitalo indirectly, the cytobiology magazine, 129:895-898,1995).A kind of such receptor tyrosine kinase (being known as " tire liver kinases 1 " (FLK-1)) is the member of III type RTK subclass.Another title of people FLK-1 is " acceptor that contains kinases insert structure territory " (KDR) (Terman etc., oncogene 6:1677-83,1991).Another title of FLK-1/KDR be " blood vessel Inner skin cell growth factor acceptor 2 " (VEGFR-2) because it combines with VEGF with high-affinity.Mouse FLK-1/VEGFR-2 is also referred to as NYK (Oelrichs etc., oncogene 8 (1): 11-15,1993).Isolated encoding murine, the DNA of rat and people FLK-1 has reported Nucleotide and amino acid sequence coded (Matthews etc., Proc.Natl.Acad.Sci.USA, 88:9026-30,1991; Terman etc., 1991, document is the same; Terman etc., Biochem.Biophys.Res.Comm.187:1579-86,1992; Sarzani etc., document is the same; With Millauer etc., cell, 72:835-846,1993).Multinomial research (Millauer etc. for example, document is the same to be reported) show that VEGF and FLK-1/KDR/VEGFR-2 are that ligand-receptor is right, they play an important role in vascularization and the growth fast (being called as blood vessel respectively takes place and vasculogenesis) at vascular endothelial cell proliferation.
Another kind is called as " fms-sample Tyrosylprotein kinase-1 " III type RTK subclass relevant (DeVries etc., science, 255:989-991,1992 with FLK-1/KDR (Flt-1); Shibuya etc., oncogene, 5:519-524,1990).Another title of Flt-1 be " vascular endothelial growth factor receptor 1 " (VEGFR-1).At present, the member who has found FLK-1/KDR/VEGFR-2 and Flt-1/VEGFR-1 subtribe mainly expresses on endotheliocyte.The member of these subclass is by member's differential stimulus of vascular endothelial growth factor (VEGF) ligand family (Klagsburn and D ' Amore, Xi Baoyinzi ﹠amp; Somatomedin comment 7:259-270,1996).With respect to for the combining of FLK-1/KDR, vascular endothelial growth factor (VEGF) combines with Flt-1 with higher affinity, and to blood vessel Inner chrotoplast have short splitting action (Terman etc., 1992, document is the same; Mustonen etc., document is the same; DeVries etc., document is the same).It is believed that in vascular development process Flt-1 is that the formation of Inner skin structure is necessary.The expression of Flt-1 is relevant with early stage vascular development in the mice embryonic, and generates relevant (Mustonen and Alitalo, document is the same) with neovascularity in the wound healing process.Flt-1 is at monocyte, and osteoclast and scleroblast and adult's tissue demonstrate another function, this function and the cell growth uncorrelated (Mustonen and Alitalo, document is the same) of this receptor as the expression in the renal glomerulus.
As indicated above, up-to-date evidence shows: VEGF generates normal and pathologic vessels and plays hormesis (Jakeman etc., incretology, 133:848-859,1993; Kolch etc., breast cancer research and treatment, 36:139-155,1995; Ferrara etc., Inner secretes comment, and 18 (1); 4-25,1997; Ferrara etc., the adjusting of vasculogenesis (compiling), 209-232,1997 by L.D.Goldberg and E.M.Rosen).In addition, VEGF also participates in controlling and strengthening permeability (Connolly etc., journal of biological chemistry, 264:20017-20024,1989 of blood vessel; Brown etc., the adjusting of vasculogenesis (compiling), 233-269,1997 by L.D.Goldberg and E.M.Rosen).Reported multi-form VEGF, comprised 4 kinds of forms of (cellular biochemistry magazine, 47:211-218,1991) descriptions such as Ferrara by the another kind of montage generation of mRNA.Ferrara etc., the same secretor type VEGF and main and the cell bonded VEGF of having identified of document, known this protein exists with the dimeric forms that is connected by disulfide linkage.
Recently, several relevant VEGF homologues have been identified.Yet, do not illustrate their effects in normal physiological and lysis yet.In addition, in a lot of tissues, the frequent and VEGF co expression of the member of VEGF family, they can form heterodimer with VEGF usually.This characteristic may change the receptor-specific and the biological action of heterodimer, and make further complicated (Korpelainen and the Alitalo of illustrating of hereinafter described its specific function, the up-to-date viewpoint of cytobiology, 159-164,1998 and the reference wherein mentioned).
Placenta growth factor (PIGF) has and the remarkable homologous aminoacid sequence of VEGF sequence (Park etc., journal of biological chemistry, 269:25646-54,1994; Maglione etc., oncogene 8:925-31,1993).About VEGF, produced PIGF not of the same race by the another kind of montage mode of mRNA, there are (Park etc., document is the same) in this protein with dimeric form.PIGF-1 and PIGF-2 combine with Flt-1 with high-affinity, and PIGF-2 tends to also that (273 (35): 22272-22278), they do not combine (Park etc., document is the same) with FLK-1/KDR for Migdal etc., journal of biological chemistry in conjunction with neuropilin-1.It is reported when VEGF with lower concentration (it is said it is) when existing because due to heterodimer forms, PIGF can strengthen vascular permeability and the VEGF short splitting action (Park etc., document is the same) to the Inner chrotoplast.
As if VEGF-B occurs with two kinds of isotypes (167 and 185 residues), and it also can be in conjunction with Flt-1/VEGFR-1.It is in the expression of passing through modulation urokinase-type plasminogen activator and plasmin activator inhibitor 1 and active in to regulate extracellular matrix degradation, (Pepper etc. work for cell adhesion and migration aspect, Proc.Natl.Acad.Sci.U.S.A. (1998), 95 (20): 11709-11714).
VEGF-C is cloned as the VEGFR-3/Flt-4 part of mainly being expressed by the lymph endotheliocyte.Also in conjunction with KDR/VEGFR-2, and can stimulate the propagation of external Inner chrotoplast and vasculogenesis (Lymboussaki etc., American Journal of Pathology, 1998,153 (2): 395-403 of migration and body inner model through the VEGF-C of processing fully; Witzenbichler etc., American Journal of Pathology, 1998,153 (2), 381-394).Transgenic over expression VEGF-C only causes lymphatic vessel propagation and expansion, and can not exert an influence to blood vessel.Different with VEGF is, the expression of VEGF-C can not by hypoxia inducible (Ristimaki etc., journal of biological chemistry, 1998,273 (14), 8413-8418).
The VEGF-D of latest find is structurally closely similar with VEGF-C.It is reported, VEGF-D at least can in conjunction with and activate two kinds of VEGFR, i.e. VEGFR-3/Flt-4 and KDR/VEGFR-2.Originally, it is cloned as fibroblastic c-fos induction type mitogen, and it mainly expresses (Achen etc., Proc.Natl.Acad.Sci.U.S.A.1998 in the mesenchymal cell of lung and skin, 95 (2), 548-553 and the reference of wherein mentioning).
About VEGF, it is said that when being injected to skin histology, VEGF-C and VEGF-D be the increase (PCT/US97/14696 of induction of vascular permeability in vivo in the Miles test; WO98/07832, Witzenbichler etc., document is the same).Physiological role and meaning aspect the endotheliocyte reaction of these parts in the tissue of modulation blood vessel high-permeability and this part of expression are still indeterminate.
Reported a kind of novel vascular Inner skin cell growth factor VEGF-E (NZ-7VEGF) recently by encoding viral, it preferentially utilizes the KDR/Flk-1 acceptor and has strong short mitotic activity, and do not contain and heparin-bounding structural domain (Meyer etc., EMBO J.1999,18 (2), 363-374; Ogawa etc., journal of biological chemistry, 1998,273 (47), 31273-31282).VEGF-E sequence and Mammals VEGF have 25% homology, and are encoded by parapoxvirus Orf virus (OV).Parapoxvirus can infect sheep and goat, once in a while also can infected person, produce the infringement of following vasculogenesis.VEGF-E is the dimer that is about 20kDa, its alkali-free structural domain, heparin there is not affinity yet, but have the characteristic cysteine knot primitive that all exists among all Mammals VEGF, surprisingly, it also has effectiveness and the biological activity that is similar to VEGF-A and heparin-bonded VEGF165 isotype, be that these two kinds of factors can both stimulate the vitro tissue factor (TF) to discharge, the propagation of the blood vessel Inner chrotoplast of cultivating, chemotaxis and quick growth and body Inner vasculogenesis.The same with VEGF165, VEGF-E can combine with vegf receptor-2 (KDR) with high-affinity, causes the receptor autophosphorylation phosphorylation, free cell Inner Ca 2+The concentration two-phase increases, and opposite with VEGF165 is that VEGF-E does not combine with vegf receptor-1 (Flt-1).
According to other VEGF of continuous discovery and the precedent of VEGFR homologue and part and acceptor heterodimerization, the effect of described VEGF homologue comprises formation VEGF part heterodimer, and/or make the acceptor heterodimerization, or combine (Witzenbichler etc., document is the same) with undiscovered VEGFR still.In addition, up-to-date report shows neuropilin-1 (Migdal etc., document is the same) or VEGFR-3/Flt-4 (Witzenbichler etc., document is the same) or the acceptor except that KDR/VEGFR-2 may participate in induction of vascular permeability (Stacker, S.A., Vitali, A., Domagala, T., Nice, E., and Wilks, A.F., " vasculogenesis and cancer " meeting, american cancer research association, in January, 1998, Orlando, FL; Williams, Diabetelogia40:S118-120 (1997)).
Tie-2 (TEK) is the member of the Inner chrotoplast specific receptors family tyrosine kinase of recent findings, and it participates in necessary angiogenesis, and for example vessel branch is grown fast, and analogue formation is ripe and stable again.Tie-2 is first mammalian receptors Tyrosylprotein kinase, has identified its agonist ligand (for example angiopoietin1 of costimulatory receptor autophosphorylation and signal transduction (" Ang1 ")) and antagonist ligand (for example angiopoietin2 (" Ang2 ")).Knocking out with transgeneic procedure of carrying out of the expression of Tie-2 and part thereof shown: the Tie-2 signal is carried out strict control on room and time be that neovasculature is suitably grown necessary.Up-to-date model shows the branch that participates in neovascularity by Ang1 ligand stimulation Tie-2 kinases directly, grows fast and grows, the collection of Inner chrotoplast on every side and interact and support to induce disease by the vital cell of containment state to keeping the blood vessel complete sum.Shortage that the Ang1 of Tie-2 stimulates or the loss that can cause blood vessel structure to contact with matrix by Ang2 inhibition Tie-2 autophosphorylation (producing with high level) in blood vessel degeneration site, cause endotheliocyte death, especially all the more so when lacking growth/survival stimulation.Yet this situation is complicated more, because reported at least two kinds of other Tie-2 parts (Ang3 and Ang4) recently, has illustrated the different oligomerize of angiopoietin of multiple agonist and antagonist form, the active ability of taking this to modify them.Therefore, target Tie-2 ligand-receptor interaction is comparatively unfavorable as the methods of treatment of angiogenesis inhibitor, preferably uses the kinase inhibition strategy.
The foundation of tumor vessel system during the eye neovascularity that breast tumor xenotransplantation and lung metastasis model and tumour cell-mediation can be destroyed in Tie-2 soluble cell outer structure territory (" ExTek ") generates.By adenovirus infection, can in rodent, reach 7 to 10 days by the ExTek of body Inner generation mg/ml level, and not have deleterious side effect.These results show that destroying the Tie-2 signal pathway in the animal of normal health can be well tolerated.Tie-2 inhibited reaction at ExTek may be the consequence that chelating ligand and/or generation have the unproductive heterodimer of total length Tie-2.
Recently, Tie-2 expresses significantly rise in the blood vessel Synovial joint screen of finder's arthritis knuckle, and this is consistent with unsuitable neovascularity nucleus formation.This discovery shows that Tie-2 works in the progress of rheumatoid arthritis.In people's venous malformation disease, identified the point mutation of the Tie-2 form that produces constitutive activation.Therefore, the Tie-2 inhibitor can be used for treating this disease, and can be used for the situation that other inappropriate neovascularity generates.
Non--receptor tyrosine kinase.Non--receptor tyrosine kinase representative lacks the extracellular and strides the set of the cellular enzymes of film sequence.At present, identified and surpass 24 independently nonreceptor tyrosine kinases, it comprises 11 subtribes (Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack and LIMK).At present, the Src subtribe of nonreceptor tyrosine kinase is made up of the PTK of maximum number, and it comprises Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.The Src subtribe of this enzyme takes place relevant with immunne response with cancer.The more detailed discussion of relevant nonreceptor tyrosine kinase can be referring to Bohlen, and 1993, oncogene 8:2025-2031 (listing this paper in as a reference).
Found that a lot of Tyrosylprotein kinases (no matter being RTK or nonreceptor tyrosine kinase) participate in the cell signal approach, described approach and multiple pathological state comprise cancer, and psoriasis is with other excess proliferative disease or excessively immunne response is relevant.
Exploitation can be modulated the compound of PTK.In view of PTK is controlling, regulate and modulation cell proliferation, the importance that disease relevant with abnormal cell proliferation and disorderly aspect are inferred, people use several different methods to carry out a lot of trials to identify acceptor and non--receptor tyrosine kinase " inhibitor ", described method comprises the part (United States Patent (USP) 4 that uses sudden change, 966,849), soluble receptors and antibody (application number WO94/10202; Kendall ﹠amp; Thomas, 1994, Proc.Natl.Acad.Sci.90:10705-09; Kim etc., 1993, natural 362:841-844), RNA part (Jellinek etc., biological chemistry 33:10450-56; Takano etc., 1993, cellular elements biology 4:358A; Kinsella etc., 1992, Exp.CellRes.199:56-62; Wright etc., 1992, the stechiology magazine, 152:448-57) and tyrosine kinase inhibitor (WO 94/03427; WO 92/21660; WO 91/15495; WO94/14808; United States Patent (USP) 5,330,992; Mariani etc., 1994, Proc.Am.Assoc.Cancer Res.35:2268).
Recently, attempted identifying the small molecules that can be used as tyrosine kinase inhibitor.For example, two monocycles, dicyclo or heterocyclic aryl compound (PCT WO 92/20642) and vinylidene-7-azaindole derivatives (PCT WO 94/14808) are described to tyrosine kinase inhibitor usually.Compound of styryl (United States Patent (USP) 5,217,999), the pyridinyl compounds of styryl-replacement (United States Patent (USP) 5,302,606), some quinazoline derivant (EP application number 0,566 266 Al; Expert Opin.Ther.Pat. (1998), 8 (4): 475-478), assorted indoles of selenium and selenide (PCT WO 94/03427), three ring polyols (PCT WO 92/21660) and benzylphosphonic acid compound (PCT WO 91/15495) are described to can be used as the compound of the tyrosine kinase inhibitor that can treat cancer.Anilino cinnolines (PCT WO97/34876) and quinazoline derived compounds (PCT WO97/22596; PCT WO97/42187) is described to the inhibitor of vasculogenesis and vascular permeability.
In addition, also attempt identifying the small molecules of useful as serine/threonine kinase enzyme inhibitors.For example, two (Indolylmaleimide) compound is described to the PKC serine/threonine kinase isotype that can suppress specific, in the VEGF-relative disease, vascular permeability-related (the PCT WO97/40830 of the signal transduction functionality of described isotype and change; PCT WO97/40831).The Plk-1 kinase inhibitor
Plk-1 is a serine/threonine kinase, and it is the important conditioning agent of cell cycle progression.It is playing an important role aspect the assembling of mitotic spindle device and the dynamic function.Known Plk-1 and relevant kinases and other Cycle Regulation agent, closely related as the activation and the deactivation of cyclin-dependent kinases.High-caliber Plk-1 expresses relevant with cell-proliferation activity.Often can in the malignant tumour in multiple source, find Plk-1.The inhibitor of Plk-1 is expected to relate to mitotic spindle and inappropriate activated cyclin-dependent kinases is blocked cancer cell multiplication by destruction.Cdc2/ cell periodic protein B kinase inhibitor (Cdc2 is also referred to as cdkl)
The Cdc2/ cell periodic protein B is the serine/threonine kinase that another kind belongs to cyclin-dependent kinases (cdks) family.Important conversion between a plurality of periods of these enzymes participation cell cycle progressions.It is believed that cell proliferation out of control (sign of cancer) depends on the cdk activity that raises in these cells.Can suppress propagation and the normal control that can recover the cell cycle process by the cdk that raises in the cdc2/ cell periodic protein B kinase inhibitor anticancer is active.
The activation of regulating CDK is complicated, but needs member (Draetta, cytobiology trend, the 3:287-289 (1993) of associating CDK and regulator subunit cyclin family; Murray and Kirschner, nature, 339:275-280 (1989); Solomon etc., the molecular biology of cell, 3:13-27 (1992)).Phosphorylation by activation and deactivation CDK subunit can be carried out the adjusting (Draetta, cytobiology trend, 3:287-289 (1993)) of another kind of level; Murray and Kirsclmer, nature, 339:275-280 (1989); Solomon etc., the molecular biology of cell, 3:13-27 (1992); Ducommun etc., EMBO J, 10:3311-3319 (1991); Gautier etc., natural 339:626-629 (1989); Gould and Nurse, nature, 342:3945 (1989); Krek and Nigg, EMBO J, 10:3331-3341 (1991); Solomon etc., cell, 63:1013-1024 (1990)).The equal activation cyclin/CDK mixture different with deactivation is necessary (Pines, biochemical science trend, 18:195-197 (1993) of cell cycle normal procedure; Sheir, cell, 73:1059-1065 (1993)).Requisite G1-S is controlled by the active activation of different cyclin/CDK with the G2-M conversion.It is believed that at G1 interim, beginning (Matsushima etc., the Fen Zi ﹠amp of cyclin D/CDK4 and cyclin E/CDK2 mediation S-phase; Cytobiology, 14:2066-2076 (1994); Ohtsubo and Roberts, science, 259:1908-1912 (1993); Quelle etc., Ji Yin ﹠amp; Grow 7:1559-1571 (1993); Resnitzky etc., Fen Zi ﹠amp; Cytobiology, 14:1669-1679 (1994)).The activity (Girard etc., cell, the 67:1169-1179 (1991) that need cyclin A/CDK2 through the process of S-phase; Pagano etc., EMBO J, 11:961-971 (1992); Rosenblatt etc., Proc.Natl.Acad.Sci.USA, 89:2824-2828 (1992); Walker and Maller, nature, 354:314-317 (1991); Zindy etc., Sheng Wuhuaxue ﹠amp; The biophysical studies communication, 182:1144-1154 (1992)), and the activation of cyclin A/cdc2 (CDK1) and cell periodic protein B/cdc2 is to begin necessary (Draetta, cytobiology trend, 3:287-289 (1993) mid-term; Murray and Kirschner, nature, 339:275-280 (1989); Solomon etc., the molecular biology of cell, 3:13-27 (1992); Girard etc., cell, 67:1169-1179 (1991); Pagano etc., EMBO J, 11:961-971 (1992); Rosenblatt etc., Proc.Natl.Acad.Sci.USA, 89:282-2828 (1992); Walker and Maller, nature, 354:314-317 (1991); Zindy etc., Sheng Wuhuaxue ﹠amp; The biophysical studies communication, 182:1144-1154 (1992)).Therefore, the excess proliferative disease beyond doubt out of control of CDK adjusting and multiple incident (Pines, the up-to-date viewpoint of cytobiology, the 4:144-148 (1992) in the cancer; Lees, the up-to-date viewpoint of cytobiology, 7:773-780 (1995); Hunter and Pines, cell, 79:573-582 (1994)).
The kinase whose inhibitor that participates in mediation or keep morbid state is being represented the new therapy of these diseases.Described kinase whose example includes but not limited to: (1) suppresses c-Src (Brickell, Critical Reviews in Oncogenesis, the 3:401406 (1992) in the cancer; Courtneidge, carcinobiology symposial, 5:236-246 (1994), raf (Powis, Yao Wuxue ﹠amp; Therapeutical agent, 62:57-95 (1994)) and cyclin-dependent kinases (CDK) 1,2 and 4 (Pines, the up-to-date viewpoint of cytobiology, 4:144-148 (1992); Lees, the up-to-date viewpoint of cytobiology, 7:773-780 (1995); Hunter and Pines, cell, 79:573-582 (1994)), (2) CDK2 or the PDGF-R kinases (Buchdunger etc. in the inhibition restenosis, Proc.Natl.Acad.Sci.USA, 92:225-2262 (1995)), (3) suppress CDK5 and the GSK3 kinases (Hosoi etc. among the Alzheimers, journal of biological chemistry (Tokyo), 117:741-749 (1995); Aplin etc., neurochemistry magazine, 67:699-707 (1996), (4) c-Src kinases (Tanaka etc., nature, the 383:528-531 (1996) in the inhibition osteoporosis, (5) GSK-3 kinases (Borthwick etc., the Sheng Wuhuaxue ﹠amp in the inhibition diabetes B; The biophysical studies communication, 210:738-745 (1995), (6) the p38 kinases (Badger etc. in the inflammation-inhibiting, pharmacology and experimental therapy agent magazine, 279:1453-1461 (1996)), (7) suppress to relate to VEGF-R 1-3 and TIE-1 and-2 kinases (Shawver etc. in the disease of vasculogenesis, today drug discovery, 2:50-63 (1997)), (8) the UL97 kinases (He etc., Journal of Virology, 71:405411 (1997)) in the inhibition virus infection, (9) CSF-1R kinases (Myers etc., the biological You Ji ﹠amp in inhibition bone and the hematopoietic disease; The pharmaceutical chemistry communication, 7:421-424 (1997) and (10) suppress Lck kinases (Myers etc., the biological You Ji ﹠amp in autoimmune disease and the transplant rejection; The pharmaceutical chemistry communication, 7:417-420 (1997)).
In addition, when some kinases is not regulated by mistake, but keep morbid state institute when essential, these kinase whose inhibitor can be used for treating disease.At this moment, suppress kinase activity and can cure or alleviate these diseases.For example, such as a lot of virus damage cell cycle of human papillomavirus and make cell enter cell cycle S-phase (Vousden, FASEBJ, 7:8720879 (1993)).After virus infection by suppressing essential S-phase initial activity, as CDK2 prevent cell enter DNA synthetic can be by preventing virus replication the break virus life cycle.Can use the normal cell of identical principle protection health avoid the cycle-toxicity (Stone etc., cancer research, the 56:3199-3202 (1996) of specificity chemotherapeutic; Kohn etc., cellular biochemistry magazine, 54:44-452 (1994)).Suppress CDK 2 or 4 and can prevent to enter the normal cell cycle, and limit to the S-phase the cytotoxic toxicity that G2 or mitotic division are worked.In addition, proved that CDK2/ cyclin E activity can regulate NF-kB.Suppress the CDK2 activity and can stimulate NF-kB-dependent form genetic expression (by the incident that interacts and mediate with p300 co-activation thing) (Perkins etc., science, 275:523-527 (1997)).NF-kB regulates and relates to the gene of inflammatory reaction (as hemopoieticgrowth factor, chemokine and leukocyte adhesion molecule) (Baeuerle and Henkel, immunity is commented academic year, 12:141-179 (1994)), and can participate in suppressing intracellular apoptosis signal (Beg and Baltimore, science, 274:782-784 (1996); Wang etc., science, 274:784-787 (1996); VanAntwerp etc., science, 274:787-789 (1996)).Therefore, suppressing CDK2 can suppress by cell toxicity medicament inductive apoptosis via the mechanism that relates to NF-kB.Show that thus inhibition CDK2 activity also can be used for NF-kB and is adjusted in other occasion that works in disease pathogen.Other example comprises fungi infestation: aspergillosis is the patient's of no immunological competence common infection (Armstrong, clinical transmissible disease, 16:1-7 (1993)).Suppress Aspergillus kinase c dc2/CDC28 or Nim A (Osmani etc., EMBOJ, 10:2669-2679 (1991); Osmani etc., cell, 67:283-291 (1991)) can cause fungi to be suppressed or death, improve the patient's who suffers from these infection result of treatment.
Therefore; the effective little compound of essential evaluation; this compound should be able to suppress signal transduction and cell proliferation by the active specificity of modulation acceptor and non-receptor tyrosine and serine/threonine kinase, thereby regulates and modulate unusual or unsuitable cell proliferation, differentiation or metabolism.Especially, method and the compound of identifying the function of specificity inhibition Tyrosylprotein kinase are favourable, and described Tyrosylprotein kinase is angiogenesis or causes edema, ascites, seepage oozes out that to blend the formation of blood vessel high-permeability of apposition and relative disease outward necessary with macromole.
The invention summary
The invention provides formula I compound With its pharmaceutical salts.
In formula I, the A ring is six Yuans aromatic nucleus or five or six Yuans assorted aromatic nucleus.The A ring is replaced by one or more following substituting groups non-imposedly: replace or unsubstituted aliphatic group, halogen, replace or unsubstituted aromatic base, replace or unsubstituted assorted aromatic base, replace or unsubstituted cycloalkyl, replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted aralkyl, replace or unsubstituted heteroaralkyl cyano group, nitro ,-NR 4R 5,-C (O) 2H ,-OH replaces or unsubstituted carbalkoxy-C (O) 2-haloalkyl, replace or unsubstituted alkylthio ether, replace or the unsubstituted alkyl sulfoxide, replace or the unsubstituted alkyl sulfone, replace or unsubstituted arylthio ether, replace or unsubstituted aryl sulfoxide, replace or unsubstituted aryl sulfone, replace or the unsubstituted alkyl carbonyl-C (O)-haloalkyl, replace or unsubstituted aliphatic ether, replace or unsubstituted aromatic oxide, replace or unsubstituted methane amide tetrazyl, the fluoroform sulfoamido, the trifluoromethyl carbonylamino replaces or unsubstituted alkynyl, replaces or the unsubstituted alkyl amide group, replace or unsubstituted aryl amido group-NR 95C (O) R 95, replace or unsubstituted styryl and replacement or unsubstituted arylalkyl amide base, wherein R 95Be aliphatic group or aromatic base.
L is one of following connection base:
-O-;-S-;-S (O)-;-S (O) 2-;-N (R)-;-N (C (O) OR)-;-N (C (O) R)-;-N (SO 2R)-;-CH 2O-;-CH 2S-;-CH 2N (R)-;-CH (NR)-;-CH 2N (C (O) R))-;-CH 2N (C (O) OR)-;-CH 2N (SO 2R)-;-CH (NHR)-;-CH (NHC (O) R)-;-CH (NHSO 2R)-;-CH (NHC (O) OR)-;-CH (OC (O) R)-;-CH (OC (O) NHR)-;-CH=CH-;-C (=NOR)-;-C (O)-;-CH (OR)-;-C (O) N (R)-;-N (R) C (O)-;-N (R) S (O)-;-N (R) S (O) 2-;-OC (O) N (R)-;-N (R) C (O) N (R)-;-NRC (O) O-;-S (O) N (R)-;-S (O) 2N (R)-; N (C (O) R) S (O)-; N (C (O) R) S (O) 2-;-N (R) S (O) N (R)-;-N (R) S (O) 2N (R)-;-C (O) N (R) C (O)-;-S (O) N (R) C (O)-;-S (O) 2N (R) C (O)-;-OS (O) N (R)-;-OS (O) 2N (R)-;-N (R) S (O) O-;-N (R) S (O) 2O-;-N (R) S (O) C (O)-;-N (R) S (O) 2C (O)-;-SON (C (O) R)-;-SO 2N (C (O) R)-;-N (R) SON (R)-;-N (R) SO 2N (R)-;-C (O) O-;-N (R) P (OR ') O-;-N (R) P (OR ')-;-N (R) P (O) (OR ') O-;-N (R) P (O) (OR ')-;-N (C (O) R) P (OR ') O-;-N (C (O) R) P (OR ')-;-N (C (O) R) P (O) (OR ') O-or-N (C (O) R) P (OR ')-.R and R ' are-H independently of one another; acyl group replaces or unsubstituted aliphatic group, replaces or unsubstituted aromatic base; replace or unsubstituted assorted aromatic base, or replacement or unsubstituted cycloalkyl.
In addition, L is-R bN (R) S (O) 2-,-R bN (R) P (O)-, or-R bN (R) P (O) O-.R bBe alkylidene group, when itself and the sulphonamide that is connected, inferior phosphonic amide, or the phosphono amido forms together the time and A ring condensed five or six membered ring.
In addition, L represents one of following structural;
Figure A9981321700561
R 85With inferior phosphonic amide, or phosphonic amide is 5-together, 6-, or 7-person's fragrance, assorted fragrance or Heterocyclylalkyl ring system.
In formula I, R 1It is the aliphatic group that replaces, the cycloalkyl that replaces, the bicyclic alkyl of replacement, the cycloalkenyl group of replacement, the aromatic base of non-imposed replacement, the assorted aromatic base of non-imposed replacement, the heteroaralkyl of non-imposed replacement, the Heterocyclylalkyl of non-imposed replacement, the assorted bicyclic alkyl of non-imposed replacement, the alkylamino of non-imposed replacement, the arylamino of non-imposed replacement, non-imposed replacement-S (O) 2-alkyl or non-imposed replacement-S (O) 2-cycloalkyl ,-C (O)-alkyl or non-imposed replacement-C (O)-alkyl.
R 1Can be replaced by one or more substituting groups.Preferably, R 1Replaced by following substituting group: replace or unsubstituted aliphatic group, replace or unsubstituted aromatic base, replace or unsubstituted assorted aromatic base, replace or unsubstituted aralkyl, replace or unsubstituted heteroaralkyl, replace or unsubstituted cycloalkyl, replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted aromatic oxide, replace or unsubstituted aliphatic ether, replace or unsubstituted carbalkoxy, replace or the unsubstituted alkyl carbonyl, replace or unsubstituted aryl carbonyl, replace or unsubstituted heteroaryl carbonyl, replace or unsubstituted aryloxy carbonyl,-OH replaces or unsubstituted aminocarboxyl oxime, replace or unsubstituted azabicycloalkyl, Heterocyclylalkyl, oxo base, aldehyde, replace or the unsubstituted alkyl sulfoamido, replace or unsubstituted aryl-sulfonyl amino, replace or unsubstituted bicyclic alkyl, replace or unsubstituted assorted bicyclic alkyl, cyano group ,-NH 2, alkylamino, urea groups, thioureido and-B-E replaces.
B replaces or unsubstituted cycloalkyl, replaces or unsubstituted Heterocyclylalkyl, replaces or unsubstituted aromatic base, replaces or unsubstituted assorted aromatic base alkylidene group, aminoalkyl group, alkylidene group carbonyl, or aminoalkyl group carbonyl.
E replaces or unsubstituted azacycloalkyl; replace or unsubstituted azacycloalkyl carbonyl; replace or unsubstituted azacycloalkyl alkylsulfonyl; replace or unsubstituted azacycloalkyl alkyl; replace or unsubstituted heteroaryl; replace or unsubstituted heteroaryl carbonyl; replace or unsubstituted heteroarylsulfonyl; replace or unsubstituted heteroaralkyl; replace or the unsubstituted alkyl sulfoamido, replace or unsubstituted aryl-sulfonyl amino, replace or unsubstituted bicyclic alkyl; replace or unsubstituted urea groups, replace or unsubstituted thioureido or replacement or unsubstituted aryl.
But, work as R 1When being aliphatic group or cycloalkyl, R 1Removing property ground can not be replaced by one or more one group of substituting group being made up of hydroxyl and lower alkyl ether that are selected from.In addition, Heterocyclylalkyl is not a 2-phenyl-1,3-dioxan-5-base, and aliphatic group removing property ground can not be replaced by one or more aliphatic groups.
In formula I, R 2Be-H, replace or unsubstituted aliphatic group, replace or unsubstituted cycloalkyl halogen,-OH, cyano group replaces or unsubstituted aryl group, replaces or unsubstituted assorted aromatic group, replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted aralkyl, replace or unsubstituted heteroaralkyl-NR 4R 5, or-C (O) NR 4R 5
In formula I, R 3Be to replace or unsubstituted cycloalkyl, replace or unsubstituted aryl group, replace or unsubstituted assorted aromatic group, replace or unsubstituted Heterocyclylalkyl.
In formula I, R 4, R 5Form 3,4,5,6 or 7-person replaces or unsubstituted Heterocyclylalkyl together with nitrogen-atoms, replace or unsubstituted assorted bicyclic alkyl or replacement or unsubstituted assorted aromatic base.
In addition, R 4And R 5Be-H azabicycloalkyl, replacement or unsubstituted alkyl or Y-Z independently of one another.
Y is-C (O)-and ,-(CH 2) p-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) pO-, (CH 2) pNH-, (CH 2) pS-, (CH 2) pS (O)-and (CH 2) pS (O) 2-.
P is 0 to about 6 integer.
Z replaces or unsubstituted alkyl, replaces or unsubstituted amino, replaces or unsubstituted aryl, replaces or unsubstituted heteroaryl or replacement or unsubstituted Heterocyclylalkyl.
J is 0 to 6 integer.
But, when L is-CH 2NR-,-C (O) NR-or-NRC (O)-, and R 3When being azacycloalkyl or azepine heteroaryl, j is 0.In addition, as L be-O-and R 3When being phenyl, j is 0.
The compounds of this invention useful as serine/Threonine and tyrosine kinase inhibitor.Particularly The compounds of this invention can be used as for excess proliferative disease, especially the inhibitor of the very important Tyrosylprotein kinase of cancer and angiogenesis.For example, some in these compounds is such as KDR, Flt-1, FGFR, PDGFR, c-Met, the inhibitor of TIE-2 or IGF-1-R receptor kinase.Because some in these compounds is anti-angiogenic agent, therefore when vasculogenesis was an important factor, they were the important substance that are used to suppress the illness development.Some compound of the present invention is as serine/threonine kinase such as PKCs, erk, and map kinase, the map kinase kinases, the map kinase kinase kinase, cdks, the inhibitor of plk-1 or Raf-1 are effective.These compounds can be used for treating cancer, excess proliferative disease.In addition, some compound is non-receptor kinase such as Src (for example, Ick, blk and lyn), Tec, Csk, jak, Map, the kinase whose effective inhibitor of Nik and Syk family.These compounds can be used for treating cancer, excess proliferative disease and Immunological diseases.
When in the presence of the relevant stimulation of VEGF-, or during with its synergistic application, some compound of the present invention is a TIE-2 kinase inhibitor optionally, and they may be anti-angiogenic agent (especially with one or more VEGFR inhibitor associatings), or preceding angiogenic agent.By this way, this class inhibitor can be used to promote the treatment vasculogenesis, thereby treatment is for example, local asphyxia, and infraction or inaccessible, or promote wound healing.
The invention provides the method for the kinase activity that suppresses Tyrosylprotein kinase and serine/threonine kinase, comprise described kinases is used its concentration and be enough to suppress the compound shown in the formula I of described kinase whose enzymic activity.
The present invention also comprises the purposes of these compounds in the pharmaceutical composition of the above-claimed cpd that comprises medicinal significant quantity and pharmaceutical carrier or vehicle.Thereby these pharmaceutical compositions can slow down or stop at the process that vasculogenesis class disease medium vessels generates individual administration, or the treatment oedema, and seepage is oozed out or ascites and other and blood vessel hypertonicity diseases associated.The some drugs composition can be to individual administration, by suppressing serine/threonine kinase such as cdks, plk-1, treatment cancer such as erk and excess proliferative disease.Detailed Description Of The Invention
Substituent definition provides below in the formula I compound of first preferred group.
Preferably, L is-NRSO 2-,-SO 2NR-,-NRC (O)-or-C (O) NR-,-NH-,-NR-or-O-.
Preferably, R 3Be to replace or unsubstituted phenyl, replace or unsubstituted naphthyl, replace or the unsubstituted pyridine base, replace or unsubstituted thienyl, replace or unsubstituted benzotriazole base, replace or unsubstituted THP trtrahydropyranyl, replace or unsubstituted tetrahydrofuran base, replace or unsubstituted dioxane, replace or unsubstituted dioxolane, replace or unsubstituted quinolines, replace or unsubstituted thiazole, replace or unsubstituted isoxzzole, replace or unsubstituted cyclopentyl, replace or unsubstituted cumarone, replace or unsubstituted thionaphthene, replace or unsubstituted imidazoles, replace or unsubstituted pyrroles, replace or unsubstituted pyrimidyl, replace or unsubstituted indyl, replace or unsubstituted benzisoxa oxazolyl, replace or unsubstituted benzisothiazole, replace or unsubstituted benzothiazole, replace or unsubstituted benzoxazoles, replace or unsubstituted benzoglyoxaline, replace or unsubstituted benzo oxadiazoles, replace or unsubstituted diazosulfide, replace or unsubstituted isoquinolyl, replace or unsubstituted quinoxalinyl, replace or unsubstituted indoles or replacement or unsubstituted pyrazoles.In addition, R 3Be to replace or unsubstituted aliphatic group, replace or unsubstituted thiazolinyl, condition be L be-SN (R)-,-S (O) N (R)-,-S (O) 2N (R)-,-N (R) S-,-N (R) S (O)-,-N (R) S (O) 2-,-N (R) SN (R ')-,-N (R) S (O) N (R ')-, or-N (R) S (O) 2N (R ')-.
In another program, R 3Be to replace or unsubstituted phenyl.
R 3Can be replaced by one or more substituting groups.For R 3Preferred substituted has F, Cl, Br, I, CH 3, NO 2, OCF 3, OCH 3, CN ,-CHO, CO 2CH 3, CF 3, the tertiary butyl, pyridyl, pyridyloxy replaces or unsubstituted oxazolyl, replaces or unsubstituted thiazolyl, replace or unsubstituted benzyl, replace or unsubstituted phenoxy, replace or unsubstituted phenyl, replace or unsubstituted amino, carboxyl, replace or unsubstituted tetrazyl styryl ,-S (O) x-(replacing or unsubstituted aryl) ,-S (O) x-x=0 wherein, 1,2-(replacing or unsubstituted heteroaryl) replaces or unsubstituted heteroaryl, replaces or unsubstituted Heterocyclylalkyl alkynyl ,-C (O) NR fR g, R cAnd CH 2OR c
R f, R gForm 3-together with nitrogen-atoms, 4-, 5-, 6-or 7-person replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted assorted bicyclic alkyl or replacement or unsubstituted heteroaryl.
In addition, R fAnd R gBe-H to replace or unsubstituted aliphatic group or replacement or unsubstituted aromatic base independently of one another.
R cBe hydrogen, or replacement or unsubstituted alkyl or replacement or unsubstituted aryl;-W-(CH 2) t-NR dR e,-W-(CH 2) t-O-alkyl ,-W-(CH 2) t-S-alkyl ,-W-(CH 2) t-OH.
T is 0 to about 6 integer.
W be chemical bond or-O-,-S-,-S (O)-,-S (O) 2-, or-NR k-.
R kBe-H or alkyl.
R d, R eForm 3-together with connected nitrogen-atoms, 4-, 5-, 6-or 7-person replace or unsubstituted Heterocyclylalkyl or replacement or unsubstituted assorted bicyclic alkyl.
In addition, R dAnd R eBe independently of one another-H, alkyl, alkyloyl or-K-D.
K is-S (O) 2-,-C (O)-,-C (O) NH-,-C (O) 2-, or directly key connects.
D replaces or unsubstituted aryl, replace or unsubstituted heteroaryl, replace or unsubstituted aralkyl, replace or unsubstituted assorted aromatic base, replace or unsubstituted heteroaralkyl, replace or unsubstituted cycloalkyl, replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted amino, replace or unsubstituted aminoalkyl group, replace or unsubstituted amino cycloalkyl COOR i, or replacement or unsubstituted alkyl.
R iBe to replace or unsubstituted aliphatic group or replacement or unsubstituted aromatic base.
Antithetical phrase R 3More preferably substituting group is F, Cl, Br, I, cyano group, nitro, OCF 3, CH 3, and CF 3
Preferably, the A ring is to replace or unsubstituted phenyl, replaces or unsubstituted thienyl, replaces or unsubstituted naphthyl, replace or the unsubstituted pyridine base, or replacement or unsubstituted indoles.In a scheme, the A ring is to replace or unsubstituted phenyl.
The A ring can be replaced by one or more substituting groups.F is arranged, Cl, Br, I, CH for A ring preferred substituted 3, NO 2, OCF 3, OCH 3, CN, CO 2CH 3, CF 3, the tertiary butyl, pyridyl; replace or unsubstituted oxazolyl, replace or unsubstituted benzyl, replace or unsubstituted benzenesulfonyl; replace or unsubstituted phenoxy, replace or unsubstituted phenyl, replace or unsubstituted amino; carboxyl replaces or unsubstituted tetrazyl styryl;-S-(replacing or unsubstituted aryl) ,-S-(replacing or unsubstituted heteroaryl) replaces or unsubstituted heteroaryl; replace or unsubstituted Heterocyclylalkyl alkynyl ,-C (O) NR fR g, R cAnd CH 2OR cR f, R gAnd R cAs above definition.
The A ring is more preferably by F, and Cl and nitro replace.
R 2Hydrogen preferably.
In another program, R 1It is the following formula group
Figure A9981321700611
M is 0 to about 3 integer.
In another program, R 1It is the following formula group M, t as above defines.R 8, R 9Form 3-together with nitrogen-atoms, 4-, 5-, 6-or 7-person replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted assorted aromatic base, or replacement or unsubstituted assorted bicyclic alkyl.In addition, R 8And R 9Be-H azabicycloalkyl, azacycloalkyl or Y independently of one another 2-Z 2Y 2Be-C (O)-,-(CH 2) q-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) qO-, (CH 2) qNH-, (CH 2) qS-, (CH 2) qS (O)-and (CH 2) qS (O) 2-.Q is 0 to about 6 integer.Z 2Be to replace or unsubstituted alkyl, replace or unsubstituted amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl or replacement or unsubstituted Heterocyclylalkyl.
In another program, R 1It is the following formula group M, t, R 8And R 9As above definition.S is 0 to 6 integer.Q is 0 to 6 integer.R 77Be-OR 78, or-NR 79R 80R 78Be-H or replacement or unsubstituted aliphatic group.R 79, R 80Form 3-together with nitrogen-atoms, 4-, 5-, 6-or 7-person replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted assorted aromatic base, or replacement or unsubstituted assorted bicyclic alkyl.In addition, R 79And R 80Be-H azabicycloalkyl, azacycloalkyl or Y independently of one another 3-Z 3Y 3Be selected from-C (O)-,-(CH 2) q-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) qO-, (CH 2) qNH-, (CH 2) qS-, (CH 2) qS (O)-and (CH 2) qS (O) 2-.Z 3Be H, replace or unsubstituted alkyl, replace or unsubstituted amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl or replacement or unsubstituted Heterocyclylalkyl.
In another program, R 1It is the following formula group V is 1 to about 3 integer.R 10Be-H azabicycloalkyl, Heterocyclylalkyl or Y 2-Z 2Y 2And Z 2As preceding definition.
In another program, R 1It is the following formula group M and R 10As preceding definition.R 11Represent one or more being independently selected from by hydrogen, hydroxyl, the oxo base, replace or unsubstituted aliphatic group, replace or unsubstituted aromatic base, replace or unsubstituted assorted aromatic base, replace or unsubstituted carbalkoxy, replace or unsubstituted alkoxyalkyl, replace or unsubstituted aminocarboxyl, replace or the unsubstituted alkyl carbonyl, replace or unsubstituted aryl carbonyl, replace or unsubstituted heteroaryl carbonyl, one group of substituting group that replacement or unsubstituted aminoalkyl group and replacement or unsubstituted aralkyl are formed, condition is that the carbon atom adjacent with nitrogen-atoms do not replaced by hydroxyl.
In another program, R 1It is the following formula group
Figure A9981321700641
R 10As preceding definition.
In another program, R 1It is the following formula group
Figure A9981321700642
R is 1 to about 6 integer.R 8And R 9As preceding definition.
In another program, R 1It is the following formula group R 8, R 9With t such as preceding definition.W is 0 to 4 integer.U is 0 or 1.R 12Be hydrogen or replacement or unsubstituted alkyl.
In another program, R 1It is the following formula group
Figure A9981321700652
W, t, R 10, R 12As preceding definition.
In another program, work as R 1When being I (g) or I (H), R 8, R 9Form the Heterocyclylalkyl of following formula together with nitrogen-atoms
Figure A9981321700653
U such as preceding definition.R 13, R 14, R 15, R 16, R 17, R 18, R 19And R 20Be low alkyl group or hydrogen independently of one another.In addition, substituent R 13And R 14R 15And R 16R 17And R 18Or R 19And R 20In at least one pair of be Sauerstoffatom together.In addition, R 13And R 15In at least one be cyano group, CONHR 21, COOR 21, CH 2OR 21Or CH 2NR 21(R 22).R 21, R 22Form 3-together with nitrogen-atoms, 4-, 5-, 6-or 7-person replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted assorted aromatic base, or replacement or unsubstituted assorted bicyclic alkyl.In addition, R 21And R 22Be-H azabicycloalkyl, azacycloalkyl or Y independently of one another 3-Z 3Y 3And Z 3As preceding definition.X is-O-,-S-, -SO-,-SO 2-,-CH 2-,-CH (OR 23)-or NR 23R 23Be-H, replace or unsubstituted alkyl, replace or unsubstituted aryl, replace or unsubstituted aralkyl-C (NH) NH 2,-C (O) R 24, or-C (O) OR 24R 24Be hydrogen, replace or unsubstituted alkyl, replace or unsubstituted aryl or replacement or unsubstituted aralkyl.
In another program, R 8, R 9Form the Heterocyclylalkyl of following formula together with nitrogen-atoms
Figure A9981321700661
T, R 21And R 22As preceding definition.R 25And R 26Be hydrogen or low alkyl group independently of one another.In addition.R 25And R 26Be Sauerstoffatom together.I is 1 to 6 integer.
In another program, R 8, R 9Form the Heterocyclylalkyl of following formula together with nitrogen-atoms
Figure A9981321700662
I such as preceding definition.R 27Be CH 2OH, C (O) NR 24R 28Or COOR 24R 24And R 28As preceding definition.
In another program, R 8, R 9Form the Heterocyclylalkyl of following formula together with nitrogen-atoms
Figure A9981321700663
R 29Be to replace or unsubstituted alkyl, replace or unsubstituted aryl, or replacement or unsubstituted aralkyl, carboxylic acid, cyano group, C (O) OR 30, CH 2OR 30, CH 2NR 21R 22Or C (O) NR 21R 22R 30Be to replace or unsubstituted alkyl 2 replacement or unsubstituted aryl, or replacement or unsubstituted aralkyl, replace or unsubstituted Heterocyclylalkyl or heterocyclic aryl.R 21And R 22As preceding definition.
In another program, R 8, R 9Be formula Y 3-D, wherein D is a following formula
Figure A9981321700671
Y 3As preceding definition.X is 0,1 or 2.T is-O-,-C (O)-and ,-S-,-SO-,-SO 2-,-CH 2-,-CH (OR 24)-or-N (R 24)-.R 24As preceding definition.
In another program, R 8And R 9At least one be formula Y 3-N (R 31) R 32, Y 3As preceding definition.R 31And R 32Be to replace or unsubstituted carboxyalkyl independently of one another, replace or unsubstituted alkoxycarbonyl alkyl, replace or unsubstituted hydroxyalkyl, replace or the unsubstituted alkyl alkylsulfonyl, replace or unsubstituted alkyl carbonyl or replacement or unsubstituted cyano group alkyl.In addition, R 31And R 32Form 5-or 6-element heterocycle alkyl with nitrogen-atoms, replace or unsubstituted assorted aromatic base or replacement or unsubstituted assorted bicyclic alkyl.
In another program, work as R 1When being I (e), Z 2Be formula N (R 35) R 36R 35And R 36Be hydrogen, alkyl, carbalkoxy, alkoxyalkyl, hydroxyalkyl, aminocarboxyl, cyano group, alkyl-carbonyl or aralkyl independently of one another.
In another program, work as R 1When being I (e), Z 2It is following formula
Figure A9981321700672
Each X 1Be CH or N independently.R 37Be hydrogen, cyano group or replacement or unsubstituted alkyl replace or unsubstituted carbalkoxy, replace or unsubstituted alkoxyalkyl, replace or unsubstituted hydroxyalkyl, replace or unsubstituted aminocarboxyl, replace or unsubstituted alkyl carbonyl or replacement or unsubstituted aralkyl.
In another program, work as R 1When being I (e), Z 2It is following formula
Figure A9981321700681
G is 0 to about 3 integer.T such as preceding definition.R 37Be hydrogen, cyano group or replacement or unsubstituted alkyl replace or unsubstituted carbalkoxy, replace or unsubstituted alkoxyalkyl, replace or unsubstituted hydroxyalkyl, replace or unsubstituted aminocarboxyl, replace or unsubstituted alkyl carbonyl or replacement or unsubstituted aralkyl.
In another program, work as R 1When being I (e), Z 2It is following formula
Figure A9981321700682
G and R 37It is unsubstituting aromatic alkyl as preceding definition.
In another program, work as R 1When being I (e), Z 2It is following formula T, g and R 37As preceding definition.
In another program, work as R 1When being I (e), Z 2It is following formula
Figure A9981321700684
R 37As preceding definition.R 38Be hydrogen, replace or unsubstituted alkyl, replace or unsubstituted carbalkoxy, replace or unsubstituted alkoxyalkyl, replace or unsubstituted aminocarboxyl perhaloalkyl radical, replace or unsubstituted thiazolinyl, replace or unsubstituted alkyl carbonyl or replacement or unsubstituted aralkyl.
In another program, R 1It is the following formula group U such as preceding definition.R 39, R 40, R 41, R 42, R 43, R 44, R 45And R 46Be methyl or hydrogen independently of one another.In addition, substituent R 39And R 40R 36And R 37R 38And R 39At least one pair of.In addition, R 40And R 41Be Sauerstoffatom together.R 47Be H, azabicycloalkyl, Heterocyclylalkyl or Y 2-Z 2Y 2And Z 2As preceding definition.In addition, R 47It is the following formula group Y is 0 or 1.R 48, R 49, R 50, R 52, R 53, R 54And R 55Be methyl or hydrogen independently of one another.In addition, substituent R 48And R 49R 50And R 51R 52And R 53Or R 54And R 55At least one pair of be Sauerstoffatom together.R 56Be-H azabicycloalkyl, Heterocyclylalkyl or Y 3-Z 3Y 3And Z 3As preceding definition.
In another program, R 1It is the following formula group
Figure A9981321700693
E, f, h, u and y are 0 or 1 independently.R 57, R 58, R 59, R 60, R 61, R 62, R 63, R 64, R 65And R 66Be methyl or hydrogen independently of one another.In addition, substituent R 57And R 58R 59And R 60R 61And R 62Or R 63And R 64At least one pair of be Sauerstoffatom together.R 67Be H, azabicycloalkyl, Heterocyclylalkyl or Y 2-Z 2Y 2And Z 2As preceding definition.In addition, R 67It is the following formula group
Figure A9981321700701
D is 0 or 1.R 68, R 69, R 70, R 71, R 72, R 73, R 74And R 75Be low alkyl group or hydrogen independently of one another.In addition, substituent R 68And R 69R 70And R 71R 72And R 73R 74And R 75At least one pair of be Sauerstoffatom together.R 76Be-H azabicycloalkyl, Heterocyclylalkyl or Y 3-Z 3Y 3And Z 3As preceding definition.
The aromatic group of this paper comprises carbocyclic ring system (for example benzyl and cinnamyl) and thick many cyclophane perfume ring systems (for example naphthyl and 1,2,3,4-tetralyl).Aromatic group is also referred to as aromatic base at this paper.
Assorted aromatic group used herein comprises heteroaryl ring system (thienyl for example, pyridyl, pyrazolyl, isoxazolyl, thiadiazolyl group, oxadiazoles base, indazolyl, furyl, pyrryl, imidazoles, pyrazoles, triazole, pyrimidine, pyrazine, thiazole, isoxzzole, isothiazole, tetrazolium, or oxadiazoles) and wherein carbocyclic ring aromatic nucleus, carbocyclic ring non-aromatic ring or heterocycle and one or more other heterocyclic fused aromatic ring (benzo (b) thiophene for example, benzoglyoxaline, benzoxazolyl, benzothiazolyl, diazosulfide base, benzo oxadiazoles base, indoles, tetrahydro indole, azaindole, indazole, imidazopyridine, purine, pyrrolo-[2,3-d] pyrimidine, pyrazolo [3,4-d] pyrimidine) and its N-oxide compound.
Aralkyl used herein is by having 1 aromatic substituent that is connected with compound to the aliphatic group of about 6 carbon atoms.
Heteroaralkyl used herein is by having the 1 assorted aromatic substituent that is connected with compound to the aliphatic group of about 6 carbon atoms.
Heterocyclylalkyl used herein is the non-aromatic ring system with 3 to 8 atoms, and comprises at least one heteroatoms, as nitrogen, and oxygen, or sulphur.
Acyl group used herein is-C (O) NR xR z,-C (O) OR x,-C (O) R x, R wherein xAnd R zBe-H to replace or unsubstituted aliphatic group or replacement or unsubstituted aryl group independently of one another.
Aliphatic group used herein comprises straight chain, and side chain or ring-type be C saturated or that contain one or more unsaturated units fully 1-C 8Alkyl." low alkyl group " is the radical of saturated aliphatic base with 1 to 6 carbon atom.
Can there be the salt with medicinal sour institute in formula I compound.The present invention includes this class salt.The example of this class salt comprises hydrochloride, hydrobromate, vitriol, mesylate, nitrate, maleate, acetate, Citrate trianion, fumarate, tartrate [for example (+) tartrate, (-)-tartrate or its mixture comprise racemic mixture], succinate, benzoate and with the salt of amino acid such as L-glutamic acid.These salt can be by this professional known method preparation.
Some has acid substituent formula I compound can exist salt with medicinal basic.The present invention includes this class salt.The example of this class salt comprises sodium salt, sylvite, lysine salt and arginic acid salt.These salt can be by this professional known method preparation.
Some formula I compound can exist more than a kind of crystal formation, the present invention includes various crystal formations and its mixture.
Some formula I compound and its salt are also with solvate, and for example hydrate forms exists, and the present invention includes all kinds of SOLVENTS thing and its mixture.
Some formula I compound can contain one or more chiral centres, and exists with different optical activity forms.When formula I compound contained a chiral centre, there were two kinds of enantiomeric forms in compound, the present invention includes the mixture of these two kinds of enantiomorphs and enantiomorph, as racemic mixture.Enantiomorph can split by this professional known method, for example can be for example by formation, and the diastereoisomeric salt that separates by crystallization; Formation can be for example by crystallization, non-enantiomer derivative that gas liquid chromatography or liquid chromatography are separated or title complex; The selective reaction of a kind of enantiomorph and enantiomorph-specific reagent, for example lipase-catalyzed esterification; Or solution-air under chiral environment or gas-chromatography, for example aliphatic chiral support for example is combined with the silica gel of chiral ligand or in the presence of chiral solvent.Should be appreciated that, when required enantiomorph is converted into another chemical entity by one of above-mentioned separating technology, need another step to discharge required enantiomeric form.In addition, specific enantiomorph can be by using the optics active agent, substrate, and catalyzer or solvent, asymmetric synthesis, or a kind of enantiomorph is converted into another kind by asymmetric transfer.
When formula I compound contains more than a chiral centre, can there be the diastereomer form.Diastereomer be to passing through this professional known method, for example chromatogram or crystallization and separate, and the single enantiomorph of each centering can separate as mentioned above.The present invention includes various diastereomers and its mixture of formula I compound.
Some formula I compound can exist different tautomeric forms or different geometrical isomers, the present invention includes various tautomers and/or geometrical isomer and its mixture of formula I compound.
Can there be different stable conformation forms that can be separated in some formula I compound.Because asymmetric singly-bound, the torsion that for example limits rotation because of sterically hindered or ring strain is asymmetric, makes the possibility that is separated into of isomorphic map not.The present invention includes various conformers and its mixture of formula I compound.
Can there be zwitterionic form in some formula I compound, the present invention includes various zwitterionic forms and its mixture of formula I compound.
Preferred compounds of formula I are: Cis -5 - (4 - phenoxy-phenyl) -7 - (4 - pyrrolidinyl cyclohex-1 - yl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine Trans-5 - (4 - phenoxy-phenyl) -7 - (4 - cyclohex-1-pyrrolidinyl - yl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine Cis-5 - (4 - phenoxy-phenyl) -7 - (4 - piperidino cyclohex-1 - yl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine hydrochloride Trans-5 - (4 - phenoxy-phenyl) -7 - (4 - piperidino-cyclohexan-1 - yl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine Trans-7 - (4 - dimethylamino-cyclohexyl) -5 - (4 - phenoxy-phenyl)-7H-pyrrolo [2,3 - d] pyrimidin-4 - yl amine Cis -7 - (4 - dimethylamino-cyclohexyl) -5 - (4 - phenoxy-phenyl)-7H-pyrrolo [2,3 - d] pyrimidin-4 - yl amine 5 - (4 - phenoxy-phenyl) -7 - (4 - piperidinyl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine 5 - (4 - phenoxy-phenyl) -7 - (3 - pyrrolidinyl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine Dihydrochloride Cis-7 - [4 - (4 - isopropyl-piperazino) cyclohexyl] -5 - (4 - phenoxy-phenyl)-7H-pyrazol Pyrrolo [2,3-d] pyrimidin-4 - yl amine Trans-7 - [4 - (4 - isopropyl-piperazino) cyclohexyl] -5 - (4 - phenoxy-phenyl)-7H-pyrazol Pyrrolo [2,3-d] pyrimidin-4 - yl amine Cis-7 - {4 - [4 - (2 - methoxyethyl) piperazino] cyclohexyl} -5 - (4 - phenoxyphenyl Yl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine Trans-7 - {4 - [4 - (2 - methoxyethyl) piperazino] cyclohexyl} -5 - (4 - phenoxyphenyl Yl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine Cis-7 - [4 - (4 - ethyl-piperazino) cyclohexyl] -5 - (4 - phenoxy-phenyl)-7H-pyrrolo And [2,3-d] pyrimidin-4 - yl amine Trans-7 - [4 - (4 - ethyl-piperazino) cyclohexyl] -5 - (4 - phenoxy-phenyl)-7H-pyrrolo And [2,3-d] pyrimidin-4 - yl amine Cis-7 - [4 - (4 - isopropyl-piperazino) cyclohexyl] -5 - (4 - phenoxy-phenyl)-7H-pyrazol Pyrrolo [2,3-d] pyrimidin-4 - yl AMINES maleate Trans-7 - [4 - (4 - isopropyl-piperazino) cyclohexyl] -5 - (4 - phenoxy-phenyl)-7H-pyrazol Pyrrolo [2,3-d] pyrimidin-4 - yl AMINES maleate Cis-7 - {4 - [4 - (2 - methoxyethyl) piperazino] cyclohexyl} -5 - (4 - phenoxyphenyl Yl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl AMINES maleate Trans-7 - {4 - [4 - (2 - methoxyethyl) piperazino] cyclohexyl} -5 - (4 - phenoxyphenyl Yl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl AMINES maleate Trans-7 - {4 - [4 - (2 - methoxyethyl) piperazino] cyclohexyl} -5 - (4 - phenoxyphenyl Yl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl AMINES maleate Cis -7 - (4 - {[3 - (1H-1-imidazolyl) propyl] amino} cyclohexyl) -5 - (4 - phenoxyphenyl Yl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl AMINES maleate Trans -7 - (4 - {[3 - (1H-1-imidazolyl) propyl] amino} cyclohexyl) -5 - (4 - phenoxyphenyl Yl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl AMINES maleate Cis-7 - [4 - (dimethylamino) cyclohexyl] -5 - (4 - phenoxy-phenyl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine dimaleate Trans-5 - (4 - phenoxy-phenyl) -7 - (4 - piperidino-cyclohexyl)-7H-pyrrolo [2,3-d] Pyrimidin-4 - yl amine dimaleate Trans-5 - (4 - phenoxy-phenyl) -7 - (4 - tetrahydro-1H-1-pyrrolyl cyclohexyl)-7H-pyrrolo And [2,3-d] pyrimidin-4 - yl amine dimaleate Cis-5 - (4 - phenoxy-phenyl) -7 - (4 - piperazinosulfonyl cyclohexyl)-7H-pyrrolo [2,3-d] Pyrimidin-4 - yl amine three maleate Trans-5 - (4 - phenoxy-phenyl) -7 - (4 - piperazino cyclohexyl)-7H-pyrrolo [2,3-d] Pyrimidin-4 - yl amine three maleate 7 - [3 - (4 - methyl-piperazino) cyclopentyl] -5 - (4 - phenoxy-phenyl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl AMINES maleate Trans-7 - [3 - (4 - methyl-piperazino) cyclohexyl] -5 - (4 - phenoxy-phenyl)-7H-pyrrolo And [2,3-d] pyrimidin-4 - yl amine Trans-7 - [3 - (4 - methyl-piperazino) cyclohexyl] -5 - (4 - phenoxy-phenyl)-7H-pyrrolo And [2,3-d] pyrimidin-4 - yl AMINES maleate Trans-7 - [3 - (4 - methyl-piperazino) cyclohexyl] -5 - (4 - phenoxy-phenyl)-7H-pyrrolo And [2,3-d] pyrimidin-4 - yl amine trihydrochloride Cis-7 - [3 - (4 - methyl-piperazino) cyclohexyl] -5 - (4 - phenoxy-phenyl)-7H-pyrrolo And [2,3-d] pyrimidin-4 - yl AMINES maleate Cis-7 - [3 - (4 - methyl-piperazino) cyclohexyl] -5 - (4 - phenoxy-phenyl)-7H-pyrrolo And [2,3-d] pyrimidin-4 - yl amine trihydrochloride Trans-5 - (2 - methyl - 4 - phenoxy-phenyl) -7 - [4 - (4 - piperazino) cyclohexyl]-7H-pyrazol Pyrrolo [2,3-d] pyrimidin-4 - yl AMINES maleate Cis-N-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} 2 - methoxy-phenyl)-carbamic acid benzyl ester maleate three Trans-N-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} 2 - methoxy-phenyl)-carbamic acid benzyl ester maleate three Trans-N1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} 2 - methoxyphenyl) benzamide Trans-N1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} 2 - methoxyphenyl) benzamide trimaleate salt Cis-N1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} 2 - methoxy-phenyl) -3 - phenyl-propionamide Trans-N1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} 2 - methoxy-phenyl) -3 - phenyl-propionamide Cis-N1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} 2 - methoxy-phenyl) -3 - phenyl-propionamide three maleate Trans-N1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} 2 - methoxy-phenyl) -3 - phenyl-propionamide three maleate Trans-N1-(4-4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 --2 - methoxy-phenyl) -3 - phenyl-propionamide three maleate Cis-2 - (4-4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - phenoxy) -6 - [(3 - methoxy-propyl) amino] benzonitrile trimaleic acid Salt Trans-2 - (4-4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - phenoxy) -6 - [(3 - methoxy-propyl) amino] benzonitrile trimaleic acid Salt Cis-2 - amino-6 - (4-4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrazol Pyrrolo [2,3-d] pyrimidin-5 - phenyl) benzonitrile trimaleate salt Trans-2 - amino-6 - (4-4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrazol Pyrrolo [2,3-d] pyrimidin-5 - phenyl) benzonitrile trimaleate salt Cis-2 - (4-4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - phenoxy) -6 - [(4 - methylphenyl) thio] benzonitrile trimaleate salt Trans-2 - (4-4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - phenoxy) -6 - [(4 - methylphenyl) thio] benzonitrile trimaleate salt Cis-2 - (4-4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - phenoxy) -6 - (2 - pyridylthio) benzonitrile three maleate Trans-2 - (4-4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - phenoxy) -6 - (2 - pyridylthio) benzonitrile three maleate Cis -5 - (2 - methyl - 4 - phenoxy-phenyl) -7 - [4 - (4 - methyl-piperazino) cyclohexyl] - 7H-pyrrolo [2,3-d] pyrimidin-4 - yl AMINES maleate Trans-5 - (2 - methyl - 4 - phenoxy-phenyl) -7 - [4 - (4 - methyl-piperazino) cyclohexyl] - 7H-pyrrolo [2,3-d] pyrimidin-4 - yl AMINES maleate Cis-N1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -4 - fluoro-1 - benzenesulfonamide three maleate Trans-N1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -4 - fluoro-1 - benzenesulfonamide three maleate N1-4-[4 - amino-7 - (1 - benzyl-4 - piperidinyl)-7H-pyrrolo [2,3-d] pyrimidin-5 - Yl] -2 - fluorophenyl-4 - fluoro-1 - benzenesulfonamide N1-4-[4 - amino-7 - (1 - benzyl-4 - piperidinyl)-7H-pyrrolo [2,3-d] pyrimidin-5 - Yl] -2 - fluoro-2 ,3 - dichloro-1 - benzenesulfonamide N1-4-[4 - amino-7 - (4 - piperidinyl)-7H-pyrrolo [2,3-d] pyrimidin-5 - yl] -2 - fluoro- Phenyl-4 - fluoro-1 - benzenesulfonamide N1-4-[4 - amino-7 - (1 - formyl-4 - piperidinyl)-7H-pyrrolo [2,3-d] pyrimidin-5 - Yl] -2 - fluorophenyl-4 - fluoro-1 - benzenesulfonamide N1-4-[4 - amino -7-1 - [(1 - methyl-1H-4-imidazol-yl) sulfonyl] -4 - piperidinyl-7H- Pyrrolo [2,3-d] pyrimidin-5 - yl) -2 - fluorophenyl]-4 - fluoro-1 - benzenesulfonamide dimaleate N1-[4 - (4 - amino -7-1 - [(1,2 - dimethyl-1H-4-imidazol-yl) sulfonyl] -4 - piperidinyl Yl-7H-pyrrolo [2,3-d] pyrimidin-5 - yl) -2 - fluorophenyl]-4 - fluoro-1 - benzenesulfonamide N1-[4 - (4 - amino -7-1 - [(1,3 - dimethyl-1H-5-pyrazolyl) carbonyl] -4 - piperidinyl - 7H-pyrrolo [2,3-d] pyrimidin-5 - yl) -2 - fluorophenyl]-4 - fluoro-1 - benzenesulfonamide N1-(4 - {4 - amino-7 - [1 - (2 - pyridinyl carbonyl) -4 - piperidinyl]-7H-pyrrolo [2,3 - d] pyrimidin-5 - yl} -2 - fluorophenyl) -4 - fluoro-1 - benzenesulfonamide N1-4-(4 - amino-7 - {4 - [1 - (1 - methyl-piperidin-4 - yl) piperidin-yl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl}) -2 - fluorophenyl) -4 - fluoro-1 - benzenesulfonamide three maleate Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - (trifluoromethoxy) -1 - benzenesulfonamide trimaleic Salt Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -5 - chloro-2 - thiophene sulfonamide benzenesulfonamide trimaleic Salt Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - chloro-4 - fluoro-1 - benzenesulfonamide benzenesulfonamide three Maleate Trans-N1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluoro-2 ,3 - dichloro-1 - benzenesulfonamide three maleate Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - chloro-4 - fluoro-1 - benzenesulfonamide three maleate Cis-N-1-(4-4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 --2 - fluorophenyl) -2,5 - difluoro-1 - benzenesulfonamide three maleate Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,6 - difluoro-1 - benzenesulfonamide three maleate Trans-N-4-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,1,3 - benzo-thiadiazol-4 - sulfonamide trimaleic Salt Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,3,4 - trifluoro-1 - benzenesulfonamide three maleate Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - nitro-1 - benzenesulfonamide three maleate Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - fluoro-1 - benzenesulfonamide three maleate Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,4,6 - trichloro-1 - benzenesulfonamide three maleate Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,6 - dichloro-1 - benzenesulfonamide three maleate Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - chloro-1 - benzenesulfonamide three maleate Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -3 - fluoro-1 - benzenesulfonamide dimaleate Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -5 - chloro-2 - thiophene sulfonamide dimaleate Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -4 - bromo-2, 6 - difluoro-1 - benzenesulfonamide trimaleic Salt Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -3 - chloro-4 - fluoro-1 - benzenesulfonamide three maleate Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - iodo-1 - benzenesulfonamide three maleate Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - (trifluoromethoxy) -1 - benzenesulfonamide trimaleic Salt Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,3 - dichloro-1 - benzenesulfonamide three maleate Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - chloro-6 - methyl-1 - benzenesulfonamide trimaleic acid Salt Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - chloro-4 - cyano-1 - benzenesulfonamide trimaleic acid Salt Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,3,4 - trifluoro-1 - benzenesulfonamide three maleate Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -3,4 - difluoro-1 - benzenesulfonamide three maleate Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -4 - bromo-2 - fluoro-1 - benzenesulfonamide three maleate Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -5 - bromo-2 - thiophene sulfonamide salt trimaleic Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,4 - dichloro-1 - benzenesulfonamide three maleate Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,3,4 - trichloro-1 - benzenesulfonamide three maleate Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -3 - bromo-5 - chloro-2 - thiophene sulfonamide trimaleic acid Salt Cis-N4-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,1,3 - benzo-thiadiazol-4 - sulfonamide trimaleic Salt Cis-N4-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl) -2 - fluorophenyl) -2,1,3 - oxadiazole benzo-4 - sulfonamide trimaleic Salt Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,5 - dichloro-1 - thiophenesulfonamide three maleate Cis-N4-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) - (7 - chloro-2 ,1,3 - benzothiadiazole) -4 - sulfonyl Amine three maleate Cis-N4-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) - (7 - methyl-2 ,1,3 - benzothiadiazole) -4 - sulfo Amide three maleate Cis-N4-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) - (5 - methyl -2,1,3 - benzothiadiazole) -4 - sulfo Amide three maleate Cis-N4-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) - (5 - chloro-2 ,1,3 - benzothiadiazole) -4 - sulfonyl Amine three maleate Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -3 - chloro-2 - methyl-1 - benzenesulfonamide trimaleic acid Salt Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - bromo-1 - benzenesulfonamide three maleate Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,5 - dibromo-3, 6 - difluoro-1 - benzenesulfonamide three Maleate Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,3 - dichloro-1 - benzenesulfonamide three maleate Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) - (2 - nitrophenyl) methanesulfonamide three maleate Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - nitro-1 - benzenesulfonamide three maleate Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - fluoro-1 - benzenesulfonamide three maleate Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,4,6 - trichloro-1 - benzenesulfonamide three maleate Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,6 - dichloro-1 - benzenesulfonamide three maleate Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - chloro-1 - benzenesulfonamide three maleate Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -3 - fluoro-1 - benzenesulfonamide dimaleate Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -4 - bromo-2 ,5 - difluoro-1 - benzenesulfonamide trimaleic Salt Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -3 - chloro-4 - fluoro-1 - benzenesulfonamide three maleate Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - iodo-1 - benzenesulfonamide three maleate Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,3 - dichloro-1 - benzenesulfonamide three maleate Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - chloro-6 - methyl-1 - benzenesulfonamide trimaleic acid Salt Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - chloro-4 - cyano-1 - benzenesulfonamide trimaleic acid Salt Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -3,4 - difluoro-1 - benzenesulfonamide three maleate Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -4 - bromo-2 - fluoro-1 - benzenesulfonamide three maleate Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -5 - bromo-2 - thiophene sulfonamide salt trimaleic Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,4 - dichloro-1 - benzenesulfonamide three maleate Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,3,4 - trichloro-1 - benzenesulfonamide three maleate Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -3 - bromo-5 - chloro-2 - thiophene sulfonamide trimaleic acid Salt Trans-N4-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,1,3 - benzo-thiadiazol-4 - sulfonamide trimaleic Salt Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,5 - dichloro-1 - thiophenesulfonamide three maleate Trans-N4-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) - (7 - chloro-2 ,1,3 - benzothiadiazole) -4 - sulfonyl Amine three maleate Trans-N4-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) - (7 - methyl-2 ,1,3 - benzothiadiazole) -4 - sulfo Amide three maleate Trans-N4-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) - (5 - methyl -2,1,3 - benzothiadiazole) -4 - sulfo Amide three maleate Trans-N4-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) - (5 - chloro-2 ,1,3 - benzothiadiazole) -4 - sulfonyl Amine three maleate Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -3 - chloro-2 - methyl-1 - benzenesulfonamide trimaleic acid Salt Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - bromo-1 - benzenesulfonamide three maleate Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,5 - dibromo-3, 6 - difluoro-1 - benzenesulfonamide three Maleate Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) - (2 - nitrophenyl) methanesulfonamide three maleate ...
The compounds of this invention has angiogenesis inhibitor character.These angiogenesis inhibitor character are because of suppressing for angiogenesis very important protein Tyrosylprotein kinase to small part.For this reason, these compounds can be used as arthritis, atherosclerosis, restenosis, psoriasis, vascular tumor, angiogenesis of cardiac muscle, crown or cerebrovascular pleurapophysis, the ischemic lymph vessels generates, local asphyxia/reperfusion injury, wound, the disease that the digestive tract ulcer spirobacteria is relevant, the angiogenic disease that virus causes, fracture, Crow-Fukase syndrome (POEMS), preeclampsia, menorrhagia, cat scratch fever, flush, glaucoma and retinopathy as with diabetic retinopathy, precocious retinopathy diseases associated, or the promoting agent of the macular degeneration relevant and so on illness with the age.In addition, in these compounds some can be used as anti-solid tumor, malignant ascite, von HippelLindau disease, erythropoiesis cancer and excess proliferative disease such as Tiroidina hyperplasia (especially Grave ' s disease), and the promoting agent of tumour (as many blood vessels of the stroma of ovary, feature of polycystic ovarian syndrome (Stein-Leventhal syndrome) and multicystic kidney disease).
And some in these compounds can be as burn, chronic lung disease, apoplexy, polyp, allergy, chronic and allergic inflammation, delayed hypersensitivity, ovarian hyperstimulation syndrome, brain tumor type cerebral edema, acrophobia, brain that wound or anoxic cause or pulmonary edema, eye or macular edema, ascites, glomerulonephritis and other are with blood vessel hypertonicity, seepage, ooze out, protein extravasation, or oedema is the promoting agent of the disease of performance.These compounds can be used for also treating wherein that protein extravasation causes scleroproein and extrtacellular matrix deposition, promote the disease of matrix hyperplasia (for example keloid, fibrosis, cirrhosis and carpal tunnel syndrome).Inflammation has been strengthened in too much VEGF generation such as monocyte replenishes and activates.Compound of the present invention also can be used for treating inflammation such as enteritis (IBD) and Crohn ' s disease.
VEGF ' s is the single-minded known angiogenesis factor that causes blood vessel hypertonicity and oedema to form.In fact, relevant with the expression of many other somatomedins or administration blood vessel hypertonicity and growth are seemingly produced by VEGF and mediation.The inflammatory division of cytoplasm stimulates VEGF to produce.Anoxic causes the obvious rise of VEGF in many tissues, and after this situation comprises infraction, obturation, and local asphyxia, anaemia, or cause that typically the circulation of replying of VEGF/VPF mediation damages.Usually follow diapedetic blood vessel hypertonicity, associated edema, the skin exchange of castrating and macromole exosmose and can cause excessive apposition, unusual matrix hyperplasia, fibrosis, or the like.After this, the hypertonicity of VEGF mediation can ascribe the imbalance of these causes of disease clearly to.
Because blastocyst is implanted, it is angiogenesis-dependent that placenta development and embryo generate, and some compound of the present invention can be used as contraceptive and anti-fertilization agent.
Imagine above-mentioned disease is mediated some by the protein tyrosine kinase activity that comprises KDR/VEGFR-2 and/or flt-1/VEGFR-1 and/or TIE-2 Tyrosylprotein kinase degree.By suppressing the activity of these Tyrosylprotein kinases, listed disease process is suppressed, because the vasculogenesis of this illness or relevant hypertonicity composition are seriously subdued.By its selectivity to the specificity Tyrosylprotein kinase, the effect of some compound of the present invention causes minimizing of side effect, and these side effects can exist when using the less tyrosine kinase inhibitor of selectivity.Some compound of the present invention also is FGFR, PDGFR, effective inhibitor of c-Met and IGF-1-R.These receptor kinases can be directly or indirectly strengthened vasculogenesis and hyper-proliferative is replied in various diseases, the process that its inhibition after this can resist the disease.
The compounds of this invention has the activity of inhibition to protein kinase.That is, these compounds are by the conduction of protein kinase conditioning signal.The compounds of this invention suppresses the protein kinase of serine/threonine and tyrosine-kinase enzyme.Particularly, these compound selective ground suppress the activity of KDR/FLK-1/VEGFR-2 Tyrosylprotein kinase.Some compound of the present invention also suppresses other Tyrosylprotein kinase such as flt-1/VEGFR-1, TIE-2, FGFR, PDGFR, IGF-1-R, c-Met, Src-subtribe kinases such as Lck, Src, fyn, the activity of yes or the like.In addition, some compound of the present invention is suppressed at serine/threonine kinase such as the PKC that plays the part of pivotal player in hyperplasia and the cell cycle process, map kinase, erk, CDKs, plk-1, or Raf-1 significantly.Generalization compound of the present invention usually can pass through substituting group (that is R, to kinase whose effectiveness of specific protein and specificity 1, R 2, R 3, A and ring 1) and character, the change of quantity and arrangement and conformation limit and change and optimizing.In addition, the metabolite of some compound also has tangible protein kinase inhibiting activity.
When to the individual administration of this compounds of needs, The compounds of this invention suppresses blood vessel hypertonicity and oedema formation in these are individual.It is believed that these compounds play a role by the activity that inhibition and blood vessel hypertonicity and oedema form relevant KDR Tyrosylprotein kinase.The KDR Tyrosylprotein kinase is also referred to as the FLK-1 Tyrosylprotein kinase, NYK Tyrosylprotein kinase or VEGFR-2 Tyrosylprotein kinase.When combining with the kdr tyrosine kinase receptor that is in blood vessel Inner chrotoplast surface, the KDR Tyrosylprotein kinase is activated when blood vessel Inner skin cell growth factor (VEGF) or other activation part (as VEGF-C, VEGF-D, VEGF-E or HIV Tat albumen).Along with the activation of this class KDR Tyrosylprotein kinase, the hypertonicity of blood vessel has just taken place, and liquid flows out vessel wall and enters a matter space from blood flow, thereby forms the oedema district.Hemocyte oozes out and usually is accompanied by this reaction.Similarly, over-drastic blood vessel hypertonicity can upset the normal molecular exchange of passing endothelium in critical tissue and organ (for example, lung and kidney), thereby causes that macromole blends deposition outward.Along with quickening the acute reaction of the KDR stimulation of angiogenesis subsequently to being considered to, the KDR Tyrosylprotein kinase of prolongation stimulates hyperplasia and chemotaxis and the neovascularization that causes vascular endothelial cell.By suppressing the KDR tyrosine kinase activity, generation by blocking-up activation part, combine with kdr tyrosine kinase receptor by blocking-up activation part, by preventing receptor dimerization and phosphoric acid transferance, the enzymic activity (the phosphorylation function of inhibitory enzyme) by suppressing the KDR Tyrosylprotein kinase or some are interrupted the mechanism (D of its downstream signal.Mukhopedhyay etc., cancer research, 58:1278-1284 (1998) and its reference), hypertonicity and relevant exosmosing, oedema subsequently form and apposition and vasculogenesis reaction, can be suppressed and minimize.
One group of preferred The compounds of this invention has the KDR tyrosine kinase activity of inhibition and not obvious inhibition Flt-1 tyrosine kinase activity (the Flt-1 Tyrosylprotein kinase is also referred to as the VEGFR-1 Tyrosylprotein kinase).KDR Tyrosylprotein kinase and Flt-1 Tyrosylprotein kinase combine with kdr tyrosine kinase receptor and Flt-1 tyrosine kinase receptor by VEGF respectively and are activated.Some preferred The compounds of this invention is single-minded, because they only suppress to be activated a kind of VEGF-receptor tyrosine kinase of part activated (KDR), and does not suppress by some other receptor tyrosine kinase of activation part activated, as Flt-1.Like this, some preferred The compounds of this invention is being optionally aspect its tyrosine-kinase enzyme inhibition activity.
In a scheme, the invention provides the illness of protein kinase-mediation of treatment patient, comprise one or more formulas I compound to patient's administering therapeutic or prevention significant quantity.
" illness of protein kinase-mediation " is medical symptom, as disease or other bad physiological status, and its generation and be developed to the activity that small part depends at least a protein kinase.Protein kinase can be, for example, and protein tyrosine kinase or albumen serine/threonine kinase.
By the patient that treated can be any animal, and Mammals preferably, as domestic animal or livestock.More preferably, the patient is the people.
" treatment significant quantity " is the process that suppresses illness wholly or in part, or alleviates the formula I compound of one or more symptoms of illness or the amount of two or more these compounds combinations to small part.The treatment significant quantity also can be the prevention significant quantity.The treatment significant quantity will depend on patient's body weight and sex, the illness of being treated, the state of an illness and required result.For given patient, the treatment significant quantity can be determined by this professional known method.
Method of the present invention can be used for treating the illness of protein kinase-mediation, as any above-mentioned illness.In a scheme, the feature of the illness of protein kinase-mediation is the vasculogenesis of disliking, oedema, or apposition.For example, this illness can be-kind or multiple ulcer, as the ulcer that causes by bacterium or fungi infestation, Mooren ulcer and ulcerative colitis.This illness also can cause by infected by microbes, as the Lyme disease, and sepsis, septic shock or by herpes simplex, zoster, the human immunodeficiency virus, protozoon, toxoplasmosis or parapoxvirus infect; The vasculogenesis disease is as Hippel Lindau disease, multicystic kidney disease, pemphigoid, Paget ' s disease and psoriasis; The reproducibility disease is as uterus Inner film dystopy, ovarian hyperstimulation syndrome, preeclampsia or menorrhagia; Fibering and oedema venereal disease disease, as sarcoma, fibrosis, cirrhosis, thyroiditis, high viscosity syndrome system, Osler-Weber-Rendu disease, chronic occlusion tuberculosis, asthma, the oedema behind the burn, wound, radiation, apoplexy, anoxic or local asphyxia; Or inflammation/immunology illness, as systemic lupus erythematous, chronic inflammatory diseases, glomerulonephritis, synovitis, enteritis, Crohn ' s disease, rheumatic arthritis, osteoarthritis, multiple sclerosis and transplant rejection reaction.The illness of suitable protein kinase-mediation also comprises Dresbach's anemia, osteoporosis, osteopetrosis, the hypercalcemia of tumour-cause and bone migration.The illness of the protein kinase-mediation of other available the inventive method treatment comprises illness in eye such as eye and macular edema, eye neovascularity disease, scleritis, the radiation corneal incision, uveitis, vitritis, myopia, eye ulcer, chronic retinal detachment, back-laser complication, conjunctivitis, sick and the Eales disease of Stargardt ' s, and retinopathy and macular degeneration.
The compounds of this invention also can be used for treating cardiovascular diseases such as atherosclerosis, restenosis, vascular occlusion and carotid artery obstruction disease.
The compounds of this invention also can be used for treating cancer relevant indication such as solid tumor, sarcoma (especially Ewing ' s knurl and osteoma), retina tumor, rhabdosarcoma, neuroblastoma, hemocyte cancer, comprise leukemia and lymphoma, pleura or pericardium that tumour causes ooze out, and malignant ascite.
The compounds of this invention also can be used for treating Crow-Fukase (POEMS) syndrome and diabetes such as glaucoma, diabetic retinopathy and microangiopathy.
Kinase whose Src, Tec, Jak, Map, Csk, pivotal player is played the part of by NFkB and Syk family in the adjusting of immunologic function.Src family comprises Fyn now, Lck, Fgr, Fes, Lyn, Src, Yrk, Fyk, Yes, Hck, and Blk.Understand Syk family now and include only Zap and Syk.TEC family comprises Tec, Btk, Rlk and Itk.Kinase whose Janus family is relevant through the conduction of a plurality of acceptors with the former inflammatory division of cytoplasm of somatomedin signal.Though BTK and ITK play the part of the less role who is familiar with as the member of kinases Tec family in immunology, its regulating effect by inhibitor can prove the treatment advantage.Csk family is believed to comprise Csk and Chk now.Kinase whose RIP, IRAK-2, NIK, the p38MAP kinases, Jnk, IKK-1 and IKK-2 and crucial former inflammatory division of cytoplasm, relevant as TNF with the IL-1 signal transduction path.Because it suppresses one or more ability of these kinases, formula I compound can be used as immunomodulator, is used to keep homotransplantation, treatment Autoimmune Disorders and treatment sepsis, septic shock.Because it regulates the T cell, the B cell, mammary gland cell, the migration or the activation of unicellular and neutrophilic leukocyte, these compounds can be used to treat the disease such as Immunological diseases and sepsis.The prevention of transplant rejection, i.e. the prevention of the anti-solid organ transplantation thing of experimenter, or the rejection of the anti-experimenter's marrow of graft is subjected to the existing toxic restriction of immunosuppressor, and obtains advantage from the active drug that improves therapeutic index.Gene target experiment the is verified dominant role of Src in osteoclast biology, this cell responds to bone resorption.Because it regulates the ability of Src, formula I compound also can be used for treating osteoporosis, osteopetrosis, Paget ' s disease, the hypercalcemia and the bone migration of tumour-cause.
Many protein kinases have been proved to be and have been proto-oncogene.Rhexis (at the ltk of karyomit(e) 5 kinases breaking point), as under the situation of Abl gene by the transposition of BCR (Philadelphia karyomit(e)), such as the brachymemma under c-Kit or the EGFR situation, or the sudden change (for example Met) cause the proteic generation of dysregulation, make it be converted into oncoprotein from proto-oncogene.In other tumour, canceration is interacted by autocrine or paracrine part/growth factor receptors and drives.The kinases member of src-family is typically relevant with the downstream signal conduction, thereby strengthens canceration, and they itself can become oncogene by overexpression or sudden change.By suppressing these proteic kinase activities, disease process can be destroyed.Vascular restenosis may be relevant with Inner chrotoplast hyperplasia with FGF and/or the promoted unstriated muscle of PDGF-.FGFR, PDGFR, the body Inner ligand stimulation of IGF1-R and c-Met is former vasculogenesis, and strengthens angiogenesis-dependent disease.Separately or unite and suppress FGFr, PDGFr, c-Met, or the IGFl-R kinase activity may be the effective strategy that suppresses these phenomenons.Therefore, suppress normal or unusual c-kit, c-met, c-fms; the member of src-family, EGFr, erbB2, erbB4; BCR-Abl, PDGFr, the formula I compound of the kinase activity of IGF1-R and other acceptor or cytoplasmic tyrosine kinase may be valuable in treating optimum and tumor proliferative disease.
In many illnesss (for example, early stage noumenal tumour and transfer, Kaposi ' s knurl, rheumatic arthritis, because that bad eye neovascularization causes is blind, psoriasis and atherosclerosis), disease process is decided according to the vasculogenesis that continues.Polypeptide growth factor is usually produced by diseased tissue or relevant inflammatory cell, and its corresponding endothelial cell specific receptor tyrosine kinase (for example, KDR/VEGFR-2, flt-1/VEGF-1, Tie-2/Tek and Tie) grow for stimulating endothelial cell, migration, organization, the differentiation of necessary new functionalized vascular system and determine it is very important.As the vascular permeability factor active of VEGF in the result aspect the mediation blood vessel hypertonicity, the kinase whose VEGF-stimulation of VEHFR also is considered in tumour ascites, brain and pulmonary edema form, pleura and pericardium ooze out, delayed-type hypersensitivity, wound, burn, after the local asphyxia, tissue edema and organ dysfunction, diabetic complication, uterus Inner film dystopy, adult property respiratory distress syndrome (ARDS), blood pressure and hypertonicity that back cardiopulmonary bypass is relevant, edema oculi causes playing an important role in glaucoma or the unusual new relevant formation blinding.Except that VEGF, the VEGF-E of the VEGF-C that determines and VEGF-D and encoding viral or HIV-Tat albumen also can cause the reaction of blood vessel hypertonicity through the kinase whose stimulation of VEGFR recently.KDR/VEGFR-2 and Tie-2 also express in selected group's raw blood stem cell.Some member in this group is many performances, and can use factors stimulated growth, is dissimilated as the Inner chrotoplast, and participates in the angiogenesis that blood vessel takes place.For this reason, these have been called as Inner skin ancester cell (EPCs) (J.Cln.Investig.103:1231-1236 (1999)).In some ancestors, Tie-2 can recover at it, bonding, figure (blood, 4317-4317 (1997)) in regulating and developing.Can block the kinase whose medicament of Inner chrotoplast specificity according to some of formula I can suppress and these condition diseases associated processes.
The blood vessel of Tie-2 antagonist ligand (Ang-2) is unbalance to be considered to induce " plastics " state in the Inner skin.In the presence of high VEGF level, can produce strong vasculogenesis reaction; But, when the stimulation that does not have VEGF or VEGF-to be correlated with, the frank pipe can take place degenerate and endothelial cell apoptosis (gene and growth, 13:1055-1066 (1999)).In a similar fashion, the Tie-2 kinase inhibitor can be respectively be with or without in the presence of the relevant stimulation of VEGF-be preceding vasculogenesis or angiogenesis inhibitor.Therefore, the Tie-2 inhibitor can stimulate with suitable preceding vasculogenesis, is used for promoting the treatment vasculogenesis under infraction and the ischemic situation such as wound as VEGF.
Formula I compound or its salt or the pharmaceutical composition that contains treatment significant quantity this compound can be used to treat protein kinase mediated illness, the proliferative disease and the disease of immune system of for example foregoing optimum and superfluous life.For example, this class disease comprises autoimmune disorder, as rheumatic arthritis, and thyroiditis, type 1 diabetes, multiple sclerosis, sarcosis, enteritis, Crohn ' s disease, myasthenia gravis and systemic lupus erythematosus; Psoriasis, organ transplantation rejection (experimenter's disease is transplanted in for example kidney rejection), optimum and superfluous proliferative disease of giving birth to, human cancer such as lung cancer, mammary cancer, cancer of the stomach, bladder cancer, colorectal carcinoma, carcinoma of the pancreas, ovarian cancer, the prostate cancer and the rectum cancer, and leukemia (leukemia and lymphatic cancer) and with disagreeable vascularization diseases associated, for example diabetes type retinopathy, the precocious retinopathy is because the choroid neovascularization that the macula lutea relevant with the age disappears and the vascular tumor of human infant.In addition, this class inhibitor can be owing to the oedema of treatment with VEGF mediation, and ascites is oozed out, and the illness relevant with transudate comprises, macular edema for example, cerebral edema, acute lung injury and adult respiratory distress syndrome (ARDS).
The compounds of this invention also can be used for preventing above-mentioned disease.
Imagine above-mentioned disease and mediate tangible degree by the protein tyrosine kinase activity that comprises vegf receptor (for example KDR, flt-1 and/or Tie-2).By suppressing the activity of these Tyrosylprotein kinases, listed disease process is suppressed, because the vasculogenesis of this illness or relevant hypertonicity composition are seriously subdued.By its selectivity to the specificity Tyrosylprotein kinase, the effect of some compound of the present invention causes minimizing of side effect, and these side effects can exist when using the less tyrosine kinase inhibitor of selectivity.
The present invention provides on the other hand as medicine, especially as protein kinase activity tyrosine kinase activity for example, the formula I compound as preceding definition of Serine and the active inhibitor of threonine kinase.The present invention also provides the purposes that is used for the medicine of arrestin kinase activity as the formula I compound of preceding definition in production on the one hand.
In the present invention, available following definition:
" physiologically acceptable salt " refers to keep the biopotency and the character of free alkali, by with mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid or organic acid such as aryl sulfonic acid, carboxylic acid, organic phosphoric acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, Whitfield's ointment, lactic acid, tartrate, the salt of toxilic acid or the like reaction gained.
" alkyl " refers to aliphatic saturated hydrocarbon, comprises the straight or branched group with 1 to 6 carbon atom, or has the cyclic hydrocarbon group of 3 to 6 carbon atoms.
" alkoxyl group " refers to " O-alkyl ", and wherein " alkyl " as above defines.Pharmaceutical preparation
The compounds of this invention can itself or with the pharmaceutical composition of suitable carriers or mixed with excipients with treatment or improve the blood vessel hypertonicity, the dosage of oedema and relative disease is to patient's administration.The mixture of these compounds also can with simple mixtures or with the preparation pharmaceutical composition to patient's administration.The treatment effective dose also refers to be enough to neovascularization, the excess proliferative disease process, and oedema, the ypotension that hypertonicity that VEGF-is relevant and/or VEGF-are relevant produces the compound amount of prevention or mitigation.Be used to prepare with the technology of administration the application compound can be at " Remington ' s Pharmaceutical Sciences, " Mack Publishing Co., Easton, PA finds in the nearest version.
Route of administration
Suitable route of administration can, for example, comprise oral, eye drip, rectum, through mucous membrane, part, or caecum administration; Parenteral delivery comprises flesh Inner, and is subcutaneous, marrow Inner injection, and sheath Inner, direct ventricle Inner, intravenously, peritonaeum Inner, nose Inner, or intraocular injection.
In addition, also can the part but not the mode of whole body is given drug compound, for example directly toward oedema district injection compound, normally to store or the sustained release preparation administration.
And, can be at the target delivery system, for example, at lipid vivo medicine-feeding with endotheliocyte-specific antibody bag quilt.Composition/preparation
Pharmaceutical composition of the present invention can for example, mix by routine with known method production, dissolving, and granulation, pill is ground into powder, and emulsification is encapsulated, captures or lyophilization.
The pharmaceutical composition that is used for the present invention can be used usual manner, comprises with one or more physiologically acceptable carriers promoting the vehicle and the auxiliary of active compound processing to be mixed with pharmaceutically useful preparation.Appropriate formulation depends on selected route of administration.
For injection, medicament of the present invention can be formulated into the aqueous solution, the preferred damping fluid that on physiology, can hold altogether, and as Hanks ' s solution, Ringer ' s solution, or the solution in the normal saline buffer solution.For through marrow Inner administration, the permeate agent that adapts with the barrier that is permeated is used in the preparation.This class permeate agent is that this specialty is known.
For oral administration, compound can easily be prepared by the professional known pharmaceutical carrier of active compound and this is combined.This class carrier can make The compounds of this invention be mixed with tablet, piller, and sugar-pill, capsule, liquid, gel, syrup, soup compound, suspension etc. are by the oral absorption of patient of being treated.Oral pharmaceutical preparation can grind the mixture of generation by active compound is combined with solid excipient non-imposedly, adds after the auxiliary, and if desired, the mixture of processing granular obtains tablet or sugar-pill core.Suitable vehicle has, and particularly, weighting agent such as carbohydrate comprise lactose, sucrose, mannitol, or Sorbitol Powder; Cellulose preparation as, for example, W-Gum, wheat starch, Starch rice, yam starch, gelatin, tragacanth gum, methylcellulose gum, HYDROXY PROPYL METHYLCELLULOSE, Xylo-Mucine, and/or Polyvinylpyrolidone (PVP) (PVP).If desired, add disintegrating agent, as cross-linking polyethylene pyrrolidone, agar, or alginic acid or its salt such as sodiun alginate.
The sugar-pill core assembles with suitable dressing.For this reason, can use priming, this solution contains gum arabic non-imposedly, talcum, Polyvinylpyrolidone (PVP), carbopol glue, polyoxyethylene glycol, and/or titanium dioxide, raw lacquer solution and appropriate organic solvent or solvent mixture.Dyestuff or pigment can be added into the different combinations that are used in tablet or the sugar-pill dressing to distinguish with the characterization active compound doses.
Can be used for oral pharmaceutical preparation and comprise the push-fit capsule of making by gelatin, and by gelatin and softening agent, as the sealing soft capsule of glycerine or Sorbitol Powder manufacturing.The push-fit capsule can contain and weighting agent such as lactose, tamanori such as starch, and/or emulsifying agent such as talcum or Magnesium Stearate and non-imposed ground stablizer blended activeconstituents.Compound can be mixed with and be used for by injection, for example bolus injection or continous pouring administered parenterally.The preparation that is used to inject can exist with unit dosage form, for example in ampoule or in multi-dose container, adds sanitas.Said composition can be taked such as the suspension in oil or aqueous carrier, the form of solution or emulsion, and can contain such as suspension agent the preparaton of stablizer and/or dispersion agent.
The pharmaceutical preparation that is used for administered parenterally comprises the aqueous solution of water-soluble form active compound.In addition, the suspension of active compound can be made oily injection suspensions.Suitable lipophilic solvent or carrier comprise fatty oil such as Viscotrol C, or Acrawax, as ethyl oleate or glycerinate, or liposome.Contain the material that water injection or suspension can contain increases the suspension stickiness, as Xylo-Mucine, Sorbitol Powder, or dextran.Non-imposed ground, suspension also can contain suitable stabilizers or increase the medicament of compound dissolution, thus the highly spissated solution of preparation.
In addition, activeconstituents can be and suitable carriers for example aseptic apirogen water powder formulated form before using.
Compound also can be formulated into the rectum composition, as suppository or enema,retention, for example, contains ordinary suppository base such as theobroma oil or other glyceryl ester.
Except that foregoing preparation, compound also can be formulated into the storage preparation.This class long duration of action preparation can be by drug delivery implant (for example subcutaneous or intramuscular or by intramuscularly).Therefore, for example, compound can with suitable polymers or hydrophobic substance preparation (for example emulsion in suitable oil) or with ion exchange resin preparation, or indissoluble derivative, for example difficulty soluble salt preparation.
The example that is used for the pharmaceutical carrier of hydrophobic compound of the present invention is a cosolvent system, comprises benzyl alcohol, non-polar surfactant, water-compatibility organic polymer, and water.Cosolvent system can be the VPD-cosolvent system.VPD is the 3%w/v benzyl alcohol, and 8%w/v non-polar surfactant polysorbate 80 and 65%w/v Liquid Macrogol add to volume in absolute ethanol.VPD-cosolvent system (VPD:5W) is made up of the VPD with the dilution in 1: 1 of 5% dextrin in aqueous solution.This cosolvent system is the solubilizing hydrophobic compound well, and produces hypotoxicity when the whole body administration.Nature, cosolvent system can have sizable variation and not destroy its solvability and toxic characteristic.And the identity of cosolvent composition can change: for example, other hypotoxicity non-polar surfactant can be used to replace polysorbate 80; The fraction size of polyoxyethylene glycol can change; Other biology holds polymkeric substance altogether can replace polyoxyethylene glycol, for example Polyvinylpyrolidone (PVP); Other sugar or polysaccharide can replace dextrin.
Can use other delivery system of hydrophobic medicinal compound.Liposome and emulsion are the known example of dewatering medicament delivery vehicles.Some organic solvent such as methyl-sulphoxide also can be used, although its toxicity is bigger.In addition, compound can be carried with slow-released system, as contains the semi-permeable matrix of the solid hydrophobic polymkeric substance of therapeutical agent.Various sustained-release materials are determined and are that those skilled in the art is known.According to its chemical property, slow releasing capsule can be several Zhou Zhizhi 100 days.According to the chemical property and the biological stability of therapeutical agent, also can use other to be used for protein stabilized strategy.
Pharmaceutical composition also can comprise suitable solid or gel phase carrier or vehicle.The example of this class carrier or vehicle includes but not limited to lime carbonate, calcium phosphate, various sugar, starch, derivatived cellulose, gelatin and such as the polymkeric substance of polyoxyethylene glycol.
Many The compounds of this invention can be and the salt that pharmaceutically is total to the counter ion that hold.Pharmaceutically the salt that holds altogether can with many acid, include but not limited to hydrochloric acid, sulfuric acid, acetate, lactic acid, tartrate, oxysuccinic acid, succsinic acid or the like forms.Salt is compared with corresponding free alkali form, in water or other protic solvent bigger solvability is arranged.Effective dose
Be applicable to that pharmaceutical composition of the present invention comprises the composition that wherein contains significant quantity activeconstituents realization purpose.More specifically, the treatment significant quantity refers to effectively to prevent the development of illness or alleviates the symptom of existence.Significant quantity fixes on the Inner of the ability of those skilled in the art really.
For any compound that is used for the inventive method, the treatment effective dose can begin to estimate from cell analysis.For example, dosage can be prepared in cell and animal model, to realize the circulation composition scope, is included in the IC that measures in the cell analysis 50(that is, realizing half maximum test compound concentration that suppresses of given protein kinase activity).In some cases, need in the presence of 3 to 5% serum albumins, measure IC 50, because this class is measured near the combine effect of plasma proteins with compound.This category information can be used for being determined at more accurately the useful dosage of human body Inner.And, the most preferred compound that is used for the whole body administration at complete cell with the level of safety in blood plasma arrestin kinase signal effectively.
The treatment effective dose instructs the compound amount of the people's doing well,improving that causes a disease.The toxicity of this compounds and treatment are renderd a service and can be measured by the standard pharmaceutical process in cell cultures or laboratory animal, for example, are used to measure maximum tolerated dose (MTD) and ED 50(effective dose of 50% peak response).Dosage between toxicity and result of treatment is than therapeutic index, and it can be with MTD and ED 50Between ratio expression.The compound that shows high therapeutic index is preferred.Can be used to prepare the dosage range that is used for human body Inner from the data of these cell culture assays and zooscopy gained.The dosage of this compounds preferably depends on and comprises having little toxicity or avirulent ED 50The circulation composition scope.This dosage can change according to used agent shape and used route of administration at this scope Inner.Concrete preparation, route of administration and dosage can be selected according to the state of an illness by concrete doctor.(referring to for example Fingl etc., 1975, at " pharmacological basis of therapeutical agent ", Ch.l pl).In treatment during crisis, need be responded fast near acute bolus or the perfusion administration of MTD.
Dosage and can being regulated providing the plasma concentration that makes active part to be enough to keep the kinases regulating effect at interval, or minimum effective concentration (MEC) by indivedual.MEC will change for each compound, but can estimate from vitro data; For example, realize that with analysis as herein described the 50-90% protein kinase suppresses the concentration that needs.The dosage that needs to realize MEC will depend on individual feature and route of administration.But HPLC analyzes or biological test can be used to measure plasma concentration.
Spacing of doses also can be used the MEC pH-value determination pH.Compound will be with making blood plasma level surpass time of 10-90%, preferred 30-90%, and the most preferably pattern administration of 50-90% is until reaching required doing well,improving.Under the situation of topical or selectivity picked-up, effective partial concn of medicine may be irrelevant with plasma concentration.
Certainly, will be depended on the experimenter who is treated, experimenter's weight, the state of an illness, administering mode and attending doctor's judgement by the amount of administration composition.Packing
If desired, composition is present in the packing of one or more unit dosage that can contain activeconstituents, or in the dispensing device.This packing can for example comprise metal or plastic foil, as blister pack.Packing, or dispensing device can have doser.Comprise the The compounds of this invention that is formulated in the common appearance pharmaceutical carrier and also can be produced, be positioned in the proper container, and the indication of mark treatment.
In some preparations, with very little size, it is useful for example using compound by the particle form of fluid energy mill gained.
The purposes of The compounds of this invention in producing pharmaceutical composition is by following narration explanation.In this narration, term " active compound " refers to any compound of the present invention, but in one embodiment final product particularly.A) capsule
In capsular preparation, the lactose of 10 parts of heavy active compounds and 240 parts of weights can be disperseed and blending.Mixture can be filled in the hard capsule, and each capsule contains a part of active compound of unitary dose or unitary dose.B) tablet
Can prepare tablet weight umber active compound 10 lactose 190 W-Gums 22 Polyvinylpyrolidone (PVP)s 10 Magnesium Stearates 3 from following ingredients
Active compound, lactose and some starch can be disperseed, blending, the mixture of generation can be used the ethanolic soln granulation of Polyvinylpyrolidone (PVP).Dry granules can with Magnesium Stearate and remaining starch blending.Then mixture is suppressed at tabletting machine Inner, provided the tablet that respectively contains a part of active compound that unitary dose or unitary dose are arranged.C) enteric coated tablets
Can prepare tablet by top (b) described method.This tablet can be with 20% cellulose ethanoate phthalic acid ester and 3% diethyl phthalate at ethanol: the solution in the methylene dichloride (1: 1) is with usual way bag casing.D) suppository
In the preparation of suppository, 100 parts of heavy active compounds can be impregnated in the Witepsol W-S 55 suppository base of 1300 parts of weights, mixture is formed respectively contain the suppository for the treatment of effective amount of actives.
In composition of the present invention, if desired, active compound can combine with other pharmacological components that can hold altogether.For example, The compounds of this invention can or prevent VEGF or the plain generation of blood vessel production with one or more other inhibition, weaken VEGF or blood vessel are produced plain cell internal reaction, blocking-up cell Inner signal transmits, suppress the blood vessel hypertonicity, reduce inflammation, or suppress or prevent the medicament Combined Preparation of oedema or neovascularization.The compounds of this invention can be before, afterwards or with the administration simultaneously of other medicaments, process only to be administered is suitable.Other medicaments include but not limited to anti-inflammatory or consumer edema steroid class, NSAIDS, ras inhibitor, the anti-TNF agent, anti--the IL1 agent, antihistaminic agent, PAF-antagonist, the COX-1 inhibitor, cox 2 inhibitor, NO synthetase inhibitors, Akt/PTB inhibitor, IGF-1R inhibitor, pkc inhibitor and PI3 kinase inhibitor.The compounds of this invention and other medicaments or the effect of adding up property ground, or collaboratively newly act on.Therefore, suppress vasculogenesis, this class Combined Preparation of material that blood vessel hypertonicity and/or inhibition oedema form is compared with other materials are individually dosed, can alleviate hyperproliferation disease greatly, vasculogenesis, the deleterious effect of blood vessel hypertonicity or oedema.With anti-hyperplasia or cytotoxicity chemotherapy combined treatment malignant disease the time, carry out hyperthermia treatment in advance, a large amount of oxygen supplys or radiotherapy.
The present invention comprises that also use formula I compound is as medicine.
The present invention provides formula I compound or its salt to be used for the treatment of Mammals in production on the other hand, especially human blood vessel hypertonicity, vasculogenesis-dependence disease, the purposes in the medicine of proliferative disease and/or disease of immune system.
The present invention also provides the treatment Mammals, especially human blood vessel hypertonicity, vasculogenesis-dependence disease, the method for proliferative disease and/or disease of immune system, this method comprises the Mammals to the needs treatment, especially the formula I compound of human administration treatment significant quantity.
The vitro efficacy of compound in suppressing these protein kinases can be measured by the following method that provides in detail.
The effectiveness of compound can be by (for example, the synthetic peptide (measure for Z.Songyang etc., nature by phosphorylated amount of suppression 373:536-539) with respect to the exogenous substrate that contrasts by test compound.Produce the KDR Tyrosylprotein kinase with the baculovirus system
The encoding sequence in people KDR intracellular region territory (aa789-1354) is used from the cDNAs of HUVEC cellular segregation and is produced through PCR.Poly--His6 sequence is introduced into this proteic N-end.This segment is cloned into the carrier pVL1393 of transfection in Xba1 and Not1 site.Recombinant baculovirus (BV) produces through cotransfection with BaculoGold transfection reagent (PharMingen).BV is by plaque purification and through the Western analytic set in reorganization.For protein production, the SF-9 cell is grown in the SF-900-II of 2 * 106ml substratum, and forms the unit infection with 0.5 spot of each cell (MOI).At back 48 hours harvested cells of infection.The purifying of KDR
Express (His) 6The SF-9 cell of KDR (aa789-1354) passes through 50ml TritonX-100 lysis buffer (20mM Tris, pH 8.0,137mM NaCl, 10% glycerine, 1%Triton X-100,1mM PMSF, 10 μ g/ml aprotinins, 1 μ g/ml leupeptin) add from the cell ball of 1L cell culture gained and cracking.Lysate 4 ℃ in Sorval SS-34 rotor centrifugal 30 minutes with 19000rpm.Cell pyrolysis liquid is used for 5ml NiCl 2Chelating sepharose post is used 50mM HEPES, pH7.5,0.3M NaCl balance.The KDR same buffer wash-out that contains the 0.25M imidazoles.The post fraction is analyzed with SDS-PAGE that measures kinase activity and ELISA test (following).The KDR of purifying is switched to 25mMHEPES, pH7.5, and 25mM NaCl is in the 5mM DTT damping fluid and-80 ℃ of storages.People Tie-2 kinases is produced and purifying
The encoding sequence in people Tie-2 intracellular region territory (aa775-1124) is used from producing through PCR as the mazolytic cDNAs of the people of template.Poly--His6 sequence is introduced into this proteic N-end, and this is structured in the carrier pVL1393 that transfection is cloned in Xba1 and Not1 site.Reorganization BV produces through cotransfection with BaculoGold transfection reagent (PharMingen).BV is by plaque purification and through the Western analytic set in reorganization.For protein production, the SF-9 insect cell is grown in the SF-900-II of 2 * 106ml substratum, and infects with 0.5 MOI.The kinase whose purifying of His-mark that is used to screen is with described similar for KDR.People Flt-1 Tyrosylprotein kinase is produced and purifying
Use rhabdovirus expression vector pVL1393 (Phar Mingen, Los Angeles, CA).The nucleotide sequence of the poly-His6 of coding is placed on 5 ' of Nucleotide district in kinases district (amino acid 786-1338) in the whole cell of coding people Flt-1.The nucleotide sequence in coding kinases district produces through PCR from the cDNAs storehouse of HUVEC cellular segregation.Histidine residues makes albumen branch affinity purifying be similar to KDR and ZAP70.EGFR Tyrosylprotein kinase source
EGFR buys (Cat#E-3641 from Sigma; And the EGF part obtains (Cat#PF011-100) from Oncogene Research Products/calbiochem 500 units/50 μ l).The expression of ZAP70
The rhabdovirus expression vector that uses be pVL1393 (Phar Mingen, Los Angeles, CA).Coded amino acid M (H) 6 L VPR 9The nucleotide sequence of S is placed on 5 ' of Nucleotide district of the whole ZAP70 of coding (amino acid/11-619).The nucleotide sequence of coding ZAP70 coding region is used from the cDNAs storehouse of the T-cellular segregation of Jurkat infinite multiplication and is produced through PCR.Histidine residues makes that albumen (seeing below) can the affinity purifying.L VPR 9The S bridge constitutes the recognition sequence by the zymoplasm protein cleavage, can remove affinity marker from enzyme.The SF-9 insect cell infects with multiple 0.5, and in back 48 hours results of infection.The extraction of ZAP70 and purifying
The SF-9 cell is by by 20mM Tris, and pH 8.0,137mM NaCl, 10% glycerine, 1%Tri ton X-100,1mM PMSF, 1 μ g/ml leupeptin, cracking in the damping fluid that 10 μ g/ml aprotinins and 1mM sodium orthovanadate are formed.The lysate of solubility is used for chelating sepharose HiTrap post (Pharmacia), uses 50mM HEPES, pH7.5,0.3M NaCl balance.Fusion rotein 25mM imidazoles wash-out.Enzyme is stored in 50mM HEPES, and pH7.5 is in 50mM NaCl and the 5mM DTT damping fluid.The protein kinase source
Lck, Fyn, Scr, Blk, Csk, and Lyn, can buy with the form of its brachymemma (for example from Upstate Biotechnology Inc. (Saranac Lake, N.Y) and Santa CruzBiotechnology Inc. (Santa Cruz, Ca.)), or with conventional method purify from known source natural or reorganization.
Enzyme linked immunosorbent assay (ELISA) for PTKs
The existence that enzyme linked immunosorbent assay (ELISA) is used to detect and measure tyrosine kinase activity.ELISA is according to for example, Voller etc., 1980, " enzyme linked immunosorbent assay; ": the clinical immunology handbook, the 2nd edition, by Rose and Friedman, pp 359-371 American Academy Of Microbiology, Wasgington, D.C. edits, described in known arrangement carry out.
Disclosed scheme is suitable for measuring the activity of specificity PTK.For example, the preferred version that carries out ELISA experiment provides below.These schemes of measuring compound activities are suitable for the adaptations of scheme of acceptor PTK family and nonreceptor tyrosine kinase at the limit of power Inner of those skilled in the art.In order to measure the inhibitor selectivity, general PTK substrate (for example poly-(Glu 4Tyr) unregulated polymer 20000-50000MW) is used in test with the concentration that approximately doubles apparent Km with ATP (typically 5 μ M).
Following process is used to analyze The compounds of this invention to KDR, Fit-1, Tie-2, EGFR, FGFR, PDGFR, IGF-1-R, c-Met, Lck, Blk, Csk, Src, Lyn, the restraining effect of Fyn and ZAP70 tyrosine kinase activity: (Glu Tyr) at-20 ℃ stores powder to damping fluid and solution: PGTPoly at 4: 1.The salt solution (PBS) that powder is dissolved in phosphoric acid buffer obtains 50mg/ml solution.Store the 1ml aliquots containig at-20 ℃.When making sheet, in Gibco PBS, be diluted to 250 μ g/ml.Reaction buffer: 100mM Hepes, 20mM MgCl 2, 4mM MnCl 2, 5mM DTT, 0.02%BSA, 200 μ M NaVO 4, pH 7.10ATP: store the 100mM aliquots containig at-20 ℃.In water, be diluted to 20 μ M lavation buffer solutions: the PBS antibody dilution buffer that contains 0.1%Tween 20: 0.1% bovine serum albumin (BSA) tmb substrate among the PBS: before using, mixed tmb substrate and peroxide solutions 9: 1, or the K-Blue substrate stop bath of use Neogen: the preparation of 1M process phosphoric acid 1. plates: in PBS, PGT liquid storage (50mg/ml, freezing) is diluted to 250 μ g/ml.Every hole of the flat high-affinity elisa plate of modifying at Corning (Corning#25805-96) adds 125 μ l.In the blank hole, add 125 μ lPBS.Cover and be incubated overnight with seal strip at 37 ℃.With 250 μ l lavation buffer solutions washing 1 time, in dry incubator in about 2 hours of 37 ℃ of dryings.At the bag Inner of sealing in 4 ℃ of plates that store to apply until use.2. tyrosine-kinase enzyme reaction :-in 20% the DMSO aqueous solution with 4 times prepared at concentrations inhibitor solution.-preparation feedback damping fluid-preparation enzyme solution, making required unit is 50 μ l, for example for KDR, makes 1ng/ μ l, every hole 50ng altogether in reaction.Be stored on ice.-the liquid storage from 100mM water is made the ATP solution of 4 part of 20 μ M.Be stored on ice-every hole adds 50 μ l enzyme solution (according to kinase whose specific activity, typically be 5-50ng enzyme/hole)-add 25 μ l, 4 * inhibitor-addings 25 μ l and be used for 4 * ATP-that inhibitor analyzes and add 25 μ l 0.05N Hcl termination reactions-the wash ultimate density that plate * * reacts at room temperature incubation 10 minutes-add 50 by every hole: 5 μ M ATP, 5%DMSO3. antibodies-the aliquots containig of 1mg/ml PY20-HRP (Pierce) antibody (phosphinylidyne tyrosine antibody) is diluted to the every hole of 50ng/ml-by two steps dilution (100 *, then 200 *) in the PBS of 0.1%BSA solution adds 100 μ l Ab.Room temperature incubation 1 hour.4 ℃ of incubations 1 hour.-washing 4 * plate 4. coloring reactions-preparation tmb substrate, and every hole adds 100 μ l-and detect OD at 650nm are until reaching 0.6-with the termination of 1M phosphoric acid.On the plate reader, vibrate.-read OD at 450nm immediately
Best incubation time and enzyme reaction condition be slight the variation with the enzyme preparation, and each batch measured by rule of thumb.
For Lck, used reaction buffer is 100mMMOPSO under similar analysis condition, and pH 6.5,4mM MnCl 2, 20 mM MgCl 2, 5mM DTT, 0.2%BSA, 200mMNaVO 4
With fixed, there is therapeutic action the protein tyrosine kinase diseases associated aspect that is suppressed by formula I compound that do not mention above comprising and undetermined to formula I compound in treatment.All all suppress FGFR, PDGFR, KDR, Tie-2, Lck, Fyn, Lyn or Src at the compound that this paper gives an example significantly at 50mM or lower concentration.Some The compounds of this invention also all suppress other tyrosine or serine/threonine kinase such as cdc2 (cdc1) significantly at 50mM or lower concentration.The cdc2 source
People's recombinase and analysis buffer can buy that (New England Biolabs, Beverly MA.USA), or purify from known source natural or reorganization with conventional method.
Cdc2 analyzes
Used scheme is to be provided by the reagent of buying, and seldom changes.Briefly, be reflected at fresh 300 μ M ATP (31 μ Ci/ml) and 30 μ g/ml histone IIIss type ultimate densities and replenish, by 50mM Tris pH 7.5,100mM NaCl, 1mM EGTA, 2mM DTT, 0.01%Brij, 5%DMSO and 10mM MgCl 2Carry out in the damping fluid of forming (commodity damping fluid).Volume is that 80 μ l contain being reflected at of unit of enzyme and are with or without inhibitor and exist down and carried out 20 minutes in 25 ℃.By adding 120 μ l, 10% acetate termination reaction.By mixing object point on phosphorylated cotton paper, then each isolates substrate with 3 washings 5 minutes of 75mM phosphoric acid from uncorporated marker.In the presence of the liquid scintillation meter, pass through the β rolling counters forward.
Some The compounds of this invention suppresses Cdc2 significantly in the concentration that is lower than 50 μ M.PKC kinases source
The catalytic subunit of PKC can be purchased (Calbiochem).The PKC kinase assay
(Yasuda, I., kirshimoto, A., Tanaka, S., Tominaga, M., Sakurai, A., Nishizuka, Y. biological chemistry and biophysical studies communication 3:166,1220-1227 (1990)) carries out the radioactivity kinase assay according to disclosed method.Briefly, institute responds and all exists, by 50mM Tris-HCl pH 7.5, and 10mM MgCl 2, 2mMDTT, 1mM EGTA, 100 μ M ATP, 8 μ M peptides, 5%DMSO and 33Carry out in the damping fluid that P ATP (Ci/mM) forms.Compound and enzyme are mixed in reactor, start reaction by adding ATP and substrate mixture.By adding 10 μ L stop buffers (solution of 5mM ATP in 75mM phosphoric acid) termination reaction, a part of mixture is put on phosphorylated cotton filter paper.The sample of being put 5 to 15 minutes Inner washing 3 times in 75mM phosphoric acid at room temperature.By liquid scintillation counter that the radio-labeled thing that mixes is quantitative.Erk2 enzyme source
The mouse enzyme and the analysis buffer of reorganization can buy (New England Biolabs, Beverly, MA.USA), or with of the source purification of conventional method from known natural or reorganization.
The Erk2 enzyme is analyzed
Briefly, be reflected at fresh 300 μ M ATP (31 μ Ci/ml) and 30 μ M myelin basic proteins and replenish, by 50mM Tris pH 7.5,1mM EGTA, 2mM DTT, 0.01%Brij, 5%DMSO and 10mM MgCl 2In the damping fluid of forming (commodity damping fluid), under the condition that the supplier recommends, carry out.Mix the reaction volume of radioactivity thing test and method as described in for PKC (top).The external model of T-cell-stimulating
For by mitogen or antigenic activation, the T-cell is supported a kind of somatomedin of its hyperplasia phase subsequently by secretion inducing IL-2.Therefore, can measure former generation T-cell or as the generation or the hyperplasia of IL-2 of the suitable T-clone that is used for T-cell-stimulating quid pro quo.These tests were all described in detail in the literature, and its parameter also all makes document (up-to-date immunological method, Vol 2, among the 7.10.1-7.11.2)
Briefly, the T-cell can by with allogeneic yield stimulant co-culture of cells, a kind ofly be referred to as unidirectional blended lymphocyte reaction and be activated.Reactor and exciter's peripheral blood lymphocytes are purified by the Ficoll-Hypaque gradient (Pharmacia) that each producer instructs.Irritation cell is the mitotic division inactivation by using ametycin (Sigma) or gamma-ray therapy.Reactor and exciter's cell are cultivated with 2: 1 ratio altogether being with or without in the presence of the test compound.Typically, 10 5Individual reactor and 5 * 10 4Individual exciter mixes and tiles (200 μ l volume) on droplet plate at the bottom of the U type (Costar Scientific).Cell is with the foetal calf serum (Hyclone Laboratories) of heat inactivation or from the human body blended AB serum of male donor gained, 5 * 10 -5Cultivate among the RPMI 1640 that M 2 mercaptoethanols and 0.5%DMSO replenish, before results (typically being 3 days), culture is with 0.5 μ Ci 3H thymus pyrimidine (Amersham) pulse one day.Culture is gathered in the crops, and (Betaplate harvester, Wallac), (Betaplate Wallac) estimates isotopic picked-up by liquid scintillator.
Identical culture system can be used for estimating by the production of measuring IL-2 the activation of T-cell.Cultivate startup after 18 to 24 hours, remove supernatant liquor, measure IL-2 concentration by carry out ELISA (R and D system) according to the producer's guidance.The body Inner model of T-cell-stimulating
Effectiveness can be proved to be to the animal model of effector with known direct measurement T-cell-stimulating or T-cell and test in the body of compound.The T-cell can activate by the ligation of T-cell receptors and mono-clonal anti-CD 3 antibodies (Ab) constant region part at body Inner.In this model, BALB/c mouse resists-CD3 Ab for sub 10 μ g at preceding 2 hours peritonaeum Inner of bloodletting.Before anti--CD3 Ab administration 1 hour, with the animal of single dose compound pre-treatment reception test medicine.Measure the serum-concentration (T-cell-stimulating indicator) of pro-inflammatory cytokine interferon-(INF-γ) and tumor necrosis factor-alpha (TNF-α) by ELISA.Similarly the model utilization is carried out T cell initiation in the body with specific antigens (as keyhole chirp hemocyanin (KLH)), then once more the dyeing lymph-node cell is carried out external attack with same antigen.As mentioned above, measure the state of activation of production of cytokines with the assessment culturing cell.Briefly, at the 0th day, use the subcutaneous immune C57BL/6 mouse of complete Freund's adjuvant (CFA) emulsive KLH with 100 micrograms.In immunity preceding 1 day, subsequently after immunity 1,2 and 3 day with compound pre-treatment animal.Collected painted lymphoglandula at the 4th day, with 6 * 10 6The density of individual cell/ml (is added with heat-inactivated foetal calf serum (Hyclone Laboratories) 5 * 10 at tissue culture medium (TCM) -5M 2 mercapto ethanol and 0.5%DMSO) in lymph-node cell was cultivated 24 hours and 48 hours.Autocrine T cell growth factor interleukin II (IL-2) and/or IFN-γ level in ELISA assessment culture supernatants then.
Also can in human disease's animal model, detect lead compound.For example experimental autoimmunization encephalomyelitis (EAE) and collagen-induced sacroiliitis (CIA) animal model.The EAE model of rat and mouse had been described, the sign (referring to FASEB J.5:2560-2566,1991 of the anthropomorphic multiple sclerosis of this pattern die; Mouse model: Lab.Invest.4 (3): 278,1981; Rodent models: Journal of Immunology, 146 (4): 1163-8,1991).Briefly, with myelin basic protein (MBP) emulsion or its neural generation peptide derivant and CFA immune mouse or rat.Add bacteriotoxin, as the Whooping cough bordetella to induce acute illness.Recur/palliate a disease by inducing through the T cell adoptive transfer of the animal of MBP/ peptide immunity.
Can be by using II Collagen Type VI immune induction CIA (Journal of Immunology: 142 (7): 2237-2243) in the DBA/1 mouse.Attacked back 10 days as far back as antigen, mouse promptly produces arthritic sign, reaches in 90 days arthritic symptom is marked after immunity.In EAE and CIA model, can be prophylactically or when disease begins administered compound.Effectively medicine should be able to reduce seriousness and/or sickness rate.
Some compound of the present invention can reduce arthritic seriousness and the sickness rate in these models, because these compounds can suppress the protein kinase (as lck) of one or more vasculogenesis acceptor PTK and/or participation inducing inflammatory reaction.
Also can (comment 10:333-58,1992 academic year as skin at mouse allogeneic model referring to immunity; Transplant: detection compound 57 (12): 1701-1706,1994) or in the heart (Am.J.Anat:113:273,1963).Briefly, the full thickness skin transplantation thing with the C57BL/6 mouse migrates to BALB/c mouse.Checked since the 6th day every day whether graft is ostracised.In the newborn heart transplantation model of mouse, the newborn heart of C57BL/6 mouse is by the auricle of heterotopic transplantation to the CBA/J mouse that grows up.Transplant 4 to the 7 days hearts in back and begin to beat, use dissecting microscope to seek dancing and stop to repel with visual assessment.Cell receptor PTK test
Use following test cell line to measure activity and the exposure level of different compound of the present invention to KDR/VEGFR2.Can use technology well-known in the art, utilize the similar acceptor PTK test of ligands specific stimulator along identical thinking for other Tyrosylprotein kinase design.
In the human umbilical vein Inner chrotoplast (HUVEC) that the Western trace is measured by VEGF-inductive KDR phosphorylation:
(San Diego CA) and according to manufacturer's explanation cultivates 1.HUVEC cell (deriving from concentrated donor) is available from Clonetics.Early stage several generations (3-8 generation) is only used in this test.Use complete EBM substratum (Clonetics), at 100mm culture dish (tissue culture Falcon; Becton Dickinson; Plymouth, Britain) middle culturing cell.
2. for the inhibition activity of assessing compound, use trypsin digestion and cell, and with 0.5-1.0 * 10 5The density of individual cells/well is inoculated in the 6-hole plate (Costar that clusters; Cambridge is in every hole MA).
3. the inoculation back is 3 to 4 days, and plate is paved with by 90-100%.Remove substratum from institute is porose, with 5 to 10ml PBS flushing cell, the EBM minimum medium (being serum starvation) that does not contain additive with 5ml is incubated 18 to 24 hours.
4. the inhibitor (final concentration is 25 μ M, 5 μ M or 1 μ M) that adds serial dilution in the cell in 1ml EBM substratum was in 37 ℃ of insulations 1 hour.The adding people VEGF that recombinates in the institute that contains 2ml EBM substratum is porose then 165(R ﹠amp; D Systems) to final concentration be 50ng/m1, and in 37 ℃ the insulation 10 minutes.Use control cells assessment background phosphorous acidifying and VEGF inductive phosphorylation unprocessed or that only handle with VEGF.
Wash all holes with 5 to the 10ml cold PBS that contain 1mM sodium vanadate (Sigma) then, scrape cell and contain proteinase inhibitor (PMSF 1mM at 200 microlitres, aprotinin 1 μ g/ml, pepstatin 1 μ g/ml, leupeptin 1 μ g/ml, vanadic acid sodium 1mM, Sodium Fluoride 1mM) and RIPA damping fluid (the 50mM Tris-HCl of 1 μ g/mlDNA enzyme, pH7,150mM NaCl, 1%NP-40,0.25% Sodium desoxycholate, lysing cell 1mM EDTA) (all compounds all derive from Sigma Chemical Company, St Louis, MO).With 14, the centrifugal lysate of the rotating speed of 000rpm is to remove stoning.
Then by adding cold (20 ℃) ethanol (2 times of volumes) minimum 1 hour or spending the night at the most with precipitation equal protein matter.Containing the Laemli sample buffer (BioRad of 5%2-mercaptoethanol; Hercules rebuilds throw out in CA) and boiled 5 minutes.By polyacrylamide gel electrophoresis (6%, 1.5mm Novex, San Deigo CA) differentiates protein and use the Novex system to be transferred on the nitrocellulose filter.With after bovine serum albumin (3%) sealing, in 4 ℃ with anti--KDR polyclonal antibody (C20, Santa Cruz Biotechnology; SantaCruz, CA) or with anti-Tyrosine O-phosphate monoclonal antibody (Lake Placid NY) surveys protein and spends the night for 4G10, UpstateBiotechnology.Washing and the goat of puting together with HRP-be anti--and rabbit or goat be anti--F (ab) of mouse IgG 2After being incubated 1 hour, use emission chemoluminescence (ECL) system (Amersham Life Sciences, ArlingtonHeight, IL) visual inspection band.Some example of the present invention significantly suppresses cell VEGE-inductive KDR Tyrosylprotein kinase phosphorylation with the concentration that is lower than 50 μ M.Body Inner uterus edema model
This test determination compound suppress the sharply ability of increase of uterus weight that the preceding several hrs of mouse after stimulating with oestrogenic hormon take place.The early stage increase of known uterus weight may be due to the oedema that is caused by the permeability increase of uterine vascular system.(incretology (1993) 133:829-837) has illustrated that VEGF mRNA expression is increased in temporal substantial connection in uterus oedema that oestrogenic hormon stimulates and the uterus for Cullinan-Bove and Koss.Use has confirmed these results at the neutralizing monoclonal antibody of VEGF, and described antibody capable significantly reduces oestrogenic hormon and stimulates the rapid increase (WO 97/42187) of uterus weight afterwards.Therefore, this system can be used as the model that body Inner suppresses VEGF signal transduction and relevant high-permeability and oedema.Material: as all hormones of lyophilized powder all available from Sigma (St.Louis, MO) or CaiBiochem (La Jolla CA), and is prepared according to manufacturer explanation.Carrier components (DMSO, Cremaphor EL) available from Sigma (St.Louis, MO).(Germantown NY), and shows loving care for and the council of use guide carries out stable breeding in bioclean Animal House according to habitual animal mouse (Balb/c, 8 to 12 week ages) available from Taconic.Method: the 1st day: the mare serum gonadotropin (PMSG) of giving 12.5 unit pregnancies of Balb/c mouse peritoneum Inner (i.p.) injection.The 3rd day: the human chorionic gonadotropin (hCG) of giving 15 units of injection in the mouse peritoneum.The 4th day: mouse is divided into 5 to 10 groups at random, and according to solvability and carrier, through peritonaeum Inner, vein Inner or p.o. approach were used test compound with the dosage of 1-100mg/kg.The vehicle Control group is only accepted carrier, stay two groups not treated.
After 30 minutes, give experimental group, vehicle group and 1 unprocessed group peritoneal injection 17-estradiol (500 μ g/kg).After 2 to 3 hours, put to death animal by sucking carbonic acid gas.After midline incision, isolate each uterus, cut to take the uterus near the uterine neck below and in uterus and oviducal junction.Carefully remove fat and reticular tissue, do not destroy the integrity in uterus in weigh (weight in wet base) before.By between two layers of filter paper with the extruding of the vial of 1 liter of filled with water blotting the fluid in the uterus, after suck dry moisture to uterus weigh (dry weight).Difference between weight in wet base and the dry weight is the fluid content in the uterus.With the average flow body burden of treatment group be untreated or the comparing of vehicle treated group.Pass through Student ' s test determination significance.Use is without the reaction of stimulated control group monitoring estradiol.
The result shows that can suppress oedema when by number of ways systemic administration some compound of the present invention forms.
Some compound of the present invention as the vasculogenesis receptor tyrosine kinase inhibitors also demonstrates activity in the Matrigel planting model that neovascularity generates.Matrigel neovascularity generation model relates to extracellular matrix " marble " interior neovascularization clearly of subcutaneous implantation, it is that (example is seen Passaniti for the inductive that exists by the tumour cell of angiogenesis factor before producing that described neovascularity generates, A etc., Lab.Investig (1992), 67 (4), 519-528; Anat.Rec, 1997,249 (1), 63-73; International journal of cancer, 1995,63 (5), 694-701; Vasc.Biol.1995,15 (11), 1857-6).Preferably this model was kept 3 to 4 days, terminal point comprises never and to carry out visual inspection/developing scoring that neovascularity generates after removing the anti-contrast of graft in the animal of handling with inhibitor, and the microscope microvessel density is measured and the quantitative assay (Drabkin method) of oxyphorase.This model also can use bFGF or HGF as stimulator.
Can suppress one or more oncogenes, some compound of the present invention of proto-oncogene or propagation-dependent protein kinase or vasculogenesis acceptor PTK also can suppress primary mouse in the mouse, rat or people's xenotransplantation growth of tumor, or the metastases in the inhibition mouse model.For example
The preparation method of present description formula I compound.These methods form another aspect of the present invention.This method is preferably under atmospheric pressure carried out.
Formula I compound can pass through following formula: compound
Figure A9981321701081
R wherein 1, R 2, R 3, L and A ring as preceding definition, with the temperature range of methane amide at 50 to 250 ℃, condensation and preparing in the presence of 4-dimethylaminopyridine catalyzer for example non-imposedly.
Formula I compound can through type (III) compound
Figure A9981321701082
R wherein xBe bromine or iodine, with one of following compounds: R 3B (OH) 2, R 3SnCH 3Or the compound represented of formula IV
Figure A9981321701091
R wherein 3As above definition is at catalyzer for example palladium (O) compound such as Pd (Ph 3) 4Existence is reacted down and is prepared.
R wherein 1The formula I compound of expression alkyl or aralkyl can be by making the formula V compound
Figure A9981321701092
R wherein 2And R 3As preceding definition, use wherein R 1Expression alkyl or aralkyl, and X ' expression leaving group, halogen atom for example, the formula R of mesyloxy or tosyloxy 1X ' alkylation and preparing.
R wherein 1The cyclic ether of representing non-imposed replacement can be by making formula VI compound as the formula I compound of tetrahydrofuran base or THP trtrahydropyranyl
Figure A9981321701101
R wherein 2And R 3As preceding definition, with X ' wherein as preceding definition, R 1The formula R that represents the cyclic ether of non-imposed replacement 1X ' alkylation and preparing.
R wherein 1The expression cyclic ether can be by making formula VI compound with R wherein as the formula I compound of non-imposed tetrahydrofuran base that is replaced by formyl radical or THP trtrahydropyranyl 1Expression is by the known method of those skilled in the art, for example acetal (referring to for example tetrahedron communication, 30 (46), 1989,6259-6262) the formula R of the cyclic ether of Bao Hu the non-imposed replacement of formyl radical 1X alkylation, then deprotection and preparing.R wherein 1The expression cyclic ether is as can be by making wherein R by the compound of (amino of non-imposed replacement) methyl substituted tetrahydrofuran base or THP trtrahydropyranyl 1The cyclic ether compound reductive amination that expression is replaced by formyl radical and preparing.
R wherein 1The furyl of representing non-imposed replacement, the formula I compound of thienyl or pyrryl can be by 4-chloro-5-iodo-7H-pyrrolo-[2,3-d] pyrimidine and suitable heteroaryl boric acid in copper salt catalyst, for example neutralized verdigris (II) exists down, at the solvent of reactant, for example halogenated solvent exists down as methylene dichloride, at siccative, for example the 4_ molecular sieve exists down, and at organic bases, for example triethylamine or pyridine exist down, 0-50 ℃ temperature range, preferred room temperature is reacted and is prepared.(for condition, referring to the tetrahedron communication, (1998), Vol.39:2942-2944 and its reference, the full text of this paper draw does this paper reference).These compounds can provide wherein R by this professional known method allotment 1The furyl that expression is replaced by formyl radical, the formula I compound of thienyl or pyrryl.In these compounds, formyl radical can provide wherein R by this professional known method preparation property amination 1The furyl that expression is replaced by amino methyl, the formula I compound of thienyl or pyrryl.In addition, R wherein 1Expression furyl, the intermediate of thienyl or pyrryl can carry out the Mannich reaction, provide middle R 1The furyl that expression is replaced by amino methyl, the intermediate of thienyl or pyrryl.
Formula I compound can be by making formula VII compound
Figure A9981321701111
R wherein 1, R 2, R 3, L and A ring as preceding definition, and R yThe expression leaving group, for example halogen atom or phenoxy group, with ammonia or ammonium salt, ammonium acetate for example, 15-250 ℃ temperature range, preferably reaction and preparing in forcer.
R wherein 2Expression chlorine, the formula I compound of bromine or iodine can be by making formula VIII compound
Figure A9981321701112
R wherein 1, R 2, R 3, L and A ring as preceding definition, with halogenating agent, iodinating agent for example, for example N-iodosuccinimide, or bromizating agent, for example N-bromosuccinimide, or chlorizating agent, for example N-chlorosuccinimide reaction and preparing.
Wherein-L-R 3Expression-NHC (O) R 3Formula I compound can be by making formula IX compound
Figure A9981321701113
R wherein 1, R 2, R 3, L and A ring as preceding definition, and Y represents protected amine are with R wherein xExpression leaving group, for example the formula R of chlorine atom 3COR xCompound reaction and prepare.In addition, wherein Y represents halogen atom, for example the formula IX compound of chlorine can with formula R 3COR xCompound reaction, its product and ammonia react provide formula I compound.Similarly method can be used for preparing wherein-L-R 3Be-NRSO 2R 3Formula I compound.Similarly method can be used to prepare wherein-L-R 3Be-NRCO 2-R 3Or-compound of NRCONR ', R and R ' are as preceding definition.
Wherein-L-R 3Be-OSO 2-formula I compound can be by making formula X compound
Figure A9981321701121
R wherein 1, R 2With A ring as preceding definition, with formula R 4SO 2R xCompound reaction and prepare.
Formula I compound then can be from the alternative preparation of this class intermediate according to described diagram 2 in back or diagram 2.
Formula II compound can prepare shown in diagram 1, and wherein IPA represents propan-2-ol.
Diagram I
Figure A9981321701122
Figure A9981321701131
Those skilled in the art should be appreciated that formula I compound can be converted into other formula compound by known chemical reactions.For example, alkoxyl group can cleavedly provide hydroxyl, and nitro can be reduced to amine, and amine again can be by acidylate, sulfonylation or phosphorylated, and the N-acyl compounds can be hydrolyzed to amine.Wherein-L-be the formula I compound of S can provide wherein by the known method of those skilled in the art is oxidized-L-represents SO and SO respectively 2Formula I compound.
The formula III compound can buy, perhaps by the known method preparation of those skilled in the art.
R wherein 2The formula V compound of expression hydrogen can prepare shown in diagram 2.Its amino in the end step is before protected, then after the final step of diagram 2, by the known method deprotection of those skilled in the art.R wherein 2The formula V compound that is not hydrogen can be by similar method preparation (referring to the pharmaceutical chemistry magazine, (1990), 33,1984).
Diagram 2
In diagram 2, (A ring)-L-R 3Can be before amination at first by coupling.And as the substituent R of preceding definition 1Before carrying out any step, can exist.
R wherein yBe-the formula VII compound of Cl can prepare shown in diagram 3.
Diagram 3
Figure A9981321701141
(A ring)-L-R wherein 3Non-existent compound can be as diagram 4 with as the pharmaceutical chemistry magazine, (1998), 31:390 and the described preparation of its reference of quoting.(A ring)-L-R wherein 3The compound that is not hydrogen can be by similar method preparation.
Diagram 4
Figure A9981321701151
Formula VII compound can be by being similar to the method for preparation formula V compound, coupling 5-iodine compound and preparing.
R 1Can modify by the method that in diagram 5 and 6, provides.In diagram 5 and 6, P represents protecting group
Diagram 5 Diagram 6
Those skilled in the art should be appreciated that, and is identical by the functional group of modified in substituting group and one of described method, or under the similar situation, these substituting groups needed protection before this method is carried out, deprotection after process.Otherwise, competitive side reaction will take place.Can use another aforesaid method, wherein substituting group does not disturb.Suitable protecting group and its adding and remove the example of method can be at T.W.Green, John Wiley and Sons find in 1981 textbooks of publishing " protecting group of organic synthesis ".For example, suitable amine protecting group is formyl radical or ethanoyl.
The generalized in the above general preparation method's preparation of the following example compound: embodiment 1:N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine benzyl ester is tetrahydrochysene-2H-4-pyranyl triflate a)
(1.7ml, (2ml is in methylene dichloride 20.97mmol) (16ml) solution 20.97mmol) to add tetrahydrochysene-2H-4-pyrans alcohol with pyridine.Flask is immersed in the ice-water bath, and drip trifluoromethanesulfanhydride anhydride (3.6ml, methylene dichloride 20.97mmol) (7ml) solution at 10 minutes Inner.After 20 minutes, reaction mixture is filtered solid washed with dichloromethane in a small amount.The filtrate water that merges, 1.0N HCl, water and salt water washing.Organic layer is dried in (sal epsom) and filters.Evaporating solvent provides tetrahydrochysene-2H-4-pyranyl triflate. 1H
NMR(CDCl 3)δ1.99(m，2H)，2.11(m，2H)，3.58(m，2H)，3.96(m，2H)，5.17
(m, 1H) .b) 4-chloro-5-iodo-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine
At 0 ℃, (3.0g, (0.891g, N 22.2mmol) is in dinethylformamide (40ml) solution 10.73mmol) to add sodium hydride with short run with 4-chloro-5-iodo-7H-pyrrolo-[2,3-d] pyrimidine.After adding, remove ice bath, the mixture of generation is stirred 30 minutes.Drip tetrahydrochysene-2H-4-pyranyl triflate, mixture was stirring at room 24 hours.Mixture is poured in the frozen water (100ml), and solid collected by filtration by recrystallization purifying, provides 4-chloro-5-iodo-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine.
1H NMR (CDCl 3) δ 2.06 (m, 2H), 3.63 (m, 2H), 4.16 (m, 2H), 5.00 (m, 1H), 7.45 (s, 1H), 8.61 (s, 1H) .LC/MS (MH +=364) N-(4-(4-chloro-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine tertiary butyl ester c)
With N-[2-methoxyl group-4-(4,4,5,5-tetramethyl--1,3,2-dioxo bora pentamethylene-2-yl) phenyl] the carboxylamine tertiary butyl ester (1.66g, 4.75mmol) in water by ultrasonic wave vacuum outgas 1 minute.With 4-chloro-5-iodo-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine (1.1g, 3.17mmol), four (triphenyl phosphine) palladium (O) (0.22g, 0.19mmol), yellow soda ash (0.8g, 7.60mmol) and 1,2-glycol dimethyl ether (30ml) adds in the aqueous mixture.The suspension that produces outgased 2 minutes once more, then 85 ℃ of heating 24 hours.Make reaction mixture be cooled to room temperature, and with solvent evaporation.Resistates is dissolved in ethyl acetate.Organic layer is washed and dry (sal epsom).Solid is made moving phase by quick purification by silica gel column chromatography with heptane/ethyl acetate (7: 3), provides N-(4-(4-chloro-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine tertiary butyl ester.
1H?NMR(CDCl 3)δ1.55(s，9H)，2.10(m，4H)，3.66(m，2H)，3.92(s，3H)，4.16
(m，2H)，5.05(m，1H)，7.06(m，2H)，7.14(s，1H)，7.32(s，1H)，8.13(br.d，J＝8
Hz, 1H), 8.64 (s, 1 H) .LC/MS (MH +=459) 4-(4-chloro-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-anisidine d)
Add in N-(4-(4-chloro-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) the carboxylamine tertiary butyl ester at 0 ℃ of methylene dichloride (50ml) solution 10% trifluoroacetic acid.After 20 minutes, remove ice bath, the solution of generation was stirring at room 4 hours.Remove and desolvate, resistates is dissolved in methylene dichloride.Add saturated sodium bicarbonate aqueous solution, separately two-layer.The water layer dichloromethane extraction.The organic layer salt water washing that merges, dry (sal epsom) filters and concentrates.Solid by the silicagel pad purifying, is made moving phase with heptane/ethyl acetate (3: 2), provide 4-(4-chloro-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-anisidine.
1H?NMR(CDCl 3)δ2.09(m，4H)，2.51(br.s，NH 2)，3.66(m，
2H)，3.91(s，3H)，4.16(m，2H)，5.05(m，1H)，6.79(d，J＝8?Hz，2H)，6.93(d，J＝8
Hz, 1H), 6.98 (s, 1H), 7.28 (s, 1H), 8.63 (s, 1H) .LC/MS (MH +=359) 5-(4-amino-3-p-methoxy-phenyl)-7H-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine e)
(4-chloro-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-(0.73g is in dioxan 2.03mmol) (25ml) solution for the 2-anisidine in penstock ammonium hydroxide (25ml) to be added 4-.With the penstock sealing and 122 ℃ of heating 2 days.Pipe is cooled to room temperature, and evaporating solvent.Add ethyl acetate, organic layer is washed, and dry (sal epsom) filters and concentrates, and provides 5-(4-amino-3-p-methoxy-phenyl)-7H-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine.
1H?NMR(DMSO-d 6)δ1.87(m，2H)，2.11(m，2H)，3.52
(m，2H)，3.79(s，3H)，3.99(m，2H)，4.87(m，3H)，6.02(br.s，NH 2)，6.73(d，J＝8
Hz，2H)，6.77(d，J＝8?Hz，1H)，6.88(s，1H)，7.33(s，1H)，8.10(s，1H).LC/MS
(MH +=340) N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine benzyl ester f)
At 0 ℃, stir down, in nitrogen atmosphere with benzyl chloroformate (16 μ L, 0.110mmol) be added drop-wise to 5-(4-amino-3-p-methoxy-phenyl)-7H-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] (25mg is in pyridine 0.074mmol) (0.7ml) and methylene dichloride (0.7ml) solution for pyrimidine-4-amine.After 10 minutes, remove ice-water bath, the mixture of generation is stirred 4 hours.With solvent evaporation, resistates is by preparation property TLC purifying, make moving phase with methylene chloride (95: 5), provide N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine benzyl ester. 1HNMR(CDCl 3)δ2.07(m，4H)，3.65(m，2H)，3.9(s，3H)，4.13(m，2H)，4.97(m，1H)，5.23(s，2H)，6.96(s，
1H)，7.03(s，1H)，7.08(d，J＝8Hz，1H)，7.42(m，6H)，8.20(br.s，J＝8?Hz，1H).
8.32 (s, 1H) .LC/MS (MH +=474). embodiment 2:N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine neo-pentyl ester
At 0 ℃, stir down, in nitrogen atmosphere with chloroformic acid neo-pentyl ester (13 μ L, 0.110mmol) be added drop-wise to 5-(4-amino-3-p-methoxy-phenyl)-7H-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] (25mg is in pyridine 0.074mmol) (0.7ml) and methylene dichloride (0.7ml) solution for pyrimidine-4-amine.After 10 minutes, remove ice-water bath, the mixture of generation is stirred 4 hours.With solvent evaporation, resistates is by preparation property TLC purifying, make moving phase with methylene chloride (95: 5), provide N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine neo-pentyl ester.
1H?NMR(CDCl 3)δ1.00(s，3H)，2.07(m，4H)，3.65(m，
2H)，3.91(s，2H)，3.94(s，3H)，4.13(m，2H)，4.97(m，1H)，5.18(s，2H)，6.97(s，
1H)，7.03(s，1H)，7.07(d，J＝8Hz，1H)，7.25(s，1H)，8.19(br.s，J＝8Hz，1H).8.33
(s, 1H) .LC/MS (MH +=454). embodiment 3:N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine phenylester
(100mg 0.294mmol) is dissolved in methylene dichloride (2ml) with 5-(4-amino-3-p-methoxy-phenyl)-7H-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine.Add pyridine (2ml) then add the chloroformic acid phenylester (44 μ L, 0.353mmol).Stir after 3 hours, add other 44 μ L phenyl methanesulfonamide acyl chlorides, reaction mixture is stirred and spends the night.Remove and desolvate, resistates provides N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl by preparation property LC/MS purifying] the carboxylamine phenylester.
1H NMR (CDCl 3-d) 6 2.09 (m, 4H), 3.66 (m, 2H), 3.98 (s, 3H), 4.16 (m, 2H), 4.98 (m, 1H), 5.24 (s, 2H), 7.09 (m, 3H), 7.23 (m, 4H), 7.41 (m, 2H), 7.62 (s, 1H), 8.20 (bd, J=7.80Hz, 1H), 8.33 (s, 1H) .LC/MS MH +=460. embodiment 4:N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] carboxylamine tetrahydrochysene-2H-4-pyranyl ester 4-nitrophenyl tetrahydrochysene-2H-4-pyranyl carbonic ether
(1.0ml 10.5mmol) mixes in methylene dichloride (20ml) with 4-methylmorpholine (2.0ml) with tetrahydrochysene-2H-4-pyrans alcohol.Slowly add in the reaction mixture 4-nitroxyl chloride manthanoate (1.98g, 9.82mmol).Stir after 5 hours, reaction mixture dilutes with methylene dichloride.The organic layer water, 1.0N HCl, saturated sodium bicarbonate, the salt water washing, dried over mgso is filtered and evaporation.Crude product is made moving phase with ethyl acetate/heptane (4: 1) by quick purification by silica gel column chromatography, provide 4-nitrophenyl tetrahydrochysene-2H-4-pyranyl carbonic ether (1.5g, 5.62mmol).1H NMR (CDCl 3-d) δ 1.87 (m, 2H), 2.06 (m, 2H), 3.58 (m, 2H), 3.98 (m, 2H), 4.97 (m, 1H), 7.40 (d, J=9.0Hz, 2H), 8.30 (d, J=9.0Hz, 2H) .a) N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] carboxylamine tetrahydrochysene-2H-4-pyranyl ester
With 5-(4-amino-3-p-methoxy-phenyl)-7H-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (57mg, 0.168mmol) and 4-nitrophenyl tetrahydrochysene-2H-4-pyranyl carbonic ether (90mg, 0.336mmol) mixing in pyridine (1ml).Stir after 5 hours, add other 90mg4-nitrophenyl tetrahydrochysene-2H-4-pyranyl carbonic ether, reaction mixture is stirred 2 days.Remove and desolvate, resistates is by the preparation of lamina chromatogram purification, provide N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] and carboxylamine tetrahydrochysene-2H-4-pyranyl ester (30mg, 0.064mmol).1H?NMR(CDCl 3-d)δ
1.78(m，4H)，2.08(m，4H)，3.60(m，4H)，3.94(s，3H)，3.97(m，2H)，4.15(m，
2H)，4.98(m，2H)，5.23(s，2H)，6.78(s，1H)，7.04(s，1H)，7.07(d，J＝8.3Hz，
1H), 8.16 (bd, J=7.90Hz, 1H), 8.33 (s, 1H) .LC/MS MH +=468. embodiment 5:N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine 3-picolyl ester hydrochloride is (3-picolyl) carbonic acid 4-nitrophenyl ester a)
(2.49g, methylene dichloride 12.3mmol) (20ml) solution cools off in ice-water bath with 4-nitroxyl chloride manthanoate.Slowly add 3-pyridyl methyl alcohol (1.0ml, 10.3mmol) and the 4-methylmorpholine (2.0ml, 18.5mmol).After 20 minutes, remove ice-water bath, make reaction mixture be warmed to room temperature.After 30 minutes, add ethyl acetate and reaction mixture is filtered.Filtrate water, saturated sodium bicarbonate, the salt water washing, dried over mgso is filtered and evaporation provides (3-picolyl) carbonic acid 4-nitrophenyl ester.
1H?NMR(CDCl-d)δ7.38(m，3H)，7.79(m，1H)，8.28(d，
J=9.09Hz, 2H), 8.65 (m, 1H), 8.72 (s, 1H) .b) N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] carboxylamine 3-picolyl ester
(25mg 0.074mmol) is dissolved in methylene dichloride (0.7ml) with 5-(4-amino-3-p-methoxy-phenyl)-7H-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine.Add pyridine (0.7ml) then add 4-nitrophenyl (3-picolyl) carbonic ether (30mg, 0.110mmol).After 100 ℃ of heated overnight, remove and desolvate, resistates provides N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2 by preparation property LC/MS purifying, 3-d] pyrimidine-5-yl)-the 2-p-methoxy-phenyl] and carboxylamine 3-picolyl ester (12mg, 0.025mmol).1H?NMR(CDCl 3-d)δ2.08(m，
4H)，3.65(m，2H)，3.92(s，3H)，4.15(m，2H)，4.96(m，1H)，5.26(s，2H)，5.54
(bs，2H)，6.97(s，1H)，7.04(s，1H)，7.08(d，J＝8.2Hz，1H)，7.35(m，2H)，7.79(d，
J＝7.8Hz，1H)，8.15(m，1H)，8.29(s，1H)，8.61(s，1H)，8.71(s，1H).LC/MS
MH +=475c) N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine 3-picolyl ester hydrochloride
With N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] (12mg 0.025mmol) is dissolved in ethyl acetate (2.0ml) to carboxylamine 3-picolyl ester.Ether (1ml) solution that slowly adds 1.0N HCl.In nitrogen, filter collecting precipitation, provide N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine 3-picolyl ester hydrochloride (13mg, 0.25mmol).1H?NMR
(DMSO-d 6)δ1.91(m，2H)，2.17(m，2H)，3.54(m，2H)，3.87(s，3H)，4.03(m，
2H)，4.97(m，1H)，5.23(s，2H)，7.05(d，J＝8.2Hz，1H)，7.13(s，1H)，7.51(m，
1H)，7.81(d，J＝8.2Hz，1H)，7.84(s，1H)，7.95(m，1H)，8.42(s，1H)，8.60(s，1H)，
8.71 (s, 1H), 8.82 (s, 1H) .LC/MS MH +=475. embodiment 6:N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine 2-morpholino ethyl ester hydrochloride
With N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] (25mg 0.054mmol) mixes with 2-morpholine-1-ethanol (0.1ml) in pyridine (0.7ml) the carboxylamine phenylester.With reaction mixture 100 ℃ of heated overnight.Remove and desolvate, resistates is by preparation property anti-phase HPLC purifying, provide N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine 2-morpholino ethyl ester hydrochloride (24mg, 0.045mmol).
1H?NMR(DMSO-
d 6)δ1.88(m，2H)，2.16(m，2H)，3.55(m，8H)，3.90(s，3H)，4.03(m，4)，4.49(m，
2H)，4.92(m，1H)，7.07(m，1H)，7.15(s，1H)，7.65(bs，2H)，7.84(s，1H)，8.45(s，
1H), 8.75 (s, 1H) 10.95 (bs, 1H) .LC/MS MH +=497. embodiment 7:N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine (4-bromo-1,3-thiazoles-5-yl) methyl ester a) 2,4-two bromo-1,3-thiazoles-5-formaldehyde
With 1,3-thiazoles-2, (3.52g, 30mmol) (43g, 150mmol) (2.56ml 34mmol) mixes the 4-diketone with dimethyl formamide with tribromo oxygen phosphorus.Then mixture was heated 1 hour at 75 ℃, and 100 ℃ of heating 5 hours.After being cooled to room temperature, mixture is added in the frozen water (500ml) the water layer dichloromethane extraction.The organic layer that merges washs with saturated sodium bicarbonate, and dried over mgso is filtered and evaporation the brown solid petroleum ether that provides.Evaporating solvent provides 2, and 4-two bromo-1,3-thiazoles-5-formaldehyde (1.74g, 6.42mmol).
1H NMR (CDCl 3-d) δ 9.90 (S, 1H) .b) (2,4-two bromo-1,3-thiazoles-5-yl) methyl alcohol
With 2, (1.74g 6.42mmol) is dissolved in methyl alcohol (70ml) at 0 ℃ to 4-two bromo-1,3-thiazoles-5-formaldehyde.With short run add sodium borohydride (0.244g, 6.42mmol).Remove ice-water bath after 10 minutes, and with mixture in stirred overnight at room temperature.Remove and desolvate, and add saturated ammonium chloride.Add 1.0N sodium hydroxide with pH regulator to 10.The water layer ethyl acetate extraction.The organic layer salt water washing that merges, dried over mgso is filtered and evaporation.Resistates is by the rapid column chromatography purifying, provide (2,4-two bromo-1,3-thiazoles-5-yl) methyl alcohol (0.946g, 3.47mmol).
1H NMR (CDCl 3-d) δ 2.11 (bs, 1H) δ 4.79 (S, 2H) .c) (4-bromo-1,3-thiazoles-5-yl) methyl alcohol
Make (2,4-two bromo-1,3-thiazoles-5-yl) methyl alcohol (0.94g, 3.44mmol), yellow soda ash trihydrate (1.34g) and Pd/C (10%, 0.07g) in methyl alcohol (33ml), mix.The mixture that produces was 60psi hydrogenation 2 days.Solid is filtered through Celite pad.Evaporating solvent, resistates be by the rapid column chromatography purifying, provide (4-bromo-1,3-thiazoles-5-yl) methyl alcohol (0.32g, 2.78mmol).
1H NMR (CDCl 3-d) δ 2.29 (bs, 1H) δ 4.86 (s, 2H), 8.72 (s, 1H) .d) N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] carboxylamine (4-bromo-1,3-thiazoles-5-yl) methyl ester
With N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-the 2-p-methoxy-phenyl] carboxylamine phenylester (28mg, 0.061mmol) (50mg 0.434mmol) mixes with (4-bromo-1,3-thiazoles-5-yl) methyl alcohol in pyridine (0.5ml).With reaction mixture 100 ℃ of heated overnight.Remove and desolvate, resistates provides N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl by preparation property anti-phase HPLC purifying] carboxylamine (4-bromo-1,3-thiazoles-5-yl) methyl ester.1H?NMR(CDCl-d)δ2.07(m，
4H)，3.65(m，2H)，3.92(s，3H)，4.13(m，2H)，4.98(m，1H)，5.35(s，1H)，5.40(s，
2H)，6.97(s，1H)，7.04(s，1H)，7.09(m，1H)，7.35(s，1H)，8.17(s，1H)，8.32(s，
1H), 8.78 (s, 1H) .LC/MS MH +=481. embodiment 8:N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] carboxylamine tetrahydrochysene-3-furyl ester
With N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] (30mg 0.065mmol) mixes with tetrahydrochysene-3-furfuralcohol (0.05ml) in pyridine (0.5ml) the carboxylamine phenylester.With reaction mixture 100 ℃ of heated overnight.Remove and desolvate, resistates provides N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl by preparation property anti-phase HPLC purifying] and carboxylamine tetrahydrochysene-3-furyl ester (14mg, 0.031mmol).
1H?NMR(CDCl-d)δ2.07(m，6H)，3.66(m，2H)，
3.96(m，7H)，4.13(m，2H)，4.98(m，1H)，5.26(s，2H)，5.40(m，1H)，6.97(s，1H)，
7.04(s，1H)，7.08(d，J＝8.2Hz，1H)，7.26(s，1H)，8.30(s，1H)，8.32(s，1H).LC/MS
MH +=455. embodiment 9 and 10:N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] carboxylamine 1,3-dioxan-5-base ester
N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] carboxylamine 1,3-dioxolane-4-ylmethyl ester
With N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] (30mg 0.065mmol) mixes with Sericosol N (0.05ml) in pyridine (0.5ml) the carboxylamine phenylester.With reaction mixture 100 ℃ of heated overnight.Remove and desolvate, resistates provides N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl by preparation property anti-phase HPLC purifying] carboxylamine 1,3-dioxan-5-base ester (2mg, 0.004mmol).
1H?NMR(CDCl-d)δ2.06(m，4H)，3.66(m，2H)，
3.92(m，3H)，4.07(m，6H)，4.79(m，1H)，4.83(d，J＝6.3Hz，1H)，4.96(m，1H)，
5.04(d，J＝6.3Hz，1H)，6.15(vbs，2H)，6.96(s，1H)，7.05(m，2H)，7.53(s，1H)，8.15
(d, J=8.2Hz, 1H), 8.22 (s, 1H) .LC/MS MH +=471 and N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] carboxylamine 1,3-dioxolane-4-ylmethyl ester (6.0mg, 0.013mmol).
1H?NMR(CDCl-d)δ2.06(m，
4H)，3.66(m，2H)，3.75(m，1H)，3.92(m，3H)，4.03(m，1H)，4.13(m，1H)，4.34(m，
2H)，4.94(s，1H)，4.97(m，1H)，5.10(s，1H)，5.32?(bs，2H)，6.97(s，1H)，7.03(m，
2H)，7.06(d，J＝8.2Hz，1H)，7.38(s，1H)，8.15(d，J＝7.9Hz，1H)，8.31(s，1H).LC/MS
MH +=471. embodiment 11:N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine 2-picolyl ester hydrochloride
With N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] (30mg 0.065mmol) mixes with 2-pyridyl methyl alcohol (0.05ml) in pyridine (0.5ml) the carboxylamine phenylester.With reaction mixture 100 ℃ of heated overnight.Remove and to desolvate, resistates is by preparation property anti-phase LC/MS purifying, provide N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine 2-picolyl ester (11mg, 0.023mmol).Solid is dissolved in ethyl acetate (2ml), slowly adds ether (0.1ml) solution of 1.0N HCl.In nitrogen, filter collecting precipitation, provide N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine 2-picolyl ester hydrochloride (12mg, 0.023mmol).
1H?NMR(DMSO-d 6)δ1.92(m，2H)，2.16(m，
2H)，3.55(m，2H)，3.89(s，3H)，4.02(m，2H)，4.91(m，1H)，5.23(s，2H)，7.05(d，
J＝8.2Hz，1H)，7.14(s，1H)，7.37(m，1H)，7.53(d，J＝7.8Hz，1H)，7.87(m，3H)，
8.42 (s, 1H), 8.57 (d, J=4.2Hz, 1H), 8.85 (s, 1H) .LC/MS MH +=475. embodiment 12:N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine 4-picolyl ester hydrochloride
With N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] (30mg 0.065mmol) mixes with 4-pyridyl methyl alcohol (0.05ml) in pyridine (0.5ml) the carboxylamine phenylester.With reaction mixture 100 ℃ of heated overnight.Remove and to desolvate, resistates is by preparation property anti-phase LC/MS purifying, provide N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine 4-picolyl ester (11mg, 0.023mmol).Solid is dissolved in ethyl acetate (2ml), slowly adds ether (0.1ml) solution of 1.0N HCl.In nitrogen, filter collecting precipitation, provide N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine 4-picolyl ester hydrochloride (12mg, 0.023mmol).
1H?NMR(DMSO-d 6)δ1.91(m，2H)，2.16(m，
2H)，3.55(m，2H)，3.90(s，3H)，4.03(m，2H)，4.92(m，1H)，5.34(s，2H)，7.06(d，
J＝8.2Hz，1H)，7.16(s，1H)，7.73(m，1H)，7.81(m，1H)，7.87(s，1H)，8.46(s，1H)，
8.76 (d, J=5.6Hz, 1H), 9.05 (s, 1H) .LC/MS:MH +=475. embodiment 13:N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine (5-methyl-3-isoxazolyl) methyl ester
With N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-the 2-p-methoxy-phenyl] (30mg 0.065mmol) mixes with (5-methyl-3-isoxazolyl) methyl alcohol (0.05ml) in pyridine (0.5ml) the carboxylamine phenylester.With reaction mixture 100 ℃ of heated overnight.Remove and desolvate, resistates is by preparation property anti-phase LC/MS purifying, provide N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine (5-methyl-3-isoxazolyl) methyl ester (18mg, 0.038mmol).1H?NMK
(CDCl-d)δ?2.06(m，4H)，2.44(s，3H)，3.64(m，2H)，3.91(s，3H)，4.13(m，2H)，4.96
(m，1H)，5.26(s，2H)，6.12(s，1H)，6.95(s，1H)，7.06(m，2H)，7.39(s，1H)，8.17(bs，
1H), 8.21 (s, 1H) .LC/MS:MH +479. embodiment 14:N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine [(2S)-and 5-oxo tetrahydrochysene-1H-2-pyrryl] methyl ester
With N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-the 2-p-methoxy-phenyl] (30mg 0.065mmol) mixes with (5S)-5-(methylol) tetrahydrochysene-1H-2-pyrrolidone (0.05ml) in pyridine (0.5ml) the carboxylamine phenylester.With reaction mixture 100 ℃ of heated overnight.Remove and desolvate, resistates is by preparation property anti-phase LC/MS purifying, provide N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-the 2-p-methoxy-phenyl) and carboxylamine [(2S)-5-oxo tetrahydrochysene-1H-2-pyrryl] methyl ester (10mg, 0.021mmol).
1H?NMR(CDCl-d)δ1.90(m，1H)，2.06(m，4H)，2.34(m，1H)，2.41(m，2H)，3.64
(m，2H)，3.94(s，3H)，4.04(m，2H)，4.14(m，2H)，4.98(m，1H)，5.33(m，3H)，
6.10(s，1H)，6.98(s，1H)，7.04(s，1H)，7.09(m，1H)，7.31(s，1H)，8.11(bs，1H)，8.32
(s, 1H) .LC/MS:MH +481. embodiment 15:N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine 4-aminobenzyl ester is N-(4-(methylol) phenyl) carboxylamine tertiary butyl ester a)
With (4-aminophenyl) methyl alcohol (1.23g, 10mmol) and diisopropyl ethyl amine (2.6ml, 15mmol) (2.62g 12mmol) mixes with heavy carbonic di-t-butyl ester in methylene dichloride (50ml).Mixture is in stirred overnight at room temperature.Add ethyl acetate, the organic layer water, 1.0N HCl, saturated sodium bicarbonate, water, the salt water washing, dried over mgso is filtered and evaporation.Crude product is by the rapid column chromatography purifying, with ethyl acetate/heptane (2: 3) wash-out, provide N-(4-(methylol) phenyl) carboxylamine tertiary butyl ester (2.16g, 9.67mmol).
1H NMR (CDCl-d) δ 1 52 (s, 9H), 4.63 (s, 2H), 6.47 (bs, 1H), 7.30 (d, 8.5Hz, 2H), 7.36 (d, 8.5Hz, 2H) .b) N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine 4-aminobenzyl ester
With N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-the 2-p-methoxy-phenyl] carboxylamine phenylester (51mg, 0.111mmol) (119mg 0.533mmol) mixes with N-(4-(methylol) phenyl) carboxylamine tertiary butyl ester in pyridine (0.8ml).With reaction mixture 100 ℃ of heated overnight.Remove and to desolvate, resistates is by preparation property anti-phase LC/MS purifying, provide N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine 4-aminobenzyl ester (9mg, 0.015mmol).1H?NMR
(CDCl-d)δ1.52(s，1H)，2.08(m，4H)，3.65(m，2H)，3.90(s，3H)，4.14(m，2H)，
4.97(m，1H)，5.17(s，2H)，5.37(bs，1H)，6.55(s，1H)，6.95(s，1H)，7.03(s，1H)，
7.06(m，1H)，7.31(s，1H)，7.38(m，3H)，8.16(bs，1H)，8.30(s，1H).LC/MS：
MH +589. embodiment 16:N1-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] benzamide
(80mg 0.236mmol) is dissolved in methylene dichloride (2.0ml) with 5-(4-amino-3-p-methoxy-phenyl)-7H-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine.Add pyridine (2.0ml) then add Benzoyl chloride (41 μ L, 0.353mmol).After the stirring at room 2 hours, remove and desolvate, resistates is dissolved in 1ml DMSO, adds methyl alcohol (1ml), forms precipitation.Solid collected by filtration provides N1-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] and benzamide (64mg, 0.144mmol).
1H?NMR(CDCl 3-d)δ2.12(m，
4H)，3.67(m，2H)，3.99(s，3H)，4.17(m，2H)，4.99(m，1H)，7.03(s，1H)，7.04(s，
1H)，7.14(d，J＝8.2Hz，1H)，7.53(m，3H)，7.94(d，J＝7.8Hz，1H)，8.33(s，1H)，8.58
(s, 1H), 8.63 (d, J=8.2Hz, 1H) .LC/MS:MH +=444 embodiment 17:N2-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl]-the 2-pyridine carboxamide
(80mg 0.236mmol) is dissolved in methylene dichloride (2.0ml) with 5-(4-amino-3-p-methoxy-phenyl)-7H-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine.Add pyridine (2.0ml) then add 2-pyridine formyl chloride hydrochloride (63mg, 0.353mmol).After the stirring at room 2 hours, remove and desolvate, resistates is dissolved in 1ml DMSO, adds methyl alcohol (1ml), forms precipitation.Solid collected by filtration provides N2-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl]-the 2-pyridine carboxamide (84mg, 0.189mmol).
1H?NMR(CDCl 3-d)δ2.12(m，
4H)，3.67(m，2H)，4.03(s，3H)，4.14(m，2H)，5.00(m，1H)，5.37(s，1H)，7.04(s，
1H)，7.09(s，1H)，7.14(d，J＝8.2Hz，1H)，7.50(m，1H)，7.92(m，1H)，8.33(s，1H)，
8.70 (d, J=8.2Hz, 1H), 10.62 (s, 1H) .LC/MS:MH +=445. embodiment 18:N5-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl]-1,3-dimethyl-1H-5-pyrazolecarboxamide
(80mg 0.236mmol) is dissolved in methylene dichloride (2.0ml) with 5-(4-amino-3-p-methoxy-phenyl)-7H-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine.Add pyridine (2.0ml) then add 2-pyridine formyl chloride hydrochloride (63mg, 0.353mmol).After the stirring at room 2 hours, remove and desolvate, resistates is dissolved in 1ml DMSO, adds methyl alcohol (1ml), forms precipitation.Solid collected by filtration provides N5-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl]-1,3-dimethyl-1H-5-pyrazolecarboxamide (30mg, 0.065mmol).
1H?NMR(CDCl 3-d)δ2.11(m，4)，2.32(s，3H)，3.66(m，2H)，3.99(s，3H)，
4.13(m，2H)，4.17(s，3H)，4.99(m，1H)，5.22(bs，2H)，6.46(s，1H)，7.03(s，1H)，
7.07(s，1H)，7.12(d，J＝8.2Hz，1H)，8.33(2，2H)，8.49(d，J＝8.2Hz，1H).LC/MS：
MH +=462. embodiment 19:N1-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl]-2,2-dimethyl propylene acid amides
(50mg 0.147mmol) is dissolved in methylene dichloride (1.5ml) with 5-(4-amino-3-p-methoxy-phenyl)-7H-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine.Add pyridine (1.5ml) and then add 2, and 2-two propionyl chlorides (31mg, 0.221mmol).After the stirring at room 2 hours, remove and desolvate, resistates is dissolved in 1ml DMSO, adds methyl alcohol (1ml), forms precipitation.Solid collected by filtration provides N1-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl]-2,2-dimethyl propylene acid amides (27mg, 0.064mmol).
1H?NMR(CDCl 3-
d)δ1.35(s，9H)，2.09(m，4H)，3.66(m，2H)，3.96(s，3H)，4.13(m，2H)，4.97(m，
1H)，5.46(bs，2H)，6.98(s，1H)，7.04(s，1H)，7.07(d，J＝8.2Hz，1H)，8.15(s，1H)，
8.29 (s, 1H), 8.49 (d, J=8.2Hz, 1H) .LC/MS:MH +=424. embodiment 20:N1-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl]-the 1-cyclopentane formamide
(50mg 0.147mmol) is dissolved in methylene dichloride (1.5ml) with 5-(4-amino-3-p-methoxy-phenyl)-7H-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine.Add pyridine (1.5ml) then add 1-pentamethylene formyl chloride (31mg, 0.221mmol).After the stirring at room 2 hours, remove and desolvate, resistates is dissolved in 1ml DMSO, adds methyl alcohol (1ml), forms precipitation.Solid collected by filtration provides N1-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl]-the 1-cyclopentane formamide (33mg, 0.076mmol).1H?NMR(CDCl 3-
d)δ1.66(m，2H)，1.81(m，2H)，1.95(m，4H)，2.06(m，4H)，2.77(m，1H)，3.65(m，
2H)，3.94(s，3H)，4.15(m，2H)，4.96(m，1H)，5.37(bs，2H)，6.98(s，1H)，7.03(s，
1H)，7.07(d，J＝8.2Hz，1H)，7.84(s，1H)，8.30(s，1H)，8.49(d，J＝8.2Hz，1H).
LC/MS:MH +=437. embodiment 21:N1-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl]-the 1-cyclopentane formamide
(50mg 0.147mmol) is dissolved in methylene dichloride (1.5ml) with 5-(4-amino-3-p-methoxy-phenyl)-7H-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine.Add pyridine (1.5ml) then add 3-phenyl propionyl chloride (37mg, 0.221mmol).After the stirring at room 2 hours, remove and desolvate, resistates is dissolved in 1ml DMSO, adds methyl alcohol (1ml), forms precipitation.Solid collected by filtration provides N1-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl]-the 1-cyclopentane formamide (7mg, 0.015mmol).
1H?NMR(CDCl 3-d)
δ2.07(m，4H)，2.75(m，2H)，3.09(m，2H)，3.65(m，2H)，3.88(s，3H)，4.13(m，2H)，
4.96(m，1H)，5.97(bs，2H)，6.93(s，1H)，7.05(m，2H)，7.26(m，5H)，7.70(s，1H)，
8.24 (s, 1H), 8.46 (d, J=8.2Hz, 1H) .LC/MS:MH +=472. embodiment 22:5-(4-Phenoxyphenyl)-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine a) under 0 ℃ of stirring, adds toluene sulfonyl chloride (12.0g) in the mixture of 3-hydroxyl tetrahydrofuran (5.0g) in pyridine (100ml) in nitrogen atmosphere in batches.Mixture stirred 2 hours at 0 ℃, was warmed to room temperature then.Mixture was stirring at room 72 hours.Mixture is cooled to 0 ℃, adds 5M hydrochloric acid (200ml).The mixture ethyl acetate extraction, the acetic acid ethyl acetate extract of merging is used the salt water washing then with 2M salt acid elution, and is dry then, filters and evaporation, provides 3-tosyloxy tetrahydrofuran (THF) oily matter.B) in nitrogen atmosphere, under the stirring, sodium hydride (120mg, the dispersion liquid in 60% the mineral oil) is added in the solution of 4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidines (906mg) and dimethyl formamide (30ml).Mixture was stirred 30 minutes, under agitation add dimethyl formamide (10ml) solution of 3-tosyloxy tetrahydrofuran (THF) (750mg) then.Mixture was heated vacuum-evaporation then 18 hours at 95 ℃.Resistates is distributed between ethyl acetate and the water.Tell ethyl acetate layer, dry and evaporation, the remaining jelly that provides is developed with ether, provides m.p.196-196.5 ℃ of the basic amine of 5-(4-Phenoxyphenyl)-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-4-.Embodiment 23:5-(4-Phenoxyphenyl)-7-(4-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
Be similar to the mode of embodiment 1, make 4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine and the reaction of 4-tosyloxy tetrahydropyrans, provide 5-(4-Phenoxyphenyl)-7-(4-tetrahydrofuran base)-7H-pyrrolo-[2 after the rapid column chromatography, 3-d] pyrimidine-4-base amine, m.p.193-193.5 ℃.Embodiment 24:4-amino-5-(4-Phenoxyphenyl)-7-[4-(N-tertbutyloxycarbonyl) tetrahydrochysene isoxazolyl]-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine a) adds heavy carbonic di-t-butyl ester (4.56g) in tetrahydrofuran (THF) (100ml) solution of 4-hydroxy tetrahydro isoxzzole (2.4g) and triethylamine (4.2g) under 0 ℃ is stirred in nitrogen atmosphere.Mixture at room temperature stirred 72 hours, filtered then.Reduction vaporization filtrate provides N-(tertbutyloxycarbonyl)-4-hydroxy tetrahydro isoxzzole oily matter, and it is directly used in the following step of present embodiment.B) with a) product (3.6g) in pyridine (50ml) in 0 ℃, in nitrogen atmosphere, stir, under agitation add toluene sulfonyl chloride (3.62g) then in 0 ℃ in batches.Mixture was stirred 1 hour at 0 ℃, be warmed to room temperature in 18 hours Inner then.Pyridine is removed in decompression, adds ethyl acetate (50ml) and citric acid (the 50ml 1M aqueous solution).Tell organic layer and with the washing of 1M citric acid solution, use the salt water washing then, drying is filtered and evaporation, and the oily matter that provides is by the rapid column chromatography purifying, and with containing the 20-30% ethyl acetate, b.p40-60 ℃ sherwood oil is made moving phase.Collect suitable fraction, merging provides N-(tertbutyloxycarbonyl)-4-tosyloxy tetrahydrochysene isoxzzole, m.p.63-65 ℃.C) under agitation, 0 ℃ in nitrogen atmosphere with 4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] dimethyl formamide (40ml) drips of solution of pyrimidine (1.0g) is added in dimethyl formamide (60ml) suspension of sodium hydride (0.145g, 60% mineral oil dispersion liquid).Mixture was stirred 1 hour at 0 ℃, adds b then) product (1.25g).Mixture 100 ℃ of heating 3 hours, is cooled to room temperature then, the water cancellation, and use ethyl acetate extraction, provide oily matter.This oily matter is developed with ethyl acetate, is filtered the solid of collecting gained, provide 4-amino-5-(4-Phenoxyphenyl)-7-[4-(N-tertbutyloxycarbonyl) tetrahydrochysene isoxazolyl]-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, m.p.162-163 ℃.Embodiment 25:5-(4-Phenoxyphenyl)-7-(4-tetrahydrochysene isoxazolyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine dihydrochloride
The product (0.29g) of embodiment 3 is dissolved in methylene dichloride (8ml),, adds trifluoroacetic acid (2.0ml) simultaneously then 0 ℃ of stirring.Make mixture be warmed to room temperature and stirring at room 2 hours.Mixture is alkalized with sodium hydrogen carbonate solution, and use dichloromethane extraction, the oily matter that provides is that ethyl acetate/methanol (9: 1) is made moving phase by the rapid column chromatography purifying with ethyl acetate then.Collect suitable fraction and merging, evaporation then, the solid that provides is dissolved in ethyl acetate, uses ether solution of hydrogen chloride (3.0ml, 1M solution) to handle then.Filter the solid of collecting gained,, provide 5-(4-Phenoxyphenyl)-7-(4-tetrahydrochysene isoxazolyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine dihydrochloride, m.p.208 ℃ (decomposition) with the ether washing and 45 ℃ of vacuum-dryings 2 hours.Embodiment 26:2-[(4-(4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] benzyl alcohol is a) at 0 ℃, in the nitrogen atmosphere with 4-chloro-5-iodo-7H-pyrrolo-[2,3-d] pyrimidine (5.0g) adds the N of sodium hydride (the mineral oil dispersion liquid of 0.79g 60%), in dinethylformamide (100ml) solution.Mixture is stirred until hydrogen and stops to overflow.Add 3-tosyloxy tetrahydrofuran (THF) (4.65g) at 0 ℃, make mixture be warmed to 90 ℃ then.Mixture is in stirring at room 2 hours, stirred overnight at room temperature then.Add entry (100ml) carefully, the mixture ethyl acetate extraction provides 4-chloro-5-iodo-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine, m.p.184-186 ℃.B) in nitrogen atmosphere, stir down, with 4-iodophenol (25.0g), 2-fluorobenzaldehyde (14.14g), the mixture of salt of wormwood (31.5g) and dimethyl formamide (500ml) was 120 ℃ of heating 15 hours.Mixture is cooled to room temperature and filtration.In filtrate, add entry, the mixture ethyl acetate extraction, the solid that provides is developed with hot hexane (500ml).Supernatant decanted liquid is with the jelly cooling of remnants.Filter the solid of collecting precipitation, provide 2-(4-iodine phenoxy group) phenyl aldehyde, m.p.84.5-86 ℃.C) make toluene (250ml) deoxidation, nitrogenization is 30 minutes then.With 2-(4-iodine phenoxy group) phenyl aldehyde (6.46g), hexa methyl ditin (10.0g) and four (triphenyl phosphine) palladium (O) (1.4g) add in the toluene.Mixture is refluxed in nitrogen to be stirred 7 hours.Making mixture be cooled to room temperature filters then.With the filtrate evaporation, resistates is made moving phase by quick purification by silica gel column chromatography with 3% ethyl acetate/b.p.40-60 ℃ sherwood oil, provides 2-(4-tin trimethyl alkyl phenoxy) phenyl aldehyde oily matter.D) with c) product (1.80g), product b) (1.76g), three (dibenzalacetones), two palladiums (228mg), the mixture of triphenylarsine (383mg) and dimethyl formamide (75ml) stirred 70 hours in 65 ℃ in nitrogen.Make mixture be cooled to room temperature and water cancellation.With the mixture ethyl acetate extraction, the resistates that provides is by quick purification by silica gel column chromatography, 30-50% ethyl acetate/b.p.40-60 ℃ sherwood oil with increment is made moving phase, the solid that provides is developed and is filtered with ether, provide 2-[(4-(4-chloro-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] the phenyl aldehyde solid.E) make d) product (360mg) be dissolved in methyl alcohol (5ml), and under 0 ℃ of stirring, add sodium borohydride (65mg).Make mixture be warmed to room temperature, and stirred 1 hour in this temperature.Mixture diluted sodium hydroxide solution cancellation, reduction vaporization then, the resistates ethyl acetate extraction that provides provides 2-[(4-(4-chloro-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] benzyl alcohol.F) with e) product (280mg), 1,4-dioxan (15ml) and strong aqua (15ml, mixture S.G.0.88) in forcer in 120 ℃ the heating 20 hours.Make mixture be cooled to room temperature and removal of solvent under reduced pressure.Resistates is dissolved in ethyl acetate, washing, dry then, filter and evaporation, the oily matter that provides is made moving phase by quick purification by silica gel column chromatography with ethyl acetate/methanol (9: 1), provides 2-[(4-(4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] the benzyl alcohol vitreous solid, m.p.92-96 ℃.Embodiment 27:2-[4-(4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group]-N, N-diethyl benzyl amine a) adds 2-[(4-(4-chloro-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2 with sodium triacetoxy borohydride (264mg) in bottle (5ml), 3-d] pyrimidine-5-yl) phenoxy group] phenyl aldehyde (330mg) and diethylamine (121mg) be 1, mixture in the 2-ethylene dichloride, and with the diaphragm seal of bottle.Make mixture stirring at room 20 hours, use saturated sodium bicarbonate aqueous solution (5ml) cancellation then.The mixture ethyl acetate extraction provides 2-[4-(4-chloro-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group]-N, N-diethyl benzyl amine.B) with a) product (280mg), strong aqua (10ml, S.G.0.88) and 1, the mixture of 4-dioxan (10ml) in forcer in 120 ℃ of heating 16 hours.Make mixture be cooled to room temperature and removal of solvent under reduced pressure.Resistates is dissolved in ethyl acetate, washing, dry then, filter and evaporation, the oily matter that provides is made moving phase by quick purification by silica gel column chromatography with ethyl acetate/methanol (9: 1), provide 2-[4-(4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group]-N, N-diethyl benzyl amine, m.p.107-110 ℃.Embodiment 28:2-[4-(4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] benzonitrile is a) in nitrogen atmosphere, stir down, with 2-fluorine benzonitrile (28.8g), 4-bromophenol (36.9g), the mixture of salt of wormwood (58.9g) and dimethyl formamide (30ml) was 120 ℃ of heating 5 hours.Mixture is spent the night in the room temperature placement, be distributed in then between ethyl acetate and the water.Tell organic layer, washing, dry and evaporation, the oily matter that provides is placed and is solidified.This solid is developed and is filtered with b.p.40-60 ℃ sherwood oil, provides 2-(4-bromine phenoxy group) benzonitrile.B) make the product (5.57g) of step a), hexa methyl ditin (10.0g) and four (triphenyl phosphine) palladium (O) (1.4g) and the mixture of the toluene (250ml) that outgased in nitrogen in 110 ℃ of heated and stirred 4.5 hours.Mixture was placed 18 hours, then the filtration over celite pad in room temperature.Should fill up with ethyl acetate washing, the filtrate of merging and elutant be evaporated in.Resistates is by quick purification by silica gel column chromatography, and the b.p.40-60 with 2% to 5% ℃ petroleum ether/ethyl ether is made moving phase, provides 2-(4-tin trimethyl alkyl phenoxy) benzonitrile.C) make 4-chloro-5-iodo-7-(3-tetrahydrofuran base) pyrrolo-[2,3-d] pyrimidine (1.80g, as preparation as described in the embodiment 5), mixture reaction with the product (1.23g) of step b), then to be similar to embodiment 5d) mode handle, provide 2-[4-(4-chloro-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] benzonitrile.D) with the product (470mg) of step c), strong aqua (33ml, S.G.0.88) and 1, the mixture of 4-dioxan (33ml) heated 18 hours in 120 ℃ in forcer together, being similar to embodiment 5 then handles, provide 2-[4-(4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] benzonitrile, m.p.201-203 ℃.Embodiment 29:2-[4-(4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] phenyl aldehyde a) is similar to embodiment 2, make 3-tosyloxy tetrahydrofuran (THF) (1.84g) and 5-(4-benzyloxy phenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (2.9g) sodium hydride (0.30g, 60% mineral oil dispersion liquid) and dimethyl formamide (40ml) reaction, just make mixture 90 ℃ of heating 4.5 hours, provide 5-(4-benzyloxy phenyl)-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine solid.B) make the product (6.0g) of step a), 10%Pd/C (3.0g), the mixture of ammonium formiate (4.9g) and ethanol (500ml) stirred 2 hours in vapor bath in nitrogen.With mixture cooling and filtration, evaporating solvent.Make the long-pending and filtration of filtrate being concentrated into-halfbody, the solid that provides is proved to be and is 4-[4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl] phenol, m.p.257-259 ℃.C) with 4-[4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl] phenol (2.55g), 2-fluorobenzaldehyde (1.07g), the mixture of salt of wormwood (2.13g) and dimethyl formamide (80ml) in nitrogen in 120 ℃ of heated and stirred 5 hours.Mixture is cooled to room temperature, the water cancellation, and use ethyl acetate extraction, and provide 2-[4-(4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] phenyl aldehyde, m.p.185-187 ℃.Embodiment 30:4-[4-amino-5-(4-phenoxy group)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] tetrahydrofuran (THF)-3-alcohol
In nitrogen atmosphere, under stirring sodium hydride (120mg 60% mineral oil dispersion liquid) is added in the solution of 4-amino-5-(4-phenoxy group)-7H-pyrrolo-[2,3-d] pyrimidines (902mg) and dimethyl formamide (30ml).Mixture was stirred 30 minutes, add 3 then, 6-two oxa-dicyclo [3.1.0] hexanes (300mg), mixture is warmed to 80 ℃.Mixture was placed 64 hours, then reduction vaporization.The development of resistates water provides an oily glue.Add ether, mixture was stirred 30 minutes fast, filtered and collected the solid that provides and use methanol wash.Solid is abandoned.Second batch of solid ethyl alcohol recrystallization that filtrate produces provides 4-[4-amino-5-(4-phenoxy group)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] tetrahydrofuran (THF)-3-alcohol, m.p.234.5-235.5 ℃.Embodiment 31:5-[4-(2-morpholino methylphenoxy) phenyl]-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
With 2-[4-(4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] phenyl aldehyde (0.15g), morpholine (64mg), sodium triacetoxy borohydride (117mg) and 1, the mixture of 2-ethylene dichloride (5ml) was stirring at room 18 hours.Add saturated sodium bicarbonate aqueous solution, mixture is filtered the EMPORE_ post.Make the filtrate evaporation, resistates is dissolved in methylene dichloride (5ml), adds three (2-amino-ethyl) amine (0.3g) and 2 Glacial acetic acid of polymkeric substance combination then, and mixture is in stirred overnight at room temperature.Leach polymkeric substance and use washed with dichloromethane, use methanol wash then.The organic filtrate and the elutant that merge are depressurized evaporation, the oily matter that provides is with ether/ethyl acetate development and be warmed to the solid dissolving, make solution in cooled on ice and filtration then, provide 5-[4-(2-morpholino methylphenoxy) phenyl]-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, m.p.169-171 ℃.Embodiment 32:5-[4-(2-piperidino-methyl benzene oxygen base) phenyl]-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
Be similar to embodiment 10, make 2-[4-(4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] phenyl aldehyde (0.15g) and piperidines (63mg) reaction, provide 5-[4-(2-piperidino-methyl benzene oxygen base) phenyl]-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, m.p.76-78 ℃ (glassy foam).Embodiment 33:5-{4-[2-(2-methoxy ethyl) amino methyl phenoxy group] phenyl }-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
Be similar to embodiment 10, make 2-[4-(4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] phenyl aldehyde (0.15g) and 2-methoxy ethyl amine (56mg) one reacts, provide 5-{4-[2-(2-methoxy ethyl) amino methyl phenoxy group] phenyl }-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, m.p.66-68 ℃ (glassy foam).Embodiment 34:4-[4-(4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] benzyl alcohol a) is similar to embodiment 9, make 4-[4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl] phenol and the reaction of 4-fluorobenzaldehyde, provide 4-[4-(4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] phenyl aldehyde.B) product (0.35g) with step a) is dissolved in methyl alcohol (10ml), and adds sodium borohydride (32mg) at 0 ℃ in this solution.Mixture is warmed to room temperature, and stirred 10 minutes in this temperature.Add 1,2-ethylene dichloride (4ml) solubilising.Mixture adds Glacial acetic acid (1ml) then stirring at room 18 hours, and mixture is depressurized evaporation.Resistates is distributed between ethyl acetate and the saturated aqueous sodium carbonate.Tell ethyl acetate, drying is filtered and evaporation, provides 4-[4-(4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] benzyl alcohol, m.p.92-95 ℃.Embodiment 35:5-[4-(4-fluorophenoxy) phenyl]-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
With 4-[4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl] phenol (0.59g), 4-fluorophenyl boric acid (0.56g), neutralized verdigris (II) (0.36g), triethylamine (1.01g), the mixture of methylene dichloride (20ml) and activatory ground 4 molecular sieves (0.5g) stirred 64 hours in the exsiccant nitrogen atmosphere.Make reaction mixture filter the silicagel pad of little prewashing, and with methylene dichloride (200ml) wash-out, ethyl acetate (250ml) wash-out is used ethyl acetate/methanol 9: 1 (250ml) wash-out at last then.Methylene dichloride and ethyl acetate fraction are merged, by quick purification by silica gel column chromatography, make moving phase with ethyl acetate/methanol, provide 5-[4-(4-fluorophenoxy) phenyl]-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, m.p.198-199 ℃.Embodiment 36:5-[4-(4-morpholino methylphenoxy) phenyl]-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
Be similar to embodiment 10, make 4-[4-(4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] phenyl aldehyde (336mg), and morpholine (146mg) reaction, provide 5-[4-(4-morpholino methylphenoxy) phenyl]-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, m.p.142-144 ℃.Embodiment 37:5-[4-(3-morpholino methylphenoxy) phenyl]-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2; 3-d] pyrimidine-4-base amine is a) with 4-[4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2; 3-d] pyrimidine-5-yl] phenol (0.297g) and 3-formyl radical phenyl-boron dihydroxide be similar to embodiment 14 reactions; provide 4-[4-(4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] phenyl aldehyde.B) make the product (100mg) of step a) and morpholine (44mg)-reinstate 10 described similar agents and conditioned responses with embodiment, provide 5-[4-(3-morpholino methylphenoxy) phenyl]-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, m.p.83-85 ℃.Embodiment 38:2-[4-(4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group]-6-(2-(4-pyridyl) ethylamino) benzonitrile
With 4-[4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl] phenol (0.517g), 2-fluoro-6-(2-(4-pyridyl) ethylamino) benzonitrile (0.42g), the mixture of salt of wormwood (0.48g) and dimethyl formamide (20ml) heated in nitrogen 8 hours.Make the mixture cooling, dilute with water, use ethyl acetate extraction then, the solid re-crystallizing in ethyl acetate that provides, the solid that provides is by quick purification by silica gel column chromatography, with ethyl acetate ethyl acetate/methanol (9: 1 then, 8: 1,4: 1) wash-out, provide 2-[4-(4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group]-6-(2-(4-pyridyl) ethylamino) benzonitrile, m.p.212-213 ℃.Embodiment 39:2-[4-(4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group]-6-(3-imidazoles-1-yl) propyl group aminobenzonitrile
With 4-[4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl] phenol (0.49g), 2-fluoro-6-(3-imidazoles-1-yl) propyl group aminobenzonitrile, salt of wormwood (0.45g) and dimethyl formamide are similar to embodiment 17 reactions, provide 2-[4-(4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group]-6-(3-imidazoles-1-yl) propyl group aminobenzonitrile, m.p.110 ℃ (glassy foam).Embodiment 40:4-amino-6-bromo-5-(4-Phenoxyphenyl)-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine is a) with 4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine (302mg) is dissolved in N,N-DIMETHYLACETAMIDE (10ml) and methylene dichloride (50ml), uses N-bromo-succinimide (178mg) to handle in methylene dichloride (10ml) then.Make mixture stirring at room 16 hours.With the mixture reduction vaporization, the development of resistates water, the solid that provides is filtered to be collected and drying, provides 4-amino-6-bromo-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine, m.p.282-283 ℃.B) mixture of product (1.14g) in exsiccant dimethyl formamide (30ml) with step a) stirs in nitrogen, adds sodium hydride (the mineral oil dispersion liquid of 120mg 60%) simultaneously.Dimethyl formamide (10ml) solution that then adds 3-tosyloxy tetrahydrofuran (THF) (0.8g).Mixture is 90 ℃ of heated overnight.Make the mixture reduction vaporization, the development of resistates water is filtered and is collected the solid that provides, drying, and the solid that provides adds entry to cloud point and also filters and purifying by being dissolved in ethanol.With filtrate evaporated under reduced pressure, the resistates that provides provides 4-amino-6-bromo-5-(4-Phenoxyphenyl)-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine, m.p.205-206 ℃ by quick purification by silica gel column chromatography.Embodiment 41:2-[4-(4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group]-6-(3-methoxy-propyl amino) benzonitrile
Be similar to embodiment 17, make 4-[4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl] phenol (0.65g), 2-fluoro-6-(3-methoxy-propyl amino) benzonitrile (0.46g), salt of wormwood (0.61g) and dimethyl formamide (40m1) heated 8 hours in 120 ℃ in nitrogen, provide 2-[4-(4-amino-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group]-6-(3-methoxy-propyl amino) benzonitrile, m.p.183-184 ℃.Embodiment 42:2-[4-(4-amino-7-(4-THP trtrahydropyranyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] benzonitrile a) makes 5-(4-benzyloxy phenyl)-7-(tetrahydropyran-4-base)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (2.83g), 10%Pd/C (1.41g), the mixture of ammonium formiate (2.31g) and ethanol (250ml) reflux 1.5 hours in nitrogen.Make mixture be cooled to room temperature, filter, then with filtrate cooling and filtration.The filtrate evaporation is provided 4-[4-amino-7-(4-THP trtrahydropyranyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl] phenol.B) in bottle, with warm 4-[4-amino-7-(4-THP trtrahydropyranyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl] phenol (0.082g) dimethyl formamide (3.4ml) solution adds in the mixture of 2-fluorine benzonitrile (80mg) and salt of wormwood (76mg).Bottle also seals with nitrogen wash.Mixture was cooled to room temperature 16 hours then 120 ℃ of vibrations 6 hours.Ethyl acetate extraction is used in mixture water (11ml) dilution then, provides 2-[4-(4-amino-7-(4-THP trtrahydropyranyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group] benzonitrile, m.p.125 ℃ (softening).
Be similar to the method for front embodiment, by 4-[4-amino-7-(4-THP trtrahydropyranyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl] compound of phenol and suitable nitrile prepared in reaction embodiment 43-48, just cycle of vibrating together of mixture is up to 48 hours.The disappearance of reaction monitoring raw material and heating reasonable time.Embodiment 49: prepare 2-[4-(4-amino-7-(4-THP trtrahydropyranyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group from 2-fluoro-6-(3-(imidazoles-1-yl) propyl group amino) benzonitrile]-6-(3-imidazoles-1-yl) propyl group aminobenzonitrile.Embodiment 50:2-[4-(4-amino-7-(4-THP trtrahydropyranyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group]-6-(2-morpholino oxyethyl group) benzonitrile.Embodiment 51: prepare 2-[4-(4-amino-7-(4-THP trtrahydropyranyl)-7H-pyrrolo-[2 from 2-fluoro-6-(2-(4-pyridyl) ethylamino) benzonitrile, 3-d] pyrimidine-5-yl) phenoxy group]-6-(2-(4-pyridyl) ethylamino) benzonitrile, m.p.120-123 ℃ (vitreum).Embodiment 52: prepare 2-[4-(4-amino-7-(4-THP trtrahydropyranyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group from 2-fluoro-6-(3-methoxy-propyl amino) benzonitrile]-6-(3-methoxy-propyl amino) benzonitrile, m.p.205-207 ℃.Embodiment 53: from 2,5-difluoro benzonitrile prepares 2-[4-(4-amino-7-(4-THP trtrahydropyranyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenoxy group]-5-fluorine benzonitrile, m.p.216-217 ℃.Method as the embodiment 54-101-
The part of the amine of listing in table 1 (with respect to used ester is 9 molar equivalents, weight range 47.5mg to 184.5mg) is by in weighing and the adding bottle separately, and (1ml) adds in each bottle with methyl alcohol.(4ml, the ratio of methyl alcohol and triethylamine is 23.1 to 2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl ethyl acetate (1 molar equivalent): the solution 1v/v) at methyl alcohol and triethylamine mixture.Reaction mixture was 60-65 ℃ of vibration 36 hours.Remove methyl alcohol and triethylamine 3 hours 50 ℃ of decompressions, in each bottle, add entry (3ml), then add methylene dichloride (3ml).Bottle was stirred 15 seconds, placed then 18 hours.Pour mixture into EMPORE_ (10mm/6ml) extracting disk tube, collect methylene dichloride and evaporated 3 hours mutually and at 50 ℃.During handling, when placing 18 hours, observe solid and in bottle, tell.With pressurized air it is passed through the water layer in each subsequently.Methylene dichloride (4ml) is added each extraction tube.Each filtrate was 50 ℃ of reduction vaporizations 3 hours.Required product or find that in original dichloromethane extraction liquid in this situation, they are indicated in the liquid and exist, or find, are called as in solid and find in insoluble solid.Some product all is found in two-phase.These are indicated in table 1.
Each sample is by lcms analysis, and in all cases, target ion is found.The residence time of each product provides in table 1.Used condition provides below.
Post: 5 μ m hypersil BDS c18 (100 * 2.1mm)
Moving phase: 0.1M ammonium acetate [pH 4.55]: acetonitrile (gradient-see
Below)
Condition: 10-100% acetonitrile 8 minutes
(gradient) 100% acetonitrile 1 minute
100-10% acetonitrile 2 minutes
(11 minutes working times of bulk analysis)
Flow velocity: 1ml/ minute (not division in MS)
Wavelength region: 250-320nm
Volume injected: 20 μ
MS method: APCI11H
Ionization APcI+ve/-ve
Mass range 100-700m/z
Taper voltage 20.
Be similar to embodiment 54-101, the amine of listing in the table 2 respectively with 2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] ethyl propionate reaction, be given in the product of listing among the embodiment 102-146 respectively.Used identical of processing and analysis condition and embodiment 54-101.In all cases, find target ion by LCMS.
The amine sequence number Title Phase The RT/min product
54 Thanomin Solid 3.44
55 D1-2-amino-1-propyl alcohol Solid 3.58
56 1-amino-2-propyl alcohol Solid 3.56
57 The 2-methoxyethyl amine Liquid 3.78
58 3-amino-1-propyl alcohol Two-phase 3.50
59 (S)-(+)-2-amino-1-propyl alcohol Two-phase 3.58
60 (R)-(-)-1-amino-2-propyl alcohol Two-phase 3.56
61 N, the N-dimethyl-ethylenediamine Two-phase 3.31
62 (+/-)-2-amino-1-butanols Solid 3.77
63 1-amino-2-butanols Two-phase 3.77
64 3-amino-1, the 2-propylene glycol Solid 3.32
65 (S)-and 3-amino-1, the 2-propylene glycol Solid 3.32
66 (R)-and 3-amino-1, the 2-propylene glycol Solid 3.32
67 The 1-methylpiperazine Two-phase 3.28
68 N, N-dimethyl-1,3-propylene diamine Liquid 3.29
69 N2, N2-dimethyl-1,2-propylene diamine Two-phase 3.37
70 1-methylamino-2-propyl group amine Liquid 3.44
71 Dl-2-amino-3-methyl isophthalic acid-butanols Solid 3.98
72 N-{2-[1-(N-morpholine)-1-oxo] ethyl } piperazine Liquid 3.56
73 2-amino-2-methyl-1-propanol Two-phase 3.86
74 2-amino-2-methyl-1, ammediol Two-phase 3.49
75 2-(2-amino ethoxy) ethanol Two-phase 3.47
76 1-(2-amino-ethyl) tetramethyleneimine Liquid 3.40
77 The high piperazine of N-methyl Liquid 3.32
78 1-amino-1-pentamethylene methyl alcohol Two-phase 4.16
79 The 2-Trans-4-Amino Cyclohexanol Solid 3.98
80 N, the N-diethyl ethylenediamine Liquid 3.44
81 N-(3-hydroxypropyl) quadrol Two-phase 3.24
82 2-((2-amino-ethyl) sulfenyl) ethanol Two-phase 3.69
83 2-(2-amino-ethyl) pyridine Liquid 3.89
84 3-(2-amino-ethyl) pyridine Liquid 3.79
85 N-(3-aminopropyl) imidazoles Liquid 3.37
86 1-[2-(N-morpholine) ethyl] piperazine Liquid 3.39
87 2-(amino methyl)-1-ethyl pyrrolidine Two-phase 3.48
88 1-(2-amino-ethyl) piperidines Two-phase 3.49
89 1-tetramethyleneimine propylamine Liquid 3.37
90 (R)-(+)-2-aminomethyl-1,2-ethyl pyrrolidine Two-phase 3.48
91 4-(2-amino-ethyl) morpholine Two-phase 3.39
92 The 3-diethyl amino propylamine Two-phase 3.43
93 N, N-dimethyl neopentane diamines Two-phase 3.47
94 1-piperazine carboxylic acid ethyl ester Liquid 4.34
95 2-(amino methyl)-2-ethyl-1, ammediol Two-phase 3.69
96 1-(3-aminopropyl)-2-Pyrrolidone Two-phase 3.68
97 1-piperidines propylamine Liquid 3.46
98 4-(3-aminopropyl) morpholine Liquid 3.33
99 N, the N-diisopropyl ethylenediamine Liquid 3.59
100 N, two (3-aminopropyl) methylamines of N- Liquid 3.03
101 Three (2-amino-ethyl) amine Liquid 3.01
Prepared compound provides below.Embodiment 54:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-(2-hydroxyethyl) ethanamide embodiment 55:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-(1-hydroxyl third-2-yl) ethanamide embodiment 56:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-(2-hydroxypropyl) ethanamide embodiment 57:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-(2-methoxy ethyl) ethanamide embodiment 58:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-(3-hydroxypropyl) ethanamide embodiment 59:(S)-4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-(1-hydroxyl third-2-yl) ethanamide embodiment 60:(R)-4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-(2-hydroxypropyl) ethanamide embodiment 61:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-[2-(N, the N-dimethylamino) ethyl] ethanamide embodiment 62:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-(1-hydroxyl fourth-2-yl) ethanamide embodiment 63:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-(2-hydroxybutyl) ethanamide embodiment 64:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-(2, the 3-dihydroxypropyl) ethanamide embodiment 65:(S)-4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-(2, the 3-dihydroxypropyl) ethanamide embodiment 66:(R)-4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-(2, the 3-dihydroxypropyl) ethanamide embodiment 67:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N, N-(3-azepine pentamethylene) ethanamide embodiment 68:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-[3-(N, the N-dimethylamino) propyl group] ethanamide embodiment 69:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-[1-(N, the N-dimethylamino) third-2-yl] ethanamide embodiment 70:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-[2-(N, the N-dimethylamino) propyl group] ethanamide embodiment 71:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-(1-hydroxy-3-methyl fourth-2-yl) ethanamide embodiment 72:7-{2-[4-(2-morpholine-2-oxoethyl) piperazine-1-yl]-the 2-oxoethyl }-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine embodiment 73:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-(1-hydroxy-3-methyl third-2-yl) ethanamide embodiment 74:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-(1,3-dihydroxyl-2-methyl-prop-2-yl) ethanamide embodiment 75:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-[2-(2-hydroxyl-oxethyl) ethyl] ethanamide embodiment 76:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-[2-(pyrroles-1-yl) ethyl] ethanamide embodiment 77:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N, N-(3-azepine hexa-methylene) ethanamide embodiment 78:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-[1-(hydroxymethyl) cyclopentyl] ethanamide embodiment 79:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-(2-hydroxy-cyclohexyl) ethanamide embodiment 80:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-[2-(N, N-diethylamino) ethyl] ethanamide embodiment 81:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-[2-(3-hydroxypropyl amino) ethyl] ethanamide embodiment 82:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-[2-(2-hydroxyl ethylmercapto group) ethyl] ethanamide embodiment 83:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-[2-(pyridine-2-yl) ethyl] ethanamide embodiment 84:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-[2-(pyridin-3-yl) ethyl] ethanamide embodiment 85:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-[3-(imidazoles-1-yl) propyl group] ethanamide embodiment 86:7-{2-[4-(2-morpholinyl ethyl) piperazine-1-yl]-the 2-oxoethyl }-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine embodiment 87:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-(N-ethyl pyrrolidine-2-yl) methylacetamide embodiment 88:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-(2-piperidyl ethyl) ethanamide embodiment 89:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-[3-(tetramethyleneimine-1-yl) propyl group] ethanamide embodiment 90:(R)-4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-(N-ethyl pyrrolidine-2-yl) methylacetamide embodiment 91:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-(2-morpholinyl ethyl) ethanamide embodiment 92:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-[3-(N, the N-diethylamino) propyl group] ethanamide embodiment 93:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-[3-(N, N-diethylamino)-2 ,-dimethyl propyl] ethanamide embodiment 94:7-[2-(4-ethoxycarbonyl piperazine-1-yl)-2-oxoethyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine embodiment 95:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-[2, two (methylol) butyl of 2-] ethanamide embodiment 96:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-[3-(2-Pyrrolidone-1-yl) propyl group] ethanamide embodiment 97:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-(3-piperidyl propyl group) ethanamide embodiment 98:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-(morpholinyl propyl group) ethanamide embodiment 99:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-(3-hydroxyl-1-methyl-prop-2-yl) ethanamide embodiment 100:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-[3-(N-3-aminopropyl, the N-methyl) aminopropyl] two (2-amino-ethyl) amino-ethyls of ethanamide embodiment 101:4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl-N-[N-] ethanamide
The sequence number of amine Title Phase The RT/min product
??102 Thanomin Two-phase ????3.68
??103 Dl-2-amino-1-propyl alcohol Two-phase ????3.78
??104 1-amino-2-propyl alcohol Two-phase ????3.81
????105 The 2-methoxyethyl amine Two-phase ????4.08
????106 3-amino-1-propyl alcohol Two-phase ????3.73
????107 (S)-(+)-2-amino-1-propyl alcohol Two-phase ????3.78
????108 (R)-(+)-1-amino-2-propyl alcohol Liquid ????3.81
????109 N, the N-dimethyl-ethylenediamine Liquid ????3.50
????110 (+/-)-2-amino-1-butanols Two-phase ????3.96
????111 1-amino-2-butanols Two-phase ????4.06
????112 3-amino-1, the 2-propylene glycol Two-phase ????3.52
????113 (S)-and 3-amino-1, the 2-propylene glycol Two-phase ????3.53
????114 (R)-and 3-amino-1, the 2-propylene glycol Two-phase ????3.53
????115 N, N-dimethyl-1,3-propylene diamine Liquid ????3.47
????116 N2, N2-dimethyl-1,2-propylene diamine Liquid ????3.57
????117 1-dimethylamino-2-propylamine Liquid ????3.67
????118 D1-2-amino-3-methyl isophthalic acid-butanols Two-phase ????4.15
????119 2-(2-aminoethylamino) ethanol Liquid ????3.40
????120 2-amino-2-methyl-1-propanol Two-phase ????4.17
????121 2-amino-2-methyl-1, ammediol Two-phase ????3.76
????122 2-(2-amino ethoxy) ethanol Liquid ????3.71
????123 1-(2-amino-ethyl) tetramethyleneimine Two-phase ????3.61
????124 1-amino-1-pentamethylene methyl alcohol Two-phase ????4.48
????125 The 2-Trans-4-Amino Cyclohexanol Two-phase ????4.19
????126 N, the N-diethyl ethylenediamine Two-phase ????3.68
????127 N-(3-hydroxypropyl) quadrol Two-phase ????3.42
????128 2-((2-amino-ethyl) sulfenyl) ethanol Liquid ????3.94
????129 2-(2-amino-ethyl) pyridine Liquid ????4.13
????130 3-(2-amino-ethyl) pyridine Two-phase ????4.05
????131 N-(3-aminopropyl) imidazoles Liquid ????3.58
????132 2-(2-aminoethylamino)-1-crassitude Two-phase ????3.56
????133 2-(amino methyl)-1-ethyl pyrrolidine Two-phase ????3.70
????134 1-(2-amino-ethyl) piperidines Two-phase ????3.70
????135 1-tetramethyleneimine propylamine Two-phase ????3.60
????136 (R)-(+)-2-(amino methyl)-1-ethyl pyrrolidine Two-phase ????3.70
????137 4-(2-amino-ethyl) morpholine Two-phase ????3.63
????138 The 3-diethyl amino propylamine Two-phase ????3.64
????138 N, N-dimethyl neopentane diamines Two-phase ????3.68
????140 2-(amino methyl)-2-ethyl-1, ammediol Two-phase ????3.94
????141 1-(3-aminopropyl)-2-Pyrrolidone Liquid ????3.91
????142 1-piperidines propylamine Two-phase ????3.70
????143 4-(3-aminopropyl) morpholine Liquid ????3.53
????144 N, the N-diisopropyl ethylenediamine Liquid ????3.86
????145 N, two (3-aminopropyl) methylamines of N- Solid ????3.21
????146 Three (20 amino-ethyl) amine Two-phase ????3.17
Embodiment 102:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-(2-hydroxyethyl) propionic acid amide embodiment 103:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-(1-hydroxyl third-2-yl) propionic acid amide embodiment 104:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-(2-hydroxypropyl) propionic acid amide embodiment 105:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-(2-methoxy ethyl) propionic acid amide embodiment 106:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-(3-hydroxypropyl) propionic acid amide embodiment 107:(S)-1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-(1-hydroxyl third-2-yl) propionic acid amide embodiment 108:(R)-]-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-(2-hydroxypropyl) propionic acid amide embodiment 109:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-[2-(N, the N-dimethylamino) ethyl] propionic acid amide embodiment 110:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-(1-hydroxyl fourth-2-yl) propionic acid amide embodiment 11 1:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-(2-hydroxybutyl) propionic acid amide embodiment 112:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-(2, the 3-dihydroxypropyl) propionic acid amide embodiment 113:(S)-1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-(2, the 3-dihydroxypropyl) propionic acid amide embodiment 114:(R)-1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-(2, the 3-dihydroxypropyl) propionic acid amide embodiment 115:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-[3-(N, the N-dimethylamino) propyl group] propionic acid amide embodiment 116:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-[2-(N, the N-dimethylamino) propyl group] propionic acid amide embodiment 117:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-[1-(N, the N-dimethylamino) third-2-yl] propionic acid amide embodiment 118:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-(1-hydroxy-3-methyl fourth-2-yl) propionic acid amide embodiment 119:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-[2-(2-hydroxyethyl amino) ethyl] propionic acid amide embodiment 120:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-(1-hydroxy-2-methyl third-2-yl) propionic acid amide embodiment 121:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-(1,3-dihydroxyl-2-methyl-prop-2-yl) propionic acid amide embodiment 122:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-[2-(2-hydroxyl-oxethyl) ethyl] propionic acid amide embodiment 123:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-[2-(tetramethyleneimine-1-yl) ethyl] propionic acid amide embodiment 124:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-[1-(hydroxymethyl) cyclopentyl] propionic acid amide embodiment 125:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-(2-hydroxy-cyclohexyl) propionic acid amide embodiment 126:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-[2-(N, the N-diethylamino) ethyl] propionic acid amide embodiment 127:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-[2-(3-hydroxypropyl amino) ethyl] propionic acid amide embodiment 128:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-[2-(2-hydroxyl ethylmercapto group) ethyl] propionic acid amide embodiment 129:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-[2-(pyridine-2-yl) ethyl] propionic acid amide embodiment 130:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-[2-(pyridin-3-yl) ethyl] propionic acid amide embodiment 131:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-[3-(imidazoles-1-yl) propyl group] propionic acid amide embodiment 132:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-[2-(N-methylpyrrolidin-2-yl) ethyl] propionic acid amide embodiment 133:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-[(N-ethyl pyrrolidine-2-yl) methyl] propionic acid amide embodiment 134:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-(2-piperidyl ethyl) propionic acid amide embodiment 135:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-[3-(tetramethyleneimine-1-yl) propyl group] propionic acid amide embodiment 136:(R)-1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-[(N-ethyl pyrrolidine-2-yl) methyl] propionic acid amide embodiment 137:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-(2-morpholinyl ethyl) propionic acid amide embodiment 138:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-[3-(N, the N-diethylamino) propyl group] propionic acid amide embodiment 139:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-[3-(N, N-dimethylamino)-2, the 2-dimethyl propyl] propionic acid amide embodiment 140:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-[2, two (methylol) butyl of 2-] propionic acid amide embodiment 141:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-[3-(2-Pyrrolidone-1-yl) propyl group] propionic acid amide embodiment 142:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-(3-piperidyl propyl group) propionic acid amide embodiment 143:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-(morpholinyl propyl group) propionic acid amide embodiment 144:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-[2-(N, N-diisopropylaminoethyl) ethyl] propionic acid amide embodiment 145:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-N-[3-(N-3-aminopropyl, the N-methyl) aminopropyl] propionic acid amide embodiment 146:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-two (2-amino-ethyl) amino-ethyls of N-[N-] propionic acid amide embodiment 147:1-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] fourth Inner ester is a) at 0 ℃, and stirring is down in the nitrogen atmosphere, 4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidines (1.0g) are added the mixture of sodium hydride (the mineral oil dispersion liquid of 0.158g 60%) in dimethyl formamide (70ml).Mixture stirred 1 hour at 0 ℃, dripped dimethyl formamide (6ml) solution of α-bromo-γ-Ding Inner ester (0.60g) then under 0 ℃ of stirring.Mixture is in stirring at room 18 hours, water (100ml) cancellation then.The mixture ethyl acetate extraction.The extraction liquid that merges is dried and evaporates, and provides 2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] fourth Inner ester oily matter, be directly used in b).B) with N, N-dimethyl-ethylenediamine (5.0ml) adds in a) the product (1.2g) and toluene (100ml) solution of pyridin-2-ones (50mg).Mixture was 100 ℃ of heating 2 hours, and reduction vaporization is to doing then.Resistates is suspended in ethyl acetate, and washes with water.Organic extract liquid is used 5M hydrochloric acid then, and (3 * 50ml) extractions, acid extract liquid washs with ethyl acetate, alkalizes with 6M sodium hydroxide at 0 ℃ then, strips with ethyl acetate then, uses dichloromethane extraction again.With the organic extract liquid drying that merges, filter and evaporation, the oily matter that provides ethylacetate/ether crystallization provides 2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] butyrolactone, m.p.178-179 ℃.Embodiment 148:2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] ethyl propionate
With sodium hydride (120mg, 60% dispersion liquid in mineral oil) adds 4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] in the mixture of pyrimidine (906mg) in exsiccant dimethyl formamide (30ml), and with mixture in nitrogen in stirring at room 30 minutes.Drip dry DMF (10ml) solution of 2 bromopropionic acid ethyl ester (543mg) at 10 minutes Inner through syringe.Mixture was placed 18 hours then stirring at room 2 hours.Make mixture vacuum-evaporation, resistates washes with water, and the solid that provides is developed with ether, provides 2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] ethyl propionate, m.p.139-140 ℃.Embodiment 149:N-(2-dimethyl aminoethyl)-2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl) propionic acid amide
With 2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] ethyl propionate (425mg), N, the mixture heating up of N-dimethyl-ethylenediamine (2ml) and methyl alcohol (20ml) refluxed 18 hours, emitted carbonic acid gas simultaneously.With mixture cooling and filtration, filtrate water (50ml) dilutes and stirs with ether.Mixture was placed 18 hours, filtered the solid of collecting precipitation, wash with water, ether washing then, drying provides N-(2-dimethyl aminoethyl)-2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl) propionic acid amide, m.p.163-164 ℃.Embodiment 150:2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] ethyl acetate
With 4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidines (906mg), the mixture of sodium hydride (120mg, 60% dispersion liquid in mineral oil) and dry dimethyl formamide (30ml) in nitrogen in stirring at room 30 minutes.Dimethyl formamide (10ml) solution that in 0-5 ℃ and 5 minutes, adds bromoethyl acetate (0.5g).Mixture stirring at room 30 minutes, was placed 18 hours then.With mixture vacuum-evaporation, resistates water and ether development.Filter the solid of collecting gained, wash with water, ether washing then provides 2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] ethyl acetate, m.p.161-161.3 ℃.Embodiment 151-156 general method
With 2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] ethyl acetate (194mg) is 62 ℃ of heating, and stirred 18 hours in methyl alcohol (12ml) with the suitable amine that 10 molar equivalents are listed below, provide following compounds: embodiment 151 after the processing
From 2-hydroxyethyl-1,1-two (methylol) ethamine obtains N-[2-hydroxyethyl-1,1-two (methylol)]-2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] ethanamide, m.p.222-223 ℃.Embodiment 152
Obtain N-[2-(piperazine-1-yl) ethyl from 2-(piperazine-1-yl) ethamine]-2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] ethanamide, m.p.222-223 ℃.Embodiment 153
Obtain N-(2-morpholinyl ethyl)-2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl from 2-morpholinyl ethamine] ethanamide, m.p.164-165 ℃.Embodiment 154
Obtain N-[3-(1-imidazoles-1-yl) propyl group from 3-(1-imidazolyl) propyl group amine]-2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] ethanamide, m.p.170-171 ℃.Embodiment 155
Obtain N-(N-ethyl pyrrolidine-2-ylmethyl)-2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl from 1-(N-ethyl pyrrolidine-2-yl) methylamine] ethanamide, m.p.122-122.5 ℃.Embodiment 156
Obtain N-[2-(2-hydroxyl-oxethyl) ethyl from 2-(2-hydroxyl-oxethyl) ethamine]-2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] ethanamide, m.p.145-147 ℃.Embodiment 157:2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] propionic acid
With 2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] ethyl propionate (201mg), the mixture boiling reflux of potassium hydroxide aqueous solution (the 2M solution of 4ml) and methyl alcohol (20ml) 1 hour.Mixture is evaporated to about 5ml water (30ml) dilution then.With the mixture filtered while hot,, occur until precipitation with the acetic acid,diluted acidifying then the filtrate cooling.Mixture is heated on hot plate, become thin solid until resulting gel.Solid collected by filtration provides 2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] propionic acid, m.p.239.5-241 ℃.Embodiment 158:4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] ethyl butyrate
With 5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (1.5g) is dissolved in DMF (30ml) and usefulness sodium hydride (0.22g is 60% dispersion liquid in mineral oil) is handled, use DMF (15ml) solution of 4-bromo-butyric acid ethyl ester (1.08g) to handle then in the mode that is similar to embodiment 95, provide 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] ethyl butyrate, m.p.104-104.5 ℃.Embodiment 159: ethyl 2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] methane amide
To be similar to the mode of embodiment 97,5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (1.0g), sodium hydride (the mineral oil dispersion liquid of 1.032g 60%), 2-bromoacetamide (0.55g) and dimethyl formamide (50m1) react, and the solid that provides after processing Virahol recrystallization provides ethyl 2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] methane amide, m.p.232-233 ℃.Embodiment 160:2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-the 2-methyl propanamide
Under agitation 4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidines (200mg) are dissolved in 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2-(1H)-pyrimidone (1.5ml), and at room temperature add sodium hydroxide (0.158g), and mixture was stirred 15 minutes.Add 2-bromo-2-methyl propanamide (0.5g), mixture in room temperature vigorous stirring 18 hours, and then adds 2-bromo-2-methyl propanamide (0.15g) in anhydrous atmosphere, and restir 24 hours.Water (3ml) is added reaction mixture, and regulate pH to 0 together with dilute hydrochloric acid (5M).This suspension is added into water (60ml), and mixture was placed 18 hours in room temperature.Solid collected by filtration, the water thorough washing is 50 ℃ of vacuum-dryings.Solid is by preparation property HPLC (reverse) purifying.Collect suitable fraction and merging, use dichloromethane extraction.The evaporation methylene dichloride provides 2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-the 2-methyl propanamide, m.p.227-228 ℃.Embodiment 161:4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] N-(2-dimethyl aminoethyl) butyramide
With 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] mixture of ethyl butyrate (100mg) in 30ml methyl alcohol be with 0.6ml 2-dimethyl aminoethyl amine reflux 18 hours.With the mixture reduction vaporization, resistates heated 18 hours in vapor bath with 2-dimethylamino ethamine (10ml).Excessive amine is removed in decompression.Water is added in the resistates, and filtering mixt provides 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] N-(2-dimethyl aminoethyl) butyramide.
By identical ester and the suitable amine reaction of listing, prepare the compound of embodiment 162,163 and 164 in the mode that is similar to embodiment 108.Embodiment 165
Prepare 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl from 3-(1-imidazolyl) propylamine] N-[3-(1-imidazolyl) propyl group] butyramide embodiment 166
Prepare 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl from 2-morpholinyl ethamine] N-(2-morpholinyl ethyl) butyramide embodiment 167
Prepare 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2 from the morpholinyl propylamine, 3-d] pyrimidin-7-yl] preparation of N-(morpholinyl propyl group) butyramide raw material a) stirs and down tert-butylamine (15ml) added 2-bromo-4 '-metaphenoxy acetophenone (12.7g, according to Tetrahedron Letters, 1993,34,3177 make 4 '-metaphenoxy acetophenone bromination preparation) propan-2-ol solution, mixture was 80 ℃ of heating 3 hours.Make mixture be cooled to 0 ℃, add concentrated hydrochloric acid (10ml).Suspension was stirring at room 18 hours, and solid collected by filtration provides 4 '-phenoxy group-2-(tertiary butyl amino) methyl phenyl ketone hydrochloride (3.75g), m.p.210-212 ℃.1) 4 '-phenoxy group-2-(tertiary butyl amino) methyl phenyl ketone hydrochloride (3.75g) is once added sodium ethylate (preparing by sodium (93mg) is dissolved in ethanol (50ml)), mixture stirred 30 minutes in nitrogen at 40 ℃.2) in the flask that separates, sodium (331mg) is dissolved in ethanol (50ml) and add propane dinitrile (858mg).Solution once is added in this solution in 4 '-phenoxy group-2-(tertiary butyl amino) methyl phenyl ketone solution of step (1) gained then stirring at room 5 minutes, gets rid of sedimentary sodium-chlor.The mixture that produces is 50 ℃ of heating 3 hours, then 80 ℃ of heating 2 hours.Removal of solvent under reduced pressure, the oily matter of generation is distributed between water and the ethyl acetate.Tell organic phase, dry and evaporation provides black solid.This solid is dissolved in hot ethanol, and the water development, filtering also, drying provides 2-amino-3-cyano group-4-(4-Phenoxyphenyl)-1-(tertiary butyl) pyrroles.B) with 2-amino-3-cyano group-4-(4-Phenoxyphenyl)-1-(tertiary butyl) pyrroles (1.9g), the mixture of methane amide (30ml) and 4-dimethylaminopyridine (10mg) was 180 ℃ of heating 6 hours.Make mixture be cooled to room temperature, and add entry, produce black solid.Solid collected by filtration washes with water, seethes with excitement in ethanol then, and heat filtering is collected insolubles and dry.Solid is by preparation property silicagel column HPLC purifying, with methylene dichloride/propan-2-ol/ethanol, make moving phase at 98: 1: 1, provide the 7-tertiary butyl-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (4-amino-5-(4-Phenoxyphenyl)-7 (tertiary butyl)-pyrrolo-es [2,3-d] pyrimidine), m.p.157-158 ℃.
1H NMR (d6 DMSO) δ 8.15 (1H, s), 7.50-7.35 (4H, m), 7.30 (1H, s), 7.15 (1H, t), 7.10 (4H, m), 6.05 (2H, brs), 1.75 (9H, s) .c) with 4-amino-5-(4-Phenoxyphenyl)-7 (tertiary butyl)-pyrrolo-es [2,3-d] pyrimidines (5.8g), Glacial acetic acid (55ml) and Hydrogen bromide (55ml 48% solution) boiling reflux 18 hours in nitrogen.Make the mixture cooling and filter collection.This solid methanol wash with the ether washing, provides 4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine hydrogen bromate, m.p.288-292 ℃ then.By with diluted sodium hydroxide solution (100ml 5%w/v solution) and the under agitation warm free alkali that is converted into of ethanol (60ml), and distillation removes and desolvates.With the mixture cooling, solid collected by filtration also washes with water, provides 5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, m.p.272 ℃.Embodiment 168:7-pentamethylene alkylsulfonyl-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
In nitrogen, stir in dry dimethyl formamide (30ml) solution that down sodium hydride (0.132g 60% mineral oil dispersion liquid) is added 5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (1.0g).Mixture is stirred 30 minutes, drips dry dimethyl formamide (5ml) solution of pentamethylene SULPHURYL CHLORIDE (0.558g, as J.O.C.1952,17, the described preparation of 1529-1533) then.Make mixture place vacuum-evaporation then 72 hours.The development of resistates water is also filtered, and the solid water thorough washing that provides stirs with ethyl acetate then, filters then.Filtrate is made moving phase by quick purification by silica gel column chromatography with ethyl acetate.Collect suitable fraction, provide 7-pentamethylene alkylsulfonyl-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, m.p.188-188.5 ℃.Embodiment 169:5-(4-Phenoxyphenyl)-7-(8-phthalimido octyl group)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
Under in nitrogen, stirring, sodium hydride (120mg 60% mineral oil dispersion liquid) is added in dry dimethyl formamide (30ml) solution of 5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (906mg).Mixture stirred in nitrogen 30 minutes, added dimethyl formamide (5ml) solution of N-(8-bromine octyl group) Phthalimide (1.4g) then.Make mixture in nitrogen in stirring at room 18 hours, be distributed in then between water and the ethyl acetate.Tell ethyl acetate layer,, make moving phase, provide 5-(4-Phenoxyphenyl)-7-(8-phthalimido octyl group)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, m.p.85-86 ℃ with ethyl acetate by quick purification by silica gel column chromatography.Embodiment 170:7-(the amino octyl group of 8-)-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine dihydrochloride dihydrate
With 5-(4-Phenoxyphenyl)-7-(8-phthalimido octyl group)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (1.0g), the mixture boiling reflux of hydrazine hydrate (1.0ml) and ethanol (40ml) 2 hours is emitted carbonic acid gas.Mixture was cooled 18 hours, and the solid of filtration collecting precipitation also abandons.With filtrate evaporated under reduced pressure, resistates is dissolved in ethyl acetate, and drying is handled by the aqueous isopropanol that drips concentrated hydrochloric acid then, until not precipitation formation.Mixture is placed spent the night, abandon supernatant liquor then, semi-solid residue is developed with ethyl acetate, provides 7-(the amino octyl group of 8-)-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine dihydrochloride dihydrate, m.p.120 ℃.Embodiment 171:N-{2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] ethyl } Phthalimide
To be similar to the mode of embodiment 468, but 90 ℃ of reheat 3 hours, make 5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine and the reaction of 2 bromoethyl benzene dicarboximide, provide N-{2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] ethyl } Phthalimide, m.p.111-112 ℃.Embodiment 172:7-(2-amino-ethyl)-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine hydrochlorate
To be similar to the mode of embodiment 469, the product of top embodiment is handled with hydrazine hydrate, provide 7-(2-amino-ethyl)-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine hydrochlorate, m.p.284-285 ℃.Embodiment 173:7-sec.-propyl-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
In nitrogen, stir and down isobutyryl chloride (1.8g) is added drop-wise to 5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (4.32g), in the mixture of dry dimethyl formamide (200ml) and dry pyridine (2ml).Mixture at room temperature stirred 1 hour and vacuum-evaporation.Resistates is distributed between water and the ethyl acetate.Tell ethyl acetate, dry and evaporation, the resistates of gained toluene recrystallization provides 7-sec.-propyl-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, m.p.160.5-161 ℃.Embodiment 174:5-(4-Phenoxyphenyl)-7-(1,4-dioxo spiro [4,5] last of the ten Heavenly stems-8-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
Under stirring at room, sodium hydride (0.26g 60% mineral oil dispersion liquid) is added in dimethyl formamide (50ml) solution of 5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (1.94g).The mixture stirring is stopped to overflow until hydrogen, add 8-tosyloxy-1 then, 4-dioxo spiro [4,5] decane (2.0g, as described in the US 4360531 from 1,4-dioxo spiro [4,5] decane-8-ketone (according to J.Med.Chem.1992,2246 preparations) preparation).Mixture heated 5 hours in 120 ℃ in nitrogen, be cooled to room temperature, the water cancellation, and use ethyl acetate extraction, the resistates that provides is by quick purification by silica gel column chromatography, use ethyl acetate, then, provide 5-(4-Phenoxyphenyl)-7-(1 with the eluent ethyl acetate that contains the methyl alcohol that is up to 6% increasing amount, 4-dioxo spiro [4,5] last of the ten Heavenly stems-the 8-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, m.p.193-194 ℃.Embodiment 175:4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] pimelinketone
With the product (500mg) of top embodiment, acetone (20ml) and 3M hydrochloric acid (10ml) in nitrogen in stirring at room 20 minutes.Then mixture was heated 1 hour at 60 ℃, acetone is removed in decompression then.Resistates is used ethyl acetate extraction then with the alkalization of 5M aqueous sodium hydroxide solution, and the solid that provides provides 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl with ether development and filtration] pimelinketone, m.p.252-254 ℃.Embodiment 176 and 177: cis-5-(4-Phenoxyphenyl)-7-(4-morpholinyl hexamethylene-1-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, with trans-5-(4-Phenoxyphenyl)-7-(4-morpholinyl hexamethylene-1-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
Above sodium triacetoxy borohydride (42mg) and Glacial acetic acid (18mg) added 1 of the product (120mg) of embodiment and morpholine (31mg), the 2-dichloroethane solution.Mixture stirred 2 hours at 40 ℃, added another batch morpholine (0.15g) and sodium triacetoxy borohydride (0.21g) then.Mixture washs with saturated sodium bicarbonate aqueous solution then stirring at room 20 hours.Mixture is filtered the EMPORE_ tube, and filtrate is used the 3M hcl as extraction agent.Acid extract liquid alkalizes with the 5M sodium hydroxide solution, and use dichloromethane extraction, the resistates that provides is by the silica gel column chromatography purifying, provide cis-5-(4-Phenoxyphenyl)-7-(4-morpholinyl hexamethylene-1-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, with trans-5-(4-Phenoxyphenyl)-7-(4-morpholinyl hexamethylene-1-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine.Embodiment 178 and 179: cis-7-(4-N-ethoxycarbonyl) piperazine-1-basic ring hexyl)-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, with trans-7-(4-N-ethoxycarbonyl) piperazine-1-basic ring hexyl)-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
To be similar to the mode of top embodiment, make 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] pimelinketone (0.4g of the material gained of 1.0g purity 40%) and 1-ethoxycarbonyl piperidines (158mg) be in the presence of sodium triacetoxy borohydride (296mg), one reacts in the methylene dichloride that contains Glacial acetic acid (60mg) (15ml), provide cis-7-(4-N-ethoxycarbonyl) piperazine-1-basic ring hexyl behind processing and the chromatography)-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine, with trans-7-(4-N-ethoxycarbonyl) piperazine-1-basic ring hexyl)-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine.Embodiment 180:2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] pyridine-3-nitrile
With 5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (906mg) reacted 5 hours in 100 ℃ in the presence of dimethyl formamide (30ml) suspension of sodium hydride (150mg) with 2-chloronicotinoyl nitrile (510mg), provide 2-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2 after the processing, 3-d] pyrimidin-7-yl] pyridine-3-nitrile, m.p.242-242.5 ℃.Embodiment 181:7-[3-(amino methyl) pyridine-2-yl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine 2-maleate
With the product (468mg) of top embodiment, use saturated ethanol of ammonia (200ml) and Raney_ nickel (2ml) in nitrogen, the pressure of 26 crust, in 80 ℃ of vibrations 6 hours, room temperature was placed 68 hours then.Mixture is filtered resistates ethanol thorough washing.Reduction vaporization filtrate, resistates are dissolved in ethyl acetate and filter.In filtrate, add the toxilic acid (135mg) that is dissolved in ethyl acetate (20ml) in batches, occur until no longer including precipitation.Mixture is obtained the jelly of residual volume by warm and decant.Jelly is further heated and decant with ethyl acetate.Make the acetic acid ethyl acetate extract cooling of merging, filter the solid of collecting precipitation, provide 7-[3-(amino methyl) pyridine-2-yl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine 2-maleate, m.p.131-134 ℃.Embodiment 182:3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-8-methyl-8-azabicyclo [3.2.1] octane
Sodium hydride (168mg, 60% mineral oil dispersion liquid) is added 5-(4-Phenoxyphenyl)-7H-pyrrolo-[2, the 3-d] pyrimidine-mixture of 4-base amine (770mg) in dimethyl formamide (30ml).Dimethyl formamide (10ml) solution that adds 3-mesyloxy-8-methyl-8-azabicyclo [3.2.1] octane (900mg, as J.A.C.S.1958,80,4679 described preparations) under in nitrogen, stirring.Make mixture 75 ℃ warm 5 hours (room temperature was placed 7 days).Removal of solvent under reduced pressure.In resistates, add entry, the mixture ethyl acetate extraction, the resistates that provides is removed raw material with ethyl acetate/methanol (50: 50) as moving phase by quick purification by silica gel column chromatography, uses ethyl acetate/methanol/triethylamine (5: 5: 1) to make the moving phase eluted product then.Merge suitable fraction, evaporation, the solid that provides is developed with ether, filters to provide 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-8-methyl-8-azabicyclo [3.2.1] octane.Embodiment 183 and 184: cis-7-(the high piperazine of N-methyl-1-basic ring hexyl)-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine and trans-7-(the high piperazine of N-methyl-1-basic ring hexyl)-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
To be similar to the mode of embodiment 176 and 177, make 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] pimelinketone (0.4g of the material gained of 1.0g purity 40%), the high piperazine of N-methyl (1 14mg), sodium triacetoxy borohydride (296mg), Glacial acetic acid (60mg) and 1,2-ethylene dichloride (15ml) reacts.After the filtration, filtrate is evaporated, resistates is by the silica gel column chromatography purifying, provide cis-7-(the high piperazine of N-methyl-1-basic ring hexyl)-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine and trans-7-(the high piperazine of N-methyl-1-basic ring hexyl)-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine.Embodiment 185 and 186: cis-7-(N methyl piperazine-1-basic ring hexyl)-5-(4-Phenoxyphenyl)-7-pyrrolo-[2,3-d] pyrimidine-4-base amine and trans-7-(N methyl piperazine-1-basic ring hexyl)-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
To be similar to the mode of front embodiment, make cyclohexanone derivative and other reagent react of N methyl piperazine (100mg) and same amount, provide cis-7-(N methyl piperazine-1-basic ring hexyl)-5-(4-Phenoxyphenyl)-7-pyrrolo-[2,3-d] pyrimidine-4-base amine and trans-7-(N methyl piperazine-1-basic ring hexyl)-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine.Embodiment 187:3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-pentamethylene-1-ketone
With 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-pentamethylene-1-alcohol (100mg), the mixture of activated manganese dioxide (500mg) and methylene dichloride (100mg) was stirring at room 18 hours, provide 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2 after the filtration, 3-d] pyrimidin-7-yl]-dichloromethane solution of pentamethylene-1-ketone, be directly used in the following examples.Embodiment 188: cis-7-(morpholinyl ring penta-1-yl)-5-(4-Phenoxyphenyl)-7-pyrrolo-[2,3-d] pyrimidine-4-base amine and trans-7-(morpholinyl ring penta-1-yl)-5-(4-Phenoxyphenyl)-7-pyrrolo-[2,3-d] pyrimidine-4-base amine
Morpholine (45mg) is added in the solution of top embodiment gained, then add sodium triacetoxy borohydride (151mg) and Glacial acetic acid (47mg).Mixture stirred in nitrogen 18 hours in room temperature, during this period methylene dichloride was evaporated.Add tetrahydrofuran (THF) (100ml), mixture restir 8 hours.With mixture process, provide cis-7-(morpholinyl ring penta-1-yl)-5-(4-Phenoxyphenyl)-7-pyrrolo-[2,3-d] pyrimidine-4-base amine and trans-7-(morpholinyl ring penta-1-yl)-5-(4-Phenoxyphenyl)-7-pyrrolo-[2,3-d] pyrimidine-4-base amine.Embodiment 189:3-(4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl) cyclopentyl N-(2-morpholinyl ethyl) carbamate hydrochloride a) at 0 ℃ toward 3-(4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl) add N-methylmorpholine (7ml) in methylene dichloride (1ml) solution of cyclopentanol (20mg), mixture is stirred 20 minutes.Remove cooling bath, add 4-chloroformate nitrophenyl ester (12.5mg), the mixture of generation is in stirred overnight at room temperature.Mixture dilutes with methylene dichloride, water, saturated sodium bicarbonate aqueous solution and salt water washing.Organic solution provides crude product with dried over mgso and evaporation.B) dichloromethane solution with the step a) crude product adds 2-morpholinyl ethamine (0.2ml), and mixture is in stirred overnight at room temperature.Mixture dilutes with ethyl acetate, water and salt water washing.Organic phase is dried, and filters and evaporation, and the crude product that provides provides 3-(4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl) cyclopentyl N-(2-morpholinyl ethyl) carbamate by preparation property HPLC purifying.C) product with step b) is dissolved in ethyl acetate (2ml), feeds hydrogen chloride gas 2 minutes in solution.Form precipitation and continue and stirred 10 minutes.With solvent evaporation and add entry solid is dissolved.Freeze-drying provides 3-(4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl) cyclopentyl N-(2-morpholinyl ethyl) carbamate hydrochloride solid.Embodiment 190:3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-cyclopentyl 2-Padil ester hydrochloride a) makes 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-cyclopentanol (50mg, 0.129mmol) and N-t-butoxycarbonyl glycine (34mg, 0.194mmol) at N, mix in the dinethylformamide (1ml).Add 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (31mg, 0.155mmol) and 4-dimethylaminopyridine (16mg, 0.129mmol).The mixture that produces in nitrogen in stirring at room 24 hours.Reaction mixture is poured into frozen water and used ethyl acetate extraction.Organic extract liquid salt water washing, dry (sal epsom) filters and evaporation.Solid is made moving phase by quick silica gel column chromatography purifying with ethyl acetate, provides 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-cyclopentyl 2-[(tertbutyloxycarbonyl) amino] acetic ester.Its structure is passed through 1HNMR confirms.B) with 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-cyclopentyl 2-[(tertbutyloxycarbonyl) amino] (39mg 0.072mmol) is dissolved in ethyl acetate (2.5ml) to acetic ester.Fed hydrogen chloride gas 1 minute.Flask is added a cover, again with solution stirring 30 minutes.Add ether and form precipitation.Solid collected by filtration provides 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-cyclopentyl 2-Padil ester hydrochloride.Its structure is passed through 1H NMR and LC/MS (MH +=444) confirm.Embodiment 191:3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-cyclopentyl (2S)-2-amino-3 Methylbutanoic acid ester hydrochloride is a) with (2S)-1-[(tertbutyloxycarbonyl) amino]-2-Methyl Butyric Acid 2,5-dioxo-2,5-dihydro-1H-1-pyrroles's carboxylic acid anhydride (114mg, 0.362mmol) adding 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-cyclopentanol (66mg, methylene dichloride 0.171mmol) (1ml) solution.Reaction mixture in nitrogen in stirring at room 24 hours.Reaction mixture is washed with ethyl acetate, and dry (sal epsom) filters and evaporation.Solid is made moving phase by quick silica gel column chromatography purifying with ethyl acetate, provides 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-cyclopentyl (2S)-2-[(tertbutyloxycarbonyl) amino] butyric ester.Its structure is passed through 1H NMR and LC/MS (MH +=586) confirm.B) with 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-cyclopentyl (2S)-2-[(tertbutyloxycarbonyl) amino] (35mg 0.060mmol) is dissolved in ethyl acetate (2.5ml) to butyric ester.Fed hydrogen chloride gas 1 minute.Flask is added a cover, again with solution stirring 30 minutes.Add ether and form precipitation.Solid collected by filtration provides 33-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-cyclopentyl (2S)-2-amino-3 Methylbutanoic acid ester hydrochloride.Its structure is passed through 1H NMR and LC/MS (MH +=486) confirm.Embodiment 192:3-(4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl) cyclopentyl N-(2-morpholinyl ethyl) carbamate hydrochloride a) under 0 ℃ of stirring in nitrogen with N-methylmorpholine (0.007ml, 0.062mmol) (12.5mg is in methylene dichloride 0.062mmol) (1ml) solution to be added drop-wise to chloroformic acid 4-nitrophenyl ester.After 20 minutes, remove ice-water bath, make mixture be warmed to room temperature.(20mg, 0.052mmol), the solution of generation is stirred 24 hours to cyclopentanol to add 3-(4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl) in the mixture.Reaction mixture dilutes with methylene dichloride, and water, saturated sodium bicarbonate and salt water washing.With organic layer drying (sal epsom), filter and evaporation, provide: 3-(4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl) cyclopentyl (4-nitrophenyl) carbonic ether.Its structure is passed through 1H NMR confirms.B) methylene dichloride (1ml) solution with 3-(4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl) cyclopentyl (4-nitrophenyl) carbonic ether (0.052mmol) adds 2-morpholinyl ethamine (0.2ml).The mixture that produces in nitrogen in stirring at room 24 hours.Reaction mixture dilutes and washing with ethyl acetate, and dry (sal epsom) filters also evaporation.Solid provides 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl by preparation property HPLC purifying] cyclopentyl N-(2-morpholinyl ethyl) carbamate.Its structure is passed through 1H NMR and LC/MS (MH +=543) confirm.C) with 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] (10mg 0.018mmol) is dissolved in ethyl acetate (2.5ml) to cyclopentyl N-(2-morpholinyl ethyl) carbamate.In solution, feed hydrogen chloride gas 2 minutes, form precipitation.Flask is added a cover solution restir 10 minutes.Solid collected by filtration provides 3-(4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl) cyclopentyl N-(2-morpholinyl ethyl) carbamate hydrochloride.Its structure is passed through 1H NMR and LC/MS (MH +=543) confirm.The preparation of raw material is a) under agitation with tert-butylamine (15ml) adding 2-bromo-4 '-metaphenoxy acetophenone (12.7g, according to Tetrahedron Letters, 1993,34,3177 make 4 '-metaphenoxy acetophenone bromination preparation) propan-2-ol solution, mixture was 80 ℃ of heating 3 hours.Make mixture be cooled to 0 ℃, add concentrated hydrochloric acid (10ml).Suspension was stirring at room 18 hours, and solid collected by filtration provides 4 '-phenoxy group-2-(tertiary butyl amino) methyl phenyl ketone hydrochloride (3.75g), m.p.210-212 ℃.B) 1) 4 '-phenoxy group-2-(tertiary butyl amino) methyl phenyl ketone hydrochloride (3.75g) is once added sodium ethylate (preparing by sodium (93mg) is dissolved in ethanol (50ml)), mixture stirred 30 minutes in nitrogen at 40 ℃.2) in the flask that separates, sodium (331mg) is dissolved in ethanol (50ml) and add propane dinitrile (858mg).Solution once is added in this solution in 4 '-phenoxy group-2-(tertiary butyl amino) methyl phenyl ketone solution of step (1) gained then stirring at room 5 minutes, gets rid of sedimentary sodium-chlor.The mixture that produces is 50 ℃ of heating 3 hours, then 80 ℃ of heating 2 hours.Removal of solvent under reduced pressure, the oily matter of generation is distributed between water and the ethyl acetate.Tell organic phase, dry and evaporation provides black solid.This solid is dissolved in hot ethanol, and the water development, filtering also, drying provides 2-amino-3-cyano group-4-(4-Phenoxyphenyl)-1-(tertiary butyl) pyrroles.C) with 2-amino-3-cyano group-4-(4-Phenoxyphenyl)-1-(tertiary butyl) pyrroles (1.9g), the mixture of methane amide (30ml) and 4-dimethylaminopyridine (10mg) was 180 ℃ of heating 6 hours.Make mixture be cooled to room temperature, and add entry, produce black solid.Solid collected by filtration washes with water, seethes with excitement in ethanol then, and heat filtering is collected insolubles and dry.Solid is by preparation property silicagel column HPLC purifying, with methylene dichloride/propan-2-ol/ethanol, make moving phase at 98: 1: 1, provide the 7-tertiary butyl-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (4-amino-5-(4-Phenoxyphenyl)-7 (tertiary butyl)-pyrrolo-es [2,3-d] pyrimidine), m.p.157-158 ℃.
1H?NMR(d6?DMSO)δ8.15(1H，s)，7.50-7.35(4H，m)，7.30
(1H, s), 7.15 (1H, t), 7.10 (4H, m), 6.05 (2H, brs), 1.75 (9H, s) .d) with 4-amino-5-(4-Phenoxyphenyl)-7 (tertiary butyl)-pyrrolo-es [2,3-d] pyrimidines (5.8g), Glacial acetic acid (55ml) and Hydrogen bromide (55ml 48% solution) boiling reflux 18 hours in nitrogen.Make the mixture cooling and filter collection.This solid methanol wash with the ether washing, provides 4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine hydrogen bromate, m.p.288-292 ℃ then.By with diluted sodium hydroxide solution (100ml 5%w/v solution) and the under agitation warm free alkali that is converted into of ethanol (60ml), and distillation removes and desolvates.With the mixture cooling, solid collected by filtration also washes with water, provides 5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine.E) with 5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (600mg) and four (triphenyl phosphine) palladium (40ml) and exsiccant methyl-sulphoxide (30ml) mixture stirring in nitrogen on the ice-water bath, then at 0 ℃ of tetrahydrofuran (THF) (10ml) solution in nitrogen through syringe adding cyclopentadiene one epoxide (200mg).Mixture stirred 66 hours in room temperature (lucifuge), and tetrahydrofuran (THF) is removed in decompression then, adds entry in resistates.Mixture is placed 18 hours, use ethyl acetate extraction then, the resistates that provides is by quick purification by silica gel column chromatography, make moving phase with ethyl acetate/industrial methylated spirit (9: 1), provide 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-ring penta-2-enol oily matter.Its structure is passed through 1H NMR and mass spectrum confirm.F) with 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-ring penta-2-enol (110mg) in ethanol (20ml) with hydrogen hydrogenation under atmospheric pressure, make catalyzer with 10%Pd/C (50mg).Filtration catalizer, filtrate is evaporated, and provides 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-cyclopentanol oily matter.Its structure is passed through 1H NMR and mass spectrum confirm.Embodiment 193: cis-5-(4-Phenoxyphenyl)-7-(4-pyrrolidyl hexamethylene-1-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine is trans-5-(4-Phenoxyphenyl)-7-(4-pyrrolidyl hexamethylene-1-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
Under in nitrogen atmosphere, stirring, with 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-cyclopentanone (2.34g, 5.9mmol) 1,2-ethylene dichloride (250ml) adds tetramethyleneimine (1.25g, 17.6mmol) and Glacial acetic acid (1.00ml, 17.6mmol), the mixture of generation was stirring at room 30 minutes.(1.87,8.8mmol), the mixture of generation is stirred 70 hours once to add sodium triacetoxy borohydride.(2 * 200ml) extract mixture with 2M hydrochloric acid.The extraction liquid that merges makes its alkalize with methylene dichloride (300ml) washing with the 12.5M aqueous sodium hydroxide solution, with methylene dichloride (3 * 200ml) extractions.The extraction liquid dried over sodium sulfate that merges by with Biotage 40S column chromatography purification, is used ethyl acetate/triethylamine (95: 5) and ethyl acetate/triethylamine/methyl alcohol (85; 10: 5) make moving phase, provide cis-5-(4-Phenoxyphenyl)-7-(4-pyrrolidyl hexamethylene-1-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (0.65g, 1.4mmol), fusing point 101-104 ℃, LC/MS Hypersil BDSc18 (100 * 201mm) 0.1M ammonium acetate/acetonitriles, 10-100% acetonitrile 8 minutes): MH +454t r=3.56 minutes and trans-5-(4-Phenoxyphenyl)-7-(4-pyrrolidyl hexamethylene-1-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (0.93g, 2.1mmol), fusing point 183-185 ℃, LC/MSHypersil BDS c18 (100 * 201mm) 0.1M ammonium acetate/acetonitriles, 10-100% acetonitrile 8 minutes): MH +454 t rEmbodiment 194 in=3.68 minutes: cis-5-(4-Phenoxyphenyl)-7-(4-piperidyl hexamethylene-1-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine hydrochlorate is trans-5-(4-Phenoxyphenyl)-7-(4-piperidyl hexamethylene-1-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
Under in nitrogen atmosphere, stirring, with 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-cyclopentanone (2.34g, 5.9mmol) 1,2-ethylene dichloride (250ml) adds piperidines (1.50g, 17.6mmol) and Glacial acetic acid (1.00ml, 17.6mmol), the mixture of generation was stirring at room 30 minutes.(1.87,8.8mmol), the mixture of generation is stirred 70 hours once to add sodium triacetoxy borohydride.(2 * 200ml) extract mixture with 2M hydrochloric acid.The extraction liquid that merges makes its alkalize with methylene dichloride (300ml) washing with the 12.5M aqueous sodium hydroxide solution, with methylene dichloride (3 * 200ml) extractions.The extraction liquid dried over sodium sulfate that merges, by using Biotage 40S column chromatography purification, make moving phase with ethyl acetate/triethylamine (95: 5), provide cis-5-(4-Phenoxyphenyl)-7-(4-piperidyl hexamethylene-1-yl)-7H-pyrrolo-[2,3-d] pyrimidine-limpid oily matter of 4-base amine (0.23g), LC/MSHypersil BDS c18 (100 * 201mm) 0.1M ammonium acetate/acetonitriles, 10-100% acetonitrile 8 minutes): MH +468 t r=3.67 minutes and trans-5-(4-Phenoxyphenyl)-7-(4-piperidyl hexamethylene-1-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine beige solid (193mg, 0.4mmol), fusing point 192-195 ℃, LC/MSHypersil BDS c18 (100 * 201mm) 0.1M ammonium acetate/acetonitriles, 10-100% acetonitrile 8 minutes): MH +468 t rEmbodiment 195 in=3.71 minutes: with cis-5-(4-Phenoxyphenyl)-7-(4-piperidyl hexamethylene-1-yl)-7H--pyrrolo-[2,3-d] pyrimidine-4-base amine is dissolved in ethyl acetate (50ml), dilute with ether (50ml), and handle with the diethyl ether solution of 1M hydrogenchloride, occur until no longer including precipitation.The solid that collect to produce use the absolute ethanol recrystallization, provide the basic amine hydrochlorate colorless solid of cis-5-(4-Phenoxyphenyl)-7-(4-piperidyl hexamethylene-1-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-(75mg, 0.2mmol), fusing point 185-189 ℃.Embodiment 196: trans-7-(4-dimethylamino cyclohexyl)-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine cis-7-(4-dimethylamino cyclohexyl)-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
In nitrogen atmosphere, with 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] pimelinketone (3.24g, 8.1mmol) methylene dichloride (1000ml) solution add N methyl piperazine (1.20g, 12.0mmol) and Glacial acetic acid (0.69ml, 12.0mmol), the solution of generation was stirring at room 10 minutes.(1.70,8.0mmol), the mixture of generation is stirred 6 hours once to add sodium triacetoxy borohydride.Repeat to add with identical scale, the solution of generation is stirred 70 hours.(2 * 300ml) extract solution with 2M hydrochloric acid.The extraction liquid that merges makes its alkalize with methylene dichloride (300ml) washing with 880 ammonia solns, with ethyl acetate (3 * 250ml) extractions.The extraction liquid that merges washs with saturated nacl aqueous solution, dried over sodium sulfate, by using Biotage 40S column chromatography purification, make moving phase with ethyl acetate/methanol/triethylamine (8: 1: 1), provide cis-7-(4-dimethylamino cyclohexyl)-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine beige solid (220mg, 0.5mmol), fusing point 180-182 ℃, LC/MS Hypersil BDS c18 (100 * 201mm) 0.1M ammonium acetate/acetonitriles, 10-100% acetonitrile 8 minutes): MH +428 t r=3.43 minutes
With pillar with ethyl acetate/methanol/triethylamine (4: 1: 1,500ml) drip washing, removal of solvent under reduced pressure.Resistates is dissolved in methylene dichloride (200ml), by using Biotage 40M column chromatography purification, with methylene chloride (9: 1 to 7: 3) wash-out, provide trans-5-(4-Phenoxyphenyl)-7-(4-piperidyl hexamethylene-1-yl)-7H-pyrrolo-[2,3-d] and pyrimidine-4-base amine beige solid (320mg, 0.75mmol), fusing point 207.5-210 ℃, LC/MS Hypersil BDSc18 (100 * 201mm) 0.1M ammonium acetate/acetonitriles, 10-100% acetonitrile 8 minutes): MH +428t r=3.48 minutes
R-(+)-4-[4-amino-5-(4-Phenoxyphenyl)-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine.Embodiment 197:4-{ (S)-tetrahydrofuran (THF)-3-yl } tosylate
0 ℃ toward (S)-3-hydroxyl tetrahydrofuran (2.0g, drip in pyridine 23mmol) (40ml) solution toluene sulfonyl chloride (4.8g, 25mmol).Solution was stirred 1 hour at 0 ℃, then in ambient temperature overnight.Vacuum-evaporation pyridine, resistates are distributed in (each 200ml) between ethyl acetate and the saturated aqueous citric acid solution.(2 * 200ml) extractions, the organic phase of merging is dried in (sodium sulfate) water layer, filters and evaporation, provides oily matter (4.5,85%) with ethyl acetate.
1H?NMR(CDCl 3，250?MHz)：7.78(2H，d)，7.35(2H，d)，5.12(1H，m)，3.76-3.93(4H，m)，2.45(3H，s)，2.01-2.20(2H，m).
Stir down past 4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine (4.83g in nitrogen, N 16mmol), (0.75g, 19mmol), mixture was stirring at room 30 minutes to add 60% sodium hydride mineral oil dispersion liquid in dinethylformamide (80ml) suspension.The black solid that produces 4-{ (S)-tetrahydrofuran (THF)-3-yl } tosylate (handle for 4.20g, N 18mmol) by the 2ml aliquots containig of dinethylformamide (20ml) solution.The solution that produces stirred 18 hours at 95 ℃ then stirring at room 30 minutes.Make solution be cooled to room temperature, pour into then in the frozen water (200ml).(3 * 200ml) extract water layer with ethyl acetate.The organic extract liquid water that merges (4 * 150ml) washings, dried over sodium sulfate, removal of solvent under reduced pressure.Resistates is warm until obtaining solution with methylene dichloride (1000ml), be cooled to room temperature, by using Biotage 40M column chromatography purification, with ethyl acetate/triethylamine (95: 5), ethyl acetate/triethylamine/methyl alcohol (90: 5: 5) is made moving phase then, provide R-(+)-4-[4-amino-5-(4-Phenoxyphenyl)-7-(3-tetrahydrofuran base)-7H-pyrrolo-[2,3-d] pyrimidine beige solid (4.35g, 12mmol), fusing point 165-166 ℃, LC/MS Hypersil BDSc18 (100 * 2.1mm) 0.1M ammonium acetate/acetonitriles, 10-100% acetonitrile 8 minutes): MH +373 t r=4.44 minutes.[α] D+ 20.5 ± 0.6 (methylene dichloride, 22.6C) embodiment 198:5-(4-Phenoxyphenyl)-7-(4-piperidyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine N-tertiary butyloxycarbonyl phenylpiperidines alcohol
0 ℃ toward N-tertbutyloxycarbonyl piperidone (10.0g, drip in methyl alcohol 50mmol) (100ml) solution sodium borohydride (1.9g, 50mmol).Stirred 1 hour at 0 ℃, then stirring at room 20 hours.With 2N sodium hydroxide (20ml) cancellation, evaporating solvent, resistates is distributed in (each 100ml) between ethyl acetate and the water.With ethyl acetate (3 * 100ml) aqueous layer extracted, and with salt solution and the water (organic layer that 1 * 100ml) washing merges.Dry (sodium sulfate) filters and concentrates, and provides N-tertiary butyloxycarbonyl phenylpiperidines alcohol colorless oil (10.5g, 100%).R in 20% ethyl acetate/hexane f=0.05 (potassium permanganate colour developing).IR (film): 3428,2939,1693cm -1Embodiment 199:4-[(4-aminomethyl phenyl) alkylsulfonyl] Oxy-1-piperidine carboxylic acid tertiary butyl ester
At 0 ℃, past N-tertiary butyloxycarbonyl phenylpiperidines alcohol (10 in the nitrogen.5g, drip in pyridine 0.052mol) (150ml) solution toluene sulfonyl chloride (9.94g, 0.052mol).Stirred 2 hours at 0 ℃.Be warmed to room temperature, and in stirred overnight at room temperature.Evaporating solvent also is distributed in citric acid solution (1M is 100ml) and between the ethyl acetate (200ml).With ethyl acetate (1 * 100ml) extraction acid layer, and with citric acid solution (1M, 2 * 100ml), salt solution (100ml) and water (100ml) wash the organic layer of merging.Dry (sodium sulfate); filter and evaporation; the oily matter that provides is by the rapid column chromatography purifying; with 10% ethyl acetate/hexanaphthene, 15% ethyl acetate/hexanaphthene wash-out then; provide the 4-[(4-aminomethyl phenyl at F-30-68) alkylsulfonyl] Oxy-1-piperidine carboxylic acid tertiary butyl ester white solid (11.0g; 60%) R in 20% ethyl acetate/hexanaphthene, f=0.17.
1H NMR (CDCl 3, 250MHz): δ 7.79 (2H, d), 7.34 (2H, d), 4.67 (1H, m), 3.58 (2H, m), 3.27 (2H, m), 2.45 (3H, s), and 1.59-1.83 (4H, m), 1.43 (9H, s) embodiment 200:4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-1-piperidine carboxylic acid tertiary butyl ester
In nitrogen in 0 ℃ toward 4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] (2.0g adds sodium hydride (0.264,60% dispersion liquid in dry DMF (100ml) solution 6.6mmol) to pyrimidine, 6.6mmol), reaction mixture is warmed to room temperature and stirred 1 hour.Add the 4-[(4-aminomethyl phenyl) alkylsulfonyl] (2.34g, 6.6mmol), the solution of generation was 95 ℃ of heating 72 hours for Oxy-1-piperidine carboxylic acid tertiary butyl ester.By adding entry (150ml) cancellation reaction carefully.With ethyl acetate (3 * 100ml) extractions, and water (4 * 100ml) and salt solution (2 * 100ml) washings. organic solution be dried (sodium sulfate), filter and evaporation, the solid that provides is absorbed on the silica gel, by quick purification by silica gel column chromatography, use ethyl acetate, 5% methanol/ethyl acetate is made eluent then, provide 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2 at F13-22,3-d] pyrimidin-7-yl]-1-piperidine carboxylic acid tertiary butyl ester (1.0g, 31%) white solid, m.p.168-169.5 ℃.R in 10% ethyl acetate/methanol f=0.4.
1H NMR (d 6DMSO, 250MHz): δ 8.14 (1H, s), 7.38-7.49 (5H, m), 7.07-7.23 (5H, m), 6.14 (2H, bs), 4.76 (1H, m), 4.11 (2H, m), 2.93 (2H, m), 1.92-2.02 (4H, m), 1.43 (9H, s). mass spectrum .C 28H 31O 3N 5(485.2430) .IR (KBr disk): 3059,1695,1588,1235cm -1Embodiment 201:5-(4-Phenoxyphenyl)-7-(4-piperidyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
At 0 ℃ of past 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-(0.69g adds TFA (5ml) in dry methylene chloride 1.4mmol) (25ml) solution to 1-piperidine carboxylic acid tertiary butyl ester.With solution at stirring at room 20 hours and evaporating solvent.(5N, 10ml), (3 * 50ml) extract the jelly of generation with ethyl acetate to add sodium hydroxide solution.With salt solution (1 * 50ml) washing.Drying is filtered and is concentrated, and the solid that provides provides 5-(4-Phenoxyphenyl)-7-(4-piperidyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (433258) white solid (500mg, 91%) with ether development and filtration.M.pt?209-211℃。1: 1 ethyl acetate: the R in the methyl alcohol f=0.1.
1H NMR (d 6DMSO, 250MHz) 8.13 (1H, s), 7.36-7.48 (4H, m), 7.29 (1H, s), 7.04-7.16 (5H, m), 5.80 (2H, bs), 4.64 (1H, m), 3.10 (2H, m), 2.80 (1H, bs), 2.67 (2H, m), 1.94 (4H, m). mass spectrum .C 23H 23ON 5(385.1902) .IR (KBr disk): 3278,1620,1585,1490,1245cm -1Embodiment 202:5-(4-Phenoxyphenyl)-7-(4-piperidyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine dihydrochloride
In 5-(4-Phenoxyphenyl)-7-(4-piperidyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (433258) ethyl acetate/methanol (15ml, 1: 1) solution (200mg), add ether.HCl solution (1.0M, 3ml).The white precipitate that produces filters in nitrogen gas stream, vacuum-evaporation 6 hours, provide 5-(4-Phenoxyphenyl)-7-(4-piperidyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine dihydrochloride (1.4 hydrate) white solid (120mg), 304 ℃ of fusing points (decomposition).
1H NMR (D 2O, 250MHz) 8.48 (1H, s), 7.69 (1H, s), 7.50-7.58 (4H, m), 7.18-7.34 (5H, m), 5.16 (1H, m), 3.81 (2H, d), 3.46 (2H, m), 2.49 (4H, m) .) .IR (KBr disk): 3937,1657.1231cm -1Embodiment 203:3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-1-pyrrolidine carboxylic acid tertiary butyl ester N-tertbutyloxycarbonyl tetramethyleneimine-3-alcohol
0 ℃ toward tetramethyleneimine-3-alcohol (10.0g, add in methylene dichloride 0.11mol) (200ml) solution triethylamine (22.2g, 30.5ml, 0.22mol), then add heavy carbonic di-t-butyl ester (28.8g, 0.13mol).Be warmed to room temperature and in stirred overnight at room temperature.With saturated aqueous citric acid solution (150ml) cancellation, water, salt solution and water (each 1 * 100ml) washing organic layer.With organic layer drying (sodium sulfate), filter and evaporation, provide the golden oily matter of N-tertbutyloxycarbonyl tetramethyleneimine-3-alcohol (20.0g, 93% thick productive rate).Embodiment 204:3-[(4-aminomethyl phenyl) alkylsulfonyl] Oxy-1-pyrrolidine carboxylic acid's tertiary butyl ester
At 0 ℃, in the nitrogen toward N-tertbutyloxycarbonyl tetramethyleneimine-3-alcohol (19.8g, drip in pyridine 0.106mol) (200ml) solution toluene sulfonyl chloride (22.3g, 0.117mol).Stirred 2 hours at 0 ℃.Be warmed to room temperature, and in stirred overnight at room temperature.With pyridine vacuum-evaporation, resistates is distributed between ethyl acetate and the citric acid solution (each 200ml).The organic layer that merges be dried (sodium sulfate), filter and evaporation, the oily matter that provides is by the rapid column chromatography purifying, with 10% ethyl acetate/cyclohexane give eluent, provide oily matter at F-40-85, with this oily matter be dissolved in small volume hexanaphthene/ether (5: 1,50ml), cooling and with the little spoon induced crystallization of swiping.Solid filtering with producing provides the 3-[(4-aminomethyl phenyl) alkylsulfonyl] Oxy-1-pyrrolidine carboxylic acid's tertiary butyl ester (10.5g, 29%) white solid.R in ethyl acetate/hexanaphthene f=0.13.
1H?NMR(CDCl 3，250MHz)：7.79(2H，d)，7.35
(2H，d)，5.04(1H，m)，3.43(4H，m)，2.46(3H，s)，2.03-2.20(2H，bm)，1.43(9H，s)
In nitrogen in 0 ℃ toward 4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] (2.0g adds sodium hydride (0.264,60% dispersion liquid in dry DMF (120ml) solution 6.6mmol) to pyrimidine, 6.6mmol), reaction mixture is warmed to room temperature and stirred 1 hour.Drip the 3-[(4-aminomethyl phenyl) alkylsulfonyl] (2.25g, 6.6mmol), the solution of generation was 95 ℃ of heating 72 hours for Oxy-1-pyrrolidine carboxylic acid's tertiary butyl ester.The water cancellation and with ethyl acetate (4 * 100ml) extractions, water (4 * 100ml) and salt solution (2 * 100ml) wash.Organic solution be dried (sodium sulfate), filter and evaporation, the solid that provides is absorbed on the silica gel, by quick purification by silica gel column chromatography, use ethyl acetate, 5% methanol/ethyl acetate is made eluent then, provide 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2 at F17-25,3-d] pyrimidin-7-yl]-1-pyrrolidine carboxylic acid tertiary butyl ester (1.0g, 32%) white solid, m.p.168-170 ℃.Ethyl acetate at 9: 1: the R in the methyl alcohol f=0.46.
1H NMR (d 6DMSO, 250MHz): 8.17 (1H, s), 7.38-7.50 (5H, m), 6.19 (2H, bs), 5.31 (1H, m), 3.77 (1H, m), 3.42-3.60 (3H, m), 2.38 (2H, m), 1.40 (9H, s). mass spectrum .471.2250 (C 27H 29O 3N 5) IR (KBr disk): 3130,1683,1585,1404,1245cm -1Embodiment 205:5-(4-Phenoxyphenyl)-7-(3-pyrrolidyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
At 0 ℃ of past 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-(0.8g adds trifluoroacetic acid (5ml) in dry methylene chloride 1.7mmol) (25ml) solution to 1-pyrrolidine carboxylic acid tertiary butyl ester.With solution at stirring at room 20 hours and evaporating solvent.(5N, 10ml), (3 * 50ml) extract the jelly of generation with ethyl acetate to add sodium hydroxide solution.With salt solution (1 * 75ml) washing.Drying is filtered and is concentrated, and the solid that provides provides 5-(4-Phenoxyphenyl)-7-(3-pyrrolidyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine white solid (0.5g, 79%) with ether development and filtration.M.pt?182-184℃。1: 1 ethyl acetate: the R in the methyl alcohol f=0.15.
1H NMR (d 6DMSO, 250MHz): 8.14 (1H, s), 7.37-7.50 (5H, m), 7.05-7.18 (5H, m), 6.14 (2H, bs), 5.23 (1H, m), 3.09-3.27 (2H, m), 2.83-2.98 (2H, m), 2.19-2.33 (1H, m), 1.88-2.01 (1H, m). mass spectrum .371.1758 (C 22H 21ON 5) .IR (KBr disk): 3106,1585,1489,1232cm -1Embodiment 206:5-(4-Phenoxyphenyl)-7-(3-pyrrolidyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine dihydrochloride
The ethyl acetate/methanol of past 5-(4-Phenoxyphenyl)-7-(3-pyrrolidyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (200mg) (2: 1,20ml) add ether in the solution.HCl solution (1.0M, 3ml).The white precipitate that produces filters in nitrogen gas stream, vacuum-evaporation 6 hours, provide 5-(4-Phenoxyphenyl)-7-(3-pyrrolidyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine dihydrochloride (0.4 hydrate) white solid (190mg), 298 ℃ of fusing points (decomposition).IR (KBr sheet): 2909,1658,1249cm -1Embodiment 207:7-perhydro-1-pyrrolidyl (pyrrolizinyl)-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine dihydrochloride a) perhydro-1-pyrrolidinol such as Schnekenburger J, Briet E, Arch.Pharm. (Wienheim) 310, the described preparation of 152-160 (1977).B) perhydro-1-pyrrolidyl methanesulfonates
With perhydro-1-pyrrolidinol (0.5g, 3.94mmol) and triethylamine (0.60g, 5.91mmol) mixture in methylene dichloride (10ml) stirs in 0 ℃ of nitrogen.Add methylsulfonyl chloride (0.68,5.91mmol), make mixture be warmed to room temperature then and stirred 8 hours.Add saturated ammonium chloride (10ml), methylene dichloride (25ml) and saturated sodium bicarbonate aqueous solution (10ml).The organic layer dried over mgso is filtered, and reduction vaporization filtrate provides resistates.This thing is made eluent by quick silica gel column chromatography purifying with heptane/ethyl acetate (1: 3), provides perhydro-1-pyrrolidyl methanesulfonates (0.54g):
1H NMR (DMSO-d 6, 400MHz) δ 4.96 (m, 1H), 3.61 (m, 1H), and 2.9-3.3 (m, 6H), 2.35 (m, 1H), 1.55-2.25 (m, 6H) .c) 7-perhydro-1-pyrrolidyl (pyrrolizinyl)-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine dihydrochloride
With 5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (0.49g, 1.62mmol) and the dispersion liquid of 60% sodium hydride in oil (100mg, 2.43mmol) mixture in DMF in nitrogen in stirring at room 15 minutes.Mixture is cooled to room temperature then 100 ℃ of heating 18 hours.(100mg 2.43mmol) also continues heating 2 hours to add the dispersion liquid of 60% sodium hydride in oil again.Make mixture be cooled to room temperature, removal of solvent under reduced pressure.Resistates is dispensed between water (10ml) and the methylene dichloride (30ml).The organic layer dried over mgso is filtered and is reduced pressure to remove from filtrate and desolvates.The resistates that produces is by preparation property C-18 RP HPLC purifying, provide the 150mg white solid, it is dissolved in ethyl acetate (10ml), and handle with the 1N ether solution of hydrogen chloride, provide 7-perhydro-1-pyrrolidyl (pyrrolizinyl)-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine dihydrochloride white solid: 1H NMR (DMSO-d 6, 400MHz) δ 8.52 (s, 1H), 7.95 (s, 1H), 7.02-7.58 (m, 1H), 5.38 (m, 1H0,4.40 (m, 1H), 1.9-3.9 (m, 10H); (Hypersil HSC18,5 μ m, 100A, 250 * 4.6mm; 25-100% acetonitrile-0.1M
Ammonium acetate 10min, 1ml/min) t r=7.62min; MS:MH +412. embodiment 208:7-(2-methyl perhydro pentamethylene is [c] pyrroles-5-yl also)-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine dihydrochloride a) 2-methyl perhydro pentamethylene also [c] pyrroles-5-alcohol as Schnekenburger J, Briet E, Arch.Pharm. (Wienheim) 301,341 (1968) described preparations.B) 4-chloro-5-iodo-7-(2-methyl perhydro pentamethylene is [c] pyrroles-5-yl also)-7H-pyrrolo-[2,3-d] pyrimidine
With 4-chloro-5-iodo-7H-pyrrolo-[2,3-d] pyrimidine (0.38g, 1.36mmol), 2-methyl perhydro pentamethylene is [c] pyrroles-5-alcohol (0.23g also, 1.63mmol) and triphenyl phosphine (0.71g, 2.72mmol) (0.474g 2.72mmol) handles, and stirring at room 2 hours with the azoethane dicarboxylic ester for mixture in tetrahydrofuran (THF) (20ml).Removal of solvent under reduced pressure, resistates are distributed between methylene dichloride (30ml) and the water (10ml).Organic layer washs with saturated sodium-chloride water solution (10ml), and dried over mgso is filtered then then, with filtrate evaporated under reduced pressure, provides resistates.Resistates by quick silica gel column chromatography purifying, is made moving phase with methylene chloride (8: 2), provides 4-chloro-5-iodo-7-(2-methyl perhydro pentamethylene is [c] pyrroles-5-yl also)-7H-pyrrolo-[2,3-d] pyrimidines (0.25g): 1HNMR (DMSO-d 6, 400MHz) δ 8.62 (s, 1H), 7.44 (s, 1H), 7.26 (s, 2H), 5.36 (m, 1H), 2.88 (m, 2H), 2.68 (m, 2H), 2.43 (m, 2H), 2.36 (s, 3H), 2.06-2.02 (m, 4H); TLC (methylene chloride 18:2) R f=0.29; RP-HPLC (Hypersil HS C18,5 μ m, 100A, 250 * 4.6mm; 25-100% acetonitrile-0.1M ammonium acetate 10min, 1ml/min) t r=6.50min; MS:MH +403.c) 7-(2-methyl perhydro pentamethylene is [c] pyrroles-5-yl also)-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine dihydrochloride
With 4-chloro-5-iodo-7-(2-methyl perhydro pentamethylene is [c] pyrroles-5-yl also)-7H-pyrrolo-[2,3-d] pyrimidine (0.25g, 0.622mmol), 4-Phenoxyphenyl boric acid (0.16g, 0.746mmol), four (triphenyl phosphine) palladium (0.043g, 0.037mmol) and yellow soda ash (0.172g, mixture 1.62mmol) in glycol dimethyl ether (8ml) and water (4ml) mixture in the nitrogen in 90 ℃ the heating 18 hours.Mixture is cooled to room temperature, removal of solvent under reduced pressure.Resistates is dispensed between water (10ml) and the methylene dichloride (30ml).Layering, the organic layer dried over mgso, filtration and concentrating under reduced pressure filtrate are to resistates (0.354g).This thing is dissolved in 1,4-dioxan (10ml) and dense (28%) ammonium hydroxide (10ml).Mixture in 120 ℃ of heating 20 hours, is cooled to room temperature then in tube sealing.Solvent evaporated under reduced pressure, pass through purification by silica gel column chromatography then, make eluent with methylene chloride (7: 3), provide 7-(2-methyl perhydro pentamethylene is [c] pyrroles-5-yl also)-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (0.05g): 1H NMR (DMSO-d 6400MHz) show two groups of peaks, corresponding to the cis of required compound and trans-isomer(ide) δ 10.6-10.8 (bs, 1H), 8.49 (s, lH), and 6.99-7.98 (m, 11H), 5.39and 5.48 (m, 1H), and 2-3.8 (m, 10H); PH 454098:RP-HPLC (Hypersil HS C18,5 μ m, 100A, 250 * 4.6mm; 25-100% acetonitrile-0.1M ammonium acetate 10min, 1ml/min) t r=7.53min; MS:MH +426. by free alkali being dissolved in the dihydrochloride that 10ml 1N hydrochloric acid and freeze-drying prepare 7-(2-methyl perhydro pentamethylene is [c] pyrroles-5-yl also)-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine.Embodiment 209: cis and trans-7-[4-(N-tertbutyloxycarbonyl-1S, 4S-2,5-diaza [2.2.1] heptyl) cyclohexyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine
With 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-1-hexanaphthene ketone (0.67g, 1.68mmol) suspension in methylene dichloride (40ml) is with (1S, 4S)-(-)-2,5-diaza [2.2.1] heptane-2-carboxylic acid tertiary butyl ester (1.0g, 5.04mmol) and Glacial acetic acid (0.30g is 5.04mmol) room temperature treatment 1 hour.Add Na (OAc) subsequently 3(0.46g 2.17mmol) and at 80 ℃ stirred 8 days BH.Add sodium bicarbonate (0.377g, 10.08mmol) water (15ml) solution, and stirring 15 minutes in the refrigerative reaction soln.Layering, (each 3 * 100ml) washing of organic layer water and salt solution.The water layer dichloromethane extraction merges organic layer, and dry (sal epsom) filters and concentrates.Solid is by quick silica gel column chromatography, (2L, 6% ethanol/methylene, 2L 10% methyl alcohol/5% ammonium hydroxide dichloromethane solution then), provide: embodiment 210: cis-7-[4-(N-tertbutyloxycarbonyl-1S, 4S-2,5-diaza [2.2.1] heptyl) cyclohexyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (605mg, 64%)
1H NMR (d 6DMSO, 400 MHz): δ 8.13 (1H, s), 7.39-7.49 (4H, m), 7.32 (1H, m), 7.07-7.17 (5H, m), 6.09 (2H, bs), 4.63 (1H, m), 4.15 (1H, m), 3.30-3.70 (2H, m), and 3.03-3.08 (2H, m), 2.80-2.90 (1H, m), and 2.70-2.75 (1H, m), 2.29-2.35, (1H, m), 2.09-2.21 (1H, m), 1.81-1.93 (4H, m), 1.60-1.80 (4H, m), 1.39 (9H, m) .HPLC/MS:Perkin Elmer Pecosphere C18,3 μ M, 33 * 4.6,3.5 ml/min100-100%50mM ammonium acetates are to acetonitrile 4.5 minutes, C 36H 44N 6O 3(581.2), 95%. embodiment 211: trans-7-[4-(N-tertbutyloxycarbonyl-1S, 4S-2,5-diaza [2.2.1] heptyl) cyclohexyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-base amine (183mg, 20%)
1H NMR (d 6DMSO, 400 MHz): δ 8.13 (1H, s), 7.39-7.47 (5H, m), 7.15-7.17 (1H, m), 7.07-7.11 (4H, m), 6.10 (2H, bs), 4.62 (1H, m), 4.1-4.2 (1H, m), 3.71 (1H, bs), 3.03 (2H, m), 2.35 (2H, m), 1.93-2.01 (6H, m), 1.60-1.68 (2H, m), 1.40 (9H, s) .HPLC/MS Perkin Elmer Pecosphere C18,3 μ M, 33 * 4.6, the 3.5ml/min100-100%50mM ammonium acetate is to acetonitrile 4.5 minutes, C 30H 36N 6O (581.2), 99%. embodiment 212: cis-N1-{4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-7 base] cyclohexyl }-N1, N2, N2-trimethylammonium-1 three maleate are trans-N1-{4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-7 base] cyclohexyl }-N1, N2, N2-trimethylammonium-1 three maleate
With 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-1-hexanaphthene ketone (1.0g, 2.51mmol), N, N, and N '-trimethylammonium quadrol (0.77g, 7.54mmol) and acetate (0.45g, 7.54mmol) 1, the mixture in the 2-ethylene dichloride (50ml) at room temperature stirred 30 minutes in nitrogen.(0.69g, 3.26mmol), mixture was stirring at room 18 hours to add sodium triacetoxy borohydride.Add entry (20ml) and sodium bicarbonate (1.26g, 15.1mmol), mixture is stirred 1 hour, the filtration over celite pad, should fill up with methylene dichloride (75ml) washing.Transfer in the separating funnel filtrate and layering.The organic layer dried over mgso is filtered, with filtrate evaporated under reduced pressure.Cis and trans-isomer(ide) are by quick silica gel column chromatography purifying, make eluent with methylene chloride (7: 3), provide cis-N1-{4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-7 base] cyclohexyl }-N1, N2-trimethylammonium-1 (0.442g) and trans-N1-{4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-7 base] cyclohexyl }-N1, N2-trimethylammonium-1 (0.336g).With cis-N1-{4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-7 base] cyclohexyl }-N1, N2-trimethylammonium-1,2-quadrol (0.44g, 0.909mmol) be dissolved in warm ethyl acetate (100ml), add toxilic acid (0.32g, ethyl acetate 2.73mmol) (30ml) solution then.The salt that produces forms the oily resistates in the bottom and the side of flask.Pour out supernatant liquor, the water-soluble and freeze-drying of resistates provides cis-N1-{4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-7 base] cyclohexyl }-N1, N2-trimethylammonium-1 three maleate (0.55g): 1HNMR (DMSO-d 6, 400MHz) δ 8.22 (s, 1H), 7.41-7.50 (m, 5H), 7.08-7.19 (m, 5H), 6.5 (bs, 2H), 6.15 (s, 6H), 4.78 (m, 1H), 3.28 (m, 2H), 3.00 (m, 2H), 2.80 (m, 1H), 2.79 (s, 6H), 2.50 (s, 3H), 2.1 9 (m, 2H), 1.99 (m, 2H), 1.78 (m, 4H); RP-HPLC (Hyoersil CPS, 5 μ m, 100A, 250 * 4.6mm; 25-100% acetonitrile-0.1M ammonium acetate
10min，1ml/min)t r＝9.27min；MS：MH +?485.
Prepare trans-N1-{4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-7 base in an identical manner from free alkali] cyclohexyl }-N1, N2-trimethylammonium-1 three maleate: 1H NMR (DMSO-d 6, 400MHz) δ 8.20 (s, 1H), 7.41-7.48 (m, 5H), 7.08-7.19 (m, 5H), 6.45 (bs, 2H), 6.15 (s, 6H), 4.62 (m, 1H), 2.9-3.3 (m, 5H), 2.74 (s, 6H), 2.56 (s, 3H), 1.9-2.2 (m, 6H), 1.73 (m, 2H); RP-HPLC (Hypersil CPS, 5 μ m, 100A, 250 * 4.6mm; 25-100% acetonitrile-0.1M
Ammonium acetate 10min, 1ml/min) t r=8.17min; MS:MH +485.
To be similar to cis-N1-{4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-7 base] cyclohexyl }-N1, N2-trimethylammonium-1, the mode of 2-quadrol prepares following compounds embodiment 214: cis-7-[4-(4-sec.-propyl piperazinyl) cyclohexyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4 amine:
1H NMR (d 6DMSO, 400MHz): δ 8.13 (1H, s), 7.39-7.50 (4H, m), 7.28 (1H, s), 7.07-7.16 (5H, m), 6.08 (2H, bs), 4.67 (1H, m), and 2.49-2.67 (9H, m), 2.06-2.16 (5H, m), and 1.70-1.72 (2H, m), 1.53-1.59 (2H, m), 0.97 (d, J=6.5Hz, 6H). mass spectrum .C 31H 38N 6O (511.2) .HPLC:(Hypersil HS C18,5 μ m, 254nm, 250 * 4.6mm; 25-100% acetonitrile-0.1N ammonium acetate 10min, 1ml/min) t r=7.817min., 99%TLC:R fIn90%CH 2Cl 2/ MeOH=0.30 (UV visible). embodiment 215: trans-7-[4-(4-sec.-propyl piperazinyl) cyclohexyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4 amine:
1H?NMR(d 6DMSO，400MHz)：δ8.13(1H，
s)，7.40-7.47(5H，m)，7.08-7.18(5H，m)，6.08(2H，bs)，4.53(1H，m)，2.45-2.55(9H，
m)，2.17-2.20(1H，m)，1.86-1.96(6H，m)，1.44-1.49(2H，m)，0.97(d，J＝5.5Hz，
6H). mass spectrum .C 31H 38N 6O (511.2) .HPLC:(Hypersil HS C18,5 μ m, 254nm, 250
* 4.6mm; 25-100% acetonitrile-0.1N ammonium acetate 10min, 1ml/min)
t r=7.367min., 91%TLC:R f90%CH 2Cl 2/ MeOH=0.21 (UV visible). embodiment 216: cis-7-{4-[4-(2-methoxy ethyl) piperazinyl] cyclohexyl }-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4 amine:
1H NMR (d 6DMSO, 400MHz): δ 8.13 (1H, s), 7.39-7.50 (4H, m), 7.27 (1H, s), 7.07-7.11 (5H, m), 6.09 (2H, bs), 4.68 (1H, m), 3.42 (2H, t, J=5.9 Hz), 3.22 (3H, s), 2.43-2.55 (9H, m), 2.03-2.16 (6H, m), 1.60-1.71 (2H, m), 1.52-1.59 (2H, m). mass spectrum .C 31H 38N 6O 2(527.2) .HPLC:(Hypersil HS C18,5 μ m, 254nm, 250 * 4.6mm; 25-100% acetonitrile-0.1N
Ammonium acetate 10min, 1ml/min) t r=7.317min, 95%TLC:R fAt 90%CH 2Cl 2/ MeOH=0.22 (UV visible). embodiment 217: trans-7-{4-[4-(2-methoxy ethyl) piperazinyl] cyclohexyl }-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4 amine:
1H NMR (d 6DMSO, 400MHz): δ 8.13 (1H, s), 7.39-7.47 (5H, m), 7.07-7.16 (5H, m), 6.09 (2H, bs), 4.55 (1H, m), 3.36-3.42 (2H, m), 3.23 (3H, s), and 2.33-2.55 (11H, m), 1.90-1.96 (6H, m), 1.44-1.47 (2H, m). mass spectrum .C 31H 38N 6O 2(527.2) .HPLC:(Hypersil HS C18,5 μ m, 254nm, 250 * 4.6mm; 25-100% acetonitrile-0.1N ammonium acetate 10min, 1ml/min) t r=7.200min, 99%TLC:R fIn90%CH 2Cl 2/ MeOH=0.31 (UV visible).Embodiment 218: cis-7-[4-(4-ethyl piperazidine base) cyclohexyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4 amine:
1H?NMR(d 6DMSO，400MHz)：δ8.23(1H，s)，7.41-7.49(4H，m)，7.07-7.17(6H，m)，6.57(2H，bs)，6.20(5H，s)，4.77(1H，m)，2.04-2.13(8H，m)，1.61-1.77(5H，m)，1.21(3H，t)。HPLC(Waters?delta?pack?C18，150×3.9mm；5-95％
Acetonitrile-0.1M ammonium acetate 30min, 1ml/min) t r=13.851,100%, trans-7-[4-(4-ethyl piperazidine base) cyclohexyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4 amine:
1H NMR (d 6DMSO, 400MHz): δ 8.19 (1H, s), 7.40-7.47 (4H, m), 7.19 (1H, m), 7.08-7.19 (5H, m), 6.40 (2H, bs), 6.18 (6H, s), 4.95 (1H, m), 3.17 (2H, bs), 2.98 (2H, bs), 2.69 (2H, bs), and 1.94-2.01 (8H, m), 1.54-1.57 (2H, d, J=7.5Hz), 1.17 (3H, t) .HPLC (Waters delta pack C18,150 * 3.9mm; 5-95% acetonitrile-0.1M
Ammonium acetate 30min, 1ml/min) t r=13.701,96%.
Trans to be similar to-N1-{4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-7 base] cyclohexyl }-N1, N2-trimethylammonium-1, the trans preparation following compounds of 2-quadrol three maleate: embodiment 219: cis-7-[4-(4-sec.-propyl piperazinyl) cyclohexyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4 amine three maleate:
1H NMR (d 6DMSO, 400MHz): δ 8.23 (1H, s), 7.40-7.49 (5H, m), 7.07-7.19 (5H, m), 6.55 (2H, bs), 6.16 (6H, s), 4.74 (1H, m), 3.26 (6H, bs), 2.04-2.49 (13H, m), 1.63-1.75 (5H, m), 1.25 (d, J=6.6Hz, 6H). mass spectrum .C 31H 38N 6O (511.1) .HPLC:(Hypersil HS C18,5 μ m, 254nm, 250 * 4.6mm; 25-100% acetonitrile-0.1N ammonium acetate 10min, 1ml/min) t r=7.967min, 99% embodiment 220: trans-7-[4-(4-sec.-propyl piperazinyl) cyclohexyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4 amine three maleate:
1H NMR (d 6DMSO, 400MHz): δ 8.20 (1H, s), 7.40-7.65 (5H, m), 7.08-7.19 (5H, m), 6.46 (2H, bs), 6.14 (6H, s), 4.60 (1H, m), 2.50-3.45 (17H, m), 1.95-2.02 (5H, m), 1.56-1.59 (2H, m), 1.20 (d, J=6.5Hz, 6H). mass spectrum .C 31H 38N 6O (511.2) .HPLC:(Hypersil HS C18,5 μ m, 254nm, 250 * 4.6mm; 25-100% acetonitrile-0.1N ammonium acetate 10min, 1ml/min) t r=7.733 min, 90% embodiment 221: cis-7-{4-[4-(2-methoxy ethyl) piperazinyl] cyclohexyl }-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4 amine three maleate:
1H NMR (d 6DMSO, 400 MHz): δ 8.23 (1H, s), 7.41-7.49 (5H, m), 7.07-7.19 (5H, m), 6.55 (2H, bs), 6.16 (6H, s), 4.75 (1H, m), 3.62 (2H, m), 3.30 (3H, s), 3.17 (6H, bs), 2.50 (9H, m), 2.02-2.16 (5H, m), 1.74 (5H, m). mass spectrum .C 31H 38N 6O 2(527.2) .HPLC:(Hypersil HS C18,5 μ m, 254nm, 250 * 4.6mm; 25-100% acetonitrile-0.1N
Ammonium acetate 10min, 1ml/min) t r=7.750min, 99% embodiment 222: trans-7-{4-[4-(2-methoxy ethyl) piperazinyl] cyclohexyl }-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4 amine three maleate:
1H NMR (d 6(DMSO, 400 MHz): δ 8.21 (1H, s), 7.41-7.48 (5H, m), 7.08-7.17 (5H, m), 6.53 (2H, bs), 6.17 (6H, s), 4.61 (1H, m), 3.45 (3H, s), 2.50-3.56 (19H, m), 1.99-2.08 (6H, m), 1.64 (2H, m). mass spectrum .C 31H 38N 6O 2(527.2) .HPLC:(Hypersil HS C18,5 μ m, 254nm, 250 * 4.6mm; 25-100% acetonitrile-0.1N ammonium acetate 10min, 1ml/min) t r=7.383min, 99% embodiment 223: cis-N1-{4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-7 base] cyclohexyl }-N2, N2-dimethyl-1,2-quadrol three maleate are trans-N1-{4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-7 base] cyclohexyl }-N2, N2-trimethylammonium-1 three maleate:
1H NMR (DMSO-d 6, 400MHz) δ 8.19 (s, 1H), 7.40-7.49 (m, 5H), 7.08-7.19 (m, 5H), 6.35 (bs, 2H), 6.13 (s, 6H), 4.78 (m, 1H), 3.15-3.45 (m, 5H), 2.74 (s, 6H), 1.8-2.25 (m, 8H); RP-HPLC (Hypersil CPS, 5 μ m, 100A, 250 * 4.6mm; 25-100% acetonitrile-0.1M
Ammonium acetate 10min, 1ml/min) t r=8.90min; MS:MH +471. embodiment 224: trans-N1-{4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-7 base] cyclohexyl }-N2, N2-dimethyl-1 2-maleate:
1H NMR (DMSO-d 6, 400MHz) δ 9.5 (bs, 1H), 8.26 (s, 1H), 7.41-7.55 (m, 5H), 7.08-7.19 (m, 5H), 6.7 (bs, 2H), 6.16 (s, 2H), 4.63 (m, 1H), 3.12-3.55 (m, 5H), 2.85 (s, 3H), 2.27 (m, 2H), 1.99-2.05 (m, 4H), 1.67-1.75 (m, 2H); RP-HPLC (HypersilCPS, 5 μ m, 100A, 250 * 4.6mm; 25-100% acetonitrile-0.1M ammonium acetate
10min, 1ml/min) t r=8.6min; MS:MH +471. embodiment 225: cis-7-(4-{[3-(1H-1-imidazolyl) propyl group] amino } cyclohexyl)-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine three maleate are trans-7-(4-{[3-(1H-1-imidazolyl) propyl group] amino } cyclohexyl)-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine 2-maleate embodiment 227: cis-7-(4-{[3-(1H-1-imidazolyl) propyl group] amino } cyclohexyl)-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine three maleate 1H NMR (DMSO-d 6, 400MHz) δ 8.78 (bs, 1H), 8.48 (bs, 2H), 8.18 (s, 1H), 7.66 (s, 1H), 7.55 (s, 1H), and 7.41-7.49 (m, 5H), 7.08-7.19 (m, 5H), 6.33 (bs, 2H), 6.12 (s, 6H), 4.78 (m, 1H), 4.27 (t, 2H), 2.99 (m, 3H), 1.8-2.25 (m, 10H); RP-HPLC (Hypersil CPS, 5 μ m, 100A, 250 * 4.6mm; 25-100% acetonitrile-0.1M ammonium acetate 10min, 1ml/min) t r=9.07min; MS:MH +508 embodiment 228: trans-7-(4-{[3-(1H-1-imidazolyl) propyl group] amino } cyclohexyl)-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine 2-maleate
1H NMR (DMSO-d 6, 400MHz) δ 8.76 (bs, 1H), 8.51 (bs, 2H), 8.18 (s, 1H), 7.66 (s, 1H), 7.55 (s, 1H), 7.40-7.47 (m, 5H), 7.08-7.21 (m, 5H), 6.3 (bs, 2H), 6.11 (s, 4H), 4.60 (m, 1H), 4.26 (t, 2H), 3.14 (m, 1H), 2.97 (m, 2H), and 1.9-2.25 (m, 8H), 1.53-1.61 (m, 2H); RP-HPLC (Hypersil CPS, 5 μ m, 100A, 250 * 4.6mm; 25-100% acetonitrile-0.1M
Ammonium acetate 10min, 1ml/min) t r=8.72min; MS:MH +508. embodiment 229: cis-7-[4-(dimethylamino) cyclohexyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4 amine 2-maleate:
1H NMR (DMSO-d 6, 400MHz) δ 9.06 (bs, 1H), 8.2 (s, 1H), 7.41-7.50 (m, 5H), 7.08-7.19 (m, 5H), 6.4 (bs, 2H), 6.13 (s, 4H), 4.83 (m, 1H), 3.34 (m, 1H), 2.88 (s, 6H), 2.10-2.17 (m, 4H), 1.88-1.99 (m, 4H); RP-HPLC (Hypersil HS C-18,5 μ m, 100A, 250 * 4.6mm; 25-100% acetonitrile-0.1M ammonium acetate 10min, 1ml/min) t r=7.38 min; MS:MH +428. embodiment 230: trans-5-(4-Phenoxyphenyl)-7-(4-piperidyl cyclohexyl)-7H-pyrrolo-[2,3-d] pyrimidine-4 amine 2-maleate:
1H NMR (DMSO-d 6, 400MHz) δ 8.92 (bs, 1H), 8.18 (s, 1H), 7.4-7.5 (m, 5H), 7.08-7.19 (m, 5H), 6.3 (bs, 2H), 6.13 (s, 4H), 4.63 (m, 1H), 3.15-3.5 (m, 3H), 2.9-3.1 (m, 2H), 1.16-2.18 (m, 14H); RP-HPLC (Hypersil HS C-18,5 μ m, 100A, 250 * 4.6mm; 25-100% acetonitrile-0.1M ammonium acetate 10min, 1ml/min) t r=7.98min; MS:MH +468. trans-5-(4-Phenoxyphenyl)-7-(4-tetrahydrochysene-1H-1-pyrryl cyclohexyl)-7H-pyrrolo-[2,3-d] pyrimidine-4 amine 2-maleate:
1H NMR (DMSO-d 6, 400MHz) δ 9.54 (bs, 1H), 5.18 (s, 1H), 7.40-7.47 (m, 5H), 7.08-7.18 (m, 5H), 6.3 (bs, 1H), 6.12 (s, 4H), 4.63 (m, 1H), 3.1-3.55 (m, 5H), 2.24 (m, 2H), 2.00 (m, 6H), 1.86 (m, 2H), 1.67 (m, 2H); RP-HPLC (Hypersil HS C-18,5 μ m, 100A, 250 * 4.6mm; 25-100% acetonitrile-0.1M ammonium acetate 10min, 1ml/min) t r=7.82 min; MS:MH +454. embodiment 231: cis-7-[4-(4-methyl isophthalic acid, 4-diaza azepines-1-yl) cyclohexyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4 amine dihydrochloride is trans-7-[4-(4-methyl isophthalic acid, 4-diaza azepines-1-yl) cyclohexyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4 amine dihydrochloride
Cis-7-[4-(4-methyl isophthalic acid, 4-diaza azepines-1-yl) cyclohexyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4 amine dihydrochloride
1H NMR (DMSO-d 6, 400MHz) δ 11.7 (d, 1H), 11.38 (d, 1H), 8.57 (s, 1H), 8.34 (d, 1H), 7.42-7.51 (m, 4H), 7.03-7.20 (m, 5H), 4.93 (m, 1H), 4.7 (bs, 2H), 3.4-3.99 (m, 9H), 2.8 (s, 3H), 1.86-2.57 (10H); RP-HPLC (Hypersil HS C-18,5 μ m, 100A, 250 * 4.6mm; 25-100% acetonitrile-0.1M ammonium acetate 10min, 1ml/min) t r=7.67min; MS:MH +Trans-7-[4-497. (4-methyl isophthalic acid, 4-diaza azepines-1-yl) cyclohexyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4 amine dihydrochloride
1H NMR (DMSO-d 6, 400MHz) δ 11.94 (d, 1H), 11.52 (d, 1H), 8.56 (s, 1H), 7.8 (s, 1H), 7.42-7.51 (m, 4H), 7.10-7.20 (m, 5H), 4.76 (1H, m)＜3.2-4.0 (m, 9H), 2.80 (s, 3H), 1.78-2.4 (m, 10H); RP-HPLC (Hypersil HS C-18,5 μ m, 100A, 250 * 4.6mm; 25-100% acetonitrile-0.1M ammonium acetate 10min, 1ml/min) t r=7.42min; MS:MH +Embodiment 232: cis-5-(4-Phenoxyphenyl)-7-(4-piperazinyl ring hexyl)-7H-pyrrolo-[2,3-d] pyrimidine-4 amine three maleate are trans-5-(4-Phenoxyphenyl)-7-(4-piperazinyl ring hexyl)-7H-pyrrolo-[2,3-d] pyrimidine-4 amine three maleate a) cis and trans 4-{4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] cyclohexyl }-1-piperazine carboxylic acid tertiary butyl ester embodiment 233: cis 4-{4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] cyclohexyl }-1-piperazine carboxylic acid tertiary butyl ester
1H NMR (DMSO-d 6, 400MHz) δ 8.14 (s, 1H), 7.3-7.5 (m, 6H), 7.077.16 (m, 5H), 6,1 (bs, 2H), 4.69 (m, 1H), 3.2-3.4 (4H, m), 2.38 (m, 4H), 2.0-2.25 (m, 5H), 1.5-1.8 (m, 4H), 1.41 (s, 9H); RP-HPLC (Hypersil HS C-18,5 μ m, 100A, 250 * 4.6mm; 25-100% acetonitrile-0.1M ammonium acetate 10min, 1ml/min) t rThe trans 4-{4-[4-amino-5-of=13.60min. (4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] cyclohexyl }-1-piperazine carboxylic acid tertiary butyl ester
1H NMR (DMSO-d 6, 400MHz) δ 8.13 (s, 1H), 7.40-7.47 (m, 6H), 7.08-7.16 (m, 5H), 6.1 (bs, 2H), 4.55 (m, 1H), 3.34 (m, 4H), 2.35-2.51 (m, 3H), 1.89-1.99 (m, 6H), 1.38-1.49 (m, 4H), 1.39 (s, 9H); RP-HPLC (Hypersil HS C-18,5 μ m, 100A, 250 * 4.6mm; 25-100% acetonitrile-0.1M
Ammonium acetate 10min, 1ml/min) t r=10.40min.b) cis-5-(4-Phenoxyphenyl)-7-(4-piperazinyl ring hexyl)-7H-pyrrolo-[2,3-d] pyrimidine-4 amine three maleate
With cis 4-{4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] cyclohexyl }-1-piperazine carboxylic acid tertiary butyl ester (1.85g, 3.27mmol) handle with 20% trifluoroacetic acid/dichloromethane solution (60ml), and stirring at room 30 minutes.Removal of solvent under reduced pressure is distributed in resistates between methylene dichloride (200ml) and the saturated sodium bicarbonate aqueous solution (30ml).The organic solution dried over mgso is filtered, and filtrate is evaporated to resistates (1.55g).(1.0g 2.15mmol) is dissolved in warm ethyl acetate (220ml), and (0.75g 0.44mmol) handles in warm ethyl acetate (75ml) to use toxilic acid then with a collection of this thing.Make mixture be cooled to room temperature, solid collected by filtration is also dry then, provides cis-5-(4-Phenoxyphenyl)-7-(4-piperazinyl ring hexyl)-7H-pyrrolo-[2,3-d] pyrimidine-4 amine three maleate (1.15g) white solid:
1H?NMR(DMSO-d 6，400MHz)δ8.5(bs，1H)，8.23(s，1H)，7.41-7.51(m，5H)，7.08-7.19(m，5H)，6.65(bs，2H)，6.16(s，6H)，4.74(m，1H)，1.16-3.2(m，17H)；RP-HPLC(Hypersil?CPS，5μm，100A，250×4.6mm；25-100％
Acetonitrile-0.1M ammonium acetate 10min, 1ml/min) t r=8.63min; MS:MH +469.c) trans-5-(4-Phenoxyphenyl)-7-(4-piperazinyl ring hexyl)-7H-pyrrolo-[2,3-d] pyrimidine-4 amine three maleate
1H NMR (DMSO-d 6, 400MHz) δ 8.22 (s, iH), 7.41-7.51 (m, 5H), 7.08-7.19 (m, 5H), 6.6 (bs, 2H), 6.16 (s, 6H), 4.58 (m, 1H), 1.4-3.2 (m, 17H); RP-HPLC (Hypersil HS C-18,5 μ m, 100A, 250 * 4.6mm; 25-100% acetonitrile-0.1M
Ammonium acetate 10min, 1ml/min) t r=8.08min; MS:MH +469. embodiment 234:7-[3-(4-methylpiperazine base) cyclopentyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4 amine tri hydrochloride
3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] pentamethylene-1-alcohol (2.14g, 0.0055mol) in 11 methylene dichloride, stirred 5 hours with the 12g activated manganese dioxide, filter and fresh Manganse Dioxide (8g) is added in the filtrate.Behind the restir 17 hours, mixture is filtered and directly use.HPLC/MS shows raw material and 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] pentamethylene ketone 62.7%, t r4.38 minute.With dichloromethane solution and 1.0g N methyl piperazine (0.01mol) and acetate (0.6g 0.01mol) stirs 15 minutes together, add then sodium triacetoxy borohydride (0.89g, 0.0042mol).After 2 hours, add the 1.0g N methyl piperazine, 0.6g acetate and 0.89g sodium triacetoxy borohydride, and with mixture stirring 17 hours.Add the 2.0gN-methylpiperazine again, 1.2g acetate and 1.2g sodium triacetoxy borohydride, and stirred 3 days, the mixture that provides is depressurized evaporation.Resistates water (200ml) and 6M hydrochloric acid (50ml) are handled, and alkalize then with ethyl acetate washing (abandoning), and with excessive ammonia.Mixture ethyl acetate extraction, and with extraction liquid drying (sodium sulfate), then by the flash chromatography purifying, with 9: 1 ethyl acetate: ethanol elution, remove impurity, follow with 8: 1: 1 ethyl acetate: ethanol: triethylamine eluted product.Removal of solvent under reduced pressure, resistates is dissolved in ethyl acetate and uses the ethyl acetate solution of toxilic acid to handle, behind 80 ℃ of drying under reduced pressure, provide 7-[3-(4-methylpiperazine base) cyclopentyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] the ethyl acetate 1.4 solvate (0.95g of pyrimidine-4 amine tri hydrochloride (444395), 0.001mol), fusing point 168-170 ℃ (decomposition).Embodiment 235:[4-(4-amino-7-cyclopentyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenyl] (phenyl)-methyl alcohol
(0.052g, (0.1g in tetrahydrofuran (THF) 0.00026mol) (4ml) solution, then adds Amberlyst-15H to (phenyl)-ketone 0.0013mol) to add [4-(4-amino-7-cyclopentyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenyl] with sodium borohydride +Mixture at room temperature stirred filtration over celite pad and removal of solvent under reduced pressure 15 minutes in the nitrogen.Resistates is by preparation property RP-HPLC (Rainin, Hypersil C18,8 μ m, 100A, 25cm; 5%-85% acetonitrile-0.1 ammonium acetate, 20 minutes, 21ml/min) purifying, provide [4-(4-amino-7-cyclopentyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) phenyl] (phenyl)-methyl alcohol (0.005g, 0.000013mol):
1H NMR (DMSO-d 6, 400MHz) δ 8.12 (s, 1H), 7.31 (m, 10H), 6.01 (br, 2H), 5.91 (d, 1H), 5.75 (d, 1H), 5.06 (m, 1H), 2.10 (br, 2H), 1.88 (br, 4H), 1.67 (br, 2H) RP-HPLC (Delta Pak C18,5 μ m, 300A, 15cm; 5%-85% acetonitrile-0.1M
Ammonium acetate 20min, 1mL/min) R t16.74 min.MH +385 embodiment 236: trans-7-[3-(4-methylpiperazine base) cyclohexyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine three maleate
Trans-7-[3-(4-methylpiperazine base) cyclohexyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (1.30g, 0.0027mol) (0.94g, the 0.0081mol) solution-treated in the 100ml ethyl acetate makes its cooling with toxilic acid in the warm ethyl acetate of 300ml.Collect colorless solid, wash with ethyl acetate, be dried to constant weight at 90 ℃/3mbar, provide 1.85g (0.0022mol) trans-7-[3-(4-methylpiperazine base) cyclohexyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] solvate of pyrimidine-4-amine three maleate and 0.18mol ethyl acetate, m.p.189 ℃ (decomposition).Embodiment 237: trans-7-[3-(4-methylpiperazine base) cyclohexyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine tri hydrochloride
Trans-7-[3-(4-methylpiperazine base) cyclohexyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (0.36g, 0.00075mol) solution-treated of usefulness 0.225ml 12M hydrochloric acid (0.0027mol) in the 2ml Virahol in the warm Virahol of 25ml, suspension is heated to boiling simply, and volatile matter is removed in decompression then.The colorless solid that produces is dried to constant weight at 84 ℃/5mbar, provide trans-7-[3-(4-methylpiperazine base) cyclohexyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] solvate (0.25g of pyrimidine-4-amine tri hydrochloride (444626) and 1mol water and 0.25mol Virahol, 0.0004mol), m.p.304-306 ℃ (decomposition).Embodiment 238: cis-7-[3-(4-methylpiperazine base) cyclohexyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine three maleate
Cis-7-[3-(4-methylpiperazine base) cyclohexyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (1.45g, 0.0030mol) in ethyl acetate, handle with 1.05g (0.0091mol) toxilic acid, after 90 ℃/3mbar is dried to constant weight, provide 2.15g cis-7-[3-(4-methylpiperazine base) cyclohexyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] solvate of pyrimidine-4-amine three maleate and 0.14mol ethyl acetate and 0.5mol water (0.0025mol), m.p.186 ℃ (decomposition).Embodiment 239: cis-7-[3-(4-methylpiperazine base) cyclohexyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine tri hydrochloride
Cis-7-[3-(4-methylpiperazine base) cyclohexyl]-(0.80g 0.0017mol) handles with 0.5ml 12M hydrochloric acid (0.006mol) in Virahol 5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine.The solid that produces is filtered, provide cis-7-[3-(4-methylpiperazine base) cyclohexyl]-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine tri hydrochloride water absorbability solid, be dried to constant weight at 80 ℃/3mbar, (0.75g, 0.OO11mol), m.p.224.5-226.5 ℃ (decomposition).Embodiment 240: trans-5-(2-methyl-4-Phenoxyphenyl)-7-[4-(4-methylpiperazine base) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-4-amine three maleate
(2.5g, 0.0136mol) (2.54g, mixture 0.0142mol) stirred 2.5 hours in nitrogen in acetonitrile (20ml) with the N-bromo-succinimide with the 3-phenoxytoluene.Removal of solvent under reduced pressure.Tetracol phenixin is added in the resistates, leach the solid of generation.Filtrate is concentrated, provide 4-bromo-3-methyl phenyl phenyl ether yellow oil (3.5g, 0.0133mol):
1H NMR (chloroform-d, 400MHz) δ 7.45 (d, 1H), 7.33 (m, 2H), 7.12 (t, 1H), 7.00 (d, 2H), 6.89 (s, 1H), 6.71 (d, 1H), 2.34 (s, 3H) RP-HPLC (Hypersil C18,5 μ im, 250 * 4.6mm; 25%-100%over23min with 0.1M ammonium acetate, 1mL/min) R t14.72min.
At 80 ℃, in the nitrogen atmosphere, with 4-bromo-3-methyl phenyl phenyl ether yellow oil (2.0g, 0.00775mol), the mixture of [1,1 '-two (diphenylphosphino) ferrocene] dichloro palladium (II) and methylene dichloride (l: 1) (0.16g, 0.OO019mol) and Potassium ethanoate (1.9g, 0.01938mol) mixture at N, heating is 22 hours in the dinethylformamide (65ml).Make mixture be cooled to room temperature, removal of solvent under reduced pressure.Methylene dichloride is added in the resistates, and the solid of generation is removed by the filtration over celite pad.With filtrate simmer down to black mixture, by quick silica gel column chromatography purifying, make moving phase with ethyl acetate/normal heptane (3: 97), provide 3-methyl-4-(4,4,5,5-tetramethyl--1,3,2-dioxo bora pentamethylene-2-yl) phenyl ether (1.05g, 0.00338mol);
1H NMR (chloroform-d, 400MHz) δ 7.73 (d, 1H), 7.33 (m, 2H), 7.08 (t, 1H), 7.01 (d, 2H), 6.79 (d, 2H), 2.51 (s, 3H), 1.34 (s, 12H) TLC (ethyl acetate/n-heptane=3: 97) R f0.28 with 4-chloro-7-(1,4-dioxo spiro [4.5] last of the ten Heavenly stems-8-yl)-5-iodo-7H-pyrrolo-[2,3-d] (20g, 47.7mmol) (60ml, 360mmol) mixture in tetrahydrofuran (THF) and acetone (600ml) at room temperature stirred 17 hours in nitrogen atmosphere pyrimidine with 6N HCl (aq).Removal of solvent under reduced pressure, with 6N HCl (aq) (20ml), tetrahydrofuran (THF) (60ml), acetone (300ml) adds in the mixture.Mixture stirred in nitrogen atmosphere 4.5 hours in room temperature.Removal of solvent under reduced pressure, yellow residue washes with water, provide 4-(4-chloro-5-iodo-7H-pyrrolo-[2,3-d] pyrimidin-7-yl)-1-hexanaphthene ketone (12.3g, 32.7mmol).RP-HPLC (Hypersil C18,5 μ m, 250 * 4.6mm; 25%-100%, 15 minutes, 0.05M ammonium acetate, 1ml/min) R t10.20min.
With 4-(4-chloro-5-iodo-7H-pyrrolo-[2,3-d] pyrimidin-7-yl)-1-hexanaphthene ketone (5.6g, 14.9mmol), N methyl piperazine (3.3ml, 29.8mmol), acetate (2.6ml, 44.7mmol), and trimethyl orthoformate (9.9ml, 89.4mmol) mixture in ethylene dichloride (100ml) in nitrogen in stirring at room 1 hour.With sodium triacetoxy borohydride (14.2g 67.05mmol) adds in the mixture, and in nitrogen in stirring at room 18 hours.Removal of solvent under reduced pressure.Resistates is distributed between saturated sodium bicarbonate aqueous solution and the ethyl acetate.Water is further used ethyl acetate extraction, the organic extract liquid dried over sodium sulfate of merging.Removal of solvent under reduced pressure, resistates is by quick silica gel column chromatography purifying, with triethylamine/methylene dichloride (2: 98), then make moving phase with methyl alcohol/triethylamine/methylene dichloride (2: 3: 95), provide trans-4-chloro-5-iodo-7-[4-(4-methylpiperazine base) cyclohexyl]-7H-pyrrolo-[2,3-d] and pyrimidine (1.7g, 3.7mmol).
1H NMR (DMSO-d 6, 400MHz) 8.63 (s, 1H), 8.12 (s, 1H), 4.63 (br, 1H), 2.15 (s, 3H), 1.94 (br, 6H), 1.45 (br, 2H) RP-HPLC (Hypersil C18,5 μ m, 250 * 4.6mm; 25%-100% 15 min with 0.05 M ammonium acetate, 1mL/min) Rt6.17 min.
In forcer with trans-4-chloro-5-iodo-7-[4-(4-methylpiperazine base) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine (0.89g, 1.9mmol) in dense ammonium hydroxide (40ml) and dioxan (40ml) in 120 ℃ the heating 18 hours.Make mixture be cooled to room temperature, removal of solvent under reduced pressure.Resistates is distributed between saturated sodium bicarbonate aqueous solution and the ethyl acetate.Water is used ethyl acetate extraction again, the salt water washing of the organic extract liquid of merging, dried over sodium sulfate.Removal of solvent under reduced pressure provides trans-5-iodo-7-[4-(4-methylpiperazine base) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (0.35g, 0.8mmol).RP-HPLC (Hypersil C18,5 μ m, 250 * 4.6mm; 25%-100%, 15 minutes, 0.1M ammonium acetate, 1ml/min) R t4.01min.MS:MH +441
With trans-5-iodo-7-[4-(4-methylpiperazine base) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (0.347g, 0.000788mol), 3-methyl-4-(4,4,5,5-tetramethyl--1,3,2-dioxo bora pentamethylene-2-yl) phenyl ether (0.27g, 0.000867mol), four (triphenyl phosphine) palladium (0) (0.054g, 0.000047mol), and yellow soda ash (0.209g, 0.00197mol) at N, the mixture in dinethylformamide (15ml) and the water (10ml) heated 16 hours in 80 ℃ in nitrogen atmosphere.Make mixture be cooled to room temperature, removal of solvent under reduced pressure.Resistates is distributed between saturated sodium bicarbonate aqueous solution and the ethyl acetate.Water is used ethyl acetate extraction again, the salt water washing of the organic extract liquid of merging, dried over sodium sulfate.Removal of solvent under reduced pressure, resistates is by quick silica gel column chromatography purifying, with triethylamine/methylene dichloride (5: 95), then methyl alcohol/triethylamine/methylene dichloride (3: 5: 92) is made moving phase, provide trans-5-(2-methyl-4-Phenoxyphenyl)-7-[4-(4-methylpiperazine base) cyclohexyl]-7H-pyrrolo-[2,3-d] and pyrimidine-4-amine (0.367g, 0.000757mol).Make trans-5-(2-methyl-4-Phenoxyphenyl)-7-[4-(4-methylpiperazine base) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (0.367g, 0.000757mol) be dissolved in the ethanol (10ml) of backflow, the toxilic acid (0.264g, ethanol 0.00227mol) (5ml) solution that add preheating.Mixture was refluxed 15 minutes, be cooled to room temperature, filter collecting precipitation, use cold washing with alcohol, dry, provide trans-5-(2-methyl-4-Phenoxyphenyl)-7-[4-(4-methylpiperazine base) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-4-amine three maleate (0.153g, 0.000181mol):
1H NMR (DMSO-d 6, 400MHz) 8.22 (s, 1H), 7.42 (m, 3H), 7.25 (d, 1H), 7.17 (t, 1H), 7.09 (d, 2H), 7.02 (s, 1H), 6.89 (d, 1H), 6.16 (s, 6H), 4.58 (m, 1H), 3.3 (br, 9H), 2.68 (s, 3H), 2.22 (s, 3H), 2.01 (br, 6H), 1.57 (br, 2H) RP-HPLC (HypersilC18,5 μ m, 250 * 4.6mm; 25%-100% 23min with 0.1 M ammonium acetate 1mL/min) R t7.30 min.MS:MH +497 embodiment 241:3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] cyclopentyl 2-Padil ester hydrochloride
With 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] cyclopentanol (50mg, 0.129mmol), the 2-[(tertbutyloxycarbonyl) amino] acetate (34mg, 0.194mmol), 1-[3-(dimethylamino) propyl group]-the 3-ethyl-carbodiimide hydrochloride (31mg, 0.155mmol) and 4-(dimethylamino) pyridine (16mg, 0.129mmol) mixture in DMF (1ml) stirred in nitrogen 24 hours.Mixture is poured in the frozen water.Water layer ethyl acetate extraction three times.The organic layer salt water washing that merges, dried over mgso is filtered and evaporation.Resistates is made moving phase by the rapid column chromatography purifying with ethyl acetate, provides 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] cyclopentyl 2-[(tertbutyloxycarbonyl) amino] acetic ester (39mg, 0.072mmol).HPLC:t r=19.22min. (Delta-Pack, C-18,5 μ m, 300A, 3.9 * 150mm; 5-85% acetonitrile-0.1M ammonium acetate, 20 minutes, 1ml/min)
With 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] cyclopentyl 2-[(tertbutyloxycarbonyl) amino] (39mg 0.072mmol) is dissolved in ethyl acetate (2.5ml) to acetic ester.Hydrogen chloride gas was fed solution 3 minutes.Reaction mixture restir 30 minutes.Add ether, by filtering collecting precipitation, provide 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl in the nitrogen] cyclopentyl 2-Padil ester hydrochloride (39mg) white solid.
1H?NMR(DMSO-d 6)δ2.20(m，5H)，2.67(m，1H)，3.83(s，2H)，5.25(m，1H)，5.31(m，1H)，7.14(m，2H)，7.43，(m，1H)，7.50(m，1H)，7.68(m，1H)，8.26(bs，2H)，8.40(s，1H).LC/MS：MH +＝444，t r＝2.25?min.(Pecospher，3C-18，3um，4.6×33?mm；0-100％
Acetonitrile-0.1 M ammonium acetate 5min, 3.5ml/min) embodiment 242:3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] cyclopentyl N-(2-morpholinyl ethyl) carbamate hydrochloride
(12.5mg, methylene dichloride 0.062mmol) (1ml) solution cools off on ice-water bath with 4-nitroxyl chloride manthanoate.Slowly add the 4-methylmorpholine (7 μ l, 0.062mmol).After 20 minutes, remove ice-water bath, make reaction mixture be warmed to room temperature.Add 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-the 1-cyclopentanol (20mg, 0.052mmol), and with reaction mixture stirring 4 days.Reaction mixture dilutes with methylene dichloride.The organic layer water, saturated sodium bicarbonate, the salt water washing, dried over mgso is filtered and evaporation, provides yellow solid.Methylene dichloride (1ml) solution of this yellow solid is added in 2-morpholine-1-ethamine (0.2ml).After the stirred overnight at room temperature, reaction mixture dilutes with ethyl acetate.Organic layer water (3 times), the salt water washing, dried over mgso is filtered and evaporation.Crude product provides 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl by the HPLC purifying] and cyclopentyl N-(2-morpholinyl ethyl) carbamate (17mg, 0.021mmol).
1H NMR (CDCl 3-d) δ 2.08 (m, 4H), 2.43 (m, 7H), 2.73 (m, 1H), 3.29 (m, 2H), 3.67, (m, 4H), 5.28 (m, 5H), 7.09 (m, 6H), 7.40 (m, 4H), 8.30 (s, 1H) .LC/MS:MH +=543, t r=2.13 min. (Pecospher, 3C-18,3um, 4.6 * 33mm; 0-100% acetonitrile-0.1 M ammonium acetate 5 min, 3.5ml/min).
With 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] (10mg 0.0184mmol) is dissolved in ethyl acetate (2.5ml) to cyclopentyl N-(2-morpholinyl ethyl) carbamate.Hydrogen chloride gas was fed solution 3 minutes.Reaction mixture restir 30 minutes.Add ether, by filtering collecting precipitation, provide 3-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl in the nitrogen] cyclopentyl N-(2-morpholinyl ethyl) carbamate hydrochloride white solid.
1H NMR (DMSO-d 6:) δ 1.99 (m, 4H), 2.55 (m, 2H), 3.32 (m, 12H), 5.08 (m, 1/2H), 5.19 (m, 1/2H), 7.16 (m, 5H), 7.45, (m, 5H), 8.26 (s, 1H) .LC/MS:MH +=543, t r=2.16 min. (Pecospher, 3C-18,3um, 4.6 * 33mm; 0-100% acetonitrile-0.1 M ammonium acetate 5 min, 3.5ml/min). embodiment 243:4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] hexalin
Stir down sodium borohydride (500mg, 13mmol)-and inferior adding 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] (780mg is in methyl alcohol 2.0mmol) (500ml) solution for hexamethylene-1-ketone, mixture stirred in nitrogen 1 hour, placed then and spent the night.Removal of solvent under reduced pressure, resistates are distributed between 2M aqueous sodium hydroxide solution (100ml) and the methylene dichloride (100ml).Tell organic layer, water layer is used methylene dichloride (2 * 100ml) extractions again.Organic extract liquid water (150ml) washing that merges, the salt of wormwood drying, by using Biotage 40S column chromatography purification, make moving phase with ethyl acetate/triethylamine (98: 2 to 95: 5) and ethyl acetate/ethanol (95: 5), provide 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] the hexalin white solid (750mg, 1.9mmol), fusing point: 199-200 ℃.LC/MS:Hypersil BDS c18 (100 * 2.1mm) 0.1M ammonium acetate/acetonitriles, 10-100% acetonitrile, 8 minutes) MH +401, t r=4.12 minutes.Embodiment 244N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] the carboxylamine phenylester
(100mg 0.294mmol) is dissolved in methylene dichloride (2ml) with 4-(4-amino-3-p-methoxy-phenyl)-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine.Add pyridine (2ml), then add the chloroformic acid phenylester (44 μ l, 0.353mmol).Stir after 3 minutes, add 44 μ l phenyl methanesulfonamide acyl chlorides again, reaction mixture is stirred and spends the night.Remove and desolvate, resistates provides N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl by preparation property LC/MS purifying] and the carboxylamine phenylester (52mg, 0.113mmol).
1H NMR (CDCl 3-d) δ 2.09 (m, 4H), 3.66 (m, 2H), 3.98 (s, 3H), 4.16 (m, 2H), 4.98 (m, 1H), 5.24 (s, 2H), 7.09 (m, 3H), 7.23 (m, 4H), 7.41 (m, 2H), 7.62 (s, 1H), 8.20 (bd, J=7.80 Hz, 1H), 8.33 (s, 1H) .LC/MS MH +=460. embodiment 245 tetrahydrochysenes-2H-4-pyranyl N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] carbamate 4-nitrophenyl tetrahydrochysene-2H-4-pyranyl carbonic ether
(1.0ml 10.5mmol) mixes in methylene dichloride (20ml) with 4-methylmorpholine (2.0ml) with tetrahydrochysene-2H-4-pyrans alcohol.Slowly add in the reaction mixture 4-nitroxyl chloride manthanoate (1.98g, 9.82mmol).Stir after 5 hours, reaction mixture dilutes with methylene dichloride.The organic layer water, 1.0N HCl, saturated sodium bicarbonate, the salt water washing, dried over mgso is filtered and evaporation.Crude product is made moving phase with ethyl acetate/heptane (4: 1) by quick purification by silica gel column chromatography, provide 4-nitrophenyl tetrahydrochysene-2H-4-pyranyl carbonic ether (1.5g, 5.62mmol).1H NMR (CDCl 3-d) δ 1.87 (m, 2H), 2.06 (m, 2H), 3.58 (m, 2H), 3.98 (m, 2H), 4.97 (m, 1H), 7.40 (d, J=9.0Hz, 2H), 8.30 (d, J=9.0Hz, 2H) .a) N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] carboxylamine tetrahydrochysene-2H-4-pyranyl ester
With 5-(4-amino-3-p-methoxy-phenyl)-7H-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (57mg, 0.168mmol) and 4-nitrophenyl tetrahydrochysene-2H-4-pyranyl carbonic ether (90mg, 0.336mmo1) mixing in pyridine (1ml).Stir after 5 hours, add other 90mg 4-nitrophenyl tetrahydrochysene-2H-4-pyranyl carbonic ether, reaction mixture is stirred 2 days.Reaction mixture was 70 ℃ of heating 2 hours.Remove and desolvate, resistates is by the preparation of lamina chromatogram purification, provide N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] and carboxylamine tetrahydrochysene-2H-4-pyranyl ester (30mg, 0.064mmol).
1H NMR (CDCl 3-d) δ 1.78 (m, 4H), 2.08 (m, 4H), 3.60 (m, 4H), 3.94 (s, 3H), 3.97 (m, 2H), 4.15 (m, 2H), 4.98 (m, 2H), 5.23 (s, 2H), 6.78 (s, 1H), 7.04 (s, 1H), 7.07 (d, J-8.3 Hz, 1H), 8.16 (bd, J=7.90 Hz, 1H), 8.33 (s, 1H) .LC/MS MH +=468. embodiment 246:N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] a) (3-picolyl) carbonic acid 4-nitrophenyl ester of carboxylamine 3-picolyl ester hydrochloride
(2.49g, methylene dichloride 12.3mmol) (20ml) solution cools off in ice-water bath with 4-nitroxyl chloride manthanoate.Slowly add 3-pyridyl methyl alcohol (1.0ml, 10.3mmol) and the 4-methylmorpholine (2.0ml, 18.5mmol).After 20 minutes, remove ice-water bath, make reaction mixture be warmed to room temperature.After 30 minutes, add ethyl acetate and reaction mixture is filtered.Filtrate water, saturated sodium bicarbonate, the salt water washing, dried over mgso, filter and evaporation provide (3-picolyl) carbonic acid 4-nitrophenyl ester (1.52g, 5.54mmol).
1H NMR (CDCl-d) δ 7.38 (m, 3H), 7.79 (m, 1H), 8.28 (d, J=9.09Hz, 2H), 8.65 (m, 1H), (8.72 s, 1H) .b) N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] carboxylamine 3-picolyl ester
(25mg 0.074mmol) is dissolved in methylene dichloride (0.7ml) with 5-(4-amino-3-p-methoxy-phenyl)-7H-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine.Add pyridine (0.7ml) then add 4-nitrophenyl (3-picolyl) carbonic ether (30mg, 0.110mmol).After 100 ℃ of heated overnight, remove and desolvate, resistates provides N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2 by preparation property LC/MS purifying, 3-d] pyrimidine-5-yl)-the 2-p-methoxy-phenyl] and carboxylamine 3-picolyl ester (12mg, 0.025mmol).1H?NMR(CDCl 3-d)δ2.08(m，
4H)，3.65(m，2H)，3.92(s，3H)，4.15(m，2H)，4.96(m，1H)，5.26(s，2H)，5.54(bs，
2H)，6.97(s，1H)，7.04(s，1H)，7.08(d，J＝8.2Hz，1H)，7.35(m，2H)，7.79(d，
J＝7.8Hz，1H)，8.15(m，1H)，8.29(s，1H)，8.61(s，1H)，8.71(s，1H).LC/MS
MH +=475c) N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] carboxylamine 3-picolyl ester hydrochloride
With N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] (12mg 0.025mmol) is dissolved in ethyl acetate (2.0m1) to carboxylamine 3-picolyl ester.Ether (1ml) solution that slowly adds 1.0N HCl.In nitrogen, filter collecting precipitation, provide N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] and carboxylamine 3-picolyl ester hydrochloride (13mg, 0.25mmol).1H?NMR(DMSO-d 6)
δ1.91(m，2H)，2.17(m，2H)，3.54(m，2H)，3.87(s，3H)，4.03(m，2H)，4.97(m，1H)，
5.23(s，2H)，7.05(d，J＝8.2Hz，1H)，7.13(s，1H)，7.51(m，1H)，7.81(d，J＝8.2Hz，
1H)，7.84(s，1H)，7.95(m，1H)，8.42(s，1H)，8.60(s，1H)，8.71(s，1H)，8.82(s，1H).
LC/MS MH +=475. embodiment 247:N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] carboxylamine 2-morpholino ethyl ester hydrochloride
With N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] (25mg 0.054mmol) mixes with 2-morpholine-1-ethanol (0.1ml) in pyridine (0.7m1) the carboxylamine phenylester.With reaction mixture 100 ℃ of heated overnight.Remove and desolvate, resistates is by preparation property anti-phase HPLC purifying, provide N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] and carboxylamine 2-morpholino ethyl ester hydrochloride (24mg, 0.048mmol).
1H?NMR(DMSO-
d 6)δ1.88(m，2H)，2.16(m，2H)，3.55(m，8H)，3.90(s，3H)，4.03(m，4H)，4.49(m，
2H)，4.92(m，1H)，7.07(m，1H)，7.15(s，1H)，7.65(bs，2H)，7.84(s，1H)，8.45(s，
1H), 8.75 (s, 1H) 10.95 (bs, 1H) .LC/MS MH +=497. embodiment 248:N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] carboxylamine (4-bromo-1,3-thiazoles-5-yl) methyl ester a) 2,4-two bromo-1,3-thiazoles-5-formaldehyde
With 1,3-thiazoles-2, (3.52g, 30mmol) (43g, 150mmol) (2.56ml 34mmol) mixes the 4-diketone with dimethyl formamide with tribromo oxygen phosphorus.Then mixture was heated 1 hour at 75 ℃, and 100 ℃ of heating 5 hours.After being cooled to room temperature, mixture is added in the frozen water (500ml) the water layer dichloromethane extraction.The organic layer that merges washs with saturated sodium bicarbonate, and dried over mgso is filtered and evaporation the brown solid petroleum ether that provides.Evaporating solvent provides 2, and 4-two bromo-1,3-thiazoles-5-formaldehyde (1.74g, 6.42mmol).1H?NMR(CDCl 3-d)δ9.90(S，1H)。B) (2,4-two bromo-1,3-thiazoles-5-yl) methyl alcohol
With 2, (1.74g 6.42mmol) is dissolved in methyl alcohol (70ml) at 0 ℃ to 4-two bromo-1,3-thiazoles-5-formaldehyde.With short run add sodium borohydride (0.244g, 6.42mmol).Remove ice-water bath after 10 minutes, and with mixture in stirred overnight at room temperature.Remove and desolvate, and add saturated ammonium chloride.Add 1.0N sodium hydroxide with pH regulator to 10.The water layer ethyl acetate extraction.The organic layer salt water washing that merges, dried over mgso is filtered and evaporation.Resistates is by the rapid column chromatography purifying, provide (2,4-two bromo-1,3-thiazoles-5-yl) methyl alcohol (0.946g, 3.47mmol).1H NMR (CDCl 3-d) δ 2.11 (bs, 1H), 4.79 (S, 2H) c) (4-bromo-1,3-thiazoles-5-yl) methyl alcohol
Make (2,4-two bromo-1,3-thiazoles-5-yl) methyl alcohol (0.94g, 3.44mmol), yellow soda ash trihydrate (1.34g) and Pd/C (10%, 0.07g) in methyl alcohol (33ml), mix.The mixture that produces was 60psi hydrogenation 2 days.Solid is filtered through Celite pad.Evaporating solvent, resistates be by the rapid column chromatography purifying, provide (4-bromo-1,3-thiazoles-5-yl) methyl alcohol (0.32g, 2.78mmol).1H?NMR(CDCl 3-d)δ2.29(bs，1H)，4.86(S，2H)，8.72(s，1H)。D) N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] carboxylamine (4-bromo-1,3-thiazoles-5-yl) methyl ester
With N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-the 2-p-methoxy-phenyl] carboxylamine phenylester (28mg, 0.061mmol) (50mg 0.434mmol) mixes with (4-bromo-1,3-thiazoles-5-yl) methyl alcohol in pyridine (0.5ml).With reaction mixture 100 ℃ of heated overnight.Remove and desolvate, resistates provides N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl by preparation property anti-phase LC/MS purifying] carboxylamine (4-bromo-1,3-thiazoles-5-yl) methyl ester.1H NMR (CDCl-d) δ 2.07 (m, 4H), 3.65 (m, 2H), 3.92 (s, 3H), 4.13 (m, 2H), 4.98 (m, 1H), 5.35 (s, 1H), 5.40 (s, 2H), 6.97 (s, 1H), 7.04 (s, 1H), 7.09 (m, 1H), 7.35 (s, 1H), 8.17 (s, 1H), 8.32 (s, 1H), 8.78 (s, 1H) .LC/MSMH +=481. embodiment 249:N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] carboxylamine tetrahydrochysene-3-furyl ester
With N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] (30mg 0.065mmol) mixes with tetrahydrochysene-3-furfuralcohol (0.05ml) in pyridine (0.5ml) the carboxylamine phenylester.With reaction mixture 100 ℃ of heated overnight.Remove and desolvate, resistates provides N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl by preparation property anti-phase HPLC purifying] and carboxylamine tetrahydrochysene-3-furyl ester (14mg, 0.031mmol).
1H NMR (CDCl-d) δ 2.07 (m, 6H), 3.66 (m, 2H), 3.96 (m, 7H), 4.13 (m, 2H), 4.98 (m, 1H), 5.26 (s, 2H), 5.40 (m, 1H), 6.97 (s, 1H), 7.04 (s, 1H), 7.08 (d, J=8.2Hz, 1H), 7.26 (s, 1H), 8.30 (s, 1H), 8.32 (s, 1H) .LC/MS MH +=455. embodiment 250:N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] carboxylamine 1,3-dioxan-5-base ester
N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] carboxylamine 1,3-dioxolane-4-ylmethyl ester
With N-[4-(4-amino-7-hydrogen-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] (30mg 0.065mmol) mixes with Sericosol N (0.05ml) in pyridine (0.5ml) the carboxylamine phenylester.With reaction mixture 100 ℃ of heated overnight.Remove and desolvate, resistates provides N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl by preparation property anti-phase HPLC purifying] carboxylamine 1,3-dioxan-5-base ester (2mg, 0.004mmol).
1H NMR (CDCl-d) δ 2.06 (m, 4H), 3.66 (m, 2H), 3.92 (m, 3H), 4.07 (m, 6H), 4.79 (m, 1H), 4.83 (d, J=6.3Hz, 1H), 4.96 (m, 1H), 5.04 (d, J=6.3Hz, 1H), 6.15 (vbs, 2H), 6.96 (s, 1H), 7.05 (m, 2H), 7.53 (s, 1H), 8.15 (d, J=8.2Hz, 1H), 8.22 (s, 1H) .LC/MS MH +=471 and N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] carboxylamine 1,3-dioxolane-4-ylmethyl ester (6.0mg, 0.013mmol).1H NMR (CDCl-d) δ 2.06 (m, 4H), 3.66 (m, 2H), 3.75 (m, 1H), 3.92 (m, 3H), 4.03 (m, 1H), 4.13 (m, 1H), 4.34 (m, 2H), 4.94 (s, 1H), 4.97 (m, 1H), 5.10 (s, 1H), 5.32 (bs, 2H), 6.97 (s, 1H), 7.03 (m, 2H), 7.06 (d, J=8.2Hz, 1H), 7.38 (s, 1H), 8.15 (d, J=7.9Hz, 1H), 8.31 (s, 1H) .IC/MS MH +=471. embodiment 251:N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine 2-picolyl ester hydrochloride
With N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] (30mg 0.065mmol) mixes with 2-pyridyl methyl alcohol (0.05ml) in pyridine (0.5ml) the carboxylamine phenylester.With reaction mixture 100 ℃ of heated overnight.Remove and to desolvate, resistates is by preparation property anti-phase LC/MS purifying, provide N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine 2-picolyl ester (11mg, 0.023mmol).Solid is dissolved in ethyl acetate (2ml), slowly adds ether (0.1ml) solution of 1.0N HCl.In nitrogen, filter collecting precipitation, provide N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine 2-picolyl ester hydrochloride (12mg, 0.023mmol).
1H?NMR(DMSO-d 6)δ1.92(m，2H)，2.16(m，2H)，3.55(m，2H)，3.89
(s，3H)，4.02(m，2H)，4.91(m，1H)，5.23(s，2H)，7.05(d，J＝8.2Hz，1H)，7.14(s，
1H)，7.37(m，1H)，7.53(d，J＝7.8Hz，1H)，7.87(m，3H)，8.42(s，1H)，8.57(d，
J=4.2Hz, 1H), 8.85 (s, 1H) .LC/MS MH +=475. embodiment 252:N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine 4-picolyl ester hydrochloride
With N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] (30mg 0.065mmol) mixes with 4-pyridyl methyl alcohol (0.05ml) in pyridine (0.5ml) the carboxylamine phenylester.With reaction mixture 100 ℃ of heated overnight.Remove and to desolvate, resistates is by preparation property anti-phase LC/MS purifying, provide N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine 4-picolyl ester (11mg, 0.023mmol).Solid is dissolved in ethyl acetate (2ml), slowly adds ether (0.1ml) solution of 1.0N HCl.In nitrogen, filter collecting precipitation, provide N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine 4-picolyl ester hydrochloride (12mg, 0.023mmol).1H?NMR(DMSO-
d 6)δ1.91(m，2H)，2.16(m，2H)，3.55(m，2H)，3.90(s，3H)，4.03(m，2H)，4.92(m，
1H)，5.34(s，2H)，7.06(d，J＝8.2Hz，1H)，7.16(s，1H)，7.73(m，1H)，7.81(m，1H)，
7.87 (s, 1H), 8.46 (s, 1H), 8.76 (d, J=5.6Hz, 1H), 9.05 (s, 1H) .LC/MS:MH +=475. embodiment 253:N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine (5-methyl-3-isoxazolyl) methyl ester
With N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-the 2-p-methoxy-phenyl] (30mg 0.065mmol) mixes with (5-methyl-3-isoxazolyl) methyl alcohol (0.05ml) in pyridine (0.5ml) the carboxylamine phenylester.With reaction mixture 100 ℃ of heated overnight.Remove and desolvate, resistates is by preparation property anti-phase LC/MS purifying, provide N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine (5-methyl-3-isoxazolyl) methyl ester (18mg, 0.038mmol).1H NMR (CDCl-d) δ 2.06 (m, 4H), 2.44 (s, 3H), 3.64 (m, 2H), 3.91 (s, 3H), 4.13 (m, 2H), 4.96 (m, 1H), 5.26 (s, 2H), 6.12 (s, 1H), 6.95 (s, 1H), 7.06 (m, 2H), 7.39 (s, 1H), 8.17 (bs, 1H), 8.21 (s, 1H) .LC/MS:MH +479. embodiment 254:N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine [(2S)-and 5-oxo tetrahydrochysene-1H-2-pyrryl] methyl ester
With N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-the 2-p-methoxy-phenyl] (30mg 0.065mmol) mixes with (5S)-5-(methylol) tetrahydrochysene-1H-2-pyrrolidone (0.05ml) in pyridine (0.5ml) the carboxylamine phenylester.With reaction mixture 100 ℃ of heated overnight.Remove and desolvate, resistates is by preparation property anti-phase LC/MS purifying, provide N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-the 2-p-methoxy-phenyl) and carboxylamine [(2S)-5-oxo tetrahydrochysene-1H-2-pyrryl] methyl ester (10mg, 0.021mmol).
1H?NMR(C)Cl-d)δ1.90(m，1H)，2.06(m，4H)，2.34(m，1H)，2.41(m，2H)，3.64
(m，2H)，3.94(s，3H)，4.04(m，2H)，4.14(m，2H)，4.98(m，1H)，5.33(m，3H)，
6.10(s，1H)，6.98(s，1H)，7.04(s，1H)，7.09(m，1H)，7.31(s，1H)，8.11(bs，1H)，8.32
(s, 1H) .LC/MS:MH +481. embodiment 255:N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine 4-aminobenzyl ester is N-(4-(methylol) phenyl) carboxylamine tertiary butyl ester a)
With (4-aminophenyl) methyl alcohol (1.23g, 10mmol) and diisopropyl ethyl amine (2.6ml, 15mmol) (2.62g 12mmol) mixes with heavy carbonic di-t-butyl ester in methylene dichloride (50ml).Mixture is in stirred overnight at room temperature.Add ethyl acetate, the organic layer water, 1.0NHCl, saturated sodium bicarbonate, water, the salt water washing, dried over mgso is filtered and evaporation.Crude product is by the rapid column chromatography purifying, with ethyl acetate/heptane (2: 3) wash-out, provide N-(4-(methylol) phenyl) carboxylamine tertiary butyl ester (2.16g, 9.67mmol).
1HNMR (CDCl-d) δ 1.52 (s, 9H), 4.63 (s, 2H), 6.47 (bs, 1H), 7.30 (d, 8.5Hz, 2H), 7.36 (d, 8.5Hz, 2H) .b) N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine 4-aminobenzyl ester
With N-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-the 2-p-methoxy-phenyl] carboxylamine phenylester (51mg, 0.111mmol) (119mg 0.533mmol) mixes with N-(4-(methylol) phenyl) carboxylamine tertiary butyl ester in pyridine (0.8ml).With reaction mixture 100 ℃ of heated overnight.Remove and to desolvate, resistates is by preparation property anti-phase LC/MS purifying, provide N-(4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl) carboxylamine 4-aminobenzyl ester (9mg, 0.015mmol).
1H NMR (CDCl-d) δ 1.52 (s, 1H), 2.08 (m, 4H), 3.65 (m, 2H), 3.90 (s, 3H), 4.14 (m, 2H), 4.97 (m, 1H), 5.17 (s, 2H), 5.37 (bs, 1H), 6.55 (s, 1H), 6.95 (s, 1H), 7.03 (s, 1H), 7.06 (m, 1H), 7.31 (s, 1H), 7.38 (m, 3H), 8.16 (bs, 1H), 8.30 (s, 1H) .LC/MS:MH +589. embodiment 256:N1-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] benzamide
(80mg 0.236mmol) is dissolved in methylene dichloride (2.0ml) with 5-(4-amino-3-p-methoxy-phenyl)-7H-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine.Add pyridine (2.0ml) then add Benzoyl chloride (41 μ L, 0.353mmol).After the stirring at room 2 hours, remove and desolvate, resistates is dissolved in 1mlDMSO, adds methyl alcohol (1ml), forms precipitation.Solid collected by filtration provides N1-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl] and benzamide (64mg, 0.144mmol).
1H?NMR(CDCl 3-d)δ2.12(m，
4H)，3.67(m，2H)，3.99(s，3H)，4.17(m，2H)，4.99(m，1H)，7.03(s，1H)，7.04(s，
1H)，7.14(d，J＝8.2Hz，1H)，7.53(m，3H)，7.94(d，J＝7.8Hz，1H)，8.33(s，1H)，8.58
(s, 1H), 8.63 (d, J=8.2Hz, 1H) .LC/MS:MH +=444 embodiment 257:N2-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl]-the 2-pyridine carboxamide
(80mg 0.236mmol) is dissolved in methylene dichloride (2.0ml) with 5-(4-amino-3-p-methoxy-phenyl)-7H-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine.Add pyridine (2.0ml) then add 2-pyridine formyl chloride hydrochloride (63mg, 0.353mmol).After the stirring at room 2 hours, remove and desolvate, resistates is dissolved in 1ml DMSO, adds methyl alcohol (1ml), forms precipitation.Solid collected by filtration provides N2-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl]-the 2-pyridine carboxamide (84mg, 0.189mmol).
1H NMR (CDCl 3-d) δ 2.12 (m, 4H), 3.67 (m, 2H), 4.03 (s, 3H), 4.14 (m, 2H), 5.00 (m, 1H), 5.37 (s, 1H), 7.04 (s, 1H), 7.09 (s, 1H), 7.14 (d, J=8.2Hz, 1H), 7.50 (m, 1H), 7.92 (m, 1H), 8.33 (s, 1H), 8.70 (d, J=8.2Hz, 1H), 10.62 (s, 1H) .LC/MS:MH +=445. embodiment 258:N5-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl]-1,3-dimethyl-1H-5-pyrazolecarboxamide
(80mg 0.236mmol) is dissolved in methylene dichloride (2.0ml) with 5-(4-amino-3-p-methoxy-phenyl)-7H-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine.Add pyridine (2.0ml) then add 2-pyridine formyl chloride hydrochloride (63mg, 0.353mmol).After the stirring at room 2 hours, remove and desolvate, resistates is dissolved in 1ml DMSO, adds methyl alcohol (1ml), forms precipitation.Solid collected by filtration provides N5-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl]-1,3-dimethyl-1H-5-pyrazolecarboxamide (30mg, 0.065mmol).
1H?NMR(CDCl 3-d)δ2.11(m，4H)，2.32(s，3H)，3.66(m，2H)，3.99(s，3H)，
4.13(m，2H)，4.17(s，3H)，4.99(m，1H)，5.22(bs，2H)，6.46(s，1H)，7.03(s，1H)，
7.07(s，1H)，7.12(d，J＝8.2Hz，1H)，8.33(2，2H)，8.49(d，J＝8.2Hz，1H).LC/MS：
MH +=462. embodiment 259:N1-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl]-2,2-dimethyl propylene acid amides
(50mg 0.147mmol) is dissolved in methylene dichloride (1.5ml) with 5-(4-amino-3-p-methoxy-phenyl)-7H-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine.Add pyridine (1.5ml) and then add 2, and 2-two propionyl chlorides (31mg, 0.221mmol).After the stirring at room 2 hours, remove and desolvate, resistates is dissolved in 1ml DMSO, adds methyl alcohol (1ml), forms precipitation.Solid collected by filtration provides N1-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl]-2,2-dimethyl propylene acid amides (27mg, 0.064mmol).1H?NMR(CDCl 3-
d)δ1.35(s，9H)，2.09(m，4H)，3.66(m，2H)，3.96(s，3H)，4.13(m，2H)，4.97(m，
1H)，5.46(bs，2H)，6.98(s，1H)，7.04(s，1H)，7.07(d，J＝8.2Hz，1H)，8.15(s，1H)，
8.29 (s, 1H), 8.49 (d, J=8.2Hz, 1H) .LC/MS:MH +=424. embodiment 260:N1-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl]-the 1-cyclopentane formamide
(50mg 0.147mmol) is dissolved in methylene dichloride (1.5ml) with 5-(4-amino-3-p-methoxy-phenyl)-7H-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine.Add pyridine (1.5ml) then add 1-pentamethylene formyl chloride (31mg, 0.221mmol).After the stirring at room 2 hours, remove and desolvate, resistates is dissolved in 1ml DMSO, adds methyl alcohol (1ml), forms precipitation.Solid collected by filtration provides N1-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl]-the 1-cyclopentane formamide (33mg, 0.076mmol).
1H NMR (CDCl 3-d) δ 1.66 (m, 2H), 1.81 (m, 2H), 1.95 (m, 4H), 2.06 (m, 4H), 2.77 (m, 1H), 3.65 (m, 2H), 3.94 (s, 3H), 4.15 (m, 2H), 4.96 (m, 1H), 5.37 (bs, 2H), 6.98 (s, 1H), 7.03 (s, 1H), 7.07 (d, J=8.2Hz, 1H), 7.84 (s, 1H), 8.30 (s, 1H), 8.49 (d, J=8.2Hz, 1H) .LC/MS:MH +=437. embodiment 261:N1-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl]-the 1-cyclopentane formamide
(50mg 0.147mmol) is dissolved in methylene dichloride (1.5ml) with 5-(4-amino-3-p-methoxy-phenyl)-7H-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-4-amine.Add pyridine (1.5ml) then add 3-phenyl propionyl chloride (37mg, 0.221mmol).After the stirring at room 2 hours, remove and desolvate, resistates is dissolved in 1ml DMSO, adds methyl alcohol (1ml), forms precipitation.Solid collected by filtration provides N1-[4-(4-amino-7-tetrahydrochysene-2H-4-pyranyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-2-p-methoxy-phenyl]-the 1-cyclopentane formamide (7mg, 0.015mmol).
1H NMR (CDCl 3-d) δ 2.07 (m, 4H), 2.75 (m, 2H), 3.09 (m, 2H), 3.65 (m, 2H), 3.88 (s, 3H), 4.13 (m, 2H), 4.96 (m, 1H), 5.97 (bs, 2H), 6.93 (s, 1H), 7.05 (m, 2H), 7.26 (m, 5H), 7.70 (s, 1H), 8.24 (s, 1H), 8.46 (d, J=8.2Hz, 1H) .LC/MS:MH +The compound of the synthetic embodiment 262-267 of the following technology of=472. usefulness: a) cis-5-(4-amino-3-p-methoxy-phenyl)-7-[4-(4-methylpiperazine base) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (0.25g, 0.575mmol), the mixture of pyridine (2.5ml) and methylene dichloride (2.5ml) is handled with suitable acyl chlorides (0.862mmol), at room temperature stirs 1 hour in nitrogen atmosphere then.Removal of solvent under reduced pressure, resistates is by the reverse chromatogram purification of preparation property.(280mg 0.460mmol) is dissolved in hot ethyl acetate (25ml), and (160mg 1.38mmol) handles, and makes mixture be cooled to room temperature, stirs then 1 hour with the toxilic acid that is dissolved in ethyl acetate (10ml) then with compound.Solid collected by filtration is also dry, provides three maleate (370mg) of compound.
With ((5 μ m 100A) obtain analytical RP-HPLC RT listed in table on 250 * 4.6mm) at the HypersilHSC18 post in 1ml/min in the 25-100% acetonitrile of linear gradient/0.1M ammonium acetate 10 minutes.The residence time, the mass spectrum molecular weight was with " MH with " TR " expression +" expression. Embodiment 262RT 6.62MH+576.3 gradient a
Figure A9981321702202
Embodiment 265RT6.85MH+540.2 gradient a
Figure A9981321702203
Embodiment 263RT 7.7MH+608.2 gradient a Embodiment 266RT 8.15MH+608.2 gradient a Embodiment 264RT 14.23MH+588.3 gradient b
Figure A9981321702206
The general salify technology of embodiment 267RT 8.15MH+642.3:
With trans-N-(4-{4-amino-7-[4-(4-methylpiperazine base) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl-the 2-p-methoxy-phenyl) the carboxylamine benzyl ester is dissolved in ethyl acetate and handles with toxilic acid (280mg).The solid that produces filters also vacuum-drying 4 hours in nitrogen gas stream, provide trans-N-(4-{4-amino-7-[4-(4-methylpiperazine base) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl-the 2-p-methoxy-phenyl) carboxylamine benzyl ester three maleate (580mg) Off-white solid.
M.pt.158 ℃ (dec.) 1H NMR (d 6DMSO, 400 MHz): 8.74 (1H, s), 8.27 (1H, s), 7.78 (1H, d), 7.35-7.77 (5H, m), 7.10 (1H, s), 7.04 (1H, s), 6.16 (6H, s), 5.17 (2H, s), 4.74 (1H, m), 3.82 (3H, s), 3.23 (5H, m), 2.78 (3H, s), 2.51 (3H, m), 2.41 (1H, s), 2.09 (4H, m), 1.70 (4H, m) .HPLC:(5to 95%CH 3CN in 0.1 N ammonium acetate aqueous solution
20min.) t r=13.30 min, 94%. prepare following salt in a similar fashion.The LCMS condition is described below.
LSMS data: Perkin Elmer
Pecosphere?C18，3mM，33
×4.6，3.5?ml/min?100-
100％50mM
Ammonium acetate is to acetonitrile 4.5
Minute
Structure retention time MH +
Figure A9981321702211
2.92 497.1
Figure A9981321702212
3.02 497.2 2.64 481.2
Figure A9981321702214
2.7 481.2 embodiment 268: cis and trans-N1-(4-4-amino-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-base-2-p-methoxy-phenyl)-the 3-Phenylpropionamide
At 0 ℃, past 4-[4-amino-7-[4-(4-methylpiperazine subbase) cyclohexyl in the nitrogen gas stream]-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-1-hexanaphthene ketone (0.8g, 2.3mmol) pyridine/methylene dichloride (1: 2.5,45ml) add hydrocinnamyl chlorine (0.57g, methylene dichloride 3.4mmol) (2ml) solution in the solution.Solution was stirred 2 hours at 0 ℃.(2 * 50ml) wash solution with saturated aqueous citric acid solution with saturated citric acid solution (50ml) cancellation, organic layer.Drying is filtered and is concentrated, and provides brown foams (1.0g).It is dissolved in methylene dichloride (100ml), add N methyl piperazine (0.63g, 6.3mmol) and acetate (0.38g, 6.3mmol).Add sodium triacetoxy borohydride in nitrogen (0.67g, 3.15mmol), compound is in stirred overnight at room temperature in batches.With saturated sodium bicarbonate aqueous solution (50ml) cancellation, and with methylene dichloride (3 * 100ml) extraction.The organic phase that merges is dried in (sodium sulfate), filters also evaporation, and the sludge that provides is by quick purification by silica gel column chromatography, with methylene chloride (100/0 to 50/50 with 5% increment) wash-out.To merge corresponding to very fast effusive fraction, provide cis-N1-(4-4-amino-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-base-2-p-methoxy-phenyl)-3-Phenylpropionamide (0.26g) vitreum.It is dissolved in ethyl acetate (5ml) and adds ethyl acetate (2ml) solution of toxilic acid (160mg).The solid that produces is filtered, and provides cis-N1-(4-4-amino-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-base-2-p-methoxy-phenyl)-3-Phenylpropionamide three maleate (260mg) white solid.Analytical LC/MS condition: post: Pecosphere, C18,3 μ m, 33 * 4.6mm, eluent: 0%B/A to 100%B/A, 4.5 minutes (B: acetonitrile, the A:50mM ammonium acetate buffer, pH 4.5), 3.5mL/min. (r t=2.86mins, 568.4).
To merge corresponding to the fraction of slow effluent, provide trans-N1-(4-4-amino-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-base-2-p-methoxy-phenyl)-3-Phenylpropionamide (0.11g) vitreum.It is dissolved in ethyl acetate (5ml) and adds ethyl acetate (2ml) solution of toxilic acid (68mg).The solid that produces is filtered, and provides trans-N1-(4-4-amino-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-base-2-p-methoxy-phenyl)-3-Phenylpropionamide three maleate (94mg) white solid.Analytical LC/MS condition: post: Pecosphere, C18,3 μ m, 33 * 4.6mm, eluent: 0%B/A to 100%B/A, 4.5 minutes (B: acetonitrile, the A:50mM ammonium acetate buffer, pH4.5), 3.5mL/min. (r t=2.68mins, 568.2).
Figure A9981321702231
With 4-[4-amino-5-(4-amino-3-p-methoxy-phenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-1-hexanaphthene ketone (2.25g, 6.5mmol), acetate (1.17g, 19.5mmol) and N methyl piperazine (1.95g 19.5mmol) is dissolved in methylene dichloride (200ml).Add sodium triacetoxy borohydride (2.07g, 9.75mmol), mixture is in stirred overnight at room temperature in batches.Add saturated sodium bicarbonate aqueous solution (150ml), (3 * 100ml) extract water layer with methylene dichloride.The organic phase that merges washes with water, and dry (sodium sulfate) filters also evaporation, and the semisolid that provides is by quick purification by silica gel column chromatography, with methylene chloride (0% methyl alcohol to 50% methyl alcohol with 5% increment) wash-out.To merge corresponding to very fast effusive fraction, evaporation provides cis-5-(4-amino-3-p-methoxy-phenyl)-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (1.2g, 43%) Off-white solid.
1H?NMR(d 6-DMSO)：δ8.1(1H，s)，7.11(1H，s)，6.87(1H，s)，6.79(1H，d)，6.05(2H，bs)，4.80(2H，bs)，4.64(1H，m)，4.08(1H，m)，3.82(3H，s)，3.17(2H，m)，2.37(6H，m)，2.2?1(3H，s)，2.08(4H，m)，1.70(2H，m)，1.53(2H，m).HPLC(r t＝11.24?min，97.6％).
To merge corresponding to slower effusive fraction, evaporation provides trans-5-(4-amino-3-p-methoxy-phenyl)-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (0.4g, 14%) white solid.
1H?NMR(d 6-DMSO)：δ8.10(1H，s)，7.26(1H，s)，6.87(1H，s)，6.77(1H，d)，6.71(1H，d)，6.05(2H，bs)，4.79(2H，s)，4.52(1H，m)，3.81(3H，s)，3.35(1H，m)，2.50(5H，m)，2.31(5H，m)，2.14(1H，m)，1.97(6H，m)，1.45(2H，m).HPLC(r t＝10.13?min，97.9％).
Toward cis-5-(4-amino-3-p-methoxy-phenyl)-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (30mg, add in pyridine 0.069mmol) (0.5ml) solution suitable acyl chlorides (2eq., 0.138mmol).Container is added a cover, and on orbital vibrator, vibrate and spend the night.(each 1 equivalent) adds other two equivalent acyl chlorides (0.138mmol) in two batches, and the mixture of generation vibrates once more and spends the night.The LCMS of mixture (little mass spectrum-post: Pecosphere, C18,3 μ m, 33 * 4.6mm, eluent: 0%B/A to 100%B/A, 4.5 minutes (B: acetonitrile, the A:50mM ammonium acetate buffer, pH 4.5), 3.5mL/min. is presented at all has product to exist under the used situation.With solution evaporation as for, the resistates of generation is dissolved in the DMF of small volume again, and by reverse preparation HPLC purifying.Its structure and suitable LCMS data provide below in detail.
The compound for preparing embodiment 269 to 293 with the method that is similar to embodiment 268.
Figure A9981321702251
Embodiment 269RT 2.61MH+576.3
Figure A9981321702252
Embodiment 270RT 3.02MH+570.3
Figure A9981321702253
Embodiment 271RT 2.61MH+600.3
Figure A9981321702261
Embodiment 272RT 3.26MH+608.3
Figure A9981321702262
Embodiment 273RT 2.74MH+570.3 Embodiment 274RT 2.78MH+558.4
Figure A9981321702271
Embodiment 275RT 3.00MH+574.3
Figure A9981321702272
Embodiment 276RT 2.76570.3
Figure A9981321702281
Embodiment 277RT 3.26MH+608.3
Figure A9981321702282
Embodiment 278RT 2.94MH+570.3
Figure A9981321702291
Embodiment 279RT 3.13MH+604.3
Figure A9981321702292
Embodiment 280RT 3.16580.3
Figure A9981321702301
Embodiment 281RT 2.68MH+565.3 Embodiment 282RT 2.90MH+585.3
Figure A9981321702311
Embodiment 283RT 2.84MH+585.3
Figure A9981321702312
Embodiment 284RT 2.90MH+576.3
Figure A9981321702321
Embodiment 285RT 2.90MH+584.4 Embodiment 286RT 2.74MH+565.6 Embodiment 287RT 3.06MH+576.3
Figure A9981321702332
Embodiment 288RT 2.53MH+575.3
Figure A9981321702341
Embodiment 289RT 3.32MH+624.3
Figure A9981321702342
Embodiment 290RT 2.85MH+594.4 Embodiment 291RT 2.76MH+592.3 Embodiment 292RT 2.86MH+583.3
Figure A9981321702352
Embodiment 293RT 2.29MH+508.3 embodiment 294-301's is general synthetic: method A
With suitable piperazine (7.60mmol), 4-[4-amino-5-(4-amino-3-p-methoxy-phenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-1-hexanaphthene ketone (2.53mmol), and the mixture of Glacial acetic acid (7.60mmol) in the 50ml methylene dichloride was stirring at room 1.5 hours.Add sodium triacetoxy borohydride (3.28mmol), mixture was stirring at room 16 hours.Add the solution of 1.35g sodium bicarbonate in 50ml, mixture is stirred 1 hour.Tell organic phase, dried over mgso is filtered, and filtrate is concentrated, and provides brown oil.By quick silica gel column chromatography purifying, provide cis and trans-7-[(4-piperazinyl) cyclohexyl]-5-(4-amino-3-p-methoxy-phenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine.Method B
With suitable tetramethyleneimine (7.53mmol), 4-[4-amino-5-(4-amino-3-p-methoxy-phenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-1-hexanaphthene ketone (2.51mmol), and the mixture of Glacial acetic acid (7.35mmol) in the 45ml ethylene dichloride was stirring at room 30 minutes.Add sodium triacetoxy borohydride (3.26mmol), mixture was stirring at room 22 hours.Add the solution of 1.35g sodium bicarbonate in 50ml, mixture is stirred 1 hour.Tell organic phase, dried over mgso is filtered, and filtrate is concentrated, and provides brown oil.By quick silica gel column chromatography purifying, provide cis and trans-7-[(4-pyrrolidyl) cyclohexyl]-5-(4-amino-3-p-methoxy-phenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine.Salify
Toward warm pyrrolopyrimidine (2.48mmol; By top method A or B preparation) ethanolic soln adds in toxilic acid (7.28mmol) ethanolic soln.When being cooled to room temperature, solution forms white precipitate.The solid by filtration that produces is separated, and vacuum-drying provides three required maleate.With the 25-100% acetonitrile of linear gradient/0.1M ammonium acetate 10 minutes (gradient a) or 25 minutes (gradient b) ((5 μ m 200A) obtain analytical RP-HPLC RT listed in table on 250 * 4.6mm) at Hypersil HyPurity Elite C18 post in 1ml/min. Embodiment 294RT 7.967MH+511.1 gradient a
Figure A9981321702372
Embodiment 296RT 13.941MH+497.1 gradient b Embodiment 298RT 14.067MH+497.1 gradient b
Figure A9981321702374
Embodiment 295RT 7.383MH+527.2 gradient a Embodiment 297RT 7.733MH+511.2 gradient a
Figure A9981321702376
Embodiment 299RT 13.891MH+497.1 gradient b
Figure A9981321702377
Embodiment 300RT 14.076MH+497.1 gradient b
Figure A9981321702378
Embodiment 301RT 7.750MH+527.2 gradient a embodiment 302: cis and trans 4-[4-amino-5-(4-amino-3-p-methoxy-phenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-1-hydroxy-cyclohexyl methyl nitrile
(0.649g, tetrahydrofuran (THF) 0.0050mol) (10ml) solution is cooled to 0 ℃ with diisopropylamine.(3.14ml, 0.0050mol) hexane solution keep temperature to be lower than 5 ℃ to drip the 1.6M n-Butyl Lithium.After adding, mixture was stirred 20 minutes at 0 ℃.Make mixture be cooled to-78 ℃, (0.175g 0.0043mol), keeps temperature to be lower than-70 ℃ to add the exsiccant acetonitrile.After adding, mixture was stirred 20 minutes at-78 ℃, add 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-1-pimelinketone (1.000g, 0.0025mmol) tetrahydrofuran (THF) (10ml) and hexamethylphosphoramide (10ml) solution, keep temperature to be lower than-70 ℃.After adding, mixture was stirred 30 minutes at-78 ℃, then stirring at room 18 hours.Mixture is distributed between methylene dichloride and the saturated ammonium chloride (aq).Organic phase water and saturated sodium bicarbonate (aq) washing, dried over mgso.Solvent removed in vacuo, separate cis and trans-isomer(ide) by quick silica gel column chromatography, make eluent with methylene chloride (95: 5), provide the less 4-[4-amino-5-of polarity (4-amino-3-p-methoxy-phenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-1-hydroxy-cyclohexyl methyl nitrile (0.120g, 0.00027mol) and bigger 4-[4-amino-5-(4-amino-3-the p-methoxy-phenyl)-7H-pyrrolo-[2 of polarity, 3-d] pyrimidin-7-yl]-1-hydroxy-cyclohexyl methyl nitrile (0.170g, 0.00038mol): the isomer that polarity is less: 1H NMR (DMSO-d 6, 400MHz) δ 8.13 (s, 1H), 7.48 (d, 2H), 7.41 (t, 2H), 7.37 (s, 1H), 7.15 (t, 1H), 7.093 (d, 2H), 7.088 (d, 2H), 6.11 (b, and 2H) 5.05 (s, 1H), 4.53-4.61 (m, 1H), 2.66 (s, 2H), 2.18 (q, 2H), 1.80 (t, and 4H) 1.66 (t, 2H); RP-HPLC (Delta PakC18,5 μ m, 300A, 15cm; 5%-85% acetonitrile-0.1M ammonium acetate 20min, 1mL/min) R t15.90.MH +440. the isomer that polarity is bigger: (may be trans, aryl-axle, OH-axle) 1H NMR (DMSO-d 6, 400MHz) δ 8.13 (s, 1H), 7.63 (s, 1H), 7.48 (d, 2H), 7.41 (t, 2H), 7.15 (t, 1H), 7.11 (d, 2H), 7.08 (d, 2H), 6.11 (b, and 2H) 5.22 (s, 1H), 4.62-4.67 (m, 1H), 2.98 (s, 2H), 1.82-1.99 (m, 6H), 1.65-1.73 (m, 2H); RP-HPLC (Delta Pak C18,5pm, 300A, 15cm; 5%-85% acetonitrile-0.1M ammonium acetate 20min, 1mL/min) R t15.88.MH +440. embodiment 303: cis-and trans-5-(4-amino-3-fluorophenyl)-7-[4-(4-methylpiperazine base) cyclohexyl]-a) N-(4-bromo-2-fluorophenyl) carboxylamine tertiary butyl ester of 7H-pyrrolo-[2,3-d] pyrimidine-4-amine
Will two (trimethyl silyl) ammonification sodium solutions in 15 minutes in nitrogen (1.0M THF solution, 2.05 equivalents, 270ml, (24.78g is in THF 130.4mmol) (250ml) solution 270mmol) to be added drop-wise to 4-bromo-2-fluoroaniline.After 15 minutes, (1.2 equivalents, 34.12g 156.3mmol) (annotate: observe slight exotherm) to drip heavy carbonic di-t-butyl ester.The reaction very thickness that becomes, 4 hours afterreactions are finished (t.1.c. analyze, with 1: 9 ethyl acetate: heptane was made eluent).To react vacuum concentration, resistates is distributed between ethyl acetate (300ml) and the saturated sodium bicarbonate aqueous solution (150ml).Water layer is used ethyl acetate again, and (2 * 200ml) extractions, the organic layer of merging is dried in (sodium sulfate), concentrating under reduced pressure.By column chromatography purification, with 10% to 15% ethyl acetate: the heptane gradient elution, provide N-(4-bromo-2-fluorophenyl) the light yellow waxy solid of carboxylamine tertiary butyl ester (30.0g, 79%), 1H NMR (400 MHz, CDCl 3) 1.51 (and 9H, s), 7.22 (1H, m) and 7.24 (2H, m) .b) N-[2-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-dioxo bora pentamethylene-2-yl) phenyl] the carboxylamine tertiary butyl ester
With N-(4-bromo-2-fluorophenyl) carboxylamine tertiary butyl ester (54.0g, 0.186mmol), two pinacol diboron hexahydrides (1.2 equivalents, 56.8g, 223.3mmol), Potassium ethanoate (3.0 equivalents, 54.7g, 558mmol) and PdCl 2(dppf) (5.58mmol) solution in the DMF (1L) of the degassing heated 16 hours in nitrogen at 80 ℃ for 0.03 equivalent, 4.65g.DMF is removed in decompression, and the black solid resistates of generation is dissolved in methylene dichloride (500ml).Leach inorganic residues through silicagel pad, filtrate is by column chromatography purification, with 10% to 15% ethyl acetate: the heptane gradient elution, provide yellow thickness oily matter, place crystallization, provide N-[2-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-dioxo bora pentamethylene-2-yl) phenyl] carboxylamine tertiary butyl ester (56.5g, 92%)
1H NMR (400 MHz, CDCl 3) 1.33 (and 12 H, s), 1.53 (9H, s), 6.82 (1H, brs), 7.46 (1H, d, J11Hz), 7.55 (1H, brd) and 8.12 (1H, brt), m/z337.2, and RP-HPLC (5 to 100%CH 3CNin 0.1N ammonium acetate aqueous solution 15min uses aHypersil HyPurityElite C18,5m, 200_250 * 4.6mm post at 1mL/min) t r=10.16 min, 90%.c) N-4-[4-chloro-7-(1,4-dioxo spiro [4,5] last of the ten Heavenly stems-8-yl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl]-2-fluorophenyl carboxylamine tertiary butyl ester
With 4-chloro-7-(1,4-dioxo spiro [4,5] last of the ten Heavenly stems-8-yl)-7H-pyrrolo-[2,3-d] and pyrimidine (31.18g, 74.41mmol), N-[2-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-dioxo bora pentamethylene-2-yl) phenyl] carboxylamine tertiary butyl ester (1.5 equivalents, 37.6g, 111.6mmol), yellow soda ash (2.5 equivalents, 19.72g, 186mmol) and Pd (PPh 3) 4(4mol%, 3.44g, 2.98mmol) DME (1.2L) and the degassing H 2Suspension among the O (230ml) heated 17 hours in 80 ℃ in nitrogen.(0.74mmol), reaction mixture continues heating 24 hours at 80 ℃ for 1mol%, 0.86g, finishes in this some reaction that (t.l.c. analyzes, and with 3: 7 ethyl acetate: heptane was made eluent, Rf=0.7) to add extra catalyzer.Removal of solvent under reduced pressure, resistates are dissolved in ethyl acetate (500ml), leach inorganics through Celite pad.Filtrate is washed with 10% aqueous sodium carbonate (200ml) and salt solution (200ml), dry (sal epsom) and vacuum concentration.With 1: 2 ethyl acetate: the heptane purification by silica gel column chromatography provided N-4-[4-chloro-7-(1,4-dioxo spiro [4,5] last of the ten Heavenly stems-8-yl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl]-2-fluorophenyl carboxylamine tertiary butyl ester beige solid (21.0g, 56%), 1HNMR (400MHz, CDCl 3) 1.55 (9H, s), 1.89 (4H, m), 2.07 (4H, m), 4.01 (4H, s), 4.89 (1H, m), 6.75 (1H, brs), 7.23 (1H, brs), 7.25 (1H, brs), 7.34 (1H, brs), 8.14 (1H, brt) and 8.64 (1H, s) and RP-HPLC (5 to 100%
CH 3CN is at 0.1 N
Ammonium acetate aqueous solution 15min uses a Hypersil HyPurityElite C18,5 μ m, 200_, 250 * 4.6mm post at 1mL/min) t r=10.48 min., 100%.d) 5-(4-amino-3-fluorophenyl)-7-(1,4-dioxo spiro [4,5] last of the ten Heavenly stems-8-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine
With N-4-[4-chloro-7-(1,4-dioxo spiro [4,5] last of the ten Heavenly stems-the 8-yl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl] a 2-fluorophenyl carboxylamine tertiary butyl ester (10.5g, 20.92mmol), ammonium hydroxide (28-30%, 100ml) and the muddy mixture of dioxan (100ml) at room temperature put into tube sealing, then 120 ℃ of heated and stirred 24 hours (t.l.c. analyzes, and with 9: 1 ethyl acetate: heptane was made eluent).To react vacuum concentration, dilute with ethyl acetate (300ml), with salt solution (2 * 150ml) washings, dry (sodium sulfate) and concentrating under reduced pressure, in earnest drying provide 5-(4-amino-3-fluorophenyl)-7-(1,4-dioxo spiro [4,5] last of the ten Heavenly stems-the 8-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine yellow solid (7.93g, 99%)
1H NMR (400MHz, d 6-DMSO) 1.74 (4H, m), 1.90 (2H, m), 2.06 (2H, m), 3.90 (4H, m), 4.64 (1H, m), 5.18 (2H, brs), 6.02 (2H, brs), 6.84 (1H, t), 6.97 (1H, d), 7.08 (1H, d), 7.26 (1H, s) and 8.10 (1H, s) and m/z384.2 (MH +) .e) 4-[4-amino-5-(4-amino-3-fluorophenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-1-hexanaphthene ketone
At 0 ℃ 5M HCl (300ml) is slowly added 5-(4-amino-3-fluorophenyl)-7-(1,4-dioxo spiro [4,5] last of the ten Heavenly stems-the 8-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (18.49g, 48.28mmol) acetone (800ml) solution, dark orange-the brown solution that produces is 60 ℃ of heating 4 hours (t.l.c. analyzes, with 10% ethanol/methylene wash-out).Acetone is removed in decompression, and the acid layer alkalizes to about pH 8 with saturated aqueous sodium carbonate.It is also conscientious dry to filter the precipitation of collecting generation, provides 4-[4-amino-5-(4-amino-3-fluorophenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-the light brown solid of 1-hexanaphthene ketone (12.67g, 77%).Mother liquor is placed and is also obtained second batch of product (2.01g, 12%),
1HNMR(400MHz，d 6-DMSO)2.27(2H，m)，2.30(4H，brd)，2.73(2H，m)，
5.14(1H，m)，5.20(2H，brs)，6.05(2H，brs)，6.85(1H，t)，6.97(1H，dd)，7.06(1
H, dd), 7.35 (1H, s) and 8.12 (1H, s) and m/z340.1 (MH +). cis-and trans-5-(4-amino-3-fluorophenyl)-7-[4-(4-methylpiperazine base) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-4-amine embodiment 304: cis-N1-(4-{4-amino-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-4-fluoro-1-benzsulfamide three maleate
Past 4-[4-amino-7-[4-(4-methylpiperazine subbase) cyclohexyl in nitrogen]-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-1-hexanaphthene ketone (1.0g, 2.95mmol), N methyl piperazine (3 equivalents, 0.885mmol, 0.98ml) and Glacial acetic acid (3 equivalents, 0.51ml, 8.85mmol) methylene dichloride (50ml) solution in add sodium triacetoxy borohydride (1.3 equivalents, 0.81g, 3.84mmol).With solution stirring 18 hours, and then (0.40g 1.9mmol), continued to stir 48 hours to add sodium triacetoxy borohydride.Reactant is distributed between methylene dichloride (100ml) and the saturated sodium bicarbonate aqueous solution (100ml) by vacuum concentration.(4 * 100ml) extract water layer with methylene dichloride.The organic phase dried over mgso that merges, evaporate as for, provide yellow foams (0.95g).By quick purification by silica gel column chromatography, with methylene chloride (9: 1 to 5: 1) gradient elution.Provide cis-5-(4-amino-3-fluorophenyl)-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-4-amine, the composition of higher appearance is Off-white solid (400mg, 32 1HNMR (d 6DMSO, 400MHz) 1.56 (3H, brt), 1.68 (2H, brd), 1.99 (5H, m), 2.20 (3H, s), 2.43 (7H, brm), 4.65 (1H, m), 5.20 (2H, s), 6.01 (2H, brs), 6.85 (1H, t, J=9.6Hz), (6.98 1H, dd, J=8.0 and 1.6Hz), 7.10 (1H, dd, J=12.4 and 1.6Hz), 7.12 (1H, s) and 8.10 (1H, s) and RP-HPLC (10to90%CH 3CNin0.1N ammonium acetate aqueous solution 12min uses aWatersSymmetryC18 at 2mL/min, 250 * 4.6mm column) tr=8.619 min., the mixing fraction of 96% gained contains cis-and trans-isomer (440mg, 50: 50 mixtures), in addition, the low fraction that occurs contains trans-5-(4-amino-3-fluorophenyl)-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-4-amine yellow solid (110mg, 9%) 1HNMR (d, 6DMSO, 400MHz) 1.94 (6H, m), 2.17 (3H, s), 2.33 (7H, brm), 2.51 (3H, m), 3.28 (1H, m), 4.51 (1H, m), 5.18 (2H, s), 6.01 (2H, brs), 6.84 (1H, t), 6.96 (1H, dd), 7.04 (1H, dd), 7.30 (1H, s) and 8.08 (1H, s) and RP-HPLC (10 to 40%CH 3CN uses aWatersSymmetryC18 at 2mL/min, 250 * 4.6mm column at 0.1 N ammonium acetate aqueous solution 12min) t r=7.595 min, 97% embodiment 305: trans-N1-(4-{4-amino-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-4-fluoro-1-benzsulfamide three maleate
At 40 ℃ with 4-fluorobenzene SULPHURYL CHLORIDE (45.9mg, 0.236mmol) adding trans-5-(4-amino-3-fluorophenyl)-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] (100mg is in pyridine 0.236mmol) (2ml) solution for pyrimidine-4-amine.At 40 ℃ after 27 hours, vacuum concentration is finished in reaction.By purification by silica gel column chromatography,, provide colorless oil (0.78mmol) with 10% to 50% ethanol/methylene gradient elution.Product is dissolved in ethanol, and the adding toxilic acid (3 equivalents, 27mg, 0.233mmol).With mixture heating up extremely evenly, crystallisation by cooling goes out trans-N1-(4-{4-amino-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-4-fluoro-1-benzsulfamide three maleate brown solid (37mg, 17%) RP-HPLC (10 to 40% acetonitriles, 0.1N ammonium acetate aqueous solution,, 12 minutes, 2ml/min is with Waters Symmetry C18,250 * 4.6mm post) t r=14.528,96% and m/z 582.0 (MH +).Embodiment 306: cis-N1-(4-{4-amino-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-4-fluoro-1-benzsulfamide
With with trans-N1-(4-{4-amino-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-prepared cis-N1-that the free alkali of 4-fluoro-1-benzsulfamide is identical (4-{4-amino-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-4-fluoro-1-benzsulfamide, just its scale is 3.36mmol.(400mg, 32%), RP-HPLC (12 minutes, 2ml/min was with Waters Symmetry C18,250 * 4.6mm post for 10 to 40% acetonitriles, 0.1N ammonium acetate aqueous solution) t r=15.232,94% and m/z 582.1 (MH +).Embodiment 307:5-(4-amino-3-fluorophenyl)-7-(1-benzyl-4-piperidyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine is 7-(1-benzyl-4-piperidyl)-7H-pyrrolo-[2,3-d] pyrimidine a)
In nitrogen in room temperature with diethylazodicarboxylate's (2.0 equivalents, 18.19g, 41.2ml, 104.8mmol) in about 1 hour, be added drop-wise to also [2,3-d] pyrimidine (14.55g of 4-chloro-3-iodol, 52.4mmol), 1-benzyl-4-hydroxy piperidine (3.0 equivalents, 30.06g, 157.16mmol) and triphenyl phosphine (2.0 equivalents, 27.51g, in THF 104.8mmol) (730ml) solution.72 hours afterreactions finish that (t.l.c. analyzes, and with 1: 1 ethyl acetate: heptane was made eluent, Rf=0.2).With the reactant vacuum concentration, add 1: 4 ethyl acetate: heptane, until precipitation in limpid solution, occurring.Filter collecting precipitation (Ph 3PO), filtrate is concentrated, be dissolved in ethyl acetate (500ml) and use hydrochloric acid (1M, 3 * 200ml) extractions.The acid layer that merges alkalizes to pH12 with aqueous sodium hydroxide solution (4N), be extracted into then ethyl acetate (in 3 * 300ml), drying (sal epsom) and vacuum concentration.With 5: 4 light benzines (30-60 ℃): the ethyl acetate purification by silica gel column chromatography, provide 2 main fractions, first fraction contains light yellow crystalline solid product, use re-crystallizing in ethyl acetate, provide 7-(1-benzyl-4-piperidyl)-7H-pyrrolo-[2,3-d] pyrimidine oyster white crystalline solid (5.7g, 24%);
1H NMR (400 MHz, CDCl 3) 2.02 (and 4H, m), 2.24 (2H, m), 3.06 (2H, brd), 3.58 (2H, s), 4.76 (1H, m), 7.27 (2H, m), 7.32 (3H, m), 7.49 (1H, s) and 8.60 (1H, s) and m/z=452.8 (MH +) .b) N-4-[7-(1-benzyl-4-piperidyl)-4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-5-yl]-2-fluorophenyl carboxylamine tertiary butyl ester
With 7-(1-benzyl-4-piperidyl)-7H-pyrrolo-[2,3-d] pyrimidine (5.7g, 12.6mmol), N-[2-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-dioxo bora pentamethylene-2-yl) phenyl] carboxylamine tertiary butyl ester (1.5 equivalents, 18.9g, 6.38mmol), yellow soda ash (2.5 equivalents, 3.34g, 31.5mmol) and Pd (PPh 3) 4(4mol%, 0.58g, 0.5mmol) DME (210mL) and the degassing H 2Suspension among the O (37ml) in nitrogen in 80 ℃ of heating 17 hours (t.l.c. analyzes, and with 1: 1 ethyl acetate: heptane was made eluent).With the reaction mixture vacuum concentration, be dissolved in ethyl acetate (400ml) also with (3 * 200ml) washings of 10% aqueous sodium carbonate.With organic layer drying (sal epsom), concentrate and pass through column chromatography purification, with 1: 1 ethyl acetate: heptane was made eluent, provide N-4-[7-(1-benzyl-4-piperidyl)-4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-5-yl]-2-fluorophenyl carboxylamine tertiary butyl ester white crystalline solid (5.2g, 9.7mmol, 77%)
1H NMR (400MHz, CDCl 3) 1.55 (9H, s), 2.05 (4H, m), 2.24 (2H, m), 3.06 (2H, brd), 3.60 (2H, s), 4.83 (1H, m), 7.25 (2H, m), 7.29 (1H, m), 7.33 (6H, m), 8.12 (1H, brt) and 8.64 (1H, s) .c) 5-(4-amino-3-fluorophenyl)-7-(1-benzyl-4-piperidyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine
With N-4-[7-(1-benzyl-4-piperidyl)-4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-5-yl]-2-fluorophenyl carboxylamine tertiary butyl ester (5.2g, 9.7mmol), ammonium hydroxide aqueous solution (28-30%, 100ml) with 1, the mixture of 4-dioxan (100ml) is at room temperature put into tube sealing, and stirs 16 hours at 120 ℃.(t.l.c. analyzes, and makes eluent with ethyl acetate).With the reactant vacuum concentration, dilute with ethyl acetate (300ml), salt solution (2 * 200ml) washings, dry (sodium sulfate) and concentrating under reduced pressure, the brown solid that provides provides 5-(4-amino-3-fluorophenyl)-7-(1-benzyl-4-piperidyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine Off-white solid (3.0g with ether (about 50ml) development, 74%)
1HNMR (400 MHz, CDCl 3) 2.06 (4H, m), 2.27 (2H, m), 3.06 (2H, m), 3.59 (2H, brs), 3.70 (2H, brs), 4.73 (1H, m), 5.12 (2H, s), 6.85 (1H, t), 7.01 (1H, s), 7.06 (1H, dd), 7.10 (1H, dd), 7.28 (2H, m), 7.34 (3H, m) and 8.31 (1H, s) and m.p.141-142 ℃ of embodiment 308:N1-4-[4-amino-7-(1-benzyl-4-piperidyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl]-2-fluorophenyl-4-fluoro-1-benzsulfamide
With with trans-N1-(4-{4-amino-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-identical prepared N1-4-[4-amino-7-(1-benzyl-4-the piperidyl)-7H-pyrrolo-[2 of free alkali of 4-fluoro-1-benzsulfamide, 3-d] pyrimidine-5-yl]-2-fluorophenyl-4-fluoro-1-benzsulfamide, just its scale is 6.96mmol.N1-4-[4-amino-7-(1-benzyl-4-piperidyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl]-2-fluorophenyl-4-fluoro-1-benzsulfamide is Off-white solid (3.2g, 80%), m/z 575 (MH +), m.p.265-6 ℃.Embodiment 309:N1-4-[4-amino-7-(1-benzyl-4-piperidyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl]-2-fluorophenyl-2,3-two chloro-1-benzsulfamides
Prepare N1-4-[4-amino-7-(1-benzyl-4-piperidyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl with method same as described above]-2-fluorophenyl-2,3-two chloro-1-benzsulfamides, its scale is 5.04mmol.N1-4-[4-amino-7-(1-benzyl-4-piperidyl)-7H-pyrrolo-[2, the 3-d] pyrimidine-5-yl that produces]-2-fluorophenyl-2,3-two chloro-1-benzsulfamides are brown solid (1.0g, 32%), m/z 625 (MH +), RP-HPLC (20 minutes, 1ml/min was with Waters Delta pack 5m C18,300A, 150 * 3.9mm post for 5 to 85% acetonitriles, 0.1N ammonium acetate aqueous solution) t r=14.963,95%.Embodiment 310:N1-4-[4-amino-7-(4-piperidyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl]-2-fluorophenyl-4-fluoro-1-benzsulfamide
To contain N1-4-[4-amino-7-(1-benzyl-4-piperidyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl]-2-fluorophenyl-4-fluoro-1-benzsulfamide (2.40g, 4.18mmol), ammonium formiate (10 equivalents, 41.8mmol 2.62g), Pd/C (10%, 1.2g) and the mixture of ethanol (100ml) reflux 6 hours under vigorous stirring, filter and vacuum concentration.Solids constituent is assigned between methylene dichloride (50ml) and the water (50ml).The brown solid that forms on the phase border is collected and analyzes, and is defined as N1-4-[4-amino-7-(4-piperidyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl]-2-fluorophenyl-4-fluoro-1-benzsulfamide (0.33g), m/z 485 (MH +), m.p.238-9 ℃ (decomposition).Embodiment 311:N1-4-[4-amino-7-(1-formyl radical-4-piperidyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl]-2-fluorophenyl-4-fluoro-1-benzsulfamide
Be prepared N1-4-[4-amino-7-(4-piperidyl)-7H-pyrrolo-[2 with less scale (0.35mmol); 3-d] pyrimidine-5-yl]-technology of 2-fluorophenyl-4-fluoro-1-benzsulfamide; wherein the organic layer that merges in the treating processes is separated; dry (sodium sulfate); removal of solvent under reduced pressure; provide white oily matter; by preparation property HPLC (100% pH 4.5; 50mM ammonium acetate to 100% acetonitrile; 8.5 minute; 1.5 minute be in 25ml/min, with Hypersil 5m BDS C18 post, 100 * 21.2mm post) purifying; provide N1-4-[4-amino-7-(1-formyl radical-4-piperidyl)-7H-pyrrolo-[2; 3-d] pyrimidine-5-yl]-2-fluorophenyl-4-fluoro-1-benzsulfamide white solid (50mg, 27%), m/z 512.9 (NH +), RP-HPLC (20 minutes, 1ml/min was with Waters Delta pack 5m C18,300A, 150 * 3.9mm post for 5 to 85% acetonitriles, 0.1N ammonium acetate aqueous solution) t r=13.091,95%.Embodiment 312:N1-4-[4-amino-7-1-[(1-methyl isophthalic acid H-4-imidazolyl) alkylsulfonyl]-4-piperidyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-the 2-fluorophenyl]-4-fluoro-1-benzsulfamide 2-maleate
With 1-Methylimidazole-4-base SULPHURYL CHLORIDE (1.1 equivalents, 0.068mmol, 12.3mg) adding 5-(4-amino-3-fluorophenyl)-7-(1-benzyl-4-piperidyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (30mg, 0.062mmol) and triethylamine (3 equivalents, 0.186mmol, 26 l) and in the suspension in methylene dichloride (1ml), stirring at room 24 hours.With the reactant vacuum concentration, be distributed between methylene dichloride (100ml) and the water (50ml), water layer is further used methylene dichloride (3 * 100ml) extractions.The organic layer that merges is with dried over mgso and vacuum concentration.By purification by silica gel column chromatography,, provide wax shape white solid (10mg) with 10% ethanol/methylene wash-out.With toxilic acid (2 equivalents; 4mg) in the product in the adding hot ethanol; crystallisation by cooling goes out N1-4-[4-amino-7-1-[(1-methyl isophthalic acid H-4-imidazolyl) alkylsulfonyl]-4-piperidyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-the 2-fluorophenyl]-4-fluoro-1-benzsulfamide 2-maleate (10mg), RP-HPLC (5 to 85% acetonitriles; 0.1N ammonium acetate aqueous solution; 20 minutes, 1ml/min was with WatersDelta pack 5m C18; 300A, 150 * 3.9mm post) t r=14.186,100%min.m/z=629 (MH +).Embodiment 313:N1-[4-(4-amino-7-1-[(1,2-dimethyl-1H-4-imidazolyl) alkylsulfonyl]-4-piperidyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-the 2-fluorophenyl]-4-fluoro-1-benzsulfamide
With synthetic N1-4-[4-amino-7-1-[(1-methyl isophthalic acid H-4-imidazolyl) alkylsulfonyl]-4-piperidyl-7H-pyrrolo-[2; 3-d] pyrimidine-5-yl)-the 2-fluorophenyl]-technology of 4-fluoro-1-benzsulfamide 2-maleate free alkali; preparation N1-[4-(4-amino-7-1-[(1; 2-dimethyl-1H-4-imidazolyl) alkylsulfonyl]-4-piperidyl-7H-pyrrolo-[2; 3-d] pyrimidine-5-yl)-the 2-fluorophenyl]-4-fluoro-1-benzsulfamide Off-white solid (9mg); m.p.217-8 ℃, m/z=643.2 (MH +).Embodiment 314:N1-[4-(4-amino-7-1-[(1,3-dimethyl-1H-5-pyrazolyl) carbonyl]-4-piperidyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-the 2-fluorophenyl]-4-fluoro-1-benzsulfamide
Under agitation, with 1,3-dimethyl pyrazole-5-carbonyl chlorine (1.5 equivalents, 14.8mg, 0.093mmol) add 5-(4-amino-3-fluorophenyl)-7-(1-benzyl-4-piperidyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine (30mg, 0.062mmol) and salt of wormwood (2 equivalents, 17.1mg, 0.124mmol) in the suspension in N-Methyl pyrrolidone (2ml), the mixture of generation in nitrogen in stirring at room 16 hours.Solvent removed in vacuo, mixture passes through purification by silica gel column chromatography, make eluent with 5% ethanol/methylene, provide N1-[4-(4-amino-7-1-[(1,3-dimethyl-1H-5-pyrazolyl) carbonyl]-4-piperidyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-the 2-fluorophenyl]-4-fluoro-1-benzsulfamide flint glass body (10mg), (100%pH 4.5 for RP-HPLC HPLC, 50mM ammonium acetate to 100% acetonitrile, 4.5 minute, be in 3.5ml/min in 0.5 minute, with Perkin Elmer Pecosphere 3m C18 post, (33 * 4.6mm) post), t r=2.98%min.96%, m/z=629 (MH +).Embodiment 315:N1-(4-{4-amino-7-[1-(2-pyridyl carbonyl)-4-piperidyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-4-fluoro-1-benzsulfamide
With with N1-[4-(4-amino-7-1-[(1,3-dimethyl-1H-5-pyrazolyl) carbonyl]-4-piperidyl-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-the 2-fluorophenyl]-prepared N1-that 4-fluoro-1-benzsulfamide is identical (4-{4-amino-7-[1-(2-pyridyl carbonyl)-4-piperidyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-4-fluoro-1-benzsulfamide (12mg), RP-HPLCHPLC (100% pH 4.5,50mM ammonium acetate to 100% acetonitrile, 4.5 minute, 0.5 minute be in 3.5ml/min, with Perkin Elmer Pecosphere 3mC18 post, (33 * 4.6mm) post), t r=2.73min.98%, m/z=590.2 (MH +).Embodiment 316:N1-4-(4-amino-7-{4-[1-(1-methyl piperidine-4-yl) piperidyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl })-the 2-fluorophenyl)-4-fluoro-1-benzsulfamide three maleate
With sodium triacetoxy borohydride (28.1mg, 0.134mmol) adding N1-4-[4-amino-7-(4-piperidyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl]-2-fluorophenyl-4-fluoro-1-benzsulfamide (50mg, 0.103mmol) and 1-methyl piperidine-4-ketone (0.92ml, 0.155mmol) solution in Glacial acetic acid (0.025ml) and NMP (3ml).Reactant is stirring at room 20 hours, and then adds sodium triacetoxy borohydride (1.3 equivalent).After 24 hours, reaction is finished, and with its vacuum concentration, is distributed between methylene dichloride (100ml) and the saturated sodium bicarbonate aqueous solution (100ml).Water layer use again methylene dichloride (4 * 100ml) extraction, the organic layer of merging with dried over mgso and the evaporation as for.By purification by silica gel column chromatography, use methylene dichloride: methyl alcohol: ammonium hydroxide (78: 19: 3) is made eluent, provides brown solid.Form three maleate by standard method then, provide N1-4-(4-amino-7-{4-[1-(1-methyl piperidine-4-yl) piperidyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl })-the 2-fluorophenyl)-4-fluoro-1-benzsulfamide three maleate brown solid (45mg, 75%), m/z=582 (MH +), RP-HPLC (20 minutes, 1ml/min was with Waters Delta pack 5mC18,300A, 150 * 3.9mm post for 5 to 85% acetonitriles, 0.1N ammonium acetate aqueous solution) t r=10.658,95%.Embodiment 317:N1-4-[4-amino-7-(4-oxo cyclohexyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl]-2-anisole yl-benzamide a) in nitrogen toward 4-chloro-5-iodo-7H-pyrrolo-[2,3-d] pyrimidine (25.0g, 0.09mol), 1,4-dioxo spiro [4,5] last of the ten Heavenly stems-8-alcohol (35.8g, 0.0267mol) and triphenyl phosphine (46.7g, and THF 0.178mol) (1.2L) solution adding diethylazodicarboxylate (30.9g, 0.178mol).With solution stirring 20 hours, evaporate most of solvent (remaining 250ml) then.Add ethyl acetate (450ml) then, filter the solid that produces, with ethyl acetate (2 * 50ml) washings, vacuum-drying, provide 4-chloro-7-(1,4-dioxo spiro [4,5] last of the ten Heavenly stems-the 8-yl)-5-iodo-7H-pyrrolo-[2,3-d] pyrimidine (22.5g, 60%) Off-white solid.
1H NMR (d 6DMSO, 400 MHz) 8.64 (1H, s), 8.10 (1H, s), 4.74 (1H, m), 3.90 (4H, m), 2.12 (2H, m), 1.91 (2H, m), 1,71-1.83 (4H, m) .R f1: 4 EtOAc:heptane=0.12.b of in) with N-[2-methoxyl group-4-(4,4,5,5-tetramethyl--1,3,2-dioxo bora pentamethylene-2-yl) phenyl] the carboxylamine tertiary butyl ester (8.2g, 23.5mmol), 4-chloro-7-(1,4-dioxo spiro [4,5] last of the ten Heavenly stems-8-yl)-5-iodo-7H-pyrrolo-[2,3-d] pyrimidine (6.57g, 15.7mmol), Pd (PPh 3) 4(1.1g, 0.93mmol), yellow soda ash (4.16g is 39.2mmol) at DME (200ml)) and H 2Solution among the O (100ml) heated 20 hours in 80 ℃ in nitrogen.The solution that produces be cooled to room temperature and be distributed in ethyl acetate (300ml) and water (100ml) between.(3 * 150ml) extractions, (1 * 150ml) washs the organic phase water of merging water layer with ethyl acetate.Organic phase is dried in (sal epsom), filters and evaporation, stays solid.Attempt to be dissolved in ethyl acetate/heptane (1: 4), obtain Off-white solid (2.5g).Filtrate is absorbed on the silica gel, with 10: 1 heptane: ethyl acetate, 4: 1 heptane: ethyl acetate, 1: 1 heptane: ethyl acetate and 4: 1 ethyl acetate: the quick purification by silica gel column chromatography of heptane.Merge suitable fraction, the white solid that provides is developed with heptane/ethyl acetate (5: 1), provide N-4-[4-chloro-7-(1,4--two-oxaspiro [4,5] last of the ten Heavenly stems-the 8-yl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl]-2-anisole aminocarbamic acid tertiary butyl ester solid (3.2g), overall yield 71%. 1H NMR (d 6DMSO, 400MHz): 8.66 (1H, s), 7.93 (2H, m), 7.74 (1H, m), 7.19 (1H, s), 7.07 (1H, d), 4.81 (1H, m), 3.93 (4H, m), 3.91 (3H, s), 2.18 (2H, m), 1.99 (2H, m), 1.79 (4H, m), 1.48 (9H, s), HPLC (condition: 5 to 95%CH 3CNin 0.1 N ammonium acetate aqueous solution 20 min.) t r=21.24 min, 100%.c) 5-(4-amino-3-fluorophenyl)-7-(1,4-dioxo spiro [4,5] last of the ten Heavenly stems-8-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine
With N-4-[4-chloro-7-(1,4-dioxo spiro [4,5] last of the ten Heavenly stems-8-yl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl]-2-anisole aminocarbamic acid tertiary butyl ester (5.7g, 0.011mol), strong aqua (100ml) and dioxan (100ml) heated 20 hours in 120 ℃ in forcer.Evaporating solvent, resistates place ethyl acetate/water (250ml/100ml) again.Tell organic layer, dry (sodium sulfate) filters and evaporation, the solid that provides carries out HPLC (condition: 5 to 95% acetonitriles, 0.1N ammonium acetate aqueous solution, 20 minutes), observe N-4-[4-chloro-7-(1,4-dioxo spiro [4,5] last of the ten Heavenly stems-the 8-yl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl]-2-anisole aminocarbamic acid tertiary butyl ester and 5-(4-amino-3-p-methoxy-phenyl)-7-(1,4-dioxo spiro [4,5] last of the ten Heavenly stems-the 8-yl)-2: 1 mixtures of 7H-pyrrolo-[2,3-d] pyrimidine-4-amine.Mixture is dissolved in acetone (200ml) and (5N, 100ml), the solution of generation at room temperature stirred and spends the night, then evaporating solvent 0.5 hour dripping hydrochloric acid.Acidic solution is with 2N sodium hydroxide (ice-cold) alkalization, and (3 * 150ml) extract with ethyl acetate.The organic phase water that merges (2 * 100ml) washings.In extraction process, be settled out solid.This solid is developed with hot ethyl acetate/methyl alcohol.The filtering insolubles, evaporated filtrate is developed the solid that produces then with ether/ethyl acetate, provide yellow solid.The organic layer of original extraction liquid is dried in (sodium sulfate), filters and evaporation.The solid that produces filters and provides 4-[4-amino-5-(4-amino-3-p-methoxy-phenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl with ether/ethyl acetate (5: 1) development]-1-hexanaphthene ketone yellow solid.(2.3g, overall yield=78%).
1H NMR (d 6DMSO, 400 MHz): 8.17 (1H, s), 7.32 (1H, s), 6.88 (1H, s), 6.77 (1H, m), 6.73 (1H, m), 6.71 (1H, m), 6.07 (2H, bs), 5.14 (1H, m), 3.81 (3H, s), 2.72 (2H, m), 2.35 (4H, m), 2.18 (2H, m) .HPLC:(5 to 95%CH 2CN in 0.1N ammonium acetate aqueous solution 20min.) t r=11.24min, 95%d) at 0 ℃, past 4-[4-amino-5-(4-amino-3-p-methoxy-phenyl)-7H-pyrrolo-[2 in the nitrogen, 3-d] pyrimidin-7-yl]-1-hexanaphthene ketone (0.105g, 0.3mmol) pyridine (5ml) solution in add Benzoyl chloride (63mg, methylene dichloride 0.45mmol) (1ml) solution.0 ℃ with solution stirring 2 hours, water (5ml) cancellation then, (1N, 40ml), water layer is with methylene dichloride (3 * 25ml) extractions to add HCl.The organic layer water that merges (1 * 30ml) washing.With organic layer drying (sodium sulfate), filter and evaporation, provide oily matter, by quick purification by silica gel column chromatography, make eluent with the 2%-10% methanol/ethyl acetate, provide N1-4-[4-amino-7-(4-oxo cyclohexyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl]-2-anisole yl-benzamide white solid (00.130g, 96%).
M.pt234-237 ℃ of .Rfin9:1 EtOAc:MeOH=0.30, HPLC:(5 to 95%CH 3The CNin0.1N ammonium acetate aqueous solution
20 min.) t r=14.82min, 96%. 1HNMR (d 6DMSO, 400 MHz): 9.43 (1H, s), 8.19 (1H, s), 7.94 (3H, m), 7.59 (4H, m), 7.18 (1H, 8), 7.06 (1H, d, J=8Hz), 6.18 (H, bs), 5.20 (1H, m), 3.92 (3H, s), 2.76 (2H, m), 2.35 (4H, m), 2.22 (2H, m). embodiment 318:N-[4-amino-7-(4-oxo cyclohexyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl]-2-anisole aminocarbamic acid tertiary butyl ester
At-5 ℃, past 4-[4-amino-5-(4-amino-3-p-methoxy-phenyl)-7H-pyrrolo-[2 in the nitrogen, 3-d] pyrimidin-7-yl]-add in 1-hexanaphthene ketone (0.40g, pyridine 1.15mmol) (5ml) and the methylene dichloride 10ml) solution benzyl chloroformate (0.29g, 1.73mmol).Solution is warmed to 0 ℃ and stirred 1 hour, and water (5ml) cancellation and evaporating solvent, resistates are distributed between ethyl acetate and the water (each 100ml), and water layer is with ethyl acetate (3 * 50ml) extractions.The organic layer that merges be dried (sodium sulfate), filter and evaporation, the solid that provides is developed with ethylacetate/ether, provides N-[4-amino-7-(4-oxo cyclohexyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl]-2-anisole aminocarbamic acid tertiary butyl ester yellow solid (0.28g).
9: 1 EtOAc:MeOH=0.24.HPLC:(5 to of M.pt 175-176 ℃ of .Rf in 95%CH 3CNin0.1N ammonium acetate aqueous solution 20 mim) t r=16.69 min, 98%. 1HNMR (d 6DMSO, 400 MHz): 8.64 (1H, s), 8.17 (1H, s), 7.75 (1H, d, J=8.4 Hz), 7.50 (1H, s), 7.36 (5H, m), 7.10 (1H, s), 7.02 (1H, d, J=8 Hz), 6.15 (2H, bs), 5.19 (3H, m), 3.81 (3H, s), 2.72 (2H, m), 2.35 (4H, m), 2.22 (2H, m). embodiment 319: cis N-(4-{4-amino-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl } the 2-p-methoxy-phenyl) carboxylamine benzyl ester three maleate and trans-N-(4-{4-amino-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl } the 2-p-methoxy-phenyl) carboxylamine benzyl ester three maleate
Past N-[4-amino-7-(4-oxo cyclohexyl)-7H-pyrrolo-[2 in nitrogen, 3-d] pyrimidine-5-yl]-2-anisole aminocarbamic acid tertiary butyl ester (0.83g, 1.74mmol), N methyl piperazine (0.52g, 5.22mmol) and Glacial acetic acid (0.31g, 5.22mmol) ethylene dichloride (100ml) solution in drip sodium triacetoxy borohydride (0.55g, 2.61mmol).With solution stirring 6 hours, then by adding sodium hydroxide (2N, 20ml) cancellation.Tell organic layer, (2 * 50ml) extract water layer with methylene dichloride.(1 * 50ml) washs the organic layer that merges with salt solution, dry (sodium sulfate), filter and evaporation, the oily matter that provides is by quick purification by silica gel column chromatography, use ethyl acetate, 9: 1 ethyl acetate: methyl alcohol, methylene dichloride and 9: 1 methylene dichloride: methanol-eluted fractions provides oily matter (480mg) at F20-25.This oily matter is dissolved in ethyl acetate, and in ethyl acetate, handles with toxilic acid (280mg).Solid that filtration produces in nitrogen gas stream and vacuum-drying 4 hours, provide cis N-(4-{4-amino-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl) 2-p-methoxy-phenyl) carboxylamine benzyl ester three maleate (580mg) Off-white solid.
M.pt.158 ℃ (dec.) 1H NMR (d 6DMSO, 400 MHz): 8.74 (1H, s), 8.27 (1H, s), 7.78 (1H, d), 7.35-7.77 (5H, m), 7.10 (1H, s), 7.04 (1H, s), 6.16 (6H, s), 5.17 (2H, s), 4.74 (1H, m), 3.82 (3H, s), 3.23 (5H, m), 2.78 (3H, s), 2.51 (3H, m), 2.41 (1H, s), 2.09 (4H, m), 1.70 (4H, m) .HPLC:(5 to 95%CH 3CNin 0.1 N ammonium acetate aqueous solution
20min.) t r=13.30 min, 94%. provide glassy foam body (186mg) at F28-45, it is dissolved in ethyl acetate (10ml), and handles in ethyl acetate (3ml) with toxilic acid (114mg).The solid that produces filters also vacuum-drying 4 hours in nitrogen, provide trans-N-(4-{4-amino-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl the 2-p-methoxy-phenyl) carboxylamine benzyl ester three maleate (250mg) Off-white solid.M.pt146-148 ℃ of .HPLC:(5 to 95%CH 3CN in 0.1 N ammonium acetate aqueous solution 20min.) t r=13.54 min, 94.6%. 1H NMR (d 6DMSO, 400 MHz): 8.72 (1H, s), 8.25 (1H, s), 7.77 (1H, d), 7.51 (1H, s), 7.35 (5H, m), 7.10 (1H, s), 7.04 (1H, d), 6.16 (6H, s), 5.17 (2H, s), 4.59 (1H, m), 3.86 (3H, s), 2.70-3.10 (11H, m), 2.50 (3H, s), 1.97 (6H, m), 1.56 (2H, m). embodiment 320: trans-N1-(4-{4-amino-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl } the 2-p-methoxy-phenyl) benzamide
Past N1-4-[4-amino-7-(4-oxo cyclohexyl)-7H-pyrrolo-[2 in nitrogen, 3-d] pyrimidine-5-yl]-2-anisole yl-benzamide (1.2g, 2.66mmol), N methyl piperazine (0.80g, 7.98mmol) and Glacial acetic acid (0.48g, 7.98mmol) ethylene dichloride (150ml) solution in drip sodium triacetoxy borohydride (0.85g, 3.99mmol).Solution in stirred overnight at room temperature, is passed through to add sodium hydroxide (2N, 20ml) cancellation then.(3 * 50ml) extract water layer with methylene dichloride.The organic layer that merges be dried (sodium sulfate), filter and evaporation, the oily matter that provides is by quick purification by silica gel column chromatography, use methylene dichloride, use 5% ethanol/methylene to 20% ethanol/methylene with 5% increment wash-out then, merging F23-36 and evaporation provide Off-white solid (0.11g), it is dissolved in ethyl acetate (10ml), and handles in ethyl acetate (5ml) with toxilic acid ().The thin solid that in nitrogen gas stream, filter to produce, provide trans-N1-(4-{4-amino-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl the 2-p-methoxy-phenyl) benzamide (0.108g) Off-white solid.
1H NMR (d 6DMSO, 400 MHz): 9.48 (1H, s), 8.28 (1H, s), 7.97 (3H, m), 7.53-7.63 (4H, m), 7.18 (1H, s), 7.08 (1H, d), 6.85 (1H, bs), 6.16 (6H, s), 4.61 (1H, m), 3,92 (3H, s), 2.70-3.11 (11H, m), 2.01 (7H, m), 1.58 (2H, m) .HPLC/MS (post=Pecosphere 3 C 183 μ
Condition=100%100mM ammonium acetate to 100% acetonitrile over 5 min), t r=1.83min, MH +=540.8 embodiment 321: cis-N1-(4-{4-amino-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl } the 2-p-methoxy-phenyl)-3-Phenylpropionamide and trans-N1-(4-{4-amino-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl } the 2-p-methoxy-phenyl)-the 3-Phenylpropionamide is a) at 0 ℃, past 4-[4-amino-5-(4-amino-3-p-methoxy-phenyl)-7H-pyrrolo-[2 in the nitrogen gas stream, 3-d] pyrimidin-7-yl]-1-hexanaphthene ketone (0.8g, 2.3mmol) pyridine (13ml) and methylene dichloride (32ml) solution in add hydrocinnamoyl chloride (0.57g, methylene dichloride 3.4mmol) (2ml) solution.Solution was stirred 2 hours at 0 ℃.Solution is by adding saturated citric acid solution (50ml) cancellation, and (2 * 50ml) wash organic layer with saturated aqueous citric acid solution.Dry (sodium sulfate) filters and evaporation, provides N1-{4-[4-amino-7-[4-(4-oxo cyclohexyl)-7H-pyrrolo-[2,3-d] pyrimidine-5-yl]-the 2-p-methoxy-phenyl)-3-Phenylpropionamide (1.0g, 92% crude product) brown foams.
1H?NMR(d 6?DMSO，400?MHz)：9.17(1H，s)，8.18(1H，s)，8.06(1H，d)，
7.51(1H，s)，7.18-7.29(6H，m)，7.09(1H，m)，6.99(1H，d)，6.21(2H，bs)，5.18(1H，
m)，3.88(3H，s)，1.99-2.93(12H，m).HPLC：(5?to?95％CH 3CN?in?0.1?N
Ammonium acetate aqueous solution 20 min.) t r=14.48 min, 92.2%.c) past purity is N1-{4-[4-amino-7-[4-(4-oxo cyclohexyl)-7H-pyrrolo-[2 of 92%, 3-d] pyrimidine-5-yl]-the 2-p-methoxy-phenyl)-3-Phenylpropionamide (1.0g), N methyl piperazine (0.63g, 6.3mmol), acetate (0.38g, in nitrogen, add in ethylene dichloride 6.3mmol) (100ml) solution in batches sodium triacetoxy borohydride (0.67g, 3.15mmol).Solution was passed through to add saturated sodium bicarbonate aqueous solution (50ml) cancellation in 20 hours then in stirring at room.Water layer with methylene dichloride (3 * 50ml) extractions, dry (sodium sulfate) filter also evaporation, and the sludge that provides is by quick purification by silica gel column chromatography, with methylene dichloride to 50% ethanol/methylene with 10% increment wash-out.★ merges F84-96, the evaporation provide cis-N1-(4-{4-amino-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl-the 2-p-methoxy-phenyl)-3-Phenylpropionamide (0.26g) oyster white spumescence vitreum.
HPLC:(5 to 95%CH 3CNin 0.1 N ammonium acetate aqueous solution eover20min.) t r=12.65min, 95.2%. 1HNMR (d 6DMSO, 400 MHz): 9.17 (1H, s), 8.14 (1H, s), 8.05 (1H, d), 7.28 (5H, m), 7.18 (1H, m), 7.10 (1H, s), 6.99 (1H, d), 6.11 (2H, bs), 4.67 (1H, m), 3.88 (3H, s), 2.90 (2H, m), 2.73 (2H, m), 2.50 (7H, m), 2.28 (3H, s), 2.06 (3H, m), 1.71 (2H, m), 1.55 (2H, m).
F121-138 is merged, evaporation, provide trans-N1-(4-{4-amino-7-[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl-the 2-p-methoxy-phenyl)-3-Phenylpropionamide (0.11g) white solid.HPLC:(5 to95%CH 3CNin 0.1 N ammonium acetate aqueous solution 20min.) t r=12.61 min, 96.2%. 1H NMR (d 6DMSO, 400 MHz): 9.16 (1H, s), 8.13 (1H, s), 8.04 (1H, d), 7.44 (1H, s), 7.29 (4H, m), 7.18 (1H, m), 7.09 (1H, s), 6.97 (1H, d), 6.11 (2H bs), 4.53 (1H, m), 3.88 (3H, s), 2.93 (2H, m), 2.71 (2H, m), 2.50 (4H, m), 2.30 (5H, m), 2.14 (3H, s), 1.89 (6H, m), 1.46 (2H, m). the general technology of the pyrrolopyrimidine aryl sulfonic acid amides of replacement is as follows:
5-(4-amino-7-[4-(4-methylpiperazine subbase) cyclohexyl]-the 0.19M pyridine solution of 7H-pyrrolo-[2,3-d] pyrimidine-4-amine is added in the aryl sulfonyl chloride that 1 equivalent replaces.With mixture heating up to 45 ℃, vibration 24 hours in Incubator Shaker simultaneously.Reaction mixture is by preparation RP-HPLC (Micromass/Gilson, Hypersil BDS C18,5 μ, 100 * 21.2mm with quality adjustment; The 100-100% ammonium acetate (0.05M, pH4.5)-acetonitrile, 12.5 minutes, 25ml/min) purifying.Comprise by above-mentioned technology synthetic compound
Title HPLC rt m/z
Min embodiment 322: trans-N-1-(4-{4-amino-7-3.18 648.39[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-2-(trifluoromethoxy)-1-benzsulfamide three maleate embodiment 323: trans-N-1-(4-{4-amino-7-3.14 604.03[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-5-chloro-2-thiophenesulfonamide benzsulfamide three maleate embodiment 324: trans-N-1-(4-{4-amino-7-3.07 616.1[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-2-chloro-4-fluoro-1-benzsulfamide benzsulfamide three Malaysias
Hydrochlorate embodiment 325: trans-N1-(4-{4-amino-7-3.39 632.12[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-2-fluorophenyl-2,3-two chloro-1-benzsulfamides three maleate embodiment 326: cis-N-1-(4-{4-amino-7-2.82 616.2[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-2-chloro-4-fluoro-1-benzsulfamide three maleate embodiment 327: cis-N-1-(4-4-amino-7-2.66 600.3[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-base-2-fluorophenyl)-2,5-two fluoro-1-benzsulfamides three maleate embodiment 328: trans-N-1-(4-{4-amino-7-2.53 600.3[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-2,6-two fluoro-1-benzsulfamides three maleate embodiment 329: trans-N-4-(4-{4-amino-7-2.63 622.1[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-2,1,3-diazosulfide-4-sulphonamide three toxilic acids
Salt embodiment 330: trans-N-1-(4-{4-amino-7-2.87 618.1[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-2,3,4-three fluoro-1-benzsulfamides three maleate embodiment 331: cis-N-1-(4-{4-amino-7-3.13 609.1[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-
2-nitro-1-benzsulfamide three maleate embodiment 332: cis-N-1-(4-{4-amino-7-2.89 582.1[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-
2-fluoro-1-benzsulfamide three maleate embodiment 333: cis-N-1-(4-{4-amino-7-3.4 668[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-2,4,6-three chloro-1-benzsulfamides three maleate embodiment 334: cis-N-1-(4-{4-amino-7-3.04 632.1[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-
2,6-two chloro-1-benzsulfamides three maleate embodiment 335: cis-N-1-(4-{4-amino-7-2.94 598.1[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-
2-chloro-1-benzsulfamide three maleate embodiment 336: cis-N-1-(4-{4-amino-7-2.76 582.1[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-
3-fluoro-1-benzsulfamide 2-maleate embodiment 337: cis-N-1-(4-{4-amino-7-3.01 604.3[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-
5-chloro-2-thiophenesulfonamide 2-maleate embodiment 338: cis-N-1-(4-{4-amino-7-3.38 718.3[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-4-bromo-2,6-two fluoro-1-benzsulfamides three toxilic acids
Salt embodiment 339: cis-N-1-(4-{4-amino-7-2.98 616.3[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-3-chloro-4-fluoro-1-benzsulfamide three maleate embodiment 340: cis-N-1-(4-{4-amino-7-3.02 690.3[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-
2-iodo-1-benzsulfamide three maleate embodiment 341: cis-N-1-(4-{4-amino-7-3.22 648.3[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-2-(trifluoromethoxy)-1-benzsulfamide three toxilic acids
Salt embodiment 342: cis-N-1-(4-{4-amino-7-2.97 600.3[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-
2,3-two chloro-1-benzsulfamides three maleate embodiment 343: cis-N-1-(4-{4-amino-7-3.12 612.3[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-2-chloro-6-methyl isophthalic acid-benzsulfamide three maleate embodiment 344: cis-N-1-(4-{4-amino-7-3.02 623.2[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-2-chloro-4-cyano group-1-benzsulfamide three maleate embodiment 345: cis-N-1-(4-{4-amino-7-3.08 618.3[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-2,3,4-three fluoro-1-benzsulfamides three maleate embodiment 346: cis-N-1-(4-{4-amino-7-2.98 600.3[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-3,4-two fluoro-1-benzsulfamides three maleate embodiment 347: cis-N-1-(4-{4-amino-7-3.13 660.2[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-4-bromo-2-fluoro-1-benzsulfamide three maleate embodiment 348: cis-N-1-(4-{4-amino-7-3.16 648.1[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-
5-bromo-2-thiophenesulfonamide three maleate embodiment 349: cis-N-1-(4-{4-amino-7-3.09 632.1[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-
2,4-two chloro-1-benzsulfamides three maleate embodiment 350: cis-N-1-(4-{4-amino-7-3.41 668.1[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-2,3,4-three chloro-1-benzsulfamides three maleate embodiment 351: cis-N-1-(4-{4-amino-7-3.29 683.9[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-3-bromo-5-chloro-2-thiophenesulfonamide three maleate embodiment 352: cis-N4-(4-{4-amino-7-3.73 622.1[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-2,1,3-diazosulfide-4-sulphonamide three toxilic acids
Salt embodiment 353: cis-N4-(4-{4-amino-7-2.8 606.1[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl)-the 2-fluorophenyl)-2,1,3-benzo oxadiazoles-4-sulphonamide three toxilic acids
Salt embodiment 354: cis-N-1-(4-{4-amino-7-3.18 638[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-2,5-two chloro-1-thiophenesulfonamides three maleate embodiment 355: cis-N4-(4-{4-amino-7-2.84 640.2[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-(7-chloro-2,1, the 3-diazosulfide)-the 4-sulphonamide
Three maleate embodiment 356: cis-N4-(4-{4-amino-7-2.89 636.2[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-(7-methyl-2,1, the 3-diazosulfide)-the 4-sulphonyl
Amine three maleate embodiment 357: cis-N4-(4-{4-amino-7-2.82 636.2[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-(5-methyl-2,1, the 3-diazosulfide)-the 4-sulphonyl
Amine three maleate embodiment 358: cis-N4-(4-{4-amino-7-2.82 656.2[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-(5-chloro-2,1, the 3-diazosulfide)-the 4-sulphonamide
Three maleate embodiment 359: cis-N-1-(4-{4-amino-7-3.01 612[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-3-chloro-2-methyl isophthalic acid-benzsulfamide three maleate embodiment 360: cis-N-1-(4-{4-amino-7-2.81 644.2[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-
2-bromo-1-benzsulfamide three maleate embodiment 361: cis-N-1-(4-{4-amino-7-3.29 758.1[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-2,5-two bromo-3,6-two fluoro-1-benzsulfamides three horses
Come hydrochlorate embodiment 362: cis-N-1-(4-{4-amino-7-2.77 632[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-2,3-two chloro-1-benzsulfamides three maleate embodiment 363: cis-N-1-(4-{4-amino-7-2.73 623.2[4-(4-methylpiperazine subbase) cyclohexyl]-7H-pyrrolo-[2,3-d] pyrimidine-5-yl }-the 2-fluorophenyl)-(2-nitrophenyl) the general synthetic methods of Toluidrin three maleate (a)
With 4-[4-amino-5-(4-amino-3-p-methoxy-phenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl]-1-hexanaphthene ketone (1.0g, 2.51mmol), (0.45g, 7.54mmol) mixture in ethylene dichloride (50ml) was stirring at room 30 minutes for suitable amine (7.54mmol) and Glacial acetic acid.(0.69g, 3.26mmol), mixture was stirring at room 18 hours to add sodium triacetoxy borohydride.(1.26g, 15.1mmol), mixture is stirred 1 hour to add entry (20ml) and sodium bicarbonate.With mixture filtration over celite pad, this pad washs with methylene dichloride (75ml).From the filtrate extracted organic phase, dried over mgso is filtered, with filtrate evaporated under reduced pressure as for.Cis and trans-isomer(ide) are used methyl alcohol: the dichloromethane gradient wash-out by quick silica gel column chromatography purifying.The suitable salt of method (b) is prepared as follows
Above-mentioned amine (0.909mmol) is dissolved in warm ethyl acetate (100ml), adds toxilic acid (0.32g, ethyl acetate 2.73mmol) (30ml) solution then.The salt that produces forms the oily resistates at drag and side.Pour out supernatant liquor, the water-soluble and freeze-drying of resistates provides salt method (c)
Guanidine is prepared as follows.Amine (0.536mmol) is dissolved in DMF (5ml) and is cooled to-5 ℃, add then 1-H pyrazoles-1-methane amide (95mg, 0.644mmol), inoculation add diisopropylethylamine (208mg, 1.6mmol).Reaction mixture was warmed to room temperature in 16 hours, then vacuum concentration.With reactant distribution between water (10ml) and ethyl acetate (10ml).Water is by freeze-drying and by the RP-HPLC purifying.HPLC scheme: 1.RP-HPLC-Hypersil HyPurity Elite C18,5mm, 200A, 250 * 4.6mm; 25-100% acetonitrile-0.1M ammonium acetate, 15 minutes, 1ml/min.2.RP-HPLC-Hypersil HyPurity Elite C18,5mm, 200A, 250 * 4.6mm; 5-100% acetonitrile-0.1M ammonium acetate, 15 minutes, 1ml/min. should be appreciated that, when needs, can use protecting group.The following example compound method for preparing:
Other chemistry of title synthetic method HPLC-RT m/z
(min)????????(MH +)
(scheme) embodiment 364: cis-4-c 14.56 511.7{4-[4-amino-5-(4-benzene (2) oxygen base phenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] cyclohexyl }-1-piperazine formyl imines (carboximidamide) embodiment 365: trans-4-c 14.25 511.7{4-[4-amino-5-(4-benzene (2) oxygen base phenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] cyclohexyl }-1-piperazine formyl Asia
Amine embodiment 366: trans-7-a, b 8.55 519.6 (4-{ methyl [2-(2-pyridine (2) base) ethyl] amino } cyclohexyl)-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidine-4-amine three toxilic acids
Salt embodiment 367: cis-3-a 10.21 472.6 is by the ({ 4-[4-amino-5-(4-benzene (2) hydrolysis prepares oxygen base phenyl)-7H-pyrrolo-[2 of ester, 3-d] pyrimidin-7-yl] cyclohexyl } amino) ({ 4-a 6.33 472.6 is by [4-amino-the 5-(4-phenoxy group (1) hydrolysis prepares phenyl)-7H-pyrrolo-[2 of ester for propionic acid embodiment 368:3-, 3-d] pyrimidin-7-yl] cyclohexyl } amino) propionic acid embodiment 369: cis-3-a, b 10.42 500.6 (4-[4-amino-5-(4-benzene (1) oxygen base phenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] and cyclohexyl } amino) ethyl propionate
The general synthetic method of 2-maleate (d)
(22mg adds suitable phosphonic acid ester (0.553mmol) in THF 0.553mmol) (2ml) solution, the mixture of generation stirred 20 minutes in this temperature, then stirring at room 10 minutes toward sodium hydride at 0 ℃.Reaction mixture being cooled to 0 ℃, adding 4-[4-amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] (200mg, THF 0.503mmol) (10ml) solution, the mixture of generation are warmed to room temperature and stirred 16 hours pimelinketone.Solvent removed in vacuo, resistates are distributed between ethyl acetate (10ml) and the water (10ml).Water layer is extracted to ethyl acetate again, and (in 3 * 5ml), (3 * 5ml) wash the organic layer water of merging, dry (sal epsom) and vacuum concentration.By quick purification by silica gel column chromatography (intermediate) or RP-HPLC (final product), provide required compound.Method (e)
Following hydrogenation.Mixture in ethanol (18ml) stirred 14 hours in nitrogen (4atm) with alkene (0.068mmol) and 10%Pd/C (12mg).Leach solid, with the filtrate vacuum concentration.Provide final compound by the RP-HPLC purifying.Method (f)
The reaction of lithium aluminum hydride is following to be carried out.With substrate (0.19mmol), (40mg, 1.07mmol) mixture in THF (5ml) was stirring at room 16 hours for lithium aluminum hydride.Fieser handles, and inoculation provides required compound by the RP-HPLC purifying.HPLC condition: RP-HPLC Pecosphere3 C18,33 * 4.6mm, 3m post; 0-100% acetonitrile-0.1M ammonium acetate, 5 minutes, flow velocity 4ml/min. should be appreciated that, when needs, can use protecting group.
Other chemistry of title synthetic method HPLC-RT m/z
(min) (MH +) embodiment 370:{4-[4-ammonia d 3.1 422.5 bases-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] inferior hexamethylene
Base } methyl nitrile embodiment 371:2-{4-[4-d 3.97 497.1 amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] cyclohexylidene } ra-butyl acetate embodiment 372:2-{4-[4-d 3.56 469.0 amino-5-(4-Phenoxyphenyl)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl] inferior hexamethylene
Base } ethyl acetate embodiment 373:2-{4-[4-d 2.69 441.5 amino-5-(4-phenoxy group benzene hydrolysis preparation base)-7H-pyrrolo-[2,3-d] pyrimidin-7-yl by ester] inferior hexamethylene
Base } acetate embodiment 374:7-[4-(2-f 2.11 428.5 is by the hydrogenation amino-ethyl) cyclohexyl]-5-aluminium lithium reduction (4-Phenoxyphenyl)-7H-unsaturated nitrile pyrrolo-[2,3-d] pyrimidine-preparation
4-amine embodiment 375:2-{4-[4-e 2.64 443.5 is by insatiable hunger amino-5-(the hydrogen base of 4-phenoxy group benzene and acid)-7H-pyrrolo-[2,3-ization preparation d] pyrimidin-7-yl] cyclohexyl }
Acetate

Claims (72)

1. the compound that following structural formula is represented With its pharmaceutical salts, wherein
The A ring is six Yuans aromatic nucleus or five or six Yuans assorted aromatic nucleus, the A ring is replaced by one or more following substituting groups non-imposedly: replace or unsubstituted aliphatic group, halogen replaces or unsubstituted aromatic base, replace or unsubstituted assorted aromatic base, replace or unsubstituted cycloalkyl, replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted aralkyl, replace or unsubstituted heteroaralkyl, cyano group, nitro ,-NR 4R 5,-C (O) 2H ,-OH replaces or unsubstituted carbalkoxy-C (O) 2-haloalkyl, replace or unsubstituted alkylthio ether, replace or the unsubstituted alkyl sulfoxide, replace or the unsubstituted alkyl sulfone, replace or unsubstituted arylthio ether, replace or unsubstituted aryl sulfoxide, replace or unsubstituted aryl sulfone, replace or the unsubstituted alkyl carbonyl-C (O)-haloalkyl, replace or unsubstituted aliphatic ether, replace or unsubstituted aromatic oxide, replace or unsubstituted methane amide tetrazyl, the fluoroform sulfoamido, the trifluoromethyl carbonylamino replaces or unsubstituted alkynyl, replaces or the unsubstituted alkyl amide group, replace or unsubstituted aryl amido group-NR 95C (O) R 95, replace or unsubstituted styryl and replacement or unsubstituted arylalkyl amide base, wherein R 95Be aliphatic group or aromatic base; L is-O-;-S-;-S (O)-;-S (O) 2-;-N (R)-;-N (C (O) OR)-;-N (C (O) R)-;-N (SO 2R);-CH 2O-;-CH 2S-;-CH 2N (R)-;-CH (NR)-;-CH 2N (C (O) R))-;-CH 2N (C (O) OR)-;-CH 2N (SO 2R)-;-CH (NHR)-;-CH (NHC (O) R)-;-CH (NHSO 2R)-;-CH (NHC (O) OR)-;-CH (OC (O) R)-;-CH (OC (O) NHR)-;-CH=CH-;-C (=NOR)-;-C (O)-;-CH (OR)-;-C (O) N (R)-;-N (R) C (O)-;-N (R) S (O)-;-N (R) S (O) 2-;-OC (O) N (R)-;-N (R) C (O) N (R)-;-NRC (O) O-;-S (O) N (R)-;-S (O) 2N (R)-; N (C (O) R) S (O)-; N (C (O) R) S (O) 2-;-N (R) S (O) N (R)-;-N (R) S (O) 2N (R)-;-C (O) N (R) C (O)-;-S (O) N (R) C (O)-;-S (O) 2N (R) C (O)-;-OS (O) N (R)-;-OS (O) 2N (R)-;-N (R) S (O) O-;-N (R) S (O) 2O-;-N (R) S (O) C (O)-;-N (R) S (O) 2C (O)-;-SON (C (O) R)-;-SO 2N (C (O) R)-;-N (R) SON (R)-;-N (R) SO 2N (R)-;-C (O) O-;-N (R) P (OR ') O-;-N (R) P (OR ')-;-N (R) P (O) (OR ') O-;-N (R) P (O) (OR ')-;-N (C (O) R) P (OR ') O-;-N (C (O) R) P (OR ')-;-N (C (O) R) P (O) (OR ') O-or-N (C (O) R) P (OR ')-, wherein R and R ' are-H independently of one another, acyl group, replace or unsubstituted aliphatic group, replace or unsubstituted aromatic base, replace or unsubstituted assorted aromatic base, or replacement or unsubstituted cycloalkyl; Or
L is-R bN (R) S (O) 2-,-R bN (R) P (O)-, or-R bN (R) P (O) O-, wherein R bBe alkylidene group, when itself and the sulphonamide that is connected, inferior phosphonic amide, or the phosphono amido forms together the time and A ring condensed five or six membered ring; Or
L represents one of following structural:
Figure A9981321700041
R wherein 85With inferior phosphonic amide, or phosphonic amide is 5-together, 6-, or 7-person's fragrance, assorted fragrance or Heterocyclylalkyl ring system;
R 1It is the aliphatic group that replaces, the cycloalkyl that replaces, the bicyclic alkyl of replacement, the cycloalkenyl group of replacement, the aromatic base of non-imposed replacement, the assorted aromatic base of non-imposed replacement, the heteroaralkyl of non-imposed replacement, the Heterocyclylalkyl of non-imposed replacement, the assorted bicyclic alkyl of non-imposed replacement, the alkylamino of non-imposed replacement, the arylamino of non-imposed replacement, non-imposed replacement-S (O) 2-alkyl or non-imposed replacement-S (O) 2-cycloalkyl ,-C (O)-alkyl or non-imposed replacement-C (O)-alkyl, condition is to work as R 1When being aliphatic group or cycloalkyl, R 1Removing property ground is not replaced by one or more substituting groups of being made up of hydroxyl and lower alkyl ether that are selected from, condition is that aliphatic group removing property ground is not replaced by one or more aliphatic groups, wherein one or more substituting groups are selected from: replace or unsubstituted aliphatic group, replace or unsubstituted aromatic base, replace or unsubstituted assorted aromatic base, replace or unsubstituted aralkyl, replace or unsubstituted heteroaralkyl, replace or unsubstituted cycloalkyl, replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted aromatic oxide, replace or unsubstituted aliphatic ether, replace or unsubstituted carbalkoxy, replace or the unsubstituted alkyl carbonyl, replace or unsubstituted aryl carbonyl, replace or unsubstituted heteroaryl carbonyl, replace or unsubstituted aryloxy carbonyl,-OH replaces or unsubstituted aminocarboxyl oxime, replace or unsubstituted azabicycloalkyl, Heterocyclylalkyl, oxo base, aldehyde, replace or the unsubstituted alkyl sulfoamido, replace or unsubstituted aryl-sulfonyl amino, replace or unsubstituted bicyclic alkyl, replace or unsubstituted assorted bicyclic alkyl, cyano group ,-NH 2, alkylamino, urea groups, thioureido and-B-E;
B replaces or unsubstituted cycloalkyl, replaces or unsubstituted Heterocyclylalkyl, replaces or unsubstituted aromatic base, replaces or unsubstituted assorted aromatic base alkylidene group, aminoalkyl group, alkylidene group carbonyl, or aminoalkyl group carbonyl;
E replaces or unsubstituted azacycloalkyl, replace or unsubstituted azacycloalkyl carbonyl, replace or unsubstituted azacycloalkyl alkylsulfonyl, replace or unsubstituted azacycloalkyl alkyl, replace or unsubstituted heteroaryl, replace or unsubstituted heteroaryl carbonyl, replace or unsubstituted heteroarylsulfonyl, replace or unsubstituted heteroaralkyl, replace or the unsubstituted alkyl sulfoamido, replace or unsubstituted aryl-sulfonyl amino, replace or unsubstituted bicyclic alkyl, replace or unsubstituted urea groups, replace or unsubstituted thioureido or replacement or unsubstituted aryl;
R 2Be-H, replace or unsubstituted aliphatic group, replace or unsubstituted cycloalkyl halogen,-OH, cyano group replaces or unsubstituted aryl group, replaces or unsubstituted assorted aromatic group, replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted aralkyl, replace or unsubstituted heteroaralkyl-NR 4R 5, or-C (O) NR 4R 5
R 3Be to replace or unsubstituted cycloalkyl, replace or unsubstituted aryl group, replace or unsubstituted assorted aromatic group, replace or unsubstituted Heterocyclylalkyl;
Condition is to work as R 3Be to replace or unsubstituted aliphatic group, when replacement or unsubstituted thiazolinyl, L is
-SN(R)-，-S(O)N(R)-，-S(O) 2N(R)-，-N(R)S-，
-N(R)S(O)-，-N(R)S(O) 2-，-N(R)SN(R’)-，-N(R)S(O)N(R’)-，
or-N(R)S(O) 2N(R’)-
Condition is to be-O--CH as L 2NR-,-C (O) NR-or-NRC (O)-, and R 3When being azacycloalkyl or azepine heteroaryl, j is 0; And
When L is-O-and R 3When being phenyl, j is 0;
R 4, R 5Form 3,4,5,6 or 7-person replaces or unsubstituted Heterocyclylalkyl together with nitrogen-atoms, replace or unsubstituted assorted bicyclic alkyl or replacement or unsubstituted assorted aromatic base; Or
R 4And R 5Be-H azabicycloalkyl, replacement or unsubstituted alkyl or Y-Z independently of one another;
Y is selected from-C (O)-and ,-(CH 2) p-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) pO-, (CH 2) pNH-, (CH 2) pS-, (CH 2) pS (O)-and (CH 2) pS (O) 2-form one group;
P is 0 to 6 integer;
Z is-H to replace or unsubstituted alkyl replacement or unsubstituted amino, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl or replacement or unsubstituted Heterocyclylalkyl; With
J is 0 to 6 integer.
2. the compound of claim 1, wherein R 3Be selected from and replace or unsubstituted phenyl, replace or unsubstituted naphthyl, replace or the unsubstituted pyridine base, replace or unsubstituted thienyl, replace or unsubstituted benzotriazole base, replace or unsubstituted THP trtrahydropyranyl, replace or unsubstituted tetrahydrofuran base, replace or unsubstituted dioxane, replace or unsubstituted dioxolane, replace or unsubstituted quinolines, replace or unsubstituted thiazole, replace or unsubstituted isoxzzole, replace or unsubstituted cyclopentyl, replace or unsubstituted cumarone, replace or unsubstituted thionaphthene, replace or unsubstituted imidazoles, replace or unsubstituted pyrroles, replace or unsubstituted pyrimidyl, replace or unsubstituted indyl, replace or unsubstituted benzisoxa oxazolyl, replace or unsubstituted benzisothiazole, replace or unsubstituted benzothiazole, replace or unsubstituted benzoxazoles, replace or unsubstituted benzoglyoxaline, replace or unsubstituted benzo oxadiazoles, replace or unsubstituted diazosulfide, replace or unsubstituted isoquinolyl, replace or unsubstituted quinoxalinyl, replace or unsubstituted indoles or replacement or unsubstituted pyrazoles.
3. the compound of claim 2, wherein R 3Be selected from following substituting group and replace by one or more: F, Cl, Br, I, CH 3, NO 2, OCF 3, OCH 3, CN ,-CHO, CO 2CH 3, CF 3, the tertiary butyl, pyridyl, pyridyloxy replaces or unsubstituted oxazolyl, replaces or unsubstituted thiazolyl, replace or unsubstituted benzyl, replace or unsubstituted phenoxy, replace or unsubstituted phenyl, replace or unsubstituted amino, carboxyl, replace or unsubstituted tetrazyl styryl ,-S (O) x-(replacing or unsubstituted aryl) ,-S (O) x-x=0 wherein, 1,2-(replacing or unsubstituted heteroaryl) replaces or unsubstituted heteroaryl, replaces or unsubstituted Heterocyclylalkyl alkynyl ,-C (O) NR fR g, R cAnd CH 2OR c
R f, R gForm 3-together with nitrogen-atoms, 4-, 5-, 6-or 7-person replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted assorted bicyclic alkyl or replacement or unsubstituted heteroaryl; Or
R fAnd R gBe-H to replace or unsubstituted aliphatic group or replacement or unsubstituted aromatic base independently of one another; With
R cBe hydrogen, or replacement or unsubstituted alkyl or replacement or unsubstituted aryl;-W-(CH 2) t-NR dR e,-W-(CH 2) t-O-alkyl ,-W-(CH 2) t-S-alkyl ,-W-(CH 2) t-OH; Or-W-(CH 2) t-OR f
T is 0 to 6 integer;
W be chemical bond or-O-,-S-,-S (O)-,-S (O) 2-, or-NR k-;
R kBe-H or alkyl; With
R d, R eForm 3-together with connected nitrogen-atoms, 4-, 5-, 6-or 7-person replace or unsubstituted Heterocyclylalkyl or replacement or unsubstituted assorted bicyclic alkyl; Or
R dAnd R eBe independently of one another-H, alkyl, alkyloyl or-K-D;
K is-S (O) 2-,-C (O)-,-C (O) NH-,-C (O) 2-, or directly key connects;
D replaces or unsubstituted aryl, replace or unsubstituted heteroaryl, replace or unsubstituted aralkyl, replace or unsubstituted assorted aromatic base, replace or unsubstituted heteroaralkyl, replace or unsubstituted cycloalkyl, replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted amino, replace or unsubstituted aminoalkyl group, replace or unsubstituted amino cycloalkyl COOR i, or replacement or unsubstituted alkyl; With
R iBe to replace or unsubstituted aliphatic group or replacement or unsubstituted aromatic base.
4. the compound of claim 3, wherein R 3Be to replace or unsubstituted phenyl.
5. the compound of claim 1, wherein the A ring is to replace or unsubstituted phenyl, replaces or unsubstituted thienyl, replaces or unsubstituted naphthyl, replace or the unsubstituted pyridine base, or replacement or unsubstituted indoles.
6. the compound of claim 5, wherein the A ring is selected from following substituting group and replaces by one or more: F, Cl, Br, I, CH 3, NO 2, OCF 3, OCH 3, CN, CO 2CH 3, CF 3, the tertiary butyl, pyridyl; replace or unsubstituted oxazolyl, replace or unsubstituted benzyl, replace or unsubstituted benzenesulfonyl; replace or unsubstituted phenoxy, replace or unsubstituted phenyl, replace or unsubstituted amino; carboxyl replaces or unsubstituted tetrazyl styryl;-S-(replacing or unsubstituted aryl) ,-S-(replacing or unsubstituted heteroaryl) replaces or unsubstituted heteroaryl; replace or unsubstituted Heterocyclylalkyl alkynyl ,-C (O) NR fR g, R cAnd CH 2OR cR f, R gForm 3-together with nitrogen-atoms, 4-, 5-, 6-or 7-person replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted assorted bicyclic alkyl or replacement or unsubstituted heteroaryl; Or
R fAnd R gBe-H to replace or unsubstituted aliphatic group or replacement or unsubstituted aromatic base independently of one another; With
R cBe hydrogen, or replacement or unsubstituted alkyl or replacement or unsubstituted aryl;-W-(CH 2) t-NR dR e,-W-(CH 2) t-O-alkyl ,-W-(CH 2) t-S-alkyl ,-W-(CH 2) t-OH; Or-W-(CH 2) t-OR f
T is 0 to 6 integer;
W be chemical bond or-O-,-S-,-S (O)-,-S (O) 2-, or-NR k-;
R kBe-H or alkyl; With
R d, R eForm 3-together with connected nitrogen-atoms, 4-, 5-, 6-or 7-person replace or unsubstituted Heterocyclylalkyl or replacement or unsubstituted assorted bicyclic alkyl; Or
R dAnd R eBe independently of one another-H, alkyl, alkyloyl or-K-D;
K is-S (O) 2-,-C (O)-,-C (O) NH-,-C (O) 2-, or directly key connects;
D replaces or unsubstituted aryl, replace or unsubstituted heteroaryl, replace or unsubstituted aralkyl, replace or unsubstituted assorted aromatic base, replace or unsubstituted heteroaralkyl, replace or unsubstituted cycloalkyl, replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted amino, replace or unsubstituted aminoalkyl group, replace or unsubstituted amino cycloalkyl COOR i, or replacement or unsubstituted alkyl; With
R iBe to replace or unsubstituted aliphatic group or replacement or unsubstituted aromatic base.
7. the compound of claim 6, wherein the A ring is to replace or unsubstituted phenyl.
8. the compound of claim 1, wherein R 1It is the following formula group Wherein m is 0 to 3 integer.
9. the compound of claim 1, wherein R 1It is the following formula group
Figure A9981321700101
Wherein: m is 0 to 3 integer; T is 1 to 6 integer; R 8, R 9Form 3-together with nitrogen-atoms, 4-, 5-, 6-or 7-person replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted assorted aromatic base, or replacement or unsubstituted assorted bicyclic alkyl; Or R 8And R 9Be-H azabicycloalkyl, azacycloalkyl or Y independently of one another 2-Z 2Y 2Be-C (O)-,-(CH 2) q-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) qO-, (CH 2) qNH-, (CH 2) qS-, (CH 2) qS (O)-and (CH 2) qS (O) 2-; Q is 0 to 6 integer; Z 2Be to replace or unsubstituted alkyl, replace or unsubstituted amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl or replacement or unsubstituted Heterocyclylalkyl.
10. the compound of claim 1, wherein R 1It is the following formula group
Figure A9981321700102
Wherein: m is 0 to 3 integer; T is 1 to 6 integer; R 8, R 9Form 3-together with nitrogen-atoms, 4-, 5-, 6-or 7-person replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted assorted aromatic base, or replacement or unsubstituted assorted bicyclic alkyl; Or R 8And R 9Be-H azabicycloalkyl, azacycloalkyl or Y independently of one another 2-Z 2Y 2Be-C (O)-,-(CH 2) q-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) qO-, (CH 2) qNH-, (CH 2) qS-, (CH 2) qS (O)-and (CH 2) qS (O) 2-; Q is 0 to 6 integer; Z 2Be to replace or unsubstituted alkyl, replace or unsubstituted amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl or replacement or unsubstituted Heterocyclylalkyl; R 77Be-OR 78, or-NR 79R 80R 78Be-H or replacement or unsubstituted aliphatic group; R 79, R 80Form 3-together with nitrogen-atoms, 4-, 5-, 6-or 7-person replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted assorted aromatic base, or replacement or unsubstituted assorted bicyclic alkyl; Or R 79And R 80Be-H azabicycloalkyl, azacycloalkyl or Y independently of one another 3-Z 3Y 3Be selected from-C (O)-,-(CH 2) q-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) qO-, (CH 2) qNH-, (CH 2) qS-, (CH 2) qS (O)-and (CH 2) qS (O) 2-; Q is 0 to 6 integer; Z 3Be-H, replace or unsubstituted alkyl, replace or unsubstituted amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl or replacement or unsubstituted Heterocyclylalkyl.
11. the compound of claim 1, wherein R 1It is the following formula group
Figure A9981321700111
Wherein: v is 1 to 3 integer; And R 10Be-H azabicycloalkyl, Heterocyclylalkyl or Y 2-Z 2Y 2Be-C (O)-,-(CH 2) q-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) qO-, (CH 2) qNH-, (CH 2) qS-, (CH 2) qS (O)-and (CH 2) qS (O) 2-; Q is 0 to 6 integer; Z 2Be to replace or unsubstituted alkyl, replace or unsubstituted amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl or replacement or unsubstituted Heterocyclylalkyl.
12. the compound of claim 1, wherein R 1It is the following formula group Wherein: m is 0 to 3 integer; R 10Be-H azabicycloalkyl, Heterocyclylalkyl or Y 2-Z 2Y 2Be-C (O)-,-(CH 2) q-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) qO-, (CH 2) qNH-, (CH 2) qS-, (CH 2) qS (O)-and (CH 2) qS (O) 2-; Q is 0 to 6 integer; And Z 2Be-H, replace or unsubstituted alkyl, replace or unsubstituted amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl or replacement or unsubstituted Heterocyclylalkyl; And R 11Represent one or more being independently selected from by hydrogen, hydroxyl, the oxo base, replace or unsubstituted aliphatic group, replace or unsubstituted aromatic base, replace or unsubstituted assorted aromatic base, replace or unsubstituted carbalkoxy, replace or unsubstituted alkoxyalkyl, replace or unsubstituted aminocarboxyl, replace or the unsubstituted alkyl carbonyl, replace or unsubstituted aryl carbonyl, replace or unsubstituted heteroaryl carbonyl, one group of substituting group that replacement or unsubstituted aminoalkyl group and replacement or unsubstituted aralkyl are formed, condition is that the carbon atom adjacent with nitrogen-atoms do not replaced by hydroxyl.
13. the compound of claim 1, wherein R 1It is the following formula group
Figure A9981321700131
Wherein: R 10Be H, azabicycloalkyl, Heterocyclylalkyl or Y 2-Z 2Y 2Be-C (O)-,-(CH 2) q-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) qO-, (CH 2) qNH-, (CH 2) qS-, (CH 2) qS (O)-and (CH 2) qS (O) 2-; Q is 0 to 6 integer; And Z 2Be-H, replace or unsubstituted alkyl, replace or unsubstituted amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl or replacement or unsubstituted Heterocyclylalkyl.
14. the compound of claim 1, wherein R 1It is the following formula group Wherein: r is 1 to 6 integer; And R 8, R 9Form 3-together with nitrogen-atoms, 4-, 5-, 6-or 7-person replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted assorted aromatic base, or replacement or unsubstituted assorted bicyclic alkyl; Or R 8And R 9Be-H azabicycloalkyl, azacycloalkyl or Y independently of one another 2-Z 2Y 2Be-C (O)-,-(CH 2) q-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) qO-, (CH 2) qNH-, (CH 2) qS-, (CH 2) qS (O)-and (CH 2) qS (O) 2-; Q is 0 to 6 integer; Z 2Be to replace or unsubstituted alkyl, replace or unsubstituted amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl or replacement or unsubstituted Heterocyclylalkyl.
15. the compound of claim 1, wherein R 1It is the following formula group Wherein: w is 0 to 4 integer; T is 0 to 6 integer; U is 0 or 1; R 12Be hydrogen or replacement or unsubstituted alkyl; R 8, R 9Form 3-together with nitrogen-atoms, 4-, 5-, 6-or 7-person replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted assorted aromatic base, or replacement or unsubstituted assorted bicyclic alkyl; Or R 8And R 9Be-H azabicycloalkyl, azacycloalkyl or Y independently of one another 2-Z 2Y 2Be-C (O)-,-(CH 2) q-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) qO-, (CH 2) qNH-, (CH 2) qS-, (CH 2) qS (O)-and (CH 2) qS (O) 2-; Q is 0 to 6 integer; Z 2Be-H, replace or unsubstituted alkyl, replace or unsubstituted amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl or replacement or unsubstituted Heterocyclylalkyl.
16. the compound of claim 1, wherein R 1It is the following formula group
Figure A9981321700151
Wherein: w is 0 to 4 integer; T is 0 to 6 integer; U is 0 or 1; R 12Be hydrogen or replacement or unsubstituted alkyl; R 8, R 9Form 3-together with nitrogen-atoms, 4-, 5-, 6-or 7-person replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted assorted aromatic base, or replacement or unsubstituted assorted bicyclic alkyl; Or R 8And R 9Be-H azabicycloalkyl, azacycloalkyl or Y independently of one another 2-Z 2Y 2Be-C (O)-,-(CH 2) q-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) qO-, (CH 2) qNH-, (CH 2) qS-, (CH 2) qS (O)-and (CH 2) qS (O) 2-; Q is 0 to 6 integer; Z 2Be-H, replace or unsubstituted alkyl, replace or unsubstituted amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl or replacement or unsubstituted Heterocyclylalkyl.
17. the compound of claim 14, wherein R 8, R 9Form the Heterocyclylalkyl of following formula together with nitrogen-atoms Wherein: R 13, R 14, R 15, R 16, R 17, R 18R 19And R 20Be low alkyl group or hydrogen independently of one another; Or substituent R 13And R 14R 15And R 16R 17And R 18Or R 19And R 20In at least one pair of be Sauerstoffatom together; Or R 13And R 15In at least one be cyano group, CONHR 21, COOR 21, CH 2OR 21Or CH 2NR 21(R 22); R 21, R 22Form 3-together with nitrogen-atoms, 4-, 5-, 6-or 7-person replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted assorted aromatic base, or replacement or unsubstituted assorted bicyclic alkyl; Or R 21And R 22Be-H azabicycloalkyl, azacycloalkyl or Y independently of one another 3-Z 3Y 3Be selected from-C (O)-,-(CH 2) q-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) qO-, (CH 2) qNH-, (CH 2) qS-, (CH 2) qS (O)-and (CH 2) qS (O) 2-; Q is 0 to 6 integer; Z 3Be-H, replace or unsubstituted alkyl, replace or unsubstituted amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl or replacement or unsubstituted Heterocyclylalkyl; X is-O--S-,-SO-,-SO 2-,-CH 2-,-CH (OR 23)-or NR 23R 23Be-H, replace or unsubstituted alkyl, replace or unsubstituted aryl, replace or unsubstituted aralkyl-C (NH) NH 2,-C (O) R 24, or-C (O) OR 24R 24Be hydrogen, replace or unsubstituted alkyl, replace or unsubstituted aryl or replacement or unsubstituted aralkyl; With u be 0 or 1.
18. the compound of claim 14, wherein R 8, R 9Form the Heterocyclylalkyl of following formula together with nitrogen-atoms Wherein: R 25And R 26Be hydrogen or low alkyl group independently of one another; Or R 25And R 26Be Sauerstoffatom together; And R 21, R 22Form 3-together with nitrogen-atoms, 4-, 5 or 6 Yuans replace or unsubstituted Heterocyclylalkyl, or R 21And R 22Be-H azabicycloalkyl, azacycloalkyl or Y independently of one another 3-Z 3Y 3Be selected from-C (O)-,-(CH 2) s-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) sO-, (CH 2) sNH-, (CH 2) sS-, (CH 2) sS (O)-and (CH 2) sS (O) 2-; S is 0 to 6 integer; And Z 3Be-H, replace or unsubstituted alkyl, replace or unsubstituted amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl or replacement or unsubstituted Heterocyclylalkyl; I is 1 to 6 integer; T is 0 to 6 integer.
19. the compound of claim 14, wherein R 8, R 9Form the Heterocyclylalkyl of following formula together with nitrogen-atoms
Figure A9981321700172
Wherein: i is 1 to 6 integer; And R 27Be CH 2OH, C (O) NR 24R 28Or COOR 24R 24And R 28Be hydrogen or replacement or unsubstituted alkyl independently of one another, replace or unsubstituted aryl or replacement or unsubstituted aralkyl.
20. the compound of claim 14, wherein R 8, R 9Form the Heterocyclylalkyl of following formula together with nitrogen-atoms
Figure A9981321700181
Wherein: R 29Be-Cl, replace or unsubstituted alkyl, replace or unsubstituted aryl, or replacement or unsubstituted aralkyl, carboxylic acid, cyano group, C (O) OR 30, CH 2OR 30, CH 2NR 21R 22Or C (O) NR 21R 22R 30Be-H, replace or unsubstituted alkyl, replace or unsubstituted aryl, or replacement or unsubstituted aralkyl, replace or unsubstituted Heterocyclylalkyl or heterocyclic aryl; HR 21, R 22Form 3-together with nitrogen-atoms, 4-, 5 or 6 Yuans replace or unsubstituted Heterocyclylalkyl, or R 21And R 22Be-H azabicycloalkyl, azacycloalkyl or Y independently of one another 3-Z 3Y 3Be selected from-C (O)-,-(CH 2) t-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) tO-, (CH 2) tNH-, (CH 2) tS-, (CH 2) tS (O)-and (CH 2) tS (O) 2-; T is 0 to 6 integer; And Z 3Be-H, replace or unsubstituted alkyl, replace or unsubstituted amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl or replacement or unsubstituted Heterocyclylalkyl.
21. the compound of claim 14, wherein R 8, R 9At least one be formula Y 3-D, wherein D is a following formula Wherein: Y 3Be selected from-C (O)-,-(CH 2) t-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) tO-, (CH 2) tNH-, (CH 2) tS-, (CH 2) tS (O)-and (CH 2) tS (O) 2-; T is 0 to 6 integer; T is-O-,-C (O)-and ,-S-,-SO-,-SO 2-,-CH 2-,-CH (OR 24)-or-N (R 24)-; R 24Be hydrogen or replacement or unsubstituted alkyl, aryl or aralkyl; With x be 0,1 or 2.
22. the compound of claim 14, wherein R 8And R 9At least one be formula Y 3-N (R 31) R 32, wherein: Y 3Be selected from-C (O)-,-(CH 2) t-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) tO-, (CH 2) tNH-, (CH 2) tS-, (CH 2) tS (O)-and (CH 2) tS (O) 2-; T is 0 to 6 integer; R 31And R 32Be to replace or unsubstituted carboxyalkyl independently of one another, replace or unsubstituted alkoxycarbonyl alkyl, replace or unsubstituted hydroxyalkyl, replace or the unsubstituted alkyl alkylsulfonyl, replace or unsubstituted alkyl carbonyl or replacement or unsubstituted cyano group alkyl; R 31And R 32, form 5-or 6-element heterocycle alkyl with nitrogen-atoms, replace or unsubstituted assorted aromatic base or replacement or unsubstituted assorted bicyclic alkyl.
23. the compound of claim 15, wherein R 8, R 9Form the Heterocyclylalkyl of following formula together with nitrogen-atoms
Figure A9981321700191
R wherein 13, R 14, R 15, R 16, R 17, R 18, R 19And R 20Be low alkyl group or hydrogen independently of one another; Or substituent R 13And R 14R 15And R 16R 17And R 18Or R 19And R 20In at least one pair of be Sauerstoffatom together; Or R 13And R 15In at least one be cyano group, CONHR 21, COOR 21, CH 2OR 21Or CH 2NR 21(R 22); R 21, R 22Form 3-together with nitrogen-atoms, 4-, 5-, 6-or 7-person replace or unsubstituted Heterocyclylalkyl, replace or unsubstituted assorted aromatic base, or replacement or unsubstituted assorted bicyclic alkyl; Or R 21And R 22Be-H azabicycloalkyl, azacycloalkyl or Y independently of one another 3-Z 3Y 3Be selected from-C (O)-,-(CH 2) s-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) sO-, (CH 2) sNH-, (CH 2) sS-, (CH 2) sS (O)-and (CH 2) sS (O) 2-; S is 0 to 6 integer; And Z 3Be-H, replace or unsubstituted alkyl, replace or unsubstituted amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl or replacement or unsubstituted Heterocyclylalkyl; X is-O--S-,-SO-,-SO 2-,-CH 2-,-CH (OR 23)-or NR 23R 23Be-H, replace or unsubstituted alkyl, replace or unsubstituted aryl, replace or unsubstituted aralkyl-C (NH) NH 2,-C (O) R 24, or-C (O) OR 24R 24Be hydrogen, replace or unsubstituted alkyl, replace or unsubstituted aryl or replacement or unsubstituted aralkyl; With y be 0 or 1.
24. the compound of claim 15, wherein R 8, R 9Form the Heterocyclylalkyl of following formula together with nitrogen-atoms
Figure A9981321700201
Wherein: R 25And R 26Be hydrogen or low alkyl group independently of one another; Or R 25And R 26Be Sauerstoffatom together; And R 21, R 22Form 3-together with nitrogen-atoms, 4-, 5 or 6 Yuans replace or unsubstituted Heterocyclylalkyl, or R 21And R 22Be-H azabicycloalkyl, azacycloalkyl or Y independently of one another 3-Z 3Y 3Be selected from-C (O)-,-(CH 2) s-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) sO-, (CH 2) sNH-, (CH 2) sS-, (CH 2) sS (O)-and (CH 2) sS (O) 2-; S is the integer of O to 6; And Z 3Be-H, replace or unsubstituted alkyl, replace or unsubstituted amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl or replacement or unsubstituted Heterocyclylalkyl; R is 1 to 6 integer; With z be 0 to 6 integer.
25. the compound of claim 15, wherein R 8, R 9Form the Heterocyclylalkyl of following formula together with nitrogen-atoms
Figure A9981321700211
Wherein: i is 1 to 6 integer; And R 27Be CH 2OH, C (O) NR 24R 28Or COOR 24R 24And R 28Be hydrogen or replacement or unsubstituted alkyl independently of one another, replace or unsubstituted aryl or replacement or unsubstituted aralkyl.
26. the compound of claim 15, wherein R 8, R 9Form the Heterocyclylalkyl of following formula together with nitrogen-atoms
Figure A9981321700212
Wherein: R 29Be to replace or unsubstituted alkyl, replace or unsubstituted aryl, or replacement or unsubstituted aralkyl, carboxylic acid, cyano group, C (O) OR 30, CH 2OR 30, CH 2NR 21R 22Or C (O) NR 21R 22R 30Be-H, replace or unsubstituted alkyl, replace or unsubstituted aryl, or replacement or unsubstituted aralkyl, replace or unsubstituted Heterocyclylalkyl or heterocyclic aryl; And R 21, R 22Form 3-together with nitrogen-atoms, 4-, 5 or 6 Yuans replace or unsubstituted Heterocyclylalkyl, or R 21And R 22Be-H azabicycloalkyl, azacycloalkyl or Y independently of one another 3-Z 3Y 3Be selected from-C (O)-,-(CH 2) s-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) sO-, (CH 2) sNH-, (CH 2) sS-, (CH 2) sS (O)-and (CH 2) sS (O) 2-; S is 0 to 6 integer; And Z 3Be-H, replace or unsubstituted alkyl, replace or unsubstituted amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl or replacement or unsubstituted Heterocyclylalkyl.
27. the compound of claim 15, wherein R 8, R 9At least one be formula Y 3-D, wherein D is a following formula
Figure A9981321700221
Wherein: Y 3Be selected from-C (O)-,-(CH 2) s-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) sO-, (CH 2) sNH-, (CH 2) sS-, (CH 2) sS (O)-and (CH 2) sS (O) 2-; S is 0 to 6 integer; T is-O-,-C (O)-and ,-S-,-SO-,-SO 2-,-CH 2-,-CH (OR)-or-N (R 33)-; R 33Be hydrogen or replacement or unsubstituted alkyl, aryl or aralkyl ,-C (NH) NH 2,-C (O) R 34, or-C (O) OR 34R 34Be hydrogen or replacement or unsubstituted alkyl, aryl or aralkyl; With x be 0,1 or 2.
28. the compound of claim 15, wherein R 8And R 9At least one be formula Y 3-N (R 31) R 32, wherein: Y 3Be selected from-C (O)-,-(CH 2) s-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) sO-, (CH 2) sNH-, (CH 2) sS-, (CH 2) sS (O)-and (CH 2) sS (O) 2-; S is 0 to 6 integer; R 31And R 32Be to replace or unsubstituted carboxyalkyl independently of one another, replace or unsubstituted alkoxycarbonyl alkyl, replace or unsubstituted hydroxyalkyl, replace or the unsubstituted alkyl alkylsulfonyl, replace or unsubstituted alkyl carbonyl or replacement or unsubstituted cyano group alkyl; R 31And R 32Form 5-or 6-element heterocycle alkyl with nitrogen-atoms, replace or unsubstituted assorted aromatic base or replacement or unsubstituted assorted bicyclic alkyl.
29. the compound of claim 12, wherein Z 2Be formula N (R 35) R 36, R wherein 35And R 36Be hydrogen, alkyl, carbalkoxy, alkoxyalkyl, hydroxyalkyl, aminocarboxyl, cyano group, alkyl-carbonyl or aralkyl independently of one another.
30. the compound of claim 12, wherein Z 2It is following formula
Figure A9981321700231
Wherein: each X 1Be CH or N independently; And R 37Be hydrogen, cyano group or replacement or unsubstituted alkyl replace or unsubstituted carbalkoxy, replace or unsubstituted alkoxyalkyl, replace or unsubstituted hydroxyalkyl, replace or unsubstituted aminocarboxyl, replace or unsubstituted alkyl carbonyl or replacement or unsubstituted aralkyl.
31. the compound of claim 12, wherein Z 2It is following formula
Figure A9981321700241
Wherein g is 0 to 3 integer; T is-O-,-C (O)-and ,-S-,-SO-, CH 2-,-CH (OR 34)-or-N (R 34)-; R 34Be hydrogen or replacement or unsubstituted alkyl, replace or unsubstituted aryl or replacement or unsubstituted aralkyl; And R 37Be hydrogen, cyano group or replacement or unsubstituted alkyl replace or unsubstituted carbalkoxy, replace or unsubstituted alkoxyalkyl, replace or unsubstituted hydroxyalkyl, replace or unsubstituted aminocarboxyl, replace or unsubstituted alkyl carbonyl or replacement or unsubstituted aralkyl.
32. the compound of claim 12, wherein Z 2It is following formula
Figure A9981321700242
Wherein g is 0 to 3 integer; And R 37Be hydrogen, cyano group or replacement or unsubstituted alkyl replace or unsubstituted carbalkoxy, replace or unsubstituted alkoxyalkyl, replace or unsubstituted hydroxyalkyl, replace or unsubstituted aminocarboxyl, replace or unsubstituted alkyl carbonyl or replacement or unsubstituted aralkyl.
33. the compound of claim 12, wherein Z 2It is following formula Wherein T is-O-,-C (O)-and ,-S-,-SO-, CH 2-,-CH (OR 34)-or-N (R 34)-; R 34Be hydrogen or replacement or unsubstituted alkyl, replace or unsubstituted aryl or replacement or unsubstituted aralkyl; And R 37Be hydrogen, cyano group or replacement or unsubstituted alkyl replace or unsubstituted carbalkoxy, replace or unsubstituted alkoxyalkyl, replace or unsubstituted hydroxyalkyl, replace or unsubstituted aminocarboxyl, replace or unsubstituted alkyl carbonyl or replacement or unsubstituted aralkyl.
34. the compound of claim 12, wherein Z 2It is following formula Wherein: R 37Be hydrogen, cyano group or replacement or unsubstituted alkyl replace or unsubstituted carbalkoxy, replace or unsubstituted alkoxyalkyl, replace or unsubstituted hydroxyalkyl, replace or unsubstituted aminocarboxyl, replace or unsubstituted alkyl carbonyl or replacement or unsubstituted aralkyl; And R 38Be hydrogen, replace or unsubstituted alkyl, replace or unsubstituted carbalkoxy, replace or unsubstituted alkoxyalkyl, replace or unsubstituted aminocarboxyl perhaloalkyl radical, replace or unsubstituted thiazolinyl, replace or unsubstituted alkyl carbonyl or replacement or unsubstituted aralkyl.
35. the compound of claim 1, wherein R 1It is the following formula group Wherein u is 0 or 1; R 39, R 40, R 41, R 42, R 43, R 44, R 45And R 46Be methyl or hydrogen independently of one another; Or substituent R 39And R 40R 36And R 37R 38And R 39, R 40And R 41At least one pair of be Sauerstoffatom together; And R 47Be H, azabicycloalkyl, Heterocyclylalkyl or Y 2-Z 2Y 2Be selected from-C (O)-,-(CH 2) q-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) qO-, (CH 2) qNH-, (CH 2) qS-, (CH 2) qS (O)-and (CH 2) qS (O) 2-; Q is 0 to 6 integer; Z 2Be-H, replace or unsubstituted alkyl, replace or unsubstituted amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl or replacement or unsubstituted Heterocyclylalkyl; Or R 47It is the following formula group
Figure A9981321700262
Wherein: y is 0 or 1; R 48, R 49, R 50, R 52, R 53, R 54And R 55Be methyl or hydrogen independently of one another; Or substituent R 48And R 49R 50And R 51R 52And R 53Or R 54And R 55At least one pair of be Sauerstoffatom together; And R 56Be-H azabicycloalkyl, Heterocyclylalkyl or Y 3-Z 3Y 3Be selected from-C (O)-,-(CH 2) t-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) tO-, (CH 2) tNH-, (CH 2) tS-, (CH 2) tS (O)-and (CH 2) tS (O) 2-; T is 0 to 6 integer; And Z 3Be-H, replace or unsubstituted alkyl, replace or unsubstituted amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl or replacement or unsubstituted Heterocyclylalkyl.
36. the compound of claim 1, wherein R 1It is the following formula group E wherein, f, h, u and y are 0 or 1 independently; R 57, R 58, R 59, R 60, R 61, R 62, R 63, R 64, R 65And R 66Be methyl or hydrogen independently of one another; Or substituent R 57And R 58R 59And R 60R 61And R 62Or R 63And R 64At least one pair of be Sauerstoffatom together; And R 67Be H, azabicycloalkyl, Heterocyclylalkyl or Y 2-Z 2Y 2Be selected from-C (O)-,-(CH 2) p-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) pO-, (CH 2) pNH-, (CH 2) pS-, (CH 2) pS (O)-and (CH 2) pS (O) 2-; P is 0 to 6 integer; Z 2Be-H, replace or unsubstituted alkyl, replace or unsubstituted amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl or replacement or unsubstituted Heterocyclylalkyl; Or R 67It is the following formula group Wherein: d is 0 or 1; R 68, R 69, R 70, R 71, R 72, R 73, R 74And R 75Be low alkyl group or hydrogen independently of one another; Or substituent R 68And R 69R 70And R 71R 72And R 73R 74And R 75At least one pair of be Sauerstoffatom together; And R 76Be-H azabicycloalkyl, Heterocyclylalkyl or Y 3-Z 3Y 3Be selected from-C (O)-,-(CH 3) p-,-S (O) 2-,-C (O) O-,-SO 2NH-,-CONH-,-(CH 2) pO-, (CH 2) pNH-, (CH 2) pS-, (CH 2) pS (O)-and (CH 2) pS (O) 2-; P is 0 to 6 integer; And Z 3Be-H, replace or unsubstituted alkyl, replace or unsubstituted amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl or replacement or unsubstituted Heterocyclylalkyl.
37. the compound of claim 1, wherein R 2Be-H.
38. the compound of claim 1, wherein L is-O-,-NHSO 2R-,-NC (O) O-, or NHC (O)-.
39. the kinase whose method of arrestin comprises compound or its physiologically acceptable salt, prodrug or the bioactive metabolites of using claim 1.
40. the method for claim 39, wherein said protein kinase is selected from KDR, FGFR-1, PDGFR α, IGF-1R, c-Met, F1t-1, TIE-2, Lck, Src, fyn, Lyn, Blk, and yes.
41. the method for claim 39, wherein said protein kinase activity influences hyperproliferation disease.
42. the method for claim 39, wherein said protein kinase activity influences vasculogenesis, blood vessel hypertonicity, immunne response or inflammation.
43. treatment has the method by the disease mediated patient of protein kinase activity, described method comprises compound or its physiologically acceptable salt as claim 1 definition to patient's administering therapeutic significant quantity, the step of prodrug or bioactive metabolites.
44. the method for claim 43, wherein said protein kinase is selected from KDR, FGFR-1, PDGFR α, IGF-1R, c-Met, Flt-1, TIE-2, Lck, Src, fyn, Lyn, Blk, and yes.
45. the method for claim 43, the illness by protein kinase mediated wherein is an excess proliferative disease.
46. the method for claim 43, wherein said protein kinase activity influences vasculogenesis, blood vessel hypertonicity, immunne response or inflammatory reaction.
47. the method for claim 43, wherein protein kinase is albumen serine/threonine kinase or protein tyrosine kinase.
48. the method for claim 43 is one or more ulcer by protein kinase mediated illness wherein.
49. the method for claim 48, wherein ulcer is caused by bacterium or fungi infestation; Perhaps ulcer is Mooren ulcer; Perhaps ulcer is ulcer illness in eye symptom.
50. the method for claim 43 is the Lyme disease by protein kinase mediated illness wherein, sepsis, or by herpes simplex, zoster, the human immunodeficiency virus, protozoon, toxoplasmosis or parapoxvirus infect.
51. the method for claim 43 is the HippelLindau disease by protein kinase mediated illness wherein, pemphigoid, psoriasis, Paget ' s disease or multicystic kidney disease.
52. the method for claim 43 is a fibrosis by protein kinase mediated illness wherein, sarcoma, cirrhosis, thyroiditis, high viscosity syndrome system, Osler-Weber-Rendu disease, chronic occlusion tuberculosis, asthma is oozed out, ascites, leural effusion, peritoneal effusion, pulmonary edema, the oedema behind cerebral edema or the burn, wound, radiation, apoplexy, anoxic or local asphyxia.
53. the method for claim 43 is an ovarian hyperstimulation syndrome by protein kinase mediated illness wherein, preeclampsia, menorrhagia, or uterus Inner film dystopy.
54. the method for claim 43 is a chronic inflammatory diseases by protein kinase mediated illness wherein, systemic lupus erythematosus, glomerulonephritis, synovitis, enteritis, Crohn ' s disease, rheumatic arthritis and osteoarthritis, multiple sclerosis and transplant rejection reaction.
55. the method for claim 43 is a Dresbach's anemia by protein kinase mediated illness wherein.
56. the method for claim 43 is an illness in eye by protein kinase mediated illness wherein.
57. the method for claim 56, illness in eye wherein are eye and macular edema, eye neovascularity disease, scleritis, radiation corneal incision, uveitis, vitritis, myopia, eye ulcer, chronic retinal detachment, back-laser complication, conjunctivitis, the sick and Eales disease of Stargardt ' s, and retinopathy and macular degeneration.
58. the method for claim 43 is a cardiovascular diseases by protein kinase mediated illness wherein.
59. the method for claim 58 is an atherosclerosis by protein kinase mediated illness wherein, restenosis, vascular occlusion and carotid artery obstruction disease.
60. the method for claim 43 is a cancer by protein kinase mediated illness wherein.
61. the method for claim 60, cancer are noumenal tumours, sarcoma, fibroblastoma, osteoma, melanoma, retinoblastoma, rhabdosarcoma, glioblastoma, neuroblastoma, malignant teratoma, hemocyte cancer, and malignant ascite.
62. the method for claim 61, wherein cancer is a Kaposi ' s sarcoma, Hodgkin ' s disease, lymphoma, myelomatosis or leukemia.
63. the method for claim 43 is Crow-Fukase (POEMS) syndrome and diabetes by protein kinase mediated illness wherein.
64. the method for claim 63, wherein diabetes is Regular Insulin-dependent diabetes mellitus glaucoma, diabetic retinopathy and microangiopathy.
65. reduce the method for patient's fertility, described method comprises compound or its physiologically acceptable salt as claim 1 definition to patient's administering therapeutic significant quantity, the step of prodrug or bioactive metabolites.
66. the method for claim 43, its Chinese style I compound or its physiologically acceptable salt, the amount administration that prodrug or bioactive metabolites take place with effective promotion vasculogenesis or blood vessel.
67. the method for claim 66, wherein protein kinase is Tie-2.
68. the method for claim 66, its Chinese style I compound or its physiologically acceptable salt, prodrug or bioactive metabolites and preceding angiogenesis growth factor Combined Preparation.
69. the method for claim 68, wherein preceding angiogenesis growth factor is selected from VEGF, VEGF-B, VEGF-C, VEGF-D, VEGF-E, HGF, FGF-1, FGF-2, its derivative and antiidiotypic antibody.
70. the method for claim 66, wherein protein kinase mediated illness is an anaemia, local asphyxia, and myocardial infarction, transplant rejection, wound, gangrenous or downright bad.
71. the method for claim 43, wherein protein kinase activity and T cell activation, the B cell activation, the mammary cell threshing, unicellular activation, inflammatory reaction strengthens or its associating.
72 is selected from the following group of compounds: Cis -5 - (4 - phenoxy-phenyl) -7 - (4 - pyrrolidinyl cyclohex-1 - yl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine, Trans-5 - (4 - phenoxy-phenyl) -7 - (4 - cyclohex-1-pyrrolidinyl - yl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine, Cis-5 - (4 - phenoxy-phenyl) -7 - (4 - piperidino cyclohex-1 - yl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine hydrochloride, Trans-5 - (4 - phenoxy-phenyl) -7 - (4 - piperidino-cyclohexan-1 - yl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine, Trans-7 - (4 - dimethylamino-cyclohexyl) -5 - (4 - phenoxy-phenyl)-7H-pyrrolo [2,3 - d] pyrimidin-4 - yl amine, Cis -7 - (4 - dimethylamino-cyclohexyl) -5 - (4 - phenoxy-phenyl)-7H-pyrrolo [2,3 - d] pyrimidin-4 - yl amine, 5 - (4 - phenoxy-phenyl) -7 - (4 - piperidinyl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine, 5 - (4 - phenoxy-phenyl) -7 - (3 - pyrrolidinyl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine Dihydrochloride, Cis-7 - [4 - (4 - isopropyl-piperazino) cyclohexyl] -5 - (4 - phenoxy-phenyl)-7H-pyrazol Pyrrolo [2,3-d] pyrimidin-4 - yl amine, Trans-7 - [4 - (4 - isopropyl-piperazino) cyclohexyl] -5 - (4 - phenoxy-phenyl)-7H-pyrazol Pyrrolo [2,3-d] pyrimidin-4 - yl amine, Cis-7 - {4 - [4 - (2 - methoxyethyl) piperazino] cyclohexyl} -5 - (4 - phenoxyphenyl Yl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine, Trans-7 - {4 - [4 - (2 - methoxyethyl) piperazino] cyclohexyl} -5 - (4 - phenoxyphenyl Yl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine, Cis-7 - [4 - (4 - ethyl-piperazino) cyclohexyl] -5 - (4 - phenoxy-phenyl)-7H-pyrrolo And [2,3-d] pyrimidin-4 - yl amine, Trans-7 - [4 - (4 - ethyl-piperazino) cyclohexyl] -5 - (4 - phenoxy-phenyl)-7H-pyrrolo And [2,3-d] pyrimidin-4 - yl amine, Cis-7 - [4 - (4 - isopropyl-piperazino) cyclohexyl] -5 - (4 - phenoxy-phenyl)-7H-pyrazol Pyrrolo [2,3-d] pyrimidin-4 - yl AMINES maleate, Trans-7 - [4 - (4 - isopropyl-piperazino) cyclohexyl] -5 - (4 - phenoxy-phenyl)-7H-pyrazol Pyrrolo [2,3-d] pyrimidin-4 - yl AMINES maleate, Cis-7 - {4 - [4 - (2 - methoxyethyl) piperazino] cyclohexyl} -5 - (4 - phenoxyphenyl Yl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl AMINES maleate, Trans-7 - {4 - [4 - (2 - methoxyethyl) piperazino] cyclohexyl} -5 - (4 - phenoxyphenyl Yl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl AMINES maleate, Trans-7 - {4 - [4 - (2 - methoxyethyl) piperazino] cyclohexyl} -5 - (4 - phenoxyphenyl Yl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl AMINES maleate, Cis -7 - (4 - {[3 - (1H-1-imidazolyl) propyl] amino} cyclohexyl) -5 - (4 - phenoxyphenyl Yl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl AMINES maleate, Trans -7 - (4 - {[3 - (1H-1-imidazolyl) propyl] amino} cyclohexyl) -5 - (4 - phenoxyphenyl Yl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl AMINES maleate, Cis-7 - [4 - (dimethylamino) cyclohexyl] -5 - (4 - phenoxy-phenyl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl amine maleate, Trans-5 - (4 - phenoxy-phenyl) -7 - (4 - piperidino-cyclohexyl)-7H-pyrrolo [2,3-d] Pyrimidin-4 - yl amine maleate, Trans-5 - (4 - phenoxy-phenyl) -7 - (4 - tetrahydro-1H-1-pyrrolyl cyclohexyl)-7H-pyrrolo And [2,3-d] pyrimidin-4 - yl amine maleate, Cis-5 - (4 - phenoxy-phenyl) -7 - (4 - piperazinosulfonyl cyclohexyl)-7H-pyrrolo [2,3-d] Pyrimidin-4 - yl AMINES maleate, Trans-5 - (4 - phenoxy-phenyl) -7 - (4 - piperazino cyclohexyl)-7H-pyrrolo [2,3-d] Pyrimidin-4 - yl AMINES maleate, 7 - [3 - (4 - methyl-piperazino) cyclopentyl] -5 - (4 - phenoxy-phenyl)-7H-pyrrolo [2,3-d] pyrimidin-4 - yl AMINES maleate, Trans-7 - [3 - (4 - methyl-piperazino) cyclohexyl] -5 - (4 - phenoxy-phenyl)-7H-pyrrolo And [2,3-d] pyrimidin-4 - yl amine, Trans-7 - [3 - (4 - methyl-piperazino) cyclohexyl] -5 - (4 - phenoxy-phenyl)-7H-pyrrolo And [2,3-d] pyrimidin-4 - yl AMINES maleate, Trans-7 - [3 - (4 - methyl-piperazino) cyclohexyl] -5 - (4 - phenoxy-phenyl)-7H-pyrrolo And [2,3-d] pyrimidin-4 - yl amine trihydrochloride Cis-7 - [3 - (4 - methyl-piperazino) cyclohexyl] -5 - (4 - phenoxy-phenyl)-7H-pyrrolo And [2,3-d] pyrimidin-4 - yl AMINES maleate, Cis-7 - [3 - (4 - methyl-piperazino) cyclohexyl] -5 - (4 - phenoxy-phenyl)-7H-pyrrolo And [2,3-d] pyrimidin-4 - yl amine trihydrochloride Trans-5 - (2 - methyl - 4 - phenoxy-phenyl) -7 - [4 - (4 - piperazino) cyclohexyl]-7H-pyrazol Pyrrolo [2,3-d] pyrimidin-4 - yl AMINES maleate, Cis-N-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} 2 - methoxy-phenyl)-carbamic acid benzyl ester maleate three, Trans-N-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} 2 - methoxy-phenyl)-carbamic acid benzyl ester maleate three, Trans-N1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} 2 - methoxy-phenyl) benzamide, Trans-N1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} 2 - methoxyphenyl) benzamide trimaleate salt, Cis-N1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} 2 - methoxy-phenyl) -3 - phenyl-propionamide, Trans-N1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} 2 - methoxy-phenyl) -3 - phenyl-propionamide, Cis-N1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} 2 - methoxy-phenyl) -3 - phenyl-propionamide three maleate, Trans-N1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} 2 - methoxy-phenyl) -3 - phenyl-propionamide three maleate, Trans-N1-(4-4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 --2 - methoxy-phenyl) -3 - phenyl-propionamide three maleate, Cis-2 - (4-4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - phenoxy) -6 - [(3 - methoxy-propyl) amino] benzonitrile trimaleic acid Salt, Trans-2 - (4-4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - phenoxy) -6 - [(3 - methoxy-propyl) amino] benzonitrile trimaleic acid Salt, Cis-2 - amino-6 - (4-4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrazol Pyrrolo [2,3-d] pyrimidin-5 - phenyl) benzonitrile three maleate, Trans-2 - amino-6 - (4-4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrazol Pyrrolo [2,3-d] pyrimidin-5 - phenyl) benzonitrile three maleate, Cis-2 - (4-4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - phenoxy) -6 - [(4 - methylphenyl) thio] benzonitrile three maleate, Trans-2 - (4-4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - phenoxy) -6 - [(4 - methylphenyl) thio] benzonitrile three maleate, Cis-2 - (4-4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - phenoxy) -6 - (2 - pyridylthio) benzonitrile three maleate, Trans-2 - (4-4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - phenoxy) -6 - (2 - pyridylthio) benzonitrile three maleate, Cis -5 - (2 - methyl - 4 - phenoxy-phenyl) -7 - [4 - (4 - methyl-piperazino) cyclohexyl] - 7H-pyrrolo [2,3-d] pyrimidin-4 - yl AMINES maleate, Trans-5 - (2 - methyl - 4 - phenoxy-phenyl) -7 - [4 - (4 - methyl-piperazino) cyclohexyl] - 7H-pyrrolo [2,3-d] pyrimidin-4 - yl AMINES maleate, Cis-N1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -4 - fluoro-1 - benzenesulfonamide three maleate, Trans-N1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -4 - fluoro-1 - benzenesulfonamide three maleate, N1-4-[4 - amino-7 - (1 - benzyl-4 - piperidinyl)-7H-pyrrolo [2,3-d] pyrimidin-5 - Yl] -2 - fluorophenyl-4 - fluoro-1 - benzenesulfonamide, N1-4-[4 - amino-7 - (1 - benzyl-4 - piperidinyl)-7H-pyrrolo [2,3-d] pyrimidin-5 - Yl] -2 - fluoro-2 ,3 - dichloro-1 - benzenesulfonamide, N1-4-[4 - amino-7 - (4 - piperidinyl)-7H-pyrrolo [2,3-d] pyrimidin-5 - yl] -2 - fluoro- Phenyl-4 - fluoro-1 - benzenesulfonamide, N1-4-[4 - amino-7 - (1 - formyl-4 - piperidinyl)-7H-pyrrolo [2,3-d] pyrimidin-5 - Yl] -2 - fluorophenyl-4 - fluoro-1 - benzenesulfonamide, N1-4-[4 - amino -7-1 - [(1 - methyl-1H-4-imidazol-yl) sulfonyl] -4 - piperidinyl-7H- Pyrrolo [2,3-d] pyrimidin-5 - yl) -2 - fluorophenyl]-4 - fluoro-1 - benzenesulfonamide dimaleate acid Salt, N1-[4 - (4 - amino -7-1 - [(1,2 - dimethyl-1H-4-imidazol-yl) sulfonyl] -4 - piperidinyl Yl-7H-pyrrolo [2,3-d] pyrimidin-5 - yl) -2 - fluorophenyl]-4 - fluoro-1 - benzenesulfonamide, N1-[4 - (4 - amino -7-1 - [(1,3 - dimethyl-1H-5-pyrazolyl) carbonyl] -4 - piperidinyl - 7H-pyrrolo [2,3-d] pyrimidin-5 - yl) -2 - fluorophenyl]-4 - fluoro-1 - benzenesulfonamide, N1-(4 - {4 - amino-7 - [1 - (2 - pyridinyl carbonyl) -4 - piperidinyl]-7H-pyrrolo [2,3 - d] pyrimidin-5 - yl} -2 - fluorophenyl) -4 - fluoro-1 - benzenesulfonamide, N1-4-(4 - amino-7 - {4 - [1 - (1 - methyl-piperidin-4 - yl) piperidin-yl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl}) -2 - fluorophenyl) -4 - fluoro-1 - benzenesulfonamide three maleate, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - (trifluoromethoxy) -1 - benzenesulfonamide trimaleic Salt, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -5 - chloro-2 - thiophene sulfonamide benzenesulfonamide trimaleic Salt, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - chloro-4 - fluoro-1 - benzenesulfonamide benzenesulfonamide three Maleate, Trans-N1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluoro-2 ,3 - dichloro-1 - benzenesulfonamide three maleate, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - chloro-4 - fluoro-1 - benzenesulfonamide three maleate, Cis-N-1-(4-4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 --2 - fluorophenyl) -2,5 - difluoro-1 - benzenesulfonamide three maleate, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,6 - difluoro-1 - benzenesulfonamide three maleate, Trans-N-4-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,1,3 - benzo-thiadiazol-4 - sulfonamide trimaleic Salt, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,3,4 - trifluoro-1 - benzenesulfonamide trimaleic acid Salt, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - nitro-1 - benzenesulfonamide three maleate, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - fluoro-1 - benzenesulfonamide three maleate, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,4,6 - trichloro-1 - benzenesulfonamide trimaleic acid Salt, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,6 - dichloro-1 - benzenesulfonamide three maleate, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - chloro-1 - benzenesulfonamide three maleate, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -3 - fluoro-1 - benzenesulfonamide dimaleate, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -5 - chloro-2 - thiophene sulfonamide dimaleate, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -4 - bromo-2, 6 - difluoro-1 - benzenesulfonamide trimaleic Salt, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -3 - chloro-4 - fluoro-1 - benzenesulfonamide three maleate, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - iodo-1 - benzenesulfonamide three maleate, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - (trifluoromethoxy) -1 - benzenesulfonamide trimaleic Salt, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,3 - dichloro-1 - benzenesulfonamide three maleate, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - chloro-6 - methyl-1 - benzenesulfonamide trimaleic acid Salt, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - chloro-4 - cyano-1 - benzenesulfonamide trimaleic acid Salt, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,3,4 - trifluoro-1 - benzenesulfonamide trimaleic acid Salt, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -3,4 - difluoro-1 - benzenesulfonamide three maleate, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -4 - bromo-2 - fluoro-1 - benzenesulfonamide three maleate, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -5 - bromo-2 - thiophene sulfonamide three maleate, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,4 - dichloro-1 - benzenesulfonamide three maleate, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,3,4 - trichloro-1 - benzenesulfonamide trimaleic acid Salt, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -3 - bromo-5 - chloro-2 - thiophene sulfonamide trimaleic acid Salt, Cis-N4-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,1,3 - benzo-thiadiazol-4 - sulfonamide trimaleic Salt, Cis-N4-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl) -2 - fluorophenyl) -2,1,3 - oxadiazole benzo-4 - sulfonamide trimaleic Salt, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,5 - dichloro-1 - thiophenesulfonamide trimaleic acid Salt, Cis-N4-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) - (7 - chloro-2 ,1,3 - benzothiadiazole) -4 - sulfonyl AMINES maleate, Cis-N4-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) - (7 - methyl-2 ,1,3 - benzothiadiazole) -4 - sulfo Trimaleic acid amide, Cis-N4-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) - (5 - methyl -2,1,3 - benzothiadiazole) -4 - sulfo Trimaleic acid amide, Cis-N4-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) - (5 - chloro-2 ,1,3 - benzothiadiazole) -4 - sulfonyl AMINES maleate, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -3 - chloro-2 - methyl-1 - benzenesulfonamide trimaleic acid Salt, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - bromo-1 - benzenesulfonamide three maleate, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,5 - dibromo-3, 6 - difluoro-1 - benzenesulfonamide three Maleate, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,3 - dichloro-1 - benzenesulfonamide three maleate, Cis-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) - (2 - nitrophenyl) methanesulfonamide three maleate, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - nitro-1 - benzenesulfonamide three maleate, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - fluoro-1 - benzenesulfonamide three maleate, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,4,6 - trichloro-1 - benzenesulfonamide trimaleic acid Salt, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,6 - dichloro-1 - benzenesulfonamide three maleate, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - chloro-1 - benzenesulfonamide three maleate, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -3 - fluoro-1 - benzenesulfonamide dimaleate, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -4 - bromo-2 ,5 - difluoro-1 - benzenesulfonamide trimaleic Salt, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -3 - chloro-4 - fluoro-1 - benzenesulfonamide three maleate, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - iodo-1 - benzenesulfonamide three maleate, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,3 - dichloro-1 - benzenesulfonamide three maleate, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - chloro-6 - methyl-1 - benzenesulfonamide trimaleic acid Salt, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - chloro-4 - cyano-1 - benzenesulfonamide trimaleic acid Salt, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -3,4 - difluoro-1 - benzenesulfonamide three maleate, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -4 - bromo-2 - fluoro-1 - benzenesulfonamide three maleate, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -5 - bromo-2 - thiophene sulfonamide three maleate, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,4 - dichloro-1 - benzenesulfonamide three maleate, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,3,4 - trichloro-1 - benzenesulfonamide trimaleic acid Salt, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -3 - bromo-5 - chloro-2 - thiophene sulfonamide trimaleic acid Salt, Trans-N4-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,1,3 - benzo-thiadiazol-4 - sulfonamide trimaleic Salt, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,5 - dichloro-1 - thiophenesulfonamide trimaleic acid Salt, Trans-N4-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) - (7 - chloro-2 ,1,3 - benzothiadiazole) -4 - sulfonyl AMINES maleate, Trans-N4-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) - (7 - methyl-2 ,1,3 - benzothiadiazole) -4 - sulfo Trimaleic acid amide, Trans-N4-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) - (5 - methyl -2,1,3 - benzothiadiazole) -4 - sulfo Trimaleic acid amide, Trans-N4-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) - (5 - chloro-2 ,1,3 - benzothiadiazole) -4 - sulfonyl AMINES maleate, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -3 - chloro-2 - methyl-1 - benzenesulfonamide trimaleic acid Salt, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2 - bromo-1 - benzenesulfonamide three maleate, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) -2,5 - dibromo-3, 6 - difluoro-1 - benzenesulfonamide three Maleate, Trans-N-1-(4 - {4 - amino-7 - [4 - (4 - methyl-piperazino) cyclohexyl]-7H-pyrrolo [2,3-d] pyrimidin-5 - yl} -2 - fluorophenyl) - (2 - nitrophenyl) methanesulfonamide trimaleic acid Salts. ...
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