CN101370788A

CN101370788A - Morpholino pyrimidine derivatives and their use in therapy

Info

Publication number: CN101370788A
Application number: CNA2007800021665A
Authority: CN
Inventors: K·G·派克; M·R·V·芬利; S·M·菲莱里; A·P·迪欣格顿
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2006-01-11
Filing date: 2007-01-08
Publication date: 2009-02-18
Also published as: ZA200805530B; GB0600483D0

Abstract

Disclosed is a compound of formula (I) or a salt, ester or prodrug thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, for example in the treatment of proliferative disease such as cancer and particularly in disease mediated by an mTOR kinase and/or one or more PI3K enzyme.

Description

Morpholino pyrimidine derivatives and its therepic use

The present invention relates to morpholino pyrimidine derivatives, its preparation method, contain their pharmaceutical composition and its therepic use, for example treat hyperplasia, cancer for example is particularly useful for treating the disease of mTOR kinases and/or the mediation of one or more PI3K enzymes.

Can thoroughly understand now, the imbalance of oncogene and tumor suppressor gene is by for example improving cell proliferation or improving the formation that cell survival impels malignant tumour.The signal path that it is also known that the mediation of PI3K/mTOR family has vital role in many cell processes (comprising propagation and survival), and the imbalance in these paths is a paathogenic factor in people's wide spectrum cancer and other disease.

The warm-blooded animal target of macrolide antibiotic rapamycin (sirolimus (sirolimus)) is enzyme mTOR.This kind of enzyme belongs to relevant kinases (PIKK) family of phosphatidylinositols (PI) kinases of protein kinase, and it also comprises ATM, ATR, DNA-PK and hSMG-1.Similar with other PIKK family member, mTOR does not have detectable lipid kinase activity, plays serine/threonine kinase on the contrary.Many understanding of mTOR signal are based on the purposes of rapamycin.Rapamycin at first combines with 12kDa immunophilin FK506-conjugated protein (FKBP12), and this mixture inhibition mTOR signal (Tee and Blenis, Seminars in CellandDevelopmental Biology, 2005,16,29-37).MTOR albumen by catalysis kinases zone, FKBP12-rapamycin in conjunction with (FRB) zone, C-near the generally acknowledged repressor zone terminal and form (Huang and Houghton at 20 series connection multiple HEAT primitives at the most of N-end and FRAP-ATM-TRRAP (FAT) and FAT C-stub area, Current Opinion in Pharmacology, 2003,3,371-377).

The mTOR kinases is the crucial conditioning agent of cell growth, and show that it can regulate many cell functions, comprise translate, transcribe, mRNA renewal, protein stability, the muscle fibrin cytoskeleton organizes again and autophagy (Jacinto and Hall, Nature Reviews Molecular and CellBiology, 2005,4,117-126).The mTOR kinases will come from the signal of somatomedin (for example Regular Insulin or rhIGF-1) and nutrient substance (for example amino acid and glucose) and accumulate, and regulate the cell growth.The mTOR kinases passes through the PI3K-Akt path and grown factor activator.The best feature function of mTOR kinases in mammalian cell is the adjusting of translating by two paths, just examine the activation of candy body S6K1, to increase the inhibition of translating and increase 4E-BP1 of mRNAs (carry 5 '-terminal oligomeric pyrimidine zone (TOP)), allow translating of CAP-dependency mRNA.

Usually, for the specificity as the mTOR of target in the born of the same parents, use them to suppress based on rapamycin and relevant forms of rapamycin analogs, the investigator has explored physiology and the pathological effect of mTOR.Yet, recent data propose, rapamycin has shown variable restraining effect for the mTOR semiotic function, and propose, directly suppress mTOR kinases zone and can show the active obviously wideer anticancer disease activity of the anticancer disease that reaches than rapamycin (people such as Edinger, Cancer Research, 2003,63,8451-8460).For this reason, the effective and selective depressant of mTOR kinase activity is useful for understanding the mTOR kinase function more up hill and dale and effective therapeutical agent being provided.

Now, considerable evidence shows, the path upstream of mTOR, and for example the PI3K path usually is active (Vivanco and Sawyers, Nature Reviews Cancer, 2002,2,489-501 in cancer; Bjornsti and Houghton, Nature Reviews Cancer, 2004,4,335-348; People such as Inoki, Nature Genetics, 2005,37,19-24).The component in the PI3K path that for example, suddenlys change in different human tumors comprises the sudden change that activates growth factor receptors and amplification and/or the overexpression of PI3K and Akt.

In addition, explanation on evidence, endothelial cell proliferation may also depend on the mTOR signal.Endothelial cell proliferation be by the vascular endothelial growth factor of PI3K-Akt-mTOR signal path (VEGF) activation excited (Dancey, Expert Opinion on InvestigationalDrugs, 2005,14,313-328).In addition, but it is believed that the mTOR kinase signal by the influence that anoxic-inducible factor-1 α (HIF-1 α) is expressed partly control VEGF synthetic (people such as Hudson, Molecular and Cellular Biology, 2002,22,7004-7014).Therefore, the vasculogenesis of tumour can depend on the mTOR kinase signal in two modes: by tumour and stroma cell by the VEGF of anoxic-cause synthetic and pass through VEGF stimulating endothelial propagation and survive by the PI3K-Akt-mTOR signal.

These discoveries show that the kinase whose pharmacological inhibitor of mTOR should have therapeutics for the treatment of various forms cancer (comprising noumenal tumour for example malignant tumour and sarcoma and leukemia and lymph malignant tumour) and be worth.Especially, the mTOR kinase inhibitor should have therapeutics for following treatment for cancer and be worth: breast cancer for example, and colorectal carcinoma, lung cancer (comprises small cell lung cancer, nonsmall-cell lung cancer and bronchioalveolar carcinoma) and prostate gland, and cholangiocarcinoma, osteocarcinoma, bladder cancer, the cancer of the brain and neck cancer, kidney, liver cancer, gastrointestinal tissue's cancer, esophagus cancer, ovarian cancer, carcinoma of the pancreas, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma, cervical cancer and carcinoma vulvae, and leukemia (comprising ALL and CML), multiple myeloma and lymphoma.

Except tumorigenicity, explanation on evidence, the mTOR kinases is played a role in a series of progonoma syndromess.Studies show that recently tumor suppressor protein for example TSC1, TSC2, PTEN and LKB1 can closely be controlled the mTOR kinase signal.The forfeiture of these tumor suppressor proteins owing to increased the mTOR kinase signal, cause certain limit the progonoma illness (Tee and Blenis, Seminars in Cell and Developmental Biology, 2005,16,29-37).Setting up the syndromes that molecule is connected with the mTOR kinases of dysregulation comprises: blackspot polyp syndromes (PJS), the Cowden disease, Bannayan-Riley-Ruvalcaba syndromes (BRRS), the Proteus syndromes, Lhermitte-Duclos disease and epiloia (TSC) (people such as Inoki, NatureGenetics, 2005,37,19-24).The patient who suffers from these syndromess forms optimum paramnesia tumour specifically in many organs.

Nearest effect (the Easton﹠amp of mTOR kinases in other disease that studies show that; Houghton, ExpertOpinion on Therapeutic Targets, 2004,8,551-564).Show, rapamycin is effective immunosuppressor, it suppresses the propagation (Sehgal of T cell, B cell and the antibody product of antigen-cause, Transplantation Proceedings, 2003,35,7S-14S), and the mTOR kinase inhibitor can be useful immunosuppressor equally thus.The inhibition of mTOR kinase activity also can be effective to prevention of restenosis, promptly respond in the vascular system disease treatment and introduce support, the control normal cell is undesirable propagation (people such as Morice in vascular system, New England Journal of Medicine, 2002,346,1773-1780).In addition, the forms of rapamycin analogs everolimus can reduce the severity of heart allograft vascular lesion and incidence (people such as Eisen, New EnglandJournal of Medicine, 2003,349,847-858).The mTOR kinase activity that increases is relevant with cardiac hypertrophy, and its primary hazard factor as heart failure is important clinically, and is sequela (the Tee ﹠amp that increases myocardial cell's cell size; Blenis, Seminars in Cell and Developmental Biology, 2005,16,29-37).Thus, except cancer, expection mTOR kinase inhibitor is preventing and is treating in the multiple disease to have value.

It is believed that in addition many this morpholino pyrimidine derivatives may have the activity of inhibition to kinase whose phosphatidylinositols (PI) 3-kinases family.

Phosphatidylinositols (PI) 3-kinases (PI3Ks) is ubiquitous lipid kinase, and it had both played the effect at the signal converter in cell surface receptor downstream, works in composition intracellular membrane and protein transportation route again.All PI3Ks are the dual specificity enzymes, and it has at the lipid kinase activity of 3-hydroxy position phosphorylation phosphoinositide and not so good characterization protein kinase activity.Comprise phosphatidylinositols 3,4,5-triguaiacyl phosphate [PI (3,4,5) P ₃], phosphatidylinositols 3,4-bisphosphate [PI (3,4) P ₂] and the lipid products of the PI3K-catalyzed reaction of phosphatidylinositols 3-Monophosphate [PI (3) P], in many signal transduction pathways, constituted the second messenger, comprised that on cell proliferation, adhesion, survival, cytoskeleton are reset and those indispensable signal transduction pathways of film bubble transportation.Be present in all cells to PI (3) P-structure, and its level does not stimulate along with agonist and changes.Otherwise, PI (3,4) P ₂And PI (3,4,5) P ₃Nominally be not present in most of cell, but they can accumulate under agonist stimulates apace.

The 3-phosphoinositide second messenger's that PI3K-produces downstream effect is that for example pleckstrin homology (PH) zone reaches the FYVE of discriminating recently and the target molecule in phox zone is mediated by containing 3-phosphoinositide calmodulin binding domain CaM.The albumen target that has better characterization for PI3K comprises PDK1 and protein kinase B (PKB).In addition, for example Btk and Itk depend on the PI3K activity to Tyrosylprotein kinase.

According to the physiology substrate specificity, the PI3K family of lipid kinase can be categorized as three groups (people such as Vanhaesebroeck, Trends in Biol.Sci., 1997,22,267).An III class PI3K enzyme phosphorylation PI.On the contrary, both also phosphorylation PI4-phosphoric acid ester [PI (4) P] of phosphorylation PI of II class PI3K enzyme.I class PI3K enzyme phosphorylation PI, PI (4) P and PI4,5-bisphosphate [PI (4,5) P ₂], but think (4, the 5) P that has only PI ₂It is physiological cell matrix.PI (4,5) P ₂Phosphorylation produce lipid second messenger PI (3,4,5) P ₃The farther relevant member of lipid kinase Superfamily is an IV class kinases, for example mTOR (discussing above) and DNA-dependant kinase, its in albumen substrate with serine/threonine residue phosphorylation.Most of research and the PI3K lipid kinase of understanding are I class PI3K enzymes.

The heterodimer that I class PI3Ks is made up of p110 catalytic subunit and regulator subunit.Based on regulating partner and regulation mechanism, this family further is divided into Ia class and Ib fermentoid.The Ia fermentoid is by (the p110 α of catalytic subunit of three uniquenesses, p110 β and p110 δ) form, the regulator subunit of catalytic subunit and five uniquenesses (p85 α, p55 α, p50 α, p85 β and p55 γ) dimerization, all catalytic subunits can interact with all regulator subunits, form many heterodimers.By specific phosphate tyrosine residues or for example interaction of IRS-1 of adaptin with activated receptor of Ia class PI3Ks regulator subunit SH2 zone, Ia class PI3Ks is activated in the response to the somatomedin-stimulation of receptor tyrosine kinase usually.Be expressed in all cells type, and p110 δ expression more is confined in leukocytes and some epithelial cells p110 α and p110 beta structure.On the contrary, simple Ib fermentoid is by forming with the interactional p110 γ of p101 regulator subunit catalytic subunit.As if in addition, the Ib fermentoid is activated in the response to G protein-coupled receptor system (GPCRs), and its expression is confined to white corpuscle and myocardial cell.

Have considerable evidence to show now, Ia class PI3K enzyme in multiple human cancer, promoted directly or indirectly tumorigenicity (Vivanco and Sawyers, Nature Reviews Cancer, 2002,2,489-501).For example, the p110 alpha subunit some tumours for example ovary (people such as Shayesteh, Nature Genetics, 1999,21,99-102) and uterine neck (people such as Ma, Oncogene, 2000,19, obtained amplification in those tumours 2739-2744).In recent years, activated mutant in the catalytic site of p110 α catalytic subunit is associated with various other tumours, for example the tumour in colorectum zone and breast and lung tumor people such as (, Science, 2004,304,554) Samuels.The relevant sudden change of tumour in p85 α regulator subunit also cancer for example obtained in ovary and the colorectal carcinoma affirmation (people such as Philp, Cancer Research, 2001,61,7426-7429).Except direct influence, the activation that it is believed that Ia class PI3Ks has promoted the tumour generation incident that occurs in the signal path upstream, for example part-dependency by receptor tyrosine kinase, GPCR system or integrin or part-independence activates (people such as Vara, Cancer Treatment Reviews, 2004,30,193-204).The example in this stream signal path comprises: the overexpression of the receptor tyrosine kinase erbB2 in the many tumours of activated that cause PI3K-mediation path (people such as Harari, Oncogene, 2000,19,6102-6114) and the overexpression of ras oncogene (people such as Kauffmann-Zeh, Nature, 1997,385,544-548).In addition, Ia class PI3Ks can impel indirectly by the caused tumorigenicity of various downstream signal incidents.For example, lose PTEN tumor inhibitor Phosphoric acid esterase with PI (3,4,5) P ₃Catalyzed conversion returns PI (4,5) P ₂Effect, by PI (3,4, the 5) P of re PI3K mediation ₃Make, relevant with the tumour of unusual wide region (Simpson and Parsons, Exp.Cell Res., 2001,264,29-41).In addition, it is believed that the effect of strengthening other PI3K-mediation signal event facilitates many cancers, for example the activation by Akt (Nicholson and Anderson, Cellular Signalling, 2002,14,381-395).

Except the effect of in tumour cell, regulating propagation and survival signal, evidence suggests that Ia class PI3K enzyme promotes tumorigenicity in the relevant stroma cell of tumour.For example, to short angiogenic factor for example in the response of VEGF, known PI3K signal in regulating endotheliocyte, generate in the vascular events and play an important role (people such as Abid, Arterioscler.Thromb.Vasc.Biol., 2004,24,294-300).Since I class PI3K enzyme also relevant with mobility and movability (Sawyer, Expert Opinion Investig.Drugs, 2004,13,1-19), so by suppressing tumour cell intrusion and metastasis, the PI3K enzyme inhibitors should provide the treatment benefit.In addition, I class PI3K enzyme in the immunocyte of the short tumour generation effect that causes inflammatory cell is regulated, play an important role (Coussens and Werb, Nature, 2002,420,860-867).

These discoveries show that the pharmacological inhibitor of I class PI3K enzyme will have therapeutics for treatment various diseases (comprise multi-form Cancerous disease, comprise noumenal tumour for example malignant tumour and sarcoma and leukemia and lymph malignant tumour) and be worth.Especially, the inhibitor of I class PI3K enzyme should have therapeutics for following treatment for cancer and be worth: breast cancer for example, colorectal carcinoma, lung cancer (comprising small cell lung cancer, nonsmall-cell lung cancer and bronchioalveolar carcinoma) and prostate gland, and cholangiocarcinoma, osteocarcinoma, bladder cancer, the cancer of the brain and neck cancer, kidney, liver cancer, gastrointestinal tissue's cancer, esophagus cancer, ovarian cancer, carcinoma of the pancreas, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma, cervical cancer and carcinoma vulvae, and leukemia (comprising ALL and CML), multiple myeloma and lymphoma.

Finally proved that in lacking the mouse of enzyme the PI3K γ of Ib class PI3K is by the GPCRs activated.Thus, derive from the neutrophil of the animal that lacks PI3K γ and scavenger cell and in the response that stimulates for various chemotaxis materials (for example IL-8, C5a, fMLP and MIP-1a), can not produce PI (3,4,5) P ₃, and be intact (people such as Hirsch, Science, 2000,287 (5455), 1049-1053 by the signal of protein tyrosine kinase-coupled receptor and Ia class PI3Ks coupling; People such as Li, Science, 2002,287 (5455), 1046-1049; People such as Sasaki, Science2002,287 (5455), 1040-1046).In addition, PI (3,4,5) P ₃The PKB phosphorylation of-mediation is not to cause by these GPCR parts in PI3K γ-null cell.In a word, the result confirms that in all the other hematopoietic cells, PI3K γ is the unique PI3K heterogeneous by the GPCRs vivo activation at least.When the neutrophil and the peritoneal macrophages of in vitro tests mouse bone marrow derived (comes from wild-type and PI3K γ ^-/-Mouse) time, observes performance reduction in chemotactic and adherence test, yet be not have fully.Yet, its be converted into the rapid damage that neutrophil leucocyte that IL-8 drives soaks in tissue (people such as Hirsch, Science, 2000,287 (5455), 1049-1053).Nearest data show, PI3K γ is relevant with the path finding process, and it is irrelevant with the generation of the mechanical force of mobility, because random move do not have impaired (people such as Hannigan in the cell that lacks PI3K γ, Proc.Nat.Acad.of Sciences of U.S.A., 2002,99 (6), 3603-8).The data that PI3K γ and respiratory system disease pathology are connected also prove, PI3K γ has important effect (people such as Yum, J.Immunology, 2001 aspect the activation of regulating lung infiltration that intracellular toxin causes and the neutrophil that causes acute lung injury, 167 (11), 6601-8).As if though PI3K γ expresses at the white cell camber, its forfeiture does not hinder the fact of hematopoiesis, and not have PI3K γ mouse be can survive and the reproducible fact shows that further this PI3K heterogeneous can be used as the potential drug targets.Utilize the work of stunning mouse also confirmed PI3K γ be mast cell's activation main toughener (people such as Laffargue, Immunity, 2002,16 (3), 441-451).

Thus, except tumorigenicity, evidence suggests I class PI3K enzyme in other disease, play a role (people such as Wymann, Trends in Pharmacological Science, 2003,24,366-376).Ia class PI3K enzyme and independent Ib fermentoid in immune cell, all have important effect (Koyasu, Nature Immunology, 2003,4,313-319), they are treatment targets of inflammatory and allergy indication thus.The mouse that nearest report proof lacks PI3K γ and PI3K δ is viable, but have the inflammatory that weakens and allergy response (people such as Ali, Nature, 2004,431 (7011), 1007-11).By means of the anti-inflammatory effect or directly influence the myocardial cell, suppress PI3K also can be used for treating cardiovascular disorder (people such as Prasad, Trends inCardiovascular Medicine, 2003,13,206-212).Thus, except cancer, expection I class PI3K enzyme inhibitors is preventing and is treating in the multiple disease to have value.

Differentiate some compounds of inhibition PI3Ks and phosphatidylinositols (PI) kinases associated kinase (PI3KKs), comprised wortmannin and quercetin derivative L Y294002.Compare with other kinases, these compounds are rational specific inhibitors of PI3Ks and PI3KKs, but they lack drug effect, and demonstrate very little selectivity in PI3K family.

Therefore, desirable is that other mTOR that effectively is used for the treatment of cancer, inflammatory or obstructive respiratory tract disease, immunity or cardiovascular disorder and/or PI3K inhibitor is provided.

Morpholino pyrimidine derivatives and PI3K inhibitor are known in this area.

International Patent Application WO 2004/048365 discloses the compound that has the PI3K enzyme inhibition activity and can be effective to treat cancer.These compounds be virtue amino-and the pyrimidine of heteroaryl amino-replacements, with regard to they virtue amino-with the heteroaryl amino substituting group with regard to, it is different from compound of the present invention.These substituting groups and of the present invention-XR ¹Substituting group is unequal.The PI3K activity inhibitor that can be used for treating cancer is also disclosed in European patent application EP 1,277 738, it has mentioned the bicyclic heteroaryl compounds of 4-morpholino-replacement, for example quinazoline and pyrido [3,2-d] tricyclic heteroaryl compounds of pyrimidine derivatives and 4-morpholino-replacement, but be not monocyclic pyrimidine derivatives.

Chemical compound lot is 4-morpholine-4-base-6-(benzenesulfonyl methyl)-2-pyridin-4-yl-pyrimidine and 4-{6-[(benzenesulfonyl for example) methyl]-2-pyridine-2-yl pyrimidines-4-yl } morpholine; in the chemical abstracts database, register; but do not point out its applicability, and do not propose these compounds and have mTOR and/or PI3K and suppress active or useful curative properties.

Unexpectedly, we find that some morpholino pyrimidine derivatives comprises some previously known compounds, has useful curative properties.Do not wish to be fettered, it is believed that the therepic use of this derivative stems from their inhibition activity to mTOR kinases and/or one or more PI3K enzymes (for example Ia fermentoid and/or Ib fermentoid) by the theoretical property restricted condition.Because the signal path of PI3K/mTOR family mediation has vital role in many cell processes (comprising propagation and survival), and, estimate that this derivative will be that treatment is effective in human wide spectrum cancer and other disease because the imbalance in these paths is a paathogenic factor.Especially, estimate that this derivative will have antiproliferative and/or apoptosis performance, this means that they will can be used for treating hyperplasia, for example cancer.Compound of the present invention also can be effective to the cell proliferation that suppresses out of control, and this cell proliferation can cause various non-malignant diseases, for example inflammatory diseases, obstructive respiratory tract disease, Immunological diseases or cardiovascular disorder.

Usually, compound of the present invention has effective inhibition activity to the mTOR kinases, but this compound also can have effective inhibition activity to one or more PI3K enzymes (for example Ia fermentoid and/or Ib fermentoid).

According to one aspect of the present invention, provide the compound of formula (I)

Formula (I)

Or its salt, ester or prodrug, as the medicine of treatment hyperplasia; Wherein

M is 0,1,2,3 or 4;

X is selected from following linking group :-CR ⁴=CR ⁵-,-CR ⁴=CR ⁵CR ⁶R ⁷-,-CR ⁶R ⁷CR ⁵=CR ⁴-,-C ≡ C-,-C ≡ CCR ⁶R ⁷-,-CR ⁶R ⁷C ≡ C-,-NR ⁴CR ⁶R ⁷-,-OCR ⁶R ⁷-,-SCR ⁶R ⁷-,-S (O) CR ⁶R ⁷-,-S (O) ₂CR ⁶R ⁷-,-C (O) NR ⁴CR ⁶R ⁷-,-NR ⁴C (O) CR ⁶R ⁷-,-NR ⁴C (O) NR ⁵CR ⁶R ⁷-,-NR ⁴S (O) ₂CR ⁶R ⁷-,-S (O) ₂NR ⁴CR ⁶R ⁷-,-C (O) NR ⁴-,-NR ⁴C (O)-,-NR ⁴C (O) NR ⁵-,-S (O) ₂NR ⁴-and-NR ⁴S (O) ₂-;

¹Y and Y ²Be N or CR independently ⁸, condition is, ¹Y and Y ²In one be N, another is CR ⁸

R ¹Be to be selected from following group: C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, carbocylic radical, carbocylic radical C _1-6Alkyl, heterocyclic radical and heterocyclic radical C _1-6Alkyl, this group is optional to be selected from following substituting group and to replace by one or more: halogen, cyano group, nitro, R ⁹,-OR ⁹,-SR ⁹,-SOR ⁹,-SO ₂R ⁹,-COR ⁹,-CO ₂R ⁹,-CONR ⁹R ¹⁰,-NR ⁹R ¹⁰,-NR ⁹COR ¹⁰,-NR ⁹CO ₂R ¹⁰,-NR ⁹CONR ¹⁰R ¹⁵,-NR ⁹COCONR ¹⁰R ¹⁵With-NR ⁹SO ₂R ¹⁰

R ²Be to be selected from following group: C _1-6Alkyl, carbocylic radical and heterocyclic radical, this group is optional to be independently selected from following substituting group and to replace by one or more: halogen, cyano group, nitro ,-R ¹¹,-OR ¹¹,-SR ¹¹,-SOR ¹¹,-SO ₂R ¹¹,-COR ¹¹,-CO ₂R ¹¹,-CONR ¹¹R ¹²,-NR ¹¹R ¹²,-NR ¹¹COR ¹²And-NR ¹¹COCONR ¹²R ¹⁶

Each R ³, when existing, be independently selected from: halogen, cyano group, nitro ,-R ¹³,-OR ¹³,-SR ¹³,-SOR ¹³,-SO ₂R ¹³,-COR ¹³,-CO ₂R ¹³,-CONR ¹³R ¹⁴,-NR ¹³R ¹⁴,-NR ¹³COR ¹⁴,-NR ¹³CO ₂R ¹⁴With-NR ¹³SO ₂R ¹⁴

R ⁴And R ⁵Be hydrogen or C independently _1-6Alkyl;

Or R ¹And R ⁴The one or more atoms that are connected with them form 5-to 10-unit's carbocyclic ring or the optional heterocycle that is replaced by N, O or S of 1,2 or 3 ring carbon atom wherein, and ring is optional to be selected from following substituting group and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _1-6Alkoxyl group, halogen C _1-6Alkyl, halogen C _1-6Alkoxyl group, hydroxyl C _1-6Alkyl, hydroxyl C _1-6Alkoxyl group, C _1-6Alkoxy C _1-6Alkyl, C _1-6Alkoxy C _1-6Alkoxyl group, amino, C _1-6Alkylamino, two (C _1-6Alkyl) amino, amino C _1-6Alkyl, (C _1-6Alkyl) amino C _1-6Alkyl, two (C _1-6Alkyl) amino C _1-6Alkyl, cyano group C _1-6Alkyl, C _1-6Alkyl sulphonyl, C _1-6Alkyl sulfonyl amino, C _1-6Alkyl sulphonyl (C _1-6Alkyl) amino, sulfamyl, C _1-6Alkylsulfamoyl group, two (C _1-6Alkyl) sulfamyl, C _1-6Alkanoylamino, C _1-6Alkyloyl (C _1-6Alkyl) amino, formamyl, C _1-6Alkyl-carbamoyl and two (C _1-6Alkyl) formamyl;

R ⁶And R ⁷Be independently selected from hydrogen, halogen, cyano group, nitro and C _1-6Alkyl;

R ⁸Be selected from hydrogen, halogen, cyano group and C _1-6Alkyl;

R ⁹And R ¹⁰Be hydrogen independently or be selected from following group: C _1-6Alkyl, carbocylic radical, carbocylic radical C _1-6Alkyl, heterocyclic radical and heterocyclic radical C _1-6Alkyl, this group is optional to be selected from following substituting group and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _1-6Alkoxyl group, halogen C _1-6Alkyl, halogen C _1-6Alkoxyl group, hydroxyl C _1-6Alkyl, hydroxyl C _1-6Alkoxyl group, C _1-6Alkoxy C _1-6Alkyl, C _1-6Alkoxy C _1-6Alkoxyl group, amino, C _1-6Alkylamino, two (C _1-6Alkyl) amino, amino C _1-6Alkyl, (C _1-6Alkyl) amino C _1-6Alkyl, two (C _1-6Alkyl) amino C _1-6Alkyl, cyano group C _1-6Alkyl, C _1-6Alkyl sulphonyl, C _1-6Alkyl sulfonyl amino, C _1-6Alkyl sulphonyl (C _1-6Alkyl) amino, sulfamyl, C _1-6Alkylsulfamoyl group, two (C _1-6Alkyl) sulfamyl, C _1-6Alkanoylamino, C _1-6Alkyloyl (C _1-6Alkyl) amino, formamyl, C _1-6Alkyl-carbamoyl and two (C _1-6Alkyl) formamyl;

R ¹¹And R ¹²Be hydrogen independently or be selected from following group: C _1-6Alkyl, carbocylic radical, carbocylic radical C _1-6Alkyl, heterocyclic radical and heterocyclic radical C _1-6Alkyl, this group is optional to be selected from following substituting group and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _1-6Alkoxyl group, halogen C _1-6Alkyl, halogen C _1-6Alkoxyl group, hydroxyl C _1-6Alkyl, hydroxyl C _1-6Alkoxyl group, C _1-6Alkoxy C _1-6Alkyl, C _1-6Alkoxy C _1-6Alkoxyl group, amino, C _1-6Alkylamino, two (C _1-6Alkyl) amino, amino C _1-6Alkyl, (C _1-6Alkyl) amino C _1-6Alkyl, two (C _1-6Alkyl) amino C _1-6Alkyl, cyano group C _1-6Alkyl, C _1-6Alkyl sulphonyl, C _1-6Alkanoylamino, C _1-6Alkyloyl (C _1-6Alkyl) amino, formamyl, C _1-6Alkyl-carbamoyl and two (C _1-6Alkyl) formamyl;

R ¹³, R ¹⁴, R ¹⁵And R ¹⁶Be hydrogen independently or be selected from following group: C _1-6Alkyl, carbocylic radical, carbocylic radical C _1-6Alkyl, heterocyclic radical and heterocyclic radical C _1-6Alkyl, this group is optional to be selected from following substituting group and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _1-6Alkoxyl group, halogen C _1-6Alkyl, halogen C _1-6Alkoxyl group, hydroxyl C _1-6Alkyl, hydroxyl C _1-6Alkoxyl group, C _1-6Alkoxy C _1-6Alkyl, C _1-6Alkoxy C _1-6Alkoxyl group, amino, C _1-6Alkylamino, two (C _1-6Alkyl) amino, amino C _1-6Alkyl, (C _1-6Alkyl) amino C _1-6Alkyl, two (C _1-6Alkyl) amino C _1-6Alkyl, cyano group C _1-6Alkyl, C _1-6Alkyl sulphonyl, C _1-6Alkyl sulfonyl amino, C _1-6Alkyl sulphonyl (C _1-6Alkyl) amino, sulfamyl, C _1-6Alkylsulfamoyl group, two (C _1-6Alkyl) sulfamyl, C _1-6Alkanoylamino, C _1-6Alkyloyl (C _1-6Alkyl) amino, formamyl, C _1-6Alkyl-carbamoyl and two (C _1-6Alkyl) formamyl; Condition is, when X be-during C (O) NH-, R ¹Be not following group:

Formula (I)

Or its salt, ester or prodrug are as the medicine of treatment hyperplasia; Wherein

M is 0,1,2,3 or 4;

X is selected from following linking group :-CR ⁴=CR ⁵-,-CR ⁴=CR ⁵CR ⁶R ⁷-,-CR ⁶R ⁷CR ⁵=CR ⁴-,-C ≡ C-,-C ≡ CCR ⁶R ⁷-,-CR ⁶R ⁷C ≡ C-,-NR ⁴CR ⁶R ⁷-,-OCR ⁶R ⁷-,-SCR ⁶R ⁷-,-S (O) CR ⁶R ⁷-,-S (O) ₂CR ⁶R ⁷-,-C (O) NR ⁴CR ⁶R ⁷-,-NR ⁴C (O) NR ⁵CR ⁶R ⁷-,-S (O) ₂NR ⁴CR ⁶R ⁷-,-C (O) NR ⁴-,-NR ⁴C (O)-,-NR ⁴C (O) NR ⁵-,-S (O) ₂NR ⁴-and-NR ⁴S (O) ₂-;

R ⁴And R ⁵Be hydrogen or C independently _1-6Alkyl;

R ⁸Be selected from hydrogen, halogen, cyano group and C _1-6Alkyl;

Formula (I)

M is 0,1,2,3 or 4;

R ¹Be to be selected from following group: C _1-6Alkyl, carbocylic radical, carbocylic radical C _1-6Alkyl, heterocyclic radical and heterocyclic radical C _1-6Alkyl, this group is optional to be selected from following substituting group and to replace by one or more: halogen, cyano group, nitro, R ⁹,-OR ⁹,-COR ⁹,-CONR ⁹R ¹⁰,-NR ⁹R ¹⁰With-NR ⁹COR ¹⁰

R ²Be to be selected from following group: C _1-6Alkyl, carbocylic radical and heterocyclic radical, this group is optional to be independently selected from following substituting group and to replace by one or more: halogen, cyano group, nitro ,-R ¹¹,-OR ¹¹,-COR ¹¹,-CONR ¹¹R ¹²,-NR ¹¹R ¹²With-NR ¹¹COR ¹²

Each R ³, when existing, be independently selected from: halogen, cyano group, nitro ,-R ¹³,-OR ¹³,-COR ¹³,-CONR ¹³R ¹⁴,-NR ¹³R ¹⁴With-NR ¹³COR ¹⁴

R ⁴And R ⁵Be hydrogen or C independently _1-6Alkyl;

R ⁸Be selected from hydrogen, halogen, cyano group and C _1-6Alkyl;

R ⁹And R ¹⁰Be hydrogen independently or be selected from following group: C _1-6Alkyl, carbocylic radical and heterocyclic radical, this group is optional to be selected from following substituting group and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _1-6Alkoxyl group, halogen C _1-6Alkyl, halogen C _1-6Alkoxyl group, hydroxyl C _1-6Alkyl, hydroxyl C _1-6Alkoxyl group, C _1-6Alkoxy C _1-6Alkyl, C _1-6Alkoxy C _1-6Alkoxyl group, amino, C _1-6Alkylamino and two (C _1-6Alkyl) amino;

R ¹¹And R ¹²Be hydrogen independently or be selected from following group: C _1-6Alkyl, carbocylic radical and heterocyclic radical, this group is optional to be selected from following substituting group and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _1-6Alkoxyl group, halogen C _1-6Alkyl, halogen C _1-6Alkoxyl group, hydroxyl C _1-6Alkyl, hydroxyl C _1-6Alkoxyl group, C _1-6Alkoxy C _1-6Alkyl, C _1-6Alkoxy C _1-6Alkoxyl group, amino, C _1-6Alkylamino and two (C _1-6Alkyl) amino;

R ¹³And R ¹⁴Be hydrogen independently or be selected from following group: C _1-6Alkyl, carbocylic radical and heterocyclic radical, this group is optional to be selected from following substituting group and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _1-6Alkoxyl group, halogen C _1-6Alkyl, halogen C _1-6Alkoxyl group, hydroxyl C _1-6Alkyl, hydroxyl C _1-6Alkoxyl group, C _1-6Alkoxy C _1-6Alkyl, C _1-6Alkoxy C _1-6Alkoxyl group, amino, C _1-6Alkylamino and two (C _1-6Alkyl) amino;

Condition is, when X be-during C (O) NH-, R ¹Be not following group:

According to another aspect of the present invention, provide the compound of formula (I)

Formula (I)

Or its salt, ester or prodrug are used for the treatment of purposes in the medicine of hyperplasia in preparation; Wherein

M is 0,1,2,3 or 4;

R ¹Be to be selected from following group: C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, carbocylic radical, carbocylic radical C _1-6Alkyl, heterocyclic radical and heterocyclic radical C _1-6Alkyl, this group is optional to be selected from following substituting group and to replace by one or more: halogen, cyano group, nitro ,-R ⁹,-OR ⁹,-SR ⁹,-SOR ⁹,-SO ₂R ⁹,-COR ⁹,-CO ₂R ⁹,-CONR ⁹R ¹⁰,-NR ⁹R ¹⁰,-NR ⁹COR ¹⁰, NR ⁹CO ₂R ¹⁰,-NR ⁹CONR ¹⁰R ¹⁵,-NR ⁹COCONR ¹⁰R ¹⁵With-NR ⁹SO ₂R ¹⁰

R ⁴And R ⁵Be hydrogen or C independently _1-6Alkyl;

R ⁸Be selected from hydrogen, halogen, cyano group and C _1-6Alkyl;

Formula (I)

M is 0,1,2,3 or 4;

R ¹Be to be selected from following group: C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, carbocylic radical, carbocylic radical C _1-6Alkyl, heterocyclic radical and heterocyclic radical C _1-6Alkyl, this group is optional to be selected from following substituting group and to replace by one or more: halogen, cyano group, nitro ,-R ⁹,-OR ⁹,-SR ⁹,-SOR ⁹,-SO ₂R ⁹,-COR ⁹,-CO ₂R ⁹,-CONR ⁹R ¹⁰,-NR ⁹R ¹⁰,-NR ⁹COR ¹⁰,-NR ⁹CO ₂R ¹⁰,-NR ⁹CONR ¹⁰R ¹⁵,-NR ⁹COCONR ¹⁰R ¹⁵With-NR ⁹SO ₂R ¹⁰

Each R ³, when existing, be independently selected from: halogen, cyano group, nitro ,-R ¹³,-OR ¹³,-SR ¹³,-SOR ¹³,-SO ₂R ¹³,-COR ¹³,-CO ₂R ¹³,-CONR ¹³R ¹⁴,-NR ¹³R ¹⁴,-NR ¹³COR ¹⁴,-R ¹³CO ₂R ¹⁴With-NR ¹³SO ₂R ¹⁴

R ⁴And R ⁵Be hydrogen or C independently _1-6Alkyl;

R ⁸Be selected from hydrogen, halogen, cyano group and C _1-6Alkyl;

Formula (I)

M is 0,1,2,3 or 4;

R ⁴And R ⁵Be hydrogen or C independently _1-6Alkyl;

R ⁸Be selected from hydrogen, halogen, cyano group and C _1-6Alkyl;

Condition is, when X be-during C (O) NH-, R ¹Be not following group:

According to further aspect of the present invention, also provide the compound of formula (I)

Formula (I)

Or its salt, ester or prodrug; Wherein

M is 0,1,2,3 or 4;

X is selected from following linking group :-CR ⁴=CR ⁵-,-CR ⁴=CR ⁵CR ⁶R ⁷-,-CR ⁶R ⁷CR ⁵=CR ⁴-,-C ≡ C-,-C ≡ CCR ⁶R ⁷-,-CR ⁶R ⁷C ≡ C-,-NR ⁴CR ⁶R ⁷-,-OCR ⁶R ⁷-,-SCR ⁶R ⁷-,-S (O) CR ⁶R ⁷-,-S (O) ₂CR ⁶R ⁷-,-C (O) NR ⁴CR ⁶R ⁷-,-NR ⁴C (O) CR ⁶R ⁷-,-NR ⁴C (O) NR ⁵CR ⁶R ⁷-,-NR ⁴S (O) ₂CR ⁶R ⁷-,-S (O) ₂NR ⁴CR ⁶R ⁷-,-C (O) NR ⁴-,-NR ⁴C (O)-,-NR ⁴C (O) NR ⁵-,-(O) ₂NR ⁴-and-NR ⁴S (O) ₂-;

R ¹Be to be selected from following group: C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, carbocylic radical, carbocylic radical C _1-6Alkyl, heterocyclic radical and heterocyclic radical C _1-6Alkyl, this group is optional to be selected from following substituting group and to replace by one or more: halogen, cyano group, nitro ,-R ⁹,-OR ⁹,-SR ⁹,-SOR ⁹,-O ₂R ⁹,-COR ⁹,-CO ₂R ⁹,-CONR ⁹R ¹⁰,-NR ⁹R ¹⁰,-NR ⁹COR ¹⁰,-NR ⁹CO ₂R ¹⁰,-NR ⁹CONR ¹⁰R ¹⁵,-NR ⁹COCONR ¹⁰R ¹⁵And NR ⁹SO ₂R ¹⁰

Each R ³, when existing, be independently selected from: halogen, cyano group, nitro ,-R ¹³,-OR ¹³,-R ¹³,-SOR ¹³,-SO ₂R ¹³,-COR ¹³,-CO ₂R ¹³,-CONR ¹³R ¹⁴,-NR ¹³R ¹⁴,-NR ¹³COR ¹⁴,-NR ¹³CO ₂R ¹⁴With-NR ¹³SO ₂R ¹⁴

R ⁴And R ⁵Be hydrogen or C independently _1-6Alkyl;

R ⁸Be selected from hydrogen, halogen, cyano group and C _1-6Alkyl;

R ¹³, R ¹⁴, R ¹⁵And R ¹⁶Be hydrogen independently or be selected from following group: C _1-6Alkyl, carbocylic radical, carbocylic radical C _1-6Alkyl, heterocyclic radical and heterocyclic radical C _1-6Alkyl, this group is optional to be selected from following substituting group and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C _1-6Alkyl, C _1-6Alkoxyl group, halogen C _1-6Alkyl, halogen C _1-6Alkoxyl group, hydroxyl C _1-6Alkyl, hydroxyl C _1-6Alkoxyl group, C _1-6Alkoxy C _1-6Alkyl, C _1-6Alkoxy C _1-6Alkoxyl group, amino, C _1-6Alkylamino, two (C _1-6Alkyl) amino, amino C _1-6Alkyl, (C _1-6Alkyl) amino C _1-6Alkyl, two (C _1-6Alkyl) amino C _1-6Alkyl, cyano group C _1-6Alkyl, C _1-6Alkyl sulphonyl, C _1-6Alkyl sulfonyl amino, C _1-6Alkyl sulphonyl (C _1-6Alkyl) amino, sulfamyl, C _1-6Alkylsulfamoyl group, two (C _1-6Alkyl) sulfamyl, C _1-6Alkanoylamino, C _1-6Alkyloyl (C _1-6Alkyl) amino, formamyl, C _1-6Alkyl-carbamoyl and two (C _1-6Alkyl) formamyl;

Condition is, the compound of formula (I) is not to list in the compound of getting rid of in the compound tabulation 1,

With condition be, when X be-during C (O) NH-, R ¹Be not following group:

Formula (I)

Or its salt, ester or prodrug; Wherein

M is 0,1,2,3 or 4;

R ⁴And R ⁵Be hydrogen or C independently _1-6Alkyl;

R ⁸Be selected from hydrogen, halogen, cyano group and C _1-6Alkyl;

With condition be, when X be-during C (O) NH-, R ¹Be not following group:

Formula (I)

Or its salt, ester or prodrug; Wherein

M is 0,1,2,3 or 4;

R ¹Be to be selected from following group: C _1-6Alkyl, carbocylic radical, carbocylic radical C _1-6Alkyl, heterocyclic radical and heterocyclic radical C _1-6Alkyl, this group is optional to be selected from following substituting group and to replace by one or more: halogen, cyano group, nitro, R ⁹,-OR ⁹,-COR ⁹,-CONR ⁹R ¹⁰,-NR ⁹R ¹⁰With-R ⁹COR ¹⁰

R ⁴And R ⁵Be hydrogen or C independently _1-6Alkyl;

R ⁸Be selected from hydrogen, halogen, cyano group and C _1-6Alkyl;

With condition be, when X be-during C (O) NH-, R ¹Be not following group:

The compound tabulation of getting rid of 1:

The 4-{6-[(methylthio group) methyl]-2-methylpyrimidine-4-yl } morpholine;

4-(6-{[(4-chloro-phenyl-) sulfenyl] methyl }-2-methylpyrimidine-4-yl) morpholine;

4-(6-{[(4-chloro-phenyl-) sulfenyl] methyl }-2-methylpyrimidine-4-yl)-2, the 6-thebaine;

The 4-{6-[(benzenesulfinyl) methyl]-2-methylpyrimidine-4-yl } morpholine;

4-(6-{[(4-chloro-phenyl-) sulfinyl] methyl }-2-methylpyrimidine-4-yl) morpholine;

The 4-{6-[(benzenesulfonyl) methyl]-2-methylpyrimidine-4-yl } morpholine;

4-(6-{[(4-chloro-phenyl-) alkylsulfonyl] methyl }-2-methylpyrimidine-4-yl) morpholine;

The 4-{6-[(methylthio group) methyl]-2-phenyl pyrimidine-4-yl } morpholine;

The 4-{6-[(thiophenyl) methyl]-2-phenyl pyrimidine-4-yl } morpholine;

4-(6-{[(4-chloro-phenyl-) sulfenyl] methyl }-2-phenyl pyrimidine-4-yl) morpholine;

4-(6-{[(4-benzyl chloride base) sulfenyl] methyl }-2-phenyl pyrimidine-4-yl) morpholine;

4-(6-{[(4-benzyl chloride base) sulfenyl] methyl }-2-phenyl pyrimidine-4-yl)-2, the 6-thebaine;

The 4-{6-[(methylsulfinyl) methyl]-2-phenyl pyrimidine-4-yl } morpholine;

The 4-{6-[(benzenesulfinyl) methyl]-2-phenyl pyrimidine-4-yl } morpholine;

4-(6-{[(4-chloro-phenyl-) sulfinyl] methyl }-2-phenyl pyrimidine-4-yl) morpholine;

The 4-{6-[(methyl sulphonyl) methyl]-2-phenyl pyrimidine-4-yl } morpholine;

The 4-{6-[(benzenesulfonyl) methyl]-2-phenyl pyrimidine-4-yl } morpholine;

The 4-{6-[(methylthio group) methyl]-2-pyridine-2-yl pyrimidines-4-yl } morpholine;

The 4-{6-[(thiophenyl) methyl]-2-pyridin-4-yl pyrimidine-4-yl } morpholine;

4-(6-{[(4-chloro-phenyl-) sulfenyl] methyl }-2-pyridine-2-yl pyrimidines-4-yl) morpholine;

The 4-{6-[(methyl sulphonyl) methyl]-2-pyridin-3-yl pyrimidine-4-yl } morpholine;

The 4-{6-[(methyl sulphonyl) methyl]-2-pyridin-4-yl pyrimidine-4-yl } morpholine;

The 4-{6-[(benzenesulfonyl) methyl]-2-pyridine-2-yl pyrimidines-4-yl } morpholine;

The 4-{6-[(benzenesulfonyl) methyl]-2-pyridin-3-yl pyrimidine-4-yl } morpholine;

The 4-{6-[(benzenesulfonyl) methyl]-2-pyridin-4-yl pyrimidine-4-yl } morpholine;

The 4-{6-[(methoxyl group) methyl]-2-methylpyrimidine-4-yl } morpholine;

The 4-{6-[(methoxyl group) methyl]-2-phenyl pyrimidine-4-yl } morpholine;

The 4-{6-[(methoxyl group) methyl]-2-phenyl pyrimidine-4-yl }-2, the 6-thebaine;

The 4-{6-[(phenoxy group) methyl]-2-(6-picoline-2-yl) pyrimidine-4-yl }-2, the 6-thebaine;

N-[5-[[3-(1-cyano group-1-methylethyl) benzoyl] amino]-the 2-aminomethyl phenyl]-2,6-two-4-morpholinyl-4-pyrimidine carboxamide;

N-[5-[[3-(1-cyano group-1-methylethyl) benzoyl] amino]-the 2-aminomethyl phenyl]-6-(4-morpholinyl)-2-(trifluoromethyl)-4-pyrimidine carboxamide;

N-[4-fluoro-3-[(pyrazinyl oxygen base) methyl] phenyl]-2,6-two-4-morpholinyl-4-pyrimidine carboxamide;

The 4-[2-methyl-6-[(1E)-2-[3-(trifluoromethyl) phenyl] vinyl]-the 4-pyrimidyl]-morpholine;

The 4-[6-methyl-2-[(1E)-2-[3-(trifluoromethyl) phenyl] vinyl]-the 4-pyrimidyl]-morpholine;

3,4,5-trimethoxy-N-[4-methyl-6-(4-morpholinyl)-2-pyrimidyl]-benzamide;

N-(2,3-dimethyl-1H-indoles-5-yl)-2,6-two-4-morpholinyl-4-pyrimidine carboxamide;

N-(2,3-dimethyl-1H-indoles-5-yl)-4,6-two-4-morpholinyl-2-pyridine carboxamide;

N-(3, the 4-3,5-dimethylphenyl)-2,6-two-4-morpholinyl-4-pyrimidine carboxamide;

N-[3-(aminocarboxyl) phenyl]-2,6-two-4-morpholinyl-4-pyrimidine carboxamide;

N-(4,6-two-4-morpholinyl-2-pyridyl)-N '-(3-aminomethyl phenyl)-urea;

N-(2,3-dimethyl-1H-indoles-5-yl)-4,6-two-4-morpholinyl-2-pyridine carboxamide;

4,6-two-4-morpholinyl-N-(1,2,3-trimethylammonium-1H-indoles-5-yl)-2-pyridine carboxamide;

N-(2,3-dimethyl-1H-indoles-5-yl)-2-[(2R, 6S)-2,6-dimethyl-4-morpholinyl]-6-(4-morpholinyl)-4-pyrimidine carboxamide;

2,6-two-4-morpholinyl-N-(1,2,3-trimethylammonium-1H-indoles-5-yl)-4-pyrimidine carboxamide;

N-[3-(dimethylamino) phenyl]-2,6-two-4-morpholinyl-4-pyrimidine carboxamide;

N-[3,4, the 5-trimethoxyphenyl]-2,6-two-4-morpholinyl-4-pyrimidine carboxamide;

2,6-two-4-morpholinyl-N-(6,7,8,9-tetrahydrochysene-5H-benzocyclohepta alkene-6-yl)-4-pyrimidine carboxamide; With 4-[2-methyl-6-[2-(5-nitro-2-furyl) vinyl]-the 4-pyrimidyl]-morpholine.

In addition, the invention provides compound or its salt, ester or the prodrug of formula (I) as herein defined, condition is

(a) when ¹Y is CH, Y ²Be N, X is-SCH ₂-,-S (O) CH ₂-or-S (O) ₂CH ₂-, and R ²When being methyl, phenyl or pyridyl, R so ¹Not methyl, phenyl, 4-chloro-phenyl-or 4-benzyl chloride base; With

(b) when ¹Y is CH, Y ²Be N, X is-OCH ₂-, and R ²When being methyl, phenyl or 2-picoline-2-base, R so ¹It or not methyl or phenyl.

Following compounds in the compound tabulation of getting rid of 1 also can be numbered by their chemical abstracts and be differentiated: N-[5-[[3-(1-cyano group-1-methylethyl) benzoyl] amino]-the 2-aminomethyl phenyl]-2,6-two-4-morpholinyl-4-pyrimidine carboxamide (873449-41-3);

N-[5-[[3-(1-cyano group-1-methylethyl) benzoyl] amino]-the 2-aminomethyl phenyl]-6-(4-morpholinyl)-2-(trifluoromethyl)-4-pyrimidine carboxamide (873449-50-4);

N-[4-fluoro-3-[(pyrazinyl oxygen base) methyl] phenyl]-2,6-two-4-morpholinyl-4-pyrimidine carboxamide (642085-32-3);

The 4-[2-methyl-6-[(1E)-2-[3-(trifluoromethyl) phenyl] vinyl]-the 4-pyrimidyl]-morpholine (425423-56-9);

The 4-[6-methyl-2-[(1E)-2-[3-(trifluoromethyl) phenyl] vinyl]-the 4-pyrimidyl]-morpholine (425423-57-0);

3,4,5-trimethoxy-N-[4-methyl-6-(4-morpholinyl)-2-pyrimidyl]-benzamide (168197-68-0);

N-(2,3-dimethyl-1H-indoles-5-yl)-2,6-two-4-morpholinyl-4-pyrimidine carboxamide (887133-39-3);

N-(2,3-dimethyl-1H-indoles-5-yl)-4,6-two-4-morpholinyl-2-pyridine carboxamide (887133-47-3);

N-(3, the 4-3,5-dimethylphenyl)-2,6-two-4-morpholinyl-4-pyrimidine carboxamide (887133-68-8);

N-[3-(aminocarboxyl) phenyl]-2,6-two-4-morpholinyl-4-pyrimidine carboxamide (87133-69-9);

N-(4,6-two-4-morpholinyl-2-pyridyl)-N '-(3-aminomethyl phenyl)-urea (87133-93-9);

N-(2,3-dimethyl-1H-indoles-5-yl)-4,6-two-4-morpholinyl-2-pyridine carboxamide (887134-72-7);

4,6-two-4-morpholinyl-N-(1,2,3-trimethylammonium-1H-indoles-5-yl)-2-pyridine carboxamide (887134-74-9);

N-(2,3-dimethyl-1H-indoles-5-yl)-2-[(2R, 6S)-2,6-dimethyl-4-morpholinyl]-6-(4-morpholinyl)-4-pyrimidine carboxamide (887136-28-9);

2,6-two-4-morpholinyl-N-(1,2,3-trimethylammonium-1H-indoles-5-yl)-4-pyrimidine carboxamide (887136-30-3);

N-[3-(dimethylamino) phenyl]-2,6-two-4-morpholinyl-4-pyrimidine carboxamide (887136-53-0);

2,6-two-4-morpholinyl-N-(6,7,8,9-tetrahydrochysene-5H-benzocyclohepta alkene-6-yl)-4-pyrimidine carboxamide (450367-63-2); With

4-[2-methyl-6-[2-(5-nitro-2-furyl) vinyl]-the 4-pyrimidyl]-morpholine (4592-48-7).

Following compounds N-[3 in the compound tabulation of getting rid of 1,4, the 5-trimethoxyphenyl]-2,6-two-4-morpholinyl-4-pyrimidine carboxamide also can be called 2,6-dimorpholine-4-base-N-(3,4, the 5-trimethoxyphenyl) pyrimidine-4-methane amide.

The compound of some formula (I) can exist with stereoisomeric forms in any ratio.All geometry that can be understood as the formula of the present invention includes (I) compound comprise the mixture of raceme with optically active isomer and it.Tautomer and its mixture also constitute one aspect of the present invention.Solvate and its mixture also constitute one aspect of the present invention.For example, the suitable solvent thing of formula (I) compound is a hydrate for example, and for example semihydrate, monohydrate, dihydrate or trihydrate or its substitute the hydrate of amount.The present invention relates to formula defined herein (I) compound with and salt.The salt that is used for pharmaceutical composition is pharmacologically acceptable salts, but other salt can be used for preparation formula (I) compound and their pharmacologically acceptable salts.Pharmacologically acceptable salts of the present invention can for example comprise the acid salt of formula defined herein (I) compound, and this compound has enough alkalescence, thereby can form this salt.This acid salt is including, but not limited to fumarate (furmarate), mesylate, hydrochloride, hydrobromate, Citrate trianion and maleate, and the salt that forms with phosphoric acid and sulfuric acid.In addition, if the compound of formula (I) is enough tart, then salt is subsalt, example is including, but not limited to an alkali metal salt, for example sodium or sylvite, alkaline earth salt is calcium or magnesium salts for example, or organic amine salt, for example triethylamine, thanomin, diethanolamine, trolamine, morpholine, N-methyl piperidine, N-ethylpiperidine, dibenzyl amine or amino acid lysine salt for example.

The compound of the formula (I) of hydrolyzable ester form in the body also can be provided.Contain in the body of formula (I) compound of carboxyl or hydroxyl hydrolyzable ester and be for example acceptable ester of pharmacy, it is cracking in human or animal body, produces parent acid or alcohol.This ester can give compound, check test subsequently that experimental animal tests by for example intravenously and be determined with the body fluid of animal.

The suitable acceptable carboxyl ester of pharmacy comprises C _1-6The alkoxy methyl ester, methoxymethyl ester for example, C _1-6Alkyloyl oxygen base methyl esters, oxy acid methyl neopentyl ester for example, phthalidyl ester, C _3-8Cyclo alkoxy carbonyl oxygen base C _1-6Alkyl ester, 1-cyclohexyl-carbonyl oxygen base ethyl ester for example, 1,3-dioxole-2-ketone group methyl esters, 5-methyl isophthalic acid for example, 3-dioxole-2-ketone group methyl ester, and C _1-6Alkoxy-carbonyl oxy ethyl ester, for example 1-methoxycarbonyl oxygen base ethyl ester; And can on any carboxyl of The compounds of this invention, form.

The suitable acceptable hydroxy ester of pharmacy comprises inorganic ester, and for example phosphoric acid ester (comprising the phosphoramidic acid cyclic ester) and α-acyloxyalkyl group ether and related compound, related compound can decompose as esterolytic result in the body and obtain parent hydroxy.The example of α-acyloxyalkyl group ether comprises acetoxyl group methoxyl group and 2,2-dimethyl propylene acyloxy methoxyl group.Comprise C with the selection of the group of hydrolyzable ester in the hydroxyl organizer _1-10Alkyloyl, formyl radical for example, ethanoyl, benzoyl, phenylacetyl, the benzoyl of replacement and phenylacetyl; C _1-10Carbalkoxy (obtaining alkyl carbonate), for example ethoxy carbonyl; Two-C _1-4Alkyl-carbamoyl and N-(two-C _1-4The alkylamino ethyl)-N-C _1-4Alkyl-carbamoyl (obtaining carbamate); Two-C _1-4Alkylamino ethanoyl and carboxyl ethanoyl.The example of the ring substituents on phenylacetyl and benzoyl comprises aminomethyl, C _1-4Alkylamino methyl and two-(C _1-4Alkyl) aminomethyl and is connected the base morpholino or the Piperazino (piperazino) that are connected with the 3-or the 4-position of benzoyl basic ring from theheterocyclic nitrogen atom by methylene radical.Hydrolyzable ester comprises for example R in other interested body ^AC (O) OC _1-6Alkyl-CO-, wherein R ^ABe benzyloxy-C for example _1-4Alkyl or phenyl.In this ester, substituting group suitable on the phenyl comprises for example 4-C _1-4Piperazinyl-C _1-4Alkyl, Piperazino-C _1-4Alkyl and morpholino-C _1-4Alkyl.

The compound of formula (I) also can give with the form of prodrug, and prodrug can decompose in human or animal body, obtains the compound of formula (I).The various forms of prodrug is known in this area.The example of this prodrug derivatives referring to:

A) Design of Prodrugs, H.Bundgaard compiles, (Elsevier, 1985) and Methodsin Enzymology, Vol.42, p.309-396, K.Widder waits the people, compiles (AcademicPress, 1985);

B) A Textbook of Drug Design and Development, Krogsgaard-Larsen and H.Bundgaard compile, the 5th chapter " Design and Application of Prodrugs ", H.Bundgaard is (1991) p.113-191;

c)H.Bundgaard，Advanced?Drug?Delivery?Reviews，8，1-38(1992)；

D) H.Bundgaard waits the people, Journal of Pharmaceutical Sciences, 77,285 (1988); With

E) N.Kakeya waits the people, Chem Pharm Bull, 32,692 (1984).

In this manual, generic term " C _P-qAlkyl " comprise straight chain and branched-chain alkyl.Yet, for single alkyl for example " propyl group ", only specify (being n-propyl and sec.-propyl) for linear form, for single branched-chain alkyl for example " tertiary butyl ", only specify for the side chain form.

At C _P-qPrefix C in alkyl and other term _P-qThe scope of the carbon atom that exists in (wherein p and q are integers) expression group, for example C _1-4Alkyl comprises C ₁Alkyl (methyl), C ₂Alkyl (ethyl), C ₃Alkyl (propyl group, for example n-propyl and sec.-propyl) and C ₄Alkyl (normal-butyl, sec-butyl, the isobutyl-and the tertiary butyl).

Term C _P-qAlkoxyl group comprises-O-C _P-qAlkyl.

Term C _P-qAlkyloyl comprises-C (O) alkyl.

Term halogen comprises fluorine, chlorine, bromine and iodine.

" carbocylic radical " is monocycle, dicyclo or the three-loop system of saturated, unsaturated or fractional saturation, contains 3 to 14 annular atomses, wherein encircles CH ₂Group can be replaced by the C=O group." carbocylic radical " comprises " aryl ", " C _P-qCycloalkyl " and " C _P-qCycloalkenyl group ".

" aryl " is fragrant monocycle, dicyclo or trinucleated carbocylic radical loop systems.

" C _P-qCycloalkenyl group " be unsaturated or the monocycle of fractional saturation, dicyclo or three ring carbocylic radical loop systems, contain at least 1 C=C key, wherein encircle CH ₂Group can be replaced by the C=O group.

" C _P-qCycloalkyl " be saturated monocycle, dicyclo or three ring carbocylic radical loop systems, wherein encircle CH ₂Group can be replaced by the C=O group.

" heterocyclic radical " is monocycle, dicyclo or the three-loop system of saturated, unsaturated or fractional saturation, contain 3 to 14 annular atomses, wherein 1,2,3 or 4 annular atoms is selected from nitrogen, sulphur or oxygen, and this ring can be that carbon or nitrogen connect, wherein nuclear nitrogen or sulphur atom can be oxidized, wherein encircle CH ₂Group can be replaced by the C=O group." heterocyclic radical " comprises " heteroaryl ", " the assorted alkyl of ring " and " the assorted thiazolinyl of ring ".

" heteroaryl " is fragrant monocycle, dicyclo or tricyclic heterocyclic base, especially has 5 to 10 annular atomses, and wherein 1,2,3 or 4 annular atoms is selected from nitrogen, sulphur or oxygen, and wherein nuclear nitrogen or sulphur can be oxidized.

" the assorted thiazolinyl of ring " is unsaturated or the monocycle of fractional saturation, dicyclo or tricyclic heterocyclic basic ring system, especially have 5 to 10 annular atomses, wherein 1,2,3 or 4 annular atoms is selected from nitrogen, sulphur or oxygen, this ring can be that carbon or nitrogen connect, wherein nuclear nitrogen or sulphur atom can be oxidized, wherein encircle CH ₂Group can be replaced by the C=O group.

" the assorted alkyl of ring " is saturated monocycle, dicyclo or tricyclic heterocyclic system, especially have 5 to 10 annular atomses, wherein 1,2,3 or 4 annular atoms is selected from nitrogen, sulphur or oxygen, and this ring can be that carbon or nitrogen connect, wherein nuclear nitrogen or sulphur atom can be oxidized, wherein encircle CH ₂Group can be replaced by the C=O group.

This specification sheets can use compound term, comprises the group of an above functional group with description.Unless this paper describes in addition, otherwise explain this term by what this area was understood.Carbocylic radical C for example _P-qAlkyl comprises: the C that is replaced by carbocylic radical _P-qAlkyl, heterocyclic radical C _P-qAlkyl comprises the C that is replaced by heterocyclic radical _P-qAlkyl, two (C _P-qAlkyl) amino comprise by 2 can be identical or different C _P-qThe amino that alkyl replaces.

Halogen C _P-qAlkyl is by one or more halogenic substituents, especially 1,2 or 3 C that halogenic substituent replaces _P-qAlkyl.Similarly, other generic term that contains halogen halogen C for example _P-qAlkoxyl group can contain one or more halogenic substituents, especially 1,2 or 3 halogenic substituent.

Hydroxyl C _P-qAlkyl is by one or more hydroxyl substituents, especially 1,2 or 3 C that hydroxyl substituent replaces _P-qAlkyl.Similarly, other generic term that contains hydroxyl hydroxyl C for example _P-qAlkoxyl group can contain one or more hydroxyl substituents, especially 1,2 or 3 hydroxyl substituent.

C _P-qAlkoxy C _P-qAlkyl is by one or more C _P-qAlkoxy substituent, especially 1,2 or 3 C _P-qThe C that alkoxy substituent replaces _P-qAlkyl.Similarly, contain C _P-qOther generic term of alkoxyl group is C for example _P-qAlkoxy C _P-qAlkoxyl group can contain one or more C _P-qAlkoxy substituent, especially 1,2 or 3 C _P-qAlkoxy substituent.

If optional substituting group is selected from " 1 or 2 ", " 1,2 or 3 " or " 1,2,3 or 4 " group or substituting group, should be appreciated that, this definition comprises all substituting groups that are selected from one of defined group, promptly all substituting groups are identical, or be selected from the substituting group of two or more defined groups, promptly substituting group is inequality.

Can name compound of the present invention by means of computer software (ACD/Name 8.0 editions).

" hyperplasia " comprises for example cancer of malignant diseases, and non-malignant diseases for example inflammatory diseases, obstructive respiratory tract disease, Immunological diseases or cardiovascular disorder.

Comprise for any R group or for any part or the substituent suitable implication of this group:

For C _1-4Alkyl: methyl, ethyl, propyl group, butyl, the 2-methyl-propyl and the tertiary butyl;

For C _1-6Alkyl: C _1-4Alkyl, amyl group, 2,2-dimethylpropyl, 3-methyl butyl and hexyl;

For C _3-6Cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

For C _3-6Cycloalkyl C _1-4Alkyl: cyclopropyl methyl, cyclopropyl ethyl, cyclobutylmethyl, cyclopentyl-methyl and cyclohexyl methyl;

For aryl: phenyl and naphthyl;

For aryl C _1-4Alkyl: benzyl, styroyl, naphthyl methyl and naphthyl ethyl;

For carbocylic radical: aryl, cyclohexenyl and C _3-6Cycloalkyl;

For halogen: fluorine, chlorine, bromine and iodine;

For C _1-4Alkoxyl group: methoxyl group, oxyethyl group, propoxy-and isopropoxy;

For C _1-6Alkoxyl group: C _1-4Alkoxyl group, pentyloxy, 1-ethyl propoxy-and hexyloxy;

For C _1-6Alkyloyl: ethanoyl, propionyl and 2-methylpropionyl;

For heteroaryl: pyridyl, imidazolyl, quinolyl, cinnolines base, pyrimidyl, thienyl, pyrryl, pyrazolyl, thiazolyl, thiazolyl, triazolyl ， oxazolyl ， isoxazolyl, furyl, pyridazinyl, pyrazinyl, indyl, benzofuryl, dibenzofuran group and benzothienyl;

For heteroaryl C _1-4Alkyl: pyrryl methyl, pyrryl ethyl, imidazolyl methyl, imidazolyl ethyl, the pyrazolyl methyl, pyrazolyl ethyl, furyl methyl, furyl ethyl, thienyl methyl, thienyl (theinyl) ethyl, pyridylmethyl, pyridyl ethyl, the pyrazinyl methyl, pyrazinyl ethyl, Pyrimidylmethyl, pyrimidinylethyl, the pyrimidyl propyl group, pyrimidyl butyl, imidazolyl propyl group, imidazolyl butyl, the quinolyl propyl group, 1,3,4-triazolyl propyl group is with the oxazolyl methyl;

For heterocyclic radical: heteroaryl, pyrrolidyl, isoquinolyl, quinoxalinyl, benzothiazolyl benzoxazolyl, piperidyl, piperazinyl, azetidinyl, morpholinyl, tetrahydro isoquinolyl, tetrahydric quinoline group, indolinyl, dihydro-2H-pyranyl and tetrahydrofuran base.

Should notice that for the example that the term that uses in the specification sheets provides be not restrictive.

M, X, ¹Y and Y ², R ¹, R ²And R ³Concrete implication as follows.Can get in touch with any aspect of the present invention or its each definition, claim or embodiment a part of and defined herein and suitably use such implication.

m

In one aspect of the invention, m is 0,1,2 or 3.

In yet another aspect, m is 0,1 or 2.

Aspect further, m is 0 or 1.

In yet another aspect, m is 0, makes R ³Do not exist.

X

In one aspect of the invention, X is selected from following linking group :-NR ⁴CR ⁶R ⁷-,-OCR ⁶R ⁷-,-SCR ⁶R ⁷-,-S (O) CR ⁶R ⁷-,-S (O) ₂CR ⁶R ⁷-,-C (O) NR ⁴CR ⁶R ⁷-,-NR ⁴C (O) NR ⁵CR ⁶R ⁷-,-S (O) ₂NR ⁴CR ⁶R ⁷-,-NR ⁴C (O)-,-C (O) NR ⁴-,-S (O) ₂NR ⁴-and-NR ⁴S (O) ₂-.

In yet another aspect, X is selected from following linking group :-NR ⁴CR ⁶R ⁷-,-OCR ⁶R ⁷-,-CR ⁶R ⁷-,-S (O) CR ⁶R ⁷-,-S (O) ₂CR ⁶R ⁷-,-C (O) NR ⁴CR ⁶R ⁷-,-NR ⁴C (O) NR ⁵CR ⁶R ⁷-,-(O) ₂NR ⁴CR ⁶R ⁷,-C (O) NR ⁴-and-NR ⁴C (O)-.

Aspect further, X is selected from following linking group :-NR ⁴CR ⁶R ⁷-,-OCR ⁶R ⁷-,-SCR ⁶R ⁷-,-S (O) CR ⁶R ⁷-,-S (O) ₂CR ⁶R ⁷-,-C (O) NR ⁴-and-NR ⁴C (O)-.

Aspect further, X is selected from following linking group :-NR ⁴CR ⁶R ⁷-,-OCR ⁶R ⁷-,-SCR ⁶R ⁷-,-S (O) CR ⁶R ⁷-and-S (O) ₂CR ⁶R ⁷-.

In yet another aspect, X is selected from following linking group :-SCR ⁶R ⁷-,-S (O) CR ⁶R ⁷-and-S (O) ₂CR ⁶R ⁷-.

In yet another aspect, X is selected from following linking group :-NR ⁴CH ₂-,-OCH ₂-,-SCH ₂-,-S (O) CH ₂-,-S (O) ₂CH ₂-,-C (O) NR ⁴-and-NR ⁴C (O)-.

In yet another aspect, X is selected from following linking group :-NR ⁴CH ₂-,-OCH ₂-,-SCH ₂-,-S (O) CH ₂-and-S (O) ₂CH ₂-.

Aspect further, X is selected from following linking group :-NHCH ₂-,-N (CH ₃) CH ₂-,-OCH ₂-,-SCH ₂-,-S (O) CH ₂-,-S (O) ₂CH ₂-,-C (O) NH-,-C (O) N (CH ₃)-,-NHC (O)-and-N (CH ₃) C (O)-.

Aspect further, X is selected from following linking group :-NHCH ₂-,-N (CH ₃) CH ₂-,-OCH ₂-,-SCH ₂-and-S (O) ₂CH ₂-.

In yet another aspect, X is-SCH ₂-or-S (O) ₂CH ₂-.

In yet another aspect, X is-S (O) ₂CH ₂-.

¹ Y and Y ²

In one aspect of the invention, ¹Y is N, Y ²Be CR ⁸

In yet another aspect, ¹Y is N, Y ²Be CH.

In yet another aspect, ¹Y is CR ⁸, Y ²Be N.

Aspect further, ¹Y is CH or CF, Y ²Be N.

Aspect further, ¹Y is CH, Y ²Be N.

R ¹

In one aspect of the invention, R ¹Be to be selected from following group: C _1-4Alkyl, C _3-6Cycloalkyl, aryl, C _3-6Cycloalkyl C _1-4Alkyl, aryl C _1-4Alkyl, the assorted alkyl of ring, heteroaryl, the assorted alkyl C of ring _1-4Alkyl, heteroaryl C _1-4Alkyl, this group is optional to be selected from following substituting group and to replace by one or more: halogen, cyano group, nitro, R ⁹,-OR ⁹,-COR ⁹,-CONR ⁹R ¹⁰,-NR ⁹R ¹⁰With-NR ⁹COR ¹⁰

In yet another aspect, R ¹Be to be selected from following group: methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, styroyl, pyrrolidyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, the pyrrolidyl methyl, pyrrolidyl ethyl, pyrryl methyl, the pyrryl ethyl, imidazolyl methyl, imidazolyl ethyl, the pyrazolyl methyl, pyrazolyl ethyl, furyl methyl, the furyl ethyl, thienyl methyl, thienyl ethyl, pyridylmethyl, pyridyl ethyl, Pyrimidylmethyl, pyrimidinylethyl, pyrazinyl methyl and pyrazinyl ethyl, this group is optional by 1,2 or 3 are selected from following substituting group and replace: halogen, cyano group, nitro, R ⁹,-OR ⁹,-COR ⁹,-CONR ⁹R ¹⁰,-NR ⁹R ¹⁰With-NR ⁹COR ¹⁰

Aspect further, R ¹Be to be selected from following group: methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclohexyl, phenyl, benzyl, styroyl, pyridyl, pyrazolyl ethyl, furyl methyl, thienyl methyl and pyrazinyl ethyl, this group is optional to be selected from following substituting group replacement by 1 or 2: halogen, cyano group, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy ,-CONH ₂With-CONHCH ₃

In yet another aspect, R ¹Be to be selected from following group: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, cyclohexyl ,-CH ₂CN ,-CH ₂C (O) NH ₂, CH ₂CH ₂NC (O) CH ₃, phenyl, 4-fluorophenyl, the 2-chloro-phenyl-, 3-chloro-phenyl-, 2-chloro-6-fluorophenyl, 3-chloro-4-fluorophenyl, 4-bromo-2-fluorophenyl, 4-trifluoromethyl, the 4-Trifluoromethoxyphen-l, 4-cyano-phenyl, 3-p-methoxy-phenyl, the 4-p-methoxy-phenyl, 3, the 4-Dimethoxyphenyl, 4-(N-methylamino carbonyl) phenyl, benzyl, 4-luorobenzyl, 2-benzyl chloride base, 2-chloro-6-luorobenzyl, 4-methoxy-benzyl, styroyl, 3-trifluoro-benzene ethyl, furans-2-ylmethyl, thiophene-2-ylmethyl, 2-pyrazine-2-base ethyl, pyridin-3-yl, 2-picoline-3-base and 2-aminocarboxyl pyridin-3-yl.

R ²

In one aspect of the invention, R ²Be selected from aryl and heteroaryl, this group is optional to be independently selected from following substituting group and to replace by one or more: halogen, cyano group, nitro ,-R ¹¹,-OR ¹¹,-COR ¹¹,-CONR ¹¹R ¹²,-NR ¹¹R ¹²With-NR ¹¹COR ¹²

In yet another aspect, R ²Be selected from phenyl, naphthyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, azaindolyl, indyl, quinolyl, benzimidazolyl-, benzofuryl, dibenzofuran group, benzothienyl, this group is optional to be independently selected from following substituting group and to replace by one or more: halogen, cyano group, nitro ,-R ¹¹,-OR ¹¹,-COR ¹¹,-CONR ¹¹R ¹²,-NR ¹¹R ¹²With-NR ¹¹COR ¹²

In yet another aspect, R ²Be selected from phenyl, naphthyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, azaindolyl, indyl, quinolyl, benzimidazolyl-, benzofuryl, dibenzofuran group, benzothienyl, this group is optional to be independently selected from following substituting group and to replace by one or more: halogen, methyl, methoxyl group, methylol, cyano methyl, phenoxy group, pyrrolidyl ,-CONH ₂,-CONHCH ₃With-CON (CH ₃) ₂

In yet another aspect, R ²Be 3-(methylol) phenyl, 4-(methylol) phenyl, 4-(cyano methyl) phenyl, 3,4-Dimethoxyphenyl, 3-fluoro-4-p-methoxy-phenyl, the 4-Phenoxyphenyl, 3-tetramethyleneimine-1-base phenyl, 3-(aminocarboxyl) phenyl, 4-(dimethylamino carbonyl) phenyl, furans-3-base, thiene-3-yl-, 5-(methylol) thiophene-2-base, pyridine-2-base, pyridin-4-yl, 2-methoxypyridine-5-base, 2-methoxy pyrimidine-5-base, 2-methoxynaphthalene-6-base, 5,7-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-2,4,8, the 10-apos, azaindolyl, indoles-5-base, 1-skatole-5-base, quinoline-6-base, benzimidazolyl-, cumarone-2-base, diphenylene-oxide-1-base and thionaphthene-3-base.

In yet another aspect, R ²Be optional quilt-NR ¹¹COR ¹²The phenyl that replaces.

Aspect further, R ²Be pyridine-2-base, 3-hydroxy phenyl, 4-hydroxy phenyl, 3-hydroxymethyl phenyl, 4-hydroxymethyl phenyl or indoles-5-base.

Aspect further, R ²Be azaindolyl, indoles-5-base, benzimidazolyl-, 3-hydroxy phenyl, 4-hydroxy phenyl, 3-hydroxymethyl phenyl or 4-hydroxymethyl phenyl.

In yet another aspect, R ²It is pyridine-2-base.

Aspect further, R ²Be 3-hydroxy phenyl or 4-hydroxy phenyl.

In yet another aspect, R ²Be 3-hydroxymethyl phenyl or 4-hydroxymethyl phenyl.

Aspect further, R ²It is indoles-5-base.

On the one hand, R ²It is morpholinyl.

In yet another aspect, R ²It is morpholino.

R ⁴

In one aspect of the invention, R ⁴Be hydrogen or methyl.

In yet another aspect, R ⁴Be hydrogen.

R ⁵

In one aspect of the invention, R ⁵Be hydrogen or methyl.

In yet another aspect, R ⁵Be hydrogen.

R ⁶

In one aspect of the invention, R ⁶Be hydrogen or methyl.

In yet another aspect, R ⁶Be hydrogen.

R ⁷

In one aspect of the invention, R ⁷Be hydrogen or methyl.

In yet another aspect, R ⁷Be hydrogen.

R ⁸

In one aspect of the invention, R ⁸It is hydrogen or halogen.

In yet another aspect, R ⁸Be hydrogen or fluorine.

Aspect further, R ⁸Be hydrogen.

R ⁹

In one aspect of the invention, R ⁹Be hydrogen or optional by 1,2 or 3 C that is selected from following substituting group replacement _1-4Alkyl: halogen, cyano group, nitro, hydroxyl, C _1-4Alkoxyl group, amino, C _1-4Alkylamino and two (C _1-4Alkyl) amino.

In yet another aspect, R ⁹Be hydrogen or the optional C that is replaced by 1,2 or 3 halogenic substituent _1-4Alkyl.

Aspect further, R ⁹Be hydrogen, methyl or trifluoromethyl.

R ¹⁰

In one aspect of the invention, R ¹⁰Be hydrogen.

R ¹¹

In one aspect of the invention, R ¹¹Be hydrogen or be selected from C _1-4The group of the assorted alkyl of alkyl, aryl and ring, this group is optional to be replaced by 1,2 or 3 group that is selected from halogen, hydroxyl and cyano group.

In yet another aspect, R ¹¹Be hydrogen, optional by methyl, phenyl or the pyrrolidyl of hydroxyl or cyano group replacement.

In yet another aspect, R ¹¹Be hydrogen or methyl.

R ¹²

In one aspect of the invention, R ¹²Be hydrogen or methyl.

In the specific category of formula (I) compound or its salt, ester or prodrug:

M is 0,1,2,3 or 4;

X is selected from following linking group :-NR ⁴CR ⁶R ⁷-,-OCR ⁶R ⁷-,-SCR ⁶R ⁷-,-S (O) CR ⁶R ⁷-,-S (O) ₂CR ⁶R ⁷-,-C (O) NR ⁴CR ⁶R ⁷-,-NR ⁴C (O) NR ⁵CR ⁶R ⁷-,-S (O) ₂NR ⁴CR ⁶R ⁷-,-NR ⁴C (O)-,-S (O) ₂NR ⁴-and-NR ⁴S (O) ₂-;

R ²Be selected from aryl and heteroaryl, this group is optional to be independently selected from following substituting group and to replace by one or more: halogen, cyano group, nitro ,-R ¹¹,-OR ¹¹,-COR ¹¹,-CONR ¹¹R ¹²,-NR ¹¹R ¹²With-NR ¹¹COR ¹²

R ⁴And R ⁵Be hydrogen or C independently _1-6Alkyl;

R ⁸Be selected from hydrogen, halogen, cyano group and C _1-6Alkyl;

Condition is

In another specific category of formula (I) compound or its salt, ester or prodrug:

M is 0,1,2,3 or 4;

X is selected from following linking group :-NR ⁴CR ⁶R ⁷-,-OCR ⁶R ⁷-,-SCR ⁶R ⁷-,-S (O) CR ⁶R ⁷-,-S (O) ₂CR ⁶R ⁷-,-C (O) NR ⁴CR ⁶R ⁷-,-NR ⁴C (O) NR ⁵CR ⁶R ⁷-,-S (O) ₂NR ⁴CR ⁶R ⁷With-NR ⁴C (O)-;

¹Y is CR ⁸, Y ²Be N;

R ¹Be to be selected from following group: C _1-4Alkyl, C _3-6Cycloalkyl, aryl, C _3-6Cycloalkyl C _1-4Alkyl, aryl C _1-4Alkyl, the assorted alkyl of ring, heteroaryl, the assorted alkyl C of ring _1-4Alkyl, heteroaryl C _1-4Alkyl, this group is optional to be selected from following substituting group and to replace by one or more: halogen, cyano group, nitro, R ⁹,-OR ⁹,-COR ⁹,-CONR ⁹R ¹⁰,-NR ⁹R ¹⁰With-NR ⁹COR ¹⁰

R ⁴And R ⁵Be hydrogen or C independently _1-6Alkyl;

R ⁸Be selected from hydrogen, halogen, cyano group and C _1-6Alkyl;

Condition is

In the further specific category of formula (I) compound or its salt, ester or prodrug:

M is 0, so R ³Do not exist.

X is selected from following linking group :-NR ⁴CR ⁶R ⁷-,-OCR ⁶R ⁷-,-SCR ⁶R ⁷-,-S (O) CR ⁶R ⁷-and-S (O) ₂CR ⁶R ⁷-.

¹Y is CH or CF, Y ²Be N.

R ¹Be to be selected from following group: methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclohexyl, phenyl, benzyl, styroyl, pyridyl, pyrazolyl ethyl, furyl methyl, thienyl methyl and pyrazinyl ethyl, this group is optional to be selected from following substituting group replacement by 1 or 2: halogen, cyano group, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy ,-CONH ²With-CONHCH ₃

R ²Be selected from phenyl, naphthyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, indyl, quinolyl, benzofuryl, dibenzofuran group, benzothienyl, this group is optional to be independently selected from following substituting group and to replace by one or more: halogen, methyl, methoxyl group, methylol, cyano methyl, phenoxy group, pyrrolidyl ,-CONH ₂,-CONHCH ₃With-CON (CH ₃) ₂

R ⁴Be hydrogen or methyl;

R ⁶Be hydrogen or methyl;

R ⁷Be hydrogen or methyl;

Condition is

Another aspect of the present invention provides and has been selected from following compound or combination of compounds:

4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-2-thiene-3-yl--pyrimidine;

2-cumarone-2-base-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine;

2-diphenylene-oxide-1-base-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine;

5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

2-(6-methoxypyridine-3-yl)-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine;

2-(6-methoxynaphthalene-2-yl)-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine;

[3-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] methyl alcohol;

[4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] methyl alcohol;

N, N-dimethyl-4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-benzamide;

2-(2-methoxy pyrimidine-5-yl)-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine;

6-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] quinoline;

3-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] benzamide;

4-(benzenesulfonyl methyl)-6-morpholine-4-base-2-thiene-3-yl--pyrimidine;

4-(benzenesulfonyl methyl)-2-(3, the 4-Dimethoxyphenyl)-6-morpholine-4-base-pyrimidine;

4-(benzenesulfonyl methyl)-2-(3-furyl)-6-morpholine-4-base-pyrimidine;

4-(benzenesulfonyl methyl)-2-thionaphthene-3-base-6-morpholine-4-base-pyrimidine;

4-(benzenesulfonyl methyl)-6-morpholine-4-base-2-(4-Phenoxyphenyl) pyrimidine;

2-[4-[4-(benzenesulfonyl methyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] acetonitrile;

4-(benzenesulfonyl methyl)-2-(3-fluoro-4-methoxyl group-phenyl)-6-morpholine-4-base-pyrimidine;

[5-[4-(benzenesulfonyl methyl)-6-morpholine-4-base-pyrimidine-2-base] thiophene-2-yl] methyl alcohol;

4-(benzenesulfonyl methyl)-6-morpholine-4-base-2-(3-tetramethyleneimine-1-base phenyl) pyrimidine;

5-[4-(benzenesulfonyl methyl)-6-morpholine-4-base-pyrimidine-2-base]-1-methyl-indoles;

5-[4-(benzenesulfonyl methyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

4-(benzenesulfonyl methyl)-2-(6-methoxypyridine-3-yl)-6-morpholine-4-base-pyrimidine;

4-morpholine-4-base-6-(phenyl sulfenyl methyl)-2-pyridine-2-base-pyrimidine;

4-(2-furyl methyl sulfenyl methyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

The 4-[(4-p-methoxy-phenyl) sulfenyl methyl]-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

4-(fourth-2-base sulfenyl methyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

4-(butyl sulfenyl methyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

4-morpholine-4-base-2-pyridine-2-base-6-(tertiary butyl sulfenyl methyl) pyrimidine;

4-morpholine-4-base-6-(third-2-base sulfenyl methyl)-2-pyridine-2-base-pyrimidine;

4-[(2-chloro-6-fluoro-phenyl) methyl sulfenyl methyl]-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

4-(cyclohexyl sulfenyl methyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

The 4-[(4-fluorophenyl) sulfenyl methyl]-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

4-(ethyl sulfenyl methyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

The 4-[(4-fluorophenyl) methyl sulfenyl methyl]-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

The 4-[(4-p-methoxy-phenyl) methyl sulfenyl methyl]-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

4-morpholine-4-base-6-(styroyl sulfenyl methyl)-2-pyridine-2-base-pyrimidine;

4-[(6-morpholine-4-base-2-pyridine-2-base-pyrimidine-4-yl) methyl sulfenyl] benzonitrile;

4-(2-methyl-propyl sulfenyl methyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

4-morpholine-4-base-6-(2-pyrazine-2-base ethyl sulfenyl methyl)-2-pyridine-2-base-pyrimidine;

4-morpholine-4-base-2-pyridine-2-base-6-(thiophene-2-ylmethyl sulfenyl methyl) pyrimidine;

4-(2-furyl methyl alkylsulfonyl methyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

The 4-[(4-p-methoxy-phenyl) alkylsulfonyl methyl]-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

4-(fourth-2-base alkylsulfonyl methyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

4-(2-methyl-propyl alkylsulfonyl methyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

4-morpholine-4-base-6-(sulfonyl propyl ylmethyl)-2-pyridine-2-base-pyrimidine;

4-(butyl alkylsulfonyl methyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

4-morpholine-4-base-6-(third-2-base alkylsulfonyl methyl)-2-pyridine-2-base-pyrimidine;

4-morpholine-4-base-2-pyridine-2-base-6-[[3-(trifluoromethyl) phenyl] the alkylsulfonyl methyl] pyrimidine;

4-morpholine-4-base-6-(2-pyrazine-2-base ethylsulfonyl methyl)-2-pyridine-2-base-pyrimidine;

4-morpholine-4-base-2-pyridine-2-base-6-(thiophene-2-ylmethyl alkylsulfonyl methyl) pyrimidine;

4-(cyclohexyl alkylsulfonyl methyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

The 4-[(4-fluorophenyl) alkylsulfonyl methyl]-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

4-(ethylsulfonyl methyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

The 4-[(4-fluorophenyl) sulfonyloxy methyl ylmethyl]-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

4-morpholine-4-base-2-pyridine-2-base-6-[[4-(trifluoromethoxy) phenyl] the alkylsulfonyl methyl] pyrimidine;

The 4-[(4-p-methoxy-phenyl) sulfonyloxy methyl ylmethyl]-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

4-[(3, the 4-Dimethoxyphenyl) the alkylsulfonyl methyl]-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

4-[(4-bromo-2-fluoro-phenyl) alkylsulfonyl methyl]-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

N-methyl-2-[(6-morpholine-4-base-2-pyridine-2-base-pyrimidine-4-yl) methyl sulphonyl] benzamide;

4-morpholine-4-base-6-(styroyl alkylsulfonyl methyl)-2-pyridine-2-base-pyrimidine;

4-morpholine-4-base-2-pyridine-2-base-6-[2-[3-(trifluoromethyl) phenyl] the ethylsulfonyl methyl] pyrimidine;

4-[(6-morpholine-4-base-2-pyridine-2-base-pyrimidine-4-yl) methyl sulphonyl] benzonitrile;

4-[(2-chloro-4-fluoro-phenyl) alkylsulfonyl methyl]-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

4-[(3-methoxyl group phenoxy group) methyl]-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

4-morpholine-4-base-6-(phenoxymethyl)-2-pyridine-2-base-pyrimidine;

4-morpholine-4-base-6-(phenyl methoxymethyl)-2-pyridine-2-base-pyrimidine;

4-(ethoxyl methyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

The 4-[(2-chlorophenoxy) methyl]-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

The 4-[(3-chlorophenoxy) methyl]-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

4-[(4-methoxyl group phenoxy group) methyl]-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

The 4-[(2-chloro-phenyl-) methoxymethyl]-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

3-[(6-morpholine-4-base-2-pyridine-2-base-pyrimidine-4-yl) methoxyl group] pyridine-2-carboxamide;

4-[(2-picoline-3-yl) oxygen ylmethyl]-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

4-morpholine-4-base-2-pyridine-2-base-6-(pyridin-3-yl oxygen ylmethyl) pyrimidine;

N-benzyl-N-methyl isophthalic acid-(6-morpholine-4-base-2-pyridine-2-base-pyrimidine-4-yl) methylamine;

N-[(6-morpholine-4-base-2-pyridine-2-base-pyrimidine-4-yl) methyl] third-2-amine;

1-(2-chloro-phenyl-)-N-[(6-morpholine-4-base-2-pyridine-2-base-pyrimidine-4-yl) methyl] methylamine;

4-(benzenesulfonyl methyl)-5-fluoro-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

5-fluoro-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

6-morpholine-4-base-N-phenyl-2-pyridine-2-base-pyrimidine-4-methane amide;

N, N-dimethyl-6-morpholine-4-base-2-pyridine-2-base-pyrimidine-4-methane amide;

5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-1, the 3-Indolin-2-one;

2-amino-5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] methyl benzoate;

[2-methoxyl group-5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] methyl alcohol;

2-methyl-5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-benzoglyoxaline;

5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-1,3-dihydrobenzo imidazoles-2-ketone;

[5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-1H-indazole-3-yl] methyl alcohol;

6-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] chroman-4-alcohol;

1-ethanoyl-5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-2H-indoles-3-ketone;

1-methyl-4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] piperazine-2-ketone;

1-(4-chloro-phenyl-)-4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] piperazine-2-ketone;

2-[3-(4,4-dimethyl-5H-1,3-oxazole-2-yl)-4-methoxyl group-phenyl]-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine;

N-(1H-benzoglyoxaline-5-yl)-2,6-dimorpholine-4-base-pyrimidine-4-methane amide;

N-(5-methyl-2H-pyrazole-3-yl)-2,6-dimorpholine-4-base-pyrimidine-4-methane amide;

N-(1H-indoles-5-yl)-2,6-dimorpholine-4-base-pyrimidine-4-methane amide;

N-[5-(methoxymethyl)-1,3,4-thiadiazoles-2-yl]-2,6-dimorpholine-4-base-pyrimidine-4-methane amide;

5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indazole;

3-methyl-5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indazole;

5-[2-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-4-yl]-the 1H-indoles;

5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-benzoglyoxaline;

4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

3-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-5,7-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-1,3,5,8-tetraene;

4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] aniline;

2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-formic acid;

[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl alcohol;

5-[4-morpholine-4-base-6-(morpholine-4-ylmethyl) pyrimidine-2-base]-the 1H-indoles;

N-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl]-1-(4-p-methoxy-phenyl) methylamine;

1-(4-chloro-phenyl-)-N-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl] methylamine;

5-[4-[(2-picoline-3-yl) oxygen ylmethyl]-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

5-[4-(methoxymethyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

5-[4-(2-furyl methyl alkylsulfonyl methyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

5-[4-(ethylsulfonyl methyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

The 5-[4-[(4-p-methoxy-phenyl) alkylsulfonyl methyl]-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

5-[4-morpholine-4-base-6-(third-2-base alkylsulfonyl methyl) pyrimidine-2-base]-the 1H-indoles;

5-[4-(fourth-2-base alkylsulfonyl methyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

5-[4-[(2-chloro-4-fluoro-phenyl) alkylsulfonyl methyl]-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

2-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl sulphonyl]-N, N-dimethyl-ethanamide;

5-[4-[(5-chloro-1,2,4-thiadiazoles-3-yl) the sulfonyloxy methyl ylmethyl]-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

5-[4-morpholine-4-base-6-(1,3-thiazoles-4-ylmethyl alkylsulfonyl methyl) pyrimidine-2-base]-the 1H-indoles;

3-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl sulphonyl] propionitrile;

2-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl sulphonyl]-1-morpholine-4-base-ethyl ketone;

5-[4-[(3,5-dimethyl-1,2-oxazole-4-yl) the sulfonyloxy methyl ylmethyl]-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

(2S)-and 1-[2-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl sulphonyl] ethanoyl] tetramethyleneimine-2-nitrile;

5-[4-morpholine-4-base-6-(pyridin-3-yl sulfonyloxy methyl ylmethyl) pyrimidine-2-base]-the 1H-indoles;

5-[4-(2-imidazoles-1-base ethylsulfonyl methyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

5-[4-[(5-ethyl-1H-imidazol-4 yl) sulfonyloxy methyl ylmethyl]-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

5-[4-(2-fluoro ethyl alkylsulfonyl methyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

4-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] the sulfonyloxy methyl ylmethyl]-2H-phthalazines-1-ketone;

4-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl sulphonyl] butyronitrile;

2-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl sulphonyl]-1-tetramethyleneimine-1-base-ethyl ketone;

2-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl sulphonyl]-N-third-2-base-ethanamide;

5-[4-[2-(2-methoxy ethoxy) ethylsulfonyl methyl]-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

The 5-[4-[(2-methyl isophthalic acid, 3-thiazole-4-yl) the sulfonyloxy methyl ylmethyl]-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

2-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl sulphonyl]-N-propyl group-ethanamide;

5-[4-(2,2-difluoro ethylsulfonyl methyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

5-[4-morpholine-4-base-6-[(5-tertiary butyl-1,3,4-thiadiazoles-2-yl) the sulfonyloxy methyl ylmethyl] pyrimidine-2-base]-the 1H-indoles;

5-[4-(3-methoxy-propyl alkylsulfonyl methyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

5-[4-morpholine-4-base-6-(Propargyl alkylsulfonyl methyl) pyrimidine-2-base]-the 1H-indoles;

5-[4-morpholine-4-base-6-(2-morpholine-4-base ethylsulfonyl methyl) pyrimidine-2-base]-the 1H-indoles;

N-[4-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] the sulfonyloxy methyl ylmethyl] phenyl] ethanamide;

2-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl sulphonyl]-the N-tertiary butyl-ethanamide;

5-[4-morpholine-4-base-6-(3-morpholine-4-base sulfonyl propyl ylmethyl) pyrimidine-2-base]-the 1H-indoles;

2-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl sulphonyl]-1-(piperidino) ethyl ketone;

5-[4-(2-ethoxyethyl group alkylsulfonyl methyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

5-[4-morpholine-4-base-6-(oxa-ring penta-2-ylmethyl alkylsulfonyl methyl) pyrimidine-2-base]-the 1H-indoles;

3-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl sulphonyl]-N, N-dimethyl-third-1-amine;

N, N-diethyl-2-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl sulphonyl] ethanamide;

5-[4-morpholine-4-base-6-(sulfonyl propyl ylmethyl) pyrimidine-2-base]-the 1H-indoles;

2-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] the sulfonyloxy methyl ylmethyl]-the 1H-benzoglyoxaline;

3-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] the sulfonyloxy methyl ylmethyl] benzonitrile;

8-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] the sulfonyloxy methyl ylmethyl]-the 5-methyl isophthalic acid, 7-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-2,4,6,8-tetraene;

N-benzyl-2-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl sulphonyl] ethanamide;

2-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl sulphonyl]-N-methyl-N-phenyl-ethanamide;

5-[4-(butyl alkylsulfonyl methyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

The 5-[4-[(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl) the sulfonyloxy methyl ylmethyl]-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

2-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl sulphonyl] ethanamide;

3-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl sulphonyl] propionic acid amide;

2-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl sulphonyl] acetonitrile;

5-amino-1-[2-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl sulphonyl] ethyl] pyrazoles-4-nitrile;

2-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl sulphonyl]-N-(2-methoxy ethyl) ethanamide;

5-[4-(2-cyclohexyl ethylsulfonyl methyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

5-[4-[3-(4-chloro-phenyl-) sulfonyl propyl ylmethyl]-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

N-[2-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl sulphonyl] ethyl] ethanamide;

2-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] the sulfonyloxy methyl ylmethyl]-the 3H-quinazoline-4-one;

5-[4-(cyclohexyl methyl alkylsulfonyl methyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

5-[4-[3-(4-fluorophenoxy) sulfonyl propyl ylmethyl]-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

5-[4-(5-methyl hexyl alkylsulfonyl methyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

4-morpholine-4-base-2-pyridine-2-base-6-(tertiary butyl alkylsulfonyl methyl) pyrimidine;

2-methyl-5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles;

4-[(5-methyl-2H-pyrazole-3-yl) oxygen ylmethyl]-6-morpholine-4-base-2-pyridine-2-base-pyrimidine;

2-(3-furyl)-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine;

4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-2-naphthalene-1-base-pyrimidine;

Or its salt, ester or prodrug, especially its pharmaceutical salts.

The further compound of the present invention comprises:

N-(1H-benzoglyoxaline-5-yl)-2,6-dimorpholine-4-base-pyrimidine-4-methane amide;

Or its salt, ester or prodrug, especially its pharmaceutical salts.

Of the present invention aspect some, for example as formula (I) compound of treatment hyperplasia medicine; Or formula (I) compound is used for the treatment of purposes in the medicine of hyperplasia in preparation; The compound of formula (I) can be 4-morpholine-4-base-6-(benzenesulfonyl methyl)-2-pyridin-4-yl-pyrimidine or 4-{6-[(benzenesulfonyl) methyl]-2-pyridine-2-yl pyrimidines-4-yl } morpholine.

The present invention also provides the method for preparation formula (I) compound or its salt, ester or prodrug.

The compound of formula (I), wherein X is-S (O) ₂CR ⁶R ⁷-, can be prepared as follows: at room temperature, in water and ethanol mixed solvent system, for example use

With the compound oxidation of formula (I), wherein X is-SCR ⁶R ⁷-.

According to further aspect of the present invention, the preparation method of the defined formula of claim 1 (I) compound is provided, wherein X is-S (O) ₂CR ⁶R ⁷-, this method utilizes wherein that X is-SCR ⁶R ⁷-formula (I) compound and oxidant reaction (for example use

At room temperature, in water and ethanol mixed solvent system).

The compound of formula (I), wherein X is-X ¹CR ⁶R ⁷-, X ¹Be-NR ⁴-,-O-,-S-,-S (O)-or-S (O) ₂-, can be prepared as follows:, under the existence of dinethylformamide, make the compound of formula (II), wherein L at suitable alkali for example tetrahydrofuran (THF) or N of triethylamine and solvent for example ¹Be for example halogen (for example chlorine), tosyl group, methylsulfonyl or the like of leavings group, and the compound of formula (III) reaction:

According to further aspect of the present invention, the method for preparation according to formula (I) compound of claim 1 is provided, wherein X is-X ¹CR ⁶R ⁷-, X ¹Be-NR ⁴-,-O-,-S-,-S (O)-or-S (O) ₂-,

Comprise: make the compound of formula (II), wherein L ¹Be leavings group (for example halogen (for example chlorine), tosyl group, methylsulfonyl or the like),

With the compound reaction of formula (III),

R ¹-X ¹H

(III)

(choosing wantonly) at suitable alkali for example tetrahydrofuran (THF) or N of triethylamine and solvent for example, under the existence of dinethylformamide.

The compound of formula (II) can be by the compound of formula (IV), wherein L ²Be for example halogen (for example chlorine), tosyl group, methylsulfonyl or the like of leavings group,

Compound prepared in reaction with formula V.

This reaction can solvent for example in the tetrahydrofuran (THF), suitable alkali for example triethylamine in the presence of carry out.

The compound of formula V can commercially be bought, and maybe can use the facilitated method of describing among that describe in the document, known to the skilled or this paper embodiment to prepare.

The compound of formula (IV) can be by the compound of formula (VI):

Work as L ²Be halogen for example during chlorine, the compound of formula (IV) can be prepared as follows: use for example phosphorus oxychloride of chlorizating agent, at high temperature, and for example from 50 ℃ to 150 ℃, especially from 75 ℃ to 125 ℃, and more specifically roughly under 100 ℃.

The compound of formula (VI) can be prepared as follows: the compound that makes formula (VII)

Compound reaction with formula (VIII).

The compound of the compound of formula (VII) and formula (VIII) can commercially be bought, and maybe can use the facilitated method of describing among that describe in the document, known to the skilled or this paper embodiment to prepare.

The compound of formula (I), wherein X is-S (O) ₂CR ⁶R ⁷-, also can be prepared as follows: in the presence of suitable metal catalyst (for example palladium or copper), use solvent (for example organic solvent for example 1, the 4-diox), make the compound of formula (IX) and suitable organometallic reagent (boric acid R for example ²B (OR) ₃Acibenzolar, wherein R is C _1-4Alkyl is methyl for example) reaction.

The compound of formula (IX) can be prepared as follows: the compound that makes formula (X)

At solvent for example tetrahydrofuran (THF) or N, in the dinethylformamide with the compound reaction of formula (XI).

The compound of formula (X) can be prepared as follows: the compound that makes formula (XII)

Compound reaction with formula V.

The compound of formula (XII) can be by the compound of formula (XIII):

Work as L ²Be halogen for example during chlorine, the compound of formula (XII) can be prepared as follows: use for example phosphorus oxychloride of chlorizating agent, at high temperature, and for example from 50 ℃ to 150 ℃, especially from 75 ℃ to 125 ℃, and more specifically roughly under 100 ℃.

The compound of formula (XII) can be prepared as follows: the compound that makes formula (VII)

Compound reaction with formula (XIV).

The compound of the compound of formula (VII) and formula (XIV) can commercially be bought, and maybe can use the facilitated method of describing among that describe in the document, known to the skilled or this paper embodiment to prepare.

The compound of formula (I), wherein X is-C (O) NR ⁴CR ⁶R ⁷-,-NR ⁴C (O) NR ⁵CR ⁶R ⁷-or-S (O) ₂NR ⁴CR ⁶R ⁷-, can be prepared as follows: suitable alkali for example triethylamine in the presence of, make the compound of formula (I), wherein X is-NH ₂CR ⁶R ⁷-, with the compound reaction of suitable formula (XVI).

Similarly, the compound of formula (I), wherein X is-C (O) NR ⁴-,-NR ⁴C (O) NR ⁵-or-S (O) ₂NR ⁴-, can be prepared as follows: suitable alkali for example triethylamine in the presence of, the compound that makes formula (XV) reacts with the compound of suitable formula (XVI).

The compound of formula (XV) can be prepared as follows: for example in the N,N-dimethylacetamide, make compound and the diphenylphosphine acyl group nitride and the triethylamine reaction of formula (XVII) at solvent.

If R ⁴Be C _1-6Alkyl after this step, can use the reduction amination condition, and aldehyde for example is in the presence of sodium cyanoborohydride, at solvent for example in the methylene dichloride, with the amino-alkylation that obtains.

The compound of formula (XVII) can be prepared as follows: make the compound and for example sodium hydroxide reaction of alkali of formula (XVIII).

The compound of formula (XVIII) can be prepared as follows: make the compound of formula (XIX), wherein L ³Be for example halogen (for example chlorine) or triflate of leavings group,

With the suitable for example tributyl tin derivative or the zincate reaction of formula (XX) of organometallic reagent, wherein Y can be a for example chlorine of halogen.If R ²Be undersaturated, for example optional aryl or the heteroaryl that replaces should use the tributyl tin derivative, and zincate should be used for R ²Situation when being saturated.

R ²-SnR ₃Or R ²-Zn-Y

(XX)

This reaction can suitable metal catalyst for example palladium or copper in the presence of, at solvent for example in the tetrahydrofuran (THF), for example carry out under 100 ℃ at high temperature.

The compound of formula (XIX) can be prepared as follows: make the compound of formula (XXI), wherein L ²Be for example halogen (for example chlorine), tosyl group, methylsulfonyl or the like of leavings group,

Compound reaction with formula V.

The compound of formula (XXI) can be by the compound of formula (XXII):

Work as L ²And L ³When being chlorine, can using phosphorus oxychloride, for example carry out chlorination under 100 ℃ at high temperature.

The compound of formula (I) also can be prepared as follows: the compound that makes formula (XXIII)

Compound reaction with formula V.

The compound of formula (XXIII), wherein X is-CR ⁴=CR ⁵-,-CR ⁴=CR ⁵CR ⁶R ⁷-,-CR ⁶R ⁷CR ⁵=CR ⁴-,-C ≡ C-,-C ≡ CCR ⁶R ⁷-or-CR ⁶R ⁷C ≡ C-can be prepared as follows: the compound that makes formula (XXIV)

With suitable formula (XXV) compound reaction, wherein M is a metal.For alkynyl compounds, M can be hydrogen and metal.

R ¹CR ⁴＝CR ⁵-M

R ¹-CR ⁴＝CR ⁵CR ⁶R ⁷-M

R ¹-CR ⁶R ⁷CR ⁵＝CR ⁴-M

(XXV)

Typically, the tributyl tin derivative be suitable metal catalyst for example palladium or copper in the presence of, organic solvent for example in the tetrahydrofuran (THF), high temperature for example 100 ℃ use down.

The compound of formula (XXIV) can be by the compound of formula (XXVI):

If L ¹And L ²Be chlorine, can use for example phosphorus oxychloride of chlorizating agent.

The compound of formula (XXVI) can be prepared as follows: make the compound of formula (XXVII), wherein PG ¹And PG ²Be C _1-6Alkyl is methyl or ethyl for example,

Compound reaction with formula (VIII).

The compound of the compound of formula (XXVII) and formula (VIII) can commercially be bought, and maybe can use the facilitated method of describing among that describe in the document, known to the skilled or this paper embodiment to prepare.

The compound of formula (I), wherein X is-NR ⁴C (O)-, can be prepared as follows: the compound that makes formula (XVII)

With amine R ⁴NH ₂With suitable activating reagent O-(7-azepine benzo triazol-1-yl)-N for example, N, N ', N '-tetramethyl-urea phosphofluoric acid reactant salt, use for example diisopropyl ethyl amine and solvent tetrahydrofuran (THF) for example of alkali.

The compound of formula (XVII) can be according to method preparation described herein.

With the compound oxidation of formula (I), wherein X is-SCR ⁶R ⁷-.

The compound of formula (I), wherein X is-X ¹CR ⁶R ⁷, X ¹Be-NR ⁴-,-O-,-S-,-S (O)-, can be prepared as follows: the compound that makes formula (XXVIII)

Compound reaction with formula V.

The compound of formula (XXVIII) can be prepared as follows: make the compound of formula (XXIX), wherein L ³Be for example halogen (for example chlorine) of leavings group,

R ²-SnR ₃Or R ²-Zn-Y

(XX)

The compound of formula (XXIX) can be by the compound of formula (XXX):

Work as L ²And L ³When being chlorine, can use for example phosphorus oxychloride of chlorizating agent.

The compound of formula (XXX) can be prepared as follows: make the compound of formula (XXVII), wherein PG ¹And PG ²Be C _1-6Alkyl is methyl or ethyl for example,

Compound reaction with formula (XXXI).

The compound of the compound of formula (XXVII) and formula (XXXI) can commercially be bought, and maybe can use the facilitated method of describing among that describe in the document, known to the skilled or this paper embodiment to prepare.

Similarly, the compound of formula (I), wherein X is-C (O) NR ⁴-,-NR ⁴C (O) NR ⁵-or-S (O) ₂NR ⁴-, can be prepared as follows: make formula (XXXII) compound and suitable formula (XVI) compound reaction.

The compound of formula (XXXII) can be prepared as follows: the compound that makes formula (XXXIII)

Compound reaction with formula V.

The compound of formula (XXXIII) can be prepared as follows: make the compound of formula (XXXVI), wherein L ³Be for example halogen (for example chlorine) of leavings group,

R ²-SnR ₃Or R ²-Zn-Y

(XX)

The compound of formula (XXXIV) can be by the compound of formula (XXXV):

The compound of formula (XXXV) can be prepared as follows: make the compound of formula (XXVII), wherein PG ¹And PG ²Be C _1-4Alkyl is methyl or ethyl for example,

Compound reaction with formula (XXXVI).

In a similar manner, wherein X is-NR ⁴S (O) ₂-compound can begin preparation, wherein PG from the compound of the compound of formula (XXVII) and formula (XXXVI) ³It is the mercaptan protecting group.

The compound of formula (I), wherein X is-X ¹CR ⁶R ⁷-, X ¹Be-NR ⁴-,-O-,-S-,-S (O)-or-S (O) ₂-, can be prepared as follows:, under the existence of dinethylformamide, make the compound of formula (XXXVII), wherein L at suitable alkali for example tetrahydrofuran (THF) or N of triethylamine or sodium hydride and solvent for example ¹Be for example halogen (for example chlorine), tosyl group, methylsulfonyl or the like of leavings group, and the compound of formula (XXXVIII) reaction:

The compound of formula (I), wherein X is-X ¹CR ⁶R ⁷-, X ¹Be-S-to be prepared as follows: at suitable alkali sodium hydroxide and solvent N for example for example, under the existence of dinethylformamide, the compound that makes formula (XXXIX) reacts with the compound of formula (XXXVIII):

The compound of formula (XXXIX) can be prepared as follows: for example in the ethanol, make the compound and the thiocarbamide reaction of formula (II) in The suitable solvent.

The compound of formula (I), wherein X is-X ¹CR ⁶R ⁷-, X ¹Be-NR ⁴-,-O-,-S-,-S (O)-or-S (O) ₂-, can be prepared as follows: in the presence of suitable metal catalyst (for example palladium or copper), use solvent for example 1, the 4-diox makes the compound of formula (XXXX) and suitable organometallic reagent (boric acid R for example ²B (OR) ₃Acibenzolar, wherein R is C _1-4Alkyl is methyl for example) reaction.

The compound of formula (XXXX) can be prepared as follows: make the compound reaction of the compound and the formula V of formula (XXXXI).

The compound of formula (I), wherein X ¹Be-S-,-S (O)-,-S (O) ₂-,-NR ⁴SO ₂-or-NR ⁴C (O)-, can be prepared as follows: suitable alkali for example sodium hydride and solvent for example tetrahydrofuran (THF) in the presence of, the compound that makes formula (I) reacts with the compound of formula (XXXXIII) and formula (XXXXIV), wherein L ¹And L ²Be for example halogen (for example chlorine), tosyl group, methylsulfonyl or the like of leavings group.

The compound of formula (XXXXII) can be prepared as follows: make the compound of formula (XXXXV) and the compound reaction of formula (III),

Or the compound of the compound of formula (XXXXVI) and formula (XXXVIII) reaction.

The compound of formula (XXXXV) can transform mutually by well-known standard functional group in the document, prepared by the compound of formula (XXXXVII).

The compound of formula (XXXXVII) can be by the compound of formula (XVIII) or its appropriate derivative N-methoxyl group-N-methyl nitrosourea and suitable organometallic reagent R for example for example ⁶MgBr and R ⁷MgBr is with a step or two-stage process preparation.

The compound of formula (I), wherein X is-NR ⁴C (O)-,-NR ⁴C (O) CR ⁶R ⁷-,-NR ⁴S (O) ₂-or-NR ⁴S (O) ₂CR ⁶R ⁷-, can suitable alkali for example triethylamine in the presence of, by the compound of formula (XXXXVIII) (X wherein ¹Be-C (O)-,-C (O) CR ⁶R ⁷-,-S (O) ₂-or-S (O) ₂CR ⁶R ⁷-, L ¹Be for example chlorine or Acibenzolar of the leavings group that suits) prepare with the amine of formula (XXXXIX).

The compound of formula (I), wherein X is-NR ⁴CHR ⁶-, can be at suitable reductive agent NaCNBH for example ₃Existence under, the amine of the compound of through type (XXXXX) and formula (XXXXIX) reacts and prepares.

Some that should be understood that various ring substituents in the The compounds of this invention can be introduced or produce by conventional modified with functional group by the substitution reaction of standard aromatics, and therefore be included in the process aspect of the present invention before above-mentioned technology or after the and then above-mentioned technology.For example, utilize substitution reaction of standard aromatics or conventional modified with functional group, the compound of formula (I) can change other compound of formula (I) into.This reaction and modification comprise and for example utilize the aromatics substitution reaction to introduce substituting group, substituent reduction, substituent alkylation and substituent oxidation.The reagent of this method and reaction conditions are known at chemical field.The object lesson of aromatics substitution reaction comprises: use concentrated nitric acid to introduce nitro, use for example acyl halide and Lewis acid (for example aluminum chloride) introducing acyl group under Friedel Crafts condition; Under Friedel Crafts condition, use alkylogen and Lewis acid (for example aluminum chloride) to introduce alkyl; With the introducing halogen group.The object lesson of modifying comprises: for example in the presence of hydrochloric acid, being accompanied by heating, by handling with the nickel catalyzator catalytic hydrogenation or with iron, is amino with nitroreduction; Alkylthio is oxidized to alkyl sulphinyl or alkyl sulphonyl.

Also should be appreciated that, in reactions more mentioned in this article, any sensitive group in the possible essential/compound that needs protection.Under situation about must or need protection, suitable guard method is known for those skilled in the art.Can use GPF (General Protection False base (for example referring to T.W.Green, Protective Groups in Organic Synthesis, John Wiley andSons, 1991) according to standard practices.Thus, if reactant comprises group for example amino, carboxyl or hydroxyl, this group may need protection in reactions more mentioned in this article.

For the suitable protecting group of amino or alkylamino is acyl group alkyloyl ethanoyl for example for example for example, and carbalkoxy is methoxycarbonyl, ethoxycarbonyl or tertbutyloxycarbonyl for example, and the aryl methoxycarbonyl is carbobenzoxy-(Cbz) for example, or aroyl benzoyl for example.The deprotection condition of above-mentioned protecting group must change with selected protecting group.Thus, for example, acyl group is alkyloyl or carbalkoxy or aroyl for example, can be for example with suitable alkali for example alkali metal hydroxide for example lithium hydroxide or sodium hydroxide hydrolysis are removed.Perhaps; acyl group for example tertbutyloxycarbonyl can be for example by with suitable acid for example hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid handle and remove, and the aryl methoxycarbonyl for example carbobenzoxy-(Cbz) can be for example by catalyzer for example carbon carry on the palladium hydrogenation or with Lewis acid for example three (trifluoroacetic acid) boron handle and remove.Other suitable protecting group of primary amino is a phthalyl group for example, and it can be with alkylamine dimethylamino propylamine or handle with hydrazine and to remove for example.

The suitable protecting group of hydroxyl is an acyl group for example, alkyloyl ethanoyl for example for example, and aroyl is benzoyl for example, or arylmethyl, for example benzyl.The deprotection condition of above-mentioned protecting group must change with selected protecting group.Thus, for example, acyl group for example alkyloyl or aroyl can be for example by with suitable alkali for example alkali metal hydroxide for example lithium hydroxide or sodium hydroxide hydrolysis are removed.Perhaps, arylmethyl for example benzyl can be for example by catalyzer for example carbon carry on the palladium hydrogenation and remove.

The suitable protecting group of carboxyl is an esterified group for example; for example methyl or ethyl; its can be for example by with alkali for example sodium hydroxide hydrolysis remove; or the tertiary butyl for example; its can be for example by with acid for example organic acid for example trifluoroacetic acid handle and remove; or benzyl for example, its can be for example by catalyzer for example carbon carry on the palladium hydrogenation and remove.

Can use the well-known conventional art of chemical field, remove protecting group in the step any convenience of synthetic.

Many intermediates defined herein are new, and provide these intermediates as further feature of the present invention.

Biological test

Can use following test to measure The compounds of this invention as the mTOR kinase inhibitor, as the PI3 kinase inhibitor, as the activated vitro inhibition agent of PI3 kinase signal path with as the effect of the vitro inhibition agent of MDA-MB-468 human breast adenocarcinoma cell propagation.

(a) External mTOR kinase assay

This test use the AlphaScreen technology (people such as Gray, Analytical Biochemistry, 2003,313:234-245), the determination test compound suppresses the ability of recombinant chou mTOR phosphorylation.

The mTOR (EMBL Accession No.L34075) of C-terminal deletion that will comprise the amino-acid residue 1362 to 2549 of mTOR stably is expressed as the fusion of FLAG-mark in the HEK293 cell, as people such as Vilella-Bach, Journal of Biochemistry, 1999,274,4266-4272 describes.MTOR (1362-2549) stabilized cell of HEK293 FLAG-mark is tied up to 37 ℃ of following 5% CO that use ₂At the modification Eagle ' of Dulbecco s growth medium (DMEM; Invitrogen Limited, Paisley, UK catalog number (Cat.No.) 41966-029) in routine remain at the most that 70-90% merges, growth medium contains the fetus calf serum (FCS of 10% heating-inactivation; Sigma, Poole, Dorset, UK, catalog number (Cat.No.) F0392), 1%L-glutamine (Gibco, catalog number (Cat.No.) 25030-024) and 2 mg/ml Geneticin (G418 vitriol; InvitrogenLimited, UK catalog number (Cat.No.) 10131-027).After in warm-blooded animal HEK293 clone, expressing, use the standard purification technology to use FLAG epi-position mark with the expressed proteins purifying.

Test compound is prepared into the stock solution of 10mM in DMSO, and is diluted to as required in the water, obtain final experimental concentration scope.The aliquot sample (2 μ l) of each diluted chemical compound thing is put into the hole of the Greiner white polystyrene board of 384 hole lower volume (LV) (Greiner Bio-one).With the mTOR enzyme of 30 μ l recombinant chou purifying, peptide matrix (the Biotin-Ahx-Lys-Lys-Ala-Asn-Gln-Val-Phe-Leu-Gly-Phe-Thr-T yr-Val-Ala-Pro-Ser-Val-Leu-Glu-Ser-Val-Lys-Glu-NH of 1 μ M biotinylation (biotinylated) ₂Bachem UK Ltd), ATP (20 μ M) and buffering solution [comprise Tris-HCl pH7.4 damping fluid (50mM), EGTA (0.1mM), bovine serum albumin (0.5mg/mL), DTT (1.25mM) and Manganous chloride tetrahydrate (10mM)] mixture at room temperature stirred 90 minutes.

Use 5%DMSO to replace test compound to create the contrast hole that produces corresponding to the peak signal of maximum enzyme activity value.Replace test compound to create the contrast hole that produces corresponding to the minimum signal of complete inhibitory enzyme by adding EDTA (83mM).These testing liquids were at room temperature cultivated 2 hours.

Contain 10 μ l EDTA (50mM) of p70S6 kinases (T389) 1A5 monoclonal antibody (Cell SignallingTechnology, catalog number (Cat.No.) 9206B), bovine serum albumin (BSA by adding; 0.5mg/mL) and the mixture of Tris-HCl pH7.4 damping fluid (50mM) each reaction is stopped, and add AlphaScreen streptavidin donor and A protein receptor bead (200ng; Perkin Elmer, catalog number (Cat.No.) are respectively 6760002B and 6760137R), test board was at room temperature in the dark placed about 20 hours.Use Packard Envision instrument to read and excite the consequential signal that causes at the 680nm place by laser.

As the result of the phosphorylation of mTOR mediation, original position has formed the biotinylation peptide of phosphorylation.The biotinylation peptide of the phosphorylation relevant with AlphaScreen streptavidin donor bead forms mixture with p70 S6 kinases (T389) 1A5 monoclonal antibody (relevant with Alphascreen A protein receptor bead).When in 680nm laser excitation, the donor bead: acceptor bead mixture produces the signal that can measure.Therefore, the existence of mTOR kinase activity produces test signal.In the presence of the mTOR kinase inhibitor, strength of signal reduces.

The mTOR enzyme of giving test compound is suppressed to be expressed as IC ₅₀Value.

(b) External PI3K enzyme test

This test use the AlphaScreen technology (people such as Gray, Analytical Biochemistry, 2003,313:234-245), the determination test compound suppresses the ability of the recombinant type I PI3K enzyme phosphorylation of lipid PI (4,5) P2.

Use standard molecular biology and PCR clone technology, from the cDNA storehouse, separate the dna fragmentation of coding people's PI3K catalysis and regulator subunit.Selected dna fragmentation is used to produce rhabdovirus expression vector.Especially, (the EMBL registration number of p110 α, p110 β and p110 δ is respectively HSU79143 with the human PI3K p110 of each p110 α, p110 β and p110 δ Ia type heterogeneous, S67334, Y10055) full length DNA subclone is to pDEST10 carrier (Invitrogen Limited, Fountain Drive, Paisley, UK) in.Carrier is the Fastbac1 that contains 6-His epi-position mark of inlet coupling pattern.Will be in the pFastBac1 carrier that contains 6-His epi-position mark corresponding to the clipped form of the human PI3K p110 of the Ib type of amino-acid residue 144-1102 (EMBL registration number X8336A) γ heterogeneous and the human p85 α regulator subunits of total length (EMBL registration number HSP13KIN) also subclone.With Ia type p110 structure and p85 α regulator subunit co expression.After use standard baculovirus expression technology is expressed, use the standard purification technology in rhabdovirus system, use His epi-position mark the marking protein purifying.

Use standard molecular biology and PCR clone technology, will from the cDNA storehouse, separate corresponding to the DNA of the amino acid 263 to 380 of the conventional acceptor in human phosphatase inositol (Grp1) PH zone.With the dna fragmentation subclone that obtains to containing GST epi-position mark (AmershamPharmacia Biotech, Rainham, Essex, UK) in the pGEX 4T1 coli expression carrier, as people such as Gray, Analytical Biochemistry, 2003,313:234-245 describes.Use standard technique, express the also Grp1 PH zone of purifying GST-mark.

Test compound is prepared into the stock solution of 10mM in DMSO, and is diluted to as required in the water, obtain final experimental concentration scope.The aliquot sample (2 μ l) of each diluted chemical compound thing is put in the hole of the white polystyrene board of Greiner 384 hole lower volume (LV) (Greiner Bio-one, Brunel Way, Stonehouse, Gloucestershire, UK catalog number (Cat.No.) 784075).PI3K enzyme (15ng), DiC8-PI (4,5) P2 matrix (40 μ M with each selected recombinant chou purifying; Cell Signals Inc., Kinnear Road, Columbus, USA, catalog number (Cat.No.) 901), Adenosine Triphosphate (ATP; 4 μ M) and buffering solution [comprise Tris-HCl pH7.6 damping fluid (40mM, 10 μ l), 3-[(3-courage amido propyl) dimethylamino]-1-propanesulfonic acid inner salt (CHAPS; 0.04%) dithiothreitol (DTT) (DTT; 2mM) and magnesium chloride (10mM)] mixture at room temperature stirred 20 minutes.

Use 5% DMSO to replace test compound, create the contrast hole that produces corresponding to the minimum signal of maximum enzyme activity value.By adding wortmannin (6 μ M; Calbiochem/MerckBioscience, Padge Road, Beeston, Nottingham, UK, catalog number (Cat.No.) 681675) replace test compound, create the contrast hole that produces corresponding to the peak signal of complete inhibitory enzyme.These testing liquids were at room temperature also stirred 20 minutes.

The mixture of EDTA (100mM), bovine serum albumin (BSA, 0.045%) and Tris-HCl pH7.6 damping fluid (40mM) by adding 10 μ l stops each reaction.

Add biotinylated-DiC8-PI (3,4,5) P3 (50nM; Cell Signals Inc., catalog number (Cat.No.) 107), GST-Grp1 PH albumen (2.5nM) and the anti-GST donor of AlphaScreen and the acceptor bead (100ng of recombinant chou purifying; Packard Bioscience Limited, Station Road, Pangbourne, Berkshire, UK, catalog number (Cat.No.) 6760603M), and at room temperature, in the dark test board was placed about 5 to 20 hours.Use the AlphaQuest instrument to read laser and excite the consequential signal that causes at the 680nm place.

Because the phosphorylation of PI (4, the 5) P2 of PI3K mediation, original position forms PI (3,4,5) P3.The GST-Grp1 PH region protein relevant with the anti-GST donor of AlphaScreen bead forms mixture with biotinylated PI (3,4,5) P3 (relevant with Alphascreen Streptavidn acceptor bead).Hasten parturition living PI (3,4,5) P3 and biotinylated PI (3,4,5) P3 of enzyme combines with the PH region protein competitively.When in 680nm laser excitation, the donor bead: acceptor bead mixture produces the signal that can measure.Therefore, form the PI3K enzymic activity of PI (3,4,5) P3 and cause the signal reduction with the competition of biotinylation PI (3,4,5) P3 subsequently.In the presence of the PI3K enzyme inhibitors, strength of signal is restored.

The PI3K enzyme of giving test compound is suppressed to be expressed as IC ₅₀Value.

(c) External phosphate-Ser473 Akt test

This test determination test compound suppress the ability of the phosphorylation of Serine 473 among the Akt, use Acumen Explorer technology (Acumen Bioscience Limited) to estimate, can use plate reader, with the characteristics of image that quantitatively produces apace by laser scanning.

With MDA-MB-468 human breast cancer cell line (LGC Promochem, Teddington, Middlesex, UK, catalog number (Cat.No.) HTB-132) 37 ℃, utilize 5% CO ₂Routine remains to 70-90% fusion at the most in the DMEM of FCS that contains 10% heat inactivation and 1%L-glutamine.

For this test, use ' Accutase ' (Innovative Cell Technologies Inc., SanDiego, CA, USA; Catalog number (Cat.No.) AT104), uses the normal structure culture method, cell is removed from culturing bottle, and be resuspended in the substratum, obtain 1.7x10 ⁵Cells/ml.To wait duplicate samples (90 μ l) to be seeded into black Packard 96 hole plate (PerkinElmer, Boston, MA, USA; In each hole in 60 holes, inside catalog number (Cat.No.) 6005182), obtain the density of every hole～15000 cell.Equal portions (90 μ l) substratum is placed in the external holes, to prevent fringing effect.Cell is used 5% CO at 37 ℃ ₂Overnight incubation adheres to them.

At the 2nd day, cell is handled with test compound, and used 5% CO at 37 ℃ ₂Cultivated 2 hours.Test compound is prepared into the stock solution of 10mM in DMSO, and uses the growth medium serial dilution as required, obtain the concentration range of 10 times of required final experimental concentration.With each diluted chemical compound thing etc. duplicate samples (10 μ l) be placed on (in triplicate) in the hole, needed to the end concentration.As the minimum response contrast, each plate comprises the hole with final concn 100 μ M LY294002 (Calbiochem, Beeston, UK, catalog number (Cat.No.) 440202).As the peak response contrast, comprise 1% DMSO in the hole and replace test compound.After the cultivation, at room temperature, by handle the inclusion that fixed plate in 1 hour with 1.6% formalin (Sigma, Poole, Dorset, UK, catalog number (Cat.No.) F1635).

Use Tecan 96 hole plate washers, carry out all suction and washing steps (pumping velocity 10mm/sec) subsequently.Remove stationary liquid, with phosphate-buffered saline (PBS; 50 μ l; Gibco, catalog number (Cat.No.) 10010015) inclusion of washing plate.At room temperature, handled 10 minutes with equal portions (50 μ l) cell permeabilization damping fluids (mixture by PBS and 0.5% Tween-20 is formed).Remove ' saturatingization ' damping fluid, and at room temperature use equal portions (50 μ l) sealing damping fluid (by 5% drying defatted breast [' Marvel ' (registered trademark) in the mixture of PBS and 0.05% Tween-20; Premier Beverages, Stafford, GB] form) handled 1 hour, seal nonspecific binding site.Remove ' sealing ' damping fluid, and cell is at room temperature used the anti-phosphate-Akt of rabbit (Ser473) antibody-solutions (every hole 50 μ l of dilution 1:500 in ' sealing ' damping fluid; CellSignalling, Hitchin, Herts, U.K., catalog number (Cat.No.) 9277) cultivated 1 hour.Cell is washed three times in the mixture of PBS and 0.05% Tween-20.Subsequently, cell is at room temperature used the anti-rabbit igg of Alexafluor488 labelled goat (every hole 50 μ l of dilution 1:500 in ' sealing ' damping fluid; Molecular Probes, Invitrogen Limited, Paisley, UK, catalog number (Cat.No.) A11008) cultivated 1 hour.The mixture of cell with PBS and 0.05% Tween-20 washed 3 times.The PBS (50 μ l) of equal portions is joined in each hole,, detect and the analysis of fluorescence signal with black plate sealer sealing plate.

Analyze the fluorescence dose response data that each compound obtains, and with the inhibition degree of Serine 473 in Akt with IC ₅₀Value representation.

(d) External MDA-MB-468 human breast cancer proliferation test

This test determination test compound suppress the ability of cell proliferation, use the CellomicsArrayscan technology to estimate.MDA-MB-468 human breast cancer cell line (LGCPromochem, catalog number (Cat.No.) HTB-132) is come conventional the maintenance according to the mode of describing in this paper biological test (b).

For proliferation test, to use Accutase that cell is removed from culturing bottle, and be seeded in 60 holes, inside of black Packard 96 hole plates, density is 8000 cells in every hole, in the complete growth medium of 100 μ l.External holes contains the aseptic PBS of 100 μ l.Cell is used 5%CO at 37 ℃ ₂Overnight incubation adheres to them.

At the 2nd day, cell is handled with test compound, and used 5% CO at 37 ℃ ₂Cultivated 48 hours.Test compound is prepared into the stock solution of 10mM in DMSO, and carries out serial dilution with growth medium as required, obtain the experimental concentration scope.With each diluted chemical compound thing etc. duplicate samples (50 μ l) be placed in the hole, and cell is used 5% CO at 37 ℃ ₂Cultivated 2 days.Each plate comprises the control wells that does not have test compound.

At the 4th day, add last dilution and be the BrdU labelled reagent of 1:1000 (Sigma, catalog number (Cat.No.) B9285), and 37 ℃ of culturing cells 2 hours.Remove substratum, handle the cell that fixed in each hole in 30 minutes by the mixture (90% ethanol, 5% Glacial acetic acid and 5% water) of at room temperature using 100 μ l ethanol and Glacial acetic acid.With PBS (100 μ l) with twice of the cell washing in each hole.(2M, 100 μ l) join in each hole with aqueous hydrochloric acid.After at room temperature 20 minutes, use twice of PBS washed cell.With hydrogen peroxide (3%, 50 μ l; Sigma, catalog number (Cat.No.) H1009) join in each hole.After at room temperature 10 minutes, use the PBS washing hole once more.

By at room temperature using mouse anti BrdU antibody (50 μ l; Caltag, Burlingame, CA, US; Catalog number (Cat.No.) MD5200) (in the PBS that comprises 1%BSA and 0.05% Tween-20, dilutes 1:40) and cultivate the introducing that detected BrdU in 1 hour.Remove unconjugated antibody with the PBS washed twice.Visual for the BrdU that makes introducing, cell is at room temperature used PBS, and (50 (1) and 0.05% Tween-20 damping fluid (the 1:1000 dilution that contains the anti-mouse IgG of Alexa fluor 488 labelled goat) was handled 1 hour.In order to make nucleus visual, add the 1:1000 dilution of Hoechst tinting material (Molecular Probes, catalog number (Cat.No.) H3570).Each plate is washed with PBS successively.Subsequently, PBS (100 μ l) is joined in each hole, use the Cellomics matrix-scanning to analyze plate, to estimate the number of whole cell numbers and BrdU positive cell.

Analyze the fluorescence dose response data that each compound obtains, and the inhibition kilsyth basalt of MDA-MB-468 cell growth is shown IC ₅₀Value.

Though the pharmacology performance of formula (I) compound changes with desirable structure, usually, it is believed that formula (I) activity that compound had can represent with following concentration or dosage in above-mentioned test (a) to (d) one or more :-

Test (a) :-chemical compound lot is to the kinase whose IC of mTOR ₅₀Value is less than 10 μ M, particularly 0.001-0.5 μ M; For embodiment 65, under three kinds of situations, measure IC ₅₀Value is 3.9,4.1 and 8.2 μ M, and mean value is 5.4 μ M.

Test (b) :-chemical compound lot is to the IC of the human PI3K of p110 γ Ib type ₅₀Value is less than 10 μ M, particularly 0.001-0.5 μ M; Chemical compound lot is to the IC of the human PI3K of p110 α Ia type ₅₀Value is less than 10 μ M, particularly 0.001-0.5 μ M; For embodiment 65, under three kinds of situations, measure IC ₅₀Value is 1.9,13.0 and 5.7 μ M, and mean value is 6.8 μ M.

Test (c) :-chemical compound lot is to the IC of the Serine among the Akt 473 ₅₀Value is less than 10 μ M, particularly 0.1-20 μ M; For embodiment 44, under five kinds of situations, measure IC ₅₀Value is 12.5,5.6,9.7,10.3 and 6.1 μ M, and mean value is 8.84 μ M.

Test (d) :-IC ₅₀Value is less than 20 μ M;

The advantage of The compounds of this invention is that they have pharmacological activity.Particularly, compound of the present invention is regulated (particularly suppressing) mTOR kinases and/or phosphatidylinositol-3-kinase (PI3K) enzyme, for example Ia class PI3K enzyme (for example PI3K α, PI3K β and PI3K δ) and Ib class PI3K enzyme (PI3K γ).More particularly, compound adjusting of the present invention (particularly suppressing) mTOR kinases.More particularly, one or more PI3K enzymes of compound adjusting of the present invention (particularly suppressing).Use the test method of listing in this paper and the experimental section, can prove the rejection of formula (I) compound.Therefore, the compound of formula (I) can be used for the condition/disease among treatment (treatment or the prevention) mankind and the non-human animal, and this condition/disease is that particularly mTOR is kinase mediated by mTOR kinases and/or one or more PI3K enzymes.

The present invention also provides pharmaceutical composition, and it comprises the combination of compound or its pharmacologically acceptable salts and the pharmacy acceptable diluent or the carrier of formula defined herein (I).

Composition of the present invention can be the form that is suitable for an orally using (tablet for example, sugar forms sediment, hard or soft capsule, water-based or oily suspensions, emulsion, dispersible powder or granule, syrup or elixir), the form of using in the part (for example emulsifiable paste, ointment, gelifying agent or water-based or oily solution or suspension), be used to suck the form (powder for example in small, broken bits or liquid aersol) that gives, be used to spray the form (powder for example in small, broken bits) that gives or be used for form that parenteral gives that (for example aseptic water-based or oily solution are used for intravenously, subcutaneous, intraperitoneal or intramuscular give, or are used for the suppository that rectum gives).

Composition of the present invention can use conventional medicine vehicle well-known in the art, be obtained by ordinary method.Thus, the composition that orally uses can contain for example one or more tinting materials, sweeting agent, seasonings and/or sanitas.

The amount that produces the activeconstituents of single formulation with one or more excipient composition must change according to host who is treated and concrete route of administration.For example, the human oral preparation for example contains (more suitably from 1 to 250 milligram of promoting agent from 1 milligram to 1 gram usually, for example from 1 to 100 milligram), promoting agent and suitable and make things convenient for the mixed with excipients of quantity, the quantity of vehicle can change between about 98% weight from about 5 of whole compositions.

For treatment or prevention purpose, the dosage size of formula I compound certainly will be according to character and severity, animal or patient's age and the sex and the route of administration of morbid state, change according to well-known medicine principle.

In the treatment of use formula (I) compound or prevention purpose, the per daily dose scope that gives usually is 1 mg/kg to 100 a mg/kg body weight for example, if necessary, gives five equilibrium dosage.Usually, when using parenteral route, give than low dosage.Thus, for example, give for intravenously, normally used dosage range is 1 mg/kg to 25 a mg/kg body weight for example.Similarly, give for suction, the dosage range of use is 1 mg/kg to 25 a mg/kg body weight for example.Typically, unit dosage contain about 10 milligrams to 0.5 the gram compound of the present invention.

According to the narration of this paper, well-known, mTOR kinases and PI3K enzyme are in tumorigenicity and much have effect in other disease.We find that the compound of formula (I) has the effective antitumour activity, think that this activity obtains by suppressing mTOR kinases and/or one or more PI3K enzymes.

Therefore, compound of the present invention has the value of anti-tumor agents.Specifically, compound of the present invention suppress and/or treatment entity and/or liquid tumors disease aspect as antiproliferative, apoptosis and/or anti-to invade medicament be valuable.Specifically, estimate that compound of the present invention can be effective to prevent or treats suppressing for example those tumours of Ia class PI3K enzyme and Ib class PI3K enzyme sensitivity of mTOR and/or one or more PI3K enzymes.Further, estimate that compound of the present invention can be effective to prevent or treat that for example Ia class PI3K enzyme and Ib class PI3K enzyme be separately or those tumours of part mediation by mTOR and/or one or more PI3K enzymes.Thus, this compound can be used to produce the mTOR enzyme and suppress effect in the warm-blooded animal of this treatment of needs.Some compound can be used to produce the PI3K enzyme and suppress effect in the warm-blooded animal of this treatment of needs.

Narration according to this paper, the inhibitor of mTOR kinases and/or one or more PI3K enzymes should have therapeutic value for the following hyperplasia of treatment: cancer for example, for example malignant tumour and sarcoma and leukemia and lymph malignant tumour of noumenal tumour particularly, particularly treat for example breast cancer, colorectal carcinoma, lung cancer (comprising small cell lung cancer, nonsmall-cell lung cancer and bronchioalveolar carcinoma disease) and prostate cancer and courage cancer, osteocarcinoma, bladder cancer, the cancer of the brain and neck cancer, kidney, liver cancer, gastrointestinal tissue's cancer, esophagus cancer, ovarian cancer, carcinoma of the pancreas, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma, cervical cancer and carcinoma vulvae, and leukemia [comprising acute lymphoblastic leukemia (ALL) and chronic marrow leukemia (CML)], multiple myeloma and lymphoma.

According to further aspect of the present invention, provide the compound of formula (I) defined herein or its pharmacologically acceptable salts warm-blooded animal for example among the people as the purposes of medicine.

According to further aspect of the present invention, provide compound or its pharmacologically acceptable salts of formula (I) defined herein for example to be used to produce anti-proliferative effect among the people warm-blooded animal.

According to further aspect of the present invention, provide compound or its pharmacologically acceptable salts of formula (I) defined herein for example to be used to produce the apoptosis effect among the people warm-blooded animal.

According to further feature of the present invention, provide the compound of formula (I) defined herein or its pharmacologically acceptable salts for example to be used to suppress among the people and/or to treat for example anti-intrusion medicament of cancer of hyperplasia warm-blooded animal.

According to further aspect of the present invention, provide the compound of formula (I) defined herein or its pharmacologically acceptable salts for example to produce the purposes of anti-proliferative effect among the people warm-blooded animal.

According to the further feature of this aspect of the present invention, provide formula (I) compound or its pharmacologically acceptable salts defined herein to be used for for example purposes of the medicine of people's generation anti-proliferative effect of warm-blooded animal in preparation.

According to further aspect of the present invention, provide the compound of formula (I) defined herein or its pharmacologically acceptable salts for example to be used to produce the purposes of apoptosis effect among the people warm-blooded animal.

According to the further feature of this aspect of the present invention, provide formula (I) compound or its pharmacologically acceptable salts defined herein to be used for for example purposes of the medicine of people's generation apoptosis effect of warm-blooded animal in preparation.

According to further feature of the present invention, provide the compound of formula (I) defined herein or its pharmacologically acceptable salts the preparation warm-blooded animal for example the people use, as suppressing and/or the treatment hyperplasia purposes in the medicine of the anti-intrusion medicament of cancer for example.

According to the further feature of this aspect of the present invention, the warm-blooded animal that provides in this treatment of needs for example produces the method for anti-proliferative effect among the people, comprises formula defined herein (I) compound or its pharmacologically acceptable salts that give described animal effective dose.

Further feature according to this aspect of the present invention, the warm-blooded animal that provides in this treatment of needs for example produces anti-method of invading effect by inhibition and/or treatment noumenal tumour disease among the people, comprises formula defined herein (I) compound or its pharmacologically acceptable salts that give described animal effective dose.

According to further aspect of the present invention, provide formula (I) compound defined herein or its pharmacologically acceptable salts to be used for preventing or to treat for example people's the hyperplasia purposes of the medicine of cancer for example of warm-blooded animal in preparation.

Further feature according to this aspect of the present invention, the warm-blooded animal that provides in this treatment of needs is prevention or the treatment hyperplasia method of cancer for example among the people for example, comprises formula defined herein (I) compound or its pharmacologically acceptable salts that give described animal effective dose.

According to further aspect of the present invention, formula (I) compound or its pharmacologically acceptable salts defined herein is provided, be used for prevention or treatment to suppressing those responsive tumours of mTOR kinases and/or one or more PI3K enzymes (for example Ia fermentoid and/or Ib class PI3K enzyme), mTOR kinases and/or one or more PI3K enzymes are relevant with the signal transduction step of the propagation that causes tumour cell, survival, intrusion and transfer ability.

Further feature according to this aspect of the present invention, formula (I) compound or its pharmacologically acceptable salts defined herein is provided, be used for prevention or the treatment purposes to the medicine that suppresses those responsive tumours of mTOR kinases and/or one or more PI3K enzymes (for example Ia fermentoid and/or Ib class PI3K enzyme) in preparation, mTOR kinases and/or one or more PI3K enzymes are relevant with the signal transduction step of the propagation that causes tumour cell, survival, intrusion and transfer ability.

Further feature according to this aspect of the present invention, provide prevention or treatment to suppressing the method for those responsive tumours of mTOR kinases and/or one or more PI3K enzymes (for example Ia fermentoid and/or Ib class PI3K enzyme), mTOR kinases and/or one or more PI3K enzymes are relevant with the signal transduction step of the propagation that causes tumour cell, survival, intrusion and transfer ability, and this method comprises formula defined herein (I) compound or its pharmacologically acceptable salts that gives described animal effective dose.

According to further aspect of the present invention, formula (I) compound or its pharmacologically acceptable salts defined herein is provided, be used to provide mTOR kinase inhibition effect and/or PI3K enzyme to suppress effect (for example Ia class PI3K enzyme or Ib class PI3K enzyme suppress effect).

According to the further feature of this aspect of the present invention, provide formula (I) compound or its pharmacologically acceptable salts defined herein to be used for providing mTOR kinase inhibition effect and/or PI3K enzyme to suppress the purposes of the medicine of effect (for example Ia class PI3K enzyme or Ib class PI3K enzyme suppress effect) in preparation.

According to further aspect of the present invention, also provide mTOR kinase inhibition effect and/or PI3K enzyme to suppress the effect method of (for example Ia class PI3K enzyme or Ib class PI3K enzyme suppress effect), this method comprises formula I compound defined herein or its pharmacologically acceptable salts that gives significant quantity.

According to further feature of the present invention, provide compound or its pharmacologically acceptable salts of formula I defined herein to be used for the treatment of cancer, inflammatory diseases, obstructive respiratory tract disease, Immunological diseases or cardiovascular disorder.

According to further feature of the present invention, provide compound or its pharmacologically acceptable salts of formula I defined herein to be used for the treatment of noumenal tumour for example malignant tumour and sarcoma and leukemia and lymph malignant tumour.

According to further feature of the present invention, provide compound or its pharmacologically acceptable salts of formula I defined herein to be used for the treatment of breast cancer, colorectal carcinoma, lung cancer (comprising small cell lung cancer, nonsmall-cell lung cancer and bronchioalveolar carcinoma) and prostate cancer.

According to further feature of the present invention, provide compound or its pharmacologically acceptable salts of formula (I) defined herein to be used for the treatment of cholangiocarcinoma, osteocarcinoma, bladder cancer, the cancer of the brain and neck cancer, kidney, liver cancer, gastrointestinal tissue's cancer, esophagus cancer, ovarian cancer, carcinoma of the pancreas, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma, cervical cancer and carcinoma vulvae, and leukemia (comprising ALL and CML), multiple myeloma and lymphoma.

According to further feature of the present invention, provide the compound of formula (I) defined herein or its pharmacologically acceptable salts to be used for the treatment of purposes in the medicine of cancer, inflammatory diseases, obstructive respiratory tract disease, Immunological diseases or cardiovascular disorder in preparation.

According to further feature of the present invention, provide the compound of formula (I) defined herein or its pharmacologically acceptable salts to be used for the treatment of for example purposes in the medicine of malignant tumour and sarcoma and leukemia and lymph malignant tumour of noumenal tumour in preparation.

According to further feature of the present invention, provide the compound of formula (I) defined herein or its pharmacologically acceptable salts to be used for the treatment of purposes in the medicine of breast cancer, colorectal carcinoma, lung cancer (comprising small cell lung cancer, nonsmall-cell lung cancer and bronchioalveolar carcinoma) and prostate cancer in preparation.

According to further feature of the present invention, provide the compound of formula (I) defined herein or its pharmacologically acceptable salts to be used for the treatment of purposes in cholangiocarcinoma, osteocarcinoma, bladder cancer, the cancer of the brain and neck cancer, kidney, liver cancer, gastrointestinal tissue's cancer, esophagus cancer, ovarian cancer, carcinoma of the pancreas, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma, cervical cancer and carcinoma vulvae and leukemia (comprising ALL and CML), multiple myeloma and the lymphadenomatous medicine in preparation.

According to further feature of the present invention, the warm-blooded animal that provides in this treatment of needs is for example treated the method for cancer, inflammatory diseases, obstructive respiratory tract disease, Immunological diseases or cardiovascular disorder among the people, and this method comprises compound or its pharmacologically acceptable salts of the formula defined herein (I) that gives significant quantity.

According to further feature of the present invention, the warm-blooded animal that provides in this treatment of needs is the treatment noumenal tumour method of malignant tumour and sarcoma and leukemia and lymph malignant tumour for example among the people for example, and this method comprises compound or its pharmacologically acceptable salts of the formula defined herein (I) that gives significant quantity.

According to further feature of the present invention, the warm-blooded animal that provides in this treatment of needs is for example treated the method for breast cancer, colorectal carcinoma, lung cancer (comprising small cell lung cancer, nonsmall-cell lung cancer and bronchioalveolar carcinoma) and prostate cancer among the people, and this method comprises compound or its pharmacologically acceptable salts of the formula defined herein (I) that gives significant quantity.

According to further feature of the present invention, the warm-blooded animal that provides in this treatment of needs is for example treated cholangiocarcinoma, osteocarcinoma, bladder cancer, the cancer of the brain and neck cancer, kidney, liver cancer, gastrointestinal tissue's cancer, esophagus cancer, ovarian cancer, carcinoma of the pancreas, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma, cervical cancer and carcinoma vulvae and leukemia (comprising ALL and CML), multiple myeloma and lymphadenomatous method among the people, and this method comprises compound or its pharmacologically acceptable salts of the formula defined herein (I) that gives significant quantity.

According to the narration of this paper, effect can partly produce by one or more metabolites in the body of formula (I) compound, and metabolite is after giving construction (I) compound, form in human or animal body.

The invention further relates to combined therapy, its Chinese style (I) compound or its pharmacologically acceptable salts or comprise the pharmaceutical composition or the preparation of formula (I) compound simultaneously or in a sequence or with combination preparation give with the treatment of another kind control tumor disease.

Particularly, treatment defined herein can be used as monotherapy and uses, or except compound of the present invention, can also comprise routine operation or radiotherapy or chemotherapy.Therefore, compound of the present invention can also be used in combination with the existing therapeutical agent of treatment cancer.

The suitable medicament that is used to make up comprises :-

(i) antiproliferative/antitumour drug and its combination are used for medical oncology, for example alkylating agent (for example cis-platinum, carboplatin, endoxan, mustargen, Melphalan, Chlorambucil, Myelosan and nitrosourea); Metabolic antagonist (for example antifolate for example 5 FU 5 fluorouracil and Tegafur of fluorine pyrimidine for example, Raltitrexed (raltitrexed), methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); Antitumor antibiotics (for example anthracycline antibiotics Zorubicin for example, bleomycin, Dx, daunorubicin, epirubicin, idarubicin, Mitomycin-C, actinomycin and mithramycin); Antimitotic agent (for example vinca alkaloids vincristin for example, vincaleucoblastine, desacetyl vinblastine amide and Vinorelbine and Japanese yew class medicine, for example pure and mild taxotere of Pacific yew (taxotere)); With local isomerase inhibitors (for example for example Etoposide and teniposide of epipodophyllotoxin, amsacrine, Hycamtin and camptothecine);

(ii) cytostatics estrogen antagonist (tamoxifen for example for example, Toremifene Citrate, Reynolds former times phenol, droloxifene and iodoxyfene), estrogen receptor is born conditioning agent (for example fulvestrant), androgen antagonist (bicalutamide for example, flutamide, Nilutamide and acetate Sai Pulong), lhrh antagonist or LHRH agonist (goserelin for example, Leuprolide and buserelin), progestogen (for example megestrol), aromatase inhibitor (Anastrozole for example, letrozole, vorozole (vorazole) and Exemestane) and the inhibitor of 5, for example finasteride;

(iii) the anti-invasion medicament (for example c-Src kinases man group inhibitor, for example 4-(6-chloro-2,3-methylene dioxo group aniline base)-7-[2-(4-methylpiperazine-1-yl) oxyethyl group]-5-tetrahydropyran-4-base oxygen base quinazoline (AZD0530; International Patent Application WO 01/94341) and N-(2-chloro-6-aminomethyl phenyl)-2-{6-[4-(2-hydroxyethyl) piperazine-1-yl]-2-methylpyrimidine-4-base is amino thiazole-5-methane amide (Dasatinib, BMS-354825; J.Med.Chem., 2004,47,6658-6661), and inhibitors of metalloproteinase, for example inhibitor of Marimastat (marimastat) and urokinase plasminogen activated receptor function);

(iv) somatomedin depressant of functions: for example this inhibitor comprises growth factor antibodies and growth factor receptor antibody (anti-erbB 2 antibody trastuzumab [Herceptin for example ^TM] and anti-erbB1 antibody Cetuximab [C225]); This inhibitor also comprises for example tyrosine kinase inhibitor, the inhibitor of epidermal growth factor family (EGFR family tyrosine kinase inhibitor for example for example, N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholino propoxy-) quinazoline-4-amine (Gefitinib for example, ZD1839), N-(3-ethynyl phenyl)-6, (the dust Lip river is for the Buddhist nun for 7-two (2-methoxy ethoxy) quinazoline-4-amine, OSI-774) and 6-acryl amido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholino propoxy-) quinazoline-4-amine (CI1033) and erbB2 tyrosine kinase inhibitor lapatinibditosylate (lapatinib) for example), the inhibitor of pHGF family, the inhibitor of platelet-derived growth factor family, imatinib for example, (for example Ras/Raf signal suppressing agent of the inhibitor of serine/threonine kinase, farnesyl transferase inhibitor for example, for example Xarelto (sorafenib) is (BAY43-9006)) and the inhibitor by MEK and/or the kinase whose cell signal of Akt;

(v) anti-angiogenic formation agent for example suppresses those medicaments of the effect of vascular endothelial growth factor, [anti-vascular endothelial cell growth factor antibody Avastin (Avastin for example ^TM) and vegf receptor tyrosine kinase inhibitor, for example 4-(4-bromo-2-fluoroanilino)-6-methoxyl group-7-(1-methyl piperidine-4-ylmethoxy) quinazoline (ZD6474; Embodiment 2 among the WO 01/32651), 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-(3-tetramethyleneimine-1-base propoxy-) quinazoline (AZD2171; Embodiment 240 among the WO 00/47212), Wa Talani (vatalanib) (PTK787; WO 98/35985) and SU11248 (Sutent (Sunitinib); WO 01/60814) and the compound that works by other mechanism (for example linomide, the inhibitor of beta 2 integrin alpha v β 3 functions and angiostatin)];

(vi) blood vessel injury agent Combretastatin A-4 4 and be disclosed in compound among International Patent Application WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and the WO 02/08213 for example;

(vii) antisense therapy, for example at those therapies of above-listed target, for example ISIS 2503, anti-ras antisense agents;

(viii) gene therapy method, comprise the method that replaces the distortion for example distored p53 of gene or distored BRCA1 or BRCA2, GDEPT (the enzyme precursor pharmacotherapy of gene guiding) method is for example used those methods of Isocytosine deaminase, thymidine kinase or bacterium nitroreductase, with the method for raising patient for the tolerance of chemotherapy or radiotherapy, for example multi-drug resistant gene therapy; With

(ix) immunotherapy method, comprise method in the immunogenic external and body that improves the patient tumors cell, for example for example interleukin 2, interleukin 4 or rHuGM-CSF carry out transfection with cytokine, reduce the method for T cell anergy, the immunocyte of use transfection is the method for cytokine-transfection dendritic cell for example, the method that the method for the tumor cell line of use cytokine transfection and the anti-spy of use answer antibody.

With reference now to following illustrative embodiment, further explains the present invention.

Except as otherwise noted, starting raw material is commercial the purchase.All solvents and commercial reagents are laboratory-scale, and former state is used.

In an embodiment, ¹H NMR spectrum writes down on Bruker DPX 300 (300MHz), BrukerDRX 400 (400MHz) instrument or Bruker DRX500 (500MHz) instrument.Chloroform-d (δ _H7.27ppm), methyl-sulphoxide-d ₆(δ _H2.50ppm) or acetone-d ₆(δ _H2.05ppm) central peak as interior mark.Use following abbreviation: s, unimodal; D, bimodal; T, triplet; Q, quartet; M, multiplet; Br, broad peak.

(0.04-0.063mm Merck) carries out column chromatography to use silica gel.Usually, KromasilKR-100-5-C18 reversed-phase column (250 x 20mm, Akzo Nobel) is used to prepare HPLC, and the mixture [containing 0.1% trifluoroacetic acid (TFA)] that uses acetonitrile and water is as elutriant, flow velocity 10 ml/min.

Following method is used for the analysis of liquid chromatography (LC)/mass spectrum (MS) :-

HPLC:Agilent1100 or Waters Alliance HT (2790 ﹠amp; 2795)

Mass spectrum: Waters ZQ ESCi

The HPLC post

Employed standard HPLC post is Phemonenex Gemini C18 5 μ m, 50 x 2mm.

Acid HPLC method

The mobile phase of using is: mobile phase A: water

Mobile phase B: acetonitrile

Moving phase C:1% formic acid is in 50:50 water: MeCN (v/v)

After each method, carried out quick balance 0.45 minute with the flow velocity of 5mL.

Can utilize four kinds of general HPLC methods:

Detected the acid method in 5 minutes

Time/minute	Mobile phase A:	Mobile phase B:	Moving phase C:	Curve	Flow velocity/ml/min
Time/minute	Mobile phase A:	Mobile phase B:	Moving phase C:	Curve	Flow velocity/ml/min	0.00	95	0	5	1	1.1
4	0	95	5	6	1.1	0.00	95	0	5	1	1.1
4	0	95	5	6	1.1	4.5	0	95	5	6	1.1

Acid method morning of the compound that goes out of wash-out early

Time/minute	Mobile phase A:	Mobile phase B:	Moving phase C:	Curve	Flow velocity/ml/min
Time/minute	Mobile phase A:	Mobile phase B:	Moving phase C:	Curve	Flow velocity/ml/min	0.00	95	0	5	1	1.1
4	57.5	37.5	5	6	1.1	0.00	95	0	5	1	1.1
4	57.5	37.5	5	6	1.1	4.5	57.5	37.5	5	6	1.1

The middle acid method of middle wash-out compound

Time/minute	Mobile phase A:	Mobile phase B:	Moving phase C:	Curve	Flow velocity/ml/min
Time/minute	Mobile phase A:	Mobile phase B:	Moving phase C:	Curve	Flow velocity/ml/min	0.00	95	0	5	1	1.1
0.01	67.5	27.5	5	6	1.1	0.00	95	0	5	1	1.1
0.01	67.5	27.5	5	6	1.1	4.5	27.5	67.5	5	6	1.1

The late acid method of the compound that late wash-out goes out

Time/minute	Mobile phase A:	Mobile phase B:	Moving phase C:	Curve	Flow velocity/ml/min
Time/minute	Mobile phase A:	Mobile phase B:	Moving phase C:	Curve	Flow velocity/ml/min	0.00	95	0	5	1	1.1
0.01	27.5	67.5	5	6	1.1	0.00	95	0	5	1	1.1
0.01	27.5	67.5	5	6	1.1	4.5	5	95	5	6	1.1

Alkali formula HPLC method

In some cases, standard acid method may be not suitable for compound ionsization or chromatographic separation needs.In the case, can utilize four kinds of similar alkali formula HPLC methods.

The mobile phase of using is: mobile phase A: water

Mobile phase B: acetonitrile

Moving phase D:0.1%880 ammonia/acetonitrile

After each method, use the 5mL flow velocity to carry out quick balance 0.45 minute.

Instantaneous detection alkali formula method

Time/minute	Mobile phase A:	Mobile phase B:	Moving phase D:	Curve	Flow velocity/ml/min
Time/minute	Mobile phase A:	Mobile phase B:	Moving phase D:	Curve	Flow velocity/ml/min	0.00	95	0	5	1	1.1
4	0	95	5	6	1.1	0.00	95	0	5	1	1.1
4	0	95	5	6	1.1	4.5	0	95	5	6	1.1

Alkali formula method morning of the compound that goes out of wash-out early

Time/minute	Mobile phase A:	Mobile phase B:	Moving phase D:	Curve	Flow velocity/ml/min
Time/minute	Mobile phase A:	Mobile phase B:	Moving phase D:	Curve	Flow velocity/ml/min	0.00	95	0	5	1	1.1
4	57.5	37.5	5	6	1.1	0.00	95	0	5	1	1.1
4	57.5	37.5	5	6	1.1	4.5	57.5	37.5	5	6	1.1

The middle alkali formula method of the compound that middle wash-out goes out

Time/minute	Mobile phase A:	Mobile phase B:	Moving phase D:	Curve	Flow velocity/ml/min
Time/minute	Mobile phase A:	Mobile phase B:	Moving phase D:	Curve	Flow velocity/ml/min	0.00	95	0	5	1	1.1
0.01	67.5	27.5	5	6	1.1	0.00	95	0	5	1	1.1
0.01	67.5	27.5	5	6	1.1	4.5	27.5	67.5	5	6	1.1

The late alkali formula method of the compound that late wash-out goes out

Following method is used for liquid chromatography (LC)/mass spectrum (MS) analysis :-instrument: Agilent 1100; Post: Waters ' Symmetry ' 2.1 x 30mm; Use chemical ioni zation (APCI) to carry out mass spectroscopy; Flow velocity: 0.7mL/min; Absorbing wavelength: 254nm; Solvent orange 2 A: water+0.1%TFA; Solvent B: acetonitrile+0.1% TFA; Solvent gradient: 15-95% solvent B, 2.7 minutes, 95% solvent B then, 0.3 minute.

Analyze the following method of using for LC :-

Method A:-instrument: Agilent 1100; Post: Kromasil C18 reverse phase silica gel, 100 x 3mm, 5 μ m granularities; Solvent orange 2 A: 0.1% TFA/ water, solvent B:0.08% TFA/ acetonitrile; Flow velocity: 1mL/min; Solvent gradient: 10-100% solvent B, 20 minutes, 100% solvent B then, 1 minute; Absorbing wavelength: 220,254 and 280nm.Usually, note the retention time of product.

Method B:-instrument: Agilent 1100; Post: Waters ' Xterra ' C8 reverse phase silica gel, 100x 3mm, 5 μ m granularities; Solvent orange 2 A: 0.015M ammonia/water, solvent B: acetonitrile; Flow velocity: 1ml/min, solvent gradient: 10-100% solvent B, 20 minutes, 100% solvent B then, 1 minute; Absorbing wavelength: 220,254 and 280nm.Usually, note the retention time of product.

This paper or the following abbreviation of use in following illustrative embodiment :-

HPLC: high pressure liquid chromatography

HBTU:O-(benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate;

HATU:O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate;

The HOBT:1-hydroxybenzotriazole;

HOAT:1-hydroxyl-7-azepine benzotriazole;

DIEA:N, the N-diisopropylethylamine;

NMP:N-methylpyrrolidin-2-ketone;

DMSO: methyl-sulphoxide;

DMF:N, dinethylformamide;

DMA:N, the N-N,N-DIMETHYLACETAMIDE;

THF: tetrahydrofuran (THF);

DME:1, the 2-glycol dimethyl ether;

DCCI: dicyclohexylcarbodiimide;

MeOH: methyl alcohol;

MeCN: acetonitrile;

DCM: methylene dichloride;

DIPEA:N, the N-diisopropylethylamine.

Utilize software to produce chemical name, this software uses the Lexichem Toolkit (v.1.40) of OpenEye ScientificSoftware (www.eyesopen.com) to produce the title that meets IUPAC.

Embodiment 1:

4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-2-thiene-3-yl--pyrimidine

With (151 milligrams of 2-methyl sulfenyl-4-(sulfonyloxy methyl ylmethyl)-6-morpholines-4-base-pyrimidine; 0.5mmol), (141 milligrams in thiophene-3-boric acid; 1.1mmol), (248 milligrams of thiophene-2-carboxylic acid copper (I); 1.3mmol), (47 milligrams of tetra-triphenylphosphine palladiums; 0.04mmol) and 1,4-diox (5 milliliters) joins in the microwave container.With nitrogen system is outgased, sealing is in microwave reactor, 130 ℃ of heating 45 minutes.The product that obtains is dissolved with NMP, by the SCX chromatogram purification, with the needed compound of 7N methanol ammonia wash-out.Use anti-phase preparation HPLC to be further purified product (referring to the detailed purifying of table back), obtain title compound (4.3 milligrams).

The LCMS spectrum: MH+340.5, retention time: 1.86, method: referring to the detailed content of following table back.

The NMR spectrum: ¹H NMR (300.132MHz, DMSO) δ 3.20 (s, 3H), 3.71 (s, 8H), 4.47 (s, 2H), 6.83 (s, 1H), 7.60 (dd, 1H), 7.76 (dd, 1H), 8.29 (dd, 1H)

Starting raw material 2-methyl sulfenyl-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine is prepared as follows:

2-methyl sulfenyl-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine

With 2-methyl sulfenyl-6-(sulfonyloxy methyl ylmethyl) pyrimidine-4-alcohol (15 grams, 63.97mmol) about 1 hour of reflux in phosphorus oxychloride (100 milliliters).Make the phosphorus oxychloride evaporation, use in the sodium hydroxide solution and resistates, and extract in the ethyl acetate.The mixture that obtains with dried over mgso filters then, and evaporate to dryness obtains crude product 4-chloro-2-methyl sulfenyl-6-(sulfonyloxy methyl ylmethyl) pyrimidine.Then it is dissolved among the DCM, adds morpholine (319mmol, 28 milliliters), at room temperature stirring reaction.When finishing, collect the precipitation white solid that obtains.Concentrated filtrate obtains more solid 2-methyl sulfenyl-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine (adding up to 13.7 grams).

The LCMS spectrum: MH+304.50, retention time: 1.49, method: the alkali formula detects

The NMR spectrum: ¹H NMR (300.132MHz, DMSO) δ 2.45 (s, 3H), 3.49-3.74 (m, 8H), 4.37 (s, 2H), 6.66 (s, 1H) ppm.

2-methyl sulfenyl-6-(sulfonyloxy methyl ylmethyl) pyrimidine-4-alcohol

(19.07 grams 100mmol) are suspended in the acetonitrile (400 milliliters) with 6-(chloromethyl)-2-methyl sulfenyl-pyrimidine-4-alcohol.In this stirred suspension, add the methyl-sulfinic acid sodium salt (12.255 grams, 120mmol) and DMF (100 milliliters).Reaction is heated to 100 ℃ then, obtains black suspension, utilize LCMS to detect.In case finish, remove and desolvate, and the product that obtains is joined among the 1:1MeOH:DCM (200 milliliters), with acetic acid (10 milliliters) acidifying.The precipitation that collection obtains, water (200 milliliters) and MeOH (100 milliliters) washing, vacuum-drying is spent the night, and obtains title compound white solid (16.45 gram).

The LCMS spectrum: MH+235.2, retention time: 0.5, method: early stage alkali formula

The NMR spectrum: ¹H NMR (300.132MHz, DMSO) δ 2.50 (s, 3H), 3.12 (s, 3H), 4.39 (s, 2H), 6.25 (s, 1H), 13.09 (s, 1H) ppm.

6-(chloromethyl)-2-methyl sulfenyl-pyrimidine-4-alcohol

With S-methyl-2-sulfo-pseudo-urea sulfuric ester (20 the gram, 71.85mmol), 4-chloracetyl vinyl acetic monomer (10.755 milliliters, 79.04mmol) and yellow soda ash (13.925 the gram, 107.78mmol) in water-soluble (100 milliliters), at room temperature the stirring spend the night.By the TLC detection reaction, in case finish, collect reaction precipitation, use in the 6N hydrochloric acid and supernatant liquor, obtain more reaction precipitations, equally with its collection.Water (x3) washing accumulative precipitation obtains the off-white color solid then.60 ℃ with its vacuum-drying 48 hours, obtain needed compound light yellow/white solid (43.2 gram).

Mass spectrum: M ⁺190

The NMR spectrum: ¹H NMR (300.132MHz, CDCl ₃) δ 2.59 (s, 3H), 4.35 (s, 2H), 6.41 (s, 1H), 12.70 (s, 1H) ppm

Prepare the compound that is shown in Table 1 according to the mode similar to 4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-2-thiene-3-yl--pyrimidine (embodiment 1), wherein annotated except.

Table 1:

Embodiment 2: ¹H NMR (300.132MHz, DMSO) δ 3.24 (s, 3H), 3.74 (s, 8H), 4.54 (s, 2H), 6.93 (s, 1H), 7.32 (t, 1H), 7.42 (t, 1H), 7.49-7.82 (m, 3H)

Embodiment 4: ¹H NMR (300.132MHz, DMSO) δ 3.25 (s, 3H), 3.74 (s, 8H), 4.50 (s, 2H), 6.55 (d, 1H), 6.81 (s, 1H), 7.39 (dd, 1H), 7.45 (d, 1H), 7.96 (s, 1H), 8.17 (dd, 1H), 8.61 (s, 1H), 11.24 (s, 1H)

Embodiment 5: ¹H NMR (300.132MHz, DMSO) δ 3.20 (s, 3H), 3.72 (s, 8H), 3.93 (s, 3H), 4.50 (s, 2H), 6.88 (s, 1H), 6.92 (d, 1H), 8.53 (dd, 1H), 9.11 (d, 1H)

Embodiment 6: ¹H NMR (300.132MHz, DMSO) δ 3.25 (s, 3H), 3.76 (s, 8H), 3.91 (s, 3H), 4.54 (s, 2H), 6.90 (s, 1H), 7.21 (dd, 1H), 7.38 (d, 1H), 7.90 (d, 1H), 7.99 (d, 1H), 8.42 (dd, 1H), 8.83 (s, 1H)

Embodiment 7: ¹H NMR (300.132MHz, DMSO) δ 3.22 (s, 3H), 3.73 (s, 8H), 4.52 (s, 2H), 4.58 (d, 2H), 5.25 (t, 1H), 6.90 (s, 1H), 7.43 (s, 1H), 7.45 (s, 1H), 8.22 (td, 1H), 8.31 (s, 1H)

Embodiment 9: ¹H NMR (300.132MHz, DMSO) δ 2.93 (s, 3H), 2.99 (s, 3H), 3.21 (s, 3H), 3.74 (s, 8H), 4.53 (s, 2H), 6.93 (s, 1H), 7.51 (d, 2H), 8.38 (d, 2H)

Embodiment 10: ¹H NMR (300.132MHz, DMSO) δ 3.19 (s, 3H), 3.72 (s, 8H), 4.01 (s, 3H), 4.50 (s, 2H), 6.94 (s, 1H), 9.38 (s, 2H)

Embodiment 11: ¹H NMR (300.132MHz, DMSO) δ 3.26 (s, 3H), 3.78 (s, 8H), 4.57 (s, 2H), 6.97 (s, 1H), 7.59 (dd, 1H), 8.12 (d, 1H), 8.55 (d, 1H), 8.71 (dd, 1H), 8.96 (m, 2H)

The purifying of embodiment 1 to 12/analysis is described in detail:

Dissolution solvent: 4 milliliters of DMF

Instrument: Waters XBridge Prep, C18 5 μ m 100 x 19mm

Post: Phenomenex Gemini 5 μ, C18 100 x 21.2mm

The fraction initiator: uv is at 254nm

Gradient: 0-1 minute, 30% MeCN, 9.5 minutes, 60% MeCN

Solvent orange 2 A: water

Solvent B: acetonitrile

Solvent C-properties-correcting agent 5%:4:3:3880 ammonia: acetonitrile: water

Flow velocity: 20 ml/min

Post diluting solvent: acetonitrile

Post dilution flow rate: 1.0 ml/min

Shift solvent: 1 milliliter of DMF+MeOH washing lotion of every pipe

LCMS: be settled to 1 milliliter by 50 μ l with MeCN

Analyze the LCMS method of using: Phenomenex Gemini 5 μ, C18 50 x 2mm, 1.2 ml/min

0 minute, 95:0:5A:B:C, 4 minutes, 0:95:5A:B:C

A:MeCN, B:H ₂O, C:1:1MeCN:H ₂O 1% propylhomoserin

Embodiment 13:

4-(benzenesulfonyl methyl)-6-morpholine-4-base-2-thiene-3-yl--pyrimidine

With 1 of 4-(benzenesulfonyl methyl)-2-methyl sulfenyl-6-morpholine-4-base-pyrimidine (183 milligrams), 3 thienylboronic acid (129.5 milligrams), thiophene-2-carboxylic acid copper (I) (248 milligrams) and tetrakis triphenylphosphine palladium (0) (47 milligrams), 4-diox (5 milliliters) suspension outgases with the dry nitrogen air-flow.With this suspension microwave reactor (Emrys Optimizer, Personal Chemistry, Sweden) in, 130 ℃ the heating 45 minutes.Use methyl alcohol then: the DCM1:9 diluted reaction mixture, at ' Isolute SCX-2 ' post (10g; International Sorbent Technology Limited, Mid Glamorgan UK) goes up this mixture of chromatogram purification, with 10 to the initial washing column of the gradient of 100% methyl alcohol/DCM, then uses methanol ammonia (7M): the mixture wash-out crude product of DCM 1:3.Evaporation methanol ammonia solution, be further purified resistates by HPLC, use Phenomenex ' Gemini ' preparation reversed-phase column (5 microns silica gel, 21.2mm diameter, 100mm length), the polarity mixture (containing 2% formic acid) decrescence that makes water and acetonitrile obtains title compound (87.3 milligrams) as elutriant.

The LCMS spectrum: MH+402.73, retention time: 1.96, method: acid detects

The NMR spectrum: ¹H NMR (300.132MHz, DMSO) δ 3.56-3.74 (m, 8H), 4.68 (s, 2H), 6.66 (s, 1H), 7.37 (dd, 1H), 7.50 (dd, 1H), 7.54-7.69 (m, 2H), 7.75 (tt, 1H), 7.78-7.84 (m, 2H), 7.90 (dd, 1H)

Starting raw material 4-(benzenesulfonyl methyl)-2-methyl sulfenyl-6-morpholine-4-base-pyrimidine is prepared as follows.

4-(benzenesulfonyl methyl)-2-methyl sulfenyl-6-morpholine-4-base-pyrimidine

With 6-(benzenesulfonyl methyl)-2-methyl sulfenyl-pyrimidine-4-alcohol (15.99 gram) and phosphorus oxychloride (87.4 milliliters) reflux 4 hours.Phosphorus oxychloride is removed in evaporation, and with aqueous sodium hydroxide solution resistates is adjusted to pH value 7.Crude product is extracted in the ethyl acetate, and the separating ethyl acetate layer is used dried over mgso.Evaporation removes and desolvates, and obtains crude product 4-(benzenesulfonyl methyl)-6-chloro-2-methyl sulfenyl-pyrimidine.It is dissolved among the DCM (100 milliliters), adds morpholine (23.6 milliliters).At room temperature stirred reaction mixture is 1 hour.Evaporation removes and desolvates, and resistates is dissolved among the DCM, and purifying on silica gel carries out wash-out with 0% to 20% methyl alcohol/DCM gradient, obtains title compound white solid (11.26 gram).

The LCMS spectrum: MH+366, retention time: 1.97, method: the alkali formula detects

The NMR spectrum: (DMSOd ₆2.14 (3H, s), 3.51-3.53 (4H, m), 3.64-3.66 (4H, m), 3.67 (1H, s), 4.57 (2H, s), 6.47 (1H, s), 7.61-7.65 (2H, m), 7.72-7.76 (1H, m), 7.77-7.80 (2H, m);

6-(benzenesulfonyl methyl)-2-methyl sulfenyl-pyrimidine-4-alcohol

6-(chloromethyl)-2-methyl sulfenyl-pyrimidine-4-alcohol (19.07 grams come from embodiment 1) is suspended in the acetonitrile (400 milliliters).In this suspension, add benzene sulfinic acid sodium salt (19.7 gram) and DMF (100 milliliters).With mixture heating up to 100 ℃, obtain dark-coloured suspension.Solvent removed in vacuo till near drying, adds the 1:1 mixture (200 milliliters) of methyl alcohol: DCM.Add acetic acid (10 milliliters) then, collect the precipitation that obtains, water (200 milliliters) and methyl alcohol (100 milliliters) washing.This material vacuum-drying is spent the night, obtain title compound white solid (19.55 gram).

The LCMS spectrum: MH+297, retention time: 0.72, method: the alkali formula detects

The NMR spectrum: (DMSOd ₆) 2.01 (s, 3H), 4.59 (s, 2H), 6.15 (s, 1H), 7.62 (t, 2H), 7.74 (tt, 1H), 7.81 (dd, 2H), 12.31-13.08 (m, 1H);

According to 4-(benzenesulfonyl methyl)-6-morpholine-similar mode of 4-base-2-thiene-3-yl--pyrimidine (embodiment 13), use suitable boric acid to prepare compound in the table 2.

Table 2:

Embodiment 15: ¹H NMR (300.132MHz, DMSO) δ 3.43-3.74 (m, 8H), 4.65 (s, 2H), 6.60 (d, 1H), 6.63 (s, 1H), 7.50-7.87 (m, 6H), 7.93 (s, 1H)

Embodiment 16: ¹H NMR (300.132MHz, DMSO) δ 3.61-3.78 (m, 8H), 4.77 (s, 2H), 6.75 (s, 1H), 7.30-7.43 (m, 2H), 7.56-7.75 (m, 3H), 7.81-7.88 (m, 2H), 8.00 (d, 1H), 8.33 (s, 1H), 8.56 (dd, 1H)

Embodiment 20: ¹(300.132MHz, DMSO) (s, 2H), (m, 8H), 4.57 (s, 2H), 6.47 (s, 1H), 7.62 (t, 2H), (m, 5H) .1xOH does not observe 7.70-7.83 3.45-3.71 δ 2.13 H NMR

Embodiment 21: ¹H NMR (300.132MHz, DMSO) δ 3.12-3.43 (m, 8H), 3.56-3.78 (m, 8H), 4.71 (s, 2H), 6.59-6.61 (m, 1H), 6.72 (s, 1H), 7.14 (t, 1H), 7.24 (d, 2H), 7.46-7.89 (m, 5H)

Embodiment 22: ¹H NMR (300.132MHz, DMSO) δ 3.58-3.77 (m, 8H), 3.80 (s, 3H), 4.72 (s, 2H), 6.48 (t, 1H), 6.67 (s, 1H), 7.34 (s, 1H), 7.36 (d, 1H), 7.57-7.69 (m, 3H), 7.69-7.89 (m, 4H)

Embodiment 26:

4-morpholine-4-base-6-(phenyl sulfenyl methyl)-2-pyridine-2-base-pyrimidine

At room temperature, in inert atmosphere, with sodium ethylate (49 milligrams, 0.72mmol) with the dosage mode join in batches phenylmercaptan (79.4 milligrams, in acetonitrile 0.72mmol) (2.5 milliliters) stirred solution.Stirred the mixture 30 minutes, then dropwise add 4-(chloromethyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine (174 milligrams, acetonitrile 0.60mmol) (2.5 milliliters) solution.Continue at room temperature and under nitrogen atmosphere to stir to spend the night, evaporate to dryness reaction mixture then, and between ethyl acetate and water, distribute resistates.The organism that merges with dried over mgso filters then, and evaporate to dryness obtains thick product.Prepare HPLC chromatogram purified product (gradient elution, 35-55%MeCN/ water) by the alkali formula, obtain needed product transparent colloid (94 milligrams, 43%).

The LCMS spectrum:The MH+365.5 retention time: 2.15, method: the alkali formula detects

The NMR spectrum: ¹H NMR (300.132MHz, DMSO) 3.67 (d, 8H), 4.22 (s, 2H), 6.83 (s, 1H), 7.20 (t, 1H), 7.32 (t, 2H), 7.42-7.50 (m, 3H), 7.91 (td, 1H), 8.25 (d, 1H), 8.70 (d, 1H)

Starting raw material 4-(chloromethyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine is prepared as follows:

4-(chloromethyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine

(14.07 grams 63.46mmol) are dissolved in the phosphorus oxychloride (50 milliliters) reflux one hour with 6-(chloromethyl)-2-pyridine-2-base-pyrimidine-4-alcohol.Evaporate phosphorus oxychloride then, and with toluene (100 milliliters) azeotropic.Add entry (100 milliliters), and mixture is adjusted to pH value 10 with sodium hydroxide.Use ethyl acetate (200 milliliters of 2 x) abstraction reaction mixture then,, use dried over mgso with salt solution (100 milliliters) washing.Evaporation obtains beige solid, 4-chloro-6-(chloromethyl)-2-pyridine-2-base-pyrimidine (3.563 gram).With 4-chloro-6-(chloromethyl)-2-pyridine-2-base-pyrimidine (3.563 grams, 14.84mmol), morpholine (1.295 grams, 14.84mmol) and DIPEA (5.745 restrain, and 44.52mmol) are dissolved among the THF (20 milliliters), and at room temperature stirring reaction is 2 hours.Add PS-isocyanate resin (5 gram) then, continue to stir 3 hours, then filter reaction mixture with the THF washing, is then used methanol wash.The organism that merges is evaporated on the silica gel, by the purified by flash chromatography product.With clean fraction evaporation, obtain needed product crystalline solid (2.7 gram).

The LCMS spectrum: MH+291.51, retention time: 1.69, method: acid detects.

The NMR spectrum: ¹HNMR (300.132MHz, DMSO) δ 3.75 (s, 8H), 4.68 (s, 2H), 7.02 (s, 1H), 7.49 (m, 1H), 7.92 (dt, 1H), 8.31 (d, 1H), 8.71 (d, 1H) ppm.

6-(chloromethyl)-2-pyridine-2-base-pyrimidine-4-alcohol

Sodium ethylate (3.6mmol, 245 milligrams) and 4-chloracetyl ritalin (3.3mmol, 498 milligrams) are joined in ethanol (10 milliliters) solution of 2-pyridyl amidine (3mmol, 364 milligrams), and reaction mixture is heated to backflow.After three hours, the vacuum concentration reaction mixture is used hcl acidifying, obtains the light beige solid of needed compound (445 milligrams).

The LCMS spectrum: MH+222.48, retention time: 0.76, method: the alkali formula detects

The NMR spectrum: ¹H NMR (300.132MHz, DMSO) δ 4.36 (d, 2H), 6.32 (s, 1H), 7.65 (ddd, 1H), 8.04 (td, 1H), 8.28 (d, 1H), 8.74 (d, 1H), 11.17-12.28 (m, 1H) ppm.

According to 4-morpholine-4-base-6-(phenyl sulfenyl methyl)-similar mode of 2-pyridine-2-base-pyrimidine (embodiment 26), react the compound in the preparation table 3 by suitable starting raw material and 4-(chloromethyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine.

Table 3:

Embodiment 31: ¹H NMR (400.132MHz, DMSO) δ 1.32 (s, 9H), 3.65 (s, 8H), 3.72 (s, 2H), 6.83 (s, 1H), 7.41 (ddd, 1H), 7.85 (td, 1H), 8.23 (dt, 1H), 8.64 (ddd, 1H)

Embodiment 39: ¹H NMR (400.132MHz, DMSO) δ 2.75-2.84 (m, 4H), 3.65 (s, 8H), 3.69 (s, 2H), 6.80 (s, 1H), 7.10-7.20 (m, 5H), 7.42 (ddd, 1H), 7.85 (td, 1H), 8.24 (dt, 1H), 8.65 (ddd, 1H)

Embodiment 44:

4-(benzenesulfonyl methyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine

At room temperature, will

(110 milligrams, 0.18mmol) aqueous solution (2.5 milliliters) joins (46.5 milligrams of 4-morpholine-4-base-6-(phenyl sulfenyl methyl)-2-pyridine-2-base-pyrimidine (embodiment 26), 0.13mmol) ethanol (2.5 milliliters) stirred solution in, and at room temperature continue to stir 3 hours.Add entry (5 milliliters) then, extract organism with DCM (10 milliliters of 3 x).With the organism that the salt water washing merges, use dried over mgso, filter, evaporate to dryness obtains thick product, prepares the HPLC chromatogram by the alkali formula and is purified (gradient elution, 25-45% MeCN/ water), obtains needed product pale solid (28.4 milligrams, 55%).

The LCMS spectrum:The MH+397.53 retention time: 1.70, method: the alkali formula detects

The NMR spectrum: ¹H NMR (300.132MHz, DMSO) δ 3.65-3.70 (m, 8H), 4.74 (s, 2H), 6.77 (s, 1H), 7.42-7.47 (m, 1H), 7.60-7.65 (m, 2H), 7.72-7.77 (m, 1H), 7.80-7.86 (m, 4H), 8.66 (ddd, 1H)

According to 4-(benzenesulfonyl methyl)-6-morpholine-4-base-similar mode of 2-pyridine-2-base-pyrimidine (embodiment 44), use the suitable starting raw material of table 3, the compound that preparation is shown in Table 4.If starting raw material is shown in the table 3, then it is according to the mode similar to embodiment 26, by preparing with suitable reactant replacement sulfur phenol.

Table 4:

Embodiment 45: ¹H NMR (500.133MHz, DMSO) δ 3.74 (s, 8H), 4.53 (s, 2H), 4.97 (s, 2H), 6.53 (d, 1H), 6.75 (d, 1H), 6.99 (s, 1H), 7.50 (m, 1H), 7.74 (s, 1H), 7.95 (td, 1H), 8.35 (d, 1H), 8.73 (d, 1H)

Embodiment 46: ¹H NMR (500.133MHz, DMSO) δ 3.62 (m, 8H), 3.76 (s, 3H), 4.58 (s, 2H), 6.68 (s, 1H), 7.04 (d, 2H), 7.38 (m, 1H), 7.66 (d, 2H), 7.74 (t, 1H), 7.80 (d, 1H), 8.60 (d, 1H)

Embodiment 47: ¹H NMR (500.133MHz, DMSO) δ 1.01 (t, 3H), 1.34 (d, 3H), 1.50 (m, 1H), 2.10 (m, 1H), 3.45 (m, 1H), 3.73 (s, 8H), 4.52 (s, 2H), 6.98 (s, 1H), 7.50 (m, 1H), 7.93 (td, 1H), 8.29 (d, 1H), 8.72 (d, 1H)

Embodiment 48: ¹H NMR (500.133MHz, DMSO) δ 1.00 (d, 6H), 2.20-2.27 (m, 1H), 3.32 (d, 2H), 3.66 (s, 8H), 4.43 (s, 2H), 6.91 (s, 1H), 7.42 (ddd, 1H), 7.87 (td, 1H), 8.23 (dt, 1H), 8.64 (ddd, 1H)

Embodiment 53: ¹H NMR (500.133MHz, DMSO) δ 3.39-3.42 (m, 2H), 3.74 (s, 8H), 3.90-3.93 (m, 2H), 4.64 (s, 2H), 7.02 (s, 1H), 7.49 (ddd, 1H), 7.90 (td, 1H), 8.53 (d, 1H), 8.59 (dd, 1H), 8.32 (dt, 1H), 8.66 (ddd, 1H), 8.76 (d, 1H)

Embodiment 54: ¹H NMR (500.133MHz, DMSO) δ 3.67 (s, 8H), 4.41 (s, 2H), 5.05 (s, 2H), 6.91 (s, 1H), 7.03 (dd, 1H), 7.35 (d, 1H), 7.42-7.45 (m, 1H), 7.53 (dd, 1H), 7.89 (td, 1H), 8.29 (d, 1H), 8.66-8.67 (m, 1H)

Embodiment 55: ¹H NMR (500.133MHz, DMSO) δ 1.08-1.40 (m, 6H), 1.78 (d, 2H), 2.16 (d, 2H), 3.42-3.47 (m, 1H), 3.66 (s, 8H), 4.41 (s, 2H), 6.90 (s, 1H), 7.43 (ddd, 1H), 7.88 (td, 1H), 8.23 (dt, 1H), 8.65 (ddd, 1H)

Embodiment 57: ¹H NMR (500.133MHz, DMSO) δ 1.32 (t, 3H), 3.35 (q, 2H), 3.73 (s, 8H), 4.51 (s, 2H), 6.98 (s, 1H), 7.49 (ddd, 1H), 7.94 (td, 1H), 8.29 (d, 1H), 8.72 (d, 1H)

Embodiment 68:

4-[(3-methoxyl group phenoxy group) methyl]-6-morpholine-4-base-2-pyridine-2-base-pyrimidine

At room temperature, with sodium hydride (18 milligrams 0.45mmol) join 3-methoxyphenol (56 milligrams in DMF 0.45mmol) (2 milliliters) stirred solution, and are continued to stir 30 minutes.DMF (1 milliliter) solution that promptly dropwise adds 4-(chloromethyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine (87 milligrams, 0.30mmol comes from embodiment 26) then then adds the sodium iodide of catalytic quantity.Stirred reaction mixture 5 minutes at room temperature then is warming up to 70 ℃ then, keeps 1.5 hours.After the evaporate to dryness, between ethyl acetate and water, distribute resistates, with the organism of dried over mgso merging, filter, reduction vaporization obtains thick product, thick product is prepared the HPLC chromatogram by the alkali formula carry out purifying, obtain needed product glassy yellow colloid (69 milligrams, 61%).

The LCMS spectrum:The MH+379.6 retention time: 2.20, method: the alkali formula detects

The NMR spectrum: ¹H NMR (300.132MHz, DMSO) δ 3.72 (s, 8H), 3.75 (s, 3H), 5.08 (s, 2H), 6.57 (m, 1H), 6.67 (m, 2H), 6.94 (s, 1H), 7.22 (t, 1H), 7.49 (ddd, 1H), 7.93 (td, 1H), 8.32 (d, 1H), 8.71 (d, 1H)

According to 4-[(3-methoxyl group phenoxy group) methyl]-6-morpholine-4-base-similar mode of 2-pyridine-2-base-pyrimidine (embodiment 68), by suitable starting raw material and 4-(chloromethyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine (coming from embodiment 26) reaction, compound shown in the preparation table 5.

Table 5:

Embodiment 69: ¹H NMR (300.132MHz, DMSO) δ 3.75 (s, 8H), 5.12 (s, 2H), 6.94 (s, 1H), 6.98 (t, 1H), 7.09 (d, 2H), 7.33 (t, 2H), 7.49 (m, 1H), 7.93 (dt, 1H), 8.32 (d, 1H), 8.71 (d, 1H),

Embodiment 70: ¹H NMR (300.132MHz, DMSO) δ 3.75 (s, 8H), 4.56 (s, 2H), 4.69 (s, 2H), 6.84 (s, 1H), 7.29-7.50 (m, 6H), 7.91 (dt, 1H), 8.29 (d, 1H), 8.69 (d, 1H),

Embodiment 71: ¹H NMR (300.132MHz, DMSO) δ 1.22 (t, 3H), 3.62 (q, 2H), 3.75 (s, 8H), 4.50 (s, 2H), 6.80 (s, 1H), 7.47 (m, 1H), 7.91 (dt, 1H), 8.29 (d, 1H), 8.69 (d, 1H),

Embodiment 72: ¹H NMR (300.132MHz, DMSO) δ 3.76 (s, 8H), 5.23 (s, 2H), 6.97 (s, 1H), 7.01 (dt, 1H), 7.32 (m, 2H), 7.49 (m, 2H), 7.93 (dt, 1H), 8.32 (d, 1H), 8.71 (d, 1H),

Embodiment 73: ¹H NMR (300.132MHz, DMSO) δ 3.77 (s, 8H), 5.16 (s, 2H), 6.97 (s, 1H), 7.07 (dt, 2H), 7.23 (t, 1H), 7.35 (t, 1H), 7.49 (m, 1H), 7.93 (dt, 1H), 8.32 (d, 1H), 8.71 (d, 1H),

Embodiment 74: ¹H NMR (300.132MHz, DMSO) δ 3.72 (s, 8H), 3.75 (s, 3H), 5.08 (s, 2H), 6.57 (m, 1H), 6.67 (m, 2H), 6.94 (s, 1H), 7.22 (t, 1H), 7.49 (ddd, 1H), 7.93 (td, 1H), 8.32 (d, 1H), 8.71 (d, 1H)

Embodiment 75: ¹H NMR (300.132MHz, DMSO) δ 3.72 (s, 11H), 5.04 (s, 2H), 6.96 (d, 5H), 7.49 (m, 1H), 7.93 (td, 1H), 8.32 (d, 1H), 8.71 (d, 1H)

Embodiment 80:

N-benzyl-N-methyl isophthalic acid-(6-morpholine-4-base-2-pyridine-2-base-pyrimidine-4-yl) methylamine

With (25 milligrams of N-methylbenzylamines, 0.2mmol) and (52 milligrams of DIPEA, 0.4mmol) join (60 milligrams of 4-(chloromethyl)-6-morpholine-4-base-2-pyridines-2-base-pyrimidine, 0.2mmol, come from embodiment 26) DMF (4 milliliters) solution in, and reaction mixture is heated to 150 ℃ in microwave, kept 20 minutes.After the cooling, by preparation HPLC direct purification product (5-40%MeCN/H ₂O), evaporation obtains needed compound colloid (25.3 milligrams).

The LCMS spectrum: MH+376.70, retention time: 2.14, method: the alkali formula detects

The NMR spectrum: ¹H NMR (300.132MHz, DMSO) δ 2.22 (s, 3H), 3.58 (s, 2H), 3.62 (s, 2H), 3.65-3.77 (m, 8H), 6.89 (s, 1H), 7.23-7.28 (m, 1H), 7.33 (d, 2H), 7.39 (t, 2H), 7.46 (dd, 1H), 7.91 (td, 1H), 8.30 (d, 1H), 8.70 (d, 1H)

Embodiment 81:

N-[(6-morpholine-4-base-2-pyridine-2-base-pyrimidine-4-yl) methyl] third-2-amine

With (25 milligrams of Isopropylamines, 0.4mmol) and (52 milligrams of DIPEA, 0.4mmol) join (60 milligrams of 4-(chloromethyl)-6-morpholine-4-base-2-pyridines-2-base-pyrimidine, 0.2mmol, come from embodiment 26) DMF (4 milliliters) solution in, and reaction mixture is heated to 150 ℃ in microwave, kept 20 minutes.After the cooling, by preparation HPLC direct purification product (5-40% MeCN/H ₂O), evaporation obtains needed compound colloid (32.6 milligrams).

The LCMS spectrum: MH+314.64, retention time: 1.71, method: the alkali formula detects

The NMR spectrum: ¹H NMR (300.132 MHz, DMSO) δ 1.03 (s, 3H), 1.05 (s, 3H), 2.77 (septet, 1H), 3.31 (s, 2H), 3.71 (s, 8H), 6.88 (s, 1H), 7.46 (ddd, 1H), 7.90 (td, 1H), 8.31 (d, 1H), 8.69 (dd, 1H), 1x NH does not observe.

According to N-[(6-morpholine-4-base-2-pyridine-2-base-pyrimidine-4-yl) methyl] the similar mode of third-2-amine (embodiment 81), use 4-(chloromethyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine (deriving from embodiment 26) and suitable amine, compound shown in the preparation table 6.

Table 6:

Embodiment 83:

4-(benzenesulfonyl methyl)-5-fluoro-6-morpholine-4-base-2-pyridine-2-base-pyrimidine

With benzene sulfinic acid sodium salt (32 milligrams, 0.19mmol) join 4-(chloromethyl)-5-fluoro-6-morpholine-4-base-2-pyridine-2-base-pyrimidine (50 milligrams, in dry DMF stirred solution 0.16mmol).With mixture heating up to 80 ℃, kept 1 hour, then concentrate.Utilize the purified by flash chromatography resistates,, obtain 4-(benzenesulfonyl methyl)-5-fluoro-6-morpholine-4-base-2-pyridine-2-base-pyrimidine white solid (47.6 milligrams, 72%) with 0-10% MeOH/DCM wash-out

The LCMS spectrum: MH+415.41, retention time: 1.44, method: acid detects

The NMR spectrum: ¹H NMR (300.132MHz, DMSO) δ 3.72-3.84 (m, 8H), 4.88 (d, 2H), 7.48-7.54 (m, 1H), 7.63-7.73 (m, 2H), 7.77-7.93 (m, 5H), 8.72 (d, 1H)

Embodiment 84:

5-fluoro-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine

Use and be used for embodiment 83 and prepare 4-(benzenesulfonyl methyl)-5-fluoro-6-morpholine-4-base-2-pyridine-2-base-pyrimidine similar methods; use (20 milligrams of methyl-sulfinic acid sodium salts; 0.19mmol); prepare this compound; obtain 5-fluoro-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine white solid (20.5 milligrams, 36%).

The LCMS spectrum: MH+353.52, retention time: 0.90, method: acid detects.

The NMR spectrum: ¹H NMR (300.132MHz, DMSO) δ 3.25 (s, 3H), 3.72-3.79 (m, 4H), 3.81-3.87 (m, 4H), 4.68 (s, 2H), 7.47-7.53 (m, 1H), 7.90-7.98 (m, 1H), 8.27 (d, 1H), 8.71 (d, 1H)

Starting raw material 4-(chloromethyl)-5-fluoro-6-morpholine-4-base-2-pyridine-2-base-pyrimidine is prepared as follows:

4-(chloromethyl)-5-fluoro-6-morpholine-4-base-2-pyridine-2-base-pyrimidine

With Selectfluor ^TM(1.35 grams 3.78mmol) join in methyl alcohol (25 milliliters) solution of 4-(chloromethyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine (1 gram, 3.44mmol comes from embodiment 26), 50 ℃ of heating 16 hours.Saturated sodium bicarbonate (5 milliliters) is joined in the reaction mixture, and vacuum is removed methyl alcohol.Water (50 milliliters) is joined in the aqueous residue, and, wash drying with water with the sedimentation and filtration that obtains.With its chromatogram purification, use eluent ethyl acetate, obtain 4-(chloromethyl)-5-fluoro-6-morpholine-4-base-2-pyridine-2-base-pyrimidine white solid (210 milligrams, 20%).

The LCMS spectrum: MH+309.35, retention time: 1.34, method: acid detects.

The NMR spectrum: ¹H NMR (300.132MHz, DMSO) δ 3.71-3.79 (m, 4H), 3.80-3.87 (m, 4H), 4.75 (d, 2H), 7.46-7.52 (m1H), 7.89-7.97 (m, 1H), 8.27 (d, H), 8.71 (d, 1H)

Embodiment 85:

6-morpholine-4-base-N-phenyl-2-pyridine-2-base-pyrimidine-4-methane amide

With (114 milligrams of DIPEA, 0.88mmol), (168 milligrams of HATU, 0.44mmol) and (41 milligrams of aniline, 0.44mmol) join (115 milligrams of 6-morpholine-4-base-2-pyridine-2-base-pyrimidines-4-carboxylic acid, 0.4mmol) THF (4 milliliters) solution in, at room temperature stirring reaction is 2 hours, then adds entry.Filter and collect the precipitation that obtains, vacuum-drying obtains title compound white solid (87 milligrams).

The LCMS spectrum: MH+362.51, retention time: 2.39, method: the alkali formula detects

The NMR spectrum: ¹H NMR (300.132MHz, DMSO) δ 3.70-3.91 (m, 8H), 7.18 (t, 1H), 7.39-7.44 (m, 3H), 7.55 (ddd, 1H), 7.87 (d, 2H), 7.99 (td, 1H), 8.66 (d, 1H), 8.77 (d, 1H), 10.48 (s, 1H) ppm.

Embodiment 86:

N, N-dimethyl-6-morpholine-4-base-2-pyridine-2-base-pyrimidine-4-methane amide

According to be used for embodiment 85 preparation 6-morpholine-4-base-N-phenyl-2-pyridine-2-base-pyrimidine-similar modes of 4-methane amide, use 6-morpholine-4-base-2-pyridine-2-base-pyrimidine-4-formic acid, prepare this compound.

The LCMS spectrum: MH+314.45, retention time: 1.26, method: the alkali formula detects

The NMR spectrum: ¹H NMR (300.132MHz, DMSO) δ 2.97 (s, 3H), 3.01 (s, 3H), 3.72 (s, 8H), 6.93 (s, 1H), 7.50 (ddd, 1H), 7.93 (td, 1H), 8.31 (d, 1H), 8.71 (d, 1H).

Starting raw material 6-morpholine-4-base-2-pyridine-2-base-pyrimidine-4-formic acid is prepared as follows.

6-morpholine-4-base-2-pyridine-2-base-pyrimidine-4-formic acid

(5 grams 29.41mmol) are suspended in the phosphorus oxychloride (50 milliliters), and mixture heating up is extremely refluxed, and keep 4 hours with the vitamin B13 methyl esters.After this, excessive phosphorus oxychloride is removed in decompression.The black residue that obtains is poured on ice, and violent stirring makes solution keep stirring, till all ice-outs simultaneously.Filter then and collect thick product, extract filtrate with ether (x2).Filtration product is joined in the ether washing lotion, use dried over mgso.Concentrated solution obtains 2 then, and (when leaving standstill, it solidifies 6-dichloro pyrimidine-4-methyl-formiate for 5.25 grams, 25.37mmol) yellow oil.(2.005 grams 25.37mmol) and THF (40 milliliters), and were at room temperature placed mixture 2 hours to wherein adding morpholine.Evaporate to dryness reaction then, (5.41 restrain, 21mmol) to obtain 2-chloro-6-morpholine-4-base-pyrimidine-4-methyl-formiate

The LCMS spectrum: MH+258.39, retention time: 1.56, method: the alkali formula detects

With 2-chloro-6-morpholine-4-base-pyrimidine-4-methyl-formiate (2.58 grams, 10mmol), 2-tributyl stannyl pyridine (4.055 grams, 11mmol) and tetrakis triphenylphosphine palladium (O) (10mol%, 1mmol, 1.116 gram) be suspended among the THF (20 milliliters), and in microwave, be heated to 100 ℃, kept 30 minutes.In this mixture, add sodium hydroxide (20 milliliters) (4M is in water), stirring reaction 1 hour.Filter and collect the precipitation that obtains, find that it is a sodium salt (1.53 gram) of 6-morpholine-4-base-2-pyridine-2-base-pyrimidine-4-formic acid.

The LCMS spectrum: (M+Na)+308.47, retention time: 1.42, method: the alkali formula detects

The NMR spectrum: ¹H NMR (300.132MHz, D ₂O) δ 3.70-3.86 (m, 8H), 7.11 (s, 1H), 7.51 (ddd, 1H), 7.94 (td, 1H), 8.28 (d, 1H), 8.60 (d, 1H) ppm.

Embodiment 87:

5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-1, the 3-Indolin-2-one

2-chloro-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine (120 milligrams) is dissolved in solvent mixture, and (18%DMF is at 7:3:2DME: water: in the ethanol) in (7 milliliters).Then with 5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycles penta-2-yl)-1, two (triphenylphosphine) palladiums (40 milligrams) of 3-Indolin-2-one (303 milligrams), 2M sodium carbonate solution (2 milliliters) and dichloro join in the solution, in microwave reactor, 100 ℃ of heated mixt 30 minutes.Reaction mixture is loaded on the SCX-2 post (10 gram), uses methanol wash, remove with 7N ammonia/methyl alcohol.The vacuum concentration material by preparation HPLC (alkali formula) purifying, obtains desired material white solid (18 milligrams).

Mass spectrumMH ⁺389.

The NMR spectrum: ¹H NMR (DMSO-d ₆) δ 3.20 (3H, s), 3.57 (2H, s), 3.71-3.73 (8H, m), 4.48 (2H, s), 6.82 (1H, s), 6.91 (1H, d), 8.20 (1H, s), 8.23-8.25 (1H, m), 10.55 (1H, s)

5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycles penta-2-yl)-1, the preparation of 3-Indolin-2-one is described below:

5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycles penta-2-yl)-1, the 3-Indolin-2-one

With 5-bromo-2, DMF (20 milliliters) mixture of 3-Indolin-2-one (500 milligrams), two (valeryls), two boron (899 milligrams) and potassium acetate (695 milligrams) degassing 5 minutes.1,1 '-two (diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (78 milligrams) is joined in the mixture, reaction is heated to 80 ℃, keep stirring 3 hours.By diatomite filtration reaction mixture, vacuum concentration.Resistates is suspended in the water (50 milliliters), extracts with ethyl acetate (50 milliliters of 2 x).Dry (MgSO ₄) organism, filtering, vacuum concentration obtains desired material brown solid (611 milligrams).

Mass spectrumM+H+MeCN ⁺301.

The NMR spectrum: ¹H NMR (DMSO-d ₆) δ 1.28 (12H, s), 3.47 (2H, s), 6.82-6.84 (1H, d), 7.51 (2H, m), 10.52 (1H, s)

The preparation of 2-chloro-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine is described below:

2-chloro-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine

With 2, DCM (230 milliliters) the suspension magnetic agitation of 4-two chloro-6-(sulfonyloxy methyl ylmethyl) pyrimidine (10.56 gram) is cooled to-5 ℃.Add triethylamine (6.78 milliliters), then dropwise add DCM (30 milliliters) solution of morpholine (3.85 milliliters), keep temperature of reaction to be lower than-5 ℃.At room temperature stirring reaction is 1 hour, the organic mixture of water (300 milliliters) washing then.Dry (MgSO ₄) organic phase, filter, be evaporated to brown solid, with its chromatographic separation on silica gel,, obtain desired material (6.81 gram) white solid with 50% ethyl acetate/DCM wash-out.

Mass spectrum: MH+292.

The NMR spectrum: ¹H NMR (DMSO-d ₆) δ 3.12 (3H, s), 3.63 (4H, s), 3.68-3.70 (4H, m), 4.45 (2H, s), 6.96 (1H, s)

2,4-two chloro-6-(sulfonyloxy methyl ylmethyl) pyrimidine

With 6-(sulfonyloxy methyl ylmethyl)-1H-pyrimidine-2,4-diketone (12.72 gram) is suspended in the phosphorus oxychloride (125 milliliters), and reflux is 14 hours in nitrogen atmosphere.Cooling solution, vacuum concentration.Frozen water (250 milliliters) is joined in the resistates at leisure, use DCM (200 milliliters of 3 x) to extract product then.The vacuum concentration organism obtains desired material brown solid (10.56 gram).

Mass spectrum: (M-H) ^-239.

The NMR spectrum: ¹H NMR (DMSO-d ₆) δ 3.14 (3H, s), 4.79 (2H, s), 7.88 (1H, s) 6-(sulfonyloxy methyl ylmethyl)-1H-pyrimidine-2,4-diketone

6-(chloromethyl) uridylic (10.00 gram) is dissolved among the DMF (300 milliliters), adds methyl-sulfinic acid sodium salt (7.64 gram).To be reflected at 125 ℃ of heating 1 hour.The cooling reaction is filtered, and vacuum concentrated filtrate obtains desired material yellow solid (12.72 gram).

The NMR spectrum: ¹H NMR (DMSO-d ₆) δ 3.10 (3H, s), 4.27 (2H, s), 5.63 (1H, s), 10.94 (1H, s), 11.16 (1H, s).

Embodiment 88:

2-amino-5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] methyl benzoate

1, the mixture in the 4-diox (10 milliliters) outgased 5 minutes with methyl-2-amino-5-bromo-benzoate (250 milligrams), potassium acetate (320 milligrams) and two (valeryls), two boron (332 milligrams).Add 1,1 '-two (diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (54 milligrams), reaction is heated to 80 ℃, kept 2.5 hours.Add 2-chloro-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine (381 milligrams), ethanol (0.75 milliliter), 2M sodium carbonate solution (2.7 milliliters) and extra 1; 1 '-two (diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (54 milligrams), and continue other 3.5 hours of heating.The refrigerative reaction mixture is seated on the SCX-2 (10 gram), removes vacuum concentrated solution with 7N ammonia/methyl alcohol.Chromatographic separation resistates on silica gel with 50% ethyl acetate/DCM wash-out, obtains desired material yellow solid (82 milligrams).

Mass spectrumMH+407

The NMR spectrum: ¹H NMR (DMSO-d ₆) δ 3.22 (3H, s), 3.69 (4H, s), 3.73 (4H, s), 3.84 (3H, s), 4.49 (2H, s), 6.77 (1H, s), 6.87 (1H, d), 7.05 (2H, s), 8.24 (1H, d), 8.79 (1H, s)

Embodiment 89:

[2-methoxyl group-5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] methyl alcohol

1, the mixture in the 4-diox (10 milliliters) outgased 5 minutes with 5-bromo-2-anisole methyl alcohol (250 milligrams), potassium acetate (339 milligrams) and two (valeryls), two boron (352 milligrams).Add 1,1 '-two (diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (57 milligrams), reaction is heated to 80 ℃, kept 3 hours.Add 2-chloro-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine (337 milligrams), ethanol (0.75 milliliter), 2M sodium carbonate solution (2.7 milliliters) and extra 1; 1 '-two (diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (57 milligrams), and continue other 66 hours of heating.Reaction mixture, vacuum concentration.Resistates is distributed between ethyl acetate (50 milliliters) and water (50 milliliters), filter.Dry (MgSO ₄) organic phase, vacuum concentration, chromatographic separation on silica gel is with 5% methyl alcohol/DCM wash-out.Repeat chromatographic separation, use the ether grinding residues, obtain needed compound white solid (158 milligrams).

Mass spectrumMH+394

The NMR spectrum: ¹H NMR (DMSO-d ₆) δ 3.23 (3H, s), 3.73-3.74 (8H, m), 3.84 (3H, d), 4.51 (2H, s), 4.54 (2H, d), 5.08 (1H, t), 6.83 (1H, s), 7.00-7.06 (1H, m), 8.23-8.26 (1H, m), 8.41 (1H, d)

Embodiment 90:

2-methyl-5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-benzoglyoxaline

1, the mixture in the 4-diox (10 milliliters) outgased 5 minutes with 5-bromo-2-methyl isophthalic acid H-benzoglyoxaline (250 milligrams), potassium acetate (349 milligrams) and two (valeryls), two boron (362 milligrams).Add 1,1 '-two (diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (59 milligrams), reaction is heated to 80 ℃, kept 18 hours.Add 2-chloro-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine (346 milligrams), ethanol (0.75 milliliter), 2M sodium carbonate solution (2.7 milliliters) and extra 1; 1 '-two (diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (59 milligrams), and continue other 3 hours of heating.With refrigerative reaction mixture vacuum concentration, be dissolved in the methyl alcohol, be loaded on the SCX-2 post (10 gram).Use the methanol wash post, remove compound with 7N ammonia/methyl alcohol.Vacuum concentrated solution by preparation HPLC (alkali formula) chromatographic separation resistates, obtains needed compound gray solid (5 milligrams).

Mass spectrumMH+388.

The preparation of 5-bromo-2-methyl isophthalic acid H-benzoglyoxaline is described below:

5-bromo-2-methyl isophthalic acid H-benzoglyoxaline

With 4-bromobenzene-1,2-diamines (1 gram) is dissolved in the phosphorus oxychloride (10 milliliters).At room temperature, acetic acid (0.297 milliliter) is joined in the mixture.Reaction is heated to 95 ℃ then, kept 2 hours.The cooling reaction, vacuum is removed excessive phosphorus oxychloride.To react the water cancellation, evaporate to dryness.Resistates is dissolved in the methyl alcohol, is loaded on the SCX-2 post (20 gram), remove compound with 7N ammonia/methyl alcohol.Vacuum concentrated solution, chromatographic separation on silica gel with 5% methyl alcohol/DCM wash-out, obtains desired material (731 milligrams) white solid.

Mass spectrum: MH+213

The NMR spectrum: ¹H NMR (DMSO-d ₆) δ 2.62 (3H, s), 7.31-7.34 (1H, m), 7.39 (1H, d), 7.67 (1H, s)

Embodiment 91:

5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-1,3-dihydrobenzo imidazoles-2-ketone

With 5-bromo-1,3-dihydrobenzo imidazoles-2-ketone (250 milligrams), potassium acetate (346 milligrams) and two (valeryls), two boron (358 milligrams) are 1, and the mixture in the 4-diox (10 milliliters) outgased 5 minutes.Add 1,1 '-two (diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (58 milligrams), reaction is heated to 80 ℃, kept 3 hours.Add 2-chloro-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine (343 milligrams), ethanol (0.75 milliliter), 2M sodium carbonate solution (2.7 milliliters) and extra 1; 1 '-two (diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (58 milligrams), and continue other 18 hours of heating.With refrigerative reaction mixture vacuum concentration, be dissolved in the methyl alcohol, be loaded on the SCX-2 post (10 gram).Use the methanol wash post, remove compound with 7N ammonia/methyl alcohol.Vacuum concentrated solution by preparation HPLC (alkali formula) chromatographic separation resistates, obtains needed compound white solid (26 milligrams).

Mass spectrumMH+390

The NMR spectrum: ¹H NMR (DMSO-d ₆) δ 3.21 (3H, s), 3.72 (8H, t), 4.50 (2H, s), 6.83 (1H, s), 7.01 (1H, d), 7.93 (1H, d), 8.04-8.07 (1H, m), 10.68 (1H, s), 10.81 (1H, s)

5-bromo-1, the preparation of 3-dihydrobenzo imidazoles-2-ketone is described below:

5-bromo-1,3-dihydrobenzo imidazoles-2-ketone

With 4-bromobenzene-1,2-diamines (1 gram) is dissolved in DCM (15 milliliters) and the triethylamine (1.50 milliliters).At 0 ℃, phosgene solution (5.3 milliliters) is joined in the solution at leisure.Reaction is warming up to room temperature, at room temperature stirred 2 hours.Water (2 milliliters) cancellation reaction, evaporate to dryness then.Chromatographic separation resistates on silica gel with 5% methyl alcohol/DCM wash-out, obtains desired material (657 milligrams) white solid.

Mass spectrum: MH+213

The NMR spectrum: ¹H NMR (DMSO-d ₆) δ 6.88 (1H, d), 7.06-7.10 (2H, m), 10.74 (2H, s)

Embodiment 92:

[5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-1H-indazole-3-yl] methyl alcohol

1, the mixture in the 4-diox (5 milliliters) outgased 5 minutes with (5-bromo-1H-indazole-3-yl) methyl alcohol (90 milligrams), potassium acetate (117 milligrams) and two (valeryls), two boron (121 milligrams).Add 1,1 '-two (diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (20 milligrams), reaction is heated to 80 ℃, kept 2.5 hours.Add 2-chloro-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine (116 milligrams), ethanol (0.4 milliliter), 2M sodium carbonate solution (1.3 milliliters) and extra 1; 1 '-two (diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (20 milligrams), and continue other 3 hours of heating.With refrigerative reaction mixture vacuum concentration, be dissolved in the methyl alcohol, be loaded on the SCX-2 post (20 gram).Use the methanol wash post, remove compound with 7N ammonia/methyl alcohol.Vacuum concentrated solution, chromatographic separation resistates on silica gel with 0-5% methyl alcohol/DCM wash-out, obtains desired material (37 milligrams) white solid.

Mass spectrumMH+404

The NMR spectrum: ¹H NMR (DMSO-d ₆) δ 3.24 (3H, s), 3.76 (8H, s), 4.51-4.54 (2H, m), 4.84 (2H, d), 5.29 (1H, t), 6.87 (1H, s), 7.50-7.59 (1H, m), 8.39-8.42 (1H, m), 8.88 (1H, s), 12.93 (1H, s)

The preparation of (5-bromo-1H-indazole-3-yl) methyl alcohol is described below:

(5-bromo-1H-indazole-3-yl) methyl alcohol

At 0 ℃, portioning adds sodium borohydride (337 milligrams) in the methyl alcohol (10 milliliters) of 5-bromo-1H-indazole-3-formaldehyde (500 milligrams) and water (1 milliliter) stirred solution.Reaction is warming up to room temperature, keeps stirring 1 hour.Water cancellation reaction is loaded on SCX-2 (10 gram) post.Use the methanol wash post, remove product with 7N ammonia/methyl alcohol.Vacuum concentrated solution, chromatographic separation resistates on silica gel with 0-5% methyl alcohol/DCM wash-out, obtains desired material (90 milligrams) white solid.

Mass spectrum: (M-H) ^-224

The NMR spectrum: ¹H NMR (DMSO-d ₆) δ 4.78 (2H, d), 5.26 (1H, t), 7.43-7.46 (1H, m), 7.47-7.50 (1H, m), 8.07 (1H, d), 12.97 (1H, s)

Embodiment 93:

6-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] chroman-4-alcohol

1, the mixture in the 4-diox (10 milliliters) outgased 5 minutes with 6-bromine chroman-4-alcohol (250 milligrams), potassium acetate (321 milligrams) and two (valeryls), two boron (333 milligrams).Add 1,1 '-two (diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (54 milligrams), reaction is heated to 80 ℃, kept 2.5 hours.Add 2-chloro-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine (319 milligrams), ethanol (0.75 milliliter), 2M sodium carbonate solution (2.7 milliliters) and extra 1; 1 '-two (diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (54 milligrams), and continue other 3 hours of heating.With refrigerative reaction mixture vacuum concentration, be dissolved in the methyl alcohol, be loaded on the SCX-2 post (20 gram).Use the methanol wash post, remove compound with 7N ammonia/methyl alcohol.Vacuum concentrated solution, chromatographic separation resistates on silica gel with 5% methyl alcohol/DCM wash-out, obtains desired material (113 milligrams) white solid.

Mass spectrumMH+406

The NMR spectrum: ¹H NMR (DMSO-d ₆) δ 1.90-1.94 (1H, m), 2.03-2.05 (1H, m), 3.21 (3H, s), 3.68-3.74 (8H, d), 4.25 (2H, d), 4.50 (2H, s), 4.70 (1H, q), 5.46 (1H, d), 6.83 (1H, d), 6.86 (1H, s), 8.14-8.16 (1H, m), 8.34 (1H, d)

Embodiment 94:

1-ethanoyl-5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-2H-indoles-3-ketone

1, the mixture in the 4-diox (10 milliliters) outgased 5 minutes with 1-ethanoyl-5-bromo-1H-indoles-3-alcohol (250 milligrams), potassium acetate (290 milligrams) and two (valeryls), two boron (300 milligrams).Add 1,1 '-two (diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (49 milligrams), reaction is heated to 80 ℃, kept 3 hours.Add 2-chloro-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine (288 milligrams), ethanol (0.75 milliliter), 2M sodium carbonate solution (2.7 milliliters) and extra 1; 1 '-two (diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (54 milligrams), and continue other 2.5 hours of heating.Vacuum concentration refrigerative reaction mixture, chromatographic separation resistates on silica gel with 5% methyl alcohol/DCM wash-out, obtains desired material (87 milligrams) white solid.

Mass spectrumMH+431

The NMR spectrum: ¹H NMR (DMSO-d ₆) δ 2.30 (3H, s), 3.21 (3H, s), 3.75 (8H, s), 4.54 (2H, s), 4.66 (2H, s), 6.92 (1H, s), 8.58-8.58 (2H, m), 8.71-8.74 (1H, m)

Embodiment 95:

1-methyl-4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] piperazine-2-ketone

In microwave reactor, at 160 ℃, with 2-chloro-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine (200 milligrams), 1-methylpiperazine-2-ketone (157 milligrams) and the mixture heating up of yellow soda ash (146 milligrams) in DMA (4 milliliters) 10 minutes.Reaction mixture is loaded on the SCX-2 post, removes product with 7N ammonia/methyl alcohol.Evaporate to dryness solution, chromatographic separation on silica gel with 0-2.5% methyl alcohol/DCM wash-out, obtains desired material (179 milligrams) white solid.

Mass spectrumMH+370

The NMR spectrum: ¹H NMR (DMSO-d ₆) δ 2.89 (3H, s), 3.13 (3H, s), 3.38 (2H, t), 3.55-3.56 (4H, m), 3.67-3.68 (4H, m), 3.93 (2H, t), 4.19 (2H, s), 4.28 (2H, s), 6.28 (1H, s)

According to similar mode, prepare following compounds by 2-chloro-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine and suitable piperazine-2-ketone.

Embodiment 96:NMR Spectrum: ¹H NMR (DMSO-d ₆) δ 3.15 (3H, s), 3.59 (4H, d), 3.68-3.69 (4H, m), 3.79-3.81 (2H, d), 4.04-4.07 (2H, m), 4.30 (2H, s), 4.40 (2H, s), 6.31 (1H, s), 7.41-7.46 (2H, m), 7.47-7.49 (2H, m).

Embodiment 97:

2-[3-(4,4-dimethyl-5H-1,3-oxazole-2-yl)-4-methoxyl group-phenyl]-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine

With 2-(5-bromo-2-p-methoxy-phenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole (250 milligrams), potassium acetate (259 milligrams) and two (valeryls), two boron (269 milligrams) are 1, the mixture degassing in 4 dioxs (10 milliliters) 5 minutes, add 1,1 '-two (diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (44 milligrams) then.Reaction is heated to 80 ℃, kept 2.5 hours.Add 2-chloro-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine (257 milligrams), ethanol (0.75 milliliter), 2M sodium carbonate solution (2.7 milliliters) and 1; 1 '-two (diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (44 milligrams) continues heating 3 hours.The vacuum concentration reaction mixture is dissolved in the methyl alcohol then.Solution by the SCX-2 post, is used the methanol wash post, go out desired material with 7N ammonia/methanol-eluted fractions then.The vacuum concentration fraction, chromatographic separation on silica gel with 5% methyl alcohol/DCM wash-out, obtains needed compound (43 milligrams) white solid then.

Mass spectrumMH+461

The NMR spectrum: ¹H NMR (DMSO-d ₆) δ 1.35 (6H, s), 3.23 (3H, s), 3.45 (2H, d), 3.74 (8H, d), 3.98 (3H, s), 4.53 (2H, s), 5.06 (1H, t), 6.87 (1H, s), 7.26 (1H, d), 8.15 (1H, s), 8.42-8.45 (1H, m), 8.85 (1H, d)

Embodiment 98:

N-(1H-benzoglyoxaline-5-yl)-2,6-dimorpholine-4-base-pyrimidine-4-methane amide

At room temperature, with 2, (45 milligrams of 6-dimorpholines-4-yl pyrimidines-4-formic acid, 0.15mmol), (65 milligrams of HATU, 0.17mmol) and 1H-benzoglyoxaline-5-amine (23 milligrams, mixture 0.17mmol) is DMF (1 milliliter) and triethylamine (0.054 milliliter is stirred in 0.31mmol) and spends the night.Add entry (4 milliliters), extract mixture with ethyl acetate (4 milliliters of 3 x).Dry (MgSO ₄) organism that merges, vacuum concentration.Chromatographic separation resistates on silica gel with 10-45% ethyl acetate/isohexane wash-out, obtains desired material light yellow solid (43.6 milligrams).

The LCMS spectrum: MH+410, retention time: 2.05, method: acid detects

The NMR spectrum: ¹H NMR (399.9MHz, CDCl ₃) δ 3.75 (m, 12H), 3.85-3.86 (m, 4H), 5.90 (s, 1H), 6.93 (m, 1H), 6.96 (m, 1H), 7.32 (m, 1H), 7.34 (s, 1H)

According to similar mode, by can commercial buy 2,6-dimorpholine-4-yl pyrimidines-4-formic acid and suitable amine prepare following compounds.

Embodiment 99: ¹H NMR (399.9MHz, CDCl ₃) δ 2.34 (s, 3H), 3.67 (m, 4H), 3.75-3.80 (m, 12H), 6.58 (s, 1H), 6.82 (s, 1H), 9.99 (s, 1H)

Embodiment 100: ¹H NMR (399.9MHz, CDCl ₃) δ 3.67 (m, 4H), 3.80 (m, 12H), 6.57 (m, 1H), 6.9 (s, 1H), 7.22 (m, 1H), 7.39 (d, 1H), 7.45 (m, 1H), 8.09 (d, 1H), 8.15 (s, 1H), 9.78 (s, 1H)

Embodiment 101: ¹H NMR (399.9MHz, DMSO-d ₆) δ 3.48 (s, 3H), 3.69 (m, 4H), 3.78 (m, 12H), 4.81 (s, 2H), 6.30 (s, 1H), 10.92 (s, 1H)

Embodiment 102:

5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indazole

At 50 ℃; with 1-(4-aminomethyl phenyl) alkylsulfonyl-5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] (95 milligrams of indazoles; 0.18mmol) and 1.0M tetrabutylammonium solution tetrahydrofuran (THF) (1.0 milliliters 1.0mmol) and in the tetrahydrofuran (THF) (5 milliliters) were heated 2 hours together.Evaporating solvent distributes resistates between water and methylene dichloride.Further wash organic solution with water, use dried over mgso, filter, concentrate, use anti-phase preparation HPLC (alkaline condition) purifying resistates, obtain 36 milligrams of title compounds.

The LCMS spectrum: MH+374, retention time: 1.28, method: acid detects

The NMR spectrum: ¹H NMR (300.132MHz, DMSO) δ 3.17 (3H, s), 3.68 (8H, s), 4.45 (2H, s), 6.79 (1H, s), 7.53 (1H, d), 8.14 (1H, s), 8.32 (1H, dd), 8.73 (1H, s), 13.12 (1H, s).

Starting raw material 1-(4-aminomethyl phenyl) alkylsulfonyl-5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] indazole is prepared as follows:

1-(4-aminomethyl phenyl) alkylsulfonyl-5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] indazole

In microwave reactor; at 100 ℃; with 1-(4-aminomethyl phenyl) alkylsulfonyl-5-(4; 4; 5; 5-tetramethyl--1; 3; 2-two oxa-boron heterocycles penta-2-yl) indazole is (209 milligrams; 0.53mmol), 2-chloro-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine (44 milligrams, 0.15mmol), two (triphenylphosphine) palladiums (II) (15 milligrams) of 2M aqueous sodium carbonate (1 milliliter), dichloro and 18% dimethyl formamide be at the 7:3:2 glycol dimethyl ether: water: heated 10 minutes in the ethanol (3.5 milliliters).Between methylene dichloride and water, distribute reaction mixture.Use dried over mgso organic solution, filter, concentrate.Residue purified by chromatography on silica gel is used eluent ethyl acetate, obtains needed compound brown solid (112 milligrams).

The LCMS spectrum: MH+528, retention time: 2.55, method: acid detects

The NMR spectrum: ¹H NMR (500.133MHz, DMSO) δ 2.31 (3H, s), 3.20 (3H, s), 3.27 (4H, s), 3.30 (4H, s), 4.52 (2H, s), 6.91 (1H, s), 7.39 (2H, d), 7.82 (2H, d), 8.21 (1H, d), 8.63 (1H, d), 8.64 (1H, s), 8.79 (1H, s)

1-(4-aminomethyl phenyl) alkylsulfonyl-5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycles penta-2-yl) indazole

At 80 ℃; in inert atmosphere; with 5-bromo-1-(4-aminomethyl phenyl) alkylsulfonyl-indazole (3.0 grams; 8.54mmol), potassium acetate (2.52 the gram; 25.62mmol), two (valeryls), two boron (3.04 grams, 11.96mmol) and (375 milligrams of 1,1 '-two (diphenylphosphino) ferrocene dichloro palladiums (II); 0.51mmol) in 1,4 diox (45 milliliters), stirred 48 hours.Evaporation removes and desolvates, and resistates is absorbed in the methyl alcohol, filters.Concentrated filtrate obtains needed compound brown solid (4.1 gram).

The LCMS spectrum: MH+399, retention time: 3.27, method: acid detects

5-bromo-1-(4-aminomethyl phenyl) alkylsulfonyl-indazole

At 0 ℃, in inert atmosphere, with 5-bromo-1H-indazole (3.8 grams, 19.29mmol, CAS 53857-57-1) dimethyl formamide (25 milliliters) solution joins 60% sodium hydride/oil (771 milligrams in dimethyl formamide 19.29mmol) (25 milliliters) mixture, were stirred 30 minutes.(5.15 grams 27.0mmol), at room temperature stirred 18 hours to add tosyl group chlorine.Reaction mixture is poured in ice/water, and violent stirring is extracted product in the ethyl acetate simultaneously.With salt water washing organic solution, use dried over mgso, filter evaporation.Resistates is dissolved in the methylene dichloride, filters by silicagel pad.Concentrated filtrate is used the ether grinding residues, and solid collected by filtration obtains needed compound (6.37 gram).

The LCMS spectrum: MH+353, retention time: 2.92, method: acid detects

The NMR spectrum: ¹H NMR (300.132MHz, DMSO) δ 2.34 (s, 3H), 7.40 (d, 2H), 7.76-7.85 (m, 3H), 8.05-8.14 (m, 2H), 8.50 (s, 1H)

Embodiment 103:

3-methyl-5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indazole

With tetrabutylammonium (1M solution; in THF; 2 milliliters) join 3-methyl isophthalic acid-(4-aminomethyl phenyl) alkylsulfonyl-5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] indazole (AZ12581939) (26 milligrams, in THF 0.05mmol) (2 milliliters) solution.Be warming up to 50 ℃, kept 3 hours, pour in the water, extract with DCM.Water (3x) washing organic phase is used MgSO ₄Drying is filtered reduction vaporization.Purifying on silica gel (gradient elution, 50% ethyl acetate/50% isohexane to 100% ethyl acetate) obtains title compound light brown solid (10.4 milligrams, 54%).

The LCMS spectrum: the MH+388.56 retention time: 2.46, method: early stage acid detects

The NMR spectrum: ¹H NMR (300.132MHz, DMSO) δ 2.55 (3H, s), 3.24 (3H, s), 3.75 (8H, s), 4.53 (2H, s), 6.86 (1H, s), 7.52 (1H, d), 8.38 (1H, dd), 8.69 (1H, s) .12.80 (1H, s)

Starting raw material 3-methyl isophthalic acid-(4-aminomethyl phenyl) alkylsulfonyl-5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] indazole is prepared as follows:

3-methyl isophthalic acid-(4-aminomethyl phenyl) alkylsulfonyl-5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] indazole

In microwave tube; at 100 ℃; with (146 milligrams of 2-chloro-4-(sulfonyloxy methyl ylmethyl)-6-morpholines-4-base-pyrimidine; 0.50mmol), 3-methyl isophthalic acid-(4-aminomethyl phenyl) alkylsulfonyl-5-(4,4,5; 5-tetramethyl--1; 3,2-two oxa-boron heterocycles penta-2-yl) indazole (413 milligrams, 1mmol), 2M sodium carbonate solution (2 milliliters) and two (triphenylphosphine) palladiums (11) (40 milligrams) of dichloro shone 10 minutes in the DME/ of 18%DMF water/EtOH (7:3:2) solution (7 milliliters).Evaporated under reduced pressure reaction then distributes resistates between DCM and water.Extract water twice, water, saturated NaHCO with DCM ₃The organism that solution and salt water washing merge.Use MgSO then ₄Drying solution is filtered reduction vaporization.Purifying resistates on the SCX2 post is used methanol-eluted fractions then, then uses 4%NH ₄The OH/ methanol-eluted fractions, wash-out goes out title compound, obtains (after the evaporation) pale solid (26 milligrams, 9%) at last.

The LCMS spectrum: the MH+542.59 retention time: 2.18, method: middle acid detects

The NMR spectrum: ¹H NMR (300.132MHz, DMSO) δ 2.33 (3H, s), 2.56 (3H, s), 3.21 (3H, s), 3.75 (8H, s), 4.54 (2H, s), 6.92 (1H, s), 7.39 (2H, d), 7.81 (2H, d), 8.18 (1H, d), 8.63-8.66 (2H, m)

3-methyl isophthalic acid-(4-aminomethyl phenyl) alkylsulfonyl-5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycles penta-2-yl) indazole

With anhydrous 1; 4 dioxs (20 milliliters) join (876.6 milligrams of 5-bromo-3-methyl isophthalic acids-(4-aminomethyl phenyl) alkylsulfonyl-indazole; 2.4mmol), two (valeryl (pinacolto)), two boron (701 milligrams, 2.76mmol), Dppf (40 milligrams, 0.072mmol), PdCl ₂(dppf) (58.8 milligrams, 0.072mmol) and potassium acetate (707 milligrams, 7.2mmol) in.With the mixture degassing 3 times, in nitrogen atmosphere, be heated to backflow then, kept 2 hours.Cooling reaction then, evaporated under reduced pressure.Between ethyl acetate and water, distribute resistates.Water (2x) washing organic phase is used 1M HCl (2x) washing then, uses the salt water washing at last.Use MgSO then ₄Drying solution, evaporate to dryness obtains brown solid (1.07 gram).Then it is applied on the silicagel column (20 gram).Carry out gradient elution with 90% isohexane/10% ethyl acetate-50% isohexane/50% ethyl acetate, obtain title compound pale solid (0.94 gram, 95%).

The LCMS spectrum: the MH+413.57 retention time: 3.22, method: acid detects

The NMR spectrum: ¹H NMR (300.132MHz, DMSO) δ 1.32 (12H, s), 2.32 (3H, s), 7.37 (2H, d), 7.76 (2H, d), 7.91 (1H, d), 8.09-8.12 (2H, m) (1x CH3 is hidden by the DMSO peak).

5-bromo-3-methyl isophthalic acid-(4-aminomethyl phenyl) alkylsulfonyl-indazole

In nitrogen atmosphere, (60% dispersion, in oil, 440 milligrams, dry DMF 11mmol) (25 milliliters) solution is cooled to 0 ℃ (ice/water-bath) with sodium hydride.Form with DMF (10 milliliters) solution dropwise adds 5-bromo-3-methyl isophthalic acid H-indazole (2.115 grams, 10mmol is according to WO2003/051366 embodiment 102C preparation).After 30 minutes, and disposable adding tosyl group chlorine (2.67 grams, 14mmol).Reaction mixture is warming up to room temperature, then stirs and spend the night.To react and go out with ice/shrend.With ethyl acetate extraction (3x).Water and salt water washing.Use MgSO ₄Drying is filtered, and reduction vaporization obtains the paste solid.Ether with a little volume grinds (removing color and less impurity).Vacuum-drying obtains title compound white solid (2.9 grams, 79%).

The LCMS spectrum: the MH+365.35/367.38 retention time: 2.82, method: acid detects

The NMR spectrum: ¹H NMR (300.132MHz, DMSO) δ 2.33 (3H, s), 2.47 (3H, s), 7.38 (2H, d), 7.76-7.80 (3H, m), 8.03 (1H, d), 8.10 (1H, d)

Embodiment 104:

5-[2-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-4-yl]-the 1H-indoles

With 5-[6-chloro-2-(sulfonyloxy methyl ylmethyl) pyrimidine-4-yl]-the 1H-indoles (110 milligrams, 0.34mmol) and morpholine (3 milliliters) in microwave reactor, 120 ℃ the heating 10 minutes.Use anti-phase preparation HPLC (alkaline condition) purification reaction solution, obtain title compound (35 milligrams).

The LCMS spectrum: MH+373, retention time: 1.38, method: acid detects

The NMR spectrum: ¹H NMR (300.132MHz, DMSO) δ 3.17 (3H, s), 3.73 (8H, s), 4.52 (2H, s), 6.54 (1H, dd), 7.28 (1H, s), 7.41 (1H, m), 7.48 (1H, d), 7.95 (1H, dd), 8.44 (1H, s), 11.27 (1H, s)

Starting raw material 5-[6-chloro-2-(sulfonyloxy methyl ylmethyl) pyrimidine-4-yl]-the 1H-indoles is prepared as follows:

5-[6-chloro-2-(sulfonyloxy methyl ylmethyl) pyrimidine-4-yl]-the 1H-indoles

In microwave reactor; at 100 ℃; with 4; (82 milligrams of 6-two chloro-2-(sulfonyloxy methyl ylmethyl) pyrimidines; 0.34mmol), indoles-5-boric acid (55 milligrams, 0.34mmol), two (triphenylphosphine) palladiums (II) (15 milligrams) of 2M aqueous sodium carbonate (1 milliliter), dichloro and 18%DMF be at the 7:3:2 glycol dimethyl ether: water: heated 10 minutes in the ethanol (3.5 milliliters).Between ethyl acetate and water, distribute reaction mixture.Use dried over mgso organic solution, filter, vacuum concentration obtains needed compound light green colloid (149 milligrams).

The LCMS spectrum: MH+322, retention time: 2.08, method: acid detects

4,6-two chloro-2-(sulfonyloxy methyl ylmethyl) pyrimidine

With 2-(sulfonyloxy methyl ylmethyl) pyrimidine-4, and the 6-glycol (2.1 grams, 5.0mmol) and phosphorus oxychloride (20 milliliters) reflux 4 hours.With the solution for vacuum concentration that obtains, with methylbenzene azeotropic.Between methylene dichloride and ice cold water, distribute resistates.Filter dry organic solution, vacuum concentration then by the PTFE frit.By the purification by flash chromatography resistates, use hexane: eluent ethyl acetate obtains needed product white solid, 87 milligrams.

The LCMS spectrum: MH+241, retention time: 1.75, method: early detection

The NMR spectrum: ¹H NMR (300.132MHz, CDCl ₃) δ 3.19 (3H, s), 4.56 (2H, s), 7.43 (1H, s)

2-(sulfonyloxy methyl ylmethyl) pyrimidine-4, the 6-glycol

With 2-methyl sulphonyl ethanamidine (ethanimidamide) (172 milligrams, 1.00mmol), salt of wormwood (143 milligrams, 1.05mmol) and diethyl malonate (1 milliliter) stirs and 150 ℃ of heating two hours.Reaction mixture, with ether dilution, solid collected by filtration, drying obtains needed product white solid (294 milligrams).

The LCMS spectrum: MH+205, retention time: 0.43, method: early detection 2-methyl sulphonyl ethanamidine

With 2-methylsulfonyl acetonitrile (11.9 the gram, 100.0mmol) in ethanol, stir, and with mixture in cooled on ice.By mixture, solid little by little dissolves with hydrochloric acid gas bubbling.With hydrochloric acid with solvent saturated after, at room temperature stirred solution spends the night.With ether diluted mixture thing, filter and collect white precipitate, drying.The solid imido ether is stirred in ethanol (200 milliliters), add 7M ammonia/methyl alcohol (13 milliliters 0.1mmol), at room temperature stirred the mixture 48 hours.Mixture is concentrated into half volume, solid collected by filtration, drying obtains needed product white solid (15.35 milligrams).

The NMR spectrum: ¹H NMR (300.132MHz, D ₂O) δ 3.30 (3H, s) 4.69 (2H, s)

Embodiment 105:

5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-benzoglyoxaline

In microwave reactor; at 100 ℃; with trimethylammonium-[2-[[5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] benzoglyoxaline-1-yl] methoxyl group] ethyl] silane (53 milligrams 0.11mmol) were heated 10 minutes in ethanol with 2M aqueous hydrochloric acid (3 milliliters).Evaporation reaction is purified by anti-phase preparation HPLC (alkaline condition) to white solid then, obtains title compound white solid (17 milligrams).

The LCMS spectrum: MH+347, retention time: 0.91, method: acid detects

The NMR spectrum: ¹H NMR (500.133MHz, DMSO) δ 3.23 (3H, s), 3.73 (8H, s), 4.51 (2H, s), 6.85 (1H, s), 7.64 (1H, d), 8.26 (1H, d), 8.30 (1H, s), 8.59 (1H, s), 12.60 (1H, s)

Starting raw material trimethylammonium-[2-[[5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] benzoglyoxaline-1-yl] methoxyl group] ethyl] silane is prepared as follows:

Trimethylammonium-[2-[[5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] benzoglyoxaline-1-yl] methoxyl group] ethyl] silane

In microwave reactor; at 160 ℃; with trimethylammonium-[2-[[5-(4; 4; 5; 5-tetramethyl--1; 3; 2-two oxa-boron heterocycles penta-2-yl) benzoglyoxaline-1-yl] methoxyl group] ethyl] (57 milligrams in silane; 0.15mmol), 2-chloro-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine (44 milligrams, 0.15mmol), two (triphenylphosphine) palladiums (II) (15 milligrams) of 2M aqueous sodium carbonate (1 milliliter), dichloro and 18% dimethyl formamide be at the 7:3:2 glycol dimethyl ether: water: heated 3.5 minutes in the ethanol (3.5 milliliters).Between methylene dichloride and water, distribute reaction mixture.Use dried over mgso organic solution, filter, concentrate.Residue purified by chromatography on silica gel is used eluent ethyl acetate, obtains needed compound brown solid (54 milligrams).

The LCMS spectrum: MH+504, retention time: 2.10, method: acid detects

Trimethylammonium-[2-[[5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycles penta-2-yl) benzoglyoxaline-1-yl] methoxyl group] ethyl] silane

In inert atmosphere, with 2-[(5-bromobenzene and imidazoles-1-yl) methoxyl group] ethyl-trimethylammonium-silane (1.42 grams, 4.33mmol), (849 milligrams of potassium acetates, 8.66mmol), two (valeryls), two boron (1.32 the gram, 5.20mmol) and 1,1 '-two (diphenylphosphino) ferrocene dichloro palladium (II) (71 milligrams, 0.09mmol) stirred 24 hours in 1,4 diox (25 milliliters) by backflow.Concentrated reaction mixture is absorbed in resistates in the ethyl acetate, filters.Use the salt solution wash filtrate, use dried over mgso, filter, evaporation.Residue purified by chromatography on silica gel is used eluent ethyl acetate, obtains needed compound light green solid (1.45 gram).

The LCMS spectrum: MH+375, retention time: 2.76, method: acid detects

2-[(5-bromobenzene and imidazoles-1-yl) methoxyl group] ethyl-trimethylammonium-silane

In inert atmosphere, dimethyl formamide (15 milliliters) solution of 5-bromo-benzoglyoxaline (2.96 grams, 15mmol, CAS 4887-88-1) is dropwise joined (660 milligrams of 60% sodium hydride/oil, 16.5mmol) dimethyl formamide (20 milliliters) suspension in, stirred 30 minutes.Reaction mixture is cooled to 0 ℃, and (2.74 grams, dimethyl formamide 16.5mmol) (15 milliliters) solution at room temperature stirred the mixture 18 hours dropwise to add 2-(trimethyl silyl) ethoxyl methyl chlorine.Reaction mixture is poured in the frozen water, stirred simultaneously, product is extracted in the ethyl acetate.Use dried over mgso organic solution, filter, concentrate.Silica gel chromatography separates resistates, with 70% ethyl acetate/hexane wash-out.The enriched product fraction is to light yellow oil, and it is the mixture (2.83 gram) of the tautomer of required compound.

The LCMS spectrum: MH+329, retention time: 2.79, method: acid detects

Embodiment 106:

4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles

With the 4-[6-[(methyl sulphonyl) methyl]-2-(methylthio group) pyrimidine-4-yl] (151 milligrams of morpholines; 0.5mmol), (141 milligrams of indoles-4-boric acid; 1.1mmol), (248 milligrams of thiophene-2-carboxylic acid copper (I); 1.3mmol), (47 milligrams of tetra-triphenylphosphine palladiums; 0.04mmol), (175 milligrams of zinc acetates; 1.1mmol) and 1,4-diox (5 milliliters) joins in the microwave container.With nitrogen system is outgased, sealing is in microwave reactor, 130 ℃ of heating 45 minutes.Reaction is poured in the water, use ethyl acetate extraction, dried over mgso is used in water, salt water washing.Use anti-phase preparation HPLC to be further purified product, obtain title compound (43 milligrams).

The LCMS spectrum: MH+373, retention time: 2.60, method: acid detects

The NMR spectrum: ¹H NMR (300.132MHz, DMSO) δ 3.20 (d, 3H), 3.75 (s, 8H), 4.56 (s, 2H), 6.87 (s, 1H), 7.19 (t, 1H), 7.38 (d, 1H), 7.44 (t, 2H), 7.54 (d, 1H), 8.07 (dd, 1H), 11.36 (s, 1H)?

According to similar mode; use 5; 7-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-1,3,5; 8-tetraene-3-ylboronic acid and 4-[6-[(methyl sulphonyl) methyl]-2-(methylthio group) pyrimidine-4-yl] morpholine; 3-[4-shown in being prepared as follows (sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-5,7-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-1,3; 5, the 8-tetraene.

Embodiment 108:

4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] aniline

With 2-methyl sulfenyl-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine (1.00 grams, 3.3mmol), 4-aminophenyl boric acid (904 milligrams, 6.60mmol), thiophene-2-carboxylic acid copper (I) (1.64 grams, 8.58mmol), Pd (PPh ₃) ₄(153 milligrams, 0.04 equivalent 0.13mmol) joins in the microwave container, adds 1,4-diox (20 milliliters).Use N ₂With system's degassing, sealing is in microwave reactor, 130 ℃ of heating 1 hour.After the cooling, reactant is poured in the water, filtered and collect the precipitation that obtains, vacuum-drying obtains title compound off-white color solid.(988mg)

The LCMS spectrum: MH+349.41, retention time: 1.43, method: acid detects

The NMR spectrum: ¹H NMR (300.132MHz, DMSO) δ 3.20 (3H, s), 3.61-3.83 (8H, m), 4.43 (2H, s), 5.57 (1H, s), 6.60 (2H, d), 6.70 (1H, s), 8.04 (2H, d)

Embodiment 109:

2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-formic acid

In microwave, at 120 ℃, divide 8 batches with 2-chloro-6-morpholine-4-base-pyrimidine-4-methyl-formiate (10.0 grams, 38.91mmol, CAS 107973-01-3), 1H-indoles-5-ylboronic acid (9.7 grams, 60.31mmol), two (triphenylphosphine) palladiums (II) of dichloro (2.1 grams, 2.92mmol) and yellow soda ash (2M, in water, 100 milliliters) at the glycol dimethyl ether of 18% DMF: water: heating is 30 minutes in ethanol (7:3:2) (320 milliliters) solution.Batch of material evaporation with merging transfers to pH value=2 with 2N HCl, stirs 30 minutes, leaches solid.It 40 ℃ of dried overnight, is obtained title compound (17 gram).

The LCMS spectrum: MH+325, retention time: 1.23, method: acid detects

The NMR spectrum ¹H NMR (300.132MHz, DMSO) δ 3.70-3.83 (8H, m), 6.56-6.57 (1H, m), 7.18 (1H, s), 7.39-7.40 (1H, m), 7.45 (1H, d), 8.22-8.25 (1H, m), 8.70 (1H, s), 11.24 (1H, s).

Embodiment 110:

[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl alcohol

At 0 ℃, (14.0 grams, (117 milliliters, stir by 116.67mmol) processing with lithium aluminium hydride (1.0M is in tetrahydrofuran (THF)) for THF 38.89mmol) (600 milliliters) solution with 2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-formic acid.After 5 hours, water (4.43 milliliters), 15%NaOH (4.43 milliliters), water (13.30 milliliters) treating mixture then then with ethyl acetate (200 milliliters) diluted mixture thing, stirred 35 minutes.The evaporation organism by the SCX residue purified by chromatography, obtains crude product.By the MPLC[35-90% ethyl acetate: isohexane] the purifying foams, obtain title compound (5.58 gram).

The LCMS spectrum: MH+310, retention time: 1.03, method: acid detects

The NMR spectrum ¹H NMR (300.132MHz, DMSO) δ 3.73-3.82 (8H, m), 4.54 (2H, d), 5.44 (1H, t), 6.57-6.61 (1H, m), 6.76 (1H, s), 7.41-7.44 (1H, m), 7.47 (1H, d), 8.20-8.24 (1H, m), 8.66 (1H, s), 11.24 (1H, s).

Embodiment 111:

5-[4-morpholine-4-base-6-(morpholine-4-ylmethyl) pyrimidine-2-base]-the 1H-indoles

With (100 milligrams of [2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl alcohol, 0.32mmol embodiment 110) be suspended in the methylene dichloride (2 milliliters), with (0.038 milliliter of methylsulfonyl chloride, 0.48mmol) and triethylamine (0.068 milliliter 0.48mmol) is handled.The mixture stirring is spent the night, then use morpholine (1 milliliter) to handle, stir once more and spend the night.Evaporating solns is by preparing HPLC[5-95% MeCN: water] purifying, obtain title compound (10 milligrams).

The LCMS spectrum: MH+379, retention time: 1.03, method: acid detects

The NMR spectrum ¹H NMR (300.132MHz, DMSO) δ 3.32-3.41 (4H, m), 3.69-3.79 (8H, m), 3.86-3.94 (4H, m), 4.35 (2H, s), 6.52-6.57 (1H, m), 6.78 (1H, d), 7.38-7.42 (1H, m), 7.46 (1H, d), 8.20 (1H, d), 8.68 (1H, s).

Embodiment 112:

N-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl]-1-(4-p-methoxy-phenyl) methylamine

To 5-[4-(methyl sulphonyl oxygen ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-add DCM (2 milliliters) solution of 4-methoxybenzylamine (28 milligrams) and DIPEA (0.040 milliliter) in DCM (4 milliliters are supposed the to comprise 50 milligrams of materials) solution of 1H-indoles.At room temperature stirring reaction spends the night, and adds NMP (1 milliliter) then, and vacuum is removed DCM.Add DIPEA (0.030 milliliter) and some potassiumiodide crystal, in microwave reactor, 100 ℃ of heated mixt 10 minutes.Evaporating mixture is loaded on the SCX-2 post, uses the methanol wash post, then uses 7N ammonia/methanol-eluted fractions product.The vacuum concentration fraction by preparation HPLC (acid) purifying resistates, obtains needed compound solid (20 milligrams).

The LCMS spectrum: MH+430, retention time: 1.40, method: acid detects

The NMR spectrum ¹H NMR (400.132MHz, DMSO) δ 3.74 (8H, s), 3.79 (3H, s), 4.15 (2H, s), 4.27 (2H, s), 6.55 (1H, d), 6.75 (1H, s), 7.03 (2H, d), 7.41 (1H, d), 7.45 (1H, s), 7.47 (1H, s), 7.49 (2H, d), 8.27 (1H, dd), 8.74 (1H, d), 9.32 (1H, s)

According to similar mode, use suitable amine to prepare following compounds.

Embodiment 113:NMR spectrum ¹H NMR (400.132MHz, DMSO) δ 3.74 (8H, s), 4.19 (2H, s), 4.34 (2H, s), 6.55 (1H, d), 6.75 (1H, s), 7.41 (1H, t), 7.46 (1H, d), 7.55 (2H, d), 7.59 (2H, d), 8.27 (1H, d), 8.74 (1H, dd), 9.45 (1H, bs)

5-[4-(methyl sulphonyl oxygen ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-preparation of 1H-indoles is described below.

5-[4-(methyl sulphonyl oxygen ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles

DCM (5 milliliters) solution of [2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl alcohol (200 milligrams) and triethylamine (0.135 milliliter) is at room temperature stirred, dropwise add methylsulfonyl chloride (0.075 milliliter).Stirring reaction 1 hour adds extra DCM (5 milliliters) and water (5 milliliters).Separate organic phase, add extra DCM (5 milliliters), use salt solution (5 milliliters) washing organism then, dry (Na ₂SO ₄), filter.Suppose that reaction is quantitative, with extra DCM with mixture diluted to 20 milliliter cumulative volume (supposition comprise amount to 250 milligrams of materials).This material need not just be further purified or characterize and can use.

Embodiment 114:

5-[4-[(2-picoline-3-yl) oxygen ylmethyl]-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles

At room temperature, to [2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl alcohol (110,40.6 milligrams of embodiment, 0.13mmol) and (0.027 milliliter of triethylamine, 0.195mmol) DCM (5 milliliters) stirred solution in dropwise add methylsulfonyl chloride (0.015 milliliter, 0.195mmol).Stirring reaction is 1 hour then, then uses DCM (5 milliliters) dilution, water (5 milliliters), salt solution (5 milliliters) washing, dry (Na ₂SO ₄), to filter, evaporation obtains the crude product mesylate.At room temperature, with 3-hydroxy-2-methyl pyridine (22 milligrams, DMF 0.19mmol) (2 milliliters) solution join in DMF (1 milliliter) sodium hydride that stirs (8 milligrams, 60% dispersion, in oil, 0.19mmol) in.After stirring 5 minutes, (50 milligrams, DCM 0.13mmol) (4 milliliters) solution at room temperature continues to stir to spend the night then to add mesylate.Solvent removed in vacuo adds entry (10 milliliters) then, and extraction with aqueous solution is arrived among ethyl acetate (2x20 milliliter, 10 milliliters of 1 x) and the DCM (10 milliliters).The organic extraction that water (5 milliliters) and salt solution (5 milliliters) washing merge, dry (MgSO ₄), evaporation obtains gelationus solid.Purifying crude product on 10 gram Isolute silicagel columns with 2% methyl alcohol/DCM wash-out, obtains white solid (22 milligrams).

The LCMS spectrum: MH+402, retention time: 1.01, method: acid detects

The NMR spectrum ¹H NMR (400.132MHz, DMSO) δ 3.28 or 3.31 (3H, s), 3.73 (8H, s), 5.15 (2H, s), 6.55 (1H, d), 6.75 (1H, s), 7.19-7.22 (1H, m), 7.38 (1H, t), 7.44 (1H, d), 7.45 (1H, d), 8.05 (1H, d), 8.18 (1H, d), 8.63 (1H, d), 11.22 (1H, s)

Embodiment 115:

5-[4-(methoxymethyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles

At room temperature, to [2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl alcohol (110,47 milligrams of embodiment, 0.15mmol) and (0.031 milliliter of triethylamine, 0.225mmol) DCM (5 milliliters) stirred solution in dropwise add methylsulfonyl chloride (0.017 milliliter, 0.225mmol).Stirring reaction is 1 hour then, then uses DCM (5 milliliters) dilution, water (5 milliliters), salt solution (5 milliliters) washing, dry (Na ₂SO ₄), to filter, evaporation obtains the crude product mesylate.Then at room temperature, it is dissolved among the MeCN (1 milliliter), joins sodium methylate (26 milligrams in methyl alcohol 0.46mmol) (3 milliliters) solution, were stirred 30 hours.Solvent removed in vacuo, purifying crude product on silicagel column with 25% ethyl acetate/DCM wash-out, obtains title compound solid (27 milligrams).

The LCMS spectrum: MH+325, retention time: 2.01, method: the alkali formula detects

The NMR spectrum ¹H NMR (300.13MHz, DMSO-d ₆) δ 3.43 (3H, s), 3.72 (8H, s), 4.42 (2H, s), 6.54 (1H, s), 6.62 (1H, s), 7.37 (1H, t), 7.42 (1H, d), 8.14-8.18 (1H, m), 8.60 (1H, s), 11.20 (1H, s)

Embodiment 116:

5-[4-(2-furyl methyl alkylsulfonyl methyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles

At room temperature, to 5-[4-(2-furyl methyl sulfenyl methyl)-6-morpholine-4-base-pyrimidine-2-base]-(adding 3-chlorine peroxybenzoic acid is (43 milligrams in 47 milligrams of) De diox/methyl alcohol (3 milliliters/0.5 milliliter) stirred solution for the 1H-indoles, 0.17mmol), and then add the 1N sodium hydroxide solution (0.180 milliliter, 0.17mmol).After 2 hours 40 minutes, further add 3-chlorine peroxybenzoic acid (17 milligrams 0.07mmol), with small amount of methanol (＜0.2 milliliter) washing, are and then used 1M sodium hydroxide solution (0.070 milliliter 0.07mmol) is washed.Further stirring reaction is 40 minutes, is loaded into then on the SCX-3 post (anticipating with 30 ml methanol).Post with methyl alcohol (30 milliliters) washing, is used 10%7N ammonia/methyl alcohol-methyl alcohol (60 milliliters) eluted product then.Evaporation obtains the brown colloid, and HPLC is purified by preparation, obtains product colorless solid (15 milligrams, 55%).

The LCMS spectrum: MH+439, retention time: 2.28, method: acid detects

According to similar mode, prepare following compounds by suitable thioether.

Starting raw material 5-[4-(2-furyl methyl sulfenyl methyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles is prepared as follows.

5-[4-(2-furyl methyl sulfenyl methyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles

At room temperature, in the MPS pipe, in nitrogen atmosphere, with sodium ethylate (18 milligrams, 0.26mmol) join furfuryl mercaptan (30 milligrams, in acetonitrile 0.26mmol) (4 milliliters) stirred solution.After stirring 70 minutes, add 5-[4-(methyl sulphonyl oxygen ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-1H-indoles (112,60 milligrams of embodiment, acetonitrile 0.15mmol) (1 milliliter) solution, stirring reaction 65 hours at room temperature then.Then reaction mixture is loaded on the SCX-3 post (anticipating) with 25 ml methanol.With methyl alcohol (25 milliliters) washing column, wash-out goes out nonbasic substances, then uses 10%7N ammonia/methyl alcohol-methyl alcohol (60 milliliters) wash-out.Evaporation obtains thioether colloid (47 milligrams).

The LCMS spectrum: MH+407, retention time: 2.60, method: the alkali formula detects

According to similar mode, by 5-[4-(methyl sulphonyl oxygen ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-1H-indoles (embodiment 112) and suitable mercaptan prepares following thioether.

Embodiment 122:

2-[[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl sulphonyl]-N, N-dimethyl-ethanamide

With [2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl sulfenyl carbonamidine (methanimidamide) 2,2,2-trifluoroacetate (0.080 gram, 0.11mmol) DMF (2 milliliters) solution join 2-bromo-N, in the DMF of N-dimethyl-ethanamide (0.11mmol) (1 milliliter) solution.With this solution with sodium hydroxide (35 milligrams, 0.87mmol)/water (1 milliliter) handles, shook 1 hour.Evaporating solvent.Resistates is dissolved in ethyl acetate/water/salt solution (4 milliliters: 2 milliliters: 1 milliliter), and supersound process stirs.Separate organism, extract water layer with ethyl acetate (2 milliliters) in addition.The organism that evaporation merges by preparation HPLC purifying, obtains thioether, and it is dissolved in diox: in the water (3 milliliters: 0.5 milliliter), (0.056 gram 0.13mmol) is handled, and (0.027 gram 0.17mmol) is handled and then to use sodium permanganate with 3-chlorine peroxybenzoic acid.At room temperature stirred the mixture about 1 hour.By SCX chromatogram purification mixture, obtain title compound (9 milligrams).

The LCMS spectrum: MH+444, retention time: 1.27, method: acid detects

According to similar mode, by [2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl sulfenyl carbonamidine 2,2,2-trifluoroacetate and suitable alkylogen prepare following compounds.

Starting raw material [2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl sulfenyl carbonamidine 2,2, the 2-trifluoroacetate is prepared as follows:

[2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl sulfenyl carbonamidine 2,2, the 2-trifluoroacetate

With [2-(1H-indoles-5-yl)-6-morpholine-4-base-pyrimidine-4-yl] methyl alcohol (embodiment 110,3.27 gram 10.55mmol) is suspended among the DCM, with methylsulfonyl chloride (1.23 milliliters, 15.82mmol) and triethylamine (2.21 milliliters, 15.82mmol) processing.After 15 minutes, evaporation suspension is dissolved in the ethanol (25 milliliters) to crude product again.Add thiocarbamide (0.882 gram, 11.60mmol), 70 ℃ of reacting by heating 30 minutes.Most of ethanol is removed in distillation.Use the ether grinding residues, remove and desolvate.Repeat this grinding more than twice, obtain the crude product solid.HPLC is purified by preparation, obtains needed compound (1.16 gram).

The LCMS spectrum: MH+369, retention time: 1.14, method: acid detects

The NMR spectrum ¹H NMR (DMSO-d ₆) δ 3.68-3.80 (8H, m), 4.42 (2H, s), 6.56 (1H, s), 6.80 (1H, s), 7.40-7.44 (1H, m), 7.46 (1H, d), 8.03-8.08 (1H, m), 8.52 (1H, s), 9.33 (1H, s), 9.84 (1H, s), 11.29 (1H, s).

Embodiment 173:

4-morpholine-4-base-2-pyridine-2-base-6-(tertiary butyl alkylsulfonyl methyl) pyrimidine

According to the similar mode of mode of embodiment 44 preparation 4-(benzenesulfonyl methyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidines, by suitable thioether preparation.

The LCMS spectrum: the MH+377.6 retention time: 3.16, method: the alkali formula detects

The NMR spectrum: ¹H NMR (500.133MHz, DMSO) δ 1.40 (9H, s), 3.73 (8H, s), 4.51 (2H, s), 6.95 (1H, s), 7.48-7.51 (1H, m), 7.94 (1H, dt), 8.31 (1H, d), 8.71-8.73 (1H, m)

According to the similar mode of mode of embodiment 26 preparation 4-morpholine-4-base-6-(phenyl sulfenyl methyl)-2-pyridine-2-base-pyrimidines, react by suitable mercaptan and 4-(chloromethyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine (embodiment 26), prepare initial thioether.

Embodiment 174:

2-methyl-5-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base]-the 1H-indoles

With (292 milligrams of 2-chloro-4-(sulfonyloxy methyl ylmethyl)-6-morpholines-4-base-pyrimidine; 1mmol), 2-methyl isophthalic acid (4-aminomethyl phenyl) alkylsulfonyl-5-(4; 4; 5,5-tetramethyl--1,3; 2-two oxa-boron heterocycles penta-2-yl) indoles is (617 milligrams; 1.5mmol), the 7:3:2DME of 2M aqueous sodium carbonate (1 milliliter), two chloro-two (triphenylphosphine) palladiums (II) (20 milligrams) and 18%DMF: water: ethanol (3.5 milliliters) solution is placed in the microwave tube, is heated to 125 ℃, keeps 30 minutes.Evaporating solvent distributes resistates between water and DCM then.Separate each layer then, extract water with DCM.Dry (MgSO ₄) organic extraction that merges, evaporation obtains oil.It is dissolved in the methanol/water mixture, handled four hours with sodium hydroxide solution (2M, 6 milliliters).With hydrochloric acid (2M) neutralization reaction, evaporation.By preparation HPLC purifying crude product solid, obtain title compound white solid (30 milligrams).

The LCMS spectrum: MH+387.60, retention time: 1.97, method: the alkali formula detects

The NMR spectrum: ¹H NMR (300.132MHz, CDCl ₃) δ 3.09 (3H, s), 3.48 (3H, s), 3.68-3.91 (8H, m), 4.27 (2H, s), 6.42 (1H, s), 6.52 (1H, s), 8.21 (1H, d), 8.29 (1H, dd), 8.40 (1H, d).

Starting raw material 2-methyl isophthalic acid-(4-aminomethyl phenyl) alkylsulfonyl-5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycles penta-2-yl) indoles is prepared as follows.

2-methyl isophthalic acid-(4-aminomethyl phenyl) alkylsulfonyl-5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycles penta-2-yl) indoles

With 5-bromo-2-methyl isophthalic acid-(4-aminomethyl phenyl) alkylsulfonyl-indoles (1.095 grams; 3mmol), two (valeryls), two boron are (915 milligrams; 3.6mmol), (25 milligrams in dichloride two (dppf) palladium methylene dichloride complex compound; 0.03mmol) and (588 milligrams of potassium acetates; 6mmol) be suspended in the diox (20 milliliters); be heated to 80 ℃, kept 10 hours.Then reaction mixture is applied on the silicagel column,, obtains title compound ceraceous solid (951 milligrams) by purification by flash chromatography (0-10% EtOAc/ isohexane).

The NMR spectrum: ¹H NMR (300.132MHz, CDCl ₃) δ 1.28 (12H, s), 2.26 (3H, s), 2.52 (3H, s), 6.26 (1H, s), 7.11 (2H, d), 7.57 (2H, d), 7.62 (1H, dd), 7.81 (1H, s), 8.07 (1H, d)

5-bromo-2-methyl isophthalic acid-(4-aminomethyl phenyl) alkylsulfonyl-indoles

(5 grams 23.8mmol) are dissolved among the DMF (50 milliliters), and (1.05 grams 26.18mmol) join in the solution portioning with sodium hydride then with 2-methyl-5-bromo indole.After 30 minutes, (5 grams, 26.18mmol), at room temperature stirring reaction is 6 hours to add tosyl group chlorine.Then reactant is poured in the water, and extracted in the ethyl acetate.Use MgSO ₄The dry organic extraction that merges, evaporation obtains solid.Be purified (0-5% ethyl acetate/isohexane) by flash chromatography, obtain title compound light brown solid (5.23 gram).

LCMS: M+H ⁺364.27, retention time: 3.29, method: the alkali formula detects

The NMR spectrum: ¹H NMR (300.132MHz, DMSO-d ₆) δ 2.32 (3H, s), 2.59 (3H, s), 6.55 (1H, s), 7.37 (2H, d), 7.41 (1H, dd), 7.69 (1H, d), 7.74 (2H, d), 7.97 (1H, d)

Embodiment 175:

4-[(5-methyl-2H-pyrazole-3-yl) oxygen ylmethyl]-6-morpholine-4-base-2-pyridine-2-base-pyrimidine

According to embodiment 68 preparation 4-[(3-methoxyl group phenoxy groups) methyl]-similar manner of the mode of 6-morpholine-4-base-2-pyridine-2-base-pyrimidine, prepare by 4-(chloromethyl)-6-morpholine-4-base-2-pyridine-2-base-pyrimidine (embodiment 26) and suitable starting raw material.

The LCMS spectrum: the MH+353.6 retention time: 1.59, method: the alkali formula detects

The NMR spectrum: ¹H NMR (300.132MHz, DMSO-d ₆) δ 2.16 (s, 3H), 3.70 (s, 8H), 5.09 (s, 2H), 5.56 (s, 1H), 6.82 (s, 1H), 7.48 (m, 1H), 7.92 (td, 1H), 8.31 (d, 1H), 8.70 (d, 1H), 11.57 (s, 1H)

Embodiment 176:

2-(3-furyl)-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine

According to the similar manner of the mode of embodiment 1 preparation 4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-2-thiene-3-yl--pyrimidine, by 2-methyl sulfenyl-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine and suitable boric acid preparation.

The LCMS spectrum: MH+324.5, retention time: 1.63, method: the alkali formula detects

Embodiment 177:

4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-2-naphthalene-1-base-pyrimidine

LCMS spectrum: MH+384.6, retention time: 2.16, method: the alkali formula detects

Claims

1. the compound of formula (I)

Formula (I)

M is 0,1,2,3 or 4;

R ⁴And R ⁵Be hydrogen or C independently _1-6Alkyl;

R ⁸Be selected from hydrogen, halogen, cyano group and C _1-6Alkyl;

2. according to formula (I) compound of claim 1, wherein X is selected from following linking group :-NR ⁴CR ⁶R ⁷-,-OCR ⁶R ⁷-,-SCR ⁶R ⁷-,-S (O) CR ⁶R ⁷-,-S (O) ₂CR ⁶R ⁷-,-C (O) NR ⁴CR ⁶R ⁷-,-NR ⁴C (O) NR ⁵CR ⁶R ⁷-,-S (O) ₂NR ⁴CR ⁶R ⁷-,-NR ⁴C (O)-,-C (O) NR ⁴-,-S (O) ₂NR ⁴-and-NR ⁴S (O) ₂-, as the medicine of treatment hyperplasia.

3. according to formula (I) compound of claim 1, wherein X is selected from following linking group :-SCR ⁶R ⁷-,-S (O) CR ⁶R ⁷-and-S (O) ₂CR ⁶R ⁷-, as the medicine of treatment hyperplasia.

4. according to each formula (I) compound of claim 1 to 3, R wherein ⁴Be hydrogen or methyl, as the medicine of treatment hyperplasia.

5. according to each formula (I) compound of claim 1 to 4, R wherein ⁵Be hydrogen or methyl, as the medicine of treatment hyperplasia.

6. according to each formula (I) compound of claim 1 to 5, R wherein ⁶Be hydrogen or methyl, as the medicine of treatment hyperplasia.

7. according to each formula (I) compound of claim 1 to 6, R wherein ⁷Be hydrogen or methyl, as the medicine of treatment hyperplasia.

8. according to each formula (I) compound of claim 1 to 7, R wherein ¹Be to be selected from following group: C _1-4Alkyl, C _3-6Cycloalkyl, aryl, C _3-6Cycloalkyl C _1-4Alkyl, aryl C _1-4Alkyl, the assorted alkyl of ring, heteroaryl, the assorted alkyl C of ring _1-4Alkyl, heteroaryl C _1-4Alkyl, this group is optional to be selected from following substituting group and to replace by one or more: halogen, cyano group, nitro, R ⁹,-OR ⁹,-COR ⁹,-CONR ⁹R ¹⁰,-NR ⁹R ¹⁰With-NR ⁹COR ¹⁰, as the medicine of treatment hyperplasia.

9. according to formula (I) compound of claim 8, R wherein ¹Be to be selected from following group: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, cyclohexyl ,-CH ₂CN ,-CH ₂C (O) NH ₂,-CH ₂CH ₂NC (O) CH ₃, phenyl, 4-fluorophenyl, the 2-chloro-phenyl-, 3-chloro-phenyl-, 2-chloro-6-fluorophenyl, 3-chloro-4-fluorophenyl, 4-bromo-2-fluorophenyl, 4-trifluoromethyl, the 4-Trifluoromethoxyphen-l, 4-cyano-phenyl, 3-p-methoxy-phenyl, the 4-p-methoxy-phenyl, 3, the 4-Dimethoxyphenyl, 4-(N-methylamino carbonyl) phenyl, benzyl, 4-luorobenzyl, 2-benzyl chloride base, 2-chloro-6-luorobenzyl, 4-methoxy-benzyl, styroyl, 3-trifluoro-benzene ethyl, furans-2-ylmethyl, thiophene-2-ylmethyl, 2-pyrazine-2-base ethyl, pyridin-3-yl, 2-picoline-3-base and 2-aminocarboxyl pyridin-3-yl is as the medicine of treatment hyperplasia.

10. according to each formula (I) compound of claim 1 to 9, R wherein ²Be selected from aryl and heteroaryl, this group is optional to be independently selected from following substituting group and to replace by one or more: halogen, cyano group, nitro ,-R ¹¹,-OR ¹¹,-COR ¹¹,-CONR ¹¹R ¹²,-NR ¹¹R ¹²With-NR ¹¹COR ¹², as the medicine of treatment hyperplasia.

11. according to formula (I) compound of claim 10, wherein R ²Be selected from phenyl, naphthyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, azaindolyl, indyl, quinolyl, benzimidazolyl-, benzofuryl, dibenzofuran group, benzothienyl, this group is optional to be independently selected from following substituting group and to replace by one or more: halogen, cyano group, nitro ,-R ¹¹,-OR ¹¹,-COR ¹¹,-CONR ¹¹R ¹²,-NR ¹¹R ¹²With-NR ¹¹COR ¹², as the medicine of treatment hyperplasia.

12. according to formula (I) compound of claim 11, wherein R ²Be 3-(methylol) phenyl, 4-(methylol) phenyl, 4-(cyano methyl) phenyl, 3,4-Dimethoxyphenyl, 3-fluoro-4-p-methoxy-phenyl, the 4-Phenoxyphenyl, 3-tetramethyleneimine-1-base phenyl, 3-(aminocarboxyl) phenyl, 4-(dimethylamino carbonyl) phenyl, furans-3-base, thiene-3-yl-, 5-(methylol) thiophene-2-base, pyridine-2-base, pyridin-4-yl, 2-methoxypyridine-5-base, 2-methoxy pyrimidine-5-base, 2-methoxynaphthalene-6-base, 5,7-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-2,4,8, the 10-apos, azaindolyl, indoles-5-base, 1-skatole-5-base, quinoline-6-base, benzimidazolyl-, cumarone-2-base, diphenylene-oxide-1-base and thionaphthene-3-base is as the medicine of treatment hyperplasia.

13. according to formula (I) compound of claim 12, wherein R ²Be azaindolyl, indoles-5-base, benzimidazolyl-, the 3-hydroxy phenyl, the 4-hydroxy phenyl, 3-hydroxymethyl phenyl or 4-hydroxymethyl phenyl are as the medicine of treatment hyperplasia.

14. according to each formula (I) compound of claim 1 to 13, wherein ¹Y is CR ⁸, Y ²Be N, as the medicine of treatment hyperplasia.

15. according to formula (I) compound of claim 14, wherein ¹Y is CH or CF, Y ²Be N, as the medicine of treatment hyperplasia.

16. according to formula (I) compound of claim 15, wherein ¹Y is CH, Y ²Be N, as the medicine of treatment hyperplasia.

17. according to each formula (I) compound of claim 1 to 16, wherein m is 0, so R ³Do not exist, as the medicine of treatment hyperplasia.

18. the defined formula of each of claim 1 to 17 (I) compound or its pharmacologically acceptable salts are used for the treatment of purposes in the medicine of hyperplasia in preparation.

19. the defined formula of each of claim 1 to 17 (I) compound or its pharmacologically acceptable salts for example produce the purposes of anti-proliferative effect among the people warm-blooded animal.

20. the defined formula of each of claim 1 to 17 (I) compound or its pharmacologically acceptable salts preparation be used for warm-blooded animal for example the people produce purposes in the medicine of anti-proliferative effect.

21. for example produce the method for anti-proliferative effect among the people the warm-blooded animal of needs treatments, this method comprises each defined formula (I) compound or its pharmacologically acceptable salts of the claim 1 to 17 that gives described animal effective dose.

22. for example treat the method for cancer, inflammatory diseases, obstructive respiratory tract disease, Immunological diseases or cardiovascular disorder among the people the warm-blooded animal of needs treatments, this method comprises compound or its pharmacologically acceptable salts of each defined formula (I) of the claim 1 to 17 that gives significant quantity.

23. the compound of the defined formula of each of claim 1 to 17 (I), condition are that the compound of formula (I) is not:

The 4-{6-[(methylthio group) methyl]-2-methylpyrimidine-4-yl } morpholine;

The 4-{6-[(benzenesulfinyl) methyl]-2-methylpyrimidine-4-yl } morpholine;

The 4-{6-[(benzenesulfonyl) methyl]-2-methylpyrimidine-4-yl } morpholine;

The 4-{6-[(methylthio group) methyl]-2-phenyl pyrimidine-4-yl } morpholine;

The 4-{6-[(thiophenyl) methyl]-2-phenyl pyrimidine-4-yl } morpholine;

The 4-{6-[(methylsulfinyl) methyl]-2-phenyl pyrimidine-4-yl } morpholine;

The 4-{6-[(benzenesulfinyl) methyl]-2-phenyl pyrimidine-4-yl } morpholine;

The 4-{6-[(methyl sulphonyl) methyl]-2-phenyl pyrimidine-4-yl } morpholine;

The 4-{6-[(benzenesulfonyl) methyl]-2-phenyl pyrimidine-4-yl } morpholine;

The 4-{6-[(thiophenyl) methyl]-2-pyridin-4-yl pyrimidine-4-yl } morpholine;

The 4-{6-[(methoxyl group) methyl]-2-methylpyrimidine-4-yl } morpholine;

The 4-{6-[(methoxyl group) methyl]-2-phenyl pyrimidine-4-yl } morpholine;

3,4,5-trimethoxy-N-[4-methyl-6-(4-morpholinyl)-2-pyrimidyl]-benzamide;

N-(2,3-dimethyl-1H-indoles-5-yl)-4,6-two-4-morpholinyl-2-pyridine carboxamide;

N-(3, the 4-3,5-dimethylphenyl)-2,6-two-4-morpholinyl-4-pyrimidine carboxamide;

N-[3-(aminocarboxyl) phenyl]-2,6-two-4-morpholinyl-4-pyrimidine carboxamide;

N-(4,6-two-4-morpholinyl-2-pyridyl)-N '-(3-aminomethyl phenyl)-urea;

N-(2,3-dimethyl-1H-indoles-5-yl)-4,6-two-4-morpholinyl-2-pyridine carboxamide;

N-[3-(dimethylamino) phenyl]-2,6-two-4-morpholinyl-4-pyrimidine carboxamide;

N-[3,4, the 5-trimethoxyphenyl]-2,6-two-4-morpholinyl-4-pyrimidine carboxamide;

24. pharmaceutical composition, it comprises the combination of the defined formula of claim 23 (I) compound or its pharmacologically acceptable salts and pharmacy acceptable diluent or carrier.

25. the defined formula of claim 23 (I) compound or its pharmacologically acceptable salts are as the purposes of medicine.

26. prepare the method for the defined formula of claim 1 (I) compound, wherein X is-S (O) ₂CR ⁶R ⁷, this method utilizes wherein that X is-SCR ⁶R ⁷-formula (I) compound and oxidant reaction (for example use , at room temperature, in water and ethanol mixed solvent system).

27. prepare the method for the defined formula of claim 1 (I) compound, wherein X is-X ¹CR ⁶R ⁷-, X ¹Be-NR ⁴-,-O-,-S-, S (O)-or-S (O) ₂-,

With the compound reaction of formula (III),

R ¹-X ¹H

(III)

28. prepare the method for the defined formula of claim 1 (I) compound, wherein X is-S (O) ₂CR ⁶R ⁷-, comprising: make the compound of formula (IX),

With suitable organometallic reagent (boric acid R for example ²B (OR) ₃Acibenzolar, wherein R is C _1-4Alkyl is methyl for example) in the presence of suitable metal catalyst (for example palladium or copper), react.

29. prepare the method for the defined formula of claim 1 (I) compound, wherein X is-C (O) NR ⁴CR ⁶R ⁷-,-NR ⁴C (O) NR ⁵CR ⁶R ⁷-or-S (O) ₂NR ⁴CR ⁶R ⁷-, comprising: make wherein that X is-NH ₂CR ⁶R ⁷-formula (I) compound,

With the compound reaction that is selected from following formula (XVI),

With

Choose wantonly in the presence of suitable alkali (for example triethylamine).

30. prepare the method for the defined formula of claim 1 (I) compound, wherein X is-C (O) NR ⁴-, NR ⁴C (O) NR ⁵-or S (O) ₂NR ⁴-, comprising: make the compound of formula (XV),

In the presence of suitable alkali (for example triethylamine), with the compound reaction that is selected from following formula (XVI)

With

31. prepare the method for the defined formula of claim 1 (I) compound, comprising: make the compound of formula (XXIII),

Compound reaction with formula V

32. prepare the method for the defined formula of claim 1 (I) compound, wherein X is-NR ⁴C (O)-, comprising: make the compound of formula (XVII),

33. prepare the method for the defined formula of claim 1 (I) compound, wherein X is-S (O) ₂CR ⁶R ⁷-,

Comprise: make wherein that X is-SCR ⁶R ⁷-formula (I) compound,

(for example use with oxygenant

At room temperature, in water and ethanol mixed solvent system) reaction.

34. prepare the method for the defined formula of claim 1 (I) compound, wherein X is-X ¹CR ⁶R ⁷-, X ¹Be-NR ⁴-,-O-,-S-, S (O)-, comprising: make the compound of formula (XXVIII),

Compound reaction with formula V

35. prepare the method for the defined formula of claim 1 (I) compound, wherein X is-C (O) NR ⁴CR ⁶R ⁷-,-NR ⁴C (O) NR ⁵CR ⁶R ⁷-or-S (O) ₂NR ⁴CR ⁶R ⁷-, comprising: make wherein that X is-NH ₂CR ⁶R ⁷-formula (I) compound,

Suitable alkali for example triethylamine in the presence of, with the compound reaction that is selected from following formula (XVI)

With

36. prepare the method for the defined formula of claim 1 (I) compound, wherein X is-C (O) NR ⁴-,-NR ⁴C (O) NR ⁵-or-S (O) ₂NR ⁴-, comprising: make the compound of formula (XXXII),

With the compound reaction that is selected from following formula (XVI),

With

37. prepare the method for the defined formula of claim 1 (I) compound, wherein X is-X ¹CR ⁶R ⁷-, X ¹Be-NR ⁴-,-O-,-S-,-S (O)-or-S (O) ₂-, comprising: make the compound of formula (XXXVII), wherein L ¹Be leavings group (for example halogen (for example chlorine), tosyl group, methylsulfonyl or the like),

Under the existence of suitable alkali (for example for example tetrahydrofuran (THF) or N of triethylamine or sodium hydride and solvent, dinethylformamide), with the compound reaction of formula (XXXVIII)

R ¹-L ¹

(XXXVIII)。

38. prepare the method for the defined formula of claim 1 (I) compound, wherein X is-X ¹CR ⁶R ⁷-, X ¹Be-S-, comprise: make the compound of formula (XXXIX),

Under the existence of suitable alkali (for example sodium hydroxide) and solvent (for example N, dinethylformamide), react with the compound of formula (XXXVIII)

R ¹-L ¹

(XXXVIII)。

39. prepare the method for the defined formula of claim 1 (I) compound, wherein X is-X ¹CR ⁶R ⁷-, X ¹Be-NR ⁴-,-O-,-S-,-S (O)-or-S (O) ₂-, comprising: make the compound of formula (XXXX),

With suitable organometallic reagent (boric acid R for example ²B (OR) ₃Acibenzolar, wherein R is C _1-4Alkyl is methyl for example) in the presence of suitable metal catalyst (for example palladium or copper), use solvent (for example 1,4-diox) to react.

40. prepare the method for the defined formula of claim 1 (I) compound, wherein X is-NR ⁴C (O)-,-NR ⁴C (O) CR ⁶R ⁷-,-NR ⁴S (O) ₂-or-NR ⁴S (O) ₂CR ⁶R ⁷-, comprising: make the compound of formula (XXXXVIII),

X wherein ¹Be-C (O)-,-C (O) CR ⁶R ⁷-,-S (O) ₂-, or-S (O) ₂CR ⁶R ⁷-, L ¹Be the leavings group (for example chlorine or Acibenzolar) that suits,

In the presence of suitable alkali (for example triethylamine), react with the amine of formula (XXXXIX)

41. prepare the method for the defined formula of claim 1 (I) compound, wherein X is-NR ⁴CHR ⁶-, comprising: make the compound of formula (XXXXX),

At suitable reductive agent (NaCNBH for example ₃) existence under, react with the amine of formula (XXXXIX)